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WO2017035362A1 - Utilisation de composés inhibiteurs de la voie du complément pour atténuer des réponses immunitaires indésirables associées à une thérapie adoptive par lymphocytes t - Google Patents

Utilisation de composés inhibiteurs de la voie du complément pour atténuer des réponses immunitaires indésirables associées à une thérapie adoptive par lymphocytes t Download PDF

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Publication number
WO2017035362A1
WO2017035362A1 PCT/US2016/048710 US2016048710W WO2017035362A1 WO 2017035362 A1 WO2017035362 A1 WO 2017035362A1 US 2016048710 W US2016048710 W US 2016048710W WO 2017035362 A1 WO2017035362 A1 WO 2017035362A1
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complement
inhibitor
pathway inhibitor
complement pathway
factor
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PCT/US2016/048710
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English (en)
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Mingjun Huang
Jason FISHERMAN
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Achillion Pharmaceuticals, Inc.
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Publication of WO2017035362A1 publication Critical patent/WO2017035362A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This invention is in the area of treating adoptive T-cell therapy-associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using complement pathway inhibitor compounds.
  • ACT adoptive T-cell therapy
  • TAAs tumor associated antigens
  • TCRs highly active T cell receptors
  • chimeric antigen receptors that recognize TAAs through single-chain variable fragments (scFvs) that are isolated from antigen specific monoclonal antibodies (mAbs)
  • mAbs antigen specific monoclonal antibodies
  • TCR-expressing cells have shown promise in clinical trials directed against melanoma (Johnson et al., Gene therapy with human and mouse T- cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • neuroblastoma Louis et al., Antitumor activity and long-term date of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood (2011) 118:6050-6056, among others.
  • ACT is not, however, without its side effects. Although most adverse events with ACT are tolerable and acceptable, the administration of ACT has, in a number of cases, resulted in severe systemic inflammatory reactions, including cytokine release syndrome and tumor lysis syndrome (Hu et al., Efficacy and safety of adoptive immunotherapy using anti-CD 19 chimeric antigen receptor transduced T-cells: a systemic review of phase I clinical trials. Leukemia Lymphoma (2013) 54:255-260; Minagawa et al., Seatbelts in CAR therapy: how safe are CARS? Pharmaceuticals (2015) 8:230-249).
  • Cytokine release syndrome is an inflammatory response clinically manifesting with fever, nausea, headache, tachycardia, hypotension, hypoxia, as well as cardiac and/or neurologic manifestations. Severe cytokine release syndrome is described as cytokine storm, and can be fatal.
  • CRS is believed to be a result of the sustained activation of a variety of cell types such as monocytes and macrophages, T cells and B cells, and is generally characterized by an increase in levels of TNFa and ⁇ FNy within 1 to 2 hours of stimulus exposure, followed by increases in interleukin (IL)-6 and IL-10 and, in some cases, IL-2 and IL-8 (Doessegger et al., Clinical development methodology for infusion-related reactions with monoclonal antibodies. Nat. Clin. Transl. Immuno. (2015) 4:e39).
  • IL interleukin
  • Tumor lysis syndrome is a metabolic syndrome that is caused by the sudden killing of tumor cells with chemotherapy, and subsequent release of cellular contents with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.
  • Catabolism of the nucleic acids to uric acid leads to hyperuricemia; the marked increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules and renal vasoconstriction, impaired autoregulation, decreased renal flow, oxidation, and inflammation, resulting in acute kidney injury.
  • Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury.
  • ACT-mediated CRS is generally treated with corticosteroids.
  • Corticosteroids are not effective in treating TLS, and certain forms of ACT-mediated CRS are corticosteroid-resistance (Xu et al., Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells, Cancer Letters (2014) 343 : 172-178).
  • chemokines When a monoclonal antibody binds with an antigen on the targeted cell, specialized cytokines called chemokines recruit immune-effector cells (e.g., monocytes, macrophages, cytotoxic T cells, natural killer cells) and complement molecules.
  • the immune-effector cells bind to the constant portion of the antibody (Fc region), thus targeting that cell for destruction either by cytolysis or phagocytosis (Breslin S: Cytokine-release syndrome: Overview and nursing implications. Clin J Oncol Nurs (2007) 11(1 Suppl):37-42).
  • cytokines e.g., interleukin, interferon, tumor necrosis factor
  • ACT T-cells are believed to eliminate tumor cells via a cell-mediated mechanism.
  • the complement system is a biochemical cascade system that is part of the innate immune system and is ultimately responsible for targeted cell death and is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phaogytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together).
  • improved methods and compositions are provided to mediate adverse inflammatory responses associated with the use of adoptive T-cell therapy (ACT) to treat cancer.
  • the invention includes administering a therapeutically effective amount of a complement pathway inhibitor to a subject undergoing ACT for the treatment of cancer, wherein the complement pathway inhibitor mediates, i.e., reduces, lessens, or prevents, an adverse inflammatory response associated with ACT treatment.
  • a complement pathway inhibitor can be used in combination with ACT treatment without interfering with the therapeutic activity of the ACT. Because of this, combining the use of complement pathway inhibitors with ACT treatment either prior to administration of ACT, or during administration of ACT, provides a mediation of an associated inflammatory response without the need to modify efficacious dosing regimens. Therefore, the use of complement pathway inhibitors with ACT maximizes the effectiveness of ACT therapy, allowing for full dosing. Alternatively, administration of a complement pathway inhibitor may allow for a higher dose of an ACT agent to be used to treat the disease compared to a dose used in the absence of administration of the complement pathway inhibitor.
  • a complement pathway inhibitor can be administered to the subject prior to treatment with an ACT agent, during treatment with an ACT agent, of following treatment with an ACT agent, or a combination thereof.
  • a complement pathway inhibitor can be administered prior to or simultaneously with— that is within about 5, about 10, about 15 minutes— the administration of ACT in order to mediate an adverse inflammatory response during ACT.
  • a complement pathway inhibitor can be administered to a subject experiencing an adverse inflammatory response associated with the administration of ACT.
  • the subject is being administered an ACT agent to treat brain cancer (e.g., a glioma), bladder cancer, breast cancer, cervical cancer, colorectal cancer, liver cancer, kidney cancer, lymphoma, leukemia, lung cancer, melanoma, metastatic melanoma, mesothelioma, neuroblastoma, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, skin cancer, thymoma, sarcoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, or uterine cancer.
  • brain cancer e.g., a glioma
  • bladder cancer e.g., breast cancer, cervical cancer, colorectal cancer
  • liver cancer e.g., kidney cancer
  • lymphoma e.g., leukemia, lung cancer, melanoma, metastatic melanoma
  • mesothelioma e.g., neuroblastom
  • the ACT agent targets CD 19 on a tumor cell.
  • the ACT agent is a CD19 gene modified Autologous Activated T cells (CART-19).
  • the ACT agent is MAGE A3 peptide primed activated autologous T cells.
  • the ACT agent is CD 19 gene modified allogeneic activated T cells (CART-19).
  • the ACT agent is gene modified MAGE/NYESO autologous T cells.
  • the ACT agent is mesothelin re-directed autologous T cells.
  • the ACT agent is autologous zinc finger modified T cells.
  • the ACT agent is gene modified gag-TCR autologous T cells.
  • the ACT agent is idiotype-KLH vaccine primed activated autologous T cells.
  • the ACT agent is JCAR015.
  • the ACT agent is Kite's KTE-C19 for refractory aggressive non-Hodgkin's lymphoma.
  • the ACT agent is the University of Pennsylvania /Novartis's CTL019. Contemplated herein is the use of complement pathway inhibitors with any ACT agent, including those described herein and below.
  • a subject may be administered a lymphodepleting preparative regimen, for example cyclophasphamid and fludarabine, prior to ACT administration.
  • the complement pathway inhibitor is administered subsequent to the lymphodepleting preparative regimen and prior to administration of ACT.
  • the complement pathway inhibitor is administered subsequent to the lymphodepleting preparative regimen and the administration of ACT.
  • the subject is administered a complement pathway inhibitor in conjunction with TCR, CAR-T, or bi-specific T-cell engager (BiTe) therapy.
  • the subject undergoing TCR, CAR-T, or BiTe therapy can be given a complement pathway inhibitor prior to or during administration of TCR, CAR-T, or BiTe in order to mediate an adverse inflammatory response generally associated with administration of a TCR, CAR-T, or BiTe agent.
  • the subject undergoing TCR, CAR-T, or BiTe therapy can be given a complement pathway inhibitor following administration of the TCR, CAR-T, or BiTe agent in order to reduce an adverse inflammatory response, for example cytokine release syndrome (CRS) or tumor lysis syndrome (TLS).
  • CRS cytokine release syndrome
  • TLS tumor lysis syndrome
  • a complement pathway inhibitor is typically administered in a manner that allows the drug facile access to the blood stream, for example via intravenous injection or sublingual, intraaortal, or other efficient blood-stream accessing route; however, oral, topical, transdermal, intranasal, intramuscular, or by inhalation such as by a solution, suspension, or emulsion, or other desired administrative routes can be used.
  • a compound is administered to the subject less than about 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 2.5 hours, 2 hours, 1 hour, 1 ⁇ 2 hour or less prior to treatment with the ACT agent.
  • a complement pathway inhibitor is administered to the subject prior to treatment with the ACT agent such that the compound reaches peak serum levels before or during administration of the ACT agent.
  • a complement pathway inhibitor is administered concomitantly, or closely thereto, with initial ACT agent exposure.
  • the complement pathway inhibitor can be administered multiple times during the ACT agent treatment to maximize inhibition of the complement system.
  • a complement pathway inhibitor is administered about 1 ⁇ 2 hour, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, or about 20 hours or greater following the administration of the ACT agent.
  • the active compound is administered between about 12 hours and 120 hours following administration of the ACT agent.
  • a complement pathway inhibitor is provided several days, weeks, or months following administration of an ACT agent. Further contemplated herein is the use of a complement pathway inhibitor to mediate an adverse immune response associated with the administration of an ACT agent that manifests itself during the ACT agent's subsequent expansion phase, which may be days, weeks, or months following the administration of the agent.
  • complement pathway inhibitors useful in the present invention can target any known complement system protein.
  • the complement pathway inhibitor targets a complement system protein associated with the classical pathway, the mannan- binding (MB)-lectin pathway, or the alternative pathway, or a combination thereof.
  • the complement pathway inhibitor targets CI, Clq, Clr, Cls, C2, C2a, C2b, C3, C3a, C3b, C4, C4a, C4b, C5, C5a, C5b, C6, C7, C8, C9, Factor B, Factor Ba, Factor Bb, Factor D, Factor H, Factor I, MBL, MASP-1, MASP-2, C3 convertase, C5 convertase, or a combination thereof, as described further below. Specific complement pathway inhibitors contemplated herein for use in the present invention are described further below.
  • a complement pathway inhibitor can be used to mediate adverse inflammatory responses associated with the administration of ACT in a subject receiving ACT for the treatment of a cancer.
  • the subject can be receiving ACT for the treatment of a solid or hematological cancer.
  • the cancer is melanoma, cervical, bile duct, a B-cell hematological cancer such as lymphoma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), lymphoma, neuroblastoma, or synovial sarcoma.
  • the complement pathway inhibitor is used in combination with an ACT agent directed against a lymphohematopoietic malignancy, for example, but not limited to, B-cell lineage leukemia or lymphoma, T-cell lineage leukemia or lymphoma, or myeloid-lineage leukemia or lymphoma, for example, but not limited to acute myeloid leukemia (AML).
  • ACT agent directed against a lymphohematopoietic malignancy
  • a complement pathway inhibitor is contemplated for use to reduce adverse immune responses associated with any ACT-targeted cancer treatment.
  • complement pathway inhibitor compound in the manufacture of a medicament for use in the mediation of adverse inflammatory responses associated with ACT.
  • a “dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • a “dosage form” can also include an implant, for example an optical implant.
  • “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • Lists of additional suitable salts may be found, e.g.,
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.
  • a “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, including but not limited to by modulation of the complement Factor D pathway.
  • the host is a human.
  • a “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird and the like.
  • a “prodrug” as used herein means a compound which when administered to a host in vivo is converted into a parent drug.
  • the term "parent drug” means any of the presently described chemical compounds described herein.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
  • "Providing a compound with at least one additional active agent” and phrases similar thereto means the compound and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the compound and the at least one additional active agent are within the blood stream of a patient.
  • the compound and the additional active agent need not be prescribed for a patient by the same medical care worker.
  • the additional active agent or agents need not require a prescription.
  • Administration of the compound or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intraaortal, transdermal, polymeric controlled delivery, non-polymeric controlled delivery, nano or microparticles, liposomes, and/or topical contact.
  • a “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or dimunition of the disease itself.
  • a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of complement Factor D in the patient's blood, serum, or tissues or reduce the symptoms or effects of an adverse inflammatory event associated with adoptive T-cell therapy.
  • TCRs T-cell receptors
  • HLA human leukocyte antigen
  • CARs are composed of an extracellular domain that recognizes cell surface antigens, which is linked to an intracellular signaling domain via a transmembrane sequence.
  • the extracellular domain usually consists of the antigen-binding variable regions (Fv) from the heavy and light chains of a monoclonal antibody that are fused into a single protein known as a single-chain variable fragment (scFv).
  • the intracellular signaling domain is usually derived from the TCR complex and can include one or more costimulatory molecules to enhance its antitumour effect (Tey, Adoptive T- cell therapy: adverse events and safety switches, Clin. Trans. Immuno. (2014) 3 :el7).
  • CAR T cells can be highly efficacious and their efficacy can be further increased with the addition of lymphodepleting chemotherapy before cell transfer. Striking responses have been observed in acute and chronic B-cell malignancies treated with CD19-targeted CAR T cells. At the same time, adverse events, such as cytokine release syndrome, have emerged. Whereas the drug concentration and biological effects of conventional pharmaceuticals fall with time, adoptively transferred T cells can persist long term and even expand with time, with the potential for prolonged effects, both therapeutic and deleterious (Tey, Adoptive T-cell therapy: adverse events and safety switches, Clin. Trans. Immuno. (2014) 3 :el7).
  • the present invention is directed to reducing deleterious inflammatory responses associated with ACT, including TCR and CAR-T therapies, by administering to a subject, for example a mammal and preferably a human, undergoing ACT therapy an inhibitor of the complement pathway.
  • ACT targeting include ACT targeting, but are not limited to: estrogen-receptor positive, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers, adenocarcinoma of the colon, adenocarcinoma of the rectum, central nervous system germ cell tumors, teratomas, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumors, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, ovarian immature teratomas, ovarian mature teratoma, ovarian monodermal and highly
  • Mesothelioma Mesothelioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, glioma anaplastic; glioblastoma multiforme,, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, pheochromocytoma, Islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm,
  • a complement pathway inhibitor can be administered in combination with ACT, wherein the ACT agent is a genetically redirected T-Cell receptor (TCR).
  • TCR genetically redirected T-Cell receptor
  • the T-cell receptor engages antigen presented by major histocompatibility complex molecules on the surface of diseased cells.
  • Tumor-specific T cells can be isolated from some tumors, and T cells can be activated ex vivo to respond against cancer cells (Dudley et al. Generation of tumor- infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother (2003) 26:332-342).
  • T cells can be used effectively as an autologous transfusion in a process termed adoptive immunotherapy (Dudley et al., Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol (2005) 23 :2346-2357).
  • Melanoma and viral-associated malignancies are particularly responsive to this type of therapy (Dudley et al., Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
  • T-cells for adoptive therapy utilize the native alpha and beta chains of a TCR specific for at tumor antigen.
  • ACT using genetically redirected TCRs has been used clinically to treat colorectal cancer (targeting Carcinoembryonic antigen (CEA)) Parkhurst et al., T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther (2011) 19:620-626), melanoma (targeting gplOO (Johnson et al., Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.
  • CEA Carcinoembryonic antigen
  • TCR can detect both intracellular and cell surface TAA, and can harness the entire signaling network normally engaged by TCR (Kershaw et al., Clinical Application of genetically modified T cells in cancer therapy. Clin. Trans. Immuno. (2014) 3 :el6). TCR can enable activation, costimulation and expansion of T cells through interaction with antigen-presenting cells. However, TCR are restricted by major histocompatibility complex and so each TCR is applicable to only a proportion of patients, and transgene TCR can be mispaired with endogenous TCR reducing their specificity and activity (Kuball et al., Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood (2007 109:2331-2338).
  • a complement pathway inhibitor can be administered in combination with ACT, wherein the ACT agent is a genetically redirected chimeric antigen receptor T-cell (CAR T).
  • CAR T genetically redirected chimeric antigen receptor T-cell
  • Redirected T-cells comprising a chimeric antigen receptor (CAR) are composed of an extracellular domain derived from a tumor-specific antibody, linked to an intracellular signaling domain.
  • CARs The specificity of CARs is derived from tumor-specific antibodies through the immunization of mice. Recombinant techniques can be used to humanize antibodies, or mice expressing human immunoglobulin genes can be used to generate fully human antibodies. Single- chain variable fragments of antibodies are used in the extracellular domain of CARs, which are joined through hinge and transmembrane regions to intracellular signaling domains (Kershaw et al., Clinical Application of genetically modified T cells in cancer therapy. Clin. Trans. Immuno. (2014) 3 :el6). Complete T-cell activation is a complex process involving a primary initiating signal, often referred to as signal 1, and secondary costimulatory signals, often referred to as signal 2.
  • Molecules mediating signal 1 include CD3 ⁇ that interacts with the TCR, whereas signal 2 molecules include CD28, CD137 and ICOS that interact with ligands on antigen-presenting cells. Together with involvement from co-receptors like CD8 and linker molecules like linker for activation of T cells, triggering of these molecules leads to activation of downstream kinase pathways to promote gene transcription and cellular responses (Kershaw et al., Clinical Application of genetically modified T cells in cancer therapy. Clin. Trans. Immuno. (2014) 3 :el6). Although inclusion of primary signaling molecules like CDS- ⁇ alone in CARs can enable responses against cancer cells, improved responses can be achieved through additional incorporation of signal 2-initiating molecules.
  • cytoplasmic domain of CD28, CD134 or CD137 can lead to increased cytokine production in response to tumor-associated antigens (TAA) and an enhanced ability of adoptively transferred T cells to mediate tumor regression (Brentjens et al., Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res (2007) 13 (18 Pt l):5426-5435; Moeller et al., A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells.
  • TAA tumor-associated antigens
  • CARs specific for a wide range of antigens have been developed, and cancers targeted in this way include leukemias and lymphomas— targeting, for example CD19 (Grupp et al., T cells engineered with a chimeric antigen receptor (CAR) targeting CD 19 (CTL019) produce significant in vivo proliferation, complete responses and long-term persistence without Gvhd in children and adults with relapsed, refractory ALL. Blood (2013) 122:67), CD20 (Till et al., Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.
  • Kite's KTE-C19 for refractory aggressive non-Hodgkin' s lymphoma also recently received the designation from both the FDA and the European Medicines Agency. And the University of Pennsylvania /Novartis's CTL019 for ALL also received breakthrough status.
  • CAR acts in a non-major histocompatibility complex-restricted manner and can potentially be used for all patients, but they can generally only detect cell surface TAAs, which can include carbohydrate moieties and glycolipids, major classes of molecules and potential sources of TAA.
  • bi-specific T-cell engagers directs T-cells to target and bind with a specific antigen on the surface of a cancer cell.
  • Blinatumomab (Amgen)
  • Amgen a BiTE has recently been approved as a second line therapy in Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.
  • Blinatumomab is given by continuous intravenous infusion in 4-week cycles.
  • BiTE agents have been associated with adverse immune responses, including cytokine release syndrome.
  • the most significantly elevated cytokines in the CRS associated with ACT include IL-10, IL-6, and IFN- ⁇ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 1 19:6226-6233).
  • the complement system is a part of the innate immune system which does not adapt to changes over the course of the host's life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens.
  • This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction.
  • Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phaogytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together).
  • Complement factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within C3 to produce C3(H20), which associates with factor B to form the C3(H20)B complex.
  • Complement factor D acts to cleave factor B within the C3(H20)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H20) to form the alternative pathway C3 convertase C3(H20)Bb.
  • C3b generated by any of the C3 convertases also associates with factor B to form C3bB, which factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb.
  • This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b.
  • C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell.
  • complement pathway inhibitors useful in the present invention can target any known complement system protein.
  • the complement pathway inhibitor targets a complement system protein associated with the classical pathway, the mannan- binding (MB)-lectin pathway, or the alternative pathway, or a combination thereof.
  • the complement pathway inhibitor targets CI, Clq, Clr, Cls, C2, C2a, C2b, C3, C3a, C3b, C4, C4a, C4b, C5, C5a, C5b, C6, C7, C8, C9, Factor B, Factor Ba, Factor Bb, Factor D, Factor H, Factor I, MBL, MASP-1, MASP-2, C3 convertase, C5 convertase, or a combination thereof.
  • Complement pathway inhibitors that target CI, Clr, Cls, Clq, or a combination thereof can be used in the present invention.
  • the CI, Clr, Cls, or Clq inhibitor can be selected from a C 1 esterase inhibitor (Cinryze - ViroPharma/Baxter) or a C 1 s monoclonal antibody (TNT003 - True North Pharmaceuticals), conestat alfa (Rhucin), or a combination thereof.
  • Complement pathway inhibitors that target C3, C3a, C3b, or iC3b can be used in the present invention.
  • the C, C3a, C3b, or iC3b inhibitor can be selected from the monoclonal antibody H17 (EluSys Therapeutics), the compstatin 4(lMeW) (POT-4 - Potentia Pharmaceuticals), the compstatin 4(lMeW) (APL-1 - Appelis Pharmaceuticals) or 4(lMeW) (APL-2 - Appellis Pharmaceuticals), the compstatin Cp40 (AMY-101 - Amyndas Pharmaceuticals) or PEG-Cp40 (Amyndas Pharmaceuticals), Staphylococcal complement inhibitor (SCIN), or a combination thereof.
  • the C, C3a, C3b, or iC3b inhibitor can be selected from the monoclonal antibody H17 (EluSys Therapeutics), the compstatin 4(lMeW) (POT-4 - Potentia
  • the complement pathway inhibitor targets C5, C5a, or C5b.
  • the C5 inhibitor can be selected from eculizumab (Soliris), pexelizumab, the monoclonal antibody LFG316 (Novartis/Morphosys), the monoclonal antibody Mubodina (Adieene), ergidina (Adieene), the recombinant protein coversin (OmCl) (Volution Immuno-Pharmaceuticals), aurin tricarboxylix acid (ATA), the aptamer ARC 1005 (Novo Nordisk), ARC 1905 (Novo Nordisk), slow off rate modified aptamers (SOMAmers - Somalogic), the affibody SOBI002 (Swedish Orphan Biovitrum (Affibody)), the cyclomimetic macrocyclic peptide RA101348 (Rapharma), anti-C5 siRNA (Alnylam), the aptamer
  • complement pathway inhibitors useful in the present invention can also target the alternative complement pathway or complement receptor proteins.
  • complement pathway inhibitor can target the alternative complement pathway proteins Factor B, Factor D, Factor H, or C3 convertase active in conjunction with an alternative complement pathway protein.
  • useful complement pathway inhibitors can include the complement Factor H- mimetic protein TT30 (CR2/CFH) (Alexion), the CFH-mimetic protein Mini-CFH (Amyndas), the CFH-mimetic protein CRIg/CFH, the complement receptor 1 (CRl)-mimetic protein sCRl (CDX- 1135) (Celldex), the CR-l-mimetic protein microcept (APT070), the CR-1 based protein TT32 (CR2/CR1) (Alexion), the Factor B monoclonal antibody TA106 (Alexion Pharmaceuticals), an anti-complement Factor B siRNA (Alnylam), a slow off rate aptamer directed to complement Factor B or D (Somalogic), or a combination thereof.
  • Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex.
  • Factor D inhibitors have been previously described. Factor D inhibitors that can be used in the present invention include those described in, for example: Biocryst Pharmaceuticals US Pat. No.
  • Complement pathway inhibitors that target the lectin pathway can also be used in the present invention.
  • an anti-MASP-3 molecule OMS721, Omeros
  • OMS721, Omeros an anti-MASP-3 molecule
  • complement pathway inhibitors include:
  • a complement pathway inhibitor in combination with a corticosteroid, for example prednisone, dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokine compounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGFp.
  • cytokines in CRS associated with ACT include IL-10, IL- 6, and IFN- ⁇ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.
  • Cytokine inhibitors that can be used in combination with complement pathway inhibitors include, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof.
  • Additional anti-inflammatory agents that can be used in combination with a complement pathway inhibitor include, but are not limited to, non-steroidal anti-inflammatory drug(s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNFa antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNFa antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex); 55 kdT F-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen); Anti-Tac (humanized anti-IL-2R
  • a complement pathway inhibitor may be provided in combination or alternation with at least one additional therapeutic agent. In one embodiment, a complement pathway inhibitor may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action. In one embodiment, a complement C5 inhibitor or C5 convertase inhibitor may be provided in combination with eculizumab. In one embodiment, a Factor D inhibitor is provided in combination with eculizumab. In one embodiment, a complement C5 inhibitor of C5 convertase inhibitor may be provided in combination with an additional inhibitor of Factor D.
  • a complement pathway inhibitor may be provided in combination with etamercept. In another specific embodiment, a complement pathway inhibitor may be provided in combination with tocilizumab. In still another embodiment, the complement pathway inhibitor is provided in combination with etanercept and tocilizumab. In a specific embodiment, a complement pathway inhibitor may be provided in combination with infliximab. In a specific embodiment, a complement pathway inhibitor may be provided in combination with golimumab.
  • a complement pathway inhibitor may be provided together with a compound that inhibits an enzyme that metabolizes an administered protease inhibitor. In one embodiment, a complement pathway inhibitor may be provided together with ritonavir.
  • a complement pathway inhibitor may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), receptor agonist, or siRNA.
  • Nonlimiting examples of active agents in these categories are:
  • Protease inhibitors plasma-derived Cl-INH concentrates, for example Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®; and recombinant human CI -inhibitors, for example Rhucin®;
  • Soluble complement regulators Soluble complement receptor 1 (TP 10) (Avant Immunotherapeutics); sCRl-sLex/TP-20 (Avant Immunotherapeutics); MLN-2222 /CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals);
  • Receptor agonists PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);
  • rhMBL Recombinant human MBL
  • rhMBL Recombinant human MBL
  • additional types of therapeutic agents include anti-inflammatory drugs, antimicrobial agents, anti- angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs and combinations thereof.
  • therapeutic agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, n
  • a complement pathway inhibitor is administered in combination or alternation with at least one additional therapeutic agent selected from: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine), indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors including Celecoxib (Celebrex); disease-
  • a complement pathway inhibitor is combined with: Aubagio (teriflunomide), Avonex (interferon beta-la), Betaseron (interferon beta-lb), Copaxone (glatiramer acetate), Extavia (interferon beta-lb), Gilenya (fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta- la), Rebif (interferon beta- la), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), or H.P. Acthar Gel (ACTH), or a combination thereof.
  • Aubagio teriflunomide
  • Avonex interferon beta-la
  • Betaseron interferon beta-lb
  • Copaxone glatiramer acetate
  • Extavia
  • a complement pathway inhibitor described herein can be combined with one or more of the following anti -inflammatory agents, for example, but not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamet
  • a complement pathway inhibitor may be provided in combination or alternation with an immunosuppressive agent or an anti-inflammatory agent.
  • a complement pathway inhibitor can be administered in combination or alternation with at least one immunosuppressive agent.
  • the immunosuppressive agent as nonlimiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A ( EORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMU E®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLO E OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A- 3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody,
  • anti-inflammatory agents examples include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofe
  • a complement inhibitor is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • a complement pathway inhibitor is administered in combination with a tumor necrosis factor-alpha (TNF-a) antagonist and/or interleukin-1 (IL-1) receptor antagonist, for example antibradykinin.
  • TNF-a tumor necrosis factor-alpha
  • IL-1 interleukin-1
  • a complement pathway inhibitor is administered in combination or alteration with an omega-3 fatty acid or a peroxisome proliferator-activated receptor (PPARs) agonist.
  • Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting DGAT and by stimulating peroxisomal and mitochondrial beta oxidation.
  • Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been found to have high affinity for both PPAR-alpha and PPAR-gamma.
  • Marine oils e.g., fish oils, are a good source of EPA and DHA, which have been found to regulate lipid metabolism.
  • Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
  • Omega-3 fatty acids lower serum triglycerides, increase serum HDL- cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor Vll-phospholipid complex.
  • omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
  • One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Omacor®. Such a form of omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of which are incorporated herein by reference.
  • Peroxisome proliferator-activated receptors are members of the nuclear hormone receptor superfamily ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. There are three distinct PPAR subtypes that are the products of different genes and are commonly designated PPAR-alpha, PPAR-beta/delta (or merely, delta) and PPAR-gamma.
  • PPAR agonists e.g., PPAR-alpha agonists, PPAR-gamma agonists and PPAR-delta agonists.
  • Some pharmacological agents are combinations of PPAR agonists, such as alpha/gamma agonists, etc., and some other pharmacological agents have dual agonist/antagonist activity.
  • Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, are PPAR-alpha agonists and are used in patients to decrease lipoproteins rich in triglycerides, to increase FIDL and to decrease atherogenic-dense LDL. Fibrates are typically orally administered to such patients.
  • Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester has been known for many years as a medicinally active principle because of its efficacy in lowering blood triglyceride and cholesterol levels.
  • Complement pathway inhibitors can be administered as the neat chemical, but are more typically administered as a pharmaceutical composition, that includes an effective amount for a host, typically a human, in need of such treatment. Accordingly, the disclosure provides administration of complement pathway inhibitor pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.
  • the complement pathway inhibitor pharmaceutical composition may contain a complement pathway inhibitor compound or salt as the only active agent, or, in an alternative embodiment, the complement pathway inhibitor compound and at least one additional active agent.
  • the complement pathway inhibitor pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active complement pathway inhibitor compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least about 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, or 1700 mg of active compound, or its salt.
  • the dosage form has 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, lOOOmg, 1200 mg, or 1600 mg of active compound, or its salt.
  • the dosage form can be administered, for example, once a day (q.d.), twice a day (b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.), once every other day (Q2d), once every third day (Q3d), as needed, or any dosage schedule that provides treatment of a disorder described herein.
  • the complement pathway inhibitor pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent.
  • the pharmaceutical composition may contain a molar ratio (i.e., complement inhibitor: additional active agent) of about 0.5: 1, about 1 : 1, about 2: 1, about 3 : 1 or from about 1.5: 1 to about 4: 1 of an anti-inflammatory or immunosuppressing agent.
  • a complement inhibitor as contemplated herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intraveneous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, intrathecal, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the compound can be administered, as desired, for example, as a solution, suspension, or other formulation via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, subchorodial, chorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device, injection, or topically administered formulation, for example a solution or suspension provided as an eye drop.
  • the complement inhibitor pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, a microparticle, a nanoparticle, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution or suspension.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • compositions, and methods of manufacturing such compositions, suitable for administration as contemplated herein are known in the art.
  • known techniques include, for example, US Patent Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303, 148, 6,395,302, 6,497,903, 7,060,296, 7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263, 128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252, incorporated by reference herein.
  • the complement inhibitor for the use contemplated here can optionally include a carrier.
  • Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, fillers, flavorants, glidents, lubricants, pH modifiers, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
  • examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
  • surface active agents include sodium lauryl sulfate and polysorbate 80.
  • Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins.
  • Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium.
  • Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
  • Examples of lubricants include magnesium stearate and calcium stearate.
  • pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids.
  • bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids.
  • buffers generally comprising mixtures of acids and the salts of said acids.
  • optionalal other active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • the complement inhibitor pharmaceutical composition for administration further includes one or more of a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20);
  • the complement inhibitor pharmaceutical preparation may include polymers for controlled deliver of the described compounds, including, but not limited to pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(l,3-dioxan-2one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates.
  • polymers may be modified with polyethylene glycol (PEG), with a carbohydrate, and/or with acyclic polyacetals derived from polysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series, 786:301, incorporated by reference herein.
  • the complement inhibitor pharmaceutical composition is formulated as a particle.
  • the particles are microparticles.
  • the particles are nanoparticles.
  • Suitable techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable methods of particle formulation are briefly described below. Pharmaceutically acceptable excipients, including pH modifying agents, disintegrants, preservatives, and antioxidants, can optionally be incorporated into the particles during particle formation.
  • the particles are derived through a solvent evaporation method.
  • a complement inhibitor is dissolved in a volatile organic solvent, such as methylene chloride.
  • the organic solution containing a compound described herein is then suspended in an aqueous solution that contains a surface active agent such as poly(vinyl alcohol).
  • the resulting emulsion is stirred until most of the organic solvent evaporated, leaving solid nanoparticles or microparticles.
  • the resulting nanoparticles or microparticles are washed with water and dried overnight in a lyophilizer. Nanoparticles with different sizes and morphologies can be obtained by this method.
  • compositions which contain labile polymers may degrade during the fabrication process due to the presence of water.
  • labile polymers such as certain polyanhydrides
  • methods which are performed in completely anhydrous organic solvents can be used to make the particles.
  • Solvent removal can also be used to prepare particles from a compound that is hydrolytically unstable.
  • the compound or polymer matrix and one or more compounds
  • a volatile organic solvent such as methylene chloride.
  • This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion.
  • Solid particles form from the emulsion, which can subsequently be isolated from the supernatant.
  • the external morphology of spheres produced with this technique is highly dependent on the identity of the drug.
  • complement inhibitor is administered to a patient in need thereof as particles formed by solvent removal.
  • the particles formed by solvent removal comprise a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by solvent removal comprise a complement inhibitor and an additional therapeutic agent.
  • the particles formed by solvent removal comprise a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by solvent removal can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by solvent removal are formulated into a tablet but the tablet is uncoated.
  • the particles are derived by spray drying.
  • a complement inhibitor or polymer matrix and one or more compounds
  • an organic solvent such as methylene chloride.
  • the solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the micro droplets, forming particles.
  • Microparticles and nanoparticles can be obtained using this method.
  • a complement inhibitor is administered to a patient in need thereof as a spray dried dispersion (SDD).
  • the complement inhibitor is provided as a spray dried dispersion (SDD) comprising a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein.
  • the SDD comprises a complement inhibitor and an additional therapeutic agent.
  • the SDD comprises a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described spray dried dispersions can be coated to form a coated tablet.
  • the spray dried dispersion is formulated into a tablet but is uncoated.
  • Particles can be formed from a complement inhibitor using a phase inversion method.
  • the complement inhibitor or polymer matrix and one or more active compounds
  • the solution is poured into a strong non-solvent for the compound to spontaneously produce, under favorable conditions, microparticles or nanoparticles.
  • the method can be used to produce nanoparticles in a wide range of sizes, including, for example, from nanoparticles to microparticles, typically possessing a narrow particle size distribution.
  • a complement inhibitor is administered to a patient in need thereof as particles formed by phase inversion.
  • the present invention provides particles formed by phase inversion comprising a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by phase inversion comprise a complement inhibitor and an additional therapeutic agent.
  • the particles formed by phase inversion comprise a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by phase inversion are formulated into a tablet but the tablet is uncoated.
  • Coacervation involves the separation of a compound (or polymer matrix and one or more compounds) solution into two immiscible liquid phases.
  • One phase is a dense coacervate phase, which contains a high concentration of the compound, while the second phase contains a low concentration of the compound.
  • the compound forms nanoscale or microscale droplets, which harden into particles.
  • Coacervation may be induced by a temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer thereby forming an interpolymer complex (complex coacervation).
  • a complement inhibitor is administered to a patient in need thereof as particles formed by coacervation.
  • the present invention provides particles formed by coacervation comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by coacervation comprise a compound of the present invention and an additional therapeutic agent.
  • the particles formed by coacervation comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by coacervation are formulated into a tablet but the tablet is uncoated.
  • a complement inhibitor for use in the present invention is administered to a patient in need thereof as particles formed by low temperature casting.
  • the present invention provides particles formed by low temperature casting comprising a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by low temperature casting comprise complement inhibitor and an additional therapeutic agent.
  • the particles formed by low temperature casting comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by low temperature casting can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by low temperature casting are formulated into a tablet but the tablet is uncoated.
  • an effective amount of a complement inhibitor is incorporated into a nanoparticle, e.g. for convenience of delivery and/or extended release delivery.
  • a nanoparticle e.g. for convenience of delivery and/or extended release delivery.
  • the use of materials in nanoscale provides one the ability to modify fundamental physical properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and/or immunogenicity.
  • a number of nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergy, and infections. These nanoscale agents may provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce health-care costs. As therapeutic delivery systems, nanoparticles can allow targeted delivery and controlled release.
  • nanoparticle-based compound delivery can be used to release compounds at a sustained rate and thus lower the frequency of administration, deliver drugs in a targeted manner to minimize systemic side effects, or deliver two or more drugs simultaneously for combination therapy to generate a synergistic effect and suppress drug resistance.
  • a number of nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drugs and polymer-based conjugates account for a large proportion of the products. See, Zhang, L., et al., Nanoparticles in Medicine: Therapeutic Applications and Developments, Clin. Pharm. and Ther., 83(5):761-769, 2008.
  • polyesters examples include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc, 115: 11010), poly (serine ester) (Zhou et al., 1990, Macromolecules, 23 :3399), poly(4- hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem.
  • the polymeric particle is between about 0.1 nm to about 10000 nm, between about 1 nm to about 1000 nm, between about 10 nm and 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm, between about 1 and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm.
  • the micro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm.
  • a compound described herein may be covalently coupled to a polymer used in the nanoparticle, for example a polystyrene particle, PLGA particle, PLA particle, or other nanoparticle.
  • compositions can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 wt.% of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound.
  • compositions suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • conventional solid carriers for example, cocoa butter
  • compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
  • microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
  • compositions suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
  • nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.
  • Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
  • inhalation drug delivery devices and methods include, for example, US 7,383,837 titled “Inhalation device” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powder inhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled “Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same” (Glaxo Group Ltd and SmithKline Beecham Corporation); US9,095,670 titled “Inhalation device and method of dispensing medicament", US 8,205,611 titled “Dry powder inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler” (Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled “Inhalation Device with Feedback System", US 8,910,625 and US/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy” (Vectura GmbH); US 6,948,
  • Additional nonlimiting examples of methods and devices for drug delivery to the eye include, for example, WO2011/106702 and US 8,889,193 titled “Sustained delivery of therapeutic agents to an eye compartment”, WO2013/138343 and US 8,962,577 titled “Controlled release formulations for the delivery of HIF-1 inhibitors", WO/2013/138346 and US2013/0272994 titled "Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents", WO2005/072710 and US 8,957,034 titled “Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers", WO2008/030557, US2010/0215580, US2013/0164343 titled “Compositions and Methods for Enhancing Transport Through Mucous", WO2012/061703, US2012/0121718, and US2013/0236556 titled “Compositions and Methods Relating to Reduced Mucoadhesion”, WO2012/0399
  • Additional nonlimiting examples of drug delivery devices and methods include, for example, US20090203709 titled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories); US20050009910 titled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug”, US 20130071349 titled “Biodegradable polymers for lowering intraocular pressure", US 8,481,069 titled “Tyrosine kinase microspheres", US 8,465,778 titled “Method of making tyrosine kinase microspheres", US 8,409,607 titled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods", US 8,512,738 and US 2014/0031408 titled “Biodegradable intravitreal tyrosine kinase implants", US 2014/0294986

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Abstract

L'invention concerne des procédés pour traiter des réponses inflammatoires indésirables associées à une thérapie adoptive par lymphocytes T, telles que le syndrome de libération de cytokines et le syndrome de lyse tumorale, à l'aide de composés inhibiteurs de la voie du complément.
PCT/US2016/048710 2015-08-26 2016-08-25 Utilisation de composés inhibiteurs de la voie du complément pour atténuer des réponses immunitaires indésirables associées à une thérapie adoptive par lymphocytes t WO2017035362A1 (fr)

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WO2021207305A1 (fr) * 2020-04-08 2021-10-14 Nostrum Pharmaceuticals, Llc Compositions et procédés utilisant l'interféron destinés au traitement d'infections virales
WO2022066774A1 (fr) 2020-09-23 2022-03-31 Achillion Pharmaceuticals, Inc. Composés pharmaceutiques pour le traitement de troubles à médiation par complément
WO2022134047A1 (fr) * 2020-12-25 2022-06-30 The Trustees Of The University Of Pennsylvania Anticorps anti-c5 humanisés et protéines de fusion du facteur h et leurs utilisations

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