WO2017035362A1 - Use of complement pathway inhibitor compounds to mitigate adoptive t-cell therapy associated adverse immune responses - Google Patents

Use of complement pathway inhibitor compounds to mitigate adoptive t-cell therapy associated adverse immune responses Download PDF

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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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French (fr)
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Mingjun Huang
Jason FISHERMAN
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Achillion Pharmaceuticals, Inc.
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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

Abstract

This invention provides methods for treating adoptive T-cell therapy-associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using complement pathway inhibitor compounds.

Description

USE OF COMPLEMENT PATHWAY INHIBITOR COMPOUNDS TO MITIGATE ADOPTIVE T-CELL THERAPY ASSOCIATED ADVERSE
INFLAMMATORY RESPONSES Related Applications
This application claims the benefit of provisional U.S. Application No. 62/210,415, filed August 26, 2015, the entirety of which is hereby incorporated by reference for all purposes.
Field of the Invention
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.
Background
Adoptive T-cell therapy (ACT) has recently emerged as an efficacious treatment against a number of hematological and solid tumors. ACT utilizes genetically modified normal peripheral blood T cells to redirect T-cell specificity to tumor associated antigens (TAAs). Two common approaches for redirecting T cell specificity include gene modifications with highly active T cell receptors (TCRs), in which variable alpha and beta chains are cloned from high affinity TAAs- specific T cell clones (Restifo et al., Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. (2012) 12:269-281) and the introduction of chimeric antigen receptors (CARs) that recognize TAAs through single-chain variable fragments (scFvs) that are isolated from antigen specific monoclonal antibodies (mAbs) (Shirasu et al., Functional design of chimeric T-cell antigen receptors for adoptive immunotherapy of cancer: architecture and outcomes. AntiCanc. Res. (2012) 32:2377-2384). 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. Blood (2009) 114:535-546) and sarcoma (Robbins et al., Tumor regression in patients with metastatic synovial cell sarcoma and melanoma sing genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. (2011) 29:917-924). Likewise, results from early clinical trials have shown therapeutic efficacy of CAR-T therapy in a number of cancers, including lymphoma (Till et al., CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1 BB domains: pilot clinical trial results. Blood (2012) 119:3940- 3950; chronic lymphocytic leukemia (CLL) (Porter et al., Chimeric antigen receptor modified T cells in chronic lymphoid leukemia. NEJM (2011) 365:725-733) acute lymphoblastic leukemia (ALL) (Grupp et al., Chimeric antigen receptor modified T cells for acute lymphoid leukemia. NEJM (2013) 368: 1509-1518), and 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). For example, in 2010, two deaths were attributed to the development of cytokine release syndrome following administration of CAR-T cells in the clinical setting (Brentjens et al., Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol. Ther. (2010) 18:666-668; Morgan et al., Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. (2010) 18:843-851).
Cytokine release syndrome (CRS) 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).
Tumor lysis syndrome (TLS) 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. High concentrations of both uric acid and phosphate potentiate the risk of acute kidney injury because uric acid precipitates more readily in the presence of calcium phosphate and vice versa that results in hyperkalemia, hyperphosphotemia, hypocalcemia, remia, and acute renal failure. It usually occurs in patients with bulky, rapidly proliferating, treatment-responsive tumors (Jagasia et al., Complications of hematopoietic neoplasms. Wintrobe MM, Greer JP, Foerster J, et al. Wintrobe's Clinical Hematology. 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003. Vol II: 1919-44).
Currently, ACT-mediated CRS is generally treated with corticosteroids. Corticosteroids, however, 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). In addition, the use of anti-cytokine molecules to ameliorate ACT-mediated CRS has been examined, as have rheumatoid arthritis drugs etanercept (Enbrel®) and tocilizumab (Actemra®), the latter of which blocks IL-6 activity, have been used to treat cytokine release syndrome associated with ACT (Grupp et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. (2013) 368(16): 1509-18).
The role of cytokines is well established with respect to ACT side effects. The role of the complement system in contributing to such undesirable inflammatory reactions, however, is less clear. Previous reports have correlated complement factor levels with the development of adverse events associated with the administration of the mAb rituximab (van der Kolk et al., Complement activation plays a key role in the side effects of rituximab treatment, Br. J. Haemt. (2001) 115:807- 811). The tumor killing activity of rituximab, however, directly requires the recruitment of complement, and the administration of rituximab results in complement activation. 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). When the cell is destroyed, the target cells and the immune effector cells both release cytokines (e.g., interleukin, interferon, tumor necrosis factor) into circulation. Unlike the humoral immune response associated with mAbs like rituximab, 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).
A number of complement pathway inhibitor compounds have been described (Risitano, Current and future pharmacologic complement inhibitors, Hematol Oncol Clin N Am (2015) 29:561-582.)
Accordingly, it is an object of the present invention to provide effective treatments which mediate ACT-associated adverse inflammatory responses which can be administered without adversely affecting ACT efficacy.
Summary of the Invention
In one embodiment, improved methods and compositions are provided to mediate adverse inflammatory responses associated with the use of adoptive T-cell therapy (ACT) to treat cancer. Specifically, 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.
Compared to standard modalities such as corticosteroids used to address adverse inflammatory responses associated with ACT treatment, it is believed that the use of a complement inhibitor does not interfere with the efficaciousness of ACT treatment. Accordingly, 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.
As contemplated herein, 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. For example, 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. Additionally, a complement pathway inhibitor can be administered to a subject experiencing an adverse inflammatory response associated with the administration of ACT. In certain embodiments, 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.
In one embodiment, the ACT agent targets CD 19 on a tumor cell. In one embodiment, the ACT agent is a CD19 gene modified Autologous Activated T cells (CART-19). In one embodiment, the ACT agent is MAGE A3 peptide primed activated autologous T cells. In one embodiment, the ACT agent is CD 19 gene modified allogeneic activated T cells (CART-19). In one embodiment, the ACT agent is gene modified MAGE/NYESO autologous T cells. In one embodiment, the ACT agent is mesothelin re-directed autologous T cells. In one embodiment, the ACT agent is autologous zinc finger modified T cells. In one embodiment, the ACT agent is gene modified gag-TCR autologous T cells. In one embodiment, the ACT agent is idiotype-KLH vaccine primed activated autologous T cells. In one embodiment, the ACT agent is JCAR015. In one embodiment, the ACT agent is Kite's KTE-C19 for refractory aggressive non-Hodgkin's lymphoma. In one embodiment, 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.
In certain treatment protocols, a subject may be administered a lymphodepleting preparative regimen, for example cyclophasphamid and fludarabine, prior to ACT administration. In one embodiment, the complement pathway inhibitor is administered subsequent to the lymphodepleting preparative regimen and prior to administration of ACT. In one embodiment, the complement pathway inhibitor is administered subsequent to the lymphodepleting preparative regimen and the administration of ACT.
In one embodiment, 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. Likewise, 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).
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. In one embodiment, 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, ½ hour or less prior to treatment with the ACT agent. Typically, 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. In one embodiment, a complement pathway inhibitor is administered concomitantly, or closely thereto, with initial ACT agent exposure. If desired, the complement pathway inhibitor can be administered multiple times during the ACT agent treatment to maximize inhibition of the complement system. In certain embodiments, a complement pathway inhibitor is administered about ½ 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. In one embodiment, the active compound is administered between about 12 hours and 120 hours following administration of the ACT agent. In one embodiment, 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.
As contemplated herein, complement pathway inhibitors useful in the present invention can target any known complement system protein. In one embodiment, 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. In one embodiment, 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.
Provided herein, 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. For example, the subject can be receiving ACT for the treatment of a solid or hematological cancer. In one embodiment, 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. In a particular embodiment, 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). As provided herein, a complement pathway inhibitor is contemplated for use to reduce adverse immune responses associated with any ACT-targeted cancer treatment. Further contemplated herein is the use of complement pathway inhibitor compound in the manufacture of a medicament for use in the mediation of adverse inflammatory responses associated with ACT. Detailed Description of the Invention
Terminology
A "dosage form" means a unit of administration of an active agent. Examples of 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. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. 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. For example, 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., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).
The term "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. Typically 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. As used herein, 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. In certain embodiments the compound and the additional active agent need not be prescribed for a patient by the same medical care worker. In certain embodiments 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. In one embodiment, 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.
Adoptive T-cell Therapy (ACT)
Gene transfer technology has allowed for the redirecting of polyclonal T cells against tumor targets. Intracellular antigens can be targeted by transducing polyclonal T cells with T-cell receptors (TCRs) that recognize specific peptide epitopes (Tey, Adoptive T-cell therapy: adverse events and safety switches, Clin. Trans. Immuno. (2014) 3 :el7). For example, T cells transduced with TCR a and β chains specific for a human leukocyte antigen (HLA)-*0201 -restricted MART- 1 epitope can bring about melanoma regression. TCR transfer, however, is limited by ULA restriction and much of the focus has now shifted to chimeric antigen receptors (CARs). 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.
Particularly attractive targets for the use of complement pathway inhibitors to mediate an adverse immune response associated with ACT 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 specialized teratomas, progesterone receptor-negative breast cancer, progesterone receptor- positive breast cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumors, recurrent extragonadal non-seminomatous germ cell tumor, recurrent extragonadal seminomas, recurrent malignant testicular germ cell tumors, recurrent melanomas, recurrent ovarian germ cell tumors, recurrent rectal cancer, stage III extragonadal non-seminomatous germ cell tumors, stage III extragonadal seminomas, stage III malignant testicular germ cell tumors, stage III ovarian germ cell tumors, stage IV breast cancers, stage IV colon cancers, stage IV extragonadal non-seminomatous germ cell tumors, stage IV extragonadal seminoma, stage IV melanomas, stage IV ovarian germ cell tumors, stage IV rectal cancers, testicular immature teratomas, testicular mature teratomas, 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, metastatic colorectal cancer, metastatic melanoma, or cisplatin-refractory, unresectable germ cell tumors, carcinoma, sarcoma, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma. 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, cystosarcoma phylloide, salivary cancers, thymic carcinomas, bladder cancer, and Wilms tumor, a blood disorder or a hematologic malignancy, including, but not limited to, myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), T-cell or K-cell lymphoma, for example, but not limited to: peripheral T- cell lymphoma; anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell Lymphoma; Enteropathy - type T-cell lymphoma; Hematosplenic gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal NK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for example lymphomas that appear after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); Hydroa vacciniforme-like lymphoma; Adult T-cell leukemia/ lymphoma; Enteropathy-associated T-cell lymphoma; Hepatosplenic T- cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma, a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality, a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma, uch as, but not limited to, an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt' s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma- Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or Waldenstrom's Macroglobulinemia; a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin' s Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL, a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia- variant; Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; T cell/histiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Large B- cell lymphoma arising in HHV8-associated multicentric; Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia; an acute myelogenous leukemia, for example an undifferentiated AML (MO); myeloblastic leukemia (Ml; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).
TCR
As contemplated herein, a complement pathway inhibitor can be administered in combination with ACT, wherein the ACT agent is a genetically redirected T-Cell receptor (TCR). 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). These 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. J Clin Oncol (2008) 26:5233-5239; Heslop et al., Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood (2010) 115:925-935) and successes in these fields have driven attempts to employ this approach against many types of cancer. Tumor- specific T cells are rare for most malignancies and consequently difficult to isolate, but genetic modification of T cells using genes encoding antigen receptors can be used to generate tumor- reactive T cells in a process termed genetic redirection of specificity.
One way to genetically redirect T-cells for adoptive therapy is to 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. Blood (2009) 114:535- 546), MART-1, MAGE-A3 (Morgan et al., Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother (2013) 36: 133-151), NY-ESO-1 (Robbins et al., Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol (2011) 29:917-924), or p53 (Davis et al., Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin Cancer Res (2010) 16:5852-5861), esophageal (targeting MAGE-A3), synovial sarcoma (targeting MAGE-A3), sarcoma (targeting NY-ESO-1), and multiple myeloma (targeting NY-ESO-1 (Rapoport et al., Adoptive transfer of gene-modified T-cells engineered to express high-affinity TCRs for cancer- testis antigens (CTAs) NY-ESO-1 or Lage-1, in MM patients post auto-SCT. 54th ASH Annual Meeting and Exposition Abstract (2012) 120:472).
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).
CAR-T
As contemplated herein, 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). 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.
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-ζ alone in CARs can enable responses against cancer cells, improved responses can be achieved through additional incorporation of signal 2-initiating molecules. Addition of the cytoplasmic domain of CD28, CD134 or CD137 to CD3^-containing CARs 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. Cancer Gene Ther (2004) 11 :371-379; Carpenito et al., Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA (2009) 106:3360-3365; Hombach et al., OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4(+) T cells. Oncoimmunology (2012) 1 :458-466).
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. Blood (2008) 112:2261-227 l)-and solid cancers including cancers of the prostate (targeting PSMA (Junghans et al., Abstract C13 : phase I trial of anti-PSMA designer T cells in advanced prostate cancer. Cancer Res (2012) 72 (4 Supplement): C13), colorectal and breast (targeting TAG or Her-2 (Ma et al., Genetically engineered T cells as adoptive immunotherapy of cancer. Cancer Chemother Biol Response Modif (2002) 20:315-34), and neuroblastoma (targeting CD171 (Park et al., Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther (2007) 15:825-833) or GD2 (Louis et al., Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood (2011) 118:6050-6056)).
In November 2014, for example, the FDA granted orphan status to Juno's JCAR015.
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.
Unlike TCR, 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
Also contemplated herein is the use of a complement pathway inhibitor to mediate an adverse immune response in patients receiving bi-specific T-cell engagers (BiTE). A bi-specific T-cell engager directs T-cells to target and bind with a specific antigen on the surface of a cancer cell. For example, Blinatumomab (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.
The use of 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-γ (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).
Complement Pathway Inhibitors
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).
The complement system has three pathways: classical, alternative and lectin. 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. Additionally, 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.
As contemplated herein, complement pathway inhibitors useful in the present invention can target any known complement system protein. In one embodiment, 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. In one embodiment, 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 described in Risitano, Current and future pharmaclologic Complement Inhibitors, Hamtol. Oncol. Clin. N. Am. (2015) 29:561-582, incorporated herewith, are particularly useful.
Complement pathway inhibitors that target CI, Clr, Cls, Clq, or a combination thereof can be used in the present invention. For example, 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. For example, 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.
In one embodiment, the complement pathway inhibitor targets C5, C5a, or C5b. For example, 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 ARC1905 (Zimura), ergidina, PMX 53, or a combination thereof.
The complement pathway inhibitors useful in the present invention can also target the alternative complement pathway or complement receptor proteins. For example, 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. For example, 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.
Complement pathway inhibitors that target Factor D may also be used. 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. 6653340 titled "Compounds useful in the complement, coagulat and kallikrein pathways and method for their preparation," incorporated herewith, describes fused bicyclic ring compounds that are potent inhibitors of factor D; Novartis PCT patent publication WO2012/093101 titled "Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration," incorporated herewith, describes certain factor D inhibitors; Novartis PCT patent publications WO2014/002057 titled "Pyrrolidine derivatives and their use as complement pathway modulators" and WO2014/009833 titled "Complement pathway modulators and uses thereof," both incorporated herewith, describe additional factor D inhibitors with heterocyclic substituents; Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002058, WO2014/002059, and WO2014/005150, all incorporated herewith; Bristol- Myers Squibb PCT patent publication WO2004/045518 titled "Open chain prolyl urea-related modulators of androgen receptor function," incorporated herewith, describes open chain prolyl urea and thiourea related compounds; Japan Tobacco Inc. PCT patent publication WO 1999/048492 titled "Amide derivatives and nociceptin antagonists," incorporated herewith, describes compounds with a proline-like core and aromatic substituents connected to the proline core through amide linkages; Ferring B.V. and Yamanouchi Pharmaceutical Co. 1TD. PCT patent publication WO 1993/020099 titled "CCK and/or gastrin receptor ligands," incorporated herewith, describes compounds with a proline-like core and heterocyclic substituents connected to the proline core through amide linkages; Alexion Pharmaceuticals PCT patent publication WO 1995/029697 titled "Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases," incorporated herewith, discloses antibodies directed to C5 of the complement pathway; Achillion Pharmaceuticals PCT Patent Application No. PCT/US2015/017523 and U.S. Patent Application No. 14/631,090 titled "Alkyne Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017538 and U.S. Patent Application No. 14/631,233 titled "Amide Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017554 and U.S. Patent Application No. 14/631,312 titled "Amino Compounds for Treatment of Complement Mediated Disorders," incorporated herewith ; PCT Patent Application No. PCT/US2015/017583 and U.S. Patent Application No. 14/631,440 titled "Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017593 and U.S. Patent Application No. 14/631,625 titled "Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017597 and U.S. Patent Application No. 14/631,683 titled "Ether Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017600 and U.S. Patent Application No. 14/631,785 titled "Phosphonate Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; PCT Patent Application No. PCT/US2015/017609 and U.S. Patent Application No. 14/631,828 titled "Compounds for Treatment of Complement Mediated Disorders," incorporated herewith; U.S. Prov. No. 62/209,927, titled "Alkyne Compounds for Treatment of Medical Disorders," incorporated herewith; U.S. Prov. No. 62/209, 931, titled "Amide Compounds for Treatment of Medical Disorders," incorporated herewith; U.S. Prov. No. 62/209,932, titled "Amino Compounds for Treatment of Medical Disorders," incorporated herewith; U.S. Prov. No. 62/209,989, titled "Carbamate, Ester, and Ketone Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/209,972 titled "Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/209,997, titled "Ether Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/210,007, titled "Phosphonate Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/210,334, titled "Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/210,362, titled "Di substituted Compounds for Treatment of Medical Disorders," incorporated herein; U.S. Prov. No. 62/210017, titled "Alkyne Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith U.S. Prov. No. 62/210,077, titled "Amide Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210, 140, titled "Amino Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210,910, titled "Carbamate, Ester, and Ketone Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/209986, titled "Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210, 116, titled "Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210,258, titled "Ether Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210,306, titled "Phosphonate Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith, U.S. Prov. No. 62/210,391, titled "Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith; U.S. Prov. No. 62/210,409, "Di substituted Compounds for Treatment of Immune and Inflammatory Disorders," incorporated herewith.
Complement pathway inhibitors that target the lectin pathway can also be used in the present invention. For example, an anti-MASP-3 molecule (OMS721, Omeros) can be used herein.
Other non-limiting examples of complement pathway inhibitors include:
Figure imgf000024_0001
Figure imgf000025_0001
Combination Therapies
Also contemplated herein is the use of 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. The most significantly elevated cytokines in CRS associated with ACT include IL-10, IL- 6, and IFN-γ (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) 119:6226-6233). 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-2Ra; Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-4; IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra (Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein); R973401 (phosphodiesterase Type IV inhibitor); MK-966 (COX-2 Inhibitor); Iloprost, leflunomide (anti-inflammatory and cytokine inhibiton); tranexamic acid (inhibitor of plasminogen activation); T-614 (cytokine inhibitor); prostaglandin El; Tenidap (non-steroidal anti-inflammatory drug); Naproxen (nonsteroidal anti-inflammatory drug); Meloxicam (non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory drug); Diclofenac (non-steroidal anti-inflammatory drug); Indomethacin (non-steroidal antiinflammatory drug); Sulfasalazine; Azathioprine; ICE inhibitor (inhibitor of the enzyme interleukin-ΐβ converting enzyme); zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 or lck); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11; interleukin-13; interleukin-17 inhibitors; gold; penicillamine; chloroquine; chlorambucil; hydroxychloroquine; cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins; orally-administered peptides and collagen; lobenzarit disodium; Cytokine Regulating Agents (CRAB) HP228 and HP466 (Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP 10; T Cell Sciences, Inc.); prednisone; orgotein; glycosaminoglycan polysulphate; minocycline; anti-IL2R antibodies; marine and botanical lipids (fish and plant seed fatty acids); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid; intravenous immune globulin; zileuton; azaribine; mycophenolic acid (RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose (therafectin); cladribine (2-chlorodeoxyadenosine).
In one embodiment, 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.
In a specific embodiment, 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.
In one embodiment, 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.
In nonlimiting embodiments, 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);
Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab
(Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S);
Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);
Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals). Examples of additional types of therapeutic agents that can be used in combination with a complement pathway inhibitor include anti-inflammatory drugs, antimicrobial agents, anti- angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs and combinations thereof. Examples of 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, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, pegaptanib, platinum analogues, polymicin B, propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide, acetazol amide, pilocarpine, ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin, voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate, tacrolimus and combinations thereof.
In certain embodiments, 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- modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex), penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologic drugs including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroids including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), and triamcinolone (Aristocort); gold salts, including Auranofin (Ridaura); Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combination thereof.
In one embodiment, 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.
In additional embodiments, 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, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations thereof.
In one aspect, a complement pathway inhibitor may be provided in combination or alternation with an immunosuppressive agent or an anti-inflammatory agent.
In one embodiment of the present invention, 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, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx), ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen. Examples of anti-inflammatory agents 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, diclofenac, and any combination thereof. In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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. Further, 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 (PPARs) 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. General classes of pharmacological agents that stimulate peroxisomal activity are known as 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.
Formulations
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.
In certain embodiments 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. In one embodiment, 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. For example, 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. For ocular delivery, 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.
Pharmaceutical compositions, and methods of manufacturing such compositions, suitable for administration as contemplated herein are known in the art. Examples of 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. Examples of 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. Examples of 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. Optional 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.
In certain embodiments, 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); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60); polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerol ricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol; poly(ethylene glycol)5000- phosphatidylethanolamine; poly(ethylene glycol)400-monostearate; phospholipid; synthetic and/or natural detergent having high surfactant properties; deoxycholate; cyclodextrin; chaotropic salt; ion pairing agent; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuramic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxy ethyl starch, carageenan, glycon, amylose, chitosan, Ν,Ο- carboxylmethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g. poly(l,3-dioxan- 2one)), polyanhydride (e.g. poly(sebacic anhydride)), polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal, polyether, polyester (e.g., polylactide, polyglycolide, polylactide- co-glycolide, polycaprolactone, polyhydroxyacid (e.g. poly((P-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene, and polyamine, polylysine, polylysine- PEG copolymer, and poly(ethyleneimine), poly(ethylene imine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, Vitamin E TPGS (also known as d-a-Tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS).
In some embodiments, 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. In some embodiments, 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.
In an additional alternative embodiment, the complement inhibitor pharmaceutical composition is formulated as a particle. In one embodiment the particles are microparticles. In an alternative embodiment the particles are nanoparticles.
Common 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.
In one embodiment, the particles are derived through a solvent evaporation method. In this 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.
Pharmaceutical compositions which contain labile polymers, such as certain polyanhydrides, may degrade during the fabrication process due to the presence of water. For these polymers, 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. In this method, the compound (or polymer matrix and one or more compounds) is dispersed or dissolved in 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.
In one embodiment complement inhibitor is administered to a patient in need thereof as particles formed by solvent removal. In another embodiment the particles formed by solvent removal comprise a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by solvent removal comprise a complement inhibitor and an additional therapeutic agent. In a further embodiment the particles formed by solvent removal comprise a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by solvent removal can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by solvent removal are formulated into a tablet but the tablet is uncoated.
In one embodiment, the particles are derived by spray drying. In this method, a complement inhibitor (or polymer matrix and one or more compounds) is dissolved in 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.
In one embodiment a complement inhibitor is administered to a patient in need thereof as a spray dried dispersion (SDD). In another embodiment 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. In another embodiment the SDD comprises a complement inhibitor and an additional therapeutic agent. In a further embodiment the SDD comprises a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described spray dried dispersions can be coated to form a coated tablet. In an alternative embodiment 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. In this method, the complement inhibitor (or polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and 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.
In one embodiment, a complement inhibitor is administered to a patient in need thereof as particles formed by phase inversion. In another embodiment the present invention provides particles formed by phase inversion comprising a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by phase inversion comprise a complement inhibitor and an additional therapeutic agent. In a further embodiment the particles formed by phase inversion comprise a complement inhibitor, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by phase inversion are formulated into a tablet but the tablet is uncoated.
Techniques for particle formation using coacervation are known in the art, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S. Patent Nos. 3,266,987, 4,794,000, and 4,460,563. 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. Within the dense coacervate phase, 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).
In one embodiment a complement inhibitor is administered to a patient in need thereof as particles formed by coacervation. In another embodiment 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. In another embodiment the particles formed by coacervation comprise a compound of the present invention and an additional therapeutic agent. In a further embodiment the particles formed by coacervation comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by coacervation are formulated into a tablet but the tablet is uncoated.
Methods for very low temperature casting of controlled release microspheres are described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, the complement inhibitor is dissolved in a solvent. The mixture is then atomized into a vessel containing a liquid non-solvent at a temperature below the freezing point of the drug solution which freezes the compound droplets. As the droplets and non-solvent for the compound are warmed, the solvent in the droplets thaws and is extracted into the non-solvent, hardening the microspheres.
In one embodiment, a complement inhibitor for use in the present invention is administered to a patient in need thereof as particles formed by low temperature casting. In another embodiment, the present invention provides particles formed by low temperature casting comprising a complement inhibitor and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment the particles formed by low temperature casting comprise complement inhibitor and an additional therapeutic agent. In a further embodiment 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. In another embodiment any of the described particles formed by low temperature casting can be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment the particles formed by low temperature casting are formulated into a tablet but the tablet is uncoated.
In one aspect of the present invention, an effective amount of a complement inhibitor is incorporated into 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.
In addition, 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.
Methods for producing nanoparticles are known in the art. For example, see Muller, R.H., et al., Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art, Eur. H. Pharm. Biopharm., 50: 161-177, 2000; US 8,691,750 to Consien et al.; WO 2012/145801 to Kanwar. US 8,580,311 to Armes, S. et al.; Petros, R.A. and DeSimone, J.M., Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews/Drug Discovery, vol. 9:615- 627, 2010; US 8,465,775; US 8,444,899; US 8,420,124; US 8,263, 129; US 8,158,728; 8,268,446; Pellegrino et al., 2005, Small, 1 :48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13 :3843; all incorporated herein by reference. Additional methods have been described in the literature (see, e.g., Doubrow, Ed., "Microcapsules and Nanoparticles in Medicine and Pharmacy," CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5: 13; Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S. Pat. Nos. 5,578,325 and 6,007,845; P. Paolicelli et al., "Surface- modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" Nanomedicine. 5(6):843-853 (2010)), U.S. Pat. No. 5,543, 158 to Gref et al., or WO publication WO2009/051837 by Von Andrian et al. Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7;(PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93 :4897; Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc, 115: 11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc, 121 :5633; and Zhou et al., 1990, Macromolecules, 23 :3399). Examples of these polyesters 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. Soc, 121 :5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc, 121 :5633; U.S. Pat. No. 6, 123,727; U.S. Pat. No. 5,804,178; U.S. Pat. No. 5,770,417; U.S. Pat. No. 5,736,372; U.S. Pat. No. 5,716,404; U.S. Pat. No. 6,095,148; U.S. Pat. No. 5,837,752; U.S. Pat. No. 5,902,599; U.S. Pat. No. 5,696,175; U.S. Pat. No. 5,514,378; U.S. Pat. No. 5,512,600; U.S. Pat. No. 5,399,665; U.S. Pat. No. 5,019,379; U.S. Pat. No. 5,010,167; U.S. Pat. No. 4,806,621; U.S. Pat. No. 4,638,045; and U.S. Pat. No. 4,946,929; Wang et al., 2001, J. Am. Chem. Soc, 123 :9480; Lim et al., 2001, J. Am. Chem. Soc, 123 :2460; Langer, 2000, Acc. Chem. Res., 33 :94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press, 1980; Principles of Polymerization by Odian, John Wiley & Sons, Fourth Edition, 2004; Contemporary Polymer Chemistry by Allcock et al., Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S. Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete et al., "Synthesis and characterization of PLGA nanoparticles" J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis "Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery" Current Drug Delivery 1 :321-333 (2004); C. Reis et al., "Nanoencapsulation I. Methods for preparation of drug- loaded polymeric nanoparticles" Nanomedicine 2:8-21 (2006); P. Paolicelli et al., "Surface- modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" Nanomedicine. 5(6):843-853 (2010); U.S. Pat. No. 6,632,671 to Unger Oct. 14, 2003, all incorporated herein by reference.
In one embodiment, 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. In one embodiment, 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. In some embodiments, 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.
The pharmaceutical 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.
Pharmaceutical 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.
Pharmaceutical 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.
Pharmaceutical 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. In one embodiment, 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.
Pharmaceutical 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). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including 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.
Additional nonlimiting examples of 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 6,948,496 titled "Inhalers", US/2005/0152849 titled "Powders comprising anti- adherent materials for use in dry powder inhalers", US 6,582,678, US 8, 137,657, US/2003/0202944, and US/2010/0330188 titled "Carrier particles for use in dry powder inhalers", US 6,221,338 titled "Method of producing particles for use in dry powder inhalers", US 6,989, 155 titled "Powders", US/2007/0043030 titled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation", US 7,845,349 titled "Inhaler", US/2012/0114709 and US 8, 101,160 titled "Formulations for Use in Inhaler Devices", US/2013/0287854 titled "Compositions and Uses", US/2014/0037737 and US 8,580,306 titled "Particles for Use in a Pharmaceutical Composition", US/2015/0174343 titled "Mixing Channel for an Inhalation Device", US 7,744,855 and US/2010/0285142 titled "Method of making particles for use in a pharmaceutical composition", US 7,541,022, US/2009/0269412, and US/2015/0050350 titled "Pharmaceutical formulations for dry powder inhalers" (Vectura Limited). Many methods and devices for drug delivery to the eye are known in the art. Nonlimiting examples are described in the following patents and patent applications (fully incorporated herein by reference). Examples are US 8,192,408 titled "Ocular trocar assembly" (Psivida Us, Inc.); US 7,585,517 titled "Transcleral delivery" (Macusight, Inc.); US 5,710,182 and US 5,795,913 titled "Ophthalmic composition" (Santen OY); US 8,663,639 titled "Formulations for treating ocular diseases and conditions", US 8,486,960 titled "Formulations and methods for vascular permeability-related diseases or conditions", US 8,367,097 and US 8,927,005 titled "Liquid formulations for treatment of diseases or conditions", US 7,455,855 titled "Delivering substance and drug delivery system using the same" (Santen Pharmaceutical Co., Ltd.); WO/2011/050365 titled "Conformable Therapeutic Shield For Vision and Pain" and WO/2009/145842 titled "Therapeutic Device for Pain Management and Vision" (Forsight Labs, LLC); US 9,066,779 and US 8,623,395 titled "Implantable therapeutic device", WO/2014/160884 titled "Ophthalmic Implant for Delivering Therapeutic Substances", US 8,399,006, US 8,277,830, US 8,795,712, US 8,808,727, US 8,298,578, and WO/2010/088548 titled "Posterior segment drug delivery", WO/2014/152959 and US20140276482 titled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant", US 8,905,963 and US 9,033,911 titled "Injector apparatus and method for drug delivery", WO/2015/057554 titled "Formulations and Methods for Increasing or Reducing Mucus", US 8,715,712 and US 8,939,948 titled "Ocular insert apparatus and methods", WO/2013/116061 titled "Insertion and Removal Methods and Apparatus for Therapeutic Devices", WO/2014/066775 titled "Ophthalmic System for Sustained Release of Drug to the Eye", WO/2015/085234 and WO/2012/019176 titled "Implantable Therapeutic Device", WO/2012/065006 titled "Methods and Apparatus to determine Porous Structures for Drug Delivery", WO/2010/141729 titled "Anterior Segment Drug Delivery", WO/2011/050327 titled "Corneal Denervation for Treatment of Ocular Pain", WO/2013/022801 titled "Small Molecule Delivery with Implantable Therapeutic Device", WO/2012/019047 titled "Subconjunctival Implant for Posterior Segment Drug Delivery", WO/2012/068549 titled "Therapeutic Agent Formulations for Implanted Devices", WO/2012/019139 titled " Combined Delivery Methods and Apparatus", WO/2013/040426 titled "Ocular Insert Apparatus and Methods", WO/2012/019136 titled "Injector Apparatus and Method for Drug Delivery", WO/2013/040247 titled "Fluid Exchange Apparatus and Methods" (ForSight Vision4, Inc.). Additional nonlimiting examples of how to deliver the active compounds are provided in WO/2015/085251 titled "Intracameral Implant for Treatment of an Ocular Condition" (Envisia Therapeutics, Inc.); WO/2011/008737 titled "Engineered Aerosol Particles, and Associated Methods", WO/2013/082111 titled "Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses", WO/2009/132265 titled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates", WO/2010/099321 titled "Interventional drug delivery system and associated methods", WO/2008/100304 titled "Polymer particle composite having high fidelity order, size, and shape particles", WO/2007/024323 titled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO/2010/009087 titled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye", (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO/2009/132206 titled "Compositions and Methods for Intracellular Delivery and Release of Cargo", WO/2007/133808 titled "Nano-particles for cosmetic applications", WO/2007/056561 titled "Medical device, materials, and methods", WO/2010/065748 titled "Method for producing patterned materials", WO/2007/081876 titled "Nanostructured surfaces for biomedical/biomaterial applications and processes thereof (Liquidia Technologies, Inc.).
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", WO2012/039979 and US2013/0183244 titled "Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain", WO2012/109363 and US2013/0323313 titled "Mucus Penetrating Gene Carriers", WO 2013/090804 and US2014/0329913 titled "Nanoparticles with enhanced mucosal penetration or decreased inflammation", WO2013/110028 titled "Nanoparticle formulations with enhanced mucosal penetration", WO2013/166498 and US2015/0086484 titled "Lipid-based drug carriers for rapid penetration through mucus linings" (The Johns Hopkins University); WO2013/166385 titled "Pharmaceutical Nanoparticles Showing Improved Mucosal Transport", US2013/0323179 titled "Nanocrystals, Compositions, And Methods that Aid Particle Transport in Mucus" (The Johns Hopkins University and Kala Pharmaceuticals, Inc.); WO/2015/066444 titled "Compositions and methods for ophthalmic and/or other applications", WO/2014/020210 and WO/2013/166408 titled "Pharmaceutical nanoparticles showing improved mucosal transport" (Kala Pharmaceuticals, Inc.); US 9,022,970 titled "Ophthalmic injection device including dosage control device", WO/2011/153349 titled "Ophthalmic compositions comprising pbo-peo-pbo block copolymers", WO/2011/140203 titled "Stabilized ophthalmic galactomannan formulations", WO/201 1/068955 titled "Ophthalmic emulsion" , WO/201 1/037908 titled "Injectable aqueous ophthalmic composition and method of use therefor", US2007/0149593 titled "Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye", US 8,632,809 titled "Water insoluble polymer matrix for drug delivery" (Alcon, Inc.);
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 titled "Microsphere Drug Delivery System for Sustained Intraocular Release", US 8,911,768 titled "Methods For Treating Retinopathy With Extended Therapeutic Effect" (Allergan, Inc.); US 6,495, 164 titled "Preparation of inj ectable suspensions having improved inj ectability" (Alkermes Controlled Therapeutics, Inc.); WO 2014/047439 titled "Biodegradable Microcapsules Containing Filling Material" (Akina, Inc.); WO 2010/132664 titled "Compositions And Methods For Drug Delivery" (Baxter International Inc. Baxter Healthcare SA); US20120052041 titled "Polymeric nanoparticles with enhanced drugloading and methods of use thereof (The Brigham and Women's Hospital, Inc.); US20140178475, US20140248358, and US20140249158 titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same" (BIND Therapeutics, Inc.); US 5,869, 103 titled "Polymer microparticles for drug delivery" (Danbiosyst UK Ltd.); US 8628801 titled "Pegylated Nanoparticles" (Universidad de Navarra); US2014/0107025 titled "Ocular drug delivery system" (Jade Therapeutics, LLC); US 6,287,588 titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof, US 6,589,549 titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles" (Macromed, Inc.); US 6,007,845 and US 5,578,325 titled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers" (Massachusetts Institute of Technology); US20040234611, US20080305172, US20120269894, and US20130122064 titled "Ophthalmic depot formulations for periocular or subconjunctival administration (Novartis Ag); US 6,413,539 titled "Block polymer" (Poly-Med, Inc.); US 20070071756 titled "Delivery of an agent to ameliorate inflammation" (Peyman); US 20080166411 titled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles" (Pfizer, Inc.); US 6,706,289 titled "Methods and compositions for enhanced delivery of bioactive molecules" (PR Pharmaceuticals, Inc.); and US 8,663,674 titled "Microparticle containing matrices for drug delivery" (Surmodics).
This specification has been described with reference to embodiments of the invention. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

Claims

We claim:
1) A method of treating a patient suffering from a systemic inflammatory reaction induced by the administration of an adoptive T-cell therapeutic agent comprising administering to the patient a therapeutically effective amount of a complement inhibitor.
2) The method of claim 1, wherein the systemic inflammatory reaction is cytokine release syndrome.
3) The method of claim 1, wherein the systemic inflammatory reaction is tumor lysis syndrome.
4) The method of any of claims 1-3, wherein the adoptive T-cell therapeutic agent is a T-cell comprising a chimeric antigen receptor.
5) The method of any of claims 1-3, wherein the adoptive T-cell therapeutic agent is a T-cell comprising a genetically redirected T-cell receptor.
6) The method of any of claims 1-5, wherein the complement inhibitor is a classical complement pathway inhibitor.
7) The method of any of claims 1-5, wherein the complement inhibitor is an alternative complement pathway inhibitor.
8) The method of any of claims 1-5, wherein the complement inhibitor is a mannan-binding (MB)-lectin complement pathway inhibitor.
9) The method of claim 7, wherein the complement inhibitor targets Factor B, Factor D, Factor H, or C3 convertase.
10) The method of claim 6, wherein the complement pathway inhibitor targets CI, Clr, Cls, or Clq.
11) The method of claim 6, wherein the complement pathway inhibitor targets C3, C3a, C3b, or iC3b.
12) The method of claim 6, wherein the complement pathway inhibitor targets C5, C5a, or C5b.
13) The method of claim 10, wherein the complement pathway inhibitor is selected from a CI esterase inhibitor, a Cls monoclonal antibody, or conestat alfa.
14) The method of claim 11, wherein the complement pathway inhibitor is selected from the monoclonal antibody HI 7, compstatin 4, compstatin Cp40, PEG-Cp40, or Staphylococcal complement inhibitor (SCIN). 15) The method of claim 12, wherein the complement pathway inhibitor is selected from eculizumab (Soliris), pexelizumab, monoclonal antibody LFG316, monoclonal antibody mubodina, ergidina, coversin, aurin tricarboxylix acid (ATA), aptamer ARC 1005, ARC 1905, a slow off rate modified aptamer, affibody SOBI002, cyclomimetic macrocyclic peptide RA101348, anti-C5 siRNA,aptamer ARC 1905, or PMX 53.
16) The method of claim 7, wherein the complement pathway inhibitor is selected from complement Factor H-mimetic protein TT30, CFH-mimetic protein Mini-CFH, CFH- mimetic protein CRIg/CFH, Factor B monoclonal antibody TA106, anti-complement Factor B siRNA, slow off rate aptamer directed to complement Factor B, or slow off rate aptamer directed to complement Factor D.
17) The method of any of claims 1-16, wherein the patient is further administered an antiinflammatory agent, an immunosuppressive agent, or an anti-cytokine agent.
18) The method of claim 17, wherein the agent is a corticosteroid.
19) The method of claim 17, wherein the agent is etanercept.
20) The method of claim 17, wherein the agent is tocilizumab.
21) A method of reducing a systemic inflammatory reaction in a patient receiving adoptive T- cell therapy comprising administering to the patient a therapeutically effective amount of a complement inhibitor prior to administration of an adoptive T-cell therapeutic agent.
22) The method of claim 21, wherein the systemic inflammatory reaction is cytokine release syndrome.
23) The method of claim 21, wherein the systemic inflammatory reaction is tumor lysis syndrome.
24) The method of any of claims 21-23, wherein the adoptive T-cell therapeutic agent is a T- cell comprising a chimeric antigen receptor.
25) The method of any of claims 21-23, wherein the adoptive T-cell therapeutic agent is a T- cell comprising a genetically redirected T-cell receptor.
26) The method of any of claims 21-25, wherein the complement inhibitor is a classical complement pathway inhibitor.
27) The method of any of claims 21-25, wherein the complement inhibitor is an alternative complement pathway inhibitor. 28) The method of any of claims 21-25, wherein the complement inhibitor is a mannan-binding (MB)-lectin complement pathway inhibitor.
29) The method of claim 27, wherein the complement inhibitor targets Factor B, Factor D, Factor H, or C3 convertase.
30) The method of claim 26, wherein the complement pathway inhibitor targets CI, CI r, CI s, or Clq.
31) The method of claim 26, wherein the complement pathway inhibitor targets C3, C3a, C3b, or iC3b.
32) The method of claim 26, wherein the complement pathway inhibitor targets C5, C5a, or C5b.
33) The method of claim 30, wherein the complement pathway inhibitor is selected from a CI esterase inhibitor, a Cls monoclonal antibody, or conestat alfa.
34) The method of claim 31, wherein the complement pathway inhibitor is selected from the monoclonal antibody HI 7, compstatin 4, compstatin Cp40, PEG-Cp40, or Staphylococcal complement inhibitor (SCIN).
35) The method of claim 32, wherein the complement pathway inhibitor is selected from
eculizumab (Soliris), pexelizumab, monoclonal antibody LFG316, monoclonal antibody mubodina, ergidina, coversin, aurin tricarboxylix acid (ATA), aptamer ARC 1005, ARC 1905, a slow off rate modified aptamer, affibody SOBI002, cyclomimetic macrocyclic peptide RA101348, anti-C5 siRNA,aptamer ARC 1905, or PMX 53.
36) The method of claim 27, wherein the complement pathway inhibitor is selected from complement Factor H-mimetic protein TT30, CFH-mimetic protein Mini-CFH, CFH- mimetic protein CRIg/CFH, Factor B monoclonal antibody TA106, anti-complement Factor B siRNA, slow off rate aptamer directed to complement Factor B, or slow off rate aptamer directed to complement Factor D.
37) The method of any of claims 21-36, wherein the patient is further administered an antiinflammatory agent, an immunosuppressive agent, or an anti-cytokine agent.
38) The method of claim 37, wherein the agent is a corticosteroid.
39) The method of claim 37, wherein the agent is etanercept.
40) The method of claim 37, wherein the agent is tocilizumab. 41) Use of a complement inhibitor in the manufacture of a medicament for the treatment of a systemic inflammatory reaction in a patient receiving adoptive T-cell therapy.
42) The use of claim 41, wherein the systemic inflammatory reaction is cytokine release syndrome.
43) The use of claim 42, wherein the systemic inflammatory reaction is tumor lysis syndrome.
44) The use of any of claims 41-43, wherein the adoptive T-cell therapeutic agent is a T-cell comprising a chimeric antigen receptor.
45) The use of any of claims 41-43, wherein the adoptive T-cell therapeutic agent is a T-cell comprising a genetically redirected T-cell receptor.
46) The use of any of claims 41-45, wherein the complement inhibitor is a classical complement pathway inhibitor.
47) The use of any of claims 41-45, wherein the complement inhibitor is an alternative complement pathway inhibitor.
48) The use of any of claims 41-45, wherein the complement inhibitor is a mannan-binding (MB)-lectin complement pathway inhibitor.
49) The use of claim 47, wherein the complement inhibitor targets Factor B, Factor D, Factor H, or C3 convertase.
50) The use of claim 46, wherein the complement pathway inhibitor targets CI, Clr, Cls, or Clq.
51) The use of claim 46, wherein the complement pathway inhibitor targets C3, C3a, C3b, or iC3b.
52) The use of claim 46, wherein the complement pathway inhibitor targets C5, C5a, or C5b.
53) The use of claim 50, wherein the complement pathway inhibitor is selected from a CI esterase inhibitor, a Cls monoclonal antibody, or conestat alfa.
54) The use of claim 51, wherein the complement pathway inhibitor is selected from the monoclonal antibody HI 7, compstatin 4, compstatin Cp40, PEG-Cp40, or Staphylococcal complement inhibitor (SCIN).
55) The use of claim 52, wherein the complement pathway inhibitor is selected from
eculizumab (Soliris), pexelizumab, monoclonal antibody LFG316, monoclonal antibody mubodina, ergidina, coversin, aurin tricarboxylix acid (ATA), aptamer ARC1005, ARC 1905, a slow off rate modified aptamer, affibody SOBI002, cyclomimetic macrocyclic peptide RA101348, anti-C5 siRNA,aptamer ARC 1905, or PMX 53.
56) The use of claim 47, wherein the complement pathway inhibitor is selected from complement Factor H-mimetic protein TT30, CFH-mimetic protein Mini-CFH, CFH- mimetic protein CRIg/CFH, Factor B monoclonal antibody TA106, anti-complement
Factor B siRNA, slow off rate aptamer directed to complement Factor B, or slow off rate aptamer directed to complement Factor D.
57) The use of any of claims 41-56, wherein the patient is further administered an antiinflammatory agent, an immunosuppressive agent, or an anti-cytokine agent.
58) The use of claim 57, wherein the agent is a corticosteroid.
59) The use of claim 57, wherein the agent is etanercept.
60) The use of claim 57, wherein the agent is tocilizumab.
61) The use of any claims 39-58, wherein the patient is a human.
PCT/US2016/048710 2015-08-26 2016-08-25 Use of complement pathway inhibitor compounds to mitigate adoptive t-cell therapy associated adverse immune responses WO2017035362A1 (en)

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017165571A1 (en) * 2016-03-22 2017-09-28 Seattle Children's Hospital (dba Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US9796741B2 (en) 2014-02-25 2017-10-24 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10000516B2 (en) 2015-08-26 2018-06-19 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of medical disorders
US10011612B2 (en) 2015-08-26 2018-07-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10092584B2 (en) 2015-08-26 2018-10-09 Achillion Pharmaceuticals, Inc. Compounds for the treatment of medical disorders
US10138225B2 (en) 2015-08-26 2018-11-27 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of medical disorders
US10385097B2 (en) 2015-08-26 2019-08-20 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of medical disorders
WO2020041301A1 (en) 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement factor d medical disorders
US10633434B2 (en) 2016-06-14 2020-04-28 Regeneron Pharmaceuticals, Inc. Anti-C5 antibodies
US10660876B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of medical disorders
US10662175B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10807952B2 (en) 2015-08-26 2020-10-20 Achillion Pharmaceuticals, Inc. Compounds for treatment of immune inflammatory disorders
US10906887B2 (en) 2015-08-26 2021-02-02 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US10919884B2 (en) 2015-08-26 2021-02-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US11001600B2 (en) 2015-08-26 2021-05-11 Achillion Pharmaceuticals, Inc. Disubstituted compounds for treatment of medical disorders
EP3682016A4 (en) * 2017-09-11 2021-06-02 RA Pharmaceuticals, Inc. Formulations for compound delivery
US11053253B2 (en) 2017-03-01 2021-07-06 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
US11084800B2 (en) 2017-03-01 2021-08-10 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
WO2021207305A1 (en) * 2020-04-08 2021-10-14 Nostrum Pharmaceuticals, Llc Compositions and methods using interferon for treating viral respiratory infections
US11365265B2 (en) 2017-12-13 2022-06-21 Regeneron Pharmaceuticals, Inc. Anti-C5 antibody combinations and uses thereof
WO2022134047A1 (en) * 2020-12-25 2022-06-30 The Trustees Of The University Of Pennsylvania Humanized anti-c5 antibodies and factor h fusion proteins and uses thereof
US11447465B2 (en) 2017-03-01 2022-09-20 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for treatment of medical disorders
US11535650B1 (en) 2014-06-12 2022-12-27 Ra Pharmaceuticals, Inc. Modulation of complement activity
US11707503B2 (en) 2015-01-28 2023-07-25 Ra Pharmaceuticals, Inc. Modulators of complement activity
US11723949B2 (en) 2016-12-07 2023-08-15 Ra Pharmaceuticals, Inc. Modulators of complement activity
US11752190B2 (en) 2015-12-16 2023-09-12 Ra Pharmaceuticals, Inc. Modulators of complement activity
US11759480B2 (en) 2017-02-28 2023-09-19 Endocyte, Inc. Compositions and methods for CAR T cell therapy
US11779602B2 (en) 2018-01-22 2023-10-10 Endocyte, Inc. Methods of use for CAR T cells
US11807627B2 (en) 2018-09-25 2023-11-07 Achillon Pharmaceuticals, Inc. Morphic forms of complement factor D inhibitors
US11814391B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for the treatment of medical disorders
US11814363B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Morphic forms of danicopan

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080075728A1 (en) * 2004-07-20 2008-03-27 Walter Newman Combination Therapies Of Hmgb And Complement Inhibitors Against Inflammation
US20080075720A1 (en) * 2004-02-10 2008-03-27 Holers Vernon M Inhibition of factor B, the alternative complement pathway and methods related thereto
WO2009091826A2 (en) * 2008-01-14 2009-07-23 The Board Of Regents Of The University Of Texas System Compositions and methods related to a human cd19-specific chimeric antigen receptor (h-car)
WO2014116880A1 (en) * 2013-01-23 2014-07-31 Baerbel Rohrer Targeting constructs based on natural antibodies and uses thereof
US20140371133A1 (en) * 2011-06-22 2014-12-18 Apellis Pharmaceuticals, Inc. Methods of treating chronic disorders with complement inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080075720A1 (en) * 2004-02-10 2008-03-27 Holers Vernon M Inhibition of factor B, the alternative complement pathway and methods related thereto
US20080075728A1 (en) * 2004-07-20 2008-03-27 Walter Newman Combination Therapies Of Hmgb And Complement Inhibitors Against Inflammation
WO2009091826A2 (en) * 2008-01-14 2009-07-23 The Board Of Regents Of The University Of Texas System Compositions and methods related to a human cd19-specific chimeric antigen receptor (h-car)
US20140371133A1 (en) * 2011-06-22 2014-12-18 Apellis Pharmaceuticals, Inc. Methods of treating chronic disorders with complement inhibitors
WO2014116880A1 (en) * 2013-01-23 2014-07-31 Baerbel Rohrer Targeting constructs based on natural antibodies and uses thereof

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10253053B2 (en) 2014-02-25 2019-04-09 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10189869B2 (en) 2014-02-25 2019-01-29 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
US9828396B2 (en) 2014-02-25 2017-11-28 Achillion Pharmaceuticals, Inc. Alkyne compounds for treatment of complement mediated disorders
US10370394B2 (en) 2014-02-25 2019-08-06 Achillion Pharmaceuticals, Inc. Carbamate, ester, and ketone compounds for treatment of complement mediated disorders
US10106563B2 (en) 2014-02-25 2018-10-23 Achillion Pharmaecuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10081645B2 (en) 2014-02-25 2018-09-25 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US9796741B2 (en) 2014-02-25 2017-10-24 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10301336B2 (en) 2014-02-25 2019-05-28 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
US10464956B2 (en) 2014-02-25 2019-11-05 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10689409B2 (en) 2014-02-25 2020-06-23 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
US10100072B2 (en) 2014-02-25 2018-10-16 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
US10550140B2 (en) 2014-02-25 2020-02-04 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10428094B2 (en) 2014-02-25 2019-10-01 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of complement mediated disorders
US11535650B1 (en) 2014-06-12 2022-12-27 Ra Pharmaceuticals, Inc. Modulation of complement activity
US11965040B2 (en) 2014-06-12 2024-04-23 Ra Pharmaceuticals, Inc. Modulation of complement activity
US11707503B2 (en) 2015-01-28 2023-07-25 Ra Pharmaceuticals, Inc. Modulators of complement activity
US10919884B2 (en) 2015-08-26 2021-02-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US11407738B2 (en) 2015-08-26 2022-08-09 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10287301B2 (en) 2015-08-26 2019-05-14 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10000516B2 (en) 2015-08-26 2018-06-19 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of medical disorders
US11926617B2 (en) 2015-08-26 2024-03-12 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10011612B2 (en) 2015-08-26 2018-07-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10660876B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of medical disorders
US10662175B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10138225B2 (en) 2015-08-26 2018-11-27 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of medical disorders
US10807952B2 (en) 2015-08-26 2020-10-20 Achillion Pharmaceuticals, Inc. Compounds for treatment of immune inflammatory disorders
US10822352B2 (en) 2015-08-26 2020-11-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10906887B2 (en) 2015-08-26 2021-02-02 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US11649223B2 (en) 2015-08-26 2023-05-16 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US11001600B2 (en) 2015-08-26 2021-05-11 Achillion Pharmaceuticals, Inc. Disubstituted compounds for treatment of medical disorders
US11649229B2 (en) 2015-08-26 2023-05-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US10092584B2 (en) 2015-08-26 2018-10-09 Achillion Pharmaceuticals, Inc. Compounds for the treatment of medical disorders
US10385097B2 (en) 2015-08-26 2019-08-20 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of medical disorders
US11752190B2 (en) 2015-12-16 2023-09-12 Ra Pharmaceuticals, Inc. Modulators of complement activity
US11518814B2 (en) 2016-03-22 2022-12-06 Seattle Children's Hospital Early intervention methods to prevent or ameliorate toxicity
CN109476743A (en) * 2016-03-22 2019-03-15 西雅图儿童医院(以西雅图儿童研究所名义营业) Prevention or the early intervention method for alleviating toxicity
EP4015536A1 (en) * 2016-03-22 2022-06-22 Seattle Children's Hospital (DBA Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US11760804B2 (en) 2016-03-22 2023-09-19 Seattle Children's Hospital Early intervention methods to prevent or ameliorate toxicity
WO2017165571A1 (en) * 2016-03-22 2017-09-28 Seattle Children's Hospital (dba Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US10633434B2 (en) 2016-06-14 2020-04-28 Regeneron Pharmaceuticals, Inc. Anti-C5 antibodies
US11479602B2 (en) 2016-06-14 2022-10-25 Regeneren Pharmaceuticals, Inc. Methods of treating C5-associated diseases comprising administering anti-C5 antibodies
US11492392B2 (en) 2016-06-14 2022-11-08 Regeneran Pharmaceuticals, Inc. Polynucleotides encoding anti-C5 antibodies
US11723949B2 (en) 2016-12-07 2023-08-15 Ra Pharmaceuticals, Inc. Modulators of complement activity
US11850262B2 (en) 2017-02-28 2023-12-26 Purdue Research Foundation Compositions and methods for CAR T cell therapy
US11759480B2 (en) 2017-02-28 2023-09-19 Endocyte, Inc. Compositions and methods for CAR T cell therapy
US11447465B2 (en) 2017-03-01 2022-09-20 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for treatment of medical disorders
US11708351B2 (en) 2017-03-01 2023-07-25 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US11718626B2 (en) 2017-03-01 2023-08-08 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
US11084800B2 (en) 2017-03-01 2021-08-10 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US11053253B2 (en) 2017-03-01 2021-07-06 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
EP3682016A4 (en) * 2017-09-11 2021-06-02 RA Pharmaceuticals, Inc. Formulations for compound delivery
US11365265B2 (en) 2017-12-13 2022-06-21 Regeneron Pharmaceuticals, Inc. Anti-C5 antibody combinations and uses thereof
US11779602B2 (en) 2018-01-22 2023-10-10 Endocyte, Inc. Methods of use for CAR T cells
WO2020041301A1 (en) 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement factor d medical disorders
US11814391B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for the treatment of medical disorders
US11814363B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Morphic forms of danicopan
US11807627B2 (en) 2018-09-25 2023-11-07 Achillon Pharmaceuticals, Inc. Morphic forms of complement factor D inhibitors
WO2021207305A1 (en) * 2020-04-08 2021-10-14 Nostrum Pharmaceuticals, Llc Compositions and methods using interferon for treating viral respiratory infections
WO2022134047A1 (en) * 2020-12-25 2022-06-30 The Trustees Of The University Of Pennsylvania Humanized anti-c5 antibodies and factor h fusion proteins and uses thereof

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