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WO2025191459A1 - Utilisation d'anticorps anti-egfr/c-met bispécifiques pour traiter des tumeurs solides - Google Patents

Utilisation d'anticorps anti-egfr/c-met bispécifiques pour traiter des tumeurs solides

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Publication number
WO2025191459A1
WO2025191459A1 PCT/IB2025/052577 IB2025052577W WO2025191459A1 WO 2025191459 A1 WO2025191459 A1 WO 2025191459A1 IB 2025052577 W IB2025052577 W IB 2025052577W WO 2025191459 A1 WO2025191459 A1 WO 2025191459A1
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WIPO (PCT)
Prior art keywords
seq
egfr
administered
antibody
dose
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PCT/IB2025/052577
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English (en)
Inventor
Mahadi BAIG
Joshua BAUML
Roland Knoblauch
Ali ALHADAB
Pamela SCHUSTER
Nahor HADDISH-BERHANE
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Janssen Biotech Inc
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Janssen Biotech Inc
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Publication of WO2025191459A1 publication Critical patent/WO2025191459A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to methods of treating an epidermal growth factor receptor (EGFR)-expressing or hepatocyte growth factor receptor (c-Met)-expressing cancer in a subject in need thereof.
  • the methods comprise administering to the subject a therapy comprising an isolated bispecific anti-EGFR/c-Met antibody, wherein the administration comprises a dose administered once per a 28-day cycle.
  • Amivantamab a low fucose, fully human IgGl -based bispecific antibody directed against the EGF and cMet receptors, shows activity against tumors with either the primary activating or second-site resistance EGFR mutations, overexpressed wild type EGFR, and activation of the cMet pathway.
  • amivantamab may disrupt these signaling pathways, thereby preventing tumor growth and progression.
  • the presence of high levels of EGFR and cMet on the surface of tumor cells allows for targeting of these cells for destruction by immune effector cells, through antibody -dependent cellular cytotoxicity (ADCC) and antibodydependent cellular phagocytosis (ADCP) mechanisms.
  • ADCC antibody -dependent cellular cytotoxicity
  • ADCP antibodydependent cellular phagocytosis
  • Amivantamab administration can cause frequent infusion-related reactions (IRRs) in a proportion of patients (67% of patients, according to Minchom A, et al. Presented at American Society of Clinical Oncology (ASCO) 2023; June 2-6, 2023; Chicago, IL, USA).
  • Signs and symptoms of IRR include but are not limited to dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.
  • Systemic IRRs, including severe reactions, upon the introduction of a new protein therapeutic infusion are frequently observed but the mechanisms inducing the reactions are varied.
  • the disclosure generally relates to methods that are useful for treating an epidermal growth factor receptor (EGFR)-expressing or hepatocyte growth factor receptor (c-Met)-expressing cancer in a subject in need thereof, comprising administering to the subject an isolated bispecific anti- EGFR/c-Met antibody comprising a first domain binding EGFR and a second domain binding c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6, and the second domain comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCD
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 3520 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 4640 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 3520 mg if the subject weighs less than 80 kg, and at a dose of about 4640 mg if the subject weighs 80 kg or more.
  • the bispecific anti-EGFR/c-Met antibody is administered once per a 28-day cycle.
  • the bispecific anti-EGFR/c-Met antibody is administered subcutaneously.
  • the bispecific anti-EGFR/c-Met antibody is co-formulated with hyaluronidase.
  • the method further comprises an initial cycle (Cycle 1) comprising administering the bispecific antibody once a week for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg, or at a dose of about 2240 mg if the subject weighs 80 kg or more.
  • an initial cycle comprising administering the bispecific antibody once a week for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg, or at a dose of about 2240 mg if the subject weighs 80 kg or more.
  • the first domain that binds EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14 and the second domain that binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain [0018]
  • the bispecific anti-EGFR/c-Met antibody has a biantennary glycan structure with a fucose content of between about 1% to about 15%.
  • the EGFR or c-Met expressing cancer is a solid tumor. In some embodiments, the EGFR or c-Met expressing cancer is non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 3520 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 4640 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 3520 mg if the subject weighs less than 80 kg, and at a dose of about 4640 mg if the subject weighs 80 kg or more.
  • the bispecific anti-EGFR/c-Met antibody is administered once per a 28-day cycle.
  • the bispecific anti-EGFR/c-Met antibody is administered subcutaneously.
  • the bispecific anti-EGFR/c-Met antibody is co-formulated with hyaluronidase.
  • the method further comprises an initial cycle (Cycle 1) comprising administering the bispecific antibody once a week for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg, or at a dose of about 2240 mg if the subject weighs 80 kg or more.
  • an initial cycle comprising administering the bispecific antibody once a week for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg, or at a dose of about 2240 mg if the subject weighs 80 kg or more.
  • the first domain that binds EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14 and the second domain that binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • the bispecific anti-EGFR/c-Met antibody has a biantennary glycan structure with a fucose content of between about 1% to about 15% or less than 20%.
  • the EGFR or c-Met expressing cancer is a solid tumor.
  • infusion related reactions are less severe in a population of subjects that is administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W).
  • infusion related reactions occur less frequently in a population of subjects that is subcutaneously administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is intravenously administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W).
  • infusion related reactions are less severe in a population of subjects that is subcutaneously administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is intravenously administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W)
  • FIG. 1 shows incidence of IRRs and IRR-related symptoms in subjects that received SC Ami Q4W (once every 4 weeks) versus subjects that received IV Ami Q2W (once every 2 weeks).
  • Ami amivantamab; h, hours; IRR, infusion-related reaction; IV, intravenous; min, minutes; SC, subcutaneous.
  • transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
  • Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”
  • “About” means 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., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.
  • antibody or “antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, full-length antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.
  • “Specific binding” or “specifically binds” or “specifically binding” or “binds” refer to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens.
  • the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (K D ) of about 5xl0' 8 M or less, for example about IxlO' 9 M or less, about IxlO' 10 M or less, about IxlO' 11 M or less, or about IxlO' 12 M or less, typically with the K D that is at least one hundred-fold less than its K D for binding to a non-specific antigen (e.g., BSA, casein).
  • K D equilibrium dissociation constant
  • the dissociation constant may be measured using known protocols.
  • Antibodies that bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). While a monospecific antibody binds one antigen or one epitope, a bispecific antibody binds two distinct antigens or two distinct epitopes.
  • CDR complementarity determining regions
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • “Full-length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM).
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3).
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL).
  • the VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • Antigen binding fragment refers to a portion of an immunoglobulin molecule that binds an antigen.
  • Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and/or the HCDR3 and the LCDR1, the LCDR2 and/or the LCDR3.
  • VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constmcts, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody ; described for example in Int. Patent Publ. Nos. W01998/44001, WO1988/01649, WO1994/13804 and W01992/01047.
  • scFv single chain Fv
  • “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation.
  • Monoclonal antibodies typically bind one antigenic epitope.
  • a bispecific monoclonal antibody binds two distinct antigenic epitopes.
  • Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.
  • Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.
  • Humanized antibodies refers to antibodies in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include intentionally introduced mutations in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.
  • Non-limiting example systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci.
  • a human antibody typically contains amino acid differences when compared to the human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, intentional substitutions in the framework or antigen binding site, and substitutions introduced during cloning or VDJ recombination in non-human animals.
  • a human antibody is at least 80% identical in amino acid sequence to an amino acid sequence encoded by a human germline or rearranged immunoglobulin gene.
  • a human antibody may contain consensus framework sequences derived from human framework sequence analyses (see, e.g., Knappik et al., J. Mol. Biol. 296:57-86 (2000)), or synthetic HCDR3 incorporated into human immune -globulin gene libraries displayed on phage (see, e.g. , Shi et al., J. Mol. Biol. 397:385-96 (2010) and Int. Pat. Publ. No. W02009/085462).
  • Bispecific refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the bispecific antibody may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.
  • Bispecific anti-EGFR/c-Met antibody or “bispecific EGFR/c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met.
  • the domains specifically binding EGFR and c-Met are typically VH/VL pairs, and the bispecific anti-EGFR/c-Met antibody is monovalent in terms of binding to EGFR and c- Met.
  • isolated refers to a homogenous population of molecules (such as synthetic polynucleotides, polypeptides vectors or viruses) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step.
  • molecules such as synthetic polynucleotides, polypeptides vectors or viruses
  • isolated refers to a molecule that is substantially free of other cellular material and/or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.
  • Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further subclassified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.
  • Low fucose or “low fucose content” as used in the application refers to antibodies with fucose content of about between 1 %- 15% or less than 20%.
  • Normal fucose or ‘normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 80% or over 85%.
  • Recombinant refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.
  • Dosage refers to the information of the amount of the therapeutic or the drug to be taken by the subject and the frequency of the number of times the therapeutic is to be taken by the subject. “Dose” refers to the amount or quantity of the therapeutic or the drug to be taken each time.
  • “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual.
  • Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.
  • “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of the selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time.
  • “Fixed combination” refers to a single pharmaceutical composition comprising two or more compounds.
  • “Non-fixed combination” refers to separate pharmaceutical compositions, wherein each comprises one or more compounds.
  • the one or more compounds or unit dosage forms can be administered as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the subject.
  • Antagonist refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein.
  • a molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.
  • Treat”, “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and/or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.
  • Prevent means preventing that a disorder occurs in subject.
  • “Responsive”, “responsiveness” or “likely to respond” refers to any kind of improvement or positive response, such as alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Subject includes any human or nonhuman animal.
  • Nonhuman animal includes all vertebrates, e.g. , mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the terms “subject” and “patient” are used interchangeably herein.
  • EGFR or c-Met expressing cancer refers to cancer that has detectable expression of EGFR or c-Met or has EGFR or c-Met mutation or amplification. EGFR or c-Met expression, amplification and mutation status can be detected using known methods, such as sequencing, next generation sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or western blotting.
  • Epidermal growth factor receptor or “EGFR” refers to the human EGFR (also known as HER1 or ErbBl (Ullrich et al., Nature 309:418-425, 1984) having the amino acid sequence shown in GenBank accession number NP 005219, as well as naturally -occurring variants thereof.
  • Hepatocyte growth factor receptor or “c-Mef ’ or “MET” as used herein refers to the human c-Met having the amino acid sequence shown in GenBank Accession No: NP 001120972 and natural variants thereof.
  • Newly diagnosed refers to a subject who has been diagnosed with a cancer, such as a solid tumor, but has not yet received treatment for cancer.
  • Metalstatic refers to a cancer wherein cancer cells separate from the original tumor, enter the bloodstream or lymph system and spread to other areas of the body.
  • Refractory refers to a disease that does not respond to a treatment.
  • a refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment.
  • Relapsed refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic.
  • Diagnosing refers to methods to determine if a subject is suffering from a given disease or condition or may develop a given disease or condition in the future or is likely to respond to treatment for a prior diagnosed disease or condition, i.e., stratifying a patient population on likelihood to respond to treatment. Diagnosis is typically performed by a physician based on the general guidelines for the disease to be diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.
  • Biological sample refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject.
  • Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissue, organ cultures or cell cultures.
  • Cmax refers to maximum observed serum concentration
  • Ctrough refers to observed serum concentration immediately prior to the next drug administration.
  • AUC(o-t) refers to area under the plasma/serum concentration time curve from time zero to time t.
  • Hyaluronidase refers to a class of enzymes that degrade hyaluronan. Hyaluronidases are endoglycosidases used to increase the dispersion and absorption of other co-administered drugs when administered subcutaneously (e.g., subcutaneous injections, subcutaneous infusion such as hypodermoclysis).
  • Hyaluronidases include, but are not limited to, bacterial hyaluronidases (EC 4.2.2.1 or EC 4.2.99.1), hyaluronidases from leeches, other parasites and crustaceans (EC 3.2.1.36), and mammalian-type hyaluronidases (EC 3.2.1.35).
  • Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa.
  • Hyaluronidases include those of non-human origin including, but not limited to, murine, canine, feline, leporine, avian, bovine, ovine, porcine, equine, piscine, ranine, bacterial, and any from leeches, other parasites, and crustaceans.
  • Exemplary human hyaluronidases include HYAL1, HYAL2, HYAL3, HYAL4, and PH20.
  • Also included amongst hyaluronidases are soluble hyaluronidases, including, ovine and bovine PH20, and soluble forms of PH20.
  • Exemplary hyaluronidases include those set forth in U.S. Pub. No.
  • 2013/0302275 which is incorporated by reference herein, including, for example, hyaluronidases set forth as SEQ ID NOs: 6, 7-31, 69, 70, 71, 72, 856-861, 869-921 from U.S. Pub. No. 2013/0302275 (which are incorporated herein by reference), mature forms thereof (lacking the signal sequence), allelic variants thereof, and truncated forms thereof that exhibit hyaluronidase activity, including C-terminal truncated variants that are soluble.
  • hyaluronidases set forth as SEQ ID NOs: 6, 7-31, 69, 70, 71, 72, 856-861, 869-921 from U.S. Pub. No. 2013/0302275 (which are incorporated herein by reference), mature forms thereof (lacking the signal sequence), allelic variants thereof, and truncated forms thereof that exhibit hyaluronidase activity, including C-terminal truncated variants
  • PH20 refers to a type of hyaluronidase that occurs in sperm and is neutral-active.
  • Soluble PH20 refers to a polypeptide characterized by its solubility under physiological conditions.
  • a soluble PH20 lacks all or a portion of a glycophosphatidyl anchor (GPI) attachment sequence, or does not otherwise sufficiently anchor to the cell membrane.
  • GPI glycophosphatidyl anchor
  • a soluble PH20 can be a C-terminally truncated variant of a PH20 lacking a contiguous sequence of amino acids that corresponds to all or a portion of a GPI anchor attachment sequence.
  • GPI glycophosphatidyl anchor
  • Soluble human PH20 includes human PH20 polypeptides that lack a contiguous sequence of amino acids from the C-terminus of human PH20 that includes all or a portion of the GPI anchor sequence (C-terminally truncated PH20 polypeptides) such that upon expression, the polypeptides are soluble under physiological conditions.
  • soluble human PH20 polypeptides are C-terminally truncated polypeptides of human PH20 in its precursor form or in its mature form lacking the signal sequence, or allelic variants thereof as set forth in SEQ ID NOs: 36-42 herein and as disclosed in U.S. Pub. No. 20130302275 as SEQ ID NOs: 6, 7, and 68-72 of that reference which are incorporated herein by reference.
  • U.S. Pub. No. 2004/0268425 which is incorporated by reference herein, describes members of the soluble, neutral active Hyaluronidase Glycoprotein family, particularly the human soluble PH-20 Hyaluronidase Glycoproteins (also referred to as sHASEGPs).
  • U.S. Pub. No. 20100143457 which is incorporated herein by reference, describes shorter active soluble PH20 (/.e., 36-469, -470, 471, and longerforms i.e., 36-495 to 36-500) the sequences of which are also incorporated herein by reference.
  • Hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid.
  • USP United States Pharmacopeia
  • XXII assay for hyaluronidase determines hyaluronidase activity indirectly by measuring the amount of higher molecular weight hyaluronic acid, or hyaluronan, (HA) substrate remaining after the enzyme is allowed to react with the HA for 30 min at 37 °C (USP XXII-NF XVII (1990) 644-645 United States Pharmacopeia Convention, Inc, Rockville, MD).
  • a Reference Standard solution can be used in an assay to ascertain the relative activity, in units, of any hyaluronidase.
  • In vitro assays to determine the hyaluronidase activity of hyaluronidases, such as PH20, including modified PH20 polypeptides, are known in the art and described herein.
  • Exemplary assays include the microturbidity assay that measures cleavage of hyaluronic acid by hyaluronidase indirectly by detecting the insoluble precipitate formed when the uncleaved hyaluronic acid binds with serum albumin.
  • Reference Standards can be used, for example, to generate a standard curve to determine the activity in Units of the hyaluronidase being tested.
  • Specific activity refers to Units of activity per mg protein.
  • the milligrams of hyaluronidase is defined by the absorption of a solution of at 280 nm assuming a molar extinction coefficient of approximately 1.7, in units of M-l cm-1.
  • Neutral active refers to the ability of a PH20 polypeptide to enzymatically catalyze the cleavage of hyaluronic acid at neutral pH, such as at a pH between or about between pH 6.0 to pH 7.8.
  • Human recombinant DNA-derived hyaluronidase enzyme PH20 is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding residues 36-482 of SEQ ID NO: 36, resulting in a heterogeneous mixture of soluble forms of human hyaluronidase (PH20) that begin at residue 36 and terminate at residues 478, 479, 480, 481, and 482 of SEQ ID NO: 36, including any one of SEQ ID NOs: 31, 35, 34, 33 and 32.
  • Variant refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions, or deletions.
  • the present inventors have developed novel dosing regimens for an EGFR-MET bispecific antibody that provide improved safety profiles over currently approved regimens while achieving comparable exposure.
  • Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that has been FDA-approved as an intravenous (IV) formulation.
  • IV intravenous
  • the EGFR/c-Met bispecific antibody administered parenterally can cause an adverse reaction or adverse event (AE) in a patient or subject, specifically an infusion-related reaction (IRR).
  • AE adverse reaction or adverse event
  • IRR infusion-related reaction
  • RYBREVANT As reported in the United States Prescribing Information for RYBREVANT (amivantamab) (www.janssenlabels.com/package-insert/product- monograph/prescribing-information/R YBREVANT-pi.pdf), among 302 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who received IV amivantamab at recommended Phase 2 dose (RP2D) as a single agent in the CHRYSALIS study, IRRs were among the most commonly occurring adverse reactions with an incidence of 66%.
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • the EGFR/c-Met bispecific antibody is amivantamab.
  • the presence of IRRs in a patient or subject is evaluated at any time starting at Cycle 1 Day 1 and ending 30 days after end of treatment with the EGFR/c-Met bispecific antibody.
  • the presence of IRRs in a patient or subject is evaluated at Cycle 1 Day 1 of treatment with the EGFR/c-Met bispecific antibody. In some embodiments, the presence of IRRs in a patient or subject is evaluated at a time up to 3 month after the start of treatment with the EGFR/c-Met bispecific antibody. In some embodiments, the presence of IRRs in a patient or subject is evaluated at any time between 1 day to 30 days after end of treatment with the EGFR/c-Met bispecific antibody. In some embodiments, the presence of IRRs in a patient or subject is evaluated at any time between 1 day to 5 days after end of treatment with the EGFR/c-Met bispecific antibody.
  • the presence of IRRs in a patient or subject is evaluated at any time between 1 day to 10 days after end of treatment with the EGFR/c-Met bispecific antibody. In some embodiments, the presence of IRRs in a patient or subject is evaluated at any time between 1 day to 15 days after end of treatment with the EGFR/c-Met bispecific antibody. In some embodiments, the presence of IRRs in a patient or subject is evaluated at any time between 1 day to 20 days after end of treatment with the EGFR/c-Met bispecific antibody.
  • the disclosure provides a method of treating an epidermal growth factor receptor (EGFR)-expressing or hepatocyte growth factor receptor (c-Met)-expressing cancer (e.g., NSCLC) in a subject in need thereof, comprising administering to the subject an isolated bispecific anti-EGFR/c-Met antibody comprising a first domain binding EGFR and a second domain binding c- Met.
  • EGFR epidermal growth factor receptor
  • c-Met hepatocyte growth factor receptor
  • the anti-EGFR/c-Met antibody is a bispecific antibody.
  • the antibody is an isolated antibody.
  • the antibody is an isolated bispecific antibody.
  • the antibody (e.g. , bispecific antibody) comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met.
  • the first domain that specifically binds EGFR comprises: a) heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3 amino acid sequences of SEQ ID NOs:l, 2 and 3, respectively; and/or b) light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:4, 5 and 6, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HCDR3 amino acid sequences of SEQ ID NOs:l, 2 and 3, respectively
  • LCDR1 light chain complementarity determining region 1
  • LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:4, 5 and 6, respectively respectively.
  • the first domain that specifically binds EGFR comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; and b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:4, 5 and 6, respectively.
  • HCDR1 TYGMH (SEQ ID NO: 1)
  • HCDR2 VIWDDGSYKYYGDSVKG (SEQ ID NO:2)
  • HCDR3 DGITMVRGVMKDYFDY (SEQ ID NO:3)
  • HCDR1 RASQDISSALV (SEQ ID NO:4)
  • HCDR2 DASSLES (SEQ ID NO:5)
  • HCDR3 QQFNSYPLT (SEQ ID NO:6)
  • the first domain comprises a heavy chain variable region (VH) amino acid sequence that is at least 90% identical to SEQ ID NO:13, e.g., about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:13.
  • VH heavy chain variable region
  • the sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the first domain comprises a VH of SEQ ID NO: 13.
  • the first domain comprises a light chain variable region (VL) amino acid sequence that is at least 90% identical to SEQ ID NO:14, e.g., about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 14.
  • VL light chain variable region
  • the sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the first domain comprises a VL of SEQ ID NO: 14.
  • the term “identical” or “has sequence identity,” refers to the extent to which two amino acid sequences have the same residues at the same positions when the sequences are aligned to achieve a maximal level of identity, expressed as a percentage.
  • sequence alignment and comparison typically one sequence is designated as a reference sequence, to which a test sequences are compared.
  • sequence identity between reference and test sequences is expressed as the percentage of positions across the entire length of the reference sequence where the reference and test sequences share the same amino acid upon alignment of the reference and test sequences to achieve a maximal level of identity.
  • two sequences are considered to have 70% sequence identity when, upon alignment to achieve a maximal level of identity, the test sequence has the same amino acid residue at 70% of the same positions over the entire length of the reference sequence.
  • the first domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and/or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14.
  • the first domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14.
  • the first domain comprises: a) a VH of SEQ ID NO:13; and/or b) a VL of SEQ ID NO: 14.
  • the first domain comprises: a) a VH of SEQ ID NO: 13; and b) a VL of SEQ ID NO: 14.
  • VH QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAV
  • the first domain comprises a first heavy chain (HC1) amino acid sequence that is at least 80% identical to SEQ ID NO: 17, e.g., about: 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 17.
  • the sequence identity is about: 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the first domain comprises a HC1 amino acid sequence of SEQ ID NO: 17.
  • the first domain comprises a first light chain (LC1) amino acid sequence that is at least 80% identical to SEQ ID NO:18, e.g., about: 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 18.
  • LC1 first light chain
  • the sequence identity is about: 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the first domain comprises a LC1 amino acid sequence of SEQ ID NO: 18.
  • the first domain comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; and/or b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18.
  • the first domain comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; and b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18.
  • the first domain comprises: a) a HC1 of SEQ ID NO: 17; and/or b) a LC1 of SEQ ID NO: 18.
  • the first domain comprises: a) a HCl of SEQ ID NO: 17; and b) a LC1 of SEQ ID NO: 18.
  • HC1 QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVA VIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMK DYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTV
  • LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASS LESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18) c-Met (MET) binding arm
  • the second domain that specifically binds c-Met comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs:7, 8 and 9, respectively; and/or b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:10, 11 and 12, respectively.
  • the second domain that specifically binds c-Met comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs:7, 8 and 9, respectively; and b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:10, 11 and 12, respectively.
  • HCDR1 SYGIS (SEQ ID NO:7)
  • HCDR2 WISAYNGYTNYAQKLQG (SEQ ID NO:8)
  • HCDR3 DLRGTNYFDY (SEQ ID NO:9)
  • HCDR1 RASQGISNWLA (SEQ ID NO: 10)
  • HCDR2 AASSLLS (SEQ ID NO: 11)
  • HCDR3 QQANSFPIT (SEQ ID NO: 12)
  • the second domain comprises a VH amino acid sequence that is at least 90% identical to SEQ ID NO:15, e.g., about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 15.
  • the sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94- 99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the second domain comprises a VH of SEQ ID NO: 15
  • the second domain comprises a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16, e.g., about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 16.
  • the sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92- 99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the second domain comprises a VL of SEQ ID NO: 16.
  • the second domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and/or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16.
  • the second domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16. [0143] In some embodiments, the second domain comprises: a) a VH of SEQ ID NO: 15; and/or b) a VL of SEQ ID NO: 16.
  • the second domain comprises: a) a VH of SEQ ID NO: 15; and b) a VL of SEQ ID NO: 16.
  • VH QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGW ISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWG QGTLVTVSS (SEQ ID NO: 15)
  • VL DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAAS SLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK (SEQ ID NO: 16)
  • the second domain comprises a second heavy chain (HC2) amino acid sequence that is at least 80% identical to SEQ ID NO: 19, e.g., about: 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:19.
  • HC2 second heavy chain amino acid sequence that is at least 80% identical to SEQ ID NO: 19, e.g., about: 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%
  • the sequence identity is about: 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the second domain comprises a HC2 amino acid sequence of SEQ ID NO: 19.
  • the second domain comprises a second light chain (LC2) amino acid sequence that is at least 80% identical to SEQ ID NO:20, e.g., about: 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:20.
  • LC2 second light chain
  • the sequence identity is about: 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • the second domain comprises a LC2 amino acid sequence of SEQ ID NO:20.
  • the second domain comprises: a) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and/or b) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.
  • the second domain comprises: a) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and b) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.
  • the second domain comprises: a) a HC2 of SEQ ID NO: 19; and/or b) a LC2 of SEQ ID NO:20.
  • the second domain comprises: a) a HC2 of SEQ ID NO: 19; and b) a LC2 of SEQ ID NO:20.
  • HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMG WISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
  • LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAAS SLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)
  • the antibody (e.g. , bispecific antibody) comprises: a) a first domain that specifically binds EGFR, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; and/or b) a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.
  • the antibody (e.g., bispecific antibody) comprises: a) a first domain that specifically binds EGFR, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; and b) a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.
  • the antibody (e.g. , bispecific antibody) comprises: a) a first domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and/or d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16.
  • the antibody (e.g., bispecific antibody) comprises: a) a first domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16.
  • the antibody (e.g. , bispecific antibody) comprises: a) a first domain comprising a VH of SEQ ID NO : 13 ; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15; and/or d) a second domain comprising a VL of SEQ ID NO: 16.
  • the antibody (e.g. , bispecific antibody) comprises: a) a first domain comprising a VH of SEQ ID NO : 13 ; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15; and d) a second domain comprising a VL of SEQ ID NO: 16.
  • the antibody (e.g., bispecific antibody) comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and/or d) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.
  • the antibody (e.g., bispecific antibody) comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and d) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.
  • the antibody (e.g., bispecific antibody) comprises: a) a HC1 of SEQ ID NO: 17; b) a LC1 of SEQ ID NO: 18; c) a HC2 of SEQ ID NO: 19; and/or d) a LC2 of SEQ ID NO:20.
  • the antibody (e.g. , bispecific antibody) comprises: a) a HC1 of SEQ ID NO: 17; b) a LC1 of SEQ ID NO: 18; c) a HC2 of SEQ ID NO: 19; and d) a LC2 of SEQ ID NO:20.
  • the antibody e.g. , bispecific antibody
  • the antibody is of the IgG isotype.
  • the antibody e.g., bispecific antibody
  • the IgGl isotype Some variation exists within the IgGl constant domain (e.g., well-known allotypes), for example, with variation at positions 214, 356, 358, 422, 431, 435 and/or 436 (residue numbering according to the EU numbering) (see e.g., IMGT Web resources; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes).
  • the bispecific anti-EGFR/c-Met antibody may be of any IgGl allotype, such as Glml7, Glm3, Glml, Glm2, Glm27 or Glm28.
  • the antibody is a human antibody.
  • the antibody is amivantamab.
  • Amivantamab is an IgGl anti- EGFR/c-Met bispecific antibody described in U.S. Pat. No. 9,593,164.
  • anti-EGFR/c-Met antibodies may also be used in the methods of the disclosure, for example, by combining publicly available EGFR binding VH/VL domains and c-Met binding VH/VL domains.
  • the antibody (e.g. , bispecific antibody) comprises a biantennary glycan structure with a fucose content of between about 1% to about 15% or less than 20%.
  • Antibodies with reduced fucose content can be made using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64(:249-65, 2012), application of a variant CHO line Lecl3 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2/0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specifically against the a 1,6-fucosyltrasfer
  • Anti-EGFR/c-Met antibodies used in the methods of the disclosure may be generated, for example, using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using co-expression.
  • the Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parental monospecific antibodies are reduced.
  • the resulting free cysteines of one of the parental monospecific antibodies form an inter heavy -chain disulfide bond with cysteine residues of a second parental monospecific antibody molecule and simultaneously CH3 domains of the parental antibodies release and reform by dissociation-association.
  • the CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization.
  • the resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope, i.e., an epitope on EGFR and an epitope on c-Met.
  • the bispecific antibodies of the invention may be generated using the technology described in Int. Pat. Publ. No.
  • Mutations F405L in one heavy chain and K409R in the other heavy chain may be used in case of IgGl antibodies.
  • IgG2 antibodies a wild-type IgG2 and a IgG2 antibody with F405L and R409K substitutions may be used.
  • IgG4 antibodies a wild-type IgG4 and a IgG4 antibody with F405L and R409K substitutions may be used.
  • the first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, and the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange.
  • the incubation conditions may optimally be restored to non-reducing.
  • Exemplary reducing agents that may be used are 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2- carboxyethyl)phosphine (TCEP), L-cysteine and beta- mercaptoethanol.
  • incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol at a pH of from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.
  • Bispecific anti-EGFR/c-Met antibodies used in the methods of the disclosure may also be generated using designs such as the Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically -matched (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and the Biclonic (Merus).
  • Knob-in-Hole Genentech
  • CrossMAbs Roche
  • electrostatically -matched Chougai, Amgen, NovoNordisk, Oncomed
  • the LUZ-Y Genentech
  • SEEDbody Strand Exchange Engineered Domain body
  • EMD Serono the Strand Exchange Engineered Domain body
  • Biclonic Biclonic
  • WO 2006/028936 select amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation.
  • An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen.
  • a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob”.
  • Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain/ modified position in the second CH3 domain of the second heavy chain): T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, F405W/T394S and T366W/T366S_L368A_Y407V.
  • SEEDbody technology may be utilized to generate bispecific antibodies of the invention.
  • SEEDbodies have, in their constant domains, select IgG residues substituted with IgA residues to promote heterodimerization as described in U.S. Patent No. US20070287170.
  • Mutations are typically made at the DNA level to a molecule such as the constant domain of the antibody using standard methods.
  • the antibody (e.g. , bispecific antibody) comprises a biantennary glycan structure with a fucose content of between about 1% to about 15%. In some embodiments, the antibody comprises a biantennary glycan structure with a fucose content of less than about 20%.
  • Antibodies with reduced fucose content can be made using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64(:249-65, 2012), application of a variant CHO line Lecl3 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2/0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specifically against the a 1,6-fucosyltrasfer
  • the anti-EGFR/c-Met antibody e.g. , bispecific antibody
  • additional therapeutic e.g. , chemotherapeutic
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the antibody is administered at a dose of about 700 mg, about 1,050 mg, about 1,400 mg, about 1,750 mg, about 2,100 mg, about 1,600 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,200 mg, about 4,320 mg, about 3,520 mg, or about 4,640 mg.
  • the antibody is administered at a dose of about 1,050 mg.
  • the antibody is administered at a dose of about 1,400 mg.
  • the antibody is administered at a dose of about 700 mg.
  • the antibody is administered at a dose of about 1,750 mg.
  • the antibody is administered at a dose of about 1,600 mg.
  • the antibody is administered at a dose of about 2,100 mg. In some embodiments, the antibody is administered at a dose of about 2,240 mg. In some embodiments, the antibody is administered at a dose of about 2,400 mg. In some embodiments, the antibody is administered at a dose of about 3,360 mg. In some embodiments, the antibody is administered at a dose of about 3,200 mg. In some embodiments, the antibody is administered at a dose of about 4,320 mg. In some embodiments, the antibody is administered at a dose of about 3,520 mg. In some embodiments, the antibody is administered at a dose of about 4,640 mg.
  • the antibody is administered at a dose of about 350 mg.
  • the antibody is administered at a dose of about 750 mg.
  • the antibody is administered at a dose of about 800 mg.
  • the antibody is administered at a dose of about 850 mg.
  • the antibody is administered at a dose of about 900 mg.
  • the antibody is administered at a dose of about 950 mg.
  • the antibody is administered at a dose of about 1,000 mg.
  • the antibody is administered at a dose of about 1,050 mg.
  • the antibody is administered at a dose of about 1,150 mg.
  • the antibody is administered at a dose of about 1,250 mg.
  • the antibody is administered at a dose of about 1,300 mg.
  • the antibody is administered at a dose of about 1,600 mg.
  • the antibody is administered at a dose of about 1,750 mg.
  • the antibody is administered at a dose of about 2,240 mg.
  • the antibody is administered at a dose of about 2,100 mg.
  • the antibody is administered at a dose of about 2,400 mg.
  • the antibody is administered at a dose of about 3,200 mg.
  • the antibody is administered at a dose of about 3,520 mg.
  • the antibody is administered at a dose of about 3,360 mg.
  • the antibody is administered at a dose of about 4,320 mg.
  • the antibody is administered at a dose of about 4,640 mg.
  • the antibody is administered at a dose of at least about 3,000 mg, or at least about 3,100 mg, or at least about 3,200 mg, or at least about 3,300 mg, or at least about 3,400 mg, or at least about 3,500 mg. In certain embodiments, the antibody is administered at a dose of greater than about 3,000 mg, or greater than about 3, 100 mg, or greater than about 3,200 mg.
  • the antibody is administered to a subject with body weight ⁇ 80 kg at a dose of at least about 3,000 mg, or at least about 3,100 mg, or at least about 3,200 mg, or at least about 3,300 mg, or at least about 3,400 mg, or at least about 3,500 mg. In certain embodiments, the antibody is administered to a subject with body weight ⁇ 80 kg at a dose of greater than about 3,000 mg, or greater than about 3,100 mg, or greater than about 3,200 mg.
  • the antibody is administered to a subject with body weight > 80 kg at a dose of at least about 4,000 mg, or at least about 4, 100 mg, or at least about 4,200 mg, or at least about 4,300 mg, or at least about 4,400 mg, or at least about 4,500 mg, or at least about 4,600 mg. In certain embodiments, the antibody is administered to a subject with body weight > 80 kg at a dose of greater than about 4,300 mg, or greater than about 4,400 mg, or greater than about 4,500 mg, or greater than about 4,600 mg.
  • the antibody is administered at a dose of 1,600 mg for body weight ⁇ 80 kg and 2,240 mg for body weight > 80 kg.
  • the antibody is administered at a dose of 3,200 mg for body weigh ⁇ 80 kg and 4,320 mg for body weight > 80 kg.
  • the antibody is administered at a dose greater than 3,200 mg for body weight ⁇ 80 kg and greater than 4,320 mg for body weight > 80 kg.
  • the antibody is administered at a dose of 3,520 mg for body weigh ⁇ 80 kg and 4,640 mg for body weight > 80 kg.
  • the antibody is administered twice a week.
  • the antibody is administered once a week.
  • the antibody is administered once every two weeks.
  • the antibody is administered once every three weeks.
  • the antibody is administered once every four weeks.
  • the antibody is administered on a 28-day cycle.
  • the subject has a body weight (BW) of ⁇ 80 kg, and the antibody (e.g. , bispecific antibody such as amivantamab) is administered at a dose of 1600 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of 3200 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (BW) of 80 kg or larger, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of 4320 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (B W) of ⁇ 80 kg
  • the antibody e.g. , bispecific antibody such as amivantamab
  • the antibody is administered at a dose of 1600 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 3,500 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (B W) of ⁇ 80 kg
  • the antibody e.g. , bispecific antibody such as amivantamab
  • the antibody is administered at a dose of 1600 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose greater than 3200 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (BW) of 80 kg or larger, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2240 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of 4640 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (BW) of 80 kg or larger, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 4600 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (BW) of 80 kg or larger, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose greater than 4,320 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • the antibody is administered subcutaneously.
  • the subject has a body weight (B W) of ⁇ 80 kg, and the antibody (e.g. , bispecific antibody such as amivantamab) is administered at a dose of 3520 mg once every 4 weeks (Q4W). In some embodiments, the antibody is administered subcutaneously.
  • B W body weight
  • the antibody e.g. , bispecific antibody such as amivantamab
  • Q4W body weight
  • the antibody is administered subcutaneously.
  • the subject has a body weight (BW) of 80 kg or larger, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 4640 mg once every 4 weeks (Q4W). In some embodiments, the antibody is administered subcutaneously.
  • BW body weight
  • the antibody e.g., bispecific antibody such as amivantamab
  • Q4W body weight
  • the antibody is administered subcutaneously.
  • the antibody e.g., bispecific antibody
  • the antibody is administered so as to produce a Cycle 2 C trO ugh value of about 325 pg/mL or AUCo-672h value of about 286612 pg*h/mL.
  • the antibody e.g. , bispecific antibody
  • the antibody is administered so as to produce a Cycle 2 value from about 300 to about 350 pg/mL.
  • the antibody is administered so as to produce a Cycle 2 Ctrough value from about 310 to about 340 pg/mL.
  • the antibody is administered so as to produce a Cycle 2 C trou gh value from about 320 to about 330 pg/mL.
  • the antibody (e.g. , bispecific antibody) is administered so as to produce a Cycle 2 AUCo-672h value of about 286000 to about 287000 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 value of about 286100 to about 286900 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 AUCo-672h value of about 286200 to about 286800 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 AUCo-672h value of about 286300 to about 286700 pg*h/mL.
  • the antibody is administered so as to produce a Cycle 2 AUCo-672h value of about 286400 to about 286700 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 AUCo-672h value of about 286500 to about 286700 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 AUCo-672h value of about 286550 to about 286650 pg*h/mL. In some embodiments, the antibody is administered so as to produce a Cycle 2 value of about 286600 to about 286650 pg*h/mL.
  • infusion related reactions occur less frequently in a population of subjects that is administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is administered the bispecific anti-EGFR/c- Met antibody once every 2 weeks (Q2W).
  • infusion related reactions are less severe in a population of subjects that is administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W).
  • infusion related reactions occur less frequently in a population of subjects that is subcutaneously administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is intravenously administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W).
  • infusion related reactions are less severe in a population of subjects that is subcutaneously administered the bispecific anti-EGFR/c-Met antibody once every 4 weeks (Q4W) compared to a population of subjects that is intravenously administered the bispecific anti-EGFR/c-Met antibody once every 2 weeks (Q2W).
  • the cancer is NSCLC
  • the bispecific anti-EGFR/c-Met antibody is amivantamab
  • the amivantamab is administered subcutaneously, wherein (i) if the subject has a body weight (BW) of ⁇ 80 kg, the amivantamab is administered at a dose of 1600 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 3,500 mg once every 4 weeks (Q4W) from Cycle 2 onwards; or (ii) if the subject has a body weight (BW) of 80 kg or larger, the amivantamab is administered at a dose of 2240 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose about 4,600 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • BW body weight
  • the cancer is NSCLC
  • the bispecific anti-EGFR/c-Met antibody is amivantamab
  • the amivantamab is administered subcutaneously, wherein (i) if the subject has a body weight (BW) of ⁇ 80 kg, the amivantamab is administered at a dose of 1600 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 3,520 mg once every 4 weeks (Q4W) from Cycle 2 onwards; or (ii) if the subject has a body weight (BW) of 80 kg or larger, the amivantamab is administered at a dose of 2240 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose about 4,640 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • BW body weight
  • the subject is further administered one or more anticancer agents.
  • the subject is further administered chemotherapeutic agent.
  • the antibody is administered as a monotherapy.
  • the method achieves a partial response or complete response in the subject, as defined by investigator assessment using Response Criteria in Solid Tumors (RECIST) version 1.1.
  • RECIST Response Criteria in Solid Tumors
  • the composition can comprise an amount of hyaluronidase enzyme that results in an increase in the dispersion of the bispecific antibody during the subcutaneous administration.
  • the hyaluronidase enzyme has no adverse effect on the molecular integrity of the bispecific antibody.
  • the hyaluronidase enzyme merely modifies the delivery of the bispecific antibody to the systemic circulation but does not possess any properties that could provide or contribute to the therapeutic effects of systemically absorbed bispecific antibody.
  • the hyaluronidase enzyme is not systemically bioavailable and does not adversely affect the molecular integrity of the bispecific antibody at the recommended storage conditions of the composition.
  • a number of suitable hyaluronidase enzymes are known.
  • the preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20.
  • the amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No. 757971-58-7. Soluble human PH20 hyaluronidases are described in Int’l Pub. No. W02004/078140 and U.S. Patent No. 7,767,429 incorporated herein by reference, in their entirety.
  • soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 31-35. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 36.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 32, namely residues 36-482 of wild type human hyaluronidase.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 33.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 34. In some embodiments, the soluble PH20 hyaluronidase comprises rHuPH20 comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 31. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one of SEQ ID NOs: 31, 32, 33, 34, and 35 in various abundance. The average molecular weight is 61 kDa.
  • rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell, of nucleic acids that encode residues 36-482 of SEQ ID NO: 36, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 36).
  • rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 36) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence.
  • rHuPH20 As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include one or more of the polypeptides 36-480, 36- 481, and 36-482 of SEQ ID NO: 36, and some shorter polypeptides, in various abundance.
  • rHuPH20 is produced in cells, such as CHO cells, for example DG44 CHO cells, that facilitate correct N-glycosylation to retain activity.
  • the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 35.
  • the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 34.
  • the subject is further administered one or more anticancer agents.
  • the anti-EGFR/c-Met antibody e.g., bispecific antibody
  • the one or more additional therapeutic agents e.g., chemotherapeutic agents
  • the antibody and the one or more additional therapeutic agents are administered separately (e.g., sequentially).
  • the one or more anti-cancer agents may be administered using recommended doses and dosages of the anti-cancer agent.
  • the one or more additional therapeutic agents are one or more anticancer therapies. In some embodiments, the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.
  • the subject is further administered a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • the TKI is lazertinib.
  • lazertinib is administered at a dose of 240 mg daily.
  • patient and “patient” can be used interchangeably herein.
  • “Patient in need thereof’ or “subject in need thereof’ refers to a mammalian subject, preferably human, diagnosed with or suspected of having a disease, to whom will be or has been administered a bi-specific anti-EGFR anti-MET antibody according to a method of the invention.
  • “Patient in need thereof’ or “subject in need thereof’ includes those subjects already with the undesired physiological change or disease as well as those subjects prone to have the physiological change or disease.
  • the subject is 18 years of age or older, e.g., 18 to less than 40 years of age, 18 to less than 45 years of age, 18 to less than 50 years of age, 18 to less than 55 years of age, 18 to less than 60 years of age, 18 to less than 65 years of age, 18 to less than 70 years of age, 18 to less than 75 years of age, 40 to less than 75 years of age, 45 to less than 75 years of age, 50 to less than 75 years of age, 55 to less than 75 years of age, 60 to less than 75 years of age, 65 to less than 75 years of age, 60 to less than 75 years of age, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older or 75 years of age or older.
  • the subject is a child.
  • the subject is 18 years of age or younger, e.g., 0-18 years of age, 0-12 years of age, 0-16 years of age, 0-17 years of age, 2-12 years of age, 2-16 years of age, 2-17 years of age, 2-18 years of age, 3-12 years of age, 3-16 years of age, 3-17 years of age, 3-18 years of age, 4-12 years of age, 4-16 years of age, 4-17 years of age, 4-18 years of age, 6-12 years of age, 6-16 years of age, 6-17 years of age, 6-18 years of age, 9-12 years of age, 9-16 years of age, 9-17 years of age, 9-18 years of age, 12-16 years of age, 12-17 years of age or 12-18 years of age.
  • the subject has been diagnosed with a cancer for at least about 1 month, e.g., at least about: 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 30 months, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years or 10 years.
  • the subject is newly diagnosed with cancer.
  • the cancer is a solid tumor. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is an advanced solid malignancy. In some embodiments, the cancer is recurrent and/or metastatic. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is unresectable.
  • the subject has been diagnosed with an advanced solid malignancy and have received all standard treatment options or is no longer eligible for additional standard treatment options.
  • the subject has EGFR or c-Met expressing cancer.
  • the subject has a cancer having an at least one mutation in EGFR.
  • the at least one mutation in EGFR is a exon 19 deletion (Exl9del) or a L858R substitution.
  • the subject is treatment naive.
  • the subject has received one or more prior anti-cancer therapies.
  • the one or more prior anti-cancer therapies comprises one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer therapies or kinase inhibitors, or any combination thereof.
  • the subject is relapsed or resistant to treatment with one or more prior anti-cancer therapies.
  • the subject has received prior treatment with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor. In some embodiments, the subject has received prior treatment with platinum-based chemotherapy. In some embodiments, the subject has received prior treatment with a PD-1/PD-L1 inhibitor.
  • the subject has not previously received anti-EGFR therapy. In some embodiments, the subject has not previously received anti-EGFR antibody therapy. In some embodiments, the subject has not previously received anti-EGFR tyrosine kinase inhibitor (TKI) therapy.
  • TKI anti-EGFR tyrosine kinase inhibitor
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • a method of subcutaneous administration of an isolated bispecific anti-EGFR/c-Met antibody comprising a first domain binding EGFR and a second domain binding c-Met to a subject having EGFR or c-Met expressing cancer wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6 and the second domain comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCDR2 of SEQ ID NO: 11, and a LCDR3 of SEQ ID NO: 12, wherein the bispecific anti-EGFR/c-Met antibody is
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • IRRs infusion related reactions
  • IRRs infusion related reactions
  • the cancer is NSCLC
  • the bispecific anti-EGFR/c-Met antibody is amivantamab
  • the amivantamab is administered subcutaneously, wherein (i) if the subject has a body weight (BW) of ⁇ 80 kg, the amivantamab is administered at a dose of 1600 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose greater than 3200 mg once every 4 weeks (Q4W) from Cycle 2 onwards; or (ii) if the subject has a body weight (BW) of 80 kg or larger, the amivantamab is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose greater than 4,320 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • BW body weight
  • the cancer is NSCLC
  • the bispecific anti-EGFR/c-Met antibody is amivantamab
  • the amivantamab is administered subcutaneously, wherein (i) if the subject has a body weight (BW) of ⁇ 80 kg, the amivantamab is administered at a dose of 1600 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 3,500 mg once every 4 weeks (Q4W) from Cycle 2 onwards; or (ii) if the subject has a body weight (BW) of 80 kg or larger, the amivantamab is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose about 4,600 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • BW body weight
  • the cancer is NSCLC
  • the bispecific anti-EGFR/c-Met antibody is amivantamab
  • the amivantamab is administered subcutaneously, wherein (i) if the subject has a body weight (BW) of ⁇ 80 kg, the amivantamab is administered at a dose of 1600 mg once every week (QI W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose of about 3,520 mg once every 4 weeks (Q4W) from Cycle 2 onwards; or (ii) if the subject has a body weight (BW) of 80 kg or larger, the amivantamab is administered at a dose of 2240 mg once every week (Q1W) for the first 4 weeks (Cycle 1 Days 1, 8, 15, and 22), and then at a dose about 4,640 mg once every 4 weeks (Q4W) from Cycle 2 onwards.
  • BW body weight
  • Example 1 Subcutaneous amivantamab administered every 4 weeks (Q4W) in patients with advanced solid malignancies: The phase lb PALOMA study.
  • Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity that has been approved as an intravenous (IV) formulation.
  • IV intravenous
  • Q2W 1600 mg (2240 mg if >80 kg)
  • Q3W (2400 mg (3360 mg if >80 kg) regimens substantially reduced IRR rates (16% for SC vs 67% for IV) and administration time ( ⁇ 7 minutes for SC vs 2-4 hours for IV) compared to historical experience (Minchom ASCO 2023).
  • SC Q4W Pharmacokinetics As previously reported, amivantamab SC Q2W dose was 1600 mg (>80 kg: 2240 mg) and SC Q3W dose was 2400 mg (>80 kg: 3360 mg) (Minchom A, et al. Presented at American Society of Clinical Oncology (ASCO) 2023; June 2-6, 2023; Chicago, IL, USA).
  • Cycle 1 weekly (QW) for the first 4 weeks (1600 mg if the subject weighed less than 80 kg [2240 mg, if the subject weighed 80 kg or more]) and
  • Cycle 2+ Q4W thereafter (3200 mg if the subject weighed less than 80 kg [4320 mg, if the subject weighed 80 kg or more]); administration was by manual push injection in the abdomen.
  • the SC Q4W dose was increased to 3520 mg if the subject weighed less than 80 kg (4640 mg, if the subject weighed 80 kg or more) as the RP2D to achieve the steady state C trO ugh of the approved IV Q2W dose with the predicted steady state C ma x of SC Q4W (not exceeding 125% of the Cmax of the approved IV dose).
  • Pharmacokinetic parameters for the Q4W SC 3520 mg (>80 kg: 4640 mg) dosing as compared with Q2W IV dosing are shown in Table 2.
  • the administration time of SC amivantamab Q4W was consistent with that of Q2W and Q3 W dosing ( ⁇ 7 to 10 min), assuming an injection rate of 3 mL/min. No antidrug antibodies have been observed with SC amivantamab
  • the SC amivantamab Q4W dose was identified to be 3520 mg (>80 kg: 4640 mg); wherein SC amivantamab Q4W was dosed weekly (QW) for the first 4 weeks (1600 mg [>80 kg: 2240 mg]) and Q4W thereafter; administration was by manual push injection in the abdomen.
  • the identified SC amivantamab Q4W dose achieved comparable exposure to the approved IV dose.
  • the administration time of SC amivantamab Q4W was consistent with that of Q2W and Q3 W dosing ( ⁇ 7 to 10 minutes).
  • the safety profile of SC amivantamab demonstrated a reduction of IRRs.
  • the observed rate of IRRs was 16%. IRRs were less severe and occurred less frequently with Q4W dosing of SC amivantamab compared to Q2W IV amivantamab.
  • Example 2 Subcutaneous (SC) amivantamab administered every 4 weeks (Q4W) plus lazertinib as first-line treatment in EGFR-mutated (EGFRm) advanced NSCLC: Results from the phase 2 PALOMA-2 study
  • IV Intravenous
  • amivantamab ami
  • lazertinib laz
  • IL first-line
  • MARIPOSA median follow-up, 22.0 mo
  • ami IV administered every 2 weeks (Q2W) + laz significantly prolonged progression-free survival (PFS) vs osimertinib (HR, 0.70; P ⁇ 0.001).
  • PFS progression-free survival
  • ORR objective response rate
  • IL ami SC Q2W + laz showed a response rate similar to historical ami IV Q2W + laz data in EGFRm NSCLC, with an improved safety profile that included significantly lower administration-related reactions (ARRs).
  • PALOMA-2 Cohort 5 evaluated the efficacy, PK, and safety of IL ami SC Q4W + laz in EGFRm NSCLC.
  • ORR was 82% (95% CI, 71-90) by investigator and 87% (95% CI, 77-94) by independent central review (ICR). Confirmed ORR was 79% (95% CI, 69-88) by investigator and 83% (95% CI, 73-91) by ICR. Median time to response was 8.1 wks (range, 7.0-16.5). Median duration of response, PFS, and overall survival were not estimable. [0290] No new safety signals were observed. Most treatment-emergent adverse events (AEs) were EGFR/MET-related, with paronychia, hypoalbuminemia, and rash being the most common. ARRs were reported in 9 (12%) pts (gr>3, 1 [1%]). In total, 67 (87%) pts received any prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 10 (13%) pts (none gr>3). Gr>3 bleeding rates were low (1%).

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Abstract

La présente invention concerne des méthodes de traitement d'un cancer exprimant le récepteur du facteur de croissance épidermique (EGFR) ou le cancer exprimant le récepteur du facteur de croissance des hépatocytes (c-Met) chez un sujet en ayant besoin. Les méthodes comprennent l'administration au sujet d'une thérapie comprenant un anticorps anti-EGFR/c-Met bispécifique isolé, l'administration comprenant une dose administrée une fois par cycle de 28 jours.
PCT/IB2025/052577 2024-03-11 2025-03-11 Utilisation d'anticorps anti-egfr/c-met bispécifiques pour traiter des tumeurs solides Pending WO2025191459A1 (fr)

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