WO2025186043A1 - Pharmaceutical formulation for anti-ccr8 antibodies - Google Patents

Abstract

The present invention relates to safe pharmaceutical formulations to stabilize a therapeutic anti-CCR8 antibody. The pharmaceutical formulation is provided as a liquid, such as a frozen liquid, or in a lyophilized from, and may be in a ready-to-use form or may be further diluted for intravenous or subcutaneous administration.

Description

PHARMACEUTICAL FORMULATION FOR ANTI-CCR8 ANTIBODIES DESCRIPTION Technical Field

The present invention relates to safe pharmaceutical formulations to stabilize a therapeutic anti-CCR8 antibody. The pharmaceutical formulation is provided as a liquid, such as a frozen liquid, or in a lyophilized form and may be in a ready-to-use form or may be further diluted for intravenous infusion or for subcutaneous injection.

Technical Problem

According to the current invention a safe and stable pharmaceutical formulation had to be identified for a set of recently developed afucosylated anti-human CCR8 antibodies.

CCR8 is predominantly expressed by activated intra-tumoral regulatory T cells (Tregs), which are responsible for the immune escape of the tumor. Despite its role as a chemokine receptor, CCR8 is not required for the chemotaxis or immunosuppression of activated Tregs. Therefore, depletion of CCR8 positive tumor infiltrating Tregs rather than blocking the function of CCR8 seems to be the key for effective anti-tumor immunotherapy. The underlying mode of action has first been disclosed by a team around George Plitas and Alexander Rudensky (Plitas, G., et al. "Abstract P4-04-11: Preferential expression of the chemokine receptor 8 (CCR8) on regulatory T cells (Treg) infiltrating human breast cancers represents a novel immunotherapeutic target." (2016): P4-04.; Plitas, George, et al. "Regulatory T cells exhibit distinct features in human breast cancer." Immunity 45.5 (2016): 1122-1134.; US10087259). Since then, researchers have tried to find clinically superior anti-human CCR8 antibodies for specific depletion of intra-tumoral Treg depletion. However, so far only few formulations have been published to store these anti-CCR8 antibodies and to formulate the resulting anti-human CCR8 antibodies for pharmaceutical use in the clinics.

The pharmaceutical formulations according to the current invention were found to be safe in cynomolgus monkeys and did not substantially induce or increase the release of cytokines. Furthermore, they stabilize the anti-human CCR8 antibodies at convenient storage conditions, e.g. by preventing/reducing aggregation and degradation and in particular by preventing excessive formation of basic antibody species.

The pharmaceutical formulations disclosed herein were initially developed to stabilize the afucosylated anti-human CCR8 antibody TPP-23411 but can also be used for other anti-CCR8 antibodies having at least partially similar properties, as exemplified elsewhere herein. TPP-23411 is an afucosylated monoclonal anti-human CCR8 antibody of the IgGl type and was first disclosed in WO2021152186. Antibodies disclosed in WO2021152186 efficiently deplete CCR8 expressing target cells via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In more detail, TPP- 23411 triggers potent and dose dependent depletion of human primary CCR8+ Tregs or ectopic human CCR8 expressing HEK293 target cells by engaging either human NK92V cells or human primary M2c macrophages as effector cells. Afucosylation significantly enhances the ADCC potency of TPP-23411 while maintaining its ADCP potency.

According to the current invention a pharmaceutical formulation is provided for anti-CCR8 antibodies to enable their stable and safe pharmaceutical use in the clinics.

Monoclonal antibodies (mAbs) are heterogeneous in their biochemical and biophysical properties due to multiple posttranslational modification and degradation events. Different variants can be observed when mAbs are analyzed by charge based-separation techniques including isoelectric focusing (IEF), capillary isoelectric focusing (clEF), cation exchange chromatography (CEX) and anion exchange chromatography (AEX).

The different variants are generally referred to as acidic or basic species in comparison with the main species. Acidic species are variants with lower apparent pl and basic species are variants with higher apparent pl relative to the main variant, when analyzed using IEF based methods.

When analyzed by chromatography-based methods, acidic species and basic species are defined based on their retention times relative to the main peak. Acidic species are the variants that elute earlier than the main peak from CEX or later then than the main peak from AEX, while basic species are the variants that elute later than the main peak from CEX or earlier than the main peak from AEX, see Du, Yi et al. "Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies.” mAbs vol. 4,5 (2012): 578-85. doi:10.4161/mabs.21328.

Charge variants may substantially affect the in vitro and in vivo properties of antibodies. It has been demonstrated using chemically-modified antibodies that charge variation can alter binding to proteins or cell membrane targets, thus affecting the tissue penetration, tissue distribution and pharmacokinetics (PK) of the antibodies. Depending on the respective antibody it is therefore important to stabilize the "right" variants.

Various mechanisms have been described that may contribute to the chemical degradation of a particular antibody and that may shift the percentage of the main variant to a different species. These mechanisms include, e.g., a. Succinimide formation, b. Oxidation of Methionine, Cysteine, Lysine, Histidine or Trypthophan leading to conformational change, c. Disulfide-mediated degradation leading to conformational change, d. Asialylation (terminal Galactose) leading to loss of COOH e. C-terminal lysine and glycine amidation leading to NHz formation or loss of COOH f. Asp isomerization leading to conformational change, g. Clipping/Fragmenting leading to loss of NH?/ Conformational change. Background Art

In U.S. Appl. No. 17/142,862 pharmaceutical formulations were suggested for anti-human CCR8 antibodies comprising PBS; 20 mM NaOAC, pH 5.2, 50 mM NaCI; and/or 10 mM NAOAC, pH 5.2, 9% Sucrose.

In WO2025/011439 Al pharmaceutical formulations were suggested for an anti-human CCR8 comprising sodium acetate as buffer at a pH value of the preparation of 4.5 to 6.0.

WO2024/240224 Al discloses formulations which do not comprise methionine and are not specifically suited for afucosylated anti-human CCR8 antibodies.

Anti-CCR8 antibodies that can be formulated using the pharmaceutical formulation of the current invention are disclosed e.g. in WO2020/138489, W02021/142002, WO2021/163064, WO2021/178749, WO2021/194942, WO2021152186, W02022/003156, and W02022/042690. Further anti-CCR8 antibodies are disclosed in WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al, W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al, WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al, WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al and WO2022/136650 Al.

Solution to Problem

According to the current invention a pharmaceutical formulation comprising an anti-human CCR8 antibody is provided, wherein the pharmaceutical formulation comprises a. 2.5 - 15 mM histidine; b. 50 - 200 ppm polysorbate, preferably 50 - 100 ppm polysorbate, preferably polysorbate 80; c. 5 % - 8 % sucrose; d. 10 - 50 mM arginine; e. 2.5 - 50 mM methionine; and f. 25 mg/mL - 150 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5.

Optimal results were obtained with a pH of the pharmaceutical formulation of approximately 6.3.

The pharmaceutical formulation is provided as a liquid, such as a frozen liquid, or in a lyophilized from, and may be in a ready-to-use form or may be further diluted for administration, e.g. intravenous infusion or subcutaneous injection. The pharmaceutical formulation is particularly suited for afucosylated antihuman CCR8 antibodies, e.g. of the human IgGl type.

The advantageous formulation provided according to the current invention

• is a liquid or lyophilized formulation • is suited for high anti-CCR8 antibody concentrations, such that an acceptable overall volume can be reached for appropriate medical dosages and administration schemes,

• stabilizes an anti-CCR8 antibody presumably via pH modulation,

• avoids an unacceptable increase of the anti-CCR8 antibody basic species upon storage, • supports convenient storage conditions, e.g. at - 30°C for at least six months or longer,

• is a non-salt (sodium chloride or sodium sulfate) formulation,

• is substantially isotonic and substantially isosmotic, and

• was finally found to be safe in cynomolgus monkeys without any unacceptable cytokine release effects. The provided pharmaceutical formulation therefore solves the problem to find an advantageous pharmaceutical formulation for anti-CCR8 antibodies.

BRIEF DESCRIPTION OF THE SEQUENCE IDs

There is a Sequence Listing associated with this application. SEQ. ID NO:1 to SEQ ID NO:800 relate to antibodies than can be formulated using the pharmaceutical formulation disclosed herein.

DEFINITIONS

Unless otherwise defined, all scientific and technical terms used in the description, figures and claims have their ordinary meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control. Where reference to a database is made, the effective data shall be the version number applicable 10.06.2022, if not indicated otherwise. The materials, methods, and examples are illustrative only and are not intended to be limiting. Unless stated otherwise, the following terms used in this document, including the description and claims, have the definitions given below.

The expression "about" or as used herein refers to a value being within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. The term "about" is also used to indicate that the amount or value in question may be the value designated or some other value that is approximately the same. The phrase is intended to convey that similar values promote equivalent results or effects as described herein. In this context "about" may refer to a range above and/or below of up to 10 %. Wherever the term "about" is specified for a certain assay or embodiment, that definition prevails for the particular context.

If not specified otherwise, the term "approximately" may refer to a range above and/or below of up to 10 %.

The terms "comprising", "including", "containing", "having" etc. shall be read expansively or open- ended and without limitation. The term comprising when used in the specification includes "consisting of".

Singular forms such as "a", "an" or "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a monoclonal antibody" includes a single monoclonal antibody as well as a plurality of monoclonal antibodies, either the same or different. Likewise reference to "cell" includes a single cell as well as a plurality of cells. Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. The terms "at least one" and "at least one of" include for example, one, two, three, four, five or more elements.

It is furthermore understood that slight variations above and below a stated range can be used to achieve substantially the same results as a value within the range. Also, unless indicated otherwise, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values.

As used herein, the terms "peptide", "polypeptide", and "protein" are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

Where generic reference is made to a gene or protein from a certain species such as mouse, the analogue from human shall likewise be meant, if not stated otherwise or obviously incompatible. This holds in particular in the context of biomarkers.

The term "isolated" when applied to a nucleic acid, polypeptide, protein or antibody, denotes that the nucleic acid, polypeptide, protein or antibody is essentially free of other cellular components with which it is associated in the natural state. It is preferably in a homogeneous state. It can be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. A protein, polypeptide or antibody that is the predominant species present in a preparation is substantially purified. In particular, an isolated gene is separated from open reading frames that flank the gene and encode a protein other than the gene of interest. An isolated polypeptide may however be immobilized, e.g. on beads or particles, e.g. via a suitable linker.

The term "purified" denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

As used herein, the term "synthetic", with reference to, for example, a synthetic nucleic acid molecule or a synthetic gene or a synthetic peptide refers to a nucleic acid molecule or polypeptide molecule that is produced by recombinant methods and/or by chemical synthesis methods. As used herein, production by recombinant means by using recombinant DNA methods means the use of the well-known methods of molecular biology for expressing proteins encoded by cloned DNA.

"Post-translational modification(s)" (PTM) refer to the covalent modification(s) of peptides or proteins, which are introduced following protein biosynthesis under natural conditions. The term includes without limitation glycosylation, phosphorylation, acylation, adenylation, farnesylation, ubiquitination, and sulfation. Post-translational modifications may influence the activity of peptides or proteins. In 2004, Gutierrez et al. have described the sulfation and glycosylation state of the murine CCR8 chemokine receptor, and the way in which these post-translational modifications affect CCR8 activity. They suggest that tyrosines at positions 14 and 15 in mouse CCR8 are sulfated amino acid residues, whereas asparagine 8 and threonines 10 and 12 are glycosylated. Furthermore, they show that the sulfations are important for the activity of CCR8 (Gutierrez, Julio, et al. "Analysis of post-translational CCR8 modifications and their influence on receptor activity." Journal of Biological Chemistry 279.15 (2004): 14726-14733.).

"Sequence identity" or "percent identity" is a number that describes how similar a query sequence is to a target sequence, more precisely how many characters in each sequence are identical after alignment. The most popular tool to calculate sequence identity is BLAST (basic local alignment search tool, https://blast.ncbi.nlm.nih.gov/), which performs comparisons between pairs of sequences, searching for regions of local similarity. Suitable alignment methods are known in the art, e.g. Needleman-Wunsch algorithm for global-global alignment, using BLOSUM62 matrix, with gap opening penalty of 11 and a gap extension penalty of 1. Afterwards, the pairs of aligned identical residues can be counted and then divided by the total length of the alignment (including gaps, internal as well as external) to arrive at the percent identity value.

For "percent similarity" or "sequence similarity" values, the same approach as for percent identity values can be used, except that what is counted, instead of pairs of identical residues, is the aligned residue pairs with BLOSUM62 values that are not negative (i.e., >0).

"Seven transmembrane receptors" (7-TM receptors) are integral membrane proteins that contain seven membrane-spanning helices. As used herein, 7-TM receptors are G protein-coupled receptors.

"Chemokine receptors" are seven transmembrane receptors. The chemokine receptor family contains 24 members in humans and can be subdivided, based on the class of chemokines they bind, into four subfamilies: CX3CR, CXCR, CCR, and XCR, all of them activating G proteins, and ACKR, containing 6 atypical receptors, unable to activate G proteins upon ligand binding.

"CXC chemokine receptors" (CXCR) are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals, named CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR6. CXCR6 is more closely related in structure to CC chemokine receptors than to other CXC chemokine receptors.

"CC chemokine receptors" (CCR, also beta chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. The subfamily of the CC chemokine receptors comprises CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9 and CCR10. The term "CCR8" refers to the C-C chemokine receptor type 8. The CCR8 protein is encoded by the gene CCR8 (NCBI gene ID 1237). Synonyms for CCR8 are inter alia CC-CKR-8, CCR-8, CDwl98, CKRL1, CMKBR8, CMKBRL2, GPRCY6, CY6, TERI. The CCR8 protein comprises human, murine, rat, rhesus macaque and further mammalian and non-mammalian homologues. Sequence(s) for human CCR8 are accessible via UniProt Identifier P51685 (CCR8_HUI\/IAN), for instance human isoform P51685-1 or P51685-2 (UniProt, November 29, 2019). Sequence(s) for murine CCR8 are accessible via UniProt Identifier P56484 (CCR8_MOUSE). Sequence(s) for Rhesus macaque CCR8 are accessible via UniProt Identifier 097665 (CCR8_M ACM U). Different isoforms and variants may exist for the different species and are all comprised by the term CCR8. Also comprised are CCR8 molecules before and after maturation, i.e., independent of cleavage of one or more pro-domains. In addition, synthetic variants of the CCR8 protein may be generated and are comprised by the term CCR8. The protein CCR8 may furthermore be subject to various modifications, e.g, synthetic or naturally occurring modifications, such as post translational modifications. Recombinant human CCR8 is commercially available or can be manufactured as known in the art. CCR8 is a receptor for the chemokine CCL1/SCYA1/I-309. Barington et al. have reported the importance of conserved extracellular disulfide bridges and aromatic residues in extracellular loop 2 (ECL-2) for ligand binding and activation in the chemokine receptor CCR8 (Barington, Line, et al. "Role of conserved disulfide bridges and aromatic residues in extracellular loop 2 of chemokine receptor CCR8 for chemokine and small molecule binding." Journal of Biological Chemistry 291.31 (2016): 16208- 16220.). Furthermore, they found that two distinct aromatic residues in ECL-2, Tyrl84 (Cys + 1) and Tyrl87 (Cys + 4), were crucial for binding of the CC chemokines CCL1 (agonist) and MC148 (antagonist), respectively, but not for small molecule binding.

"Programmed Death-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes without limitation human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863 (November 29, 2019).

"Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down regulate T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes without limitation human PD-L1 (hPDLl), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll. The complete hPDLl sequence can be found under GenBank Accession No. Q9NZQ7 (November 29, 2019).

"F0XP3" is a 50-55 kD transcription factor, also known as Forkhead box protein P3, Scurfin, JM2, or IPEX. It is proposed to be a master regulatory gene and more specific marker of T regulatory cells than most cell surface markers. Transduced expression of F0XP3 in CD4+/CD25- cells has been shown to induce GITR, CD103, and CTLA4 and impart a T regulatory cell phenotype. Biolegend antibody clones 206D and 259D recognize a human F0XP3 epitope in the region of amino acids 105-235. Poly6238 recognizes both human and mouse F0XP3 and was raised against the N-terminal portion of F0XP3.

The term "modulation" refers to any alteration of an existing process or behavior, such as blocking (antagonism) and induction (agonism). For example, modulation of G protein independent signaling refers to any significant alteration of G-protein independent signaling.

The term "internalization" of an antibody, fragment or conjugate refers to the uptake of the antibody, fragment or conjugate into a cell. Preferably, internalization is determined for a cell line with endogenous target expression, e.g. as described elsewhere herein for human or murine CCR8. Preferably, internalization is determined by measuring total internalized fluorescence intensity per cell and is quantified relative to an isotype control, e.g. as described in example 10.5. In brief, the antibody, fragment or conjugate and a matching isotype control are labeled with a dye and internalized fluorescence is determined and quantified for the antibody, fragment or conjugate relative to the isotype control. A "non-internalizing antibody" is defined as an antibody showing substantially the same internalization as a corresponding isotype control. A "low internalizing antibody" is defined as an antibody showing an internalization which is equal to or lower than the 10-fold of the internalization of the isotype control, preferably lower than the 9-, 8-, 7-, 6-, 5-, 4-, 3-, 2-, 1.5-, 1.4-, 1.3-, 1.2-, or 1.1-fold of the internalization of the isotype control. A "medium internalizing antibody" is defined as an antibody showing an internalization which is equal to or lower than the 21-fold of the internalization of the isotype control and higher than the 10-fold of the internalization of the isotype control. A "high internalizing antibody" is defined as an antibody showing an internalization which is higher than the 21-fold of the internalization of the isotype control.

In the alternative, internalization can furthermore be quantified based on t( 1/2), i.e. as time until half of the amount of antibody, fragment or conjugate has been internalized. Preferably, antibodies according to the current invention are characterized by a time until half of the amount of antibody, fragment or conjugate has been internalized which is > 2 hours, preferably > 4, > 5, > 6, > 7, > 8, > 9, > 10, > 11, > 12, > 13, > 14, > 15, > 16, > 17, > 18, > 19, > 20, > 21, > 22, > 23, > 24, > 26, > 28, > 30, or > 48 hours. Most preferably, antibodies according to the current invention are not internalized at all, i.e., no time can be defined until which half of the amount of antibody, fragment or conjugate has been internalized. An "isotype control" is an antibody or fragment that does not bind a target but has the same class and type as the reference antibody or fragment recognizing the target.

An antibody or fragment is termed "cross-reactive" or "cross reactive" if the antibody or fragment binds an antigen from two or more different species, e.g. with a KD value of 10-7 M or less, more preferably of less than 10-8 M, even more preferably in the range from 10-9 M to 10-11 M.

By the term "specifically binds" as used herein with respect to an antibody, is meant an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample: An antibody characterized by substantial unspecific binding would lack therapeutic applicability, such that these embodiments are excluded. However, as known in the art, specific binding of an antibody or binder does not necessarily exclude an antibody or binder binding to further antigens/target molecules. An antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more further species. Such cross-species reactivity does not itself alter the classification of an antibody as specific.

In some instances, the terms "specific binding" or "specifically binding" can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A" and the antibody, will reduce the amount of labeled A bound to the antibody.

In case of doubt, specific binding of an antibody or binder preferably describes binding of an antibody, antibody fragment or binder to its antigen/target with an affinity of at least 10-7 M (as KD value; i.e. preferably those with KD values smaller than 10-7 M), with the antibody or binder having an at least two times lower affinity for a non-specific antigen which is not the predetermined antigen/target molecule or a closely related antigen/target molecule.

"Polyspecificity", also "polyreactivity" or "unspecific binding" refers to the binders' or antibodies' ability to bind a defined set of unrelated antigens. Unspecific binding is substantial, if the (therapeutic) applicability of the antibody is compromised. Polyspecificity for non-protein structures including without limitation target negative cell lines or tissues, baculo virus particle (BVP), insulin or DNA, may be evaluated as known in the art and as described herein. For example, unspecific binding to target negative human cell lines can be determined e.g. by FACS analysis using mock transfected CHO or HEK cells. In a second example, unspecific binding to different tissues can be analyzed by FACS analysis of a cell line or panel of cell lines derived from the respective tissue. In a third example, unspecific binding to immune cell populations can be analyzed by FACS after sorting the immune cell populations as known in the art. In a fourth example, unspecific binding to BVP, insulin or DNA can be analyzed using ELISA, e.g. as described in Hbtzel, Isidro, et al. "A strategy for risk mitigation of antibodies with fast clearance." MAbs. Vol. 4. No. 6. Taylor & Francis, 2012.; Avery, Lindsay B., et al. "Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics." MAbs. Vol. 10. No. 2. Taylor & Francis, 2018., and Jain, Tushar, et al. "Biophysical properties of the clinical-stage antibody landscape." Proceedings of the National Academy of Sciences 114.5 (2017): 944-949., incorporated herein in their entirety and in particular with regards to the technical details necessary to analyze and quantify unspecific binding. An antibody without substantial unspecific binding is preferably characterized by an unspecific binding that is lower than unspecific binding of reference antibody Gantenerumab (Roche) and most preferably lower than unspecific binding of reference antibody Remicade (Janssen Biotech).

The term "off target binding" refers to the ability of an antibody to bind individual proteins different from the intended target, for example proteins of the targets' protein family. Off target binding may be evaluated using commercial assays known in the art such as the Retrogenix off target profiling assay. In brief, antibodies are tested on microarrays containing HEK293 cells individually expressing several thousand human membrane proteins and secreted proteins. Binding of the antibody to a potential off target has to be confirmed by FACS using cells overexpressing the potential off target.

The term "affinity" is a term of the art and describes the strength of binding between a binder, antibody or antibody fragment and a target. The "affinity" of antibodies and fragments thereof for a target can be determined using techniques well known in the art or described herein, for example by ELISA, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), flow cytometry or fluorescent polarization assays. Preferably the affinity is provided as dissociation constant KD.

The "dissociation constant" (KD) has molar units (M) and corresponds to the concentration of the binder/antibody at which half of the target proteins are occupied at equilibrium. The smaller the dissociation constant is, the higher is the affinity between the binder or antibody and its target.

According to the current invention, the antibodies preferably have a target affinity of at least 10-7 M (as KD value), more preferably of at least 10-8 M, even more preferably in the range from 10-9 M to 10-11 M. The KD values can be preferably determined by means of surface plasmon resonance spectroscopy, e.g. as described elsewhere herein. Where assay conditions were found to influence the determined KD, the assay setup with the least standard deviation shall be used.

"Half maximal effective concentration" (EC50) refers to the concentration of a drug, antibody, fragment, conjugate or molecule which induces a response halfway between the baseline and maximum after a specified incubation time. In the context of antibody binding, the EC50 thus reflects the antibody concentration needed for half-maximal binding. An EC50 can be determined if an inflection point can be determined by mathematical modeling (e.g., non-linear regression) of the dose-response curve describing the relationship between applied drug, antibody, fragment, conjugate or molecule concentration and signal. For example, if the dose-response curve follows a sigmoidal curve, an EC50 can be determined. Where the response is an inhibition, the EC50 is termed half maximal inhibitory concentration (IC50). EC80 can be determined mutatis mutandis.

The "isoelectric point" (pl), is the pH at which a molecule carries no net electrical charge or is electrically neutral.

The term "antibody" (Ab) refers to an immunoglobulin molecule (e.g. without limitation human IgGl, lgG2, lgG3, lgG4, IgM, IgD, IgE, IgAl, lgA2, mouse IgGl, lgG2a, lgG2b, lgG2c, lgG3, IgA, IgD, IgE or IgM, rat IgGl, lgG2a, lgG2b, lgG2c, IgA, IgD, IgE or IgM, rabbit IgAl, lgA2, lgA3, IgE, IgG, IgM, goat IgA, IgE, IgGl, lgG2, IgE, IgM or chicken IgY) that specifically binds to, or is immunologically reactive with, a particular antigen. Antibodies or antibody fragments comprise complementarity determining regions (CDRs), also known as hypervariable regions, in both the light chain and heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). As is known in the art, the amino acid position/boundary delineating a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. As used herein, numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al.. The variable domains of native heavy and light chains each comprise four FR regions. The three CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies, see Kabat, E. A., et al. "Sequences of Proteins of Immunological Interest (Natl. Inst. Health, Bethesda, MD), GPO Publ." Nol65-462 (1987). The term antibody as used herein also refers to antibody fragments, except where explicitly stated otherwise. Depending on the respective context, the term antibody may also refer to any proteinaceous binding molecule with immunoglobulin-like function.

The term "CDR" refers to the complementary determining region of the antibody. As known in the art complementarity-determining regions (CDRs) are part of the variable chains in antibodies and T cell receptors. A set of CDRs constitutes a paratope. CDRs are crucial to the diversity of antigen specificities. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively on the amino acid sequence of a variable domain of an antigen receptor. Since the antigen receptors are typically composed of two variable domains (on two different polypeptide chains, heavy and light chain), there are usually six CDRs for each antigen receptor that can collectively come into contact with the antigen. The CDRs of the light chain are LCDR1, LCDR2 and LCDR3. The CDRs of the heavy chain are termed HCDR1, HCDR2 and HCDR3. HCDR3 is the most variable complementary determining region (see, e.g., Chothia, Cyrus, and Arthur M. Lesk. "Canonical structures for the hypervariable regions of immunoglobulins." Journal of molecular biology 196.4 (1987): 901-917.; Kabat, E. A., et al. "Sequences of proteins of immunological interest. Bethesda, MD: US Department of Health and Human Services." Public Health Service, National Institutes of Health (1991): 103-511.). The "constant region" refers to the portion of the antibody molecule that confers effector functions. The heavy chain constant region can be selected from any of the five isotypes: alpha (a), delta (6), epsilon (E), gamma (g), or mu (p).

The term "Fc domain", "Fc region" or "Fc part" as used herein refers to a C-terminal region of an antibody heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. For example, a human IgG heavy chain Fc region may extend from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.

Antibodies or binding fragments according to the current invention may have been modified to alter at least one constant region-mediated biological effector function. For example, in some embodiments, an antibody may be modified to reduce or enhance at least one constant region-mediated biological effector function relative to the unmodified antibody, e.g., reduced or improved binding to the Fc receptor (FcyR). FcyR binding may be reduced, e.g. by mutating the immunoglobulin constant region segment of the antibody at particular regions necessary for FcyR interactions (see, e.g., Canfield, Stephen M., and Sherie L. Morrison. "The binding affinity of human IgG for its high affinity Fc receptor is determined by multiple amino acids in the CH2 domain and is modulated by the hinge region." The Journal of experimental medicine 173.6 (1991): 1483-1491; and Lund, John, et al. "Human Fc gamma Rl and Fc gamma RII interact with distinct but overlapping sites on human IgG." The Journal of Immunology 147.8 (1991): 2657-2662.). FcyR binding may be enhanced, e.g. by afucosylation. Reducing FcyR binding may also reduce other effector functions which rely on FcyR interactions, such as opsonization, phagocytosis and antigen-dependent cellular cytotoxicity ("ADCC").

Furthermore, addressing the interaction of Fc with FcRn allows to modulate the half-life of antibodies in vivo. Abrogating the interaction by e.g. introduction of mutation H435A leads to an extremely short halflife, since the antibody is no longer protected from lysosomal degradation by FcRn recycling. In some preferred embodiments according to all aspects, the antibody according to the current invention comprises mutation H435A or has otherwise been engineered for a reduced half-life.

In contrast, antibodies comprising "YTE" mutations (M252Y/S254T/T256E) and/or equivalent mutations such as "LS" mutations (M428L/N434S) have been shown to significantly extend the half-life by more efficient recycling from endosomes in both pre-clincal species as well as humans (Dall'Acqua, William F., et al. "Increasing the affinity of a human IgGl for the neonatal Fc receptor: biological consequences." The Journal of Immunology 169.9 (2002): 5171-5180.; Zalevsky, Jonathan, et al. "Enhanced antibody halflife improves in vivo activity." Nature biotechnology 28.2 (2010): 157-159.). In some preferred embodiments according to all aspects, the antibody according to the current invention comprises YTE mutations (M252Y/S254T/T256E) and/or equivalent mutations such as LS (M428L/N434S) or has otherwise been engineered for an improved half-life. Suitable Fc engineering approaches for extension of half-life can be found in Haraya, Kenta, Tatsuhiko Tachibana, and Tomoyuki Igawa. "Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering." Drug metabolism and pharmacokinetics 34.1 (2019): 25-41., and/or Lee, Chang-Han, et al. "An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence." Nature communications 10.1 (2019): 1-11., both incorporated herein by reference.

"Afucosylated" antibodies are antibodies engineered such that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. Glycosylation of an antibody can alter its function. For example, if glycosylation at N297 in the CH2 domain of an IgG is completely eliminated, binding to FcyRs is lost. However, modulation of the specific carbohydrate composition at N297 can have the opposite effect and enhance the ADCC activity of the antibody. In brief, the affinity of an antibody for the activating FcyRs depends on the composition of the N297 N-linked oligosaccharide. There are 32 different possible combinations of oligosaccharides that can occur at this site. Naturally occurring human IgG and those produced by hybridomas or other common expression systems are usually composed of N-acetylglucosamine (GIcNAc) and three mannose residues that form a core carbohydrate. This core is attached to two additional GIcNAc groups to form biantennary branches. The addition of galactose at each branch can occur as well as the terminal addition of sialic acid to these galactose molecules. Fucose is often part of the core GIcNAc. This fucose, through steric hindrance, obstructs the interaction of the antibody with the FcyRIIIA. Thus, elimination of this fucose molecule while maintaining other forms of glycosylation at this site increases the binding of the antibody to the activating FcyRs, enhancing its ability to elicit ADCC and/or ADCP (Almagro, Juan C., et al. "Progress and challenges in the design and clinical development of antibodies for cancer therapy." Frontiers in immunology 8 (2018): 1751.). Methods of preparing fucose-less antibodies include growth in rat myeloma YB2/0 cells (ATCC CRL 1662). YB2/0 cells express low levels of FUT8 mRNA, which encodes a-l,6-fucosyltransferase, an enzyme necessary for fucosylation of polypeptides. Afucosylated antibodies are preferred for the current invention.

"Antibody-dependent cellular cytotoxicity" ("ADCC"), also referred to as "antibody-dependent cell- mediated cytotoxicity", is a mechanism of cell-mediated immune defense whereby an immune cell actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. ADCC is mediated via interaction of the antibody or fragment with FcyRllla. In humans, FcyRIII exists in two different forms: FcyRllla (CD16a) and FcyRlllb (CD16b). While FcyRllla is expressed on monocytes, neutrophils, mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcyRlllb is only expressed on neutrophils. These receptors bind to the Fc portion of IgG antibodies, which then activates antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by the human effector cells. Different assay systems to determine ADCC induction in human subjects have been described in the literature and are suitable for characterization of the subject matter disclosed herein. For example, Yao- Te Hsieh et al. have studied different ADCC assay systems, namely assays based on (i) natural killer cells from human donors (FcyRIIIA + primary NK), (ii) FcyRIIIA engineered NK-92 cells and (iii) FcyRIIIA/NFAT- RE/luc2 engineered Jurkat T cells (Hsieh, Yao-Te, et al. "Characterization of FcyRIIIA effector cells used in in vitro ADCC bioassay: comparison of primary NK cells with engineered NK-92 and Jurkat T cells." Journal of Immunological Methods 441 (2017): 56-66, incorporated herein in entirety; in particular, reference is made to the method description for these assays). In brief, all three effector cell systems differentially express FcyRIIIA and provide dose-dependent ADCC pathway activity, yet only primary NK and engineered NK-92 cells are capable of inducing ADCC-mediated cell lysis. For functional assessment of ADCC activity, primary NK or NK-92 (V-158) cells thus better reflect the physiologically relevant ADCC mechanism of action. As an engineered cell line, NK-92 cells may behave more reproducibly than primary NK and is therefore the preferred assay system to determine ADCC response in human subjects, e.g. in case of doubt.

An antibody or antigen-binding fragment inducing ADCC (or having ADCC activity) is an antibody which may elicit a substantial amount of lysis of target cells in the presence of NK effector cells. Preferably, the ADCC induction results in the lysis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells.

"Antibody-dependent cellular phagocytosis" ("ADCP") is the mechanism by which antibody-opsonized target cells activate the FcyRs on the surface of macrophages to induce phagocytosis, resulting in internalization and degradation of the target cell. For ADCP, binding to macrophages as effector cells typically occurs via the interaction of the antibodies FC part with FcyRlla (CD32a) expressed by macrophages.

An antibody or antigen-binding fragment inducing ADCP (or having ADCP activity) is an antibody which may elicit a substantial amount of phagocytosis of target cells in the presence of macrophages. Preferably, the ADCP induction results in the phagocytosis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells.

"Complement-dependent cytotoxicity" ("CDC") is an effector function of IgG and IgM antibodies. When they are bound to a surface antigen on a target cell (e.g. bacterial or viral infected cell), the classical complement pathway is triggered by bonding protein Clq to these antibodies, resulting in formation of a membrane attack complex (MAC) and target cell lysis. Complement system is efficiently activated by human IgGl, lgG3 and IgM antibodies, weakly by lgG2 antibodies and is not activated by lgG4 antibodies. It is one mechanism of action by which therapeutic antibodies - also specific embodiments of the antibodies according to the current invention - can achieve an antitumor effect. Several laboratory methods exist for determining the efficacy of CDC and are known in the art.

An antibody or antigen-binding fragment inducing CDC is an antibody which may elicit a substantial amount of formation of a membrane attack complex and lysis of target cells. Preferably, the CDC induction results in the lysis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells. Antibodies comprising an Fc region may or may not comprise a modification promoting the association of the first and the second subunit of the Fc domain.

A "modification promoting the association of the first and the second subunit of the Fc domain" is a manipulation of the peptide backbone or the post-translational modifications of an Fc domain subunit that reduces or prevents the association of a polypeptide comprising the Fc domain subunit with an identical polypeptide to form a homodimer. Antibodies comprising an Fc region may or may not comprise a modification promoting the association of the first and the second subunit of the Fc domain. A modification promoting association as used herein particularly includes separate modifications made to each of the two Fc domain subunits desired to associate (i.e. the first and the second subunit of the Fc domain), wherein the modifications are complementary to each other so as to promote association of the two Fc domain subunits. For example, a modification promoting association may alter the structure or charge of one or both of the Fc domain subunits so as to make their association sterically or electrostatically favorable. Thus, (hetero)dimerization occurs between a polypeptide comprising the first Fc domain subunit and a polypeptide comprising the second Fc domain subunit, which might be nonidentical, e.g. in the sense that further components fused to each of the subunits (e.g. antigen binding moieties) are not the same. In some embodiments the modification promoting association comprises an amino acid mutation in the Fc domain, specifically an amino acid substitution. In a particular embodiment, the modification promoting association comprises a separate amino acid mutation, specifically an amino acid substitution, in each of the two subunits of the Fc domain.

A "fragment" of an antibody as used herein is required to substantially retain the desired affinity of the full-length antibody. As such, suitable fragments of an anti-human CCR8 antibody will retain the ability to bind to the target chemokine receptor, e.g. to bind to human CCR8 receptor. Fragments of an antibody comprise a portion of a full-length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, single-chain antibody molecules, diabodies and domain antibodies, see Holt, Lucy J., et al. "Domain antibodies: proteins for therapy." Trends in biotechnology 21.11 (2003): 484-490.

A "Fab fragment" contains the constant domain of the light chain and the first constant domain (CH2) of the heavy chain.

"Fab' fragments" differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH2 domain including one or more cysteines from the antibody hinge region.

"F(ab') fragments" are produced by cleavage of the disulfide bond at the hinge cysteines of the F(ab')2 pepsin digestion product. Additional chemical couplings of antibody fragments are known to those of ordinary skill in the art. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation of animals, and may have less non-specific tissue binding than an intact antibody, see, e.g., Wahl, Richard L., Charles W. Parker, and Gordon W. Philpott. "Improved radioimaging and tumor localization with monoclonal F (ab¹) 2." Journal of nuclear medicine: official publication, Society of Nuclear Medicine 24.4 (1983): 316-325.

An "Fv fragment" is the minimum fragment of an antibody that contains a complete target recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. Often, the six CDRs confer antigen binding specificity upon the antibody. However, in some instances even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) may have the ability to recognize and bind the antigen, although at a lower affinity than the entire binding site.

"Single-chain Fv" or "scFv" antibody fragments comprise the VH and VL domains of an antibody in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.

"Single domain antibodies" are composed of single VH or VL domains which exhibit sufficient affinity to the target. In a specific embodiment, the single domain antibody is a camelized antibody, see, e.g., Riechmann, Lutz, and Serge Muyldermans. "Single domain antibodies: comparison of camel VH and camelised human VH domains." Journal of immunological methods 231.1-2 (1999): 25-38.

"Bispecific antibodies" are monoclonal antibodies that have binding specificities for at least two different epitopes on the same or different antigens. In the present disclosure, one of the binding specificities can be directed towards the target chemokine receptor such as CCR8, the other can be for any other antigen, e.g., without limitation for a cell-surface protein, receptor, receptor subunit, tissuespecific antigen, viral ly derived protein, virally encoded envelope protein, bacterial ly derived protein, or bacterial surface protein. Bispecific antibody constructs according to the invention also encompass multispecific antibody constructs comprising multiple binding domains/binding sites, such as trispecific antibody constructs, where the construct comprises three binding domains.

"Derivatized antibodies" are typically modified by glycosylation, acetylation, pegylation, phosphorylation, sulfation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-natural amino acids, e.g., using ambrx technology, see, e.g., Wolfson, Wendy. "Amber codon flashing ambrx augments proteins with unnatural amino acids." Chemistry & biology 13.10 (2006): 1011- 1012. Antibodies according to the current invention may be derivatized, e.g. glycosylated or sulfated.

"Monoclonal antibodies" are substantially homogenous populations of antibodies binding a particular antigen. Monoclonal immunoglobulins may be obtained by methods well known to those skilled in the art (see for example, Kohler, Georges, and Cesar Milstein. "Continuous cultures of fused cells secreting antibody of predefined specificity." nature 256.5517 (1975): 495-497., and U.S. Patent No. 4,376,110). An immunoglobulin or immunoglobulin fragment with specific binding affinity can be isolated, enriched, or purified from a prokaryotic or eukaryotic organism. Routine methods known to those skilled in the art enable production of both immunoglobulins or immunoglobulin fragments and proteinaceous binding molecules with immunoglobulin-like functions, in both prokaryotic and eukaryotic organisms. The antibodies according to the current invention are preferably monoclonal.

"Humanized antibodies" contain CDR regions derived from a non-human species, such as mouse, that have, for example, been engrafted, along with any necessary framework back-mutations, into human sequence-derived V regions. Thus, for the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and capacity. See, for example, U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205, each herein incorporated by reference. In some instances, framework residues of the human immunoglobulin are replaced by corresponding non- human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity). In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence. The humanized antibody optionally comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details see Jones, Peter T., et al. "Replacing the complementaritydetermining regions in a human antibody with those from a mouse." Nature 321.6069 (1986): 522-525.; Riechmann, Lutz, et al. "Reshaping human antibodies for therapy." Nature 332.6162 (1988): 323-327.; and Presta, Leonard G. "Antibody engineering." Current Opinion in Structural Biology 2.4 (1992): 593- 596., each incorporated herein by reference.

Fully human antibodies (human antibodies) comprise human derived CDRs, i.e. CDRs of human origin. Preferably, a fully human antibody according to the current invention is an antibody having at least 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 % or 100 % sequence identity with the closest human VH germline gene (e.g. sequence extracted from recommended list and analyzed in IMGT/Domain-gap-align).

As accepted by usual nomenclature systems such as the INN species subsystem in force until 2017, fully human antibodies may comprise a low number of germline deviations compared with the closest human germline reference determined based on the IMGT database (http://www.imgt.org, November 29, 2019). For example, a fully human antibody according to the current invention may comprise up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 germline deviations in the CDRs compared with the closest human germline reference. Fully human antibodies can be developed from human derived B cells by cloning techniques in combination with a cell enrichment or immortalization step. The majority of fully human antibodies in clinical use, however, were isolated either from immunized mice transgenic for the human IgG locus or from sophisticated combinatorial libraries by phage display (Bruggemann, Marianne, et al. "Human antibody production in transgenic animals." Archivum immunologiae et therapiae experimentalis 63.2 (2015): 101-108.; Carter, Paul J. "Potent antibody therapeutics by design." Nature reviews immunology 6.5 (2006): 343-357.; Frenzel, Andre, Thomas Schirrmann, and Michael Hust. "Phage display-derived human antibodies in clinical development and therapy." MAbs. Vol. 8. No. 7. Taylor & Francis, 2016.; Nelson, Aaron L., Eugen Dhimolea, and Janice M. Reichert. "Development trends for human monoclonal antibody therapeutics." Nature reviews drug discovery 9.10 (2010): 767-774.).

Several techniques are available to generate fully human antibodies or to generate antibodies comprising human derived CDRs (cf. W02008112640). Cambridge Antibody Technologies (CAT) and Dyax have obtained antibody cDNA sequences from peripheral B cells isolated from immunized humans and devised phage display libraries for the identification of human variable region sequences of a particular specificity. Briefly, the antibody variable region sequences are fused either with the Gene III or Gene VIII structure of the M13 bacteriophage. These antibody variable region sequences are expressed either as Fab or single chain Fv (scFv) structures at the tip of the phage carrying the respective sequences. Through rounds of a panning process using different levels of antigen binding conditions (stringencies), phages expressing Fab or scFv structures that are specific for the antigen of interest can be selected and isolated. The antibody variable region cDNA sequences of selected phages can then be elucidated using standard sequencing procedures. These sequences may then be used for the reconstruction of a full antibody having the desired isotype using established antibody engineering techniques. Antibodies constructed in accordance with this method are considered fully human antibodies (including the CDRs). In order to improve the immunoreactivity (antigen binding affinity and specificity) of the selected antibody, an in vitro maturation process can be introduced, including a combinatorial association of different heavy and light chains, deletion/addition/mutation at the CDR3 of the heavy and light chains (to mimic V-J, and V- D-J recombination), and random mutations (to mimic somatic hypermutation). An example of a "fully human" antibody generated by this method is the anti-tumor necrosis factor a antibody, Humira (adalimumab).

The term "Atezolizumab" (TECENTRIQ) refers to a further PD-L1 blocking antibody likewise indicated for the treatment of patients across a number of cancer indications. Dosage forms and strength are solutions for injection provided in a single-dose vial with 840 mg/14 mL (60 mg/mL) or 1200 mg/20 mL (60 mg/mL). Atezolizumab can be administered by intravenous infusion after dilution, e.g. at a dose of 840 mg every two weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

The term "Avelumab" (BAVENCIO) refers to a fully human monoclonal antibody targeting PD-L1. Avelumab was developed by Merck KGaA and is used as a cancer medication, e.g. for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma. The term "Durvalumab" (IMFINZI) is a PD-L1 blocking antibody indicated for various cancer types. Dosage forms and strength are solutions for injection provided in a single-dose vial with 500 mg/10 mL or 120 mg/2.4 mL (each 50 mg/mL). Durvalumab can be administered by intravenous infusion after dilution, e.g. at a dose of 10 mg/kg every two weeks or 1500 mg every 3 weeks as part of a combination scheme.

The term "Nivolumab" (OPDIVO) refers to another PD-1 blocking antibody indicated for the treatment of patients across a number of cancer indications. Dosage forms and strength are solutions for injection provided in a single-dose vial with lOmg/mL (4mL, lOmL). Nivolumab can be administered by intravenous infusion after dilution, e.g. at a dose of 240 mg every two weeks, 360 mg every 3 weeks or 480 mg every 4 weeks.

The term "Pembrolizumab" (KEYTRUDA) refers to a potent humanized lgG4 mAb with high specificity of binding to PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of patients across a number of cancer indications. Dosage forms and strength of pembrolizumab are solutions for injection provided in a single-dose vial with 100 mg/4 mL (25 mg/mL) solution. Pembrolizumab can be administered e.g. at a dose of 200 mg once every three weeks, or 400 mg once every 6 weeks. Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, either as a monotherapy or in combination with other treatment modalities.

The term "Toripalimab" refers to a recombinant, humanized PD-1 monoclonal antibody that binds to PD-1 and prevents binding of PD-1 with PD-L1 and PD-L2. Toripalimab was developed by Shanghai Junshi Bioscience Co., Ltd for the treatment of various cancers. The approved dosage of toripalimab is 3 mg/kg every two weeks as an intravenous (IV) infusion.

The term "Zimberelimab" (Arcus Biosciences) is a monoclonal antibody that binds PD-1 restoring the antitumor activity of T cells. Zimberelimab is in clinical studies for various cancer indications, e.g. for the treatment of first-line metastatic non-small cell lung cancer, e.g. in combination with domvanalimab, an anti-TIGIT monoclonal antibody, and etrumadenant, a dual A2a/A2b adenosine receptor antagonist. Zimberelimab can be administered by intravenous infusion after dilution, e.g. at a dose of 360 mg every 3 weeks.

"Treating" a disease in a subject or "treating" a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening. The terms "prevent", "preventing", "prevention" and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.

The term "effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount sufficient to achieve a particular biological result or to modulate or ameliorate a symptom in a subject, or the time of onset of a symptom, typically by at least about 10 %; usually by at least about 20 %, preferably at least about 30 %, or more preferably at least about 50 %. Efficacy of the use of an antibody in cancer therapy can be assessed based on the change in tumor burden. Both tumor shrinkage (objective response) and time to the development of disease progression are important endpoints in cancer clinical trials. Standardized response criteria, known as RECIST (Response Evaluation Criteria in Solid Tumors), were published in 2000. An update (RECIST 1.1) was released in 2009. RECIST criteria are typically used in clinical trials where objective response is the primary study endpoint, as well as in trials where assessment of stable disease, tumor progression or time to progression analyses are undertaken because these outcome measures are based on an assessment of anatomical tumor burden and its change over the course of the trial. An effective amount for a particular subject may vary depending on factors such as the condition being treated, the overall health of the subject, the method, route, and dose of administration and the severity of side effects. When in combination, an effective amount is in ratio to a combination of components and the effect is not limited to individual components alone.

If not defined otherwise, "Complete Response" (CR) is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. For "Partial Response" (PR) at least a 30 % decrease in the sum of diameters of target lesions has to be reached, taking as reference the baseline sum diameters. For "Progressive Disease" (PD) at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. In "Stable Disease" (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD is observed, taking as reference the smallest sum diameters while on study.

Secondary outcome measures that can be used to determine the therapeutic benefit of the inventive antibodies described herein include the following: "Objective Response Rate" (ORR) is defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR). "Progression Free Survival" (PFS) is defined as the time from the first dose date of an antibody to either disease progression or death, whichever occurs first. "Overall Survival" (OS) is defined as the length of time from either the date of diagnosis or the start of treatment for a disease, that patients diagnosed with the disease are still alive. "Duration of Overall Response" (DOR) is defined as the time from the participant's initial CR or PR to the time of disease progression. "Depth of Response" (DpR) is defined as the percentage of tumor shrinkage observed at the maximal response point compared to baseline tumor load. Clinical endpoints for both ORR and PFS can be determined based on RECIST 1.1 criteria described above.

Where non-human subjects are analyzed, the aforementioned parameters to determine therapeutic efficacy and benefit have to be adapted as discussed elsewhere herein, cf. example 12 ff.

Typical "subjects" according to the current invention include human and non-human subjects. Subjects can be mammals such as mice, rats, cats, dogs, primates and/or humans.

The term "pharmaceutical formulation" (also "pharmaceutical composition" or "therapeutic formulation" or "dosage form") as used herein refers to a mixture of active ingredients and inactive compounds that can be administered to a subject or patient. For example, a pharmaceutical formulation can be prepared by mixing an antibody, antibody fragment or conjugate having the desired degree of purity with physiologically acceptable carriers, excipients or stabilizers, e.g. according to Remington's Pharmaceutical Sciences (18th ed.; Mack Pub. Co.: Eaton, Pa., 1990). Acceptable carriers, excipients, or stabilizers for pharmaceutical formulations are nontoxic to recipients at the dosages and concentrations employed.

There are various different formulation types for different routes of administration such a enteral, parenteral or topical formulations.

"Enteral formulations" comprise without limitation tablets, capsules or sustained release formulations. "Parenteral formulations" comprise without limitation liquids or lyophilized formulations.

"Topical formulations" comprise without limitation creams, ointments, gels, pastes and powders.

A "liquid" or "liquid (pharmaceutical) formulation" comprises the active ingredient and usually further compounds to ensure a stable active medication following storage. These further compounds may be without limitation solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants. If concentrated by evaporation, the liquid formulation may be further diluted before administration. For IV administration, the liquid formulation may be transferred from a vial to an IV bag and may be mixed with other compounds or materials.

A "frozen liquid" is a liquid formulation in a solid state of matter, for example where a liquid formulation has been transferred into a solid state of matter by freezing.

A "lyophilized formulation" (also: lyophilizate) can be obtained by removing solvent (e.g. water) from a liquid drug or liquid formulation thereby creating a solid powder, or cake. The lyophilized formulation is stable for extended periods of time and allows storage at higher temperatures. Stabilizers can be added to replace the water/solvent and preserve the structure of the antibody or fragment thereof. Before administration, a lyophilized formulation is usually reconstituted as a liquid. This can be achieved by combining a liquid diluent (with or without further ingredients) with the lyophilized formulation and mixing or otherwise resuspending it. A lyophilizate is "arranged for dilution to further specified concentrations" of the ingredients, if dilution with a solvent results in a liquid characterized by these further specified ingredient concentrations.

The term "histidine" as used herein refers to the essential amino acid "histidine" or salts thereof, such as without limitation histidine basic component and histidine HCI monohydrate. Histidine contains an a- amino group (which may occur in the protonated -NH3+ form), a carboxylic acid group (which may occur in the deprotonated -COO- form), and an imidazole side chain (which may be partially protonated). Histidine may be used as part of a pharmaceutical formulation. "L-histidine" is the L-enantiomer of the amino acid histidine and refers e.g. to L-histidine basic component and L-histidine HCI monohydrate.

The term "arginine" as used herein refers to the amino acid "arginine" or salts thereof, such as arginine HCI. Arginine contains an a-amino group, a carboxylic acid group, and a guanidino group. Arginine may be used as part of a pharmaceutical formulation. "L-arginine" is the L-enantiomer of the amino acid arginine.

The term "methionine" as used herein refers to the essential amino acid "methionine" or salts thereof. Methionine contains an a-amino group, a carboxylic acid group, and a S-methyl thioether side chain. Methionine may be used as part of a pharmaceutical formulation. "L-methionine" is the L-enantiomer of the amino acid methionine.

"Polysorbate 80" is derived from polyethoxylated sorbitan and oleic acid. It is sold inter alia under the brand name Tween 80. The hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following polysorbate refers to the lipophilic group, in this case, the oleic acid. The full chemical names for polysorbate 80 are: Polyoxyethylene (20) sorbitan monooleate or (x)- sorbitan mono-9-octadecenoate poly(oxy-l,2-ethanediyl).

"Sucrose" (also "(2R,3R,4S,5S,6R)-2-{[(2S,3S,4S,5R)-3,4-Dihydroxy-2,5-bis(hydroxymethyl)oxolan-2- yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol)" or "P-D-Fructofuranosyl a-D-glucopyranoside") is a disaccharide sugar. In sucrose, the monomers glucose and fructose are linked via an ether bond between Cl on the glucosyl subunit and C2 on the fructosyl unit. A pharmaceutical solution comprising 6 % sucrose comprises approximately 175 mM sucrose, while a pharmaceutical solution comprising 8 % sucrose comprises approximately 234 mM sucrose.

The term "intravenous administration" or "intravenous infusion" refers to a method of putting fluids, including pharmaceutical compositions or drugs, into the bloodstream.

The term "subcutaneous administration" "subcutaneous infusion" refers to a method of the insertion of medications, pharmaceutical compositions or drugs beneath the skin either by injection or infusion.

The term "aqueous dextrose solution" refers to a solution of dextrose (glucose) in aqueous solution such as water or normal saline (0.9% w/v of NaCI). The solution may come in a number of strengths including 5% (D5W), 10%, and 50% dextrose. The percentage can for example be a mass-volume percentage, such that a 5% solution contains 50 g/L of glucose/dextrose, which equals 278 mmol/L dextrose.

A "host cell" is a cell that is used to receive, maintain, reproduce and amplify a vector. A host cell also can be used to express the polypeptide, e.g. an antibody or fragment thereof encoded by the vector. The nucleic acid contained in the vector is replicated when the host cell divides, thereby amplifying the nucleic acids. Preferred host cells are mammalian cells, such as CHO cells or HEK cells. Further preferred host cells are rat myeloma YB2/0 cell.

A "cell with endogenous target expression" is a cell which expresses a target protein at a level which is comparable to the physiological or diseased situation. Typically, cells which have been engineered for overexpression express a target protein at much higher levels.

The term "intra-tumoral", "intratumoral", "tumor infiltrating" or "tumoral" in the context of cells, structures, proteins, antibodies, or markers refers to their localization within the tumor tissue.

Cells which are "positive" or "+" for a certain marker or protein are cells characterized by substantial expression of that marker or protein. Marker or protein expression can be determined and quantified as known in the art, e.g. to define different cell populations. For the characterization of (immune) cell populations, the marker expression can be determined by FACS or using any other technique described herein.

"T cells" are immune cells expressing TCRaP, CD3, and CD8 or CD4. As used herein, the term includes naive T cells, CD4+ T cells, CD8+ T cells, regulatory T cells, memory T cells, activated T cells, anergic T cells, tolerant T cells, chimeric B cells, and antigen- specific T cells and further T cell populations known in the art. In some embodiments, the presence of a T cell receptor (TCR) on the cell surface distinguishes T cells from other lymphocytes.

"CD8+ T cells" (also "cytotoxic T cell", "TC", "cytotoxic T lymphocyte", "CTL", "T-killer cell", "cytolytic T cell", "CD8+ T-cell" or "killer T cell") are T cells expressing CD3, CD45 and CD8. CD8+ T cells can kill cancer cells, cells that are infected (particularly with viruses), or otherwise damaged cells.

"CD4+ T cells" (also "T helper cells", "Th cells") are immune cells expressing CD3, CD4 and CD45. There are several subsets of T helper cells, such as, without limitation, Thl, Th2, and Thl7. CD4+ T cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

As used herein, the term "Treg cells" (also "Tregs", "regulatory T cells", "T regulatory cells", "suppressor T cells") refers to immune cells expressing CD3, CD4, CD45, and FoxP3, and furthermore expressing high levels of CD25 and low levels of CD127. Identification of Treg cells may be performed as described elsewhere herein. Treg cells typically also express high levels of CTLA-4, GITR, and LAG-3. In the literature, Tregs have furthermore been classified based on memory marker CD45RO. Under physiological conditions, Treg cells maintain immunological tolerance. During an immune response, Treg cells stop T cell-mediated immunity and suppress auto-reactive T cells that have escaped negative selection within the thymus. Treg cells can also suppress other types of immune cells such as NK cells and B cells. Adaptive Treg cells (called Th3 or Tri cells) are thought to be generated during an immune response.

Treg cells furthermore play an important role in immune escape by suppressing antitumor immunity, thereby providing an environment of immune tolerance. T cells that recognize cancer cells are often present in large numbers in tumors, but their cytotoxic function is suppressed by nearby immune- suppressor cells. Tregs are abundant in many different cancers, are highly enriched in the tumor microenvironment, and are well known for their role in tumor progression.

"Activated Treg cells" express CD4, CD45, FoxP3, CD69 and CCR8, and furthermore have a high expression of CD25, and have a low expression of CD127. CD69 is a T cell activation marker.

"CCR8 positive regulatory T cells" or "CCR8+ regulatory T cells" are Tregs expressing CCR8.

"CD4conv cells" are conventional CD4+, CD25- T cells.

"B cells" are immune cells expressing CD19, and mature B cells express CD20 and CD22. B cells upon activation via CD40 undergo differentiation where somatic hypermutation and enhanced immunoglobulin class switch occur resulting in mature B cells or plasma cells (capable of secreting Abs). B cells are involved in humoral immunity of the adaptive immune system, and are antigen presenting cells.

"Macrophages" are immune cells expressing low CD14, high CD16, CDllb, CD68, CD163, and CD206. Macrophages engulf and digest cellular debris, foreign substances, microbes or cancer cells by phagocytosis. Besides phagocytosis, macrophages play a critical role in innate immunity and also help initiate adaptive immunity by recruiting other immune cells. For example, macrophages are important as antigen presenters to T cells. Macrophages that encourage inflammation are called Ml macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages.

As used herein, "Ml macrophages" are a subset of macrophages expressing ACOD1. Ml macrophages have pro-inflammatory, bactericidal, and phagocytic functions.

As used herein, "M2 macrophages" are a subset of macrophages expressing MRC1 (CD206). M2 macrophages secrete anti-inflammatory interleukins, play a role in wound healing and are needed for revascularization and reepithelialization. Tumor-associated macrophages are mainly of the M2 phenotype and seem to actively promote tumor growth.

"Dendritic Cells" (DCs) are bone marrow derived leukocytes and are the most potent type of antigen- presenting cells. DCs are specialized to capture and process antigens, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules recognized by T cells. As defined herein, DCs are characterized by expression of CDlc, CD14, CD16, CD141, CDllc and CD123. Different subpopulations of Dendritic cells exist. In human, DC1 are immunogenic while DC2 cells are tolerogenic. Mature DC express CD83, while plasmacytoid DC express CD123.

"NK cells" (also natural killer cells) are immune cells which express CD45, CD16, CD56, NKG2D, but are CD3 negative. NK cells do not require activation to kill cells that are missing "self" markers of MHC class 1. NCR1 (also referred to as CD335 or NKp46) is expressed on NK cells and on a subset of NKT cells.

"Natural killer T (NKT) cells" are a heterogeneous group of T cells that share properties of both T cells and natural killer cells.

As known in the art, "effector cells" are immune cells that actively support immune response after stimulation. As used herein, effector cells refer to immune cells expressing Fey receptors and are therefore able to mediate ADCC or ADCP. Non-limiting examples of effector cells are monocytes, neutrophils, mast cells, and, preferably, macrophages, and natural killer cells.

Dosing schemes are abbreviated as known in the art, e.g. every day (QD), every 2 days (Q2D), or every 3 days (Q3D).

"Capillary isoelectric focusing" (clEF) is a high-resolution analytical technique that allows the separation of protein/peptide mixtures, protein glycoforms and other charge variants, based on their isoelectric point (pl). clEF is based on the principle of capillary gel electrophoresis (cGE). In general, electrophoresis is a separation technique based on the migration of charged molecules in response to an electric field, toward the electrode of opposite charge. To separate molecules based on pl, a pH gradient inside the gel is established by ampholyte mixtures. The molecule of interest migrates along the electrical field until it reaches the pH corresponding to its pl, where it has a net charge of zero and stops migrating. The UV absorption over the whole capillary is measured throughout the separation, allowing real-time observation as well as a final quantification. clEF can be used for monitoring charge heterogeneity as well as oxidation and deamidation analysis of therapeutic (glyco)proteins or antibodies, and in the context of product characterization or comparability studies.

"Capillary gel electrophoresis" (cGE) allows for the qualitative analysis of molecular weight and quantitative analysis of protein aggregates and fragments. cGE is a high-resolution and automated variation of the SDS-PAGE technique. In general, electrophoresis is a separation technique based on the migration of charged molecules in response to an electric field, toward the electrode of opposite charge. It is usually performed in polyacrylamide gels. In cGE, the gel is located inside a capillary through which the sample components must migrate. The larger the molecular weight, the longer the migration time. A detection system, mostly UV or fluorescence detection, detects and quantifies the migrating species. For monoclonal antibodies cGE can be performed under reducing or non-reducing conditions. Reducing conditions have the benefit of improved resolution as well as the ability to detect fragments associated with the mAb via disulfide bonding. Non-reducing analysis can provide additional information on fragments such as free light chain and HHL. Non-reducing conditions also provide resolution of covalent aggregates. "Size exclusion HPLC" (SE-HPLC) is a chromatographic technique that employs porous particles in the column to separate molecules by virtue of their size in solution. SE-HPLC can be used to separate aggregates, monomers, and fragments in the analysis of monoclonal antibodies.

"Osmolality" is defined as the number of osmoles (Osm) of solute per kilogram of solvent (osmol/kg or Osm/kg). As such, larger numbers indicate a greater concentration of solutes in the plasma. Osmolality is a critical attribute for injectable formulations. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. Preventing injection of hypo- or hyperosmotic solutions is a key element of parenteral formulation development. The osmolality of monoclonal antibody (mAb) formulations is typically determined using freezing point depression or vapor pressure osmometers.

EMBODIMENTS

According to a first aspect of the current invention, there is provided a pharmaceutical formulation comprising an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the pharmaceutical formulation comprises: a. 2.5 - 15 mM histidine; b. 50 - 200 ppm polysorbate, preferably 50 - 100 ppm polysorbate, preferably polysorbate 80; c. 5 % - 8 % sucrose; d. 10 - 50 mM arginine; e. 2.5 - 50 mM methionine; and f. 25 mg/mL - 150 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5.

The pharmaceutical formulation may be provided as a liquid, such as a frozen liquid. For example, the pharmaceutical formulation is a liquid or a frozen liquid. The pharmaceutical formulation may also be provided as a lyophilizate arranged for dilution to the provided concentrations.

In a preferred embodiment, the pharmaceutical formulation is provided as a liquid. For example, the liquid can be stored in a freezer e.g. at 4°C or below, e.g. for at least 3 or 6 months or at 5 °C or 6 °C for at least 6 months preferably at least 36 months.

In the same or a different preferred embodiment, the pharmaceutical formulation is provided as a frozen liquid. For example, the frozen liquid can be stored in a freezer or in liquid nitrogen, at -20°C, - 30°C or below, for at least 3 months, at least 6 months, at least 12 months, or at least 36 months.

In a different preferred embodiment, the pharmaceutical formulation is provided in lyophilized form for dilution to the specified concentrations. Lyophilization (also: freeze-drying) may occur as known in the art, e.g. by withdrawing the water by sublimation under vacuum. The lyophilized formulation can subsequently be regenerated by dissolving it with water or an alternative pharmaceutically acceptable solution.

The pharmaceutical formulation may be in a ready-to-use form, e.g. for subcutaneous administration, or may be further diluted for intravenous infusion. It may also be further diluted for subcutaneous administration. In a preferred embodiment the pharmaceutical formulation is provided ready-to-use for immediate administration to a patient.

In an alternative preferred embodiment, the pharmaceutical formulation is provided for further dilution in a pharmaceutically acceptable solution. Such a pharmaceutically acceptable solution can be for example an aqueous dextrose solution.

In some preferred embodiments the pharmaceutical formulation is a solution for intravenous (i.v.) injection. In some other preferred embodiments the pharmaceutical formulation is a solution for subcutaneous administration.

The pharmaceutical formulation needs to be sterile and have a low level of endotoxins / be substantially free of endotoxins. This can be achieved as known in the art, e.g. as described elsewhere herein.

The pharmaceutical formulation according to the current invention may be stored at -30°C or lower for extended periods of time. In particular the pharmaceutical formulation according to the current invention may be stored at -30°C for at least 6 months. Experiments to demonstrate the stability over several years are ongoing.

FORMULATION INGREDIENTS

Histidine

In some embodiments, the formulation comprises 2.5 - 15 mM histidine, preferably 5 - 15 mM histidine, most preferably 7.5 - 12.5 mM histidine.

For example, the formulation may comprise 2.5 mM, 3 mM, 3.5 mM, 4 mM, 4.5 mM, 5 mM, 5.5 mM, 6 mM, 6.5 mM, 7 mM, 7.5 mM, 8 mM, 8.5 mM, 9 mM, 9.5 mM, 10 mM, 10.5 mM, 11 mM, 11.5 mM, 12 mM, 12,5 mM, 13 mM, 13.5 mM, 14 mM, 14.5 mM or 15 mM histidine.

The amount of histidine as buffer agent, in particular in combination with sucrose may impact osmotic pressure and solution viscosity.

In some preferred embodiments the histidine is composed of approximately equal amounts of L- histidine HCI monohydrate and L-histidine basic component for buffering the pharmaceutical formulation.

In an utmost preferred embodiment the pharmaceutical formulation comprises approximately 10 mM histidine and the histidine is composed of approximately 4.7 mM L-histidine HCI monohydrate and approximately 5.3 mM L-histidine basic component.

In some preferred embodiments, the formulation comprises 5 to 12.5 mM L- histidine, preferably approximately 10 mM L-histidine, most preferably wherein the 10 mM L-histidine is composed of approximately 5 mM L-histidine HCI monohydrate and approximately 5 mM L-histidine basic component or approximately 4.7 mM L-histidine HCI monohydrate and approximately 5.3 mM L-histidine basic component.

Arginine

In some embodiments, the formulation comprises 10 - 50 mM arginine, preferably 15 - 45 mM arginine, most preferably 20 - 40 mM arginine, such as 25 - 35 mM arginine.

For example, the formulation may comprise 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM of arginine.

In an utmost preferred embodiment the pharmaceutical formulation comprises approximately 30 mM arginine.

In some preferred embodiments the arginine is L-arginine, most preferably wherein the arginine is L- arginine HCI.

In some preferred embodiments, the formulation comprises 20 to 40 mM arginine, preferably approximately 30 mM arginine, most preferably wherein the arginine is L-arginine HCI.

Methionine

In some cases, the formulation comprises 2.5 - 50 mM methionine, preferably 5 - 40 mM methionine, most preferably 5 - 30 mM methionine, 5 - 20 mM methionine, 5 - 15 mM methionine or approximately 10 mM methionine.

In some preferred embodiments the methionine is L-methionine.

In some preferred embodiments, the formulation comprises approximately 5 to 50 mM methionine, preferably 10 mM methionine, preferably wherein the methionine is L-methionine.

Polysorbate

Any of the above formulations may also comprise 50 - 200 ppm polysorbate 20 or 80, 50 - 100 ppm polysorbate 20 or 80, 55 - 95 ppm polysorbate 20 or 80, 60 - 90 ppm polysorbate 20 or 80, 65 - 85 ppm polysorbate 20 or 80, 70 - 80 ppm polysorbate 20 or 80, or approximately 75 ppm polysorbate 20 or 80. In some cases the above formulation comprises 50 ppm, 52.5 ppm, 55 ppm, 57.5 ppm, 60 ppm, 62.5 ppm, 65 ppm, 67.5 ppm, 70 ppm, 72.5 ppm, 75 ppm, 77.5 ppm, 80 ppm, 82.5 ppm, 85 ppm, 87.5 ppm, 90 ppm, 92.5 ppm, 95 ppm, 97.5 ppm, 100 ppm , 150 ppm, 200 ppm polysorbate 20 or 80.

Preferably the formulation comprises polysorbate 80, most preferably 75 ppm polysorbate 80.

In some preferred embodiments, the formulation comprises 100 to 200 ppm polysorbate 80, preferably approximately 150 ppm polysorbate 80.

In some preferred embodiments, the formulation comprises 70 to 80 ppm polysorbate 80, preferably approximately 75 ppm polysorbate 80.

Sucrose

In some cases, the formulation comprises 5 % - 8 % (w/v) sucrose, preferably 5.5 % - 7.5 % sucrose, 5.5 % - 7 % sucrose, and most preferably approximately 6 % (w/v) sucrose. As known in the art, 6 % sucrose corresponds to 175 mM sucrose and to 8 % sucrose corresponds to 234 mM sucrose. The skilled person can easily calculate the amount in mM for each percentage provided.

Anti-human CCR8 antibody

The pharmaceutical formulation according to the current invention is particularly useful to formulate comparably high amounts of an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity.

For example, between 25 mg/mL - 150 mg/mL or 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof can be formulated in the pharmaceutical formulation according to the current invention.

Preferably, the pharmaceutical formulation comprises 25 mg/mL to 100 mg/mL, 30 mg/mL to 95 mg/m, 35 mg/mL to 90 mg/mL, 40 mg/mL to 85 mg/mL, 45 mg/mL to 80 mg/mL, 45 mg/mL to 75 mg/mL, 45 mg/mL to 70 mg/mL, 45 mg/mL to 65 mg/mL, 45 mg/mL to 60 mg/mL, and most preferably 45 to 55 of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity.

In an utmost preferred embodiment, the pharmaceutical formulation comprises 50 mg/mL of the antihuman CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity. In another utmost preferred embodiment, the pharmaceutical formulation comprises 75 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity. In a third utmost preferred embodiment, the pharmaceutical formulation comprises 100 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity. These amounts of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity are advantageous because they allow for a convenient preparation of amounts that are required for appropriate dosing while maintaining appropriate viscosity and stability for handling and storage. For example, the pharmaceutical formulation according to the current invention may be provided in a glass vial, e. g. with an antibody concentration of 50, 75 or 100 mg/mL. The pharmaceutical formulation is particularly suited for afucosylated anti-human CCR8 antibodies, e.g. of the human IgG type. Anti-CCR8 antibodies that can be formulated using the pharmaceutical formulation of the current invention are disclosed e.g. in WO2020/138489, W02021/142002, WO2021/163064, WO2021/178749, WO2021/194942, WO2021152186,

W02022/003156, and W02022/042690.

Preferably, the pharmaceutical formulation comprises an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is a human IgGl antibody.

Most preferably, the pharmaceutical formulation comprises an anti-human CCR8 antibody or antigenbinding fragment thereof having ADCC activity and/or ADCP activity, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is afucosylated. The pharmaceutical formulation is also suited for an anti-human CCR8 antibody or antigen-binding fragment thereof that is a low-internalizing or a non-internalizing antibody. Preferably the anti-human CCR8 antibody or antigen-binding fragment thereof is a non-internalizing antibody.

The pharmaceutical formulation is also suited for an anti-human CCR8 antibody or antigen-binding fragment thereof which has an isoelectric point of 7.5 to 9, preferably 8.3.

In some examples, the anti-human CCR8 antibody or antigen-binding fragment thereof comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:8, SEQ ID NO:22, SEQ ID NO:36, SEQ ID NO:50, SEQ ID NO:68, SEQ ID NO:86, SEQ ID NQ:104, SEQ ID NO:122, SEQ ID NQ:140, SEQ ID NO:158, SEQ ID NO:176, SEQ ID NO:194, SEQ ID NO:212, SEQ ID NO:232, SEQ ID NQ:250, SEQ ID NQ:270, SEQ ID NQ:290, SEQ ID NQ:310, SEQ ID NQ:330, SEQ ID NQ:350, SEQ ID NO:368, SEQ ID NO:388, SEQ ID NQ:406, SEQ ID NO:424, SEQ ID NO:442, SEQ ID NQ:460, SEQ ID NO:478, SEQ ID NO:496, SEQ ID NO:514, SEQ ID NO:534, SEQ ID NO:554, SEQ ID NO:565, SEQ ID NO:586, SEQ ID NQ:606, SEQ ID NO:626, SEQ ID NO:646, SEQ ID NO:666, SEQ ID NO:686, SEQ ID NQ:706, SEQ ID NO:726, SEQ ID NO:746, SEQ ID NO:757, SEQ ID NO:769, SEQ ID NO:781, or SEQ ID NO:793.

According to some highly preferred embodiments, the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:554.

More specifically, the anti-human CCR8 antibody or antigen-binding fragment thereof may be characterized by six CDR sequences, a. wherein each of the six CDR sequences is at least 90%, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NQ:10, SEQ ID NO:11 or SEQ ID NO:12, b. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:25, c. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NQ:40, d. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NQ:50, SEQ ID NO:52, SEQ ID NO:53 or SEQ ID NO:54, e. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NQ:70, SEQ ID NO:71 or SEQ ID NO:72, f. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:89 or SEQ ID NO:90, g. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:102, SEQ ID NQ:103, SEQ ID NQ:104, SEQ ID NQ:106, SEQ ID NQ:107 or SEQ ID NQ:108, h. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:125 or SEQ ID NO:126, i. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:138, SEQ ID NO:139, SEQ ID NQ:140, SEQ ID NO:142, SEQ ID NO:143 or SEQ ID NO:144, j. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NQ:160, SEQ ID NO:161 or SEQ ID NO:162, k. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:178, SEQ ID NO:179 or SEQ ID NQ:180, l. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:196, SEQ ID NO:197 or SEQ ID NO:198, m. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:214, SEQ ID NO:215 or SEQ ID NO:216, n. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:234, SEQ ID NO:235 or SEQ ID NO:236, o. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:248, SEQ ID NO:249, SEQ ID NQ:250, SEQ ID NO:252, SEQ ID NO:253, or SEQ ID NO:254, p. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:268, SEQ ID NO:269, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:273 or SEQ ID NO:274, q. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:288, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:292, SEQ ID NO:293 or SEQ ID NO:294, r. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:308, SEQ ID NO:309, SEQ ID NO:310, SEQ ID NO:312, SEQ ID NO:313 or SEQ ID NO:314, s. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:328, SEQ ID NO:329, SEQ ID NQ:330, SEQ ID NO:332, SEQ ID NO:333 or SEQ ID NO:334, t. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:348, SEQ ID NO:349, SEQ ID NQ:350, SEQ ID NO:352, SEQ ID NO:353 or SEQ ID NO:354, u. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:366, SEQ ID NO:367, SEQ ID NO:368, SEQ ID NQ:370, SEQ ID NO:371 or SEQ ID NO:372, v. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:386, SEQ ID NO:387, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391 or SEQ ID NO:392, w. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:404, SEQ ID NQ:405, SEQ ID NQ:406, SEQ ID NQ:408, SEQ ID NQ:409 or SEQ ID NQ:410, x. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:422, SEQ ID NO:423, SEQ ID NO:424, SEQ ID NO:426, SEQ ID NO:427 or SEQ ID NO:428, y. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:440, SEQ ID NO:441, SEQ ID NO:442, SEQ ID NO:444, SEQ ID NO:445 or SEQ ID NO:446, z. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:458, SEQ ID NO:459, SEQ ID NQ:460, SEQ ID NO:462, SEQ ID NO:463 or SEQ ID NO:464, aa. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NQ:480, SEQ ID NO:481 or SEQ ID NO:482, bb. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:498, SEQ ID NO:499 or SEQ ID NQ:500, cc. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:516, SEQ ID NO:517 or SEQ ID NO:518, dd. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:532, SEQ ID NO:533, SEQ ID NO:534, SEQ ID NO:, 536 SEQ ID NO:537 or SEQ ID NO:538, ee. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID NO:558, ff. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:563, SEQ ID NO:564, SEQ ID NO:565, SEQ ID NO:567, SEQ ID NO:568 or SEQ ID NO:569, gg. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:584, SEQ ID NO:585, SEQ ID NO:586, SEQ ID NO:588, SEQ ID NO:589 or SEQ ID NQ:590, hh. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:604, SEQ ID NQ:605, SEQ ID NQ:606, SEQ ID NQ:608, SEQ ID NQ:609 or SEQ ID NQ:610, ii. ii. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:624, SEQ ID NO:625, SEQ ID NO:626, SEQ ID NO:628, SEQ ID NO:629 or SEQ ID NQ:630, jj. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:644, SEQ ID NO:645, SEQ ID NO:646, SEQ ID NO:648, SEQ ID NO:649 or SEQ ID NQ:650, kk. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:664, SEQ ID NO:665, SEQ ID NO:666, SEQ ID NO:668, SEQ ID NO:669 or SEQ ID NQ:670,

II. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:684, SEQ ID NO:685, SEQ ID NO:686, SEQ ID NO:688, SEQ ID NO:689 or SEQ ID NQ:690, mm. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:704, SEQ ID NQ:705, SEQ ID NQ:706, SEQ ID NQ:708, SEQ ID NQ:709 or SEQ ID NQ:710, nn. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:724, SEQ ID NO:725, SEQ ID NO:726, SEQ ID NO:728, SEQ ID NO:729 or SEQ ID NQ:730, oo. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:744, SEQ ID NO:745, SEQ ID NO:746, SEQ ID NO:748, SEQ ID NO:749 or SEQ ID NQ:750, pp. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:755, SEQ ID NO:756, SEQ ID NO:757, SEQ ID NO:759, SEQ ID NQ:760 or SEQ ID NO:761, qq. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:767, SEQ ID NO:768, SEQ ID NO:769, SEQ ID NO:771, SEQ ID NO:772 or SEQ ID NO:773, rr. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:779, SEQ ID NQ:780, SEQ ID NO:781, SEQ ID NO:783, SEQ ID NO:784 or SEQ ID NO:785, ss. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:791, SEQ ID NO:792, SEQ ID NO:793, SEQ ID NO:795, SEQ ID NO:796 or SEQ ID NO:797.

According to some highly preferred embodiments, the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation comprises six CDR sequences wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID

NO:558.

In some embodiments, the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by a. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:13 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:14, b. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 27 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:28, c. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 41 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:42, d. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:55 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:56, e. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:73 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:74, f. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:91 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:92, g. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:109 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:110, h. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:127 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:128, i. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:145 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:146, j. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:163 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:164, k. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:181 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:182, l. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:199 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:200, m. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:217 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:218, n. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:237 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:238, o. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:255 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:256, p. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:275 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:276, q. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:295 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:296, r. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:315 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:316, s. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:335 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:336, t. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:355 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:356, u. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:373 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:374, v. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:393 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:394, w. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:411 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:412, x. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:429 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:430, y. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:447 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:448, z. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:465 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:466, aa. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:483 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:484, bb. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:501 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:502, cc. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:519 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:520, dd. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:539 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:540, ee. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:560, ff. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:571 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:572, gg. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:591 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:592, hh. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:611 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:612, ii. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:631 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:632, jj. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:651 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:652, kk. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:671 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:672,

II. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:691 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:692, mm. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:711 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:712, nn. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:731 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:732, oo. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:751 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:752, pp. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:763 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:764, qq. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:775 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:776, rr. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:787 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:788, or ss. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:799 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:800.

According to some of these highly preferred embodiments, the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation further comprises a. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and b. a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:560.

In some embodiments, the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by a. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:5 and a light chain at least 98 % or 100 % identical to SEQ ID NO:9, b. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:19 and a light chain at least 98 % or 100 % identical to SEQ ID NO:23, c. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:33 and a light chain at least 98 % or 100 % identical to SEQ ID NO:37, d. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:47 and a light chain at least 98 % or 100 % identical to SEQ ID NO:51, e. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:65 and a light chain at least 98 % or 100 % identical to SEQ ID NO:69, f. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:83 and a light chain at least 98 % or 100 % identical to SEQ ID NO:87, g. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:101 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:105, h. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:119 and a light chain at least 98 % or 100 % identical to SEQ ID NO:123, i. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:137 and a light chain at least 98 % or 100 % identical to SEQ ID NO:141, j. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:155 and a light chain at least 98 % or 100 % identical to SEQ ID NO:159, k. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:173 and a light chain at least 98 % or 100 % identical to SEQ ID NO:177, l. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:191 and a light chain at least 98 % or 100 % identical to SEQ ID NO:195, m. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:209 and a light chain at least 98 % or 100 % identical to SEQ ID NO:213, n. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:229 and a light chain at least 98 % or 100 % identical to SEQ ID NO:233, o. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:247 and a light chain at least 98 % or 100 % identical to SEQ ID NO:251, p. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:267 and a light chain at least 98 % or 100 % identical to SEQ ID NO:271, q. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:287 and a light chain at least 98 % or 100 % identical to SEQ ID NO:291, r. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:307 and a light chain at least 98 % or 100 % identical to SEQ ID NO:311, s. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:327 and a light chain at least 98 % or 100 % identical to SEQ ID NO:331, t. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:347 and a light chain at least 98 % or 100 % identical to SEQ ID NO:351, u. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:365 and a light chain at least 98 % or 100 % identical to SEQ ID NO:369, v. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:385 and a light chain at least 98 % or 100 % identical to SEQ ID NO:389, w. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:403 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:407, x. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:421 and a light chain at least 98 % or 100 % identical to SEQ ID NO:425, y. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:439 and a light chain at least 98 % or 100 % identical to SEQ ID NO:443, z. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:457 and a light chain at least 98 % or 100 % identical to SEQ ID NO:461, aa. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:475 and a light chain at least 98 % or 100 % identical to SEQ ID NO:479, bb. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:493 and a light chain at least 98 % or 100 % identical to SEQ ID NO:497, cc. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:511 and a light chain at least 98 % or 100 % identical to SEQ ID NO:515, dd. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:531 and a light chain at least 98 % or 100 % identical to SEQ ID NO:535, ee. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and a light chain at least 98 % or 100 % identical to SEQ ID NO:555, ff. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:566 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:570, gg. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:583 and a light chain at least 98 % or 100 % identical to SEQ ID NO:587, hh. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:603 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:607, ii. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:623 and a light chain at least 98 % or 100 % identical to SEQ ID NO:627, jj. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:643 and a light chain at least 98 % or 100 % identical to SEQ ID NO:647, kk. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:663 and a light chain at least 98 % or 100 % identical to SEQ ID NO:667,

II. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:683 and a light chain at least 98 % or 100 % identical to SEQ ID NO:687, mm. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:703 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:707, nn. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:723 and a light chain at least 98 % or 100 % identical to SEQ ID NO:727, oo. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:743 and a light chain at least 98 % or 100 % identical to SEQ ID NO:747, pp. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:758 and a light chain at least 98 % or 100 % identical to SEQ ID NO:762, qq. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:770 and a light chain at least 98 % or 100 % identical to SEQ ID NO:774, rr. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:782 and a light chain at least 98 % or 100 % identical to SEQ ID NO:786, or ss. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:794 and a light chain at least 98 % or 100 % identical to SEQ ID NO:798.

According to some of these highly preferred embodiments, the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation further comprises a. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and b. a light chain at least 98 % or 100 % identical to SEQ ID NO:555.

In some preferred embodiments of the inventive pharmaceutical formulation, the anti-CCR8 antibody is characterized by the CDRs of any of the antibodies disclosed in WO2021/178749 Al, WQ2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WQ2023/230473 Al, WQ2021/142002 Al,

WQ2021/163064 Al, WQ2022/042690 Al, WO2022/256563 Al, WQ2022/081718 Al, WO2023/288241 Al, WQ2023/010054 Al, WQ2022/078277 Al, WO2023/137466 Al, WQ2023/098888 Al,

WO2023/174396 Al, WQ2023/206938 Al, WQ2023/201812 Al, WQ2023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al and WO2022/136650 Al.

In some preferred embodiments of the inventive pharmaceutical formulation, the anti-CCR8 antibody is an antibody selected from the list of antibodies disclosed in any of WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al, W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al, WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al, WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al or WO2022/136650 Al.

In some embodiments, the pharmaceutical formulation further comprises an anti-human PD(L)1 antibody, preferably wherein the anti-PD(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab. In these embodiments, the total amount of antibodies should not exceed 100 mg/mL.

According to a preferred embodiment, there is provided a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 50 - 200 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5.

According to a further preferred embodiment, there is provided a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 150 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5. According to utmost preferred embodiment, there is provided a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 75 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5.

In a preferred embodiment the pharmaceutical formulation according to the current invention is characterized by a pH of 6.3 ± 0.5. For the current formulation this pH was found to be advantageous, because it avoided the formation of basic antibody species. Furthermore, the pH of 6.3 +/- 0.5 ensures isotonicity and iso-osmolality of the pharmaceutical formulation.

No adverse reactions were observed for the inventive pharmaceutical formulation in cynomolgus monkeys.

According to a second aspect of the current invention, there is provided a method for preparing a pharmaceutical formulation for intravenous or subcutaneous administration, wherein the method comprises diluting a pharmaceutical formulation according to the first aspect with aqueous dextrose solution, preferably with sterile 5 % aqueous dextrose solution.

According to a third aspect of the current invention, there is provided the pharmaceutical formulation as described herein for use in a method of treatment. In the alternative, there is provided a method of treatment comprising administering the pharmaceutical formulation as described herein to a patient in need of an anti-CCR8 antibody treatment. In the alternative, there is provided the pharmaceutical formulation as described herein for the manufacture of a medicament.

According to a preferred embodiment the method of treatment comprises a. thawing a glass vial comprising the pharmaceutical formulation according to the first aspect, and b. diluting the pharmaceutical formulation according to the first aspect, e.g. with 5 % aqueous dextrose solution to obtain a solution for intravenous or subcutaneous administration, and c. administering intravenously or subcutaneously the solution to a patient in need thereof. According to a preferred embodiment the method of treatment comprises a. thawing a glass vial comprising the pharmaceutical formulation according to the first aspect, and b. administering the undiluted pharmaceutical formulation subcutaneously to a patient in need thereof. In some preferred embodiments of this aspect, the method of treatment is a method of treating cancer, preferably wherein the cancer is non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), melanoma, gastric cancer, renal cell carcinoma (RCC), HPV-driven urogenital cancer, hypermutated tumors, gastro-esophageal junction tumors, or a skin cancer other than melanoma. In some preferred embodiments of this aspect, the treatment is a treatment of a tumor or a disease characterized by CCR8 positive cells, such as CCR8 positive tumor cells or CCR8 positive regulatory T cells.

In some preferred embodiments of this aspect, the treatment comprises administering the anti-CCR8 antibody, preferentially intravenously or subcutaneously, in a total amount of a. 1 to 250 mg once every week (QW), b. 10 to 750 mg once every two weeks (Q2W), or c. 16 to 1500 mg once every three weeks (Q3W).

More specifically, the treatment comprises administering the anti-CCR8 antibody, preferentially intravenously or subcutaneously, in a total amount of a. Approximately 1, 2.5, 3, 10, 30, 50, 75, 100, 125, 175 or 250 mg once every week, b. Approximately 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 450, 500, 750 mg once every two weeks, or c. Approximately 16, 30, 50, 75, 100, 125, 150, 175, 200, 450, 500, 750, 1000 or 1500 mg once every three weeks.

In one embodiment the total amount of the anti-CCR8 antibody is approximately 2.5 mg once every week. In another embodiment the total amount of the anti-CCR8 antibody is approximately 10 mg once every week. In a preferred embodiment the total amount of the anti-CCR8 antibody is approximately 30 mg once every week. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 50 mg once every week. In a further preferred embodiment the total amount of the anti- CCR8 antibody is approximately 75 mg once every week. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every week. In another preferred embodiment the total amount of the anti-CCR8 antibody is approximately 125 mg once every week. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every week. In another preferred embodiment the total amount of the anti-CCR8 antibody is approximately 250 mg once every week.

In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 25 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 50 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 75 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 125 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 150 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 200 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 250 mg once every two weeks. In a further preferred embodiment the total amount of the anti-CCR8 antibody is approximately 500 mg once every two weeks.

In one highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 75 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every three weeks. In one highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 125 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 150 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks. In one preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 200 mg once every three weeks. In another preferred embodiment the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks. In another embodiment the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks. In one embodiment the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three weeks. In another embodiment the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three weeks. Data showing the successful mode of action for these dosing schedules (Treg depletion / CD8+ T cell induction) are available.

The suggested medical use with a QW dosing schedule is superior because the anti-CCR8 antibody is provided with pharmacologically relevant plasma exposure levels, and also because the medical use allows for plasma Ctrough concentrations of the anti-CCR8 antibody above the estimated EC80 values for CCR8+ cell killing, which the inventors derived from in vitro studies.

The medical use with a dosing schedule of Q2W comes with higher doses but is advantageous because these can be administered less frequently while still achieving the required plasma exposures during a dosing interval to produce the desired pharmacological response (CCR8+ Treg killing).

The medical use with a dosing schedule of Q3W comes with higher doses but is advantageous because these can be administered less frequently while still achieving the required plasma exposures during a dosing interval to produce the desired pharmacological response (CCR8+ Treg killing). The suggested Q3W dosing schedule also provides convenience of dosing and alignment with infusion of other drugs. As understood by the skilled person, the total amount in the embodiments described herein is designed for a patient with an average weight of 70 kg and can be scaled based on the actual weight of the patient, i.e. by using the appropriate mg/kg.

For the preparation of the intravenous infusions the required volume of the anti-CCR8 antibody formulation can be withdrawn from (a) vial(s) and transferred into an intravenous (IV) bag containing 0.9 % Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution can be mixed by gentle inversion without shaking. The final concentration of the diluted solution can be for example between 1 mg/mL to 10 mg/mL.

Administration of the anti-CCR8 infusion (e.g. of the diluted solution) can occur intravenously over 15 to 120 minutes, preferably over 30 to 60 minutes, most preferably over 30, 45, 60 or 75 minutes. Administration of the diluted solution can occur through an intravenous line, e.g. containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. Given the variability of infusion pumps from site to site, a window between -5 min and +10 min is permitted (i.e., infusion time is 30 min [-5 min/+10 min]).

Administration of the anti-CCR8 can also occur via subcutaneous administration. Subcutaneous administration is very convenient for patients.

The medical use or treatment according to the current aspect may further comprise administering intravenously or subcutaneously to a patient in need thereof an anti-PD-(L)l antibody, preferably wherein the anti-PD(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab, toripalimab, or zimberelimab.

The medical use or treatment according to the current aspect may further comprise administering intravenously to a patient in need thereof an anti-PD-(L)l antibody in a total amount of i. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ii. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ill. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or iv. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or v. Approximately 480 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or vi. Approximately 840 mg every two weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or vii. Approximately 1200 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or viii. Approximately 1680 mg every four weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or ix. Approximately 360 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is Zimberelimab, or x. Approximately 3 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or xi. Approximately 10 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or xii. Approximately 1500 mg every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks, wherein the anti-PD-(L)l antibody is pembrolizumab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 240 mg once every two weeks, or approximately 360 mg once every three weeks, or approximately 480 mg once every four weeks, wherein the anti-PD-(L)l antibody is nivolumab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 840 mg every two weeks, approximately 1200 mg every three weeks, or approximately 1680 mg every four weeks, wherein the anti-PD-(L)l antibody is atezolizumab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 360 mg every three weeks, wherein the anti-PD-(L)l antibody is Zimberelimab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 3 mg/kg every two weeks, wherein the anti-PD-(L)l antibody is Toripalimab.

For example, preferably, the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks, wherein the anti-PD-(L)l antibody is Durvalumab. In the alternative, the medical use of treatment according to this aspect may comprise administering intravenously or subcutaneously to a patient in need thereof an anti-PD-(L)l antibody in a total amount of a. Approximately 200 mg once every three weeks, or b. Approximately 480 mg once every four weeks, or c. Approximately 480 mg once every six weeks.

In this alternative, the anti-PD-(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.

Using a fixed dose for the anti-PD-(L)l antibody reduces dosing complexity and comes with a reduced potential for dosing errors. While the administration in a different order or even in a concomitant setup may be possible, the anti-PD-(L)l antibody is preferably administered after the anti-CCR8 antibody.

In a preferred embodiment of the current aspect the medical use or treatment a. comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 10 mg to 250 mg once every week, b. and preferably further comprises administering to the patient an anti-PD-(L)l antibody in a total amount of i. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ii. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ill. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or iv. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or v. Approximately 480 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or vi. Approximately 840 mg every two weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or vii. Approximately 1200 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or viii. Approximately 1680 mg every four weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or ix. Approximately 360 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is Zimberelimab, or x. Approximately 3 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or xi. Approximately 10 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or xii. Approximately 1500 mg every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab.

In a preferred embodiment of the current aspect the medical use or treatment a. comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 10 mg to 750 mg once every two weeks, b. and preferably further comprises administering to the patient an anti-PD-(L)l antibody in a total amount of i. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ii. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ill. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or iv. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or v. Approximately 480 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or vi. Approximately 840 mg every two weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or vii. Approximately 1200 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or viii. Approximately 1680 mg every four weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or ix. Approximately 360 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is Zimberelimab, or x. Approximately 3 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or xi. Approximately 10 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or xii. Approximately 1500 mg every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab. In another preferred embodiment of the current aspect the medical use or treatment a. comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 16 mg to 450 mg once every three weeks, b. and preferably further comprises administering to the patient an anti-PD-(L)l antibody in a total amount of i. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ii. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ill. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or iv. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or v. Approximately 480 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or vi. Approximately 840 mg every two weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or vii. Approximately 1200 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or viii. Approximately 1680 mg every four weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or ix. Approximately 360 mg every three weeks, preferably wherein the anti-PD-(L)l antibody is Zimberelimab, or x. Approximately 3 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or xi. Approximately 10 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or xii. Approximately 1500 mg every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab.

For the preparation of intravenous infusions, the required volume of the anti-PD-(L)l antibody solution can be withdrawn from one or more vial(s), which may or may not comprise a formulation according to the current invention, and transferred into an intravenous (IV) bag containing 0.9 % Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution can be mixed by gentle inversion without shaking. The final concentration of the diluted solution can be for example between 1 mg/mL to 10 mg/mL. For example, the intravenous administration of the anti-PD-(L)l antibody may occur as a 15- to 60- minute intravenous infusion, and preferably as a 30-minute intravenous infusion.

Administration of the anti-PD-(L)l antibody may occur through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. Given the variability of infusion pumps from site to site, a window between -5 min and +10 min is permitted (i.e., infusion time is 30 min [-5 min/+10 min]).

For example, the intravenous administration of the anti-PD-(L)l antibody may occur using the same IV line that was previously used for the intravenous administration of the inventive formulation. This setup is preferred and advantageous because the complexity of treatment administration is reduced and because this is highly convenient for both patients and medical professionals. Preferably the IV line is flushed with saline prior to the intravenous administration of second antibody, i.e. the anti-human PD- (L)l antibody formulation.

In a preferred embodiment, the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks. For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.

For example, in one embodiment, the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.

In a preferred embodiment, the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.

In a preferred example, the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

For example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example, in one embodiment the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In another preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.

In a preferred example, the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.

In a preferred embodiment, the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

In a preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.

The medical use according to the first aspect preferably comprises at least one 21-day dosing cycle. In some preferred of these embodiments, the anti-CCR8 antibody and the anti-PD-(L)l antibody are both administered on day 1 of the 21-day dosing cycle.

It was furthermore interestingly found, that certain side reactions to anti-CCR8 antibody administration could be prevented by administration of an effective dose of antihistamines, acetaminophen, corticosteroids or a combination thereof (data not shown). In consequence, the medical use or treatment according to the current aspect may furthermore comprises administration of an effective dose of antihistamines, acetaminophen, corticosteroids or a combination thereof, preferably

A. At least 500 mg or at least 650 mg paracetamol prior to the administration of the anti-CCR8 antibody formulation, and/or b. At least 50 mg or at least 100 mg diphenhydramine prior to the administration of anti-CCR8 antibody formulation and/or c. At least 8 mg dexamethasone prior to the administration of anti-CCR8 antibody formulation.

For example the acetaminophen may be administered orally. For example the diphenhydramine may be administered orally.

According to a fourth aspect of the current invention, there is provided a kit of parts comprising the pharmaceutical formulation according to the first aspect and optionally instructions for use.

In some embodiments the pharmaceutical formulation according to the first aspect is contained in a container. In certain embodiments said container is a vial. In further preferred embodiments the pharmaceutical formulation according to the first aspect is contained in a prefilled syringe. In some embodiments, the kit furthermore comprises an anti-PD(L)l antibody, preferably wherein the anti- PD(L)1 antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, toripalimab, zimberelimab or durvalumab.

In some different or the same embodiments, the kit comprises one or more further therapeutically active compounds, preferably selected from a. an antibody or a small molecule targeting a checkpoint protein, such as PD1, PD-L1 or CTLA-4, b. an antibody targeting a further chemokine receptor, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 or CXCR1, c. an antibody targeting a protein which is specifically expressed by tumor cells, d. an antibody or a small molecule targeting HER2 and/or EGFR, e. the standard of care for any of head and neck cancer, breast cancer, gastric cancer, lung cancer, squamous cell carcinoma, esophageal tumor, melanoma, bladder cancer, liver cancer, and/or prostate cancer, f. a chemotherapeutic agent, preferably a taxane, paclitaxel, doxorubicin, cis-platin, carboplatin, oxaliplatin, or gemcitabine, and/or g. a targeted kinase inhibitor, such as Sorafenib, Regorafenib, or MEKi-1.

Preferably the instructions for use comprise a label describing a. at least one step for preparing the use of the pharmaceutical formulation in a method of treatment or b. at least one step for using the pharmaceutical formulation in a method of treatment.

For example, the label may include a description with instructions to perform step a., b. and/or c. according to the third aspect of the current invention.

EXAMPLES

Example 1: Formulation preparation

Standard techniques were used for antibody production. Cell Culture started with thawing the cell bank vial and recombinant protein expression was performed in a Chinese hamster ovary (CHO) cell line using a fed-batch cell culture process and harvest. The harvest was followed by three chromatography steps (Protein A Affinity chromatography, Ion Exchange chromatography), two viral reduction steps (low-pH hold after affinity chromatography and viral filtration), and an ultrafiltration/diafiltration step to obtain the appropriate bulk drug substance concentration and formulation for long-term frozen storage.

Multiple formulations comprising histidine as buffer system were prepared for anti-CCR8 antibodies and a histidine-buffered formulation was developed to stabilize anti-human CCR8 antibodies and is presented in two dosage forms: liquid and lyophilized. This formulation was particularly suited to formulate an IgGl anti-human CCR8 antibody with a high pl, such as TPP-23411.

The anti-CCR8 antibody was formulated in the histidine buffer system according to Table 1.1.

Table 1.1: Buffer Composition 1. HCI: hydrochloride

As discussed elsewhere herein, the optimal pH for anti-human CCR8 antibody stability and solubility was found to be 6.3 ± 0.5 (as measured according to Ph. Eur. 2.2.3).

The formulations were sterile filtered with Millipore 0.22 pm filter and then sterile filled in 10 ml type I plus glass tubing vials with 1 mL fill volume and stoppered with either gray bromobutyl or chlorobutyl rubber stoppers for liquid and lyophilized formulations, respectively.

The resulting Buffer Composition 1 was a clear to slightly opalescent and colorless to slightly yellow liquid. Where it is prepared for i.v. administration, it needs to be sterile and have a low level of endotoxins / be substantially free of endotoxins.

The nominal content of the Drug Product was 250 mg antibody per vial, equivalent to a 5.0 mL fill of sterile filtered antibody solution per vial. There is an overfill of 0.3 mL, resulting in a total fill of 5.3 mL.

The resulting Buffer Composition 1 was prepared as a frozen liquid in a glass vial or as a lyophilized formulation, such that the provided concentrations were reached after dilution. The frozen liquid Buffer Composition 1 is ready for injection after thawing the glass vial followed by dilution with 5 % aqueous dextrose solution. After thawing it has a concentration of approximately 50 mg/mL active ingredient.

Example 2: Stability of anti-CCR8 antibody in liquid and lyophilized histidine buffer formulation

Duration of the study

• Liquid development stability: 24 months

• Lyophilized development stability: 12 months

• Preclinical stability

The liquid antibody formulation was prepared as specified elsewhere herein and was stored at 5°C for up to 3 months.

The stability of a liquid or lyophilized antibody formulation was analyzed at different time points. Table 2.1 shows the raw data for the stability of the liquid antibody formulation, Table 2.2 shows the rate of change for the liquid antibody formulation, Table 2.3 shows the raw data for the stability of the lyophilized antibody formulation, and Table 2.4 shows the rate of change for the lyophilized antibody formulation. Both dosage forms, liquid and lyophilized, were found to be stable.

The anti-CCR8 mAb formulations were analysed by

• size-exclusion high-performance liquid chromatography (SE-HPLC) for aggregation and degradation changes,

• liquid chromatography-mass spectrometry (LC-MS) for structural changes,

• UV/VIS Spectroscopy (A280) for concentration,

• imaged capillary isoelectric focusing (icIEF) for quantification and characterization of antibody charge variants (i.e. acidic region, basic region and main region), and

• reducing (R) and non-reducing (NR) capillary gel electrophoresis (CGE) was performed for post translational modifications

• visual inspection to evaluate that the pharmaceutical formulation is practically free from particles (Ph. Eur. 2.9.20).

The density was measured to be 1.036 g/cm3. The osmolality was measured to be 308 mOsm/kg. The pH was measured at 20 - 25°C.

Table 2.1: Stability of the liquid antibody formulation (Raw Data). High molecular weight forms (HMW, aggregates), main peak (monomer), and low molecular weight forms (LMW) are listed for SE-HPLC.

Table 2.2: Stability of a liquid antibody formulation (Rate of Change). High molecular weight forms (HMW, aggregates), main peak (monomer), and low molecular weight forms (LMW) are listed for SE- HPLC. a: This calculation is based on 3-months (92 days) data relative to time T = 0. b: The zero and negative values are represented as zero.

Table 2.3: Stability of lyophilized antibody formulation (Raw Data).

Table 2.4: Stability of lyophilized antibody formulation (Rate of Change), a: This calculation is based on 3-months (92 days) data relative to time T = 0. b: The zero and negative values are represented as zero. Table 2.5: Stability of liquid antibody formulation at a specified temperature and relative humidity (Raw

Data). RH: Relative humidity. "NT" = Not Tested Table 2.6: Stability of a liquid antibody formulation at a specified temperature and relative humidity (Rate of Change).

These results indicate that Buffer Composition 1 is suited as a pharmaceutical formulation for anti-CCR8 antibodies such as TPP-23411. The antibody is sufficiently stabilized and can be stored under convenient conditions while no substantial increase of basic charge variants was observed. This has been an issue for similar liquid formulations, where an increase in the basic charge variant from 11 % to 25 % had been observed after 30 months at 5°C.

While changing the amount of the excipients of Buffer Composition 1 is possible to a certain degree without substantial impact on the increase of the basic charge variant, lowering the pH (i.e., to pH 4 and 5) seems to promote the basic species formation. In any case, with Buffer Composition 1 a stable formulation was developed where the anti-CCR8 antibody is soluble at the required concentration (25-100 mg/mL), that is stable under the intended storage conditions (e.g. as a frozen liquid), where precipitation and aggregation is largely avoided, where formation of basic antibody species is largely avoided, and that is isosmotic for better patient compliance.

In this invention, it was found that formulating the Ab at pH 6-8 would lead to increased stability, and reduced phase change, such as precipitation or aggregation.

Example 3: Mass Spectrometric Analysis to understand the Mechanism of Basic Species Formation

For an antibody liquid formulation (100 mg/ml, 5°C) at low pH, changes were mostly observed for succinimide by tryptic map and clipping (Tryptic LC-MS).

The neutral pH and reduced tryptic digests of the antibody were analysed by LC-MS/MS and queried for potential sites of post translational modifications using Biopharma Finder software. All samples were prepared and analysed in the same manner.

A trend for increased heavy chain (HC) aspartic acid (Asp, D105) succinimidation (water loss leading to succinimide intermediate formation) was observed for three samples with

• T = 0: 1.7 %,

• T = 6 months: 2.6 %, and

• T = 12 months: 3.3%.

In literature, succinimide formation, Asp isomerization, and clipping have been shown to be associated with an increase in the % basic charged species. Additionally, the post translational modification analysis of samples held at 40°C for up to 3 months showed elevated levels of HC D105 isomerization and HC D105 succinimidation.

• At T = 0, the % isomerization was 0.1%.

In contrast, the % isomerization at 40°C was

• 15.3% after 1 month,

• increased to 23.7% after 2 months,

• and further increased to 27% after 3 months of storage.

It is likely that the succinimide intermediate is stable at 25°C, while it is not stable at 40°C and rapidly converts back to Asp and iso-Asp. The isomerization reaction is acid catalysed at a pH between 4 and 6.

Example 4: Formulation scouting studies for reducing the basic peaks

In the assessment of the pH impact on the formulation stability and degradation, formulation scouting studies for reducing the basic peak were performed.

In one study with an lgG2 monoclonal antibody, the iCIEF data supported the hypothesis that increasing the pH reduces the basic peak.

In an excipients range-finding study for a further antibody in a liquid dosage form, higher pH seemed to enhance protein aggregation but also seemed to minimize basic species formation with an opposite effect at the other end of the pH range. Of the liquid formulations with pH of 4, 5, or 6 evaluated at 25°C for 6 months, the basic peak was significantly increased in all formulations except formulations with a pH of approximately 6. The data suggest that basic species can form during storage at 25°C and the formulations with a pH 6 are superior for minimization of basic species formation. It was noted that these formulations are more prone to protein aggregation. Therefore, formulation selection needs to balance these two different degradation pathways.

A high concentration antibody dosage form may present many challenges in formulation development. The first challenge is antibody solubility. When the antibody concentration reaches or is close to the solubility limit, phase separation will occur through several different mechanisms, including precipitation, gelation, and crystallization.

The second challenge is antibody stability. At a high antibody concentration, the stability of antibody can be problematic because protein molecules would have high probability of collision and result in more protein-protein interactions, which would cause protein aggregation, including the formation of soluble and insoluble aggregates.

Therefore, it is critical to balance the antibody pl with the pH of the formulation.

The advantageous formulation provided according to the current invention

• is a liquid formulation stabilizing an anti-CCR8 antibody via pH modulation, and

• is suited for high anti-CCR8 antibody concentrations, such that an acceptable overall volume can be reached for appropriate medical dosages and administration schemes, and

• that supports convenient storage conditions,

• while avoiding an unacceptable increase of the anti-CCR8 antibody basic species upon storage,

• that furthermore is a non-salt (sodium chloride or sodium sulfate) formulation,

• that is finally substantially isotonic and substantially isosmotic.

Example 5: Preparation of a Dilution for Injection from frozen liquid

To prepare a dilution for injection, Buffer Composition 1 was provided as a frozen liquid in a glass vial. After thawing, Buffer Composition 1 had a concentration of 50 mg/mL active ingredient. It was further diluted with 5 % aqueous dextrose solution to prepare a dilution for injection, i.e. for intravenous injection.

Example 6: Preparation of a Dilution for Injection from lyophilized formulation

To prepare a dilution for injection, Buffer Composition 1 was provided as a lyophilized formulation. The lyophilized formulation was dissolved in water to reach a concentration of 50 mg/mL active ingredient. It was further diluted with 5 % aqueous dextrose solution to prepare a dilution for injection. Example 7: Local tolerability in cynomolgus monkey

The local tolerability of Buffer Composition 1 in 5 % dextrose solution was evaluated as part of repeatdose toxicity studies in monkeys. There was no indication for enduring adverse effects at the sites of injection.

Example 8: Nonclinical pharmacokinetics and drug metabolism

Pharmacokinetics of TPP-23411 was studied in vivo in male Cynomolgus monkeys after single i.v. and s.c. administration of TPP-23411. TPP-23411 was measured in monkey plasma using an anti-human IgG generic assay (IgG-ELISA). Anti-TPP-23411 antibody formation was monitored with a validated TPP- 23411-based bridging ELISA method (described elsewhere).

Table 10.1: Overview of single dose pharmacokinetics, in vivo study, i.v.: intravenous; s.c.: subcutaneous; PK: pharmacokinetics; m: male. Observation intervals were 336 hours for the low and 504 hours for the high dose.

After single intravenous bolus administration of 1 and 10 mg/kg TPP-23411 to male cynomolgus monkeys, the exposure in terms of AUCnorm increased slightly more than dose-proportionally from 391 kg-h/L to 617 kg-h/L with no hints for target mediated drug disposition. The plasma elimination was bi-phasic and the plasma clearance was 2.55 mL/(h-kg) for the 1 mg/kg and 1.62 mL/(h-kg) (mean values) for the 10 mg/kg dose. The volume of distribution amounted to 0.154 and 0.110 L/kg (mean values) for the 1 and 10 mg/kg dose, respectively. The effective half-lives were short with 41.9 and 46.8 hours reflecting a relatively fast elimination of the antibody and the pharmacologically less relevant terminal elimination half-lives were 108 and 148 hours.

After single subcutaneous administration of 3 and 10 mg/kg TPP-23411 a dose-proportional increase of exposure in terms of AUCnorm from 331 kg-h/L to 403 kg-h/L and Cmax,norm from 2.22 kg/L to 2.95 kg/L was observed (mean values). Cmax was reached at 8 to 30 h hours (mean values) after administration. TPP-23411 was eliminated from plasma with terminal half-lives of 81 and 109 h (mean values) at dose levels of 3 and 10 mg/kg, respectively, with plasma concentrations running in parallel to the intravenous profile. Bioavailability in both dose groups was moderate to high and ranged from 54% to 103%.

Table 10.2: Pharmacokinetics of TPP-23411 after a single dose (non-rodent). ^a: bioavailability, calculated with the IV AUCnorm value of 1 mg/kg b.w. in case of 3 mg/kg s.c. and calculated with the IV AUCnorm value of 10 mg/kg b.w. in case of 10 mg/kg s.c; ^b: not calculated.

Example 9: Long term stability of anti-CCR8 antibody in liquid buffer formulation

Table 9.1: Buffer Composition 1. HCI: hydrochloride

Long term stability of TPP-23411 was tested with buffer composition 1. Standard techniques were used for characterization. As shown below this formulation was particularly suited to formulate an IgGl antihuman CCR8 antibody with a high pl, such as TPP-23411.

Long term stability was evaluated up to 36 months. No significant differences were observed between storage at -30 °C and storage at 5 °C. This shows how well the formulation is suited to formulate an IgGl anti-human CCR8 antibody with a high pl, such as TPP-23411.

Duration of the study

• Liquid development stability: 36 months

• Preclinical stability

The liquid antibody formulation was prepared as specified elsewhere herein and was stored at 5 °C and -30 °C.

The stability of a liquid formulation was analyzed at different time points.

The anti-CCR8 mAb formulations were analysed by

• size-exclusion high-performance liquid chromatography (SE-HPLC) for aggregation and degradation changes,

• liquid chromatography-mass spectrometry (LC-MS) for structural changes,

• UV/VIS Spectroscopy (A280) for concentration,

• imaged capillary isoelectric focusing (icIEF) for quantification and characterization of antibody charge variants (i.e. acidic region, basic region and main region), and

• reducing (R) and non-reducing (NR) capillary gel electrophoresis (CGE) was performed for post translational modifications

• visual inspection to evaluate that the pharmaceutical formulation is practically free from particles (Ph. Eur. 2.9.20). Results are shown in the following tables:

Table 9.2: Stability data for TPP-23411:

Test and Current Storage _₃QO_{C 5} O_C

Acceptance Time .

„ . _r , , Upright Horizontal

Criteria [months]

Purity Initial 95.1 95.1

(Electrophoresis, _{± [day]} non-reduced)

Intact: Min. 90.0 ³ [^daysl

[%] 5 [days]

7 [days] - 94.9

0.5

1

3 95.1 95.1

6 95.1 95.0

9 94.8 94.7

12 95.7 95.6

18 95.5 95.4

24 95.0 94.5

36 95.1 94.6

Purity Initial 97.6 97.6

(Electrophoresis, _{± [day]} reduced) HC+LC

Min. 90.0 [%] ³ t^daysl

5 [days]

7 [days] - 97.9

0.5

1

3 97.3 97.2

6 97.6 97.4

9 97.1 97.3

12 97.6 97.3

18 97.8 97.4

24 97.1 97.1

36 97.7 97.4

Test and Current Storage _₃QO_{C 5} O_C

Acceptance Time .

„ . _r , , Upright Horizontal

Criteria [months]

Sub-visible Initial 1 1

Particles > 25 pm 1 [day]

NMT 600 / container ³ [days]

5 [days]

7 [days]

0.5

1

3

6 0

9

12 1 7

18 3

24 1 25

36 0 13

Appearance of initial Water - Water -

Solution, Clarity RS I RS I and Degree of 1 [day]

Opalescence Max. Reference ³ [days] suspension 5 [days]

( 'RS) ' IV 7 _r [d .ays !]

0.5

1

3

6 RS I RS 1 - II

9

12 RS II RS II

18 RS I

24 RS II RS II

36 Clear Clear

Claims

1. A pharmaceutical formulation comprising an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the pharmaceutical formulation comprises: a. 2.5 - 15 mM histidine; b. 50 - 200 ppm polysorbate, preferably 50 - 100 ppm polysorbate, preferably polysorbate 80; c. 5 % - 8 % sucrose; d. 10 - 50 mM arginine; e. 2.5 - 50 mM methionine; and f. 25 mg/mL - 150 mg/mL of the anti-human CCR8 IgG antibody, and wherein the pharmaceutical formulation is characterized by a pH of 6.3 ± 0.5.

2. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is a liquid or a frozen liquid.

3. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is a lyophilizate arranged for dilution to the concentrations according to claim 1.

4. The pharmaceutical formulation according to any of claims 1 to 3, wherein the pharmaceutical formulation is sterile.

5. The pharmaceutical formulation according to a previous claim, wherein the pharmaceutical formulation is stable at -30 °C or lower for at least 6 months, preferably at least 36 month, or wherein the pharmaceutical formulation is stable at 5 °C or 6 °C for at least 6 months preferably at least 36 month.

6. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is a human IgGl antibody.

7. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is afucosylated.

8. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is a low or non-internalizing antibody.

9. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof has an isoelectric point of 7.5 to 9, preferably 8.3.

10. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises 5 to 12.5 mM L-histidine, preferably approximately 10 mM L-histidine, more preferably wherein the 10 mM L-histidine is composed of approximately 5 mM L- histidine HCI monohydrate and approximately 5 mM L-histidine basic component, most preferably 4.7 mM L-histidine HCI monohydrate and 5.3 mM L-histidine basic component.

11. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises 70 to 80 ppm polysorbate 80, preferably approximately 75 ppm polysorbate 80.

12. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises 5 % to 8 % sucrose, preferably approximately 6 % sucrose.

13. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises 20 to 40 mM arginine, preferably approximately 30 mM arginine, most preferably wherein the arginine is L-arginine HCI.

14. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises approximately 5 to 50 mM methionine, preferably 10 mM methionine, preferably wherein the methionine is L-methionine.

15. The pharmaceutical formulation according to a previous claim, wherein the formulation comprises 25 mg/mL to 100 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof.

16. The pharmaceutical formulation according to a previous claim, wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 50 - 200 ppm polysorbate 80, preferably approximately 75 ppm polysorbate 80; c. Approximately 6 % (= 175 mM) to 8 % (= 234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL to 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ± 0.5.

17. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:8, SEQ ID NO:22, SEQ ID NO:36, SEQ ID NO:50, SEQ ID NO:68, SEQ ID NO:86, SEQ ID NQ:104, SEQ ID NO:122, SEQ ID NQ:140, SEQ ID NO:158, SEQ ID NO:176, SEQ ID NO:194, SEQ ID NO:212, SEQ ID NO:232, SEQ ID NQ:250, SEQ ID NQ:270, SEQ ID NQ:290, SEQ ID NQ:310, SEQ ID NQ:330, SEQ ID NQ:350, SEQ ID NO:368, SEQ ID NO:388, SEQ ID NQ:406, SEQ ID NO:424, SEQ ID NO:442, SEQ ID NQ:460, SEQ ID NO:478, SEQ ID NO:496, SEQ ID NO:514, SEQ ID NO:534, SEQ ID NO:554, SEQ ID NO:565, SEQ ID NO:586, SEQ ID NQ:606, SEQ ID NO:626, SEQ ID NO:646, SEQ ID NO:666, SEQ ID NO:686, SEQ ID NQ:706, SEQ ID NO:726, SEQ ID NO:746, SEQ ID NO:757, SEQ ID NO:769, SEQ ID NO:781, or SEQ ID NO:793.

18. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:554.

19. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by six CDR sequences, a. wherein each of the six CDR sequences is at least 90%, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NQ:10, SEQ ID NO:11 or SEQ ID NO:12, b. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:25, c. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NQ:40, d. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NQ:50, SEQ ID NO:52, SEQ ID NO:53 or SEQ ID NO:54, e. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NQ:70, SEQ ID NO:71 or SEQ ID NO:72, f. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:89 or SEQ ID NQ:90, g. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:102, SEQ ID NQ:103, SEQ ID NQ:104, SEQ ID NQ:106, SEQ ID NQ:107 or SEQ ID NQ:108, h. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:125 or SEQ ID NO:126, i. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:138, SEQ ID NO:139, SEQ ID NQ:140, SEQ ID NO:142, SEQ ID NO:143 or SEQ ID NO:144, j. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NQ:160, SEQ ID NO:161 or SEQ ID NO:162, k. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:178, SEQ ID NO:179 or SEQ ID NQ:180, l. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:196, SEQ ID NO:197 or SEQ ID NO:198, m. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:214, SEQ ID NO:215 or SEQ ID NO:216, n. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:234, SEQ ID NO:235 or SEQ ID NO:236, o. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:248, SEQ ID NO:249, SEQ ID NQ:250, SEQ ID NO:252, SEQ ID NO:253, or SEQ ID NO:254, p. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:268, SEQ ID NO:269, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:273 or SEQ ID NO:274, q. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:288, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:292, SEQ ID NO:293 or SEQ ID NO:294, r. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:308, SEQ ID NO:309, SEQ ID NO:310, SEQ ID NO:312, SEQ ID NO:313 or SEQ ID NO:314, s. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:328, SEQ ID NO:329, SEQ ID NQ:330, SEQ ID NO:332, SEQ ID NO:333 or SEQ ID NO:334, t. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:348, SEQ ID NO:349, SEQ ID NQ:350, SEQ ID NO:352, SEQ ID NO:353 or SEQ ID NO:354, u. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:366, SEQ ID NO:367, SEQ ID NO:368, SEQ ID NQ:370, SEQ ID NO:371 or SEQ ID NO:372, v. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:386, SEQ ID NO:387, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391 or SEQ ID NO:392, w. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:404, SEQ ID NQ:405, SEQ ID NQ:406, SEQ ID NQ:408, SEQ ID NQ:409 or SEQ ID NQ:410, x. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:422, SEQ ID NO:423, SEQ ID NO:424, SEQ ID NO:426, SEQ ID NO:427 or SEQ ID NO:428, y. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:440, SEQ ID NO:441, SEQ ID NO:442, SEQ ID NO:444, SEQ ID NO:445 or SEQ ID NO:446, z. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:458, SEQ ID NO:459, SEQ ID NQ:460, SEQ ID NO:462, SEQ ID NO:463 or SEQ ID NO:464, aa. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NQ:480, SEQ ID NO:481 or SEQ ID NO:482, bb. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:498, SEQ ID NO:499 or SEQ ID NQ:500, cc. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:516, SEQ ID NO:517 or SEQ ID NO:518, dd. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:532, SEQ ID NO:533, SEQ ID NO:534, SEQ ID NO:, 536 SEQ ID NO:537 or SEQ ID NO:538, ee. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID NO:558, ff. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:563, SEQ ID NO:564, SEQ ID NO:565, SEQ ID NO:567, SEQ ID NO:568 or SEQ ID NO:569, gg. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:584, SEQ ID NO:585, SEQ ID NO:586, SEQ ID NO:588, SEQ ID NO:589 or SEQ ID NQ:590, hh. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:604, SEQ ID NQ:605, SEQ ID NQ:606, SEQ ID NQ:608, SEQ ID NQ:609 or SEQ ID NQ:610, ii. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:624, SEQ ID NO:625, SEQ ID NO:626, SEQ ID NO:628, SEQ ID NO:629 or SEQ ID NQ:630, jj. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:644, SEQ ID NO:645, SEQ ID NO:646, SEQ ID NO:648, SEQ ID NO:649 or SEQ ID NQ:650, kk. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:664, SEQ ID NO:665, SEQ ID NO:666, SEQ ID NO:668, SEQ ID NO:669 or SEQ ID NQ:670,

II. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:684, SEQ ID NO:685, SEQ ID NO:686, SEQ ID NO:688, SEQ ID NO:689 or SEQ ID NQ:690, mm. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:704, SEQ ID NQ:705, SEQ ID NQ:706, SEQ ID NQ:708, SEQ ID NQ:709 or SEQ ID NQ:710, nn. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:724, SEQ ID NO:725, SEQ ID NO:726, SEQ ID NO:728, SEQ ID NO:729 or SEQ ID NQ:730, oo. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:744, SEQ ID NO:745, SEQ ID NO:746, SEQ ID NO:748, SEQ ID NO:749 or SEQ ID NQ:750, pp. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:755, SEQ ID NO:756, SEQ ID NO:757, SEQ ID NO:759, SEQ ID NQ:760 or SEQ ID NO:761, qq. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:767, SEQ ID NO:768, SEQ ID NO:769, SEQ ID NO:771, SEQ ID NO:772 or SEQ ID NO:773, rr. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:779, SEQ ID NQ:780, SEQ ID NO:781, SEQ ID NO:783, SEQ ID NO:784 or SEQ ID NO:785, ss. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:791, SEQ ID NO:792, SEQ ID NO:793, SEQ ID NO:795, SEQ ID NO:796 or SEQ ID NO:797.

20. The pharmaceutical formulation according to a previous claim, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by six CDR sequences, wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID NO:558.

21. The antibody formulation according to a previous claim, wherein the anti-CCR8 antibody is an antibody characterized by a. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:13 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:14, b. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 27 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:28, c. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 41and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:42, d. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:55 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:56, e. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:73 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:74, f. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:91 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:92, g. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:109 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:110, h. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:127 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:128, i. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:145 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:146, j. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:163 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:164, k. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:181 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:182, l. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:199 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:200, m. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:217 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:218, n. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:237 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:238, o. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:255 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:256, p. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:275 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:276, q. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:295 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:296, r. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:315 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:316, s. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:335 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:336, t. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:355 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:356, u. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:373 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:374, v. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:393 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:394, w. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:411 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:412, x. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:429 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:430, y. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:447 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:448, z. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:465 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:466, aa. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:483 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:484, bb. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:501 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:502, cc. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:519 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:520, dd. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:539 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:540, ee. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:560, ff. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:571 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:572, gg. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:591 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:592, hh. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:611 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:612, ii. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:631 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:632, jj. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:651 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:652, kk. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:671 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:672,

II. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:691 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:692, mm. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:711 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:712, nn. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:731 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:732, oo. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:751 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:752, pp. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:763 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:764, qq. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:775 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:776, rr. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:787 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:788, or ss. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:799 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:800.

22. The antibody formulation according to a previous claim, wherein the anti-CCR8 antibody is an antibody characterized by a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID

NQ:560.

23. The antibody formulation according to a previous claim, wherein the anti-CCR8 antibody is an antibody characterized by a. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:5 and a light chain at least 98 % or 100 % identical to SEQ ID NO:9, b. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:19 and a light chain at least 98 % or 100 % identical to SEQ ID NO:23, c. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:33 and a light chain at least 98 % or 100 % identical to SEQ ID NO:37, d. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:47 and a light chain at least 98 % or 100 % identical to SEQ ID NO:51, e. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:65 and a light chain at least 98 % or 100 % identical to SEQ ID NO:69, f. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:83 and a light chain at least 98 % or 100 % identical to SEQ ID NO:87, g. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:101 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 105, h. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:119 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 123, i. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:137 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 141, j. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:155 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 159, k. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:173 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 177, l. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:191 and a light chain at least 98 % or 100 % identical to SEQ ID NO: 195, m. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:209 and a light chain at least 98 % or 100 % identical to SEQ ID NO:213, n. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:229 and a light chain at least 98 % or 100 % identical to SEQ ID NO:233, o. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:247 and a light chain at least 98 % or 100 % identical to SEQ ID NO:251, p. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:267 and a light chain at least 98 % or 100 % identical to SEQ ID NO:271, q. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:287 and a light chain at least 98 % or 100 % identical to SEQ ID NO:291, r. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:307 and a light chain at least 98 % or 100 % identical to SEQ ID NO:311, s. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:327 and a light chain at least 98 % or 100 % identical to SEQ ID NO:331, t. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:347 and a light chain at least 98 % or 100 % identical to SEQ ID NO:351, u. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:365 and a light chain at least 98 % or 100 % identical to SEQ ID NO:369, v. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:385 and a light chain at least 98 % or 100 % identical to SEQ ID NO:389, w. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:403 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:407, x. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:421 and a light chain at least 98 % or 100 % identical to SEQ ID NO:425, y. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:439 and a light chain at least 98 % or 100 % identical to SEQ ID NO:443, z. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:457 and a light chain at least 98 % or 100 % identical to SEQ ID NO:461, aa. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:475 and a light chain at least 98 % or 100 % identical to SEQ ID NO:479, bb. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:493 and a light chain at least 98 % or 100 % identical to SEQ ID NO:497, cc. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:511 and a light chain at least 98 % or 100 % identical to SEQ ID NO:515, dd. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:531 and a light chain at least 98 % or 100 % identical to SEQ ID NO:535, ee. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and a light chain at least 98 % or 100 % identical to SEQ ID NO:555, ff. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:566 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:570, gg. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:583 and a light chain at least 98 % or 100 % identical to SEQ ID NO:587, hh. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:603 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:607, ii. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:623 and a light chain at least 98 % or 100 % identical to SEQ ID NO:627, jj. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:643 and a light chain at least 98 % or 100 % identical to SEQ ID NO:647, kk. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:663 and a light chain at least 98 % or 100 % identical to SEQ ID NO:667,

II. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:683 and a light chain at least 98 % or 100 % identical to SEQ ID NO:687, mm. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:703 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:707, nn. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:723 and a light chain at least 98 % or 100 % identical to SEQ ID NO:727, oo. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:743 and a light chain at least 98 % or 100 % identical to SEQ ID NO:747, pp. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:758 and a light chain at least 98 % or 100 % identical to SEQ ID NO:762, qq. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:770 and a light chain at least 98 % or 100 % identical to SEQ ID NO:774, rr. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:782 and a light chain at least 98 % or 100 % identical to SEQ ID NO:786, ss. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:794 and a light chain at least 98 % or 100 % identical to SEQ ID NO:798.

24. The antibody formulation according to a previous claim, wherein the anti-CCR8 antibody is an antibody characterized by a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and a light chain at least 98 % or 100 % identical to SEQ ID NO:555.

25. The antibody formulation according to any of claims 1 to 16, wherein the anti-CCR8 antibody is characterized by the CDRs of any of the antibodies disclosed in WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al,

W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al,

WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al,

WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al,

WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al and WO2022/136650 Al.

26. The antibody formulation according to any of claims 1 to 16, wherein the anti-CCR8 antibody is an antibody selected from the list of antibodies disclosed in any of WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al,

W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al,

WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al,

WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al,

WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al or WO2022/136650 Al.

27. The pharmaceutical formulation according to a previous claim furthermore comprising an anti- PD(L)1 antibody, preferably wherein the anti-PD(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, toripalimab, or zimberelimab.

28. A method for preparing a pharmaceutical formulation for intravenous administration, said method comprising diluting a pharmaceutical formulation according to any previous claim with aqueous dextrose solution, preferably with 5 % aqueous dextrose solution.

29. The pharmaceutical formulation according to any of claims 1 to 27, for use in a method of treatment.

30. The use of the pharmaceutical formulation according to any of claims 1 to 27 for the manufacture of a medicament.

31. The pharmaceutical formulation for use in a method of treatment according to claim 29, wherein the method of treatment comprises administering the solution intravenously or subcutaneously to a patient in need thereof.

32. The pharmaceutical formulation for use in a method of treatment according to claim 29, wherein the method of treatment comprises a. thawing a glass vial comprising the pharmaceutical formulation according to any of claims

1 to 25, and b. diluting the pharmaceutical formulation according to any of claims 1 to 25 with 5 % aqueous dextrose solution to obtain a solution for intravenous or subcutaneous administration, and c. administering intravenously or subcutaneously the solution to a patient in need thereof.

33. The pharmaceutical formulation for use in a method of treatment according to any of claims 29, 31 or 32, wherein the method of treatment is a method of treating cancer, preferably wherein the cancer is non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), melanoma, gastric cancer, renal cell carcinoma (RCC), HPV-driven urogenital cancer, gastro-esophageal junction tumors, hypermutated tumors, or a skin cancer other than melanoma.

34. The pharmaceutical formulation for use in a method of treatment according to any of claims 29, 31 or 32, wherein the treatment is a treatment of a tumor or a disease characterized by CCR8 positive cells, such as CCR8 positive tumor cells or CCR8 positive regulatory T cells.

35. The pharmaceutical formulation for use in a method of treatment according to any of claims 29 to 34, wherein the treatment comprises administering to a patient in need thereof, a. 1 to 250 mg anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity once every week, preferably approximately 1, 2.5, 3, 10, 30, 50, 75, 100, 125, 175 or 250 mg once every week, b. 10 to 750 mg anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity once every two weeks, preferably approximately 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 450, 500, 750 mg once every two weeks, or c. 16 to 1500 mg anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, preferably approximately 16, 50, 75, 100, 125, 175, 150, 200, 450, 500, 750, 1000 or 1500 mg once every three weeks.

36. The pharmaceutical formulation for use in a method of treatment according to any of claims 29 to 35, wherein the treatment comprises administering to a patient in need thereof, an anti-PD- (L)l antibody in a total amount of a. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or b. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or c. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or d. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or e. Approximately 480 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or f. Approximately 840 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or g. Approximately 1200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or h. Approximately 1680 mg once every four weeks, preferably wherein the anti-PD-(L)l antibody is atezolizumab, or i. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is Zimberelimab, or j. Approximately 3 mg/kg once every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or k. Approximately 10 mg/kg once every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or l. Approximately 1500 mg once every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab.

37. The pharmaceutical formulation according to any of claims 1 to 27, wherein said formulation is contained in a container.

38. The pharmaceutical formulation of claim 37, wherein the container is a vial.

39. The pharmaceutical formulation of claim 37, wherein the container is a prefilled syringe.

40. A kit of parts comprising the pharmaceutical formulation according to a previous claim, optionally with instructions for use.

41. The kit of parts according to claim 40, wherein the kit comprises an anti-PD(L)l antibody, preferably wherein the anti-PD(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, toripalimab, zimberelimab or durvalumab.

42. The kit of parts according to claim 40 or 41, wherein the kit comprises one or more further therapeutically active compounds, preferably selected from a. an antibody or a small molecule targeting a checkpoint protein, such as PD1, PD-L1 or CTLA- 4, b. an antibody targeting a further chemokine receptor, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 or CXCR1, c. an antibody targeting a protein which is specifically expressed by tumor cells, d. an antibody or a small molecule targeting HER2 and/or EGFR, e. the standard of care for any of head and neck cancer, breast cancer, gastric cancer, lung cancer, squamous cell carcinoma, esophageal tumor, melanoma, bladder cancer, liver cancer, and/or prostate cancer, f. a chemotherapeutic agent, preferably a taxane, paclitaxel, doxorubicin, cis-platin, carboplatin, oxaliplatin, or gemcitabine, and/or g. a targeted kinase inhibitor, such as Sorafenib, Regorafenib, or MEKi-1.