WO2022243846A1 - Combination therapies - Google Patents

Combination therapies Download PDF

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Publication number
WO2022243846A1
WO2022243846A1 PCT/IB2022/054546 IB2022054546W WO2022243846A1 WO 2022243846 A1 WO2022243846 A1 WO 2022243846A1 IB 2022054546 W IB2022054546 W IB 2022054546W WO 2022243846 A1 WO2022243846 A1 WO 2022243846A1
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inhibitor
cancer
mutations
seq
administered
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PCT/IB2022/054546
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French (fr)
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Glenn Dranoff
Wolfgang Hackl
Javier Alberto OTERO
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Novartis Ag
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom

Definitions

  • HIF2 ⁇ hypoxia-inducible factor-2 ⁇
  • the combination therapies can be used to treat or prevent cancerous conditions and disorders.
  • BACKGROUND Hypoxia-inducible factors (HIFs) such as HIF1 ⁇ and HIF2 ⁇ are transcription factors well known as master regulators of oxygen homeostasis that control transcriptional responses to reduced oxygen availability (hypoxia).
  • HIFs are heterodimeric proteins composed of an oxygen-regulated HIF- ⁇ subunit (HIF1 ⁇ and HIF2 ⁇ ) and a constitutively expressed HIF-1 ⁇ subunit also known as ARNT.
  • VHL von Hippel-Lindau
  • PHD prolyl hydroxylases
  • HIF1 ⁇ and HIF2 ⁇ regulate the expression of many genes involved in critical physiological functions such as development, metabolism, angiogenesis, cell proliferation and cell survival. While HIF1 ⁇ is broadly expressed, HIF2 ⁇ transcripts are restricted to particular cell types, including vascular endothelial cells, neural crest cell derivatives, lung type II pneumocytes, liver parenchyma, and interstitial cells in the kidney. HIF2 ⁇ is described as a key mediator of the cellular adaptation to oxygen deprivation (hypoxia), playing important roles in physiological processes, such as erythropoiesis and vascularization. HIF2 ⁇ is also required for normal embryonic development, with postnatal ablation leading to severe anemia and impaired erythroid development.
  • hypoxia and HIFs activation are reported in many advanced human cancers such as cancers of the brain, breast, colon, lung and renal cell carcinoma.
  • ccRCC clear cell renal cell carcinoma
  • HIF2 ⁇ is expressed in most ccRCC tumor samples, only a subset accumulates HIF1 ⁇ (Gordan et al., HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma, Cancer Cell, 9;14(6):435-46 (2008)).
  • HIF2 ⁇ is described to be the key oncogenic event while HIF1 ⁇ displays tumor suppressor properties (Shen et al., The VHL/HIF axis in clear cell renal carcinoma, Semin Cancer Biol., 23(1):18-25 (2013)).
  • overexpression of HIF2 ⁇ leads to an increase in the in vivo growth of the VHL-deficient 786-0 RCC tumor xenografts.
  • down regulation of HIF2 ⁇ by inducible shRNA or pharmacological inhibition seems sufficient to suppress tumor growth in VHL-defective RCC tumor models (Kondo, 2002; Kondo, 2003; Zimmer, 2004; Cho, 2016; Chen 2016).
  • HIF2 ⁇ selective inhibitors in ccRCC have further supported HIF2 ⁇ as an attractive target for anti- cancer therapy.
  • HIF2 ⁇ selective inhibitors also seem to show clinical benefit in ccRCC patients who had been administered with prior therapies, including TKIs (Courtney et. al., Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor- 2 ⁇ Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma, J Clin Oncol, 36 (9), 867-874 (2016)).
  • TKIs tyrosine kinase inhibitors
  • PT2977 also known as HIF2 ⁇ inhibitor MK-6482
  • the tumors demonstrated a reduction in the number of immunosuppressive myeloid-derived cells, in addition to an influx of mature dendritic cells (Wong et al., PT2977, a novel HIF-2a antagonist, has potent antitumor activity and remodels the immunosuppressive tumor microenvironment in clear cell renal cell cancer [abstract].
  • HIF1 ⁇ binds to the promotor region of CD73 (ecto-5’-nucleotidase) and increases CD73 enzyme levels, which in turn increases adenosine levels in the tumor microenvironment.
  • A2aR and A2bR are also direct transcriptional targets of HIF2 ⁇ and HIF1 ⁇ , respectively, that may increase the adenosine immunosuppressive pathway even further on these tumors (Lee at al., Hypoxia signaling in human diseases and therapeutic targets, Exp Mol Med; 51(6):1-13 (2019)).
  • Ciforadenant an A2aR antagonist
  • antitumor activity has demonstrated antitumor activity as single-agent and in combination with anti–PD-L1 therapy in patients with refractory RCC, in both the immunotherapy naive and pretreated settings (Lawrence et al., Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer, Cancer Discov, (10) (1) 40-53 (2020)).
  • this combined immunotherapy may not be sufficient if a tumor is protected by the HIFs–mediated immunosuppressive activity.
  • HIF2 ⁇ inhibitor may complement the antitumor effects of combined immunotherapy by preventing the HIF-driven accumulation of immunosuppressive extracellular adenosine and other immunosuppressive molecules in addition to the direct antitumoral activity of the HIF2 ⁇ inhibitor in ccRCC cells.
  • HIF2 ⁇ hypoxia-inducible factor-2 ⁇
  • the one or more therapeutic agents can be chosen from one or more of: an inhibitor of an inhibitory molecule (e.g., an inhibitor of a checkpoint inhibitor), an activator of a costimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein.
  • the pharmaceutical combination further comprises an inhibitor of humanized anti-programmed death-1 (PD-1) IG4 antibody and an adenosine receptor-2a (A2aR) antagonist.
  • PD-1 humanized anti-programmed death-1
  • A2aR adenosine receptor-2a
  • Pharmaceutical compositions and dose formulations relating to the combinations described herein are also provided. The combinations described herein can be used to treat or prevent disorders, such as cancerous disorders (e.g., solid cancers).
  • the disclosure features a method of treating cancer, e.g., renal cell carcinoma (RCC) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2 ⁇ inhibitor and one or more therapeutic agents.
  • CRC renal cell carcinoma
  • the disclosure features a method of treating a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2 ⁇ inhibitor and one or more therapeutic agents.
  • HIF stabilizing mutations e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes
  • the disclosure features a method of treating cancer, e.g., renal cell carcinoma (RCC) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2 ⁇ inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist.
  • RCC renal cell carcinoma
  • the disclosure features a method of treating a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes), in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2 ⁇ inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist.
  • HIF stabilizing mutations e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes
  • the HIF2 ⁇ inhibitor is the compound (S)-1'-chloro-8- (difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2- a]pyridine-2,5'-isoquinoline], or a pharmaceutically acceptable salt thereof, having the structure of formula (I), or Compound I, as originally described in PCT/CN2020/087831 under Example 31.
  • Compound I is administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg every week.
  • Compound I is administered at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg once daily. In some embodiments, Compound I is administered at a dose of about 50 mg to about 600 mg. In some embodiments, Compound I is administered at a dose of about 400 mg. In some embodiments, Compound I is administered once every four weeks. In some embodiments, Compound I is administered at a dose of about 50 mg every week. In some embodiments, Compound I is administered at a dose of about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 100 mg every day. In some embodiments, Compound I is administered orally.
  • the HIF2 ⁇ inhibitor is the fumarate salt of Compound I.
  • the PD-1 inhibitor comprises spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224.
  • the PD-1 inhibitor comprises spartalizumab.
  • the PD-1 inhibitor comprises tislelizumab.
  • the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg every three or four weeks.
  • the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD- 1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg every three weeks. In some embodiments, the PD- 1 inhibitor is administered at a dose of about 300 mg every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg every four weeks.
  • the PD-1 inhibitor is administered at a dose of about 400 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered intravenously. In some embodiments, the PD-1 inhibitor is administered over a period of about 20 to about 40 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes.
  • the A2aR antagonist comprises istradefylline, tozadenant, preladenant, vipadenan, taminadenant (PBF-509), ATL-444, MSX-3, SCH-58261, SCH- 412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, ZM-241,385, or MEDI9447.
  • the A2aR antagonist is taminadenant.
  • the A2aR antagonist is administered at a dose of about 80 mg, about 160 mg, or about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 80 mg twice daily.
  • the A2aR antagonist is administered at a dose about 160 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered orally. In some embodiments, the HIF2 ⁇ inhibitor is administered on the same day as the A2aR antagonist. In some embodiments, the HIF2 ⁇ inhibitor is administered before the A2aR antagonist. In some embodiments, the HIF2 ⁇ inhibitor is administered after the A2aR antagonist. In some embodiments, the HIF2 ⁇ inhibitor is administered at the same time as the A2aR antagonist. In some embodiments, the PD-1 inhibitor is administered on the same day as the HIF2 ⁇ inhibitor is administered on the same day as the A2aR antagonist.
  • the PD-1 inhibitor is administered after the HIF2 ⁇ inhibitor and the A2aR antagonist are administered.
  • the methods described can be used to treat proliferative disease.
  • the proliferative disease is a cancer (e.g., a solid tumor).
  • the cancer is adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
  • the cancer is renal cell carcinoma, more particularly, clear cell renal cell carcinoma (ccRCC).
  • the cancer is glioblastoma.
  • the cancer is breast cancer.
  • the cancer is colorectal cancer.
  • the proliferative disease is a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes).
  • the proliferative disease is a malignancy with VHL mutations (e.g. Von Hippel-Lindau disease).
  • the proliferative disease is a malignancy with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma).
  • FH mutations e.g. Hereditary leiomyomatosis and renal cell carcinoma.
  • the proliferative disease is a malignancy with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome).
  • the proliferative disease is a malignancy with EPAS1/HIF2A mutations
  • the proliferative disease is a malignancy with ELOC/TCEB1 mutations.
  • the disclosure features a composition (e.g., one or more compositions or dosage forms), that includes a HIF2 ⁇ inhibitor and one or more anticancer therapies, as described herein.
  • the composition includes a HIF2 ⁇ inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist.
  • Formulations, e.g., dosage formulations, and kits, e.g., therapeutic kits, that include a HIF2 ⁇ inhibitor, are also described herein.
  • the kit includes a HIF2 ⁇ inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist.
  • the composition or kit is used to treat renal cell carcinoma (RCC).
  • RRCC renal cell carcinoma
  • the composition or kit is used to treat a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes).
  • HIF stabilizing mutations e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes.
  • Fig.2 shows anti-tumor activity of Compound I (CPD I) in female nude mice bearing HKIX2207 human primary ccRCC xenografts.
  • Fig.3 shows anti-tumor activity of Compound I (CPD I) in female nude mice bearing HKIX2967 human primary ccRCC xenografts.
  • Fig.4 shows the study design of the Phase I/Ib, open-label, multi-center study of Compound I (CPD I) as a single agent and in combination with Everolimus or IO agents in patients with advanced, relapsed ccRCC and other malignancies with HIF2 ⁇ stabilizing mutations.
  • agents that can be used in combination with a HIF2 ⁇ inhibitor can be, but are not limited to, an inhibitor of an inhibitory molecule (e.g., a checkpoint inhibitor), an activator of a costimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein.
  • a HIF2 ⁇ inhibitor described herein is used in combination with one or more therapeutic agents chosen from: a PD-1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2aR antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist, for treating a patient with cancer.
  • the HIF2 ⁇ inhibitor described herein is used in combination with a PD-1 inhibitor and an A2aR antagonist, for treating a patient with cancer.
  • subject or “patient” as used herein includes animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer.
  • an “effective amount” or “therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure in combination with the second therapeutic agent that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the terms “pharmaceutical formulation” or “pharmaceutical composition” refers to a composition comprising one or more pharmaceutically active ingredients.
  • a pharmaceutical formulation comprises (a) a HIF-2a inhibitor of the present disclosure and (b) one or more additional therapeutic agents, preferably also including at least one pharmaceutically acceptable excipient or carrier, and more preferably where the pharmaceutically acceptable excipient or carrier does not react with the pharmaceutically active ingredients.
  • Carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • a patient is “in need of” a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).
  • the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating”, or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
  • the terms “treat”, “treatment” and “treating” -refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
  • “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. “Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. “Administer”, “administering”, or “administration” means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound, formulation, or combination comprising a compound or formulation to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • HIF-2a inhibitor of the present disclosure refers to the HIF2 ⁇ inhibitor is the compound (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro- 3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline], or a pharmaceutically acceptable salt thereof, having the structure of formula , or Compound I, as originally described in PCT/CN2020/087831 under Example 31.
  • composition therapy refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer).
  • administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
  • administration encompasses co- administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.
  • the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the combination therapy can provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • alternation therapy a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median- effect equation (Chou, T. C. and Talalay, P., Adv.
  • Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • pharmaceutical combination refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g.
  • fixed combination and “fixed dose” and “single formulation” as used herein refer to single carrier or vehicle or dosage forms formulated to deliver an amount, which is jointly therapeutically effective for the treatment of cancer, of two or more therapeutic agents to a patient.
  • the single vehicle is designed to deliver an amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • non-fixed combination means that the active ingredients, e.g., the HIF-2a inhibitor of the present disclosure and second agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the warm- blooded animal in need thereof.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • unit dose is used herein to mean simultaneous administration of two or three agents together, in one dosage form, to the patient being treated. In some embodiments, the unit dose is a single formulation.
  • the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients.
  • the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, or the like, administered to the patient at the same time.
  • An “oral dosage form” includes a unit dosage form prescribed or intended for oral administration.
  • the terms “comprising” and “including” is used herein in their open-ended and non- limiting sense unless otherwise noted. “Cancer” means any cancer caused by the uncontrolled proliferation of aberrant cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like.
  • cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
  • cancers include, but are not limited to, mesothelioma, leukemias, and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin’s lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia
  • myelodisplastic syndrome childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms’ tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, and nasopharyngeal), esophageal cancer, genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer, pancreatic cancer, melanoma, and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin’s syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer
  • Additional exemplary forms of cancer which may be treated by the compounds and compositions described herein include, but are not limited to, adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
  • ccRCC clear cell renal cell carcinoma
  • GBM glioblastoma multiforme
  • glioma glioma
  • head and neck cancer hepatocellular carcinoma
  • kidney cancer lung cancer
  • malignant glioma ocular cancer
  • pancreatic cancer paraganglioma
  • pheochromocytoma prostate cancer
  • renal cell carcinoma e.g., both terms encompass solid and liquid,
  • cancer or “tumor” includes premalignant, as well as malignant cancers and tumors.
  • second agent “one or more second agents,” or “one or more additional therapeutic agents” can be an anti-cancer agent.
  • anti-cancer or “anti-cancer agent” pertains to an agent which treats a cancer (i.e., a compound, antibody, etc. which is useful in the treatment of a cancer).
  • the anti-cancer effect may arise through one or more mechanisms, including, but not limited to, the regulation of cell growth or proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cells into neighboring normal structures), the inhibition of a checkpoint molecule, or the promotion of apoptosis.
  • the anti-cancer agent is can be an anti-proliferative agent or an immunomodulatory agent.
  • the second agent is an immunomodulatory agent.
  • the term “antiproliferative” or “antiproliferative agent” as used herein pertains to an agent, which inhibits cell growth or cell proliferation.
  • the anti-proliferative agent can be a cytotoxic agent (e.g., alkylating agent, antimetabolites, etc.), a targeted agent (e.g., EGF inhibitor, Tyrosine protein kinase inhibitor, angiogenesis inhibitor, etc.), or a hormonal agent (e.g., estrogens selective estrogen receptor modulators, etc.).
  • cytotoxic agent e.g., alkylating agent, antimetabolites, etc.
  • a targeted agent e.g., EGF inhibitor, Tyrosine protein kinase inhibitor, angiogenesis inhibitor, etc.
  • a hormonal agent e.g., estrogens selective estrogen receptor modulators, etc.
  • antiproliferative agents include alkylating agents, anti-metabolites, an antibiotic, a detoxifying agent, an EGFR inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a multi-kinase inhibitor, a serine/threonine inhibitor, a tyrosine kinase inhibitor, a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, an inhibitor of a molecular target or enzyme.
  • immunomodulatory agent is agent that modifies the immune response or the functioning of the immune system (as by the stimulation of antibody formation or the inhibition of white blood cell activity).
  • the immunomodulatory agents can be an immunomodulator, a cytokine, a vaccine, or an anti-body.
  • immunomodulator is an inhibitor of an immune checkpoint molecule.
  • Simultaneously or “simultaneous” when referring to a method of treating or a therapeutic use means with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time.
  • “Separately” or “separate” when referring to a method of treating or a therapeutic use means with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.
  • therapeutic administration “over a period of time” means, when referring to a method of treating or a therapeutic use with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times.
  • the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins.
  • Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, the HIF-2a inhibitor of the present disclosure and the one or more second agents the therapeutic administration over a period of time could be such that the HIF-2a inhibitor of the present disclosure is administered once every day or once a week and the one or more second agent(s) is administered once every four weeks.)
  • the additional therapeutic agent is administered at a therapeutic or lower-than therapeutic dose.
  • the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition is lower when the second therapeutic agent is administered in combination with the first therapeutic agent, e.g., HIF2 ⁇ inhibitor, than when the second therapeutic agent is administered individually. In certain embodiments, the concentration of the first therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower when the first therapeutic agent is administered in combination with the second therapeutic agent than when the first therapeutic agent is administered individually.
  • the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition is lower than the therapeutic dose of the second therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80- 90% lower.
  • the concentration of the first therapeutic agent that is required to achieve inhibition, e.g., growth inhibition is lower than the therapeutic dose of the first therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.
  • inhibitor includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor.
  • a certain parameter e.g., an activity, of a given molecule
  • an immune checkpoint inhibitor e.g., an enzyme that catalyzes the production of a protein
  • inhibition of an activity e.g., a PD-1 or PD-L1 activity
  • inhibition e.g., a PD-1 or PD-L1 activity
  • activation includes an increase in a certain parameter, e.g., an activity, of a given molecule, e.g., a costimulatory molecule.
  • an activity e.g., a costimulatory activity
  • increase of an activity e.g., a costimulatory activity
  • a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in life expectancy, decrease in cancer cell proliferation, decrease in cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous condition.
  • An “anti-cancer effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies in prevention of the occurrence of cancer in the first place.
  • anti-tumor effect refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival.
  • antigen presenting cell or “APC” refers to an immune system cell such as an accessory cell (e.g., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC’s) on its surface.
  • MHC major histocompatibility complexes
  • T-cells may recognize these complexes using their T-cell receptors (TCRs).
  • APCs process antigens and present them to T-cells.
  • costimulatory molecule refers to the cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation.
  • Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response.
  • Costimulatory molecules include, but are not limited to, an MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signalling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, I
  • Immuno effector cell refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response.
  • immune effector cells include T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes.
  • T cells e.g., alpha/beta T cells and gamma/delta T cells
  • B cells natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes.
  • NK natural killer
  • NKT natural killer T
  • an immune effector function or response refers a property of a T or NK cell that promotes killing or the inhibition of growth or proliferation, of a target cell.
  • primary stimulation and co-stimulation are examples of immune effector function or response.
  • effector function refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.
  • the compositions, formulations, and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 85%, 90%, 95% identical or higher to the sequence specified.
  • amino acid sequence in the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity.
  • amino acid sequences that contain a common structural domain having at least about 85%, 90%.91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.
  • nucleotide sequence in the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity.
  • the term “functional variant” refers to polypeptides that have a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally-occurring sequence. Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
  • the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence.
  • the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.
  • a particularly preferred set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W.
  • nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases, for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10.
  • Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25:3389-3402.
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions describes conditions for hybridization and washing.
  • Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used.
  • Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at about 45 o C, followed by two washes in 0.2X SSC, 0.1% SDS at least at 50 o C (the temperature of the washes can be increased to 55 o C for low stringency conditions); 2) medium stringency hybridization conditions in 6X SSC at about 45 o C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60 o C; 3) high stringency hybridization conditions in 6X SSC at about 45 o C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65 o C; and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65 o C, followed by one or more washes at 0.2X SSC, 1% SDS at 65 o C.
  • amino acid is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids.
  • exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing.
  • amino acid includes both the D- or L- optical isomers and peptidomimetics.
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • polypeptide “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
  • the polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.
  • nucleic acid refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • the polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
  • the sequence of nucleotides may be interrupted by non-nucleotide components.
  • a polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • the nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a nonnatural arrangement.
  • isolated refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring).
  • a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated.
  • Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature.
  • the HIF-2a inhibitor of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. For example, synergistic effects can occur with other cancer agents.
  • therapeutic agents pharmaceutical combinations
  • modalities e.g., non-drug therapies.
  • synergistic effects can occur with other cancer agents.
  • dosages of the co-administered HIF-2a inhibitor will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • the HIF-2a inhibitor can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • a therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.
  • the HIF-2a inhibitor of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.
  • the HIF-2a inhibitor of the present disclosure are administered in combination with one or more second agent(s) selected from a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2aR antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, a CTLA-4 inhibitor, a TIGIT inhibitor, a chimeric antigen receptor, an estrogen receptor antagonist, a CDK4/6 inhibitor, a CXCR2 inhibitor, a CSF- 1/1R binding agent, an IDO inhibitor, a Galectin inhibitor, a MEK inhibitor, a c-MET inhibitor, a TGF-b inhibitor, an IL-1b inhibitor, an MDM2 inhibitor, and a TLR7 agonist, to treat a disease, e.g., cancer.
  • a second agent(s) selected from a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2a
  • the HIF-2a inhibitor is used in combination with an agonist of a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
  • a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
  • the HIF-2a inhibitor is used in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF ⁇ .
  • an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF ⁇ .
  • one or more chemotherapeutic agents are used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer, wherein said chemotherapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl- 5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cyto
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more other anti-HER2 antibodies, e.g., trastuzumab, pertuzumab, margetuximab, or HT-19 described above, or with other anti-HER2 conjugates, e.g., ado- trastuzumab emtansine (also known as Kadcyla®, or T-DM1).
  • the HIF-2a inhibitors of the present disclosure is used in combination with one or more tyrosine kinase inhibitors, including but not limited to, EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors, for treating a disease, e.g., cancer.
  • tyrosine kinase inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro- 5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.6,780,996); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); Zactima (ZD6474); and Imatinib or
  • Epidermal growth factor receptor (EGFR) inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®), Gefitinib (Iressa®); N-[4-[(3-Chloro-4- fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]- 4(dimethylamino)-2-butenamide, Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5- yl)methyl)piperidin-3-ol (BMS690514); Canertinib dihydrochloride (CI-1033); 6-[4-[(4- Ethyl-1-pipe
  • EGFR antibodies include but are not limited to, Cetuximab (Erbitux®); Panitumumab (Vectibix®); Matuzumab (EMD-72000); Nimotuzumab (hR3); Zalutumumab; TheraCIM h- R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).
  • HER2 inhibitors include but are not limited to, Neratinib (HKI-272, (2E)-N-[4- [[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4- (dimethylamino)but-2-enamide, and described PCT Publication No.
  • HER3 inhibitors include but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.
  • MET inhibitors include but are not limited to, Cabozantinib (XL184, CAS 849217- 68-1); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4- yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); Cryzotinib (Xalkori®, PF-02341066); (3Z
  • IGFR inhibitors include but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. See e.g., Yee, JNCI, 104; 975 (2012) for review.
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more proliferation signalling pathway inhibitors, including but not limited to, MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors, and CDK inhibitors, for treating a disease, e.g., cancer.
  • one or more proliferation signalling pathway inhibitors including but not limited to, MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors, and CDK inhibitors, for treating a disease, e.g., cancer.
  • mitogen-activated protein kinase (MEK) inhibitors include but are not limited to, XL-518 (also known as GDC-0973, CAS No.1029872-29-4, available from ACC Corp.); 2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352 and described in PCT Publication No.
  • BRAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX- 4032, CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®).
  • Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(1H- Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4- yl]morpholine (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib; and described in PCT Publication Nos.
  • PI3K inhibitors include, but are not limited to, 4-[2-(1H- Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4- yl]morpholine (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib; and described in PCT Publication Nos.
  • mTOR inhibitors include but are not limited to, Temsirolimus (Torisel®); Ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30- dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4- azatricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2- methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No.
  • CDK inhibitors include but are not limited to, Palbociclib (also known as PD- 0332991, Ibrance®, 6-Acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(1-piperazinyl)-2- pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin-7(8H)-one).
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more pro-apoptotics, including but not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors, for treating a disease, e.g., cancer.
  • IAP inhibitors include but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711.
  • Other examples of IAP inhibitors include but are not limited to those disclosed in WO04/005284, WO 04/007529, WO05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US2006/0014700, US2006/0025347, WO 06/069063, WO 06/010118, WO 06/017295, and WO08/134679, all of which are incorporated herein by reference.
  • BCL-2 inhibitors include but are not limited to, 4-[4-[[2-(4-Chlorophenyl)-5,5- dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1- [(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No.
  • Proapoptotic receptor agonists including DR4 (TRAILR1) and DR5 (TRAILR2), including but are not limited to, Dulanermin (AMG-951, RhApo2L/TRAIL); Mapatumumab (HRS-ETR1, CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816- 02-6); Apomab (Apomab®); Conatumumab (AMG655, CAS 896731-82-1); and Tigatuzumab(CS1008, CAS 946415-34-5, available from Daiichi Sankyo).
  • PARAs Proapoptotic receptor agonists
  • Checkpoint Kinase (CHK) inhibitors include but are not limited to, 7- Hydroxystaurosporine (UCN-01); 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3- piperidinylpyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3- Fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)- 6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7- AAD), Isogranulatimide
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more immunomodulators (e.g., one or more of an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule), for treating a disease, e.g., cancer.
  • the immunomodulator is an activator of a costimulatory molecule.
  • the agonist of the costimulatory molecule is selected from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
  • an agonist e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion
  • a GITR agonist is used in combination with a HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the GITR agonist is GWN323 (Novartis), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen) or INBRX-110 (Inhibrx).
  • the GITR agonist is an anti-GITR antibody molecule.
  • the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846, published on April 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy,” incorporated by reference in its entirety.
  • the anti-GITR antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of MAB7 disclosed in Table 1), or encoded by a nucleotide sequence shown in Table 1.
  • CDRs complementarity determining regions
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 1). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 1). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
  • amino acid substitutions e.g., conservative amino acid substitutions
  • the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9a, a VHCDR2 amino acid sequence of SEQ ID NO: 11a, and a VHCDR3 amino acid sequence of SEQ ID NO: 13a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 14a, a VLCDR2 amino acid sequence of SEQ ID NO: 16a, and a VLCDR3 amino acid sequence of SEQ ID NO: 18a, each disclosed in Table 1.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 1a. In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 2a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 2a. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1a and a VL comprising the amino acid sequence of SEQ ID NO: 2a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 5a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 5a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 6a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 6a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 5a and a VL encoded by the nucleotide sequence of SEQ ID NO: 6a.
  • the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 3a. In one embodiment, the anti- GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 4a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 4a. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3a and a light chain comprising the amino acid sequence of SEQ ID NO: 4a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 7a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 8a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 8a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 8a.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in WO 2016/057846, incorporated by reference in its entirety.
  • Table 1 Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecule GT C A C C C T G C G A T G C G A G (CHOTHIA) Other Exemplary GITR Agonists
  • the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156.
  • BMS-986156 and other anti-GITR antibodies are disclosed, e.g., in US 9,228,016 and WO 2016/196792, incorporated by reference in their entirety.
  • the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986156, e.g., as disclosed in Table 2.
  • the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, e.g., in US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al. Cancer Res.2017; 77(5):1108-1118, incorporated by reference in their entirety.
  • the anti- GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MK-4166 or MK-1248.
  • the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, e.g., in US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al. (2010) Clinical Immunology; 135:S96, incorporated by reference in their entirety.
  • the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TRX518.
  • the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, e.g., in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety.
  • the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCAGN1876.
  • the anti-GITR antibody molecule is AMG 228 (Amgen).
  • AMG 228 and other anti-GITR antibodies are disclosed, e.g., in US 9,464,139 and WO 2015/031667, incorporated by reference in their entirety.
  • the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of AMG 228.
  • the anti-GITR antibody molecule is INBRX-110 (Inhibrx).
  • the GITR agonist comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INBRX-110.
  • the GITR agonist e.g., a fusion protein
  • MEDI 1873 MedImmune
  • MEDI 1873 and other GITR agonists are disclosed, e.g., in US 2017/0073386, WO 2017/025610, and Ross et al.
  • the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873.
  • GITRL glucocorticoid-induced TNF receptor ligand
  • Further known GITR agonists include those described, e.g., in WO 2016/054638, incorporated by reference in its entirety.
  • the anti-GITR antibody is an antibody that competes for binding with, and/or binds to the same epitope on GITR as, one of the anti-GITR antibodies described herein.
  • the GITR agonist is a peptide that activates the GITR signalling pathway.
  • the GITR agonist is an immunoadhesin binding fragment (e.g., an immunoadhesin binding fragment comprising an extracellular or GITR binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • Table 2 Amino acid sequence of other exemplary anti-GITR antibody molecules
  • the immunomodulator is an inhibitor of an immune checkpoint molecule.
  • the immunomodulator is an inhibitor of PD-1, PD- L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFRbeta.
  • the inhibitor of an immune checkpoint molecule inhibits PD- 1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.
  • the term “inhibition” or “inhibitor” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor.
  • inhibition of an activity e.g., a PD-1 or PD-L1 activity
  • inhibition need not be 100%.
  • Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level.
  • an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
  • the inhibitor of an inhibitory signal is a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as “an antibody molecule”) that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta, or a combination thereof.
  • a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as “an antibody molecule”) that binds to PD-1, PD
  • the antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)).
  • the antibody molecule has a heavy chain constant region (Fc) selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly, selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of IgG1 or IgG4 (e.g., human IgG1 or IgG4).
  • Fc heavy chain constant region
  • the heavy chain constant region is human IgG1 or human IgG4.
  • the constant region is altered, e.g., mutated, to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).
  • the antibody molecule is in the form of a bispecific or multispecific antibody molecule.
  • the bispecific antibody molecule has a first binding specificity to PD-1 or PD-L1 and a second binding specificity, e.g., a second binding specificity to TIM-3, LAG-3, or PD-L2.
  • the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3.
  • any combination of the aforesaid molecules can be made in a multispecific antibody molecule, e.g., a trispecific antibody that includes a first binding specificity to PD-1 or PD-1, and a second and third binding specificities to two or more of TIM-3, LAG-3, or PD-L2.
  • the immunomodulator is an inhibitor of PD-1, e.g., human PD-1.
  • the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1.
  • the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1.
  • the PD-1 or PD-L1 inhibitor can be administered alone, or in combination with other immunomodulators, e.g., in combination with an inhibitor of LAG-3, TIM-3 or CTLA4.
  • the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule is administered in combination with a LAG-3 inhibitor, e.g., an anti- LAG-3 antibody molecule.
  • the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule is administered in combination with a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule.
  • the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 antibody molecule is administered in combination with a LAG-3 inhibitor, e.g., an anti-LAG-3 antibody molecule, and a TIM-3 inhibitor, e.g., an anti- TIM-3 antibody molecule.
  • a LAG-3 inhibitor e.g., an anti-LAG-3 antibody molecule
  • a TIM-3 inhibitor e.g., an anti- TIM-3 antibody molecule.
  • Other combinations of immunomodulators with a PD-1 inhibitor e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR
  • Any of the antibody molecules known in the art or disclosed herein can be used in the aforesaid combinations of inhibitors of checkpoint molecule.
  • the HIF-2a inhibitor of the present disclosure i used in combination with a CTLA-4 inhibitor to treat a disease, e.g., cancer.
  • the PD-1 inhibitor is selected from Ipilimumab (MDX-010, MDX-101, or Yervoy, Bristol- Myers Squibb) , tremelilumab (ticilimumab. Pfizer/AstraZeneca), AGEN1181 (Agenus), Zalifrelimab (AGEN1884, Agenus), IBI310 (Innovent Biologics).
  • the HIF-2a inhibitor of the present disclosure is used in combination with a PD-1 inhibitor to treat a disease, e.g., cancer.
  • the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (J
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety.
  • the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 3 (e.g., from the heavy and light chain variable region sequences of BAP049- Clone-E or BAP049-Clone-B disclosed in Table 3), or encoded by a nucleotide sequence shown in Table 3.
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 3).
  • the CDRs are according to the Chothia definition (e.g., as set out in Table 3).
  • the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 3).
  • the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 213).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 3, or encoded by a nucleotide sequence shown in Table 3.
  • the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 22a, a VHCDR2 amino acid sequence of SEQ ID NO: 23a, and a VHCDR3 amino acid sequence of SEQ ID NO: 24a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 31a, a VLCDR2 amino acid sequence of SEQ ID NO: 32a, and a VLCDR3 amino acid sequence of SEQ ID NO: 286a, each disclosed in Table 3.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 45a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 46a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 47a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 50a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 51a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 52a, each disclosed in Table 3.
  • the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 27a. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 41a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 41a. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 37a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 37a.
  • the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a and a VL comprising the amino acid sequence of SEQ ID NO: 41a. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a and a VL comprising the amino acid sequence of SEQ ID NO: 37a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 28a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 28a.
  • the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 42a or 38a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 42a or 38a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 28a and a VL encoded by the nucleotide sequence of SEQ ID NO: 42a or 38a.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 29a.
  • the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 43a. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 39a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 39a. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a and a light chain comprising the amino acid sequence of SEQ ID NO: 43a.
  • the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a and a light chain comprising the amino acid sequence of SEQ ID NO: 39a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 30a.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 44a or 40a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 44a or 40a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 44a or 40a.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety. Table 3. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules Other Exemplary PD-1 Inhibitors In some embodiments, the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4).
  • Nivolumab is a fully human IgG4 monoclonal antibody, which specifically blocks PD1.
  • Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in US Pat No.8,008,449 and PCT Publication No. WO2006/121168, incorporated by reference in their entirety.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Nivolumab, e.g., as disclosed in Table 4.
  • the anti-PD-1 antibody is Pembrolizumab.
  • Pembrolizumab (Trade name KEYTRUDA formerly Lambrolizumab, also known as Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1.
  • Pembrolizumab is disclosed, e.g., in Hamid, O. et al.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pembrolizumab, e.g., as disclosed in Table 4.
  • the anti-PD-1 antibody is Pidilizumab.
  • Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1.
  • the anti- PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pidilizumab, e.g., as disclosed in Table 4.
  • Other anti-PD1 antibodies are disclosed in US Patent No.8,609,089, US Publication No.2010028330, and/or US Publication No.20120114649, incorporated by reference in their entirety.
  • Other anti-PD1 antibodies include AMP 514 (Amplimmune).
  • the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493, incorporated by reference in their entirety.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MEDI0680.
  • the anti-PD-1 antibody molecule is Cemiplimab (Regeneron), also known as REGN2810.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of REGN2810. In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of PF-06801591. In one embodiment, the anti-PD-1 antibody molecule is Tislelizumab (Beigene), also known as BGB-A317, or BGB-108.
  • Beigene also known as BGB-A317, or BGB-108.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BGB-A317 or BGB-108.
  • the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCSHR1210.
  • the anti-PD-1 antibody molecule is Dostarlimab (Tesaro), also known as TSR-042, also known as ANB011.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-042.
  • the anti-PD-1 antibody molecule is Balstilimab (Agenus), also known as AGEN2035.
  • the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Balstilimab.
  • the anti-PD-1 antibody molecule is Sintilimab (InnoVent), In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Sintilimab. In one embodiment, the anti-PD-1 antibody molecule is Toripalimab (Shanghai Junshi Bioscience). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Toripalimab.
  • the anti-PD-1 antibody molecule is Camrelizumab (Jiangsu Hengrui Medicine Co.). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Camrelizumab.
  • anti-PD-1 antibodies include those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entirety.
  • the anti-PD-1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-1 as, one of the anti-PD-1 antibodies described herein.
  • the PD-1 inhibitor is a peptide that inhibits the PD-1 signalling pathway, e.g., as described in US 8,907,053, incorporated by reference in its entirety.
  • the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety). Table 4.
  • the HIF-2a inhibitor of the present disclosure is used in combination with a PD-L1 inhibitor for treating a disease, e.g., cancer.
  • the PD-L1 inhibitor is selected from FAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (MedImmune/AstraZeneca), or BMS- 936559 (Bristol-Myers Squibb).
  • the PD-L1 inhibitor is an anti-PD-L1 antibody molecule.
  • the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as disclosed in US 2016/0108123, published on April 21, 2016, entitled “Antibody Molecules to PD-L1 and Uses Thereof,” incorporated by reference in its entirety.
  • the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 5 (e.g., from the heavy and light chain variable region sequences of BAP058- Clone O or BAP058-Clone N disclosed in Table 5), or encoded by a nucleotide sequence shown in Table 5.
  • CDRs complementarity determining regions
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 5). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 5). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 5). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 214).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 5, or encoded by a nucleotide sequence shown in Table 5.
  • amino acid substitutions e.g., conservative amino acid substitutions
  • deletions e.g., conservative amino acid substitutions
  • the anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 62a, a VHCDR2 amino acid sequence of SEQ ID NO: 63a, and a VHCDR3 amino acid sequence of SEQ ID NO: 64a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 70a, a VLCDR2 amino acid sequence of SEQ ID NO: 71a, and a VLCDR3 amino acid sequence of SEQ ID NO: 72a, each disclosed in Table 5.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-PD-L1 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 89a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 90a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 91a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 94a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 95a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 96a, each disclosed in Table 5.
  • the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 67a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 77a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 77a.
  • the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 81a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 85a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 85a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67a and a VL comprising the amino acid sequence of SEQ ID NO: 77a.
  • the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81a and a VL comprising the amino acid sequence of SEQ ID NO: 85a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 68a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 68a.
  • the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 78a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 78a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 82a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 86a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 86a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 68a and a VL encoded by the nucleotide sequence of SEQ ID NO: 78a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82a and a VL encoded by the nucleotide sequence of SEQ ID NO: 86a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 69a.
  • the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 79a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 79a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 83a.
  • the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 87a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 87a.
  • the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69a and a light chain comprising the amino acid sequence of SEQ ID NO: 79a.
  • the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83a and a light chain comprising the amino acid sequence of SEQ ID NO: 87a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 76a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 80a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 80a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 84a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 88a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 88a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 80a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 88a.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2016/0108123, incorporated by reference in its entirety. Table 5. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules
  • the PD-L1 inhibitor is anti-PD-L1 antibody.
  • the anti-PD-L1 inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as A09-246-2) disclosed in, e.g., WO 2013/0179174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).
  • the PD-L1 inhibitor is MDX-1105.
  • MDX-1105 also known as BMS-936559, is an anti-PD-L1 antibody described in PCT Publication No. WO 2007/005874.
  • the PD-L1 inhibitor is YW243.55.S70.
  • the YW243.55.S70 antibody is an anti-PD-L1 described in PCT Publication No. WO 2010/077634.
  • the PD-L1 inhibitor is MDPL3280A (Genentech / Roche) also known as Atezolizumabm, RG7446, RO5541267, YW243.55.S70, or TECENTRIQTM.
  • MDPL3280A is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1.
  • the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Atezolizumab, e.g., as disclosed in Table 6.
  • the PD-L2 inhibitor is AMP-224.
  • AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Amplimmune; e.g., disclosed in PCT Publication Nos. WO2010/027827 and WO2011/066342).
  • the PD-L1 inhibitor is an anti-PD-L1 antibody molecule.
  • the anti-PD-L1 antibody molecule is Avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, incorporated by reference in its entirety.
  • the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Avelumab, e.g., as disclosed in Table 6.
  • the anti-PD-L1 antibody molecule is Durvalumab (MedImmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, incorporated by reference in its entirety.
  • the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Durvalumab, e.g., as disclosed in Table 6.
  • the anti-PD-L1 antibody molecule is BMS-936559 (Bristol- Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7,943,743 and WO 2015/081158, incorporated by reference in their entirety.
  • the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-936559, e.g., as disclosed in Table 6.
  • anti-PD-L1 antibodies include those described, e.g., in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, incorporated by reference in their entirety.
  • the anti-PD-L1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-L1 as, one of the anti-PD-L1 antibodies described herein. Table 6. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules
  • the HIF-2a inhibitor of the present disclosure is used in combination with a LAG-3 inhibitor to treat a disease, e.g., cancer.
  • the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).
  • Exemplary LAG-3 Inhibitors In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as disclosed in US 2015/0259420, published on September 17, 2015, entitled “Antibody Molecules to LAG-3 and Uses Thereof,” incorporated by reference in its entirety.
  • the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 7 (e.g., from the heavy and light chain variable region sequences of BAP050- Clone I or BAP050-Clone J disclosed in Table 7), or encoded by a nucleotide sequence shown in Table 7.
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 7).
  • the CDRs are according to the Chothia definition (e.g., as set out in Table 7).
  • the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 7).
  • the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 173).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 7, or encoded by a nucleotide sequence shown in Table 7.
  • the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 108a, a VHCDR2 amino acid sequence of SEQ ID NO: 109a, and a VHCDR3 amino acid sequence of SEQ ID NO: 110a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 117a, a VLCDR2 amino acid sequence of SEQ ID NO: 118a, and a VLCDR3 amino acid sequence of SEQ ID NO: 119a, each disclosed in Table 7.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 143a or 144a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 145a or 146a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 147a or 148a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153a or 154a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155a or 156a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157a or 158a, each disclosed in Table 7.
  • the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 165a or 144a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 166a or 146a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 167a or 148a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153a or 154a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155a or 156a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157a or 158a, each disclosed in Table 7.
  • the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 113a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 125a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 125a.
  • the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 131a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 137a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 137a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113a and a VL comprising the amino acid sequence of SEQ ID NO: 125a.
  • the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131a and a VL comprising the amino acid sequence of SEQ ID NO: 137a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 114a or 115a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 114a or 115a.
  • the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 126a or 127a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 126a or 127a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 132a or 133a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 132a or 133a.
  • the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 138a or 139a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 138a or 139a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 114a or 115a and a VL encoded by the nucleotide sequence of SEQ ID NO: 126a or 127a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 132a or 133a and a VL encoded by the nucleotide sequence of SEQ ID NO: 138a or 139a.
  • the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 116a.
  • the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 128a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 128a. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 134a.
  • the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 140a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 140a.
  • the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116a and a light chain comprising the amino acid sequence of SEQ ID NO: 128a.
  • the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134a and a light chain comprising the amino acid sequence of SEQ ID NO: 140a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123a or 124a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 123a or 124a.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 129a or 130a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 129a or 130a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135a or 136a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 135a or 136a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 141a or 142a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 141a or 142a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123a or 124a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 129a or 130a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135a or 136a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 141a or 142a.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0259420, incorporated by reference in its entirety. Table 7. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules
  • the LAG-3 inhibitor is an anti-LAG-3 antibody molecule.
  • the LAG-3 inhibitor is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016.
  • BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839, incorporated by reference in their entirety.
  • the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986016, e.g., as disclosed in Table 8.
  • the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-033. In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059, incorporated by reference in their entirety.
  • the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP731, e.g., as disclosed in Table 8.
  • the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of GSK2831781.
  • the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed).
  • the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP761.
  • Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, incorporated by reference in their entirety.
  • the anti-LAG-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on LAG-3 as, one of the anti-LAG-3 antibodies described herein.
  • the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), e.g., as disclosed in WO 2009/044273, incorporated by reference in its entirety. Table 8. Amino acid sequences of other exemplary anti-LAG-3 antibody molecules
  • the inhibitor of an immune checkpoint molecule is an inhibitor of TIM-3.
  • the HIF-2a inhibitor of the present disclosure is used in combination with a TIM-3 inhibitor to treat a disease, e.g., cancer.
  • the TIM-3 inhibitor is MGB453 (Novartis), LY3321367 (Eli Lilly), Sym023 (Symphogen), BGB-A425 (Beigene), INCAGN-2390 (Agenus/Incyte), MBS-986258 (BMS/Five Prime), RO-7121661 (Roche), LY-3415244 (Eli Lilly), or TSR-022 (Tesaro).
  • the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as disclosed in US 2015/0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” incorporated by reference in its entirety.
  • the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 9 (e.g., from the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 9), or encoded by a nucleotide sequence shown in Table 9.
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 9).
  • the CDRs are according to the Chothia definition (e.g., as set out in Table 9).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 9, or encoded by a nucleotide sequence shown in Table 9.
  • amino acid substitutions e.g., conservative amino acid substitutions
  • deletions e.g., conservative amino acid substitutions
  • the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 174a, a VHCDR2 amino acid sequence of SEQ ID NO: 175a, and a VHCDR3 amino acid sequence of SEQ ID NO: 176a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 183a, a VLCDR2 amino acid sequence of SEQ ID NO: 184a, and a VLCDR3 amino acid sequence of SEQ ID NO: 185a, each disclosed in Table 9.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 174a, a VHCDR2 amino acid sequence of SEQ ID NO: 193a, and a VHCDR3 amino acid sequence of SEQ ID NO: 176a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 183a, a VLCDR2 amino acid sequence of SEQ ID NO: 184a, and a VLCDR3 amino acid sequence of SEQ ID NO: 185a, each disclosed in Table 9.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 179a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 189a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 189a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 195a.
  • the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 199a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 199a.
  • the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179a and a VL comprising the amino acid sequence of SEQ ID NO: 189a.
  • the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195a and a VL comprising the amino acid sequence of SEQ ID NO: 199a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 180a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 180a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 190a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 190a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 196a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 200a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 200a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 180a and a VL encoded by the nucleotide sequence of SEQ ID NO: 190a.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196a and a VL encoded by the nucleotide sequence of SEQ ID NO: 200a.
  • the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 181a.
  • the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 191a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 191a.
  • the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 197a. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 201a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 201a. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181a and a light chain comprising the amino acid sequence of SEQ ID NO: 191a.
  • the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197a and a light chain comprising the amino acid sequence of SEQ ID NO: 201a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 182a.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 192a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 192a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 198a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 202a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 202a.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 192a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 202a.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0218274, incorporated by reference in its entirety. Table 9. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules
  • the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-022. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of APE5137 or APE5121, e.g., as disclosed in Table 10.
  • the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule is LY3321367 (Eli Lilly).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of LY3321367.
  • the anti-TIM-3 antibody molecule is Sym023 (Symphogen).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of Sym023.
  • the anti-TIM-3 antibody molecule is BGB-A425 (Beigene).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of BGB-A425.
  • the anti-TIM-3 antibody molecule is INCAGN-2390 (Agenus/Incyte).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain or light chain sequence of INCAGN-2390.
  • the anti-TIM-3 antibody molecule is BMS-986258 (BMS/Five Prime).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of BMS-986258.
  • the anti-TIM-3 antibody or inhibitor molecule is RO-7121661 (Roche).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of the TIM-3 binding arm of RO-7121661.
  • the anti-TIM-3 antibody or inhibitor molecule is LY-3415244 (Eli Lilly).
  • the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of the TIM-3 binding arm of LY-3415244.
  • Further known anti-TIM-3 antibodies include those described, e.g., in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, incorporated by reference in their entirety.
  • the anti-TIM-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on TIM-3 as, one of the anti-TIM-3 antibodies described herein.
  • Table 10 Amino acid sequences of other exemplary anti-TIM-3 antibody molecules Cytokines
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more cytokines, including but not limited to, interferon, IL-2, IL-15, IL-7, or IL21.
  • HIF-2a inhibitor of the present disclosure is administered in combination with an IL-15/IL-15Ra complex.
  • the IL- 15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor) or CYP0150 (Cytune).
  • exemplary IL-15/IL-15Ra complexes the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra).
  • the IL-15/IL-15Ra complex may comprise IL-15 covalently or noncovalently bound to a soluble form of IL-15Ra.
  • the human IL-15 is noncovalently bonded to a soluble form of IL-15Ra.
  • the human IL-15 of the formulation comprises an amino acid sequence of SEQ ID NO: 207a in Table 11 or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 207a
  • the soluble form of human IL-15Ra comprises an amino acid sequence of SEQ ID NO: 208a in Table 11, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 208a, as described in WO 2014/066527, incorporated by reference in its entirety.
  • the molecules described herein can be made by vectors, host cells, and methods described in WO 2007084342, incorporated by reference in its entirety. Table 11.
  • IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety.
  • the IL-15/IL- 15Ra Fc fusion protein comprises the sequences as disclosed in Table 12.
  • the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune).
  • the sushi domain of IL-15Ra refers to a domain beginning at the first cysteine residue after the signal peptide of IL-15Ra, and ending at the fourth cysteine residue after said signal peptide.
  • the complex of IL-15 fused to the sushi domain of IL-15Ra is described in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entirety.
  • the IL-15/IL-15Ra sushi domain fusion comprises the sequences as disclosed in Table 12. Table 12.
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more agonists of toll like receptors (TLRs, e.g., TLR7, TLR8, TLR9) to treat a disease, e.g., cancer.
  • TLRs toll like receptors
  • a compound of the present disclosure can be used in combination with a TLR7 agonist or a TLR7 agonist conjugate.
  • the TLR7 agonist comprises a compound disclosed in International Application Publication No. WO2011/049677, which is hereby incorporated by reference in its entirety.
  • the TLR7 agonist comprises 3-(5-amino-2-(4- (2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin- 8-yl)propanoic acid.
  • the TLR7 agonist comprises a compound of formula:
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more angiogenesis inhibitors to treat cancer, e.g., Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-Fluoro-2- methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2- aminopropanoate); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326-83- 4); Foretin
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more heat shock protein inhibitors to treat cancer, e.g., Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17- AAG, available from SIGMA, and described in US Patent No.4,261,989); Retaspimycin (IPI504), Ganetespib (STA-9090); [6-Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)- 9H-purin-2-yl]amine (BIIB021 or -CNF2024, CAS 848695-25-0); trans-4-[[2- (Aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol- 1-yl]phenyl]amino]cyclohexyl glycine
  • HIF-2a inhibitor of the present disclosure is used in combination with one or more HDAC inhibitors or other epigenetic modifiers.
  • HDAC inhibitors include, but not limited to, Voninostat (Zolinza®); Romidepsin (Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF- 1023A); Trapoxin B (RF-10238); Cyclo[( ⁇ S,2S)- ⁇ -amino- ⁇ -oxo-2-oxiraneoctanoyl-O- methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[( ⁇ S,2S)- ⁇ -amino- ⁇ -oxo-2- oxiraneoct
  • epigenetic modifiers include but not limited to inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryonic ectoderm development), or LSD1 (lysine-specific histone demethylase 1A or KDM1A).
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more inhibitors of indoleamine-pyrrole 2,3-dioxygenase (IDO), for example, Indoximod (also known as NLG-8189), ⁇ -Cyclohexyl-5H-imidazo[5,1-a]isoindole- 5-ethanol (also known as NLG919), or (4E)-4-[(3-Chloro-4-fluoroanilino)- nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB024360), to treat cancer.
  • IDO indoleamine-pyrrole 2,3-dioxygenase
  • Chimeric Antigen Receptors The present disclosure provides for the HIF-2a inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in combination with adoptive immunotherapy methods and reagents such as chimeric antigen receptor (CAR) immune effector cells, e.g., T cells, or chimeric TCR-transduced immune effector cells, e.g., T cells, as described herein.
  • CAR chimeric antigen receptor
  • T cells e.g., T cells
  • TCR-transduced immune effector cells e.g., T cells
  • Estrogen Receptor Antagonists In some embodiments, an estrogen receptor (ER) antagonist is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • SERDs are estrogen receptor antagonists which bind to the receptor and result in e.g., degradation or down-regulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479).
  • ER is a hormone-activated transcription factor important for e.g., the growth, development and physiology of the human reproductive system. ER is activated by, e.g., the hormone estrogen (17beta estradiol). ER expression and signaling is implicated in cancers (e.g., breast cancer), e.g., ER positive (ER+) breast cancer.
  • the SERD is chosen from LSZ102, fulvestrant, brilanestrant, or elacestrant.
  • the SERD comprises a compound disclosed in International Application Publication No. WO 2014/130310, which is hereby incorporated by reference in its entirety.
  • the SERD comprises LSZ102.
  • LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid.
  • the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8), or a compound disclosed in International Application Publication No.
  • Fulvestrant is also known as ICI 182780, ZM 182780, FASLODEX®, or (7 ⁇ ,17 ⁇ )-7- ⁇ 9-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]nonyl ⁇ estra-1,3,5(10)-triene-3,17-diol. Fulvestrant is a high affinity estrogen receptor antagonist with an IC50 of 0.29 nM.
  • the SERD comprises elacestrant (CAS Registry Number: 722533-56-4), or a compound disclosed in U.S. Patent No.7,612,114, which is incorporated by reference in its entirety.
  • Elacestrant is also known as RAD1901, ER-306323 or (6R)-6- ⁇ 2- [Ethyl( ⁇ 4-[2-(ethylamino)ethyl]phenyl ⁇ methyl)amino]-4-methoxyphenyl ⁇ -5,6,7,8- tetrahydronaphthalen-2-ol.
  • Elacestrant is an orally bioavailable, non-steroidal combined selective estrogens receptor modulator (SERM) and a SERD.
  • SERM selective estrogens receptor modulator
  • Elacestrant is also disclosed, e.g., in Garner F et al., (2015) Anticancer Drugs 26(9):948-56.
  • the SERD is brilanestrant (CAS Registry Number: 1365888- 06-7), or a compound disclosed in International Application Publication No. WO 2015/136017, which is incorporated by reference in its entirety.
  • Brilanestrant is also known as GDC-0810, ARN810, RG-6046, RO-7056118 or (2E)-3- ⁇ 4-[(1E)-2-(2-chloro-4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl]phenyl ⁇ prop-2-enoic acid.
  • Brilanestrant is a next-generation, orally bioavailable selective SERD with an IC50 of 0.7 nM.
  • the SERD is chosen from RU 58668, GW7604, AZD9496, apeledoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, e.g., as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887.
  • CDK4/6 Inhibitors an inhibitor of Cyclin-Dependent Kinases 4 or 6 (CDK4/6) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the CDK4/6 inhibitor is chosen from ribociclib, abemaciclib (Eli Lilly), or palbociclib.
  • the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3), or a compound disclosed in U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety.
  • the CDK4/6 inhibitor comprises a compound disclosed in International Application Publication No. WO 2010/020675 and U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety.
  • the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3).
  • Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl- N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide.
  • the CDK4/6 inhibitor comprises abemaciclib (CAS Registry Number: 1231929-97-7).
  • Abemaciclib is also known as LY835219 or N-[5-[(4-Ethyl-1- piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H- benzimidazol-6-yl]-2-pyrimidinamine.
  • Abemaciclib is a CDK inhibitor selective for CDK4 and CDK6 and is disclosed, e.g., in Torres-Guzman R et al.
  • the CDK4/6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2).
  • Palbociclib is also known as PD-0332991, IBRANCE® or 6-Acetyl- 8-cyclopentyl-5-methyl-2- ⁇ [5-(1-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin- 7(8H)-one.
  • Palbociclib inhibits CDK4 with an IC50 of 11nM, and inhibits CDK6 with an IC50 of 16nM, and is disclosed, e.g., in Finn et al. (2009) Breast Cancer Research 11(5):R77.
  • CXCR2 Inhibitors an inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the CXCR2 inhibitor is chosen from 6-chloro-3- ((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide, danirixin, reparixin, or navarixin.
  • the CXCR2 inhibitor comprises a compound disclosed in U.S.
  • the CXCR2 inhibitor comprises 6-chloro-3- ((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide or a choline salt thereof. In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)- 2-hydroxy-N-methoxy-N-methylbenzenesulfonamide choline salt.
  • the CXCR2 inhibitor is 2-Hydroxy-N,N,N-trimethylethan-1-aminium 3-chloro-6-( ⁇ 3,4- dioxo-2-[(pentan-3-yl)amino]cyclobut-1-en-1-yl ⁇ amino)-2-(N-methoxy-N- methylsulfamoyl)phenolate (i.e., 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en- 1-yl)amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide choline salt) and has the following chemical structure: .
  • the CXCR2 inhibitor comprises danirixin (CAS Registry Number: 954126-98-8).
  • Danirixin is also known as GSK1325756 or 1-(4-chloro-2-hydroxy- 3-piperidin-3-ylsulfonylphenyl)-3-(3-fluoro-2-methylphenyl)urea.
  • Danirixin is disclosed, e.g., in Miller et al. Eur J Drug Metab Pharmacokinet (2014) 39:173–181; and Miller et al. BMC Pharmacology and Toxicology (2015), 16:18.
  • the CXCR2 inhibitor comprises reparixin (CAS Registry Number: 266359-83-5).
  • Reparixin is also known as repertaxin or (2R)-2-[4-(2- methylpropyl)phenyl]-N-methylsulfonylpropanamide.
  • Reparixin is a non-competitive allosteric inhibitor of CXCR1/2.
  • Reparixin is disclosed, e.g., in Zarbock et al. Br J Pharmacol.2008; 155(3):357-64.
  • the CXCR2 inhibitor comprises navarixin.
  • Navarixin is also known as MK-7123, SCH 527123, PS291822, or 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide.
  • Navarixin is disclosed, e.g., in Ning et al. Mol Cancer Ther.2012; 11(6):1353-64.
  • CSF-1/1R Binding Agents In some embodiments, a CSF-1/1R binding agent is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the CSF-1/1R binding agent is chosen from an inhibitor of macrophage colony-stimulating factor (M-CSF), e.g., a monoclonal antibody or Fab to M-CSF (e.g., MCS110), a CSF-1R tyrosine kinase inhibitor (e.g., 4-((2-(((1R,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a receptor tyrosine kinase inhibitor (RTK) (e.g., pexidartinib), or an antibody targeting CSF-1R (e.g., emactuzumab or FPA008).
  • M-CSF macrophage colony-stimulating factor
  • MCS110 monoclonal antibody or Fab to M-CSF
  • CSF-1R tyrosine kinase inhibitor e
  • the CSF-1/1R inhibitor is BLZ945.
  • the CSF-1/1R binding agent is MCS110.
  • the CSF-1/1R binding agent is pexidartinib.
  • Exemplary CSF-1 binding agents In some embodiments, the CSF-1/1R binding agent comprises an inhibitor of macrophage colony-stimulating factor (M-CSF). M-CSF is also sometimes known as CSF-1.
  • the CSF-1/1R binding agent is an antibody to CSF-1 (e.g., MCS110). In other embodiments, the CSF-1/1R binding agent is an inhibitor of CSF-1R (e.g., BLZ945).
  • the CSF-1/1R binding agent comprises a monoclonal antibody or Fab to M-CSF (e.g., MCS110/H-RX1), or a binding agent to CSF-1 disclosed in International Application Publication Nos. WO 2004/045532 and WO 2005/068503, including H-RX1 or 5H4 (e.g., an antibody molecule or Fab fragment against M-CSF) and US9079956, which applications and patent are incorporated by reference in their entirety. Table 13.
  • the CSF-1/1R binding agent comprises a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N- methyl picolinamide (BLZ945), or a compound disclosed in International Application Publication No. WO 2007/121484, and U.S. Patent Nos.7,553,854, 8,173,689, and 8,710,048, which are incorporated by reference in their entirety.
  • the CSF-1/1R binding agent comprises pexidartinib (CAS Registry Number 1029044-16-3).
  • Pexidrtinib is also known as PLX3397 or 5-((5-chloro-1H- pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2- amine.
  • Pexidartinib is a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3.
  • RTK receptor tyrosine kinase
  • PLX3397 can bind to and inhibit phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease.
  • the CSF-1/1R binding agent is emactuzumab.
  • Emactuzumab is also known as RG7155 or RO5509554.
  • Emactuzumab is a humanized IgG1 mAb targeting CSF1R.
  • the CSF-1/1R binding agent is FPA008.
  • FPA008 is a humanized mAb that inhibits CSF1R.
  • A2aR Antagonists In some embodiments, an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of A2aR pathway, e.g., an adenosine inhibitor, e.g., an inhibitor of A2aR or CD-73) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • A2aR adenosine A2a receptor
  • the A2aR antagonist is selected from PBF509 (NIR178) (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genentech), AZD4635/HTL- 1071 (AstraZeneca/Heptares), Vipadenant (Redox/Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences), Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant/SYN- 115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences), and Preladenant/SCH 420814 (Merck/Schering).
  • PBF509 NIR178
  • CPI444/V81444 Corvus/Genentech
  • AZD4635/HTL- 1071 AdstraZeneca/Heptares
  • Vipadenant Re
  • the A2aR antagonist comprises PBF509 (NIR178) or a compound disclosed in U.S. Patent No.8,796,284 or in International Application Publication No. WO 2017/025918, herein incorporated by reference in their entirety.
  • PBF509 (NIR178) is also known as NIR178.
  • Other Exemplary A2aR antagonists In certain embodiments, the A2aR antagonist comprises CPI444/V81444. CPI-444 and other A2aR antagonists are disclosed in International Application Publication No. WO 2009/156737, herein incorporated by reference in its entirety.
  • the A2aR antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.
  • the A2aR antagonist is (R)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, or racemate thereof.
  • the A2aR antagonist is 7-(5-methylfuran-2-yl)-3-((6- (((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 5-amine.
  • the A2aR antagonist is AZD4635/HTL-1071.
  • A2aR antagonists are disclosed in International Application Publication No. WO 2011/095625, herein incorporated by reference in its entirety.
  • the A2aR antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.
  • the A2aR antagonist is ST-4206 (Leadiant Biosciences).
  • the A2aR antagonist is an A2aR antagonist described in U.S. Patent No.9,133,197, herein incorporated by reference in its entirety.
  • the A2aR antagonist is an A2aR antagonist described in U.S. Patent Nos.8,114,845 and 9,029,393, U.S. Application Publication Nos.2017/0015758 and 2016/0129108, herein incorporated by reference in their entirety.
  • the A2aR antagonist is istradefylline (CAS Registry Number: 155270-99-8). Istradefylline is also known as KW-6002 or 8-[(E)-2-(3,4- dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione. Istradefylline is disclosed, e.g., in LeWitt et al. (2008) Annals of Neurology 63 (3): 295–302). In some embodiments, the A2aR antagonist is tozadenant (Biotie).
  • Tozadenant is also known as SYN115 or 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)-4- methylpiperidine-1-carboxamide. Tozadenant blocks the effect of endogenous adenosine at the A2a receptors, resulting in the potentiation of the effect of dopamine at the D2 receptor and inhibition of the effect of glutamate at the mGluR5 receptor.
  • the A2aR antagonist is preladenant (CAS Registry Number: 377727-87-2).
  • Preladenant is also known as SCH 420814 or 2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1- piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine.
  • Preladenant was developed as a drug that acted as a potent and selective antagonist at the adenosine A2A receptor.
  • the A2aR antagonist is vipadenan.
  • Vipadenan is also known as BIIB014, V2006, or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5- d]pyrimidin-5-amine.
  • Other exemplary A2aR antagonists include, e.g., ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, and ZM-241,385.
  • the A2aR antagonist is an A2aR pathway antagonist (e.g., a CD-73 inhibitor, e.g., an anti-CD73 antibody) is MEDI9447.
  • MEDI9447 is a monoclonal antibody specific for CD73. Targeting the extracellular production of adenosine by CD73 may reduce the immunosuppressive effects of adenosine.
  • MEDI9447 was reported to have a range of activities, e.g., inhibition of CD73 ectonucleotidase activity, relief from AMP- mediated lymphocyte suppression, and inhibition of syngeneic tumor growth.
  • MEDI9447 can drive changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment.
  • IDO Inhibitors In some embodiments, an inhibitor of indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • IDO indoleamine 2,3-dioxygenase
  • TDO tryptophan 2,3-dioxygenase
  • the IDO inhibitor is chosen from (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3- amine (also known as epacadostat or INCB24360), indoximod (), (1-methyl-D-tryptophan), ⁇ -cyclohexyl-5H-Imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), indoximod, and BMS-986205 (formerly F001287).
  • the IDO/TDO inhibitor is indoximod (New Link Genetics).
  • the D isomer of 1-methyl-tryptophan is an orally administered small-molecule indoleamine 2,3-dioxygenase (IDO) pathway inhibitor that disrupts the mechanisms by which tumors evade immune-mediated destruction.
  • IDO/TDO inhibitor is NLG919 (New Link Genetics). NLG919 is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM in cell-free assays.
  • the IDO/TDO inhibitor is epacadostat (CAS Registry Number: 1204669-58-8).
  • Epacadostat is also known as INCB24360 or INCB024360 (Incyte). Epacadostat is a potent and selective indoleamine 2,3-dioxygenase (IDO1) inhibitor with IC50 of 10 nM, highly selective over other related enzymes such as IDO2 or tryptophan 2,3- dioxygenase (TDO).
  • IDO1 indoleamine 2,3-dioxygenase
  • TDO tryptophan 2,3- dioxygenase
  • the IDO/TDO inhibitor is F001287 (Flexus/BMS).
  • F001287 is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1).
  • a STING agonist is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the STING agonist is cyclic dinucleotide, e.g., a cyclic dinucleotide comprising purine or pyrimidine nucleobases (e.g., adenosine, guanine, uracil, thymine, or cytosine nucleobases).
  • the nucleobases of the cyclic dinucleotide comprise the same nucleobase or different nucleobases.
  • the STING agonist comprises an adenosine or a guanosine nucleobase. In some embodiments, the STING agonist comprises one adenosine nucleobase and one guanosine nucleobase. In some embodiments, the STING agonist comprises two adenosine nucleobases or two guanosine nucleobases. In some embodiments, the STING agonist comprises a modified cyclic dinucleotide, e.g., comprising a modified nucleobase, a modified ribose, or a modified phosphate linkage.
  • the modified cyclic dinucleotide comprises a modified phosphate linkage, e.g., a thiophosphate.
  • the STING agonist comprises a cyclic dinucleotide (e.g., a modified cyclic dinucleotide) with 2’,5’ or 3’,5’ phosphate linkages.
  • the STING agonist comprises a cyclic dinucleotide (e.g., a modified cyclic dinucleotide) with Rp or Sp stereochemistry around the phosphate linkages.
  • the STING agonist is MK-1454 (Merck).
  • MK-1454 is a cyclic dinucleotide Stimulator of Interferon Genes (STING) agonist that activates the STING pathway.
  • STING Interferon Genes
  • Exemplary STING agonist are disclosed, e.g., in PCT Publication No. WO 2017/027645.
  • Galectin Inhibitors In some embodiments, a Galectin, e.g., Galectin-1 or Galectin-3, inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the combination comprises a Galectin-1 inhibitor and a Galectin-3 inhibitor.
  • the combination comprises a bispecific inhibitor (e.g., a bispecific antibody molecule) targeting both Galectin-1 and Galectin-3.
  • the Galectin inhibitor is chosen from an anti-Galectin antibody molecule, GR- MD-02 (Galectin Therapeutics), Galectin-3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck).
  • Galectins are a family of proteins that bind to beta galactosidase sugars. The Galectin family of proteins comprises at least of Galectin-1, Galectin-2, Galectin- 3, Galectin-4, Galectin-7, and Galectin-8.
  • Galectins are also referred to as S-type lectins, and are soluble proteins with, e.g., intracellular and extracellular functions. Galectin-1 and Galectin-3 are highly expressed in various tumor types. Galectin-1 and Galectin-3 can promote angiogenesis and/or reprogram myeloid cells toward a pro-tumor phenotype, e.g., enhance immunosuppression from myeloid cells. Soluble Galectin-3 can also bind to and/or inactivate infiltrating T cells. Exemplary Galectin Inhibitors In some embodiments, a Galectin inhibitor is an antibody molecule. In an embodiment, an antibody molecule is a monospecific antibody molecule and binds a single epitope.
  • the Galectin inhibitor is an anti-Galectin, e.g., anti-Galectin-1 or anti-Galectin-3, antibody molecule. In some embodiments, the Galectin inhibitor is an anti-Galectin-1 antibody molecule. In some embodiments, the Galectin inhibitor is an anti-Galectin-3 antibody molecule.
  • an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domains sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope.
  • the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein).
  • the first and second epitopes overlap. In an embodiment, the first and second epitopes do not overlap.
  • the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein).
  • a multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain.
  • a multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or tetraspecific antibody molecule.
  • the Galectin inhibitor is a multispecific antibody molecule.
  • a multispecific antibody molecule is a bispecific antibody molecule.
  • a bispecific antibody has specificity for no more than two antigens.
  • a bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.
  • the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein).
  • the first and second epitopes overlap.
  • the first and second epitopes do not overlap.
  • the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein).
  • a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope.
  • the Galectin inhibitor is a bispecific antibody molecule.
  • the first epitope is located on Galectin-1, and the second epitope is located on Galectin-3.
  • Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; including but not limited to, for example, the “knob in a hole” approach described in, e.g., US5731168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., US4433059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or
  • the anti-Galectin e.g., anti-Galectin-1 or anti-Galectin-3, antibody molecule
  • a monospecific, bispecific, or multispecific antibody molecule is covalently linked, e.g., fused, to another partner e.g., a protein, e.g., as a fusion molecule for example a fusion protein.
  • a bispecific antibody molecule has a first binding specificity to a first target (e.g., to Galectin-1), a second binding specificity to a second target (e.g., Galectin-3).
  • a Galectin inhibitor is a peptide, e.g., protein, which can bind to, and inhibit Galectin, e.g., Galectin-1 or Galectin-3, function.
  • the Galectin inhibitor is a peptide which can bind to, and inhibit Galectin-3 function.
  • the Galectin inhibitor is the peptide Galectin-3C.
  • the Galectin inhibitor is a Galectin-3 inhibitor disclosed in U.S.
  • Galectin-3C is an N-terminal truncated protein of Galectin-3, and functions, e.g., as a competitive inhibitor of Galectin-3. Galectin-3C prevents binding of endogenous Galectin-3 to e.g., laminin on the surface of, e.g., cancer cells, and other beta-galactosidase glycoconjugates in the extracellular matrix (ECM).
  • ECM extracellular matrix
  • Galectin-3C and other exemplary Galectin inhibiting peptides are disclosed in U.S. Patent 6,770,622.
  • Galectin-3C comprises the amino acid sequence of SEQ ID NO: 279, or an amino acid substantially identical (e.g., 90, 95 or 99%) identical thereto.
  • GAPAGPLIVPYNLPLPGGVVPRMLITILGTVKPNANRIALDFQRGNDVAFHFNPRFNE NNRRVIVCNTKLDNNWGREERQSVFPFESGKPFKIQVLVEPDHFKVAVNDAHLLQY NHRVKKLNEISKLGISGDIDITSASYTMI SEQ ID NO: 279.
  • the Galectin inhibitor is a peptide, which can bind to, and inhibit Galectin-1 function.
  • the Galectin inhibitor is the peptide Anginex: Anginex is an anti-angiogenic peptide that binds Galectin-1 (Salomonsson E, et al., (2011) Journal of Biological Chemistry, 286(16):13801-13804). Binding of Anginex to Galectin-1 can interfere with, e.g., the pro-angiongenic effects of Galectin-1.
  • the Galectin, e.g., Galectin-1 or Galectin-3, inhibitor is a non- peptidic topomimetic molecule.
  • the non-peptidic topomimetic Galectin inhibitor is OTX-008 (OncoEthix).
  • the non-peptidic topomimetic is a non-peptidic topomimetic disclosed in U.S. Patent 8,207,228, which is herein incorporated by reference in its entirety.
  • OTX-008 also known as PTX-008 or Calixarene 0118, is a selective allosteric inhibitor of Galectin-1.
  • OTX-008 has the chemical name: N-[2-(dimethylamino)ethyl]-2- ⁇ [26,27,28-tris( ⁇ [2- (dimethylamino)ethyl]carbamoyl ⁇ methoxy) pentacyclo[19.3.1.1,7.1,.15,]octacosa- 1(25),3(28),4,6,9(27),1012,15,17,19(26),21,23-dodecaen-25-yl]oxy ⁇ acetamide.
  • the Galectin e.g., Galectin-1 or Galectin-3, inhibitor is a carbohydrate based compound.
  • the Galectin inhibitor is GR-MD-02 (Galectin Therapeutics).
  • GR-MD-02 is a Galectin-3 inhibitor.
  • GR-MD-02 is a galactose- pronged polysaccharide also referred to as, e.g., a galactoarabino-rhamnogalaturonate.
  • GR- MD-02 and other galactose-pronged polymers, e.g., galactoarabino-rhamnogalaturonates are disclosed in U.S. Patent 8,236,780 and U.S. Publication 2014/0086932, the entire contents of which are herein incorporated by reference in their entirety.
  • a MEK inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the MEK inhibitor is chosen from Trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or G02443714.
  • the MEK inhibitor is Trametinib.
  • Exemplary MEK inhibitors In some embodiments, the MEK inhibitor is trametinib.
  • Trametinib is also known as JTP-74057, TMT212, N-(3- ⁇ 3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl ⁇ phenyl)acetamide, or Mekinist (CAS Number 871700-17-3).
  • the MEK inhibitor comprises selumetinib which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1- methyl-1H-benzimidazole-6-carboxamide.
  • Selumetinib is also known as AZD6244 or ARRY 142886, e.g., as described in PCT Publication No. WO2003077914.
  • the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188.
  • the MEK inhibitor comprises 2-[(2-Chloro-4- iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI- 1040 or PD184352), e.g., as described in PCT Publication No. WO2000035436).
  • the MEK inhibitor comprises N-[(2R)-2,3- Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide (also known as PD0325901), e.g., as described in PCT Publication No. WO2002006213).
  • the MEK inhibitor comprises 2’-amino-3’-methoxyflavone (also known as PD98059) which is available from Biaffin GmbH & Co., KG, Germany.
  • the MEK inhibitor comprises 2,3-bis[amino[(2- aminophenyl)thio]methylene]-butanedinitrile (also known as U0126), e.g., as described in US Patent No.2,779,780).
  • the MEK inhibitor comprises XL-518 (also known as GDC- 0973) which has a CAS No.1029872-29-4 and is available from ACC Corp.
  • the MEK inhibitor comprises G-38963.
  • the MEK inhibitor comprises G02443714 (also known as AS703206) Additional examples of MEK inhibitors are disclosed in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference.
  • MEK inhibitors include, but are not limited to, 2,3-Bis[amino[(2-aminophenyl)thio]methylene]- butanedinitrile (also known as U0126 and described in US Patent No.2,779,780); (3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro- 1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201, described in PCT Publication No.
  • WO2003076424 vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3- Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6- oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-Difluoro-2-[(2-fluoro-4- iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2
  • a c-MET inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • a disease e.g., cancer.
  • c-MET a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.
  • Inhibition of c-MET may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein.
  • the c-MET inhibitor is chosen from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, MSC2156119J, crizotinib, tivantinib, or golvatinib.
  • Exemplary c-MET Inhibitors In some embodiments, the c-MET inhibitor comprises capmatinib (INC280), or a compound described in U.S. Patent Nos.7,767,675, and US 8,461,330, which are incorporated by reference in their entirety.
  • Other Exemplary c-MET Inhibitors In some embodiments, the c-MET inhibitor comprises JNJ-38877605.
  • JNJ-38877605 is an orally available, small molecule inhibitor of c-Met. JNJ-38877605 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signal transduction pathways.
  • the c-Met inhibitor is AMG 208.
  • AMG 208 is a selective small- molecule inhibitor of c-MET. AMG 208 inhibits the ligand-dependent and ligand- independent activation of c-MET, inhibiting its tyrosine kinase activity, which may result in cell growth inhibition in tumors that overexpress c-Met.
  • the c-Met inhibitor comprises AMG 337.
  • AMG 337 is an orally bioavailable inhibitor of c-Met.
  • AMG 337 selectively binds to c-MET, thereby disrupting c-MET signal transduction pathways.
  • the c-Met inhibitor comprises LY2801653.
  • LY2801653 is an orally available, small molecule inhibitor of c-Met.
  • LY2801653 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signal transduction pathways.
  • c-Met inhibitor comprises MSC2156119J.
  • MSC2156119J is an orally bioavailable inhibitor of c-Met.
  • MSC2156119J selectively binds to c-MET, which inhibits c-MET phosphorylation and disrupts c-Met-mediated signal transduction pathways.
  • the c-MET inhibitor is capmatinib.
  • Capmatinib is also known as INCB028060.
  • Capmatinib is an orally bioavailable inhibitor of c-MET.
  • Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways.
  • the c-MET inhibitor comprises crizotinib.
  • Crizotinib is also known as PF-02341066.
  • Crizotinib is an orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.
  • the c-MET inhibitor comprises golvatinib.
  • Golvatinib is an orally bioavailable dual kinase inhibitor of c-MET and VEGFR-2 with potential antineoplastic activity. Golvatinib binds to and inhibits the activities of both c-MET and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases.
  • the c-MET inhibitor is tivantinib.
  • Tivantinib is also known as ARQ 197. Tivantinib is an orally bioavailable small molecule inhibitor of c-MET.
  • Tivantinib binds to the c-MET protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-Met protein.
  • TGF- ⁇ Inhibitors a transforming growth factor beta (also known as TGF- ⁇ TGF ⁇ , TGFb, or TGF-beta, used interchangeably herein) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • a combination described herein comprises a transforming growth factor beta (also known as TGF- ⁇ TGF ⁇ , TGFb, or TGF-beta, used interchangeably herein) inhibitor.
  • TGF- ⁇ belongs to a large family of structurally-related cytokines including, e.g., bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and inhibins.
  • BMPs bone morphogenetic proteins
  • the TGF- ⁇ inhibitors described herein can bind and/or inhibit one or more isoforms of TGF- ⁇ (e.g., one, two, or all of TGF- ⁇ 1, TGF- ⁇ 2, or TGF- ⁇ 3).
  • TGF- ⁇ maintains homeostasis and limits the growth of epithelial, endothelial, neuronal and hematopoietic cell lineages, e.g., through the induction of anti-proliferative and apoptotic responses.
  • TGF- ⁇ /Smad canonical pathway can mediate the anti-proliferative effects of TGF- ⁇ .
  • the non-canonical TGF- ⁇ pathway can activate additional intra-cellular pathways, e.g., mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/Protein Kinase B, Rho-like GTPases (Tian et al. Cell Signal.2011; 23(6):951-62; Blobe et al.
  • MAPK mitogen-activated protein kinases
  • phosphatidylinositol 3 kinase/Protein Kinase B Rho-like GTPases
  • TGF- ⁇ signaling pathway modulates epithelial to mesenchymal transition (EMT) and/or cell motility.
  • EMT epithelial to mesenchymal transition
  • Alterations of TGF- ⁇ signaling pathway are associated with human diseases, e.g., cancers, cardio-vascular diseases, fibrosis, reproductive disorders, and wound healing.
  • diseases e.g., cancers, cardio-vascular diseases, fibrosis, reproductive disorders, and wound healing.
  • the role of TGF- ⁇ in cancer is dependent on the disease setting (e.g., tumor stage and genetic alteration) and/or cellular context.
  • TGF- ⁇ can modulate a cancer- related process, e.g., by promoting tumor growth (e.g., inducing EMT), blocking anti-tumor immune responses, increasing tumor-associated fibrosis, or enhancing angiogenesis (Wakefield and Hill Nat Rev Cancer.2013; 13(5):328-41).
  • a combination comprising a TGF- ⁇ inhibitor described herein is used to treat a cancer in a late stage, a metastatic cancer, or an advanced cancer.
  • Preclinical evidence indicates that TGF- ⁇ plays an important role in immune regulation (Wojtowicz-Praga Invest New Drugs.2003; 21(1):21-32; Yang et al.
  • TGF- ⁇ can down-regulate the host-immune response via several mechanisms, e.g., shift of the T-helper balance toward Th2 immune phenotype; inhibition of anti-tumoral Th1 type response and M1-type macrophages; suppression of cytotoxic CD8+ T lymphocytes (CTL), NK lymphocytes and dendritic cell functions, generation of CD4+CD25+ T-regulatory cells; or promotion of M2-type macrophages with pro-tumoral activity mediated by secretion of immunosuppressive cytokines (e.g., IL10 or VEGF), pro-inflammatory cytokines (e.g., IL6, TNF ⁇ , or IL1) and generation of reactive oxygen species (ROS) with genotoxic activity (Yang et al.
  • immunosuppressive cytokines e.g., IL10 or VEGF
  • pro-inflammatory cytokines e.g., IL6, TNF ⁇ , or IL1
  • the TGF- ⁇ inhibitor comprises XOMA 089, or a compound disclosed in International Application Publication No. WO 2012/167143, which is incorporated by reference in its entirety.
  • XOMA 089 is also known as XPA.42.089.
  • XOMA 089 is a fully human monoclonal antibody that specifically binds and neutralizes TGF-beta 1 and 2 ligands.
  • the heavy chain variable region of XOMA 089 has the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGT ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWG QGTLVTVSS (SEQ ID NO: 284) (disclosed as SEQ ID NO: 6 in WO 2012/167143).
  • the light chain variable region of XOMA 089 has the amino acid sequence of: SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIP ERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO: 285) (disclosed as SEQ ID NO: 8 in WO 2012/167143).
  • XOMA 089 binds with high affinity to the human TGF- ⁇ isoforms. Generally, XOMA 089 binds with high affinity to TGF- ⁇ 1 and TGF- ⁇ 2, and to a lesser extent to TGF- ⁇ 3.
  • XOMA 089 is expected to bind to TGF- ⁇ 1, 2 and 3 at a dose of XOMA 089 as described herein.
  • XOMA 089 cross-reacts with rodent and cynomolgus monkey TGF- ⁇ and shows functional activity in vitro and in vivo, making rodent and cynomolgus monkey relevant species for toxicology studies.
  • the TGF- ⁇ inhibitor comprises fresolimumab (CAS Registry Number: 948564-73-6). Fresolimumab is also known as GC1008. Fresolimumab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2 and 3.
  • the heavy chain of fresolimumab has the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDI ANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQG TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP
  • the light chain of fresolimumab has the amino acid sequence of: ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPG IPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 281).
  • Fresolimumab is disclosed, e.g., in International Application Publication No. WO 2006/086469, and U.S.
  • IL-1 ⁇ Inhibitors The Interleukin-1 (IL-1) family of cytokines is a group of secreted pleotropic cytokines with a central role in inflammation and immune response. Increases in IL-1 are observed in multiple clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Dinarello (2010) Eur. J. Immunol. p.599-606).
  • the IL-1 family comprises, inter alia, IL-1 beta (IL-1b), and IL-1alpha (IL-1a).
  • IL-1b is elevated in lung, breast and colorectal cancer (Voronov et al. (2014) Front Physiol. p.114) and is associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol. p.277-88).
  • secreted IL-1b derived from the tumor microenvironment and by malignant cells, promotes tumor cell proliferation, increases invasiveness and dampens anti-tumor immune response, in part by recruiting inhibitory neutrophils (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Miller et al. (2007) J. Immunol.
  • an interleukin-1 beta (IL-1 ⁇ ) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the IL-1 ⁇ inhibitor is chosen from canakinumab, gevokizumab, Anakinra, or Rilonacept.
  • the IL-1 ⁇ inhibitor is canakinumab.
  • the IL-1 ⁇ inhibitor is canakinumab.
  • Canakinumab is also known as ACZ885 or ILARIS®.
  • Canakinumab is a human monoclonal IgG1/ ⁇ antibody that neutralizes the bioactivity of human IL-1 ⁇ .
  • Canakinumab is disclosed, e.g., in WO 2002/16436, US 7,446,175, and EP 1313769.
  • the heavy chain variable region of canakinumab has the amino acid sequence of: MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNW VRQAPGKGLEWVAIIWYDGDNQYYADSVKGRFTISRDNSKNTLYLQMNGLRAEDT AVYYCARDLRTGPFDYWGQGTLVTVSS (SEQ ID NO: 282) (disclosed as SEQ ID NO: 1 in US 7,446,175).
  • the light chain variable region of canakinumab has the amino acid sequence of: MLPSQLIGFLLLWVPASRGEIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKP DQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPFTFG PGTKVDIK (SEQ ID NO: 283) (disclosed as SEQ ID NO: 2 in US 7,446,175).
  • Canakinumab has been used, e.g., for the treatment of Cryopyrin Associated Periodic Syndromes (CAPS), in adults and children, for the treatment of systemic juvenile idiopathic arthritis (SJIA), for the symptomatic treatment of acute gouty arthritis attacks in adults, and for other IL-1 ⁇ driven inflammatory diseases.
  • Cryopyrin Associated Periodic Syndromes Cryopyrin Associated Periodic Syndromes
  • SJIA systemic juvenile idiopathic arthritis
  • IL-1 ⁇ driven inflammatory diseases e.g., for the treatment of Cryopyrin Associated Periodic Syndromes (CAPS), in adults and children, for the treatment of systemic juvenile idiopathic arthritis (SJIA), for the symptomatic treatment of acute gouty arthritis attacks in adults, and for other IL-1 ⁇ driven inflammatory diseases.
  • IL-1 ⁇ inhibitors can increase anti- tumor immune response, e.g., by blocking one or more functions of IL-1b including, e.g., recruitment of immunosuppressive neutrophils to the tumor microenvironment, stimulation of tumor angiogenesis, and/or promotion of metastasis (Dinarello (2010) Eur. J. Immunol. p. 599-606).
  • the combination described herein includes an IL-1 ⁇ inhibitor, canakinumab, or a compound disclosed in WO 2002/16436, and an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule).
  • IL-1 is a secreted pleotropic cytokine with a central role in inflammation and immune response. Increases in IL-1 are observed in multiple clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Dinarello (2010) Eur. J. Immunol. p.599-606).
  • IL-1b is elevated in lung, breast and colorectal cancer (Voronov et al.
  • an IL-1 ⁇ inhibitor e.g., canakinumab
  • an IL-1 ⁇ inhibitor enhances, or is used to enhance, an immune-mediated anti-tumor effect of an inhibitor of PD- 1 (e.g., an anti-PD-1 antibody molecule).
  • MDM2 inhibitors In some embodiments, a mouse double minute 2 homolog (MDM2) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer.
  • the human homolog of MDM2 is also known as HDM2.
  • an MDM2 inhibitor described herein is also known as a HDM2 inhibitor.
  • the MDM2 inhibitor is chosen from HDM201 or CGM097.
  • the MDM2 inhibitor comprises (S)-1-(4-chlorophenyl)-7- isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1- yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011/076786 to treat a disorder, e.g., a disorder described herein).
  • an MDM2 inhibitor comprises an inhibitor of p53 and/or a p53/Mdm2 interaction.
  • the MDM2 inhibitor comprises (S)-5-(5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)- 1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (also known as HDM201), or a compound disclosed in PCT Publication No.
  • WO2013/111105 to treat a disorder, e.g., a disorder described herein.
  • a therapeutic agent disclosed herein is used in combination with HDM201.
  • HDM201 is administered orally.
  • the combination disclosed herein is suitable for the treatment of cancer in vivo.
  • the combination can be used to inhibit the growth of cancerous tumors.
  • the combination can also be used in combination with one or more of: a standard of care treatment (e.g., for cancers or infectious disorders), a vaccine (e.g., a therapeutic cancer vaccine), a cell therapy, a radiation therapy, surgery, or any other therapeutic agent or modality, to treat a disorder herein.
  • the combination can be administered together with an antigen of interest.
  • Multispecific Binding Molecules the HIF-2a inhibitor of the present disclosure is used in combination with a multispecific binding molecule (“MBM”).
  • MBM multispecific binding molecule
  • the term “MBM” refers to a binding molecule that recognizes two or more different epitopes.
  • MBMs include bispecific binding molecules (“BBMs”), which recognize two different epitopes, and trispecific binding molecules (“TBMs”), which recognize three different epitopes.
  • BBMs bispecific binding molecules
  • TBMs trispecific binding molecules
  • the epitopes can be present on the same target or on different targets.
  • the MBMs suitable for use or administration in combination with the HIF-2a inhibitors of the disclosure thus comprise at least two antigen binding domains (“ABDs”) that bind to different epitopes.
  • ABSD antigen binding domain
  • the term “antigen-binding domain” or “ABD” as used herein refers to a portion of an MBM that has the ability to bind to an epitope non-covalently, reversibly and specifically.
  • TAA tumor-associated antigen
  • TAA tumor-associated antigen
  • a molecule typically a protein, carbohydrate, lipid or some combination thereof
  • a TAA is a marker that may be expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells.
  • a TAA may also be a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1-fold overexpression, 2-fold overexpression, 3- fold overexpression or more in comparison to a normal cell.
  • a TAA may be a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell.
  • Certain TAAs may be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of a normal cell.
  • TAA tumor-specific antigens
  • cancer refers to a disease characterized by the uncontrolled (and often rapid) growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, leukemia, multiple myeloma, asymptomatic myeloma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.
  • the TAA is expressed on cancerous B cells.
  • TAAs that can be targeted by the MBMs (e.g., BBMs or TBMs) useful in combination with the HIF-2a inhibitors of the disclosure include TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD44v6, B7H3, KIT, IL-13Ra2, IL-11Ra, PSCA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, MUC1, EGFR, EGFRvIII, NCAM, CAIX, LMP2, EphA2, fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, GD2, folate receptor alpha, folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a
  • the TAAs are expressed on cancerous blood cells, e.g., cancerous B cells.
  • TAAs expressed on cancerous B cells include, but are not limited to, CD19, CD20, CD22, CD123, BCMA, CD33, CLL1, CD138 (also known as Syndecan-1, SDC1), CS1, CD38, CD133, FLT3, CD52, TNFRSF13C (TNF Receptor Superfamily Member 13C, also referred to in the art as BAFFR: B-Cell-Activating Factor Receptor), TNFRSF13B (TNF Receptor Superfamily Member 13B, also referred to in the art as TACI: Transmembrane Activator And CAML Interactor), CXCR4 (C-X-C Motif Chemokine Receptor 4), PD-L1 (programmed death-ligand 1), LY9 (lymphocyte antigen 9, also referred to in the art as CD229), CD200, FCGR2B (Fc fragment
  • MBMs useful in combination with the HIF-2a inhibitors of the disclosure can engage the immune system, for example a T cell or an NK cell. Engagement of T cells can be achieved through targeting CD3 or other component(s) of a TCR complex, for example TCR- ⁇ , TCR- ⁇ , or a TCR- ⁇ / ⁇ dimer.
  • a TCR complex for example TCR- ⁇ , TCR- ⁇ , or a TCR- ⁇ / ⁇ dimer.
  • Exemplary ABDs that recognize CD3 or other components of the TCR complex are described in WO 2020/052692 and WO2019/104075 (for example see Sections 7.8.1, 7.8.2 and 7.8.3 of WO 2020/052692 and Section 6.5 of WO 2019/104075, incorporated by reference herein).
  • the MBMs can further include an ABD that binds to CD2, for example as generally disclosed in WO 2019/104075.
  • CD2 can be targeted through the use of its ligand CD58 and CD2-binding portions thereof as ABDs, as described in Section 6.6.2 of WO 2019/104075, incorporated by reference herein.
  • Engagement of NK cells can be achieved through targeting CD16, NKp46, NKG2D, NKp30, NKp44, NKp46, or a combination thereof, e.g., a combination of CD16 and NKp46. See, e.g., Hu et al., 2019, Front. Immunol. 10:1205, Gauthier et al., 2019, Cell 177(7):1701-1713.
  • the MBM is a BBM that binds to B cell maturation antigen, or BCMA, and a component of the TCR complex, preferably CD3.
  • the MBM is a TBM that binds to BCMA, a component of the TCR complex, preferably CD3, as well as either a second TAA or CD2 (e.g., through a CD58-based ABD, e.g., an ABD containing amino acids residues 30-123 of CD58).
  • BCMA B cell maturation antigen
  • CD3 a component of the TCR complex
  • BCMA cancers with increased expression of BCMA include some hematological cancers, such as multiple myeloma, Hodgkin’s and non- Hodgkin’s lymphoma, various leukemias, and glioblastoma.
  • WO 2019/229701 describes a number of MBMs that specifically bind to human BCMA as well as sequences of exemplary BCMA binding sequences that can be included in MBMs that bind to BCMA (see for example the BCMA binding sequences set disclosed in paragraph [0149] and Table 1 of WO 2019/229701, incorporated by reference herein).
  • WO 2019/229701 also describes BBMs that are directed against BCMA and CD3 (see for example Section 7.3.3.1 of PCT WO 2019/229701, incorporated by reference herein).
  • the MBM is a BBM that binds CD19 and a component of the TCR complex, preferably CD3.
  • the MBM is a TBM that binds to CD19, a component of the TCR complex, preferably CD3, as well as either a second TAA or CD2 (e.g., through a CD58-based ABD, e.g., an ABD containing amino acids residues 30- 123 of CD58).
  • a TBM that binds to CD19, CD3 and CD2 can have the general configuration depicted in Fig.1D of WO2019/104075, for example where X in Fig.1D is a CD19 ABD, X is a CD3 ABM and Z is a CD2 ABM, and more specifically the configurations shown in Figs.12A, 12B and 12C of WO2019/104075, all of which figures and accompanying text are incorporated by reference herein.
  • CD19 is expressed during early pre-B cell development and remains until plasma cell differentiation.
  • CD19 is expressed on both normal B cells and malignant B cells whose abnormal growth can lead to B-cell lymphomas.
  • CD19 is expressed on B-cell lineage malignancies, including, but not limited to non-Hodgkin’s lymphoma (B-NHL), chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
  • B-NHL non-Hodgkin’s lymphoma
  • chronic lymphocytic leukemia chronic lymphocytic leukemia
  • acute lymphoblastic leukemia acute lymphoblastic leukemia.
  • MBMs useful in combination with the HIF-2a inhibitors of the disclosure need not engage immune cells such as T cells or NK cells.
  • MBMs can be used to inhibit the angiogenesis pathways, for example by targeting VEG-F and another antigen such as Delta-like Ligand 4 (DLL-4), a transmembrane ligand for the Notch receptor or angiopoietin 2 (ANG-2).
  • DLL-4 Delta-like Ligand 4
  • ANG-2 angiopoietin 2
  • ABDs include antigen-binding fragments and portions of both immunoglobulin and non-immunoglobulin based scaffolds that retain the ability of binding an antigen non-covalently, reversibly and specifically.
  • the term “antigen-binding domain” encompasses antibody fragments that retain the ability of binding an antigen non-covalently, reversibly and specifically.
  • binding fragments include, but are not limited to, single-chain Fvs (scFv), a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment which consists of a VH domain; and an isolated complementarity determining region (CDR).
  • scFv single-chain Fvs
  • Fab fragment monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • Fd fragment consisting of the VH and CH1 domains
  • Fv fragment consisting of the VL and VH domains of a single arm of an antibody
  • dAb fragment which consists of a VH domain
  • CDR complementarity determining region
  • the MBMs of the disclosure can also include non-immunoglobulin-based ABDs, or a combination of immunoglobulin and non- immunoglobulin based ABDs.
  • Immunoglobulin-based ABDs that can be used are described in WO 2019/104075 and WO 2019/229701 (see for example Sections 7.2 and 7.3.1 of WO 2019/229701 and Section 6.2.1 of WO 2019/104075, incorporated by reference herein).
  • Non-immunoglobulin-based ABDs which include Kunitz domains, Adnexins, Affibodies, DARPins, Avimers, Anticalins, Lipocalins, fibronectins scaffolds, Affimers, and Fynomers, are described in WO 2019/104075 and WO 2019/229701 (see for example Section 7.4 of WO 2019/229701 and Section 6.3 of WO 2019/104075 and Fig.2 and Table 1 of Hober et al., 2019, Methods 154:143–152, incorporated by reference herein).
  • a suitable ABD is CD58 or a fragment thereof, as described in Section 6.6.2 of WO 2019/104075, incorporated by reference herein.
  • BBMs comprise at least two ABDs but can also contain more than two ABDs.
  • WO 2019/229701 relates to BCMA binding molecules, which can suitably be used in combination with the HIF-2a inhibitors of the disclosure
  • the BBM formats described therein are also applicable to any epitope / antigen pairing, for example any TAA and T cell receptor component pair or a TAA and NK cell activating receptor such as CD16, NKp46, NKG2D, NKp30, NKp44 or NKp46.
  • TBMs have at least three ABDs (i.e., a TBM is at least trivalent), but can also contain more than three ABDs.
  • a TBM can have four ABDs (i.e., is tetravalent), five ABDs (i.e., is pentavalent), or six ABDs (i.e., is hexavalent), provided that the TBM has at least one ABD that can bind one epitope, at least one ABD that can bind a second epitope, and at least one ABD that can bind a third epitope.
  • Exemplary trivalent, tetravalent, pentavalent, and hexavalent TBM configurations are described in WO 2019/104075 and WO 2019/195535 (for example Figure 1 and Section 6.4 of WO 2019/104075 and Figure 1 and Section 7.4 of WO 2019/195535, incorporated by reference herein).
  • WO 2019/104075 relates to TBMs that bind to CD2, CD3 (or another T cell receptor component) and a tumor-associated antigen (TAA) and WO 2019/195535 relates to TBMs that bind to CD3 (or another T cell receptor component) and two TAAs, both of which can suitably be used in combination with the HIF-2a inhibitors of the disclosure
  • the TBM formats described therein are also applicable to any combination of three epitopes or antigens.
  • a TBM can target a TAA and two NK cell activating receptors, for example any two of CD16, NKp46, NKG2D, NKp30, NKp44 or NKp46.
  • a TBM useful in combination with the HIF-2a inhibitors of the disclosure can target a TAA, CD16 and NKp46 (see, e.g., Gauthier et al., 2019, Cell 177(7):1701-1713).
  • the ABDs of an MBM (or portions thereof) can be connected to each other, for example, by short peptide linkers or by an Fc domain. Methods of connecting ABDs to form an MBM are described in WO 2019/104075 and WO 2019/229701 (see for example Section 7.3.2 of WO 2019/229701 and Section 6.2.2 of WO 2019/104075, incorporated by reference herein).
  • the MBMs can have an Fc region formed by the association of two Fc domains.
  • the Fc domains can be homodimeric or heterodimeric. Exemplary heterodimerization strategies, which include knob-into-hole and polar bridge formats, are described in Table 2 and Section 6.3.1.5 of WO 2019/104075 and subsections thereof, incorporated by reference herein.
  • the Fc region can have altered effector function.
  • effector function refers to an activity of an antibody molecule that is mediated by binding through a domain of the antibody other than the antigen binding domain, usually mediated by binding of effector molecules. Effector function includes complement-mediated effector function, which is mediated by, for example, binding of the C1 component of the complement to the antibody. Activation of complement is important in the opsonization and lysis of cell pathogens.
  • effector function also includes Fc receptor (FcR)- mediated effector function, which may be triggered upon binding of the constant domain of an antibody to an Fc receptor (FcR). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody- coated target cells by killer cells (called antibody-dependent cell-mediated cytotoxicity, or ADCC), release of inflammatory mediators, placental transfer and control of immunoglobulin production.
  • FcR Fc receptor
  • An effector function of an antibody may be altered by altering, e.g., enhancing or reducing, the affinity of the antibody for an effector molecule such as an Fc receptor or a complement component.
  • Fc regions with altered effector function are described, for example, in Sections 6.3.1.1 through 6.3.1.5 of WO 2019/104075, incorporated by reference herein, and can include, for example altered binding to one or more Fc receptors such as FcRN, modified disulfide bond architecture, or altered glycosylation patterns as compared to a wild type Fc region.
  • Exemplary MBMs that can be used in combination with the HIF-2a inhibitors of the disclosure are set forth in the foregoing tables and figures as well as in Table 14 below. Table 14.
  • Exemplary MBMs Accordingly, the molecules of the disclosure can be administered in combination with any MBM described [Table 14], for example to treat a cancer indicated for that MBM in [Table 14] above.
  • the MBM described in [Table 14] binds to BCMA, for example the AMG701, AMG701, CC-93269, JNJ-64007957, PF-06863135, or REGN5458.
  • the molecules of the disclosure can be used in combination with any of the foregoing BCMA-targeting MBMs to treat hematologic cancers such as multiple myeloma, Hodgkin’s and non- Hodgkin’s lymphoma, various leukemias, and glioblastoma.
  • the MBM described in [Table 14] binds to CD19, for example the MBM is A-319, AMG562, Blinatumomab, MGD011, or OXS-1550.
  • the molecules of the disclosure can be used in combination with any of the foregoing CD19-targeting MBMs to treat hematologic cancers such as non-Hodgkin’s lymphoma (B-NHL), chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
  • B-NHL non-Hodgkin’s lymphoma
  • the HIF-2a inhibitor of the present disclosure is used in combination with one or more of the therapeutic agents listed in Table 2156 or listed in the patent and patent applications cited in Table 15, to treat cancer.
  • Each publication listed in Table 15 is herein incorporated by reference in its entirety, including all structural formulae therein. Table 15.
  • Other Exemplary Therapeutic Agents Specific Embodiments Embodiment 1 A pharmaceutical combination comprising a HIF2 ⁇ inhibitor and one or more therapeutic agents.
  • Embodiment 2 The pharmaceutical combination of embodiment 1, wherein the HIF2 ⁇ inhibitor is a compound having the structure of formula (I):
  • Embodiment 3 The pharmaceutical combination of embodiment 1, wherein one or more therapeutic agents is a PD-1 inhibitor and optionally an A2aR antagonist.
  • Embodiment 4 The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224.
  • Embodiment 5 The pharmaceutical combination of embodiment 3, wherein the A2aR antagonist is selected from istradefylline, tozadenant, preladenant, vipadenan, taminadenant (PBF-509), ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER- 6947, VER-7835, CGS-15943, ZM-241,385, or MEDI9447.
  • Embodiment 6 The pharmaceutical combination of embodiment 3, wherein the HIF2 ⁇ inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are in 2 or 3 separate formulations.
  • Embodiment 7 The pharmaceutical combination of embodiment 3, wherein the HIF2 ⁇ inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are administered simultaneously or sequentially.
  • Embodiment 8 The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is spartalizumab and the A2aR antagonist is taminadenant.
  • Embodiment 9 The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is tislelizumab and the A2aR antagonist is taminadenant.
  • Embodiment 10 A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of any one of embodiments 1-9.
  • Embodiment 11 The method of embodiment 10, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
  • Embodiment 12 The method of embodiment 11, wherein the cancer is renal cell carcinoma.
  • Embodiment 13 The method of embodiment 10, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
  • Embodiment 14 The method of embodiment 13, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
  • Embodiment 15 The pharmaceutical combination of any one of embodiments 1-9, for use in the treatment of cancer.
  • Embodiment 16 The pharmaceutical combination of any one of embodiment 1-9, for use in the manufacture of a medicament for the treatment of cancer.
  • Embodiment 17 The pharmaceutical combination of embodiments 15 or 16, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
  • Embodiment 18 The pharmaceutical combination of embodiment 17, wherein the cancer is renal cell carcinoma.
  • Embodiment 19 The pharmaceutical combination of embodiments 15 or 16, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
  • Embodiment 20 The pharmaceutical combination of embodiment 19, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
  • Embodiment 21 Use of a pharmaceutical combination of any one of embodiments 1- 9 for the manufacture of a medicament for the treatment or prevention of cancer.
  • Embodiment 22 Use of a pharmaceutical combination of any one of embodiments 1- 9 for the treatment or prevention of cancer.
  • Embodiment 23 The use of embodiments 21 or 22, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
  • ccRCC clear cell renal cell carcinoma
  • GBM glioblastoma multiforme
  • glioma glioma
  • head and neck cancer hepatocellular carcinoma
  • kidney cancer lung cancer
  • malignant glioma ocular cancer
  • pancreatic cancer paraganglioma
  • pheochromocytoma prostate cancer
  • renal cell carcinoma renal cell carcinoma
  • Embodiment 25 The use of embodiment 21 or 22, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
  • Embodiment 26 The use of embodiment 25, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
  • Compound I is administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg every week.
  • Compound I is administered at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg once daily. In some embodiments, Compound I is administered at a dose of about 50 mg to about 600 mg. In some embodiments, Compound I is administered at a dose of about 400 mg. In some embodiments, Compound I is administered once every four weeks. In some embodiments, Compound I is administered at a dose of about 50 mg every week. In some embodiments, Compound I is administered at a dose of about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 100 mg every day. In some embodiments, Compound I is administered orally.
  • the HIF2 ⁇ inhibitor is the fumarate salt of Compound I.
  • the PD-1 inhibitor comprises spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224.
  • the PD-1 inhibitor comprises spartalizumab.
  • the PD-1 inhibitor comprises tislelizumab.
  • the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg every three or four weeks.
  • the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD- 1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg every three weeks. In some embodiments, the PD- 1 inhibitor is administered at a dose of about 300 mg every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg every four weeks.
  • the PD-1 inhibitor is administered at a dose of about 400 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered intravenously. In some embodiments, the PD-1 inhibitor is administered over a period of about 20 to about 40 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the A2aR antagonist is administered at a dose of about 80 mg, about 160 mg, or about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 80 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 160 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 240 mg twice daily.
  • the A2aR antagonist is administered orally.
  • Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily.
  • Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 100 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily.
  • Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily.
  • Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily.
  • compositions e.g., pharmaceutically acceptable compositions, which includes HIF-2a inhibitor (e.g., a HIF-2a inhibitor described herein), in combination with a second therapeutic agent (e.g., a therapeutic agent described herein), formulated together with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g. by injection or infusion).
  • the compositions of this disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions.
  • the mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular).
  • the composition is administered by intravenous infusion or injection. In another embodiment, the composition is administered by intramuscular or subcutaneous injection.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high antibody concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • a HIF-2a inhibitor e.g., a HIF-2a inhibitor described herein
  • a second therapeutic agent e.g., a therapeutic agent described herein
  • a formulation e.g., a dose formulation or dosage form
  • administration e.g., intravenous administration
  • the therapeutic agents e.g., inhibitors, antagonist or binding agents, can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • a therapeutic agent or compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions can also be administered with medical devices known in the art. Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the pharmaceutical compositions of the disclosure may include a "therapeutically effective amount” or a “prophylactically effective amount” of a compound of the disclosure.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound is outweighed by the therapeutically beneficial effects.
  • a "therapeutically effective dosage” preferably inhibits a measurable parameter, e.g., tumor growth rate by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • a measurable parameter e.g., tumor growth rate
  • the ability of a compound to inhibit a measurable parameter e.g., cancer, can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. Additional features or embodiments of the methods, compositions, dosage formulations, and kits described herein include one or more of the following. Further embodiments In another aspect, the disclosure features kits that may include a HIF-2a inhibitor and one or more additional agents in suitable packaging with written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • the kit may further contain another agent.
  • the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit.
  • the compound of the present invention and the agent are provided as a single composition within a container in the kit.
  • kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
  • the disclosure provides methods for further combination therapies in which, in addition to a HIF-2a inhibitor, one or more other therapeutic agents known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target proteins is used, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • such therapy includes but is not limited to the combination of the composition comprising a HIF-2a inhibitor as described herein with one or more of other HIF-2a inhibitors as described herein, chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, where desired, a synergistic or additive therapeutic effect.
  • Additional therapeutic agents useful in the methods of the invention include any agent capable of modulating a target molecule, either directly or indirectly.
  • Non-limiting examples of target molecules modulated by second agents include enzymes, enzyme substrates, products of transitions, antibodies, antigens, membrane proteins, nuclear proteins, cytosolic proteins, mitochondrial proteins, lysosomal proteins, scaffold proteins, lipid rafts, phosphoproteins, glycoproteins, membrane receptors, G-protein-coupled receptors, nuclear receptors, protein tyrosine kinases, protein serine/threonine kinases, phosphatases, proteases, hydrolases, lipases, phospholipases, ligases, reductases, oxidases, synthases, transcription factors, ion channels, RNA, DNA, RNAse, DNAse, phospholipids, sphingolipids, nuclear receptors, ion channel proteins, nucleotide-binding proteins, calcium-binding proteins, chaperones, DNA binding proteins, RNA binding proteins, scaffold proteins, tumor suppressors, cell cycle proteins, and hi stones.
  • Additional therapeutic agents may target one or more signaling molecules including but not limited to the following: 4EPB-1, 5 -lipoxygenase, Al, Abl, Acetyl-CoAa Carboxylase, actin, adaptor/scaffold proteins, adenylyl cyclase receptors, adhesion molecules, AFT, Aktl, Akt2, Akt3, ALK, AMPKs, APC/C, ARaf, Arf-GAPs, Arfs, ASK, ASKl, asparagine hydroxylase FIH transferases, ATF2, ATF-2, ATM, ATP citrate lyase, ATR, Auroras, B cell adaptor for PI3- kinase (BCAP), Bad, Bak, Bax, Bcl-2, Bcl-B, Bcl-w, Bcl- XL, Bid, Bik, Bim, BLNK, Bmf, BMP receptors, Bok, BRAF, Btk, Bub
  • Preferred additional therapeutic agents may target one or more signaling molecules including but not limited to the following: 4EPB-1, Aktl, Akt2, Akt3, asparagine hydroxylase FIH transferases, Cdk 1, Cdk 2, Cdk 4, Cdk 6, Cdk 7, Cdks, E2Fs, eIF4E-binding protein, FGF receptors, FOXO, Grb2, Grb2 associated binder (GAB), GSK3a, GSK3p, Hdm, HER receptors, HIFs, histone acetylases, histone deacetylases, Histone H3K4 demethylases, Hsp27, Hsp70, Hsp90s, hydrolases, hydroxylases, IL-2, inositol phosphatases, interferon- alpha (IFN-alpha), Mek 1, Mek 2, Met receptor, mTOR (in particular everolimus), Myc, p53, p70S6 Kinase,
  • this invention also relates to methods and pharmaceutical compositions for inhibiting abnormal cell growth in a mammal which comprises a therapeutically effective amount of a HIF-2a inhibitor in combination with an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).
  • an anti-cancer agent e.g., a chemotherapeutic agent
  • Many chemotherapeutics are presently known in the art and can be used in combination with a HIF-2a inhibitor disclosed herein.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, immunotherapeutic agents (in particular Anti-PD1, Anti-PD-L1, Anti-LAG-3, Anti-TIM-3, GITR agonist, IL15/IL-15Ra complexes, TGf beta inhibitors, A2aR inhibitors, Anti-CD73, Anti-ENTPD2), proapoptotic agents, and anti-androgens.
  • mitotic inhibitors alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, immunotherapeutic agents (in particular Anti-PD1, Anti-PD-L1, Anti-LAG-3, Anti-TIM-3, GITR agonist
  • Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Tykerb/Tyverb (lapatinib), Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents.
  • chemotherapeutic agents such as Tykerb/Tyverb (lapatinib), Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents.
  • Non-limiting examples of chemotherapeutic agents include 2,2',2"-trichlorotriethylamine; 2-ethylhydrazide; aceglatone; aldophosphamide glycoside; alkyl sulfonates such as busulfan, improsulfan and piposulfan; alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); aminolevulinic acid; amsacrine; anti-adrenals such as aminoglutethimide, mitotane, trilostane; antibiotics such as anthracyclins, actinomycins and bleomycins including aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunor
  • chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum or platinum analogs and complexes such as cisplatin and carboplatin; anti -microtubule such as diterpenoids, including paclitaxel and docetaxel, or Vinca alkaloids including vinblastine, vincristine, vinflu
  • the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, and Velcade®.
  • This invention further relates to a method for using the compounds or pharmaceutical composition in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, or implants, e.g., with corticosteroids, hormones, or used as radiosensitizers.
  • One such approach may be, for example, radiation therapy in inhibiting abnormal cell growth or treating the proliferative disorder in the mammal.
  • Radiotherapy refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site.
  • Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids.
  • the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir- 192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
  • the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90.
  • the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
  • the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells.
  • this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation, which comprises administering to the mammal an amount of a HIF-2a inhibitor, which is effective in sensitizing abnormal cells to treatment with radiation.
  • the amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • Further therapeutic agents that can be combined with a subject compound may be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.
  • compositions and methods further comprise administering, separately or simultaneously one or more additional agents (e.g.1, 2, 3, 4, 5, or more).
  • Additional agents can include those useful in wound healing.
  • additional agents include antibiotics (e.g. Aminoglycosides, Cephalosporins, Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones, Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's, Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes (e.g. Testosterone), Cholestanes (e.g.
  • Cholesterol Cholic acids (e.g. Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g. Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcotic analgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol, Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone, Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine), chemotherapy (e.g.
  • Cholic acids e.g. Cholic acid
  • Corticosteroids e.g. Dexamethasone
  • Estraenes e.g. Estradiol
  • Pregnanes e.g. Progesterone
  • narcotic and non-narcotic analgesics e.g. Morphine, Codeine, Heroin
  • anticancer drugs such as but not limited to Altretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine, dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin, Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone, Procarbazine, Streptozocin, Tamoxifen, Ten
  • 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; Decanoate; Deflazacort; Delatestryl; Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; D
  • Ethanolamines like diphenhydrmine carbinoxamine
  • Ethylenediamine like tripelennamine pyrilamine
  • Alkylamine like chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine
  • other anti-histamines like astemizole, loratadine, fexofenadine, bropheniramine, clemastine, acetaminophen, pseudoephedrine, triprolidine.
  • Example 1 Non-clinical pharmacology Compound I anti-tumor activity has been assessed in VHL-deficient ccRCC cell lines- derived and patient-derived xenograft mouse models. 786-O and SKRCO-1 xenograft mouse models The effects of Compound I on ratio tumor volume in the 786-0 xenograft mouse model (A) and SKRCO-1 xenograft mouse model (B) are illustrated in Fig.1. In the case of 786-0 subcutaneous xenografts (A), female nude mice were treated with Compound I at 0.3, 1, 3, 10 and 30 mg/kg p.o.
  • qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 34 days post tumor inoculation and lasted 20 days. Initial tumor volume at day 0 was approximately 280 mm 3 .
  • SKRCO-1 subcutaneous xenografts B
  • Changes in body weight represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals.
  • Initial body weight at day 0 was 24-26 g.
  • Initial tumor volume at day 0 was approximately 260 mm 3 .
  • Changes in body weight (%corr) represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals.
  • Initial body weight at day 0 was 24-26 g.
  • Compound I demonstrated dose-dependent efficacy.
  • Compound I achieved maximal attainable efficacy at doses of 40 mg/kg p.o. qd.
  • HKIX2967 tumor model The effects of Compound I on ratio tumor volume in HKIX2967 tumor models are illustrated in Fig.3.
  • Initial body weight at day 0 was 23-27 g.
  • Changes in body weight represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals.
  • Initial body weight at day 0 was 26-27 g.
  • Compound I also demonstrated dose-dependent efficacy.
  • Compound I achieved maximal attainable efficacy at doses of 40 mg/kg p.o. qd.
  • Compound I achieved maximal attainable efficacy in ccRCC tumor mouse models at doses with good tolerability.
  • Example 2 A Phase I/Ib, open-label, multi-center study of Compound I as a single agent and in combination with Everolimus or IO agents in patients with advanced/relapsed ccRCC and other malignancies with HIF2 ⁇ stabilizing mutations
  • a first-in-human (FIH) study will be run to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of Compound I as a single agent and in combination with everolimus, or spartalizumab plus taminadenant in adult patients with advanced, relapsed clear cell renal cell carcinoma (ccRCC).
  • FSH first-in-human
  • the study will also explore the use of single agent Compound I in patients older than 12 years old with malignancies harboring a HIF2 ⁇ stabilizing mutation.
  • Primary objectives To characterize the safety and tolerability of Compound I as a single agent and in combination with everolimus, or spartalizumab plus taminadenant in patients with advanced ccRCC and HIF (hypoxia-inducible factor) stabilizing mutations.
  • Endpoints for primary objectives Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory parameters, vital signs and electrocardiograms (ECGs)
  • AEs adverse events
  • SAEs serious adverse events
  • ECGs electrocardiograms
  • Tolerability Dose interruptions, reductions and dose intensity for both dose escalation and expansion
  • Escalation Only Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for Compound I as a single agent and in combinations
  • DLTs Dose Limiting Toxicities
  • Endpoints for secondary objectives ⁇ Overall Response Rate (ORR), Best Overall Response (BOR), Progression Free Survival (PFS) (for RD only), Duration of Response (DOR) (for RD only), Disease Control Rate (DCR) per RECIST v1.1 ⁇ Plasma concentration of Compound I and Taminadenant, whole blood concentration of Everolimus, serum concentration of Spartalizumab, and derived PK parameters for each analyte Exploratory objectives and endpoints
  • Study design This is a FIH, open-label, phase I/Ib, multi-center study consists of 3 dose escalation parts (Arms 1, 2 and 3), each followed by a dose expansion part.
  • the study design is summarized in Fig.4.
  • the first dose escalation part (Arm 1) will initially evaluate Compound I weekly (QW) dosing and may also include evaluation of daily (QD) dosing.
  • the dose escalation part for groups receiving Compound I in combination with everolimus (Arm 2) or spartalizumab and taminadenant (Arm 3) will open after at least two dose levels of single agent Compound I have been evaluated and shows to satisfy Escalation with Overdose Control (EWOC).
  • EWOC Escalation with Overdose Control
  • the dose and dosing frequency identified for Compound I single agent that satisfies EWOC at the time of start of combination will be used with the partners in the corresponding dose escalation arms of the study.
  • a staggered approach will be utilized for enrollment and will occur as follows: ⁇ 1st patient dosed, wait at least 24 hours ⁇ 2nd patient dosed, wait at least 24 hours ⁇ 3rd patient dosed
  • the optimal dose and dosing frequency is identified for Compound I as a single agent, the corresponding dose expansion arms will be opened in the single agent arm (Arm 1A and Arm 1B).
  • the dose expansion arms (Arm 2A and Arm 3A) for the combination therapies will be opened once the recommended dose (RD) for combination is identified in the escalation arms.
  • the dose expansion part of Compound I single agent will include two treatment arms: Arm1A will enroll ccRCC patients and Arm1B will enroll patients with malignancies harboring HIF2 ⁇ stabilizing mutations. Arm1B will enroll patients who are 12 years or older with refractory/relapsed malignancies and known mutations in at least one of the following genes as per local diagnostic test: VHL, FH, SDHx, EPAS1/HIF2A, ELOC/TCEB1.
  • Treatment period The treatment period commences on Day 1 of Cycle 1. For the purpose of scheduling and evaluations, a treatment cycle will consist of 28 days for patients. End of treatment period & Follow-up (FU) period-patients who discontinue treatment due to disease progression will be followed for safety evaluations 150 days after treatment discontinuation in Arm 3/3A and 30 days after treatment discontinuation in Arm 1/1A/1B and Arm 2/2A.
  • FU Treatment period & Follow-up
  • the study will be guided by a Bayesian Hierarchical Logistic Regression Model (BHLRM).
  • BHLRM Bayesian Hierarchical Logistic Regression Model
  • the BHLRM is a well-established method to estimate the MTD/RD in cancer subjects.
  • the adaptive BHLRM will be guided by the escalation with overdose control (EWOC) principle to control the risk of DLT in future subjects on study.
  • EWOC overdose control
  • Bayesian response adaptive models for small datasets has been accepted by EMEA (“Guideline on clinical trials in small populations”, February 1, 2007) and endorsed by numerous publications (Babb et al., “Cancer phase I clinical trials: efficient dose escalation with overdose control,” Stat Med.17(10):1103-20, 1998); (Neuenschwander et al.2008); (Neuenschwander et al.2010); (Neuenschwander et al.2014), and its development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
  • Preclinical safety data in 4-week GLP toxicology studies in rats (25 and 75 mg/kg/day or 200 mg/kg/wk) and dogs (10 mg/kg/day or 25 mg/kg/wk) provide support for a starting dose up to 25 mg daily or up to 120 mg weekly and provisional top doses of 100 mg daily or 600 mg weekly in humans.
  • the dose escalation of Compound I in FIH as a single agent will start with 50 mg weekly.
  • PK/PD data from mouse xenograft models indicate that pharmacological activity by inhibition of HIF2 ⁇ is anticipated at the starting dose. If the t1/2 of Compound I is significantly shorter than the predicted values, there is an option to reduce-dosing frequency from weekly to daily.
  • the provisional QD dose will start at 25 mg which is expected to be therapeutically active based on preclinical pharmacology data.
  • the provisional QD doses will be adjusted based on emerging PK data.
  • the starting dose and dose regimen of Compound I will be determined based on the data from the single agent arm of the study and will be at least one dose level below the highest dose of single agent Compound I that also satisfies the EWOC at the time of starting the combo.
  • the starting dose for spartalizumab will be 400 mg i.v. every 4 weeks and the starting dose for taminadenant will be 80 mg twice daily based on previous clinical studies.
  • boosting the activity of the immune checkpoint inhibitor spartalizumab, with the A2aR antagonist taminadenant and the HIF2 ⁇ inhibitor Compound I may complement the antitumor effects of this immunotherapy in addition to the direct anti-tumoral activity of Compound I in ccRCC.
  • Study Population This study will be conducted in adult patients (age 18 or older) with a confirmed diagnosis of advanced, relapsed clear cell Renal Cell Carcinoma following standard of care treatment; with the exception of a single agent expansion group (Arm 1B) that will be conducted in patients 12 years of age or older with HIF stabilizing mutations as described below (inclusion criteria #4) with no available therapies of proven clinical benefit.
  • ECOG performance status ⁇ 1 For Arm 1B 1. Male and female of age ⁇ 12 years of age. 2. Histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes: ⁇ Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease) ⁇ Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma) ⁇ Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g.
  • Hereditary paraganglioma and pheochromocytoma syndrome ⁇ Malignancies with EPAS1/HIF2A mutations ⁇ Malignancies with ELOC/TCEB1 mutations 3. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. 4. For patients age ⁇ 16 years: ECOG performance status ⁇ 1; for patients age ⁇ 12 and ⁇ 16 years: Lansky performance status ⁇ 70. Key exclusion criteria 1. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
  • Patients with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment prior to study entry and at doses ⁇ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment. 2.
  • ⁇ Absolute neutrophil count (ANC) ⁇ 1.0 ⁇ 109/L ⁇ Platelets ⁇ 75 ⁇ 109/L ⁇ Hemoglobin (Hgb) ⁇ 10g/dL ⁇ Serum creatinine > 1.5 ⁇ ULN or creatinine clearance ⁇ 40mL/min using Cockcroft- Gault formula ⁇ Total bilirubin > 1.5 ⁇ ULN , except for patients with Gilbert’s syndrome > 3.0 ⁇ ULN or direct bilirubin > 1.5 ⁇ ULN ⁇ Aspartate aminotransferase (AST) > 3 ⁇ ULN ⁇ Alanine aminotransferase (ALT) > 3 ⁇ ULN ⁇ Serum electrolytes ⁇ grade 2 despite adequate supplementation.
  • AST Aspartate aminotransferase
  • ALT Alanine aminotransferase
  • the starting dose for taminadenant in combination with Compound I and spartalizumab is 80 mg twice daily (BID), while spartalizumab is fixed at 400 mg Q4W intravenously.
  • the starting doses for the combination arms must satisfy EWOC criteria.
  • Provisional dose levels Table 17 describes the provisional starting dose and dose levels of Compound I with weekly dosing regimen that may be evaluated during the trial. Dose level -1 represents a dose that may be evaluated if higher doses are not well tolerated. The actual doses evaluated in the study may be different from those shown in the table, as clinical experience is used to elucidate the relationships between dose, systemic exposure, pharmacological activity and toxicity. Additional dose levels may be added during the study. Table 17. Provisional QW dose levels for Compound I (Scenario 1)
  • Efficacy assessments ⁇ Tumor assessment per RECIST v1.1. In Arm 3, iRECIST will also be utilized.
  • Pharmacokinetic assessments ⁇ Plasma concentration of Compound I and taminadenant (and its metabolite NJI765) serum concentration of spartalizumab and derived PK parameters.
  • Key safety assessments ⁇ Adverse event (AE) monitoring will be conducted on ongoing basis, with physical examinations, monitory of laboratory markers and other safety parameters (e.g. changes in ECG and EEG). ⁇ Frequency, severity and seriousness of AEs, laboratory abnormalities will be evaluated.

Abstract

The present disclosure relates to pharmaceutical combinations comprising inhibitors of hypoxia-inducible factor-2α (HIF2α). The combination therapies can be used to treat or prevent cancerous conditions and disorders.

Description

COMBINATION THERAPIES TECHNICAL FIELD The present disclosure relates to pharmaceutical combinations comprising inhibitors of hypoxia-inducible factor-2α (HIF2α). The combination therapies can be used to treat or prevent cancerous conditions and disorders. BACKGROUND Hypoxia-inducible factors (HIFs) such as HIF1α and HIF2α are transcription factors well known as master regulators of oxygen homeostasis that control transcriptional responses to reduced oxygen availability (hypoxia). HIFs are heterodimeric proteins composed of an oxygen-regulated HIF-α subunit (HIF1α and HIF2α) and a constitutively expressed HIF-1β subunit also known as ARNT. Under well-oxygenated or normoxic conditions, HIF-α is bound by the von Hippel-Lindau (VHL) protein, which recruits a ubiquitin ligase that targets HIF-α for proteasomal degradation (Kaelin et al, Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell; 30(4):393-402 (2008)). VHL binding is dependent upon hydroxylation of a specific proline residue in HIF-α by the prolyl hydroxylases PHD, which use oxygen as a substrate such that its activity is inhibited under hypoxic conditions. HIF1α and HIF2α regulate the expression of many genes involved in critical physiological functions such as development, metabolism, angiogenesis, cell proliferation and cell survival. While HIF1α is broadly expressed, HIF2α transcripts are restricted to particular cell types, including vascular endothelial cells, neural crest cell derivatives, lung type II pneumocytes, liver parenchyma, and interstitial cells in the kidney. HIF2α is described as a key mediator of the cellular adaptation to oxygen deprivation (hypoxia), playing important roles in physiological processes, such as erythropoiesis and vascularization. HIF2α is also required for normal embryonic development, with postnatal ablation leading to severe anemia and impaired erythroid development. Hypoxia and HIFs activation are reported in many advanced human cancers such as cancers of the brain, breast, colon, lung and renal cell carcinoma. Independently of oxygen levels in clear cell renal cell carcinoma (ccRCC), frequently reported genetic alterations in the VHL gene (e.g. mutation or silencing) leads to the accumulation of HIF-α in the tumor in normoxic conditions. While HIF2α is expressed in most ccRCC tumor samples, only a subset accumulates HIF1α (Gordan et al., HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma, Cancer Cell, 9;14(6):435-46 (2008)). Furthermore, in ccRCC, HIF2α is described to be the key oncogenic event while HIF1α displays tumor suppressor properties (Shen et al., The VHL/HIF axis in clear cell renal carcinoma, Semin Cancer Biol., 23(1):18-25 (2013)). For example, overexpression of HIF2α leads to an increase in the in vivo growth of the VHL-deficient 786-0 RCC tumor xenografts. In contrast, down regulation of HIF2α by inducible shRNA or pharmacological inhibition seems sufficient to suppress tumor growth in VHL-defective RCC tumor models (Kondo, 2002; Kondo, 2003; Zimmer, 2004; Cho, 2016; Chen 2016). Clinical data using HIF2α selective inhibitors in ccRCC have further supported HIF2α as an attractive target for anti- cancer therapy. In addition, HIF2α selective inhibitors also seem to show clinical benefit in ccRCC patients who had been administered with prior therapies, including TKIs (Courtney et. al., Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor- 2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma, J Clin Oncol, 36 (9), 867-874 (2018)). Current treatments for advanced/metastatic RCC disease are based on either antiangiogenic treatment with tyrosine kinase inhibitors (TKIs) affecting downstream targets of the HIFs (VEGF, VEGFR, PDGFR) or immunotherapy with immune checkpoint inhibitors. The combination of PD-1 blockade and TKIs is emerging as standard of care in RCC. The combination of Pembrolizumab plus Axitinib (Keynote-426) has resulted in significantly longer overall survival (OS) compared with Sunitinib, achieving an ORR of 59% with a median PFS of 15.1 months (Rini et al., Pembrolizumab plus Sunitinib for Advanced Renal-Cell Carcinoma, N Engl J Med; 380:1116-1127 (2019)). Nevertheless, RCC disease will progress in almost all patients. Outcomes in relapsed RCC are poor and new drugs with new targets and mechanisms of action relevant to renal-cell carcinoma are needed. There is pre-clinical data to support the potential synergistic effect of HIF2α inhibition with immunotherapy agents. When ccRCC xenografts were treated with PT2977 (also known as HIF2α inhibitor MK-6482), the tumors demonstrated a reduction in the number of immunosuppressive myeloid-derived cells, in addition to an influx of mature dendritic cells (Wong et al., PT2977, a novel HIF-2a antagonist, has potent antitumor activity and remodels the immunosuppressive tumor microenvironment in clear cell renal cell cancer [abstract]. Mol Cancer Ther;17(1 Suppl):nr B140A (2018)). These observations suggest that HIF2α inhibition, beyond the known effects on angiogenesis and direct tumor cell proliferation and apoptosis, has the potential to remodel the immuno-suppressive tumor microenvironment, and suggests this novel mechanism may be a promising candidate for use in combination with other agents to enhance T cell function (Chiappori et al., A Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC, J Clin Oncol; 36(15 suppl):9089-9089 (2018)). In addition, effects on the immuno-suppressive tumor microenvironment could be partially explained by the induction of HIF1α and its activation of the adenosine pathway. HIF1α binds to the promotor region of CD73 (ecto-5’-nucleotidase) and increases CD73 enzyme levels, which in turn increases adenosine levels in the tumor microenvironment. A2aR and A2bR are also direct transcriptional targets of HIF2α and HIF1α, respectively, that may increase the adenosine immunosuppressive pathway even further on these tumors (Lee at al., Hypoxia signaling in human diseases and therapeutic targets, Exp Mol Med; 51(6):1-13 (2019)). The first-in-human study of Ciforadenant, an A2aR antagonist, has demonstrated antitumor activity as single-agent and in combination with anti–PD-L1 therapy in patients with refractory RCC, in both the immunotherapy naive and pretreated settings (Lawrence et al., Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer, Cancer Discov, (10) (1) 40-53 (2020)). However, this combined immunotherapy may not be sufficient if a tumor is protected by the HIFs–mediated immunosuppressive activity. The addition of a HIF2α inhibitor may complement the antitumor effects of combined immunotherapy by preventing the HIF-driven accumulation of immunosuppressive extracellular adenosine and other immunosuppressive molecules in addition to the direct antitumoral activity of the HIF2α inhibitor in ccRCC cells. In spite of numerous treatment options for cancer patients, there remains a need for effective and safe therapeutic agents and a need for their preferential use in combination therapy. In particular, there is a need for effective methods of treating cancers, especially those cancers that have been resistant and/or refractive to current therapies. SUMMARY Disclosed herein, at least in part, are pharmaceutical combinations comprising an inhibitor of hypoxia-inducible factor-2α (HIF2α) and one or more therapeutic agents. The one or more therapeutic agents can be chosen from one or more of: an inhibitor of an inhibitory molecule (e.g., an inhibitor of a checkpoint inhibitor), an activator of a costimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein. In one embodiment, the pharmaceutical combination further comprises an inhibitor of humanized anti-programmed death-1 (PD-1) IG4 antibody and an adenosine receptor-2a (A2aR) antagonist. Pharmaceutical compositions and dose formulations relating to the combinations described herein are also provided. The combinations described herein can be used to treat or prevent disorders, such as cancerous disorders (e.g., solid cancers). Thus, methods, including dosage regimens, for treating various disorders using the combinations are disclosed herein. In one aspect, the disclosure features a method of treating cancer, e.g., renal cell carcinoma (RCC) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2α inhibitor and one or more therapeutic agents. In another aspect, the disclosure features a method of treating a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2α inhibitor and one or more therapeutic agents. In another aspect, the disclosure features a method of treating cancer, e.g., renal cell carcinoma (RCC) in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2α inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist. In another aspect, the disclosure features a method of treating a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes), in a subject, comprising administering to the subject a pharmaceutical combination of a HIF2α inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist. In some embodiments, the HIF2α inhibitor is the compound (S)-1'-chloro-8- (difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro-3H,6'H-spiro[imidazo[1,2- a]pyridine-2,5'-isoquinoline], or a pharmaceutically acceptable salt thereof, having the structure of formula (I), or Compound I, as originally described in PCT/CN2020/087831 under Example 31. In some embodiments, Compound I is administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg once daily. In some embodiments, Compound I is administered at a dose of about 50 mg to about 600 mg. In some embodiments, Compound I is administered at a dose of about 400 mg. In some embodiments, Compound I is administered once every four weeks. In some embodiments, Compound I is administered at a dose of about 50 mg every week. In some embodiments, Compound I is administered at a dose of about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 100 mg every day. In some embodiments, Compound I is administered orally. In some embodiments, the HIF2α inhibitor is the fumarate salt of Compound I. In some embodiments, the PD-1 inhibitor comprises spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224. In some embodiments, the PD-1 inhibitor comprises spartalizumab. In some embodiments, the PD-1 inhibitor comprises tislelizumab. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg every three or four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD- 1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg every three weeks. In some embodiments, the PD- 1 inhibitor is administered at a dose of about 300 mg every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered intravenously. In some embodiments, the PD-1 inhibitor is administered over a period of about 20 to about 40 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the A2aR antagonist comprises istradefylline, tozadenant, preladenant, vipadenan, taminadenant (PBF-509), ATL-444, MSX-3, SCH-58261, SCH- 412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, ZM-241,385, or MEDI9447. In some embodiments, the A2aR antagonist is taminadenant. In some embodiments, the A2aR antagonist is administered at a dose of about 80 mg, about 160 mg, or about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 80 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 160 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered orally. In some embodiments, the HIF2α inhibitor is administered on the same day as the A2aR antagonist. In some embodiments, the HIF2α inhibitor is administered before the A2aR antagonist. In some embodiments, the HIF2α inhibitor is administered after the A2aR antagonist. In some embodiments, the HIF2α inhibitor is administered at the same time as the A2aR antagonist. In some embodiments, the PD-1 inhibitor is administered on the same day as the HIF2α inhibitor is administered on the same day as the A2aR antagonist. In some embodiments, the PD-1 inhibitor is administered after the HIF2α inhibitor and the A2aR antagonist are administered. The methods described can be used to treat proliferative disease. In some embodiments, the proliferative disease is a cancer (e.g., a solid tumor). In some embodiments, the cancer is adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma. In a particular embodiment, the cancer is renal cell carcinoma, more particularly, clear cell renal cell carcinoma (ccRCC). In a particular embodiment, the cancer is glioblastoma. In a particular embodiment, the cancer is breast cancer. In a particular embodiment, the cancer is colorectal cancer. In some embodiments, the proliferative disease is a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes). In a particular embodiment, the proliferative disease is a malignancy with VHL mutations (e.g. Von Hippel-Lindau disease). In a particular embodiment, the proliferative disease is a malignancy with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma). In a particular embodiment, the proliferative disease is a malignancy with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome). In a particular embodiment, the proliferative disease is a malignancy with EPAS1/HIF2A mutations In a particular embodiment, the proliferative disease is a malignancy with ELOC/TCEB1 mutations. In another aspect, the disclosure features a composition (e.g., one or more compositions or dosage forms), that includes a HIF2α inhibitor and one or more anticancer therapies, as described herein. In certain embodiments, the composition includes a HIF2α inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist. Formulations, e.g., dosage formulations, and kits, e.g., therapeutic kits, that include a HIF2α inhibitor, are also described herein. In certain embodiments, the kit includes a HIF2α inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist. In certain embodiments, the composition or kit is used to treat renal cell carcinoma (RCC). In certain embodiments, the composition or kit is used to treat a malignancy with one or more HIF stabilizing mutations (e.g., mutations in VHL, FH, SDHx, EPAS1/HIF2A, or ELOC/TCEB1 genes). All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig.1 shows anti-tumor activity of Compound I (CPD I) in 786-O (A) and SKRCO-1 (B) in VHL- ccRCC cell lines-derived xenograft mouse models. Fig.2 shows anti-tumor activity of Compound I (CPD I) in female nude mice bearing HKIX2207 human primary ccRCC xenografts. Fig.3 shows anti-tumor activity of Compound I (CPD I) in female nude mice bearing HKIX2967 human primary ccRCC xenografts. Fig.4 shows the study design of the Phase I/Ib, open-label, multi-center study of Compound I (CPD I) as a single agent and in combination with Everolimus or IO agents in patients with advanced, relapsed ccRCC and other malignancies with HIF2α stabilizing mutations. DETAILED DESCRIPTION The present disclosure provides pharmaceutical combinations comprising a HIF2α inhibitor and one or more therapeutic agents. The disclosure further provides formulations, methods of treating a disease (e.g., cancer), dosing, dosing regimens and schedules, and other relevant clinical features. According to the present disclosure, agents that can be used in combination with a HIF2α inhibitor can be, but are not limited to, an inhibitor of an inhibitory molecule (e.g., a checkpoint inhibitor), an activator of a costimulatory molecule, a chemotherapeutic agent, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, or any of the therapeutic agents disclosed herein. In some embodiments, a HIF2α inhibitor described herein is used in combination with one or more therapeutic agents chosen from: a PD-1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2aR antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist, for treating a patient with cancer. In one embodiment, the HIF2α inhibitor described herein is used in combination with a PD-1 inhibitor and an A2aR antagonist, for treating a patient with cancer. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions Certain terms used herein are described below. Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the meaning that is commonly understood by one of skill in the art to which the present disclosure belongs. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used herein, the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise. “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Pharmaceutical Administration and Treatment Terms and Conventions The term “subject” or “patient” as used herein includes animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals. In the preferred embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer. An “effective amount” or “therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure in combination with the second therapeutic agent that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. As used herein, the terms “pharmaceutical formulation” or “pharmaceutical composition” refers to a composition comprising one or more pharmaceutically active ingredients. In particular, a pharmaceutical formulation comprises (a) a HIF-2a inhibitor of the present disclosure and (b) one or more additional therapeutic agents, preferably also including at least one pharmaceutically acceptable excipient or carrier, and more preferably where the pharmaceutically acceptable excipient or carrier does not react with the pharmaceutically active ingredients. “Carrier” encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. A patient is “in need of” a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human). As used herein, the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term “treat”, “treating”, or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. In specific embodiments, the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat”, “treatment” and “treating” -refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments, the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count. “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. “Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. “Administer”, “administering”, or “administration” means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound, formulation, or combination comprising a compound or formulation to the subject, which can form an equivalent amount of active compound within the subject’s body. “Prodrug” means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. “HIF-2a inhibitor of the present disclosure” refers to the HIF2α inhibitor is the compound (S)-1'-chloro-8-(difluoromethoxy)-8',8'-difluoro-6-(trifluoromethyl)-7',8'-dihydro- 3H,6'H-spiro[imidazo[1,2-a]pyridine-2,5'-isoquinoline], or a pharmaceutically acceptable salt thereof, having the structure of formula
Figure imgf000012_0001
, or Compound I, as originally described in PCT/CN2020/087831 under Example 31. The term “combination therapy” or “in combination with” refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer). Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co- administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. The combination therapy can provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median- effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul.22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. The term “pharmaceutical combination” as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect The terms “fixed combination” and “fixed dose” and “single formulation” as used herein refer to single carrier or vehicle or dosage forms formulated to deliver an amount, which is jointly therapeutically effective for the treatment of cancer, of two or more therapeutic agents to a patient. The single vehicle is designed to deliver an amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension. The term “non-fixed combination,” “kit of parts,” and “separate formulations” means that the active ingredients, e.g., the HIF-2a inhibitor of the present disclosure and second agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the warm- blooded animal in need thereof. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. The term “unit dose” is used herein to mean simultaneous administration of two or three agents together, in one dosage form, to the patient being treated. In some embodiments, the unit dose is a single formulation. In certain embodiments, the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, or the like, administered to the patient at the same time. An “oral dosage form” includes a unit dosage form prescribed or intended for oral administration. The terms “comprising” and “including” is used herein in their open-ended and non- limiting sense unless otherwise noted. “Cancer” means any cancer caused by the uncontrolled proliferation of aberrant cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. For example, cancers include, but are not limited to, mesothelioma, leukemias, and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin’s lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms’ tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, and nasopharyngeal), esophageal cancer, genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer, pancreatic cancer, melanoma, and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin’s syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). Additional exemplary forms of cancer which may be treated by the compounds and compositions described herein include, but are not limited to, adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma. The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. The “second agent,” “one or more second agents,” or “one or more additional therapeutic agents” can be an anti-cancer agent. The term “anti-cancer” or “anti-cancer agent” pertains to an agent which treats a cancer (i.e., a compound, antibody, etc. which is useful in the treatment of a cancer). The anti-cancer effect may arise through one or more mechanisms, including, but not limited to, the regulation of cell growth or proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cells into neighboring normal structures), the inhibition of a checkpoint molecule, or the promotion of apoptosis. The anti-cancer agent is can be an anti-proliferative agent or an immunomodulatory agent. In one embodiment, the second agent is an immunomodulatory agent. The term “antiproliferative” or “antiproliferative agent” as used herein pertains to an agent, which inhibits cell growth or cell proliferation. The anti-proliferative agent can be a cytotoxic agent (e.g., alkylating agent, antimetabolites, etc.), a targeted agent (e.g., EGF inhibitor, Tyrosine protein kinase inhibitor, angiogenesis inhibitor, etc.), or a hormonal agent (e.g., estrogens selective estrogen receptor modulators, etc.). Examples of antiproliferative agents include alkylating agents, anti-metabolites, an antibiotic, a detoxifying agent, an EGFR inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a multi-kinase inhibitor, a serine/threonine inhibitor, a tyrosine kinase inhibitor, a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, an inhibitor of a molecular target or enzyme. The term “immunomodulatory agent” is agent that modifies the immune response or the functioning of the immune system (as by the stimulation of antibody formation or the inhibition of white blood cell activity). The immunomodulatory agents can be an immunomodulator, a cytokine, a vaccine, or an anti-body. The term “immunomodulator” is an inhibitor of an immune checkpoint molecule. “Simultaneously” or “simultaneous” when referring to a method of treating or a therapeutic use means with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time. “Separately” or “separate” when referring to a method of treating or a therapeutic use means with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time. By therapeutic administration “over a period of time” means, when referring to a method of treating or a therapeutic use with a combination of the HIF-2a inhibitor of the present disclosure and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times. In some embodiments, the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins. In this way, it is possible to administer a one of the active ingredients (i.e., the HIF-2a inhibitor of the present disclosure or one or more second agent(s)) for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, the HIF-2a inhibitor of the present disclosure and the one or more second agents the therapeutic administration over a period of time could be such that the HIF-2a inhibitor of the present disclosure is administered once every day or once a week and the one or more second agent(s) is administered once every four weeks.) In embodiments, the additional therapeutic agent is administered at a therapeutic or lower-than therapeutic dose. In certain embodiments, the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower when the second therapeutic agent is administered in combination with the first therapeutic agent, e.g., HIF2α inhibitor, than when the second therapeutic agent is administered individually. In certain embodiments, the concentration of the first therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower when the first therapeutic agent is administered in combination with the second therapeutic agent than when the first therapeutic agent is administered individually. In certain embodiments, in a combination therapy, the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80- 90% lower. In certain embodiments, in a combination therapy, the concentration of the first therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the first therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. The term “inhibition,” “inhibitor,” or “antagonist” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of an activity, e.g., a PD-1 or PD-L1 activity, of at least 5%, 10%, 20%, 30%, 40% or more is included by this term. Thus, inhibition need not be 100%. The term “activation,” “activator,” or “agonist” includes an increase in a certain parameter, e.g., an activity, of a given molecule, e.g., a costimulatory molecule. For example, increase of an activity, e.g., a costimulatory activity, of at least 5%, 10%, 25%, 50%, 75% or more is included by this term. The term “anti-cancer effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in life expectancy, decrease in cancer cell proliferation, decrease in cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An “anti-cancer effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies in prevention of the occurrence of cancer in the first place. The term “anti-tumor effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival. The term “antigen presenting cell” or “APC” refers to an immune system cell such as an accessory cell (e.g., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC’s) on its surface. T-cells may recognize these complexes using their T-cell receptors (TCRs). APCs process antigens and present them to T-cells. The term “costimulatory molecule” refers to the cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response. Costimulatory molecules include, but are not limited to, an MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signalling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. “Immune effector cell,” or “effector cell” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes. “Immune effector” or “effector” “function” or “response,” as that term is used herein, refers to function or response, e.g., of an immune effector cell, that enhances or promotes an immune attack of a target cell. E.g., an immune effector function or response refers a property of a T or NK cell that promotes killing or the inhibition of growth or proliferation, of a target cell. In the case of a T cell, primary stimulation and co-stimulation are examples of immune effector function or response. The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. The compositions, formulations, and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 85%, 90%.91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein. In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein. The term “functional variant” refers to polypeptides that have a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally-occurring sequence. Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases, for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid (SEQ ID NO: 1) molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See ncbi.nlm.nih.gov. As used herein, the term “hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions” describes conditions for hybridization and washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at about 45oC, followed by two washes in 0.2X SSC, 0.1% SDS at least at 50oC (the temperature of the washes can be increased to 55oC for low stringency conditions); 2) medium stringency hybridization conditions in 6X SSC at about 45oC, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60oC; 3) high stringency hybridization conditions in 6X SSC at about 45oC, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65oC; and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65oC, followed by one or more washes at 0.2X SSC, 1% SDS at 65oC. Very high stringency conditions (4) are the preferred conditions and the ones that should be used unless otherwise specified. It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions. The term "amino acid" is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term "amino acid" includes both the D- or L- optical isomers and peptidomimetics. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). The terms “polypeptide,” “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures. The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," or "polynucleotide sequence," and "polynucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a nonnatural arrangement. The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature. Various aspects of the invention are described in further detail below. Additional definitions are set out throughout the specification. Combination Therapy The HIF-2a inhibitor of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. For example, synergistic effects can occur with other cancer agents. Where the HIF-2a inhibitor of the disclosure are administered in conjunction with other therapies, dosages of the co-administered HIF-2a inhibitor will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth. The HIF-2a inhibitor can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure. In one aspect, the HIF-2a inhibitor of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof. In some embodiments, the HIF-2a inhibitor of the present disclosure are administered in combination with one or more second agent(s) selected from a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2aR antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, a CTLA-4 inhibitor, a TIGIT inhibitor, a chimeric antigen receptor, an estrogen receptor antagonist, a CDK4/6 inhibitor, a CXCR2 inhibitor, a CSF- 1/1R binding agent, an IDO inhibitor, a Galectin inhibitor, a MEK inhibitor, a c-MET inhibitor, a TGF-b inhibitor, an IL-1b inhibitor, an MDM2 inhibitor, and a TLR7 agonist, to treat a disease, e.g., cancer. In some embodiments, the HIF-2a inhibitor is used in combination with an agonist of a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand. In some embodiments, the HIF-2a inhibitor is used in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFβ. In another embodiment, one or more chemotherapeutic agents are used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer, wherein said chemotherapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl- 5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5- fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX- DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®). In other embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with one or more other anti-HER2 antibodies, e.g., trastuzumab, pertuzumab, margetuximab, or HT-19 described above, or with other anti-HER2 conjugates, e.g., ado- trastuzumab emtansine (also known as Kadcyla®, or T-DM1). In other embodiments, the HIF-2a inhibitors of the present disclosure is used in combination with one or more tyrosine kinase inhibitors, including but not limited to, EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors, for treating a disease, e.g., cancer. For example, tyrosine kinase inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro- 5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.6,780,996); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); Zactima (ZD6474); and Imatinib or Imatinib mesylate (Gilvec® and Gleevec®). Epidermal growth factor receptor (EGFR) inhibitors include but are not limited to, Erlotinib hydrochloride (Tarceva®), Gefitinib (Iressa®); N-[4-[(3-Chloro-4- fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]- 4(dimethylamino)-2-butenamide, Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5- yl)methyl)piperidin-3-ol (BMS690514); Canertinib dihydrochloride (CI-1033); 6-[4-[(4- Ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]- 7H-Pyrrolo[2,3-d]pyrimidin-4- amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569); Afatinib (Gilotrif®); Neratinib (HKI-272); N-[4-[[1-[(3-Fluorophenyl)methyl]-1H-indazol-5- yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3- morpholinylmethyl ester (BMS599626); N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7- [[(3a^,5^,6a^)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]- 4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-Phenylethyl]amino]-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-phenol (PKI166, CAS187724-61-4). EGFR antibodies include but are not limited to, Cetuximab (Erbitux®); Panitumumab (Vectibix®); Matuzumab (EMD-72000); Nimotuzumab (hR3); Zalutumumab; TheraCIM h- R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1). Other HER2 inhibitors include but are not limited to, Neratinib (HKI-272, (2E)-N-[4- [[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4- (dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443); Lapatinib or Lapatinib ditosylate (Tykerb®); (3R,4R)-4-amino-1-((4-((3- methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4-(dimethylamino)-2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1- [(3-Fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]- carbamic acid, (3S)-3-morpholinylmethyl ester (BMS 599626, CAS 714971-09-2); Canertinib dihydrochloride (PD183805 or CI-1033); and N-(3,4-Dichloro-2-fluorophenyl)-6- methoxy-7-[[(3a^,5^,6a^)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]- 4- quinazolinamine (XL647, CAS 781613-23-8). HER3 inhibitors include but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A. MET inhibitors include but are not limited to, Cabozantinib (XL184, CAS 849217- 68-1); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4- yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); Cryzotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-Dihydro-1H-indol-1- ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2- yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-Chlorophenyl)-3-({3,5- dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2- oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-Chlorophenyl)-3-{[3,5-dimethyl-4-(3- morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU11606); 6-[Difluoro[6-(1-methyl-1Hpyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3- yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(Quinolin-6-ylmethyl)-1H- [1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27- 4); N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (MK2461, CAS 917879-39-1); 6-[[6-(1- Methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin 3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7); and (3Z)-5-[[(2,6-Dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4- [[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3- dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7). IGFR inhibitors include but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. See e.g., Yee, JNCI, 104; 975 (2012) for review. In another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more proliferation signalling pathway inhibitors, including but not limited to, MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors, and CDK inhibitors, for treating a disease, e.g., cancer. For example, mitogen-activated protein kinase (MEK) inhibitors include but are not limited to, XL-518 (also known as GDC-0973, CAS No.1029872-29-4, available from ACC Corp.); 2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. WO2000035436); N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]- benzamide (also known as PD0325901 and described in PCT Publication No. WO2002006213); 2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in US Patent No.2,779,780); N-[3,4-Difluoro-2-[(2-fluoro-4- iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]- cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO2007014011); (3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16- trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO2003076424); 2’-Amino-3’- methoxyflavone (also known as PD98059 available from Biaffin GmbH & Co., KG, Germany); (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9); and Trametinib dimethyl sulfoxide (GSK- 1120212, CAS 1204531-25-80). BRAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX- 4032, CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®). Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(1H- Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4- yl]morpholine (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib; and described in PCT Publication Nos. WO 09/036082 and WO 09/055730); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4- thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5- (Acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4- (methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8); 8-Phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (also known as BYL719 or Alpelisib); 2-(4-(2- (1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (also known as GDC0032, RG7604, or Taselisib). mTOR inhibitors include but are not limited to, Temsirolimus (Torisel®); Ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30- dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4- azatricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2- methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383); Everolimus (Afinitor® or RAD001); Rapamycin (AY22989, Sirolimus®); Simapimod (CAS 164301-51-3); (5-{2,4-Bis[(3S)-3- methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)- 4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); and N2-[1,4- dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L- arginylglycyl-L-^-aspartylL-serine-, inner salt (SF1126, CAS 936487-67-1). CDK inhibitors include but are not limited to, Palbociclib (also known as PD- 0332991, Ibrance®, 6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2- pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one). In yet another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more pro-apoptotics, including but not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors, for treating a disease, e.g., cancer. For examples, IAP inhibitors include but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include but are not limited to those disclosed in WO04/005284, WO 04/007529, WO05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US2006/0014700, US2006/0025347, WO 06/069063, WO 06/010118, WO 06/017295, and WO08/134679, all of which are incorporated herein by reference. BCL-2 inhibitors include but are not limited to, 4-[4-[[2-(4-Chlorophenyl)-5,5- dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1- [(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); Tetrocarcin A; Antimycin; Gossypol ((-)BL-193); Obatoclax; Ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2- ethoxy-2-oxoethyl)-4Hchromone-3-carboxylate (HA14 –1); Oblimersen (G3139, Genasense®); Bak BH3 peptide; (-)-Gossypol acetic acid (AT-101); 4-[4-[(4'-Chloro[1,1'- biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1- [(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9); and Navitoclax (ABT-263, CAS 923564-51-6). Proapoptotic receptor agonists (PARAs) including DR4 (TRAILR1) and DR5 (TRAILR2), including but are not limited to, Dulanermin (AMG-951, RhApo2L/TRAIL); Mapatumumab (HRS-ETR1, CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816- 02-6); Apomab (Apomab®); Conatumumab (AMG655, CAS 896731-82-1); and Tigatuzumab(CS1008, CAS 946415-34-5, available from Daiichi Sankyo). Checkpoint Kinase (CHK) inhibitors include but are not limited to, 7- Hydroxystaurosporine (UCN-01); 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3- piperidinylpyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3- Fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)- 6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7- AAD), Isogranulatimide, debromohymenialdisine; N-[5-Bromo-4-methyl-2-[(2S)-2- morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45- 2); Sulforaphane (CAS 4478-93-7, 4-Methylsulfinylbutyl isothiocyanate); 9,10,11,12- Tetrahydro- 9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine- 1,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO: 33)), and CBP501 ((d-Bpa)sws(d-Phe- F5)(d-Cha)rrrqrr). In a further embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more immunomodulators (e.g., one or more of an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule), for treating a disease, e.g., cancer. In certain embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is selected from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand. GITR Agonists In some embodiments, a GITR agonist is used in combination with a HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the GITR agonist is GWN323 (Novartis), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen) or INBRX-110 (Inhibrx). Exemplary GITR Agonists In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846, published on April 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy,” incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of MAB7 disclosed in Table 1), or encoded by a nucleotide sequence shown in Table 1. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 1). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 1). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 9a, a VHCDR2 amino acid sequence of SEQ ID NO: 11a, and a VHCDR3 amino acid sequence of SEQ ID NO: 13a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 14a, a VLCDR2 amino acid sequence of SEQ ID NO: 16a, and a VLCDR3 amino acid sequence of SEQ ID NO: 18a, each disclosed in Table 1. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 1a. In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 2a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 2a. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 1a and a VL comprising the amino acid sequence of SEQ ID NO: 2a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 5a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 5a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 6a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 6a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 5a and a VL encoded by the nucleotide sequence of SEQ ID NO: 6a. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 3a. In one embodiment, the anti- GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 4a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 4a. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3a and a light chain comprising the amino acid sequence of SEQ ID NO: 4a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 7a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 8a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 8a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 7a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 8a. The antibody molecules described herein can be made by vectors, host cells, and methods described in WO 2016/057846, incorporated by reference in its entirety. Table 1: Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecule
Figure imgf000031_0001
Figure imgf000032_0001
GT C A C C C T G C G A T G C G A G
Figure imgf000033_0001
(CHOTHIA) Other Exemplary GITR Agonists In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, e.g., in US 9,228,016 and WO 2016/196792, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986156, e.g., as disclosed in Table 2. In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, e.g., in US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al. Cancer Res.2017; 77(5):1108-1118, incorporated by reference in their entirety. In one embodiment, the anti- GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MK-4166 or MK-1248. In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, e.g., in US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al. (2010) Clinical Immunology; 135:S96, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TRX518. In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, e.g., in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCAGN1876. In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, e.g., in US 9,464,139 and WO 2015/031667, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of AMG 228. In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, e.g., in US 2017/0022284 and WO 2017/015623, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INBRX-110. In one embodiment, the GITR agonist (e.g., a fusion protein) is MEDI 1873 (MedImmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, e.g., in US 2017/0073386, WO 2017/025610, and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract nr 561, incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873. Further known GITR agonists (e.g., anti-GITR antibodies) include those described, e.g., in WO 2016/054638, incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody is an antibody that competes for binding with, and/or binds to the same epitope on GITR as, one of the anti-GITR antibodies described herein. In one embodiment, the GITR agonist is a peptide that activates the GITR signalling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment (e.g., an immunoadhesin binding fragment comprising an extracellular or GITR binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). Table 2: Amino acid sequence of other exemplary anti-GITR antibody molecules
Figure imgf000035_0001
In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD- L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFRbeta. In one embodiment, the inhibitor of an immune checkpoint molecule inhibits PD- 1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof. The term “inhibition” or “inhibitor” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of an activity, e.g., a PD-1 or PD-L1 activity, of at least 5%, 10%, 20%, 30%, 40%, 50% or more is included by this term. Thus, inhibition need not be 100%. Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other embodiments, the inhibitor of an inhibitory signal is a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as “an antibody molecule”) that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta, or a combination thereof. In one embodiment, the antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)). In yet other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly, selected from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of IgG1 or IgG4 (e.g., human IgG1 or IgG4). In one embodiment, the heavy chain constant region is human IgG1 or human IgG4. In one embodiment, the constant region is altered, e.g., mutated, to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function). In certain embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity to PD-1 or PD-L1 and a second binding specificity, e.g., a second binding specificity to TIM-3, LAG-3, or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. Any combination of the aforesaid molecules can be made in a multispecific antibody molecule, e.g., a trispecific antibody that includes a first binding specificity to PD-1 or PD-1, and a second and third binding specificities to two or more of TIM-3, LAG-3, or PD-L2. In certain embodiments, the immunomodulator is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1. In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1. The PD-1 or PD-L1 inhibitor can be administered alone, or in combination with other immunomodulators, e.g., in combination with an inhibitor of LAG-3, TIM-3 or CTLA4. In an exemplary embodiment, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a LAG-3 inhibitor, e.g., an anti- LAG-3 antibody molecule. In another embodiment, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule. In yet other embodiments, the inhibitor of PD-1 or PD-L1, e.g., the anti-PD-1 antibody molecule, is administered in combination with a LAG-3 inhibitor, e.g., an anti-LAG-3 antibody molecule, and a TIM-3 inhibitor, e.g., an anti- TIM-3 antibody molecule. Other combinations of immunomodulators with a PD-1 inhibitor (e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR) are also within the present disclosure. Any of the antibody molecules known in the art or disclosed herein can be used in the aforesaid combinations of inhibitors of checkpoint molecule. CTLA-4 Inhibitors In some embodiments, the HIF-2a inhibitor of the present disclosure i used in combination with a CTLA-4 inhibitor to treat a disease, e.g., cancer. In some embodiments, the PD-1 inhibitor is selected from Ipilimumab (MDX-010, MDX-101, or Yervoy, Bristol- Myers Squibb) , tremelilumab (ticilimumab. Pfizer/AstraZeneca), AGEN1181 (Agenus), Zalifrelimab (AGEN1884, Agenus), IBI310 (Innovent Biologics). PD-1 Inhibitors In some embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with a PD-1 inhibitor to treat a disease, e.g., cancer. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), or AMP-224 (Amplimmune). Exemplary PD-1 Inhibitors In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 3 (e.g., from the heavy and light chain variable region sequences of BAP049- Clone-E or BAP049-Clone-B disclosed in Table 3), or encoded by a nucleotide sequence shown in Table 3. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 3). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 3). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 3). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 213). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 3, or encoded by a nucleotide sequence shown in Table 3. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 22a, a VHCDR2 amino acid sequence of SEQ ID NO: 23a, and a VHCDR3 amino acid sequence of SEQ ID NO: 24a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 31a, a VLCDR2 amino acid sequence of SEQ ID NO: 32a, and a VLCDR3 amino acid sequence of SEQ ID NO: 286a, each disclosed in Table 3. In one embodiment, the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 45a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 46a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 47a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 50a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 51a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 52a, each disclosed in Table 3. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 27a. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 41a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 41a. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 37a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 37a. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a and a VL comprising the amino acid sequence of SEQ ID NO: 41a. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 27a and a VL comprising the amino acid sequence of SEQ ID NO: 37a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 28a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 28a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 42a or 38a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 42a or 38a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 28a and a VL encoded by the nucleotide sequence of SEQ ID NO: 42a or 38a. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 29a. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 43a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 43a. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 39a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 39a. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a and a light chain comprising the amino acid sequence of SEQ ID NO: 43a. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29a and a light chain comprising the amino acid sequence of SEQ ID NO: 39a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 30a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 44a or 40a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 44a or 40a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 30a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 44a or 40a. The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety. Table 3. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Other Exemplary PD-1 Inhibitors In some embodiments, the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4). Alternative names for Nivolumab include MDX-1106, MDX-1106-04, ONO- 4538, BMS-936558 or OPDIVO®. Nivolumab is a fully human IgG4 monoclonal antibody, which specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in US Pat No.8,008,449 and PCT Publication No. WO2006/121168, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Nivolumab, e.g., as disclosed in Table 4. In other embodiments, the anti-PD-1 antibody is Pembrolizumab. Pembrolizumab (Trade name KEYTRUDA formerly Lambrolizumab, also known as Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab is disclosed, e.g., in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134–44, PCT Publication No. WO2009/114335, and US Patent No. 8,354,509, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pembrolizumab, e.g., as disclosed in Table 4. In some embodiments, the anti-PD-1 antibody is Pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in PCT Publication No. WO2009/101611, incorporated by reference in their entirety. In one embodiment, the anti- PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pidilizumab, e.g., as disclosed in Table 4. Other anti-PD1 antibodies are disclosed in US Patent No.8,609,089, US Publication No.2010028330, and/or US Publication No.20120114649, incorporated by reference in their entirety. Other anti-PD1 antibodies include AMP 514 (Amplimmune). In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MEDI0680. In one embodiment, the anti-PD-1 antibody molecule is Cemiplimab (Regeneron), also known as REGN2810. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of REGN2810. In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of PF-06801591. In one embodiment, the anti-PD-1 antibody molecule is Tislelizumab (Beigene), also known as BGB-A317, or BGB-108. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BGB-A317 or BGB-108. In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCSHR1210. In one embodiment, the anti-PD-1 antibody molecule is Dostarlimab (Tesaro), also known as TSR-042, also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-042. In one embodiment, the anti-PD-1 antibody molecule is Balstilimab (Agenus), also known as AGEN2035. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Balstilimab. In one embodiment, the anti-PD-1 antibody molecule is Sintilimab (InnoVent), In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Sintilimab. In one embodiment, the anti-PD-1 antibody molecule is Toripalimab (Shanghai Junshi Bioscience). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Toripalimab. In one embodiment, the anti-PD-1 antibody molecule is Camrelizumab (Jiangsu Hengrui Medicine Co.). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Camrelizumab. Further known anti-PD-1 antibodies include those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-1 as, one of the anti-PD-1 antibodies described herein. In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signalling pathway, e.g., as described in US 8,907,053, incorporated by reference in its entirety. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety). Table 4. Amino acid sequences of other exemplary anti-PD-1 antibody molecules
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Q PD-L1 Inhibitors In some embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with a PD-L1 inhibitor for treating a disease, e.g., cancer. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (MedImmune/AstraZeneca), or BMS- 936559 (Bristol-Myers Squibb). Exemplary PD-L1 Inhibitors In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as disclosed in US 2016/0108123, published on April 21, 2016, entitled “Antibody Molecules to PD-L1 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 5 (e.g., from the heavy and light chain variable region sequences of BAP058- Clone O or BAP058-Clone N disclosed in Table 5), or encoded by a nucleotide sequence shown in Table 5. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 5). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 5). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 5). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 214). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 5, or encoded by a nucleotide sequence shown in Table 5. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 62a, a VHCDR2 amino acid sequence of SEQ ID NO: 63a, and a VHCDR3 amino acid sequence of SEQ ID NO: 64a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 70a, a VLCDR2 amino acid sequence of SEQ ID NO: 71a, and a VLCDR3 amino acid sequence of SEQ ID NO: 72a, each disclosed in Table 5. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 89a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 90a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 91a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 94a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 95a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 96a, each disclosed in Table 5. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 67a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 77a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 77a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 81a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 85a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 85a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 67a and a VL comprising the amino acid sequence of SEQ ID NO: 77a. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81a and a VL comprising the amino acid sequence of SEQ ID NO: 85a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 68a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 68a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 78a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 78a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 82a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 86a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 86a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 68a and a VL encoded by the nucleotide sequence of SEQ ID NO: 78a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 82a and a VL encoded by the nucleotide sequence of SEQ ID NO: 86a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 69a. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 79a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 79a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 83a. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 87a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 87a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69a and a light chain comprising the amino acid sequence of SEQ ID NO: 79a. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83a and a light chain comprising the amino acid sequence of SEQ ID NO: 87a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 76a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 80a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 80a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 84a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 88a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 88a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 80a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 84a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 88a. The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2016/0108123, incorporated by reference in its entirety. Table 5. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules
Figure imgf000054_0001
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Figure imgf000059_0001
Figure imgf000060_0001
Other Exemplary PD-L1 Inhibitors In some embodiments, the PD-L1 inhibitor is anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as A09-246-2) disclosed in, e.g., WO 2013/0179174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified). In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in PCT Publication No. WO 2007/005874. In one embodiment, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PD-L1 described in PCT Publication No. WO 2010/077634. In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech / Roche) also known as Atezolizumabm, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. MDPL3280A is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Patent No.: 7,943,743 and U.S Publication No.: 20120039906 incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Atezolizumab, e.g., as disclosed in Table 6. In other embodiments, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Amplimmune; e.g., disclosed in PCT Publication Nos. WO2010/027827 and WO2011/066342). In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the anti-PD-L1 antibody molecule is Avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Avelumab, e.g., as disclosed in Table 6. In one embodiment, the anti-PD-L1 antibody molecule is Durvalumab (MedImmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Durvalumab, e.g., as disclosed in Table 6. In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol- Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7,943,743 and WO 2015/081158, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-936559, e.g., as disclosed in Table 6. Further known anti-PD-L1 antibodies include those described, e.g., in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-L1 as, one of the anti-PD-L1 antibodies described herein. Table 6. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules
Figure imgf000062_0001
Figure imgf000063_0001
LAG-3 Inhibitors In some embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with a LAG-3 inhibitor to treat a disease, e.g., cancer. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). Exemplary LAG-3 Inhibitors In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as disclosed in US 2015/0259420, published on September 17, 2015, entitled “Antibody Molecules to LAG-3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 7 (e.g., from the heavy and light chain variable region sequences of BAP050- Clone I or BAP050-Clone J disclosed in Table 7), or encoded by a nucleotide sequence shown in Table 7. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 7). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 7). In some embodiments, the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 7). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 173). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 7, or encoded by a nucleotide sequence shown in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 108a, a VHCDR2 amino acid sequence of SEQ ID NO: 109a, and a VHCDR3 amino acid sequence of SEQ ID NO: 110a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 117a, a VLCDR2 amino acid sequence of SEQ ID NO: 118a, and a VLCDR3 amino acid sequence of SEQ ID NO: 119a, each disclosed in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 143a or 144a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 145a or 146a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 147a or 148a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153a or 154a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155a or 156a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157a or 158a, each disclosed in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 165a or 144a, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 166a or 146a, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 167a or 148a; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 153a or 154a, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 155a or 156a, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 157a or 158a, each disclosed in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 113a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 125a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 125a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 131a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 137a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 137a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 113a and a VL comprising the amino acid sequence of SEQ ID NO: 125a. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 131a and a VL comprising the amino acid sequence of SEQ ID NO: 137a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 114a or 115a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 114a or 115a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 126a or 127a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 126a or 127a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 132a or 133a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 132a or 133a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 138a or 139a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 138a or 139a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 114a or 115a and a VL encoded by the nucleotide sequence of SEQ ID NO: 126a or 127a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 132a or 133a and a VL encoded by the nucleotide sequence of SEQ ID NO: 138a or 139a. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 116a. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 128a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 128a. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 134a. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 140a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 140a. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 116a and a light chain comprising the amino acid sequence of SEQ ID NO: 128a. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134a and a light chain comprising the amino acid sequence of SEQ ID NO: 140a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123a or 124a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 123a or 124a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 129a or 130a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 129a or 130a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135a or 136a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 135a or 136a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 141a or 142a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 141a or 142a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 123a or 124a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 129a or 130a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 135a or 136a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 141a or 142a. The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0259420, incorporated by reference in its entirety. Table 7. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Other Exemplary LAG-3 Inhibitors In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of BMS-986016, e.g., as disclosed in Table 8. In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-033. In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP731, e.g., as disclosed in Table 8. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of GSK2831781. In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of IMP761. Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on LAG-3 as, one of the anti-LAG-3 antibodies described herein. In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), e.g., as disclosed in WO 2009/044273, incorporated by reference in its entirety. Table 8. Amino acid sequences of other exemplary anti-LAG-3 antibody molecules
Figure imgf000077_0001
Figure imgf000078_0001
TIM-3 Inhibitors In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM-3. In some embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with a TIM-3 inhibitor to treat a disease, e.g., cancer. In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis), LY3321367 (Eli Lilly), Sym023 (Symphogen), BGB-A425 (Beigene), INCAGN-2390 (Agenus/Incyte), MBS-986258 (BMS/Five Prime), RO-7121661 (Roche), LY-3415244 (Eli Lilly), or TSR-022 (Tesaro). Exemplary TIM-3 Inhibitors In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as disclosed in US 2015/0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 9 (e.g., from the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 9), or encoded by a nucleotide sequence shown in Table 9. In some embodiments, the CDRs are according to the Kabat definition (e.g., as set out in Table 9). In some embodiments, the CDRs are according to the Chothia definition (e.g., as set out in Table 9). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 9, or encoded by a nucleotide sequence shown in Table 9. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 174a, a VHCDR2 amino acid sequence of SEQ ID NO: 175a, and a VHCDR3 amino acid sequence of SEQ ID NO: 176a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 183a, a VLCDR2 amino acid sequence of SEQ ID NO: 184a, and a VLCDR3 amino acid sequence of SEQ ID NO: 185a, each disclosed in Table 9. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 174a, a VHCDR2 amino acid sequence of SEQ ID NO: 193a, and a VHCDR3 amino acid sequence of SEQ ID NO: 176a; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 183a, a VLCDR2 amino acid sequence of SEQ ID NO: 184a, and a VLCDR3 amino acid sequence of SEQ ID NO: 185a, each disclosed in Table 9. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 179a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 189a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 189a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 195a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 199a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 199a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 179a and a VL comprising the amino acid sequence of SEQ ID NO: 189a. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 195a and a VL comprising the amino acid sequence of SEQ ID NO: 199a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 180a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 180a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 190a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 190a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 196a. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 200a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 200a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 180a and a VL encoded by the nucleotide sequence of SEQ ID NO: 190a. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 196a and a VL encoded by the nucleotide sequence of SEQ ID NO: 200a. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 181a. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 191a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 191a. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 197a. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 201a, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 201a. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 181a and a light chain comprising the amino acid sequence of SEQ ID NO: 191a. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 197a and a light chain comprising the amino acid sequence of SEQ ID NO: 201a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 182a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 192a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 192a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 198a. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 202a, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 202a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 182a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 192a. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 198a and a light chain encoded by the nucleotide sequence of SEQ ID NO: 202a. The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0218274, incorporated by reference in its entirety. Table 9. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Other Exemplary TIM-3 Inhibitors In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-022. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of APE5137 or APE5121, e.g., as disclosed in Table 10. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule is LY3321367 (Eli Lilly). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of LY3321367. In one embodiment, the anti-TIM-3 antibody molecule is Sym023 (Symphogen). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of Sym023. In one embodiment, the anti-TIM-3 antibody molecule is BGB-A425 (Beigene). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of BGB-A425. In one embodiment, the anti-TIM-3 antibody molecule is INCAGN-2390 (Agenus/Incyte). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain or light chain sequence of INCAGN-2390. In one embodiment, the anti-TIM-3 antibody molecule is BMS-986258 (BMS/Five Prime). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of BMS-986258. In one embodiment, the anti-TIM-3 antibody or inhibitor molecule is RO-7121661 (Roche). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of the TIM-3 binding arm of RO-7121661. In one embodiment, the anti-TIM-3 antibody or inhibitor molecule is LY-3415244 (Eli Lilly). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain variable region sequence and/or light chain variable region sequence, or the heavy chain sequence and/or light chain sequence of the TIM-3 binding arm of LY-3415244. Further known anti-TIM-3 antibodies include those described, e.g., in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, incorporated by reference in their entirety. In one embodiment, the anti-TIM-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on TIM-3 as, one of the anti-TIM-3 antibodies described herein. Table 10. Amino acid sequences of other exemplary anti-TIM-3 antibody molecules
Figure imgf000088_0001
Cytokines In yet another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more cytokines, including but not limited to, interferon, IL-2, IL-15, IL-7, or IL21. In certain embodiments, HIF-2a inhibitor of the present disclosure is administered in combination with an IL-15/IL-15Ra complex. In some embodiments, the IL- 15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor) or CYP0150 (Cytune). Exemplary IL-15/IL-15Ra complexes In one embodiment, the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra). The IL-15/IL-15Ra complex may comprise IL-15 covalently or noncovalently bound to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 is noncovalently bonded to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 of the formulation comprises an amino acid sequence of SEQ ID NO: 207a in Table 11 or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 207a, and the soluble form of human IL-15Ra comprises an amino acid sequence of SEQ ID NO: 208a in Table 11, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 208a, as described in WO 2014/066527, incorporated by reference in its entirety. The molecules described herein can be made by vectors, host cells, and methods described in WO 2007084342, incorporated by reference in its entirety. Table 11. Exemplary Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes
Figure imgf000089_0001
Other exemplary IL-15/IL-15Ra complexes In one embodiment, the IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL- 15Ra Fc fusion protein comprises the sequences as disclosed in Table 12. In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to a domain beginning at the first cysteine residue after the signal peptide of IL-15Ra, and ending at the fourth cysteine residue after said signal peptide. The complex of IL-15 fused to the sushi domain of IL-15Ra is described in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entirety. In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises the sequences as disclosed in Table 12. Table 12. Exemplary Amino acid sequences of other exemplary IL-15/IL-15Ra complexes
Figure imgf000089_0002
Figure imgf000090_0002
In yet another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more agonists of toll like receptors (TLRs, e.g., TLR7, TLR8, TLR9) to treat a disease, e.g., cancer. In some embodiments, a compound of the present disclosure can be used in combination with a TLR7 agonist or a TLR7 agonist conjugate. In some embodiments, the TLR7 agonist comprises a compound disclosed in International Application Publication No. WO2011/049677, which is hereby incorporated by reference in its entirety. In some embodiments, the TLR7 agonist comprises 3-(5-amino-2-(4- (2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin- 8-yl)propanoic acid. In some embodiments, the TLR7 agonist comprises a compound of formula:
Figure imgf000090_0001
In another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more angiogenesis inhibitors to treat cancer, e.g., Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-Fluoro-2- methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2- aminopropanoate); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326-83- 4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319- 70-8); Tivozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03- 7); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-Amino-1-((4-((3- methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2- methylcyclopenta[c]pyrrol-5-yl]methoxy]- 4-quinazolinamine (XL647, CAS 781613-23-8); 4-Methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3- (trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); or Aflibercept (Eylea®). In another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more heat shock protein inhibitors to treat cancer, e.g., Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17- AAG, available from SIGMA, and described in US Patent No.4,261,989); Retaspimycin (IPI504), Ganetespib (STA-9090); [6-Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)- 9H-purin-2-yl]amine (BIIB021 or -CNF2024, CAS 848695-25-0); trans-4-[[2- (Aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol- 1-yl]phenyl]amino]cyclohexyl glycine ester (SNX5422 or PF04929113, CAS 908115-27-5); 5-[2,4-Dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]- 3- Isoxazolecarboxamide (AUY922, CAS 747412-49-3); or 17-Dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG). In yet another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more HDAC inhibitors or other epigenetic modifiers. Exemplary HDAC inhibitors include, but not limited to, Voninostat (Zolinza®); Romidepsin (Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF- 1023A); Trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O- methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[(αS,2S)-α-amino-η-oxo-2- oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); Cyclic[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiraneoctanoyl-D-prolyl] (HC-toxin); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2- piperidinecarbonyl] (WF-3161); Chlamydocin ((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D- prolyl-η-oxo-L-α-aminooxiraneoctanoyl); Apicidin (Cyclo(8-oxo-L-2-aminodecanoyl-1- methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl); Romidepsin (Istodax®, FR- 901228); 4-Phenylbutyrate; Spiruchostatin A; Mylproin (Valproic acid); Entinostat (MS-275, N-(2-Aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); Depudecin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy- D-threo-D-ido-Undeca-1,6-dienitol); 4-(Acetylamino)-N-(2-aminophenyl)-benzamide (also known as CI-994); N1-(2- Aminophenyl)-N8-phenyl-octanediamide (also known as BML-210); 4-(Dimethylamino)-N- (7-(hydroxyamino)-7-oxoheptyl)benzamide (also known as M344); (E)-3-(4-(((2-(1H-indol- 3-yl)ethyl)(2-hydroxyethyl)amino)-methyl)phenyl)-N-hydroxyacrylamide; Panobinostat(Farydak®); Mocetinostat, and Belinostat (also known as PXD101, Beleodaq®, or (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide), or chidamide (also known as CS055 or HBI-8000, (E)-N-(2-amino-5-fluorophenyl)-4-((3-(pyridin-3- yl)acrylamido)methyl)benzamide). Other epigenetic modifiers include but not limited to inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryonic ectoderm development), or LSD1 (lysine-specific histone demethylase 1A or KDM1A). In yet another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more inhibitors of indoleamine-pyrrole 2,3-dioxygenase (IDO), for example, Indoximod (also known as NLG-8189), α-Cyclohexyl-5H-imidazo[5,1-a]isoindole- 5-ethanol (also known as NLG919), or (4E)-4-[(3-Chloro-4-fluoroanilino)- nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB024360), to treat cancer. Chimeric Antigen Receptors The present disclosure provides for the HIF-2a inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in combination with adoptive immunotherapy methods and reagents such as chimeric antigen receptor (CAR) immune effector cells, e.g., T cells, or chimeric TCR-transduced immune effector cells, e.g., T cells, as described herein. Estrogen Receptor Antagonists In some embodiments, an estrogen receptor (ER) antagonist is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor degrader (SERD). SERDs are estrogen receptor antagonists which bind to the receptor and result in e.g., degradation or down-regulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479). ER is a hormone-activated transcription factor important for e.g., the growth, development and physiology of the human reproductive system. ER is activated by, e.g., the hormone estrogen (17beta estradiol). ER expression and signaling is implicated in cancers (e.g., breast cancer), e.g., ER positive (ER+) breast cancer. In some embodiments, the SERD is chosen from LSZ102, fulvestrant, brilanestrant, or elacestrant. Exemplary Estrogen Receptor Antagonists In some embodiments, the SERD comprises a compound disclosed in International Application Publication No. WO 2014/130310, which is hereby incorporated by reference in its entirety. In some embodiments, the SERD comprises LSZ102. LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid. Other Exemplary Estrogen Receptor Antagonists In some embodiments, the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8), or a compound disclosed in International Application Publication No. WO 2001/051056, which is hereby incorporated by reference in its entirety. Fulvestrant is also known as ICI 182780, ZM 182780, FASLODEX®, or (7α,17β)-7-{9-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol. Fulvestrant is a high affinity estrogen receptor antagonist with an IC50 of 0.29 nM. In some embodiments, the SERD comprises elacestrant (CAS Registry Number: 722533-56-4), or a compound disclosed in U.S. Patent No.7,612,114, which is incorporated by reference in its entirety. Elacestrant is also known as RAD1901, ER-306323 or (6R)-6-{2- [Ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8- tetrahydronaphthalen-2-ol. Elacestrant is an orally bioavailable, non-steroidal combined selective estrogens receptor modulator (SERM) and a SERD. Elacestrant is also disclosed, e.g., in Garner F et al., (2015) Anticancer Drugs 26(9):948-56. In some embodiments, the SERD is brilanestrant (CAS Registry Number: 1365888- 06-7), or a compound disclosed in International Application Publication No. WO 2015/136017, which is incorporated by reference in its entirety. Brilanestrant is also known as GDC-0810, ARN810, RG-6046, RO-7056118 or (2E)-3-{4-[(1E)-2-(2-chloro-4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl]phenyl}prop-2-enoic acid. Brilanestrant is a next-generation, orally bioavailable selective SERD with an IC50 of 0.7 nM. Brilanestrant is also disclosed, e.g., in Lai A. et al. (2015) Journal of Medicinal Chemistry 58 (12): 4888– 4904. In some embodiments, the SERD is chosen from RU 58668, GW7604, AZD9496, bazedoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, e.g., as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887. Other exemplary estrogen receptor antagonists are disclosed, e.g., in WO 2011/156518, WO 2011/159769, WO 2012/037410, WO 2012/037411, and US 2012/0071535, all of which are hereby incorporated by reference in their entirety. CDK4/6 Inhibitors In some embodiments, an inhibitor of Cyclin-Dependent Kinases 4 or 6 (CDK4/6) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the CDK4/6 inhibitor is chosen from ribociclib, abemaciclib (Eli Lilly), or palbociclib. Exemplary CDK4/6 Inhibitors In some embodiments, the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3), or a compound disclosed in U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety. In some embodiments, the CDK4/6 inhibitor comprises a compound disclosed in International Application Publication No. WO 2010/020675 and U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety. In some embodiments, the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl- N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide.
Other Exemplary CDK4/6 Inhibitors In some embodiments, the CDK4/6 inhibitor comprises abemaciclib (CAS Registry Number: 1231929-97-7). Abemaciclib is also known as LY835219 or N-[5-[(4-Ethyl-1- piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H- benzimidazol-6-yl]-2-pyrimidinamine. Abemaciclib is a CDK inhibitor selective for CDK4 and CDK6 and is disclosed, e.g., in Torres-Guzman R et al. (2017) Oncotarget 10.18632/oncotarget.17778. In some embodiments, the CDK4/6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2). Palbociclib is also known as PD-0332991, IBRANCE® or 6-Acetyl- 8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin- 7(8H)-one. Palbociclib inhibits CDK4 with an IC50 of 11nM, and inhibits CDK6 with an IC50 of 16nM, and is disclosed, e.g., in Finn et al. (2009) Breast Cancer Research 11(5):R77. CXCR2 Inhibitors In some embodiments, an inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the CXCR2 inhibitor is chosen from 6-chloro-3- ((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide, danirixin, reparixin, or navarixin. Exemplary CXCR2 inhibitors In some embodiments, the CXCR2 inhibitor comprises a compound disclosed in U.S. Patent Nos.7989497, 8288588, 8329754, 8722925, 9115087, U.S. Application Publication Nos. US 2010/0152205, US 2011/0251205 and US 2011/0251206, and International Application Publication Nos. WO 2008/061740, WO 2008/061741, WO 2008/062026, WO 2009/106539, WO2010/063802, WO 2012/062713, WO 2013/168108, WO 2010/015613 and WO 2013/030803. In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3- ((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide or a choline salt thereof. In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)- 2-hydroxy-N-methoxy-N-methylbenzenesulfonamide choline salt. In some embodiments, the CXCR2 inhibitor is 2-Hydroxy-N,N,N-trimethylethan-1-aminium 3-chloro-6-({3,4- dioxo-2-[(pentan-3-yl)amino]cyclobut-1-en-1-yl}amino)-2-(N-methoxy-N- methylsulfamoyl)phenolate (i.e., 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en- 1-yl)amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide choline salt) and has the following chemical structure:
Figure imgf000096_0001
. Other Exemplary CXCR2 Inhibitors In some embodiments, the CXCR2 inhibitor comprises danirixin (CAS Registry Number: 954126-98-8). Danirixin is also known as GSK1325756 or 1-(4-chloro-2-hydroxy- 3-piperidin-3-ylsulfonylphenyl)-3-(3-fluoro-2-methylphenyl)urea. Danirixin is disclosed, e.g., in Miller et al. Eur J Drug Metab Pharmacokinet (2014) 39:173–181; and Miller et al. BMC Pharmacology and Toxicology (2015), 16:18. In some embodiments, the CXCR2 inhibitor comprises reparixin (CAS Registry Number: 266359-83-5). Reparixin is also known as repertaxin or (2R)-2-[4-(2- methylpropyl)phenyl]-N-methylsulfonylpropanamide. Reparixin is a non-competitive allosteric inhibitor of CXCR1/2. Reparixin is disclosed, e.g., in Zarbock et al. Br J Pharmacol.2008; 155(3):357-64. In some embodiments, the CXCR2 inhibitor comprises navarixin. Navarixin is also known as MK-7123, SCH 527123, PS291822, or 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide. Navarixin is disclosed, e.g., in Ning et al. Mol Cancer Ther.2012; 11(6):1353-64. CSF-1/1R Binding Agents In some embodiments, a CSF-1/1R binding agent is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the CSF-1/1R binding agent is chosen from an inhibitor of macrophage colony-stimulating factor (M-CSF), e.g., a monoclonal antibody or Fab to M-CSF (e.g., MCS110), a CSF-1R tyrosine kinase inhibitor (e.g., 4-((2-(((1R,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a receptor tyrosine kinase inhibitor (RTK) (e.g., pexidartinib), or an antibody targeting CSF-1R (e.g., emactuzumab or FPA008). In some embodiments, the CSF-1/1R inhibitor is BLZ945. In some embodiments, the CSF-1/1R binding agent is MCS110. In other embodiments, the CSF-1/1R binding agent is pexidartinib. Exemplary CSF-1 binding agents In some embodiments, the CSF-1/1R binding agent comprises an inhibitor of macrophage colony-stimulating factor (M-CSF). M-CSF is also sometimes known as CSF-1. In certain embodiments, the CSF-1/1R binding agent is an antibody to CSF-1 (e.g., MCS110). In other embodiments, the CSF-1/1R binding agent is an inhibitor of CSF-1R (e.g., BLZ945). In some embodiments, the CSF-1/1R binding agent comprises a monoclonal antibody or Fab to M-CSF (e.g., MCS110/H-RX1), or a binding agent to CSF-1 disclosed in International Application Publication Nos. WO 2004/045532 and WO 2005/068503, including H-RX1 or 5H4 (e.g., an antibody molecule or Fab fragment against M-CSF) and US9079956, which applications and patent are incorporated by reference in their entirety. Table 13. Amino acid and nucleotide sequences of an exemplary anti-M-CSF antibody molecule (MCS110)
Figure imgf000097_0001
In another embodiment, the CSF-1/1R binding agent comprises a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N- methyl picolinamide (BLZ945), or a compound disclosed in International Application Publication No. WO 2007/121484, and U.S. Patent Nos.7,553,854, 8,173,689, and 8,710,048, which are incorporated by reference in their entirety. Other Exemplary CSF-1/1R Binding Agents In some embodiments, the CSF-1/1R binding agent comprises pexidartinib (CAS Registry Number 1029044-16-3). Pexidrtinib is also known as PLX3397 or 5-((5-chloro-1H- pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2- amine. Pexidartinib is a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3. FLT3, CSF1R and FLT3 are overexpressed or mutated in many cancer cell types and play major roles in tumor cell proliferation and metastasis. PLX3397 can bind to and inhibit phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. In some embodiments, the CSF-1/1R binding agent is emactuzumab. Emactuzumab is also known as RG7155 or RO5509554. Emactuzumab is a humanized IgG1 mAb targeting CSF1R. In some embodiments, the CSF-1/1R binding agent is FPA008. FPA008 is a humanized mAb that inhibits CSF1R. A2aR Antagonists In some embodiments, an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of A2aR pathway, e.g., an adenosine inhibitor, e.g., an inhibitor of A2aR or CD-73) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the A2aR antagonist is selected from PBF509 (NIR178) (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genentech), AZD4635/HTL- 1071 (AstraZeneca/Heptares), Vipadenant (Redox/Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences), Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant/SYN- 115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences), and Preladenant/SCH 420814 (Merck/Schering). Exemplary A2aR antagonists In some embodiments, the A2aR antagonist comprises PBF509 (NIR178) or a compound disclosed in U.S. Patent No.8,796,284 or in International Application Publication No. WO 2017/025918, herein incorporated by reference in their entirety. PBF509 (NIR178) is also known as NIR178. Other Exemplary A2aR antagonists In certain embodiments, the A2aR antagonist comprises CPI444/V81444. CPI-444 and other A2aR antagonists are disclosed in International Application Publication No. WO 2009/156737, herein incorporated by reference in its entirety. In certain embodiments, the A2aR antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In certain embodiments, the A2aR antagonist is (R)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, or racemate thereof. In certain embodiments, the A2aR antagonist is 7-(5-methylfuran-2-yl)-3-((6- (((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 5-amine. In certain embodiments, the A2aR antagonist is AZD4635/HTL-1071. A2aR antagonists are disclosed in International Application Publication No. WO 2011/095625, herein incorporated by reference in its entirety. In certain embodiments, the A2aR antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In certain embodiments, the A2aR antagonist is ST-4206 (Leadiant Biosciences). In certain embodiments, the A2aR antagonist is an A2aR antagonist described in U.S. Patent No.9,133,197, herein incorporated by reference in its entirety. In certain embodiments, the A2aR antagonist is an A2aR antagonist described in U.S. Patent Nos.8,114,845 and 9,029,393, U.S. Application Publication Nos.2017/0015758 and 2016/0129108, herein incorporated by reference in their entirety. In some embodiments, the A2aR antagonist is istradefylline (CAS Registry Number: 155270-99-8). Istradefylline is also known as KW-6002 or 8-[(E)-2-(3,4- dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione. Istradefylline is disclosed, e.g., in LeWitt et al. (2008) Annals of Neurology 63 (3): 295–302). In some embodiments, the A2aR antagonist is tozadenant (Biotie). Tozadenant is also known as SYN115 or 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)-4- methylpiperidine-1-carboxamide. Tozadenant blocks the effect of endogenous adenosine at the A2a receptors, resulting in the potentiation of the effect of dopamine at the D2 receptor and inhibition of the effect of glutamate at the mGluR5 receptor. In some embodiments, the A2aR antagonist is preladenant (CAS Registry Number: 377727-87-2). Preladenant is also known as SCH 420814 or 2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1- piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine. Preladenant was developed as a drug that acted as a potent and selective antagonist at the adenosine A2A receptor. In some embodiments, the A2aR antagonist is vipadenan. Vipadenan is also known as BIIB014, V2006, or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5- d]pyrimidin-5-amine. Other exemplary A2aR antagonists include, e.g., ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, and ZM-241,385. In some embodiments, the A2aR antagonist is an A2aR pathway antagonist (e.g., a CD-73 inhibitor, e.g., an anti-CD73 antibody) is MEDI9447. MEDI9447 is a monoclonal antibody specific for CD73. Targeting the extracellular production of adenosine by CD73 may reduce the immunosuppressive effects of adenosine. MEDI9447 was reported to have a range of activities, e.g., inhibition of CD73 ectonucleotidase activity, relief from AMP- mediated lymphocyte suppression, and inhibition of syngeneic tumor growth. MEDI9447 can drive changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment. These changes include, e.g., increases in CD8 effector cells and activated macrophages, as well as a reduction in the proportions of myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes. IDO Inhibitors In some embodiments, an inhibitor of indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the IDO inhibitor is chosen from (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3- amine (also known as epacadostat or INCB24360), indoximod (), (1-methyl-D-tryptophan), α-cyclohexyl-5H-Imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), indoximod, and BMS-986205 (formerly F001287). Exemplary IDO inhibitors In some embodiments, the IDO/TDO inhibitor is indoximod (New Link Genetics). Indoximod, the D isomer of 1-methyl-tryptophan, is an orally administered small-molecule indoleamine 2,3-dioxygenase (IDO) pathway inhibitor that disrupts the mechanisms by which tumors evade immune-mediated destruction. In some embodiments, the IDO/TDO inhibitor is NLG919 (New Link Genetics). NLG919 is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM in cell-free assays. In some embodiments, the IDO/TDO inhibitor is epacadostat (CAS Registry Number: 1204669-58-8). Epacadostat is also known as INCB24360 or INCB024360 (Incyte). Epacadostat is a potent and selective indoleamine 2,3-dioxygenase (IDO1) inhibitor with IC50 of 10 nM, highly selective over other related enzymes such as IDO2 or tryptophan 2,3- dioxygenase (TDO). In some embodiments, the IDO/TDO inhibitor is F001287 (Flexus/BMS). F001287 is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). STING Agonists In some embodiments, a STING agonist is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the STING agonist is cyclic dinucleotide, e.g., a cyclic dinucleotide comprising purine or pyrimidine nucleobases (e.g., adenosine, guanine, uracil, thymine, or cytosine nucleobases). In some embodiments, the nucleobases of the cyclic dinucleotide comprise the same nucleobase or different nucleobases. In some embodiments, the STING agonist comprises an adenosine or a guanosine nucleobase. In some embodiments, the STING agonist comprises one adenosine nucleobase and one guanosine nucleobase. In some embodiments, the STING agonist comprises two adenosine nucleobases or two guanosine nucleobases. In some embodiments, the STING agonist comprises a modified cyclic dinucleotide, e.g., comprising a modified nucleobase, a modified ribose, or a modified phosphate linkage. In some embodiments, the modified cyclic dinucleotide comprises a modified phosphate linkage, e.g., a thiophosphate. In some embodiments, the STING agonist comprises a cyclic dinucleotide (e.g., a modified cyclic dinucleotide) with 2’,5’ or 3’,5’ phosphate linkages. In some embodiments, the STING agonist comprises a cyclic dinucleotide (e.g., a modified cyclic dinucleotide) with Rp or Sp stereochemistry around the phosphate linkages. In some embodiments, the STING agonist is MK-1454 (Merck). MK-1454 is a cyclic dinucleotide Stimulator of Interferon Genes (STING) agonist that activates the STING pathway. Exemplary STING agonist are disclosed, e.g., in PCT Publication No. WO 2017/027645. Galectin Inhibitors In some embodiments, a Galectin, e.g., Galectin-1 or Galectin-3, inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the combination comprises a Galectin-1 inhibitor and a Galectin-3 inhibitor. In some embodiments, the combination comprises a bispecific inhibitor (e.g., a bispecific antibody molecule) targeting both Galectin-1 and Galectin-3. In some embodiments, the Galectin inhibitor is chosen from an anti-Galectin antibody molecule, GR- MD-02 (Galectin Therapeutics), Galectin-3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck). Galectins are a family of proteins that bind to beta galactosidase sugars. The Galectin family of proteins comprises at least of Galectin-1, Galectin-2, Galectin- 3, Galectin-4, Galectin-7, and Galectin-8. Galectins are also referred to as S-type lectins, and are soluble proteins with, e.g., intracellular and extracellular functions. Galectin-1 and Galectin-3 are highly expressed in various tumor types. Galectin-1 and Galectin-3 can promote angiogenesis and/or reprogram myeloid cells toward a pro-tumor phenotype, e.g., enhance immunosuppression from myeloid cells. Soluble Galectin-3 can also bind to and/or inactivate infiltrating T cells. Exemplary Galectin Inhibitors In some embodiments, a Galectin inhibitor is an antibody molecule. In an embodiment, an antibody molecule is a monospecific antibody molecule and binds a single epitope. E.g., a monospecific antibody molecule having a plurality of immunoglobulin variable domain sequences, each of which binds the same epitope. In an embodiment, the Galectin inhibitor is an anti-Galectin, e.g., anti-Galectin-1 or anti-Galectin-3, antibody molecule. In some embodiments, the Galectin inhibitor is an anti-Galectin-1 antibody molecule. In some embodiments, the Galectin inhibitor is an anti-Galectin-3 antibody molecule. In an embodiment an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domains sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In an embodiment, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment, the first and second epitopes overlap. In an embodiment, the first and second epitopes do not overlap. In an embodiment, the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In an embodiment, a multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain. In an embodiment, a multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or tetraspecific antibody molecule. In an embodiment, the Galectin inhibitor is a multispecific antibody molecule. In an embodiment, a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In an embodiment, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment, the first and second epitopes overlap. In an embodiment, the first and second epitopes do not overlap. In an embodiment, the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In an embodiment a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In an embodiment, a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In an embodiment, a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In an embodiment, a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope. In an embodiment, the Galectin inhibitor is a bispecific antibody molecule. In an embodiment, the first epitope is located on Galectin-1, and the second epitope is located on Galectin-3. Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; including but not limited to, for example, the “knob in a hole” approach described in, e.g., US5731168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., US4433059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., US 4444878; trifunctional antibodies, e.g., three Fab' fragments cross-linked through sulfhdryl reactive groups, as described in, e.g., US5273743; biosynthetic binding proteins, e.g., pair of scFvs cross-linked through C-terminal tails preferably through disulfide or amine-reactive chemical cross-linking, as described in, e.g., US5534254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized through leucine zippers (e.g., c-fos and c-jun) that have replaced the constant domain, as described in, e.g., US5582996; bispecific and oligospecific mono-and oligovalent receptors, e.g., VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody typically with associated light chains, as described in, e.g., US5591828; bispecific DNA-antibody conjugates, e.g., crosslinking of antibodies or Fab fragments through a double stranded piece of DNA, as described in, e.g., US5635602; bispecific fusion proteins, e.g., an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a full constant region, as described in, e.g., US5637481; multivalent and multispecific binding proteins, e.g., dimer of polypeptides having first domain with binding region of Ig heavy chain variable region, and second domain with binding region of Ig light chain variable region, generally termed diabodies (higher order structures are also disclosed creating bispecific, trispecific, or tetraspecific molecules, as described in, e.g., US5837242; minibody constructs with linked VL and VH chains further connected with peptide spacers to an antibody hinge region and CH3 region, which can be dimerized to form bispecific/multivalent molecules, as described in, e.g., US5837821; VH and VL domains linked with a short peptide linker (e.g., 5 or 10 amino acids) or no linker at all in either orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described in, e.g., US5844094; String of VH domains (or VL domains in family members) connected by peptide linkages with crosslinkable groups at the C-terminus further associated with VL domains to form a series of FVs (or scFvs), as described in, e.g., US5864019; and single chain binding polypeptides with both a VH and a VL domain linked through a peptide linker are combined into multivalent structures through non-covalent or chemical crosslinking to form, e.g., homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody type format, as described in, e.g., US5869620. Additional exemplary multispecific and bispecific molecules and methods of making the same are found, for example, in US5910573, US5932448, US5959083, US5989830, US6005079, US6239259, US6294353, US6333396, US6476198, US6511663, US6670453, US6743896, US6809185, US6833441, US7129330, US7183076, US7521056, US7527787, US7534866, US7612181, US2002/004587A1, US2002/076406A1, US2002/103345A1, US2003/207346A1, US2003/211078A1, US2004/219643A1, US2004/220388A1, US2004/242847A1, US2005/003403A1, US2005/004352A1, US2005/069552A1, US2005/079170A1, US2005/100543A1, US2005/136049A1, US2005/136051A1, US2005/163782A1, US2005/266425A1, US2006/083747A1, US2006/120960A1, US2006/204493A1, US2006/263367A1, US2007/004909A1, US2007/087381A1, US2007/128150A1, US2007/141049A1, US2007/154901A1, US2007/274985A1, US2008/050370A1, US2008/069820A1, US2008/152645A1, US2008/171855A1, US2008/241884A1, US2008/254512A1, US2008/260738A1, US2009/130106A1, US2009/148905A1, US2009/155275A1, US2009/162359A1, US2009/162360A1, US2009/175851A1, US2009/175867A1, US2009/232811A1, US2009/234105A1, US2009/263392A1, US2009/274649A1, EP346087A2, WO00/06605A2, WO02/072635A2, WO04/081051A1, WO06/020258A2, WO2007/044887A2, WO2007/095338A2, WO2007/137760A2, WO2008/119353A1, WO2009/021754A2, WO2009/068630A1, WO91/03493A1, WO93/23537A1, WO94/09131A1, WO94/12625A2, WO95/09917A1, WO96/37621A2, WO99/64460A1. The contents of the above-referenced applications are incorporated herein by reference in their entireties. In other embodiments, the anti-Galectin, e.g., anti-Galectin-1 or anti-Galectin-3, antibody molecule (e.g., a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, e.g., fused, to another partner e.g., a protein, e.g., as a fusion molecule for example a fusion protein. In one embodiment, a bispecific antibody molecule has a first binding specificity to a first target (e.g., to Galectin-1), a second binding specificity to a second target (e.g., Galectin-3). This disclosure provides an isolated nucleic acid molecule encoding the above antibody molecule, vectors and host cells thereof. The nucleic acid molecule includes but is not limited to RNA, genomic DNA and cDNA. In some embodiments, a Galectin inhibitor is a peptide, e.g., protein, which can bind to, and inhibit Galectin, e.g., Galectin-1 or Galectin-3, function. In some embodiments, the Galectin inhibitor is a peptide which can bind to, and inhibit Galectin-3 function. In some embodiments, the Galectin inhibitor is the peptide Galectin-3C. In some embodiments, the Galectin inhibitor is a Galectin-3 inhibitor disclosed in U.S. Patent 6,770,622, which is hereby incorporated by reference in its entirety. Galectin-3C is an N-terminal truncated protein of Galectin-3, and functions, e.g., as a competitive inhibitor of Galectin-3. Galectin-3C prevents binding of endogenous Galectin-3 to e.g., laminin on the surface of, e.g., cancer cells, and other beta-galactosidase glycoconjugates in the extracellular matrix (ECM). Galectin-3C and other exemplary Galectin inhibiting peptides are disclosed in U.S. Patent 6,770,622. In some embodiments, Galectin-3C comprises the amino acid sequence of SEQ ID NO: 279, or an amino acid substantially identical (e.g., 90, 95 or 99%) identical thereto. GAPAGPLIVPYNLPLPGGVVPRMLITILGTVKPNANRIALDFQRGNDVAFHFNPRFNE NNRRVIVCNTKLDNNWGREERQSVFPFESGKPFKIQVLVEPDHFKVAVNDAHLLQY NHRVKKLNEISKLGISGDIDITSASYTMI (SEQ ID NO: 279). In some embodiments, the Galectin inhibitor is a peptide, which can bind to, and inhibit Galectin-1 function. In some embodiments, the Galectin inhibitor is the peptide Anginex: Anginex is an anti-angiogenic peptide that binds Galectin-1 (Salomonsson E, et al., (2011) Journal of Biological Chemistry, 286(16):13801-13804). Binding of Anginex to Galectin-1 can interfere with, e.g., the pro-angiongenic effects of Galectin-1. In some embodiments, the Galectin, e.g., Galectin-1 or Galectin-3, inhibitor is a non- peptidic topomimetic molecule. In some embodiments, the non-peptidic topomimetic Galectin inhibitor is OTX-008 (OncoEthix). In some embodiments, the non-peptidic topomimetic is a non-peptidic topomimetic disclosed in U.S. Patent 8,207,228, which is herein incorporated by reference in its entirety. OTX-008, also known as PTX-008 or Calixarene 0118, is a selective allosteric inhibitor of Galectin-1. OTX-008 has the chemical name: N-[2-(dimethylamino)ethyl]-2-{[26,27,28-tris({[2- (dimethylamino)ethyl]carbamoyl}methoxy) pentacyclo[19.3.1.1,7.1,.15,]octacosa- 1(25),3(28),4,6,9(27),1012,15,17,19(26),21,23-dodecaen-25-yl]oxy}acetamide. In some embodiments, the Galectin, e.g., Galectin-1 or Galectin-3, inhibitor is a carbohydrate based compound. In some embodiments, the Galectin inhibitor is GR-MD-02 (Galectin Therapeutics). In some embodiments, GR-MD-02 is a Galectin-3 inhibitor. GR-MD-02 is a galactose- pronged polysaccharide also referred to as, e.g., a galactoarabino-rhamnogalaturonate. GR- MD-02 and other galactose-pronged polymers, e.g., galactoarabino-rhamnogalaturonates, are disclosed in U.S. Patent 8,236,780 and U.S. Publication 2014/0086932, the entire contents of which are herein incorporated by reference in their entirety. MEK inhibitors In some embodiments, a MEK inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the MEK inhibitor is chosen from Trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or G02443714. In some embodiments, the MEK inhibitor is Trametinib. Exemplary MEK inhibitors In some embodiments, the MEK inhibitor is trametinib. Trametinib is also known as JTP-74057, TMT212, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide, or Mekinist (CAS Number 871700-17-3). Other Exemplary MEK inhibitors In some embodiments the MEK inhibitor comprises selumetinib which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1- methyl-1H-benzimidazole-6-carboxamide. Selumetinib is also known as AZD6244 or ARRY 142886, e.g., as described in PCT Publication No. WO2003077914. In some embodiments, the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188. In some embodiments, the MEK inhibitor comprises 2-[(2-Chloro-4- iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI- 1040 or PD184352), e.g., as described in PCT Publication No. WO2000035436). In some embodiments, the MEK inhibitor comprises N-[(2R)-2,3- Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide (also known as PD0325901), e.g., as described in PCT Publication No. WO2002006213). In some embodiments, the MEK inhibitor comprises 2’-amino-3’-methoxyflavone (also known as PD98059) which is available from Biaffin GmbH & Co., KG, Germany. In some embodiments, the MEK inhibitor comprises 2,3-bis[amino[(2- aminophenyl)thio]methylene]-butanedinitrile (also known as U0126), e.g., as described in US Patent No.2,779,780). In some embodiments, the MEK inhibitor comprises XL-518 (also known as GDC- 0973) which has a CAS No.1029872-29-4 and is available from ACC Corp. In some embodiments, the MEK inhibitor comprises G-38963. In some embodiments, the MEK inhibitor comprises G02443714 (also known as AS703206) Additional examples of MEK inhibitors are disclosed in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference. Further examples of MEK inhibitors include, but are not limited to, 2,3-Bis[amino[(2-aminophenyl)thio]methylene]- butanedinitrile (also known as U0126 and described in US Patent No.2,779,780); (3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro- 1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201, described in PCT Publication No. WO2003076424); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3- Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6- oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-Difluoro-2-[(2-fluoro-4- iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655). c-MET Inhibitors In some embodiments, a c-MET inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. c-MET, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein. In some embodiments, the c-MET inhibitor is chosen from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, MSC2156119J, crizotinib, tivantinib, or golvatinib. Exemplary c-MET Inhibitors In some embodiments, the c-MET inhibitor comprises capmatinib (INC280), or a compound described in U.S. Patent Nos.7,767,675, and US 8,461,330, which are incorporated by reference in their entirety. Other Exemplary c-MET Inhibitors In some embodiments, the c-MET inhibitor comprises JNJ-38877605. JNJ-38877605 is an orally available, small molecule inhibitor of c-Met. JNJ-38877605 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signal transduction pathways. In some embodiments, the c-Met inhibitor is AMG 208. AMG 208 is a selective small- molecule inhibitor of c-MET. AMG 208 inhibits the ligand-dependent and ligand- independent activation of c-MET, inhibiting its tyrosine kinase activity, which may result in cell growth inhibition in tumors that overexpress c-Met. In some embodiments, the c-Met inhibitor comprises AMG 337. AMG 337 is an orally bioavailable inhibitor of c-Met. AMG 337 selectively binds to c-MET, thereby disrupting c-MET signal transduction pathways. In some embodiments, the c-Met inhibitor comprises LY2801653. LY2801653 is an orally available, small molecule inhibitor of c-Met. LY2801653 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signal transduction pathways. In some embodiments, c-Met inhibitor comprises MSC2156119J. MSC2156119J is an orally bioavailable inhibitor of c-Met. MSC2156119J selectively binds to c-MET, which inhibits c-MET phosphorylation and disrupts c-Met-mediated signal transduction pathways. In some embodiments, the c-MET inhibitor is capmatinib. Capmatinib is also known as INCB028060. Capmatinib is an orally bioavailable inhibitor of c-MET. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. In some embodiments, the c-MET inhibitor comprises crizotinib. Crizotinib is also known as PF-02341066. Crizotinib is an orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth. In some embodiments, the c-MET inhibitor comprises golvatinib. Golvatinib is an orally bioavailable dual kinase inhibitor of c-MET and VEGFR-2 with potential antineoplastic activity. Golvatinib binds to and inhibits the activities of both c-MET and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. In some embodiments, the c-MET inhibitor is tivantinib. Tivantinib is also known as ARQ 197. Tivantinib is an orally bioavailable small molecule inhibitor of c-MET. Tivantinib binds to the c-MET protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-Met protein. TGF-β Inhibitors In some embodiments, a transforming growth factor beta (also known as TGF-β TGFβ, TGFb, or TGF-beta, used interchangeably herein) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In certain embodiments, a combination described herein comprises a transforming growth factor beta (also known as TGF-β TGFβ, TGFb, or TGF-beta, used interchangeably herein) inhibitor. TGF-β belongs to a large family of structurally-related cytokines including, e.g., bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and inhibins. In some embodiments, the TGF-β inhibitors described herein can bind and/or inhibit one or more isoforms of TGF-β (e.g., one, two, or all of TGF-β1, TGF-β2, or TGF-β3). Under normal conditions, TGF-β maintains homeostasis and limits the growth of epithelial, endothelial, neuronal and hematopoietic cell lineages, e.g., through the induction of anti-proliferative and apoptotic responses. Canonical and non-canonical signaling pathways are involved in cellular responses to TGF-β. Activation of the TGF-β/Smad canonical pathway can mediate the anti-proliferative effects of TGF-β. The non-canonical TGF-β pathway can activate additional intra-cellular pathways, e.g., mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/Protein Kinase B, Rho-like GTPases (Tian et al. Cell Signal.2011; 23(6):951-62; Blobe et al. N Engl J Med.2000; 342(18):1350- 8), thus modulating epithelial to mesenchymal transition (EMT) and/or cell motility. Alterations of TGF-β signaling pathway are associated with human diseases, e.g., cancers, cardio-vascular diseases, fibrosis, reproductive disorders, and wound healing. Without wishing to be bound by theory, it is believed that in some embodiments, the role of TGF-β in cancer is dependent on the disease setting (e.g., tumor stage and genetic alteration) and/or cellular context. For example, in late stages of cancer, TGF-β can modulate a cancer- related process, e.g., by promoting tumor growth (e.g., inducing EMT), blocking anti-tumor immune responses, increasing tumor-associated fibrosis, or enhancing angiogenesis (Wakefield and Hill Nat Rev Cancer.2013; 13(5):328-41). In certain embodiments, a combination comprising a TGF-β inhibitor described herein is used to treat a cancer in a late stage, a metastatic cancer, or an advanced cancer. Preclinical evidence indicates that TGF-β plays an important role in immune regulation (Wojtowicz-Praga Invest New Drugs.2003; 21(1):21-32; Yang et al. Trends Immunol.2010; 31(6):220-7). TGF-β can down-regulate the host-immune response via several mechanisms, e.g., shift of the T-helper balance toward Th2 immune phenotype; inhibition of anti-tumoral Th1 type response and M1-type macrophages; suppression of cytotoxic CD8+ T lymphocytes (CTL), NK lymphocytes and dendritic cell functions, generation of CD4+CD25+ T-regulatory cells; or promotion of M2-type macrophages with pro-tumoral activity mediated by secretion of immunosuppressive cytokines (e.g., IL10 or VEGF), pro-inflammatory cytokines (e.g., IL6, TNFα, or IL1) and generation of reactive oxygen species (ROS) with genotoxic activity (Yang et al. Trends Immunol.2010; 31(6):220- 7; Truty and Urrutia Pancreatology.2007; 7(5-6):423-35; Achyut et al Gastroenterology. 2011; 141(4):1167-78). Exemplary TGF-β Inhibitors In some embodiments, the TGF-β inhibitor comprises XOMA 089, or a compound disclosed in International Application Publication No. WO 2012/167143, which is incorporated by reference in its entirety. XOMA 089 is also known as XPA.42.089. XOMA 089 is a fully human monoclonal antibody that specifically binds and neutralizes TGF-beta 1 and 2 ligands. The heavy chain variable region of XOMA 089 has the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGT ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWG QGTLVTVSS (SEQ ID NO: 284) (disclosed as SEQ ID NO: 6 in WO 2012/167143). The light chain variable region of XOMA 089 has the amino acid sequence of: SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIP ERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO: 285) (disclosed as SEQ ID NO: 8 in WO 2012/167143). XOMA 089 binds with high affinity to the human TGF-β isoforms. Generally, XOMA 089 binds with high affinity to TGF-β1 and TGF-β2, and to a lesser extent to TGF- β3. In Biacore assays, the KD of XOMA 089 on human TGF-β is 14.6 pM for TGF-β1, 67.3 pM for TGF-β2, and 948 pM for TGF-β3. Given the high affinity binding to all three TGF-β isoforms, in certain embodiments, XOMA 089 is expected to bind to TGF-β1, 2 and 3 at a dose of XOMA 089 as described herein. XOMA 089 cross-reacts with rodent and cynomolgus monkey TGF-β and shows functional activity in vitro and in vivo, making rodent and cynomolgus monkey relevant species for toxicology studies. Other Exemplary TGF-β Inhibitors In some embodiments, the TGF-β inhibitor comprises fresolimumab (CAS Registry Number: 948564-73-6). Fresolimumab is also known as GC1008. Fresolimumab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2 and 3. The heavy chain of fresolimumab has the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDI ANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQG TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 280). The light chain of fresolimumab has the amino acid sequence of: ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPG IPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 281). Fresolimumab is disclosed, e.g., in International Application Publication No. WO 2006/086469, and U.S. Patent Nos.8,383,780 and 8,591,901, which are incorporated by reference in their entirety. IL-1β Inhibitors The Interleukin-1 (IL-1) family of cytokines is a group of secreted pleotropic cytokines with a central role in inflammation and immune response. Increases in IL-1 are observed in multiple clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Dinarello (2010) Eur. J. Immunol. p.599-606). The IL-1 family comprises, inter alia, IL-1 beta (IL-1b), and IL-1alpha (IL-1a). IL-1b is elevated in lung, breast and colorectal cancer (Voronov et al. (2014) Front Physiol. p.114) and is associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol. p.277-88). Without wishing to be bound by theory, it is believed that in some embodiments, secreted IL-1b, derived from the tumor microenvironment and by malignant cells, promotes tumor cell proliferation, increases invasiveness and dampens anti-tumor immune response, in part by recruiting inhibitory neutrophils (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Miller et al. (2007) J. Immunol. p.6933-42). Experimental data indicate that inhibition of IL-1b results in a decrease in tumor burden and metastasis (Voronov et al. (2003) Proc. Natl. Acad. Sci. U.S.A. p.2645-50). In some embodiments, an interleukin-1 beta (IL-1β) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. In some embodiments, the IL-1β inhibitor is chosen from canakinumab, gevokizumab, Anakinra, or Rilonacept. In some embodiments, the IL-1β inhibitor is canakinumab. Exemplary IL-1β inhibitors In some embodiments, the IL-1β inhibitor is canakinumab. Canakinumab is also known as ACZ885 or ILARIS®. Canakinumab is a human monoclonal IgG1/κ antibody that neutralizes the bioactivity of human IL-1β. Canakinumab is disclosed, e.g., in WO 2002/16436, US 7,446,175, and EP 1313769. The heavy chain variable region of canakinumab has the amino acid sequence of: MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNW VRQAPGKGLEWVAIIWYDGDNQYYADSVKGRFTISRDNSKNTLYLQMNGLRAEDT AVYYCARDLRTGPFDYWGQGTLVTVSS (SEQ ID NO: 282) (disclosed as SEQ ID NO: 1 in US 7,446,175). The light chain variable region of canakinumab has the amino acid sequence of: MLPSQLIGFLLLWVPASRGEIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKP DQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPFTFG PGTKVDIK (SEQ ID NO: 283) (disclosed as SEQ ID NO: 2 in US 7,446,175). Canakinumab has been used, e.g., for the treatment of Cryopyrin Associated Periodic Syndromes (CAPS), in adults and children, for the treatment of systemic juvenile idiopathic arthritis (SJIA), for the symptomatic treatment of acute gouty arthritis attacks in adults, and for other IL-1β driven inflammatory diseases. Without wishing to be bound by theory, it is believed that in some embodiments, IL-1β inhibitors, e.g., canakinumab, can increase anti- tumor immune response, e.g., by blocking one or more functions of IL-1b including, e.g., recruitment of immunosuppressive neutrophils to the tumor microenvironment, stimulation of tumor angiogenesis, and/or promotion of metastasis (Dinarello (2010) Eur. J. Immunol. p. 599-606). In some embodiments, the combination described herein includes an IL-1β inhibitor, canakinumab, or a compound disclosed in WO 2002/16436, and an inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule). IL-1 is a secreted pleotropic cytokine with a central role in inflammation and immune response. Increases in IL-1 are observed in multiple clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. p.387-408; Dinarello (2010) Eur. J. Immunol. p.599-606). IL-1b is elevated in lung, breast and colorectal cancer (Voronov et al. (2014) Front Physiol. p.114) and is associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol. p.277- 88). Without wishing to be bound by theory, it is believed that in some embodiments, secreted IL-1b, derived from the tumor microenvironment and by malignant cells, promotes tumor cell proliferation, increases invasiveness and dampens anti-tumor immune response, in part by recruiting inhibitory neutrophils (Apte et al. (2006) Cancer Metastasis Rev. p.387- 408; Miller et al. (2007) J. Immunol. p.6933-42). Experimental data indicate that inhibition of IL-1b results in a decrease in tumor burden and metastasis (Voronov et al. (2003) Proc. Natl. Acad. Sci. U.S.A. p.2645-50). Canakinumab can bind IL-1b and inhibit IL-1-mediated signalling. Accordingly, in certain embodiments, an IL-1β inhibitor, e.g., canakinumab, enhances, or is used to enhance, an immune-mediated anti-tumor effect of an inhibitor of PD- 1 (e.g., an anti-PD-1 antibody molecule). In some embodiments, the IL-1β inhibitor, canakinumab, or a compound disclosed in WO 2002/16436, and the inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule), each is administered at a dose and/or on a time schedule, that in combination, achieves a desired anti-tumor activity. MDM2 inhibitors In some embodiments, a mouse double minute 2 homolog (MDM2) inhibitor is used in combination with the HIF-2a inhibitor of the present disclosure for treating a disease, e.g., cancer. The human homolog of MDM2 is also known as HDM2. In some embodiments, an MDM2 inhibitor described herein is also known as a HDM2 inhibitor. In some embodiments, the MDM2 inhibitor is chosen from HDM201 or CGM097. In an embodiment the MDM2 inhibitor comprises (S)-1-(4-chlorophenyl)-7- isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1- yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011/076786 to treat a disorder, e.g., a disorder described herein). In one embodiment, a therapeutic agent disclosed herein is used in combination with CGM097. In an embodiment, an MDM2 inhibitor comprises an inhibitor of p53 and/or a p53/Mdm2 interaction. In an embodiment, the MDM2 inhibitor comprises (S)-5-(5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)- 1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (also known as HDM201), or a compound disclosed in PCT Publication No. WO2013/111105 to treat a disorder, e.g., a disorder described herein. In one embodiment, a therapeutic agent disclosed herein is used in combination with HDM201. In some embodiments, HDM201 is administered orally. In one embodiment, the combination disclosed herein is suitable for the treatment of cancer in vivo. For example, the combination can be used to inhibit the growth of cancerous tumors. The combination can also be used in combination with one or more of: a standard of care treatment (e.g., for cancers or infectious disorders), a vaccine (e.g., a therapeutic cancer vaccine), a cell therapy, a radiation therapy, surgery, or any other therapeutic agent or modality, to treat a disorder herein. For example, to achieve antigen-specific enhancement of immunity, the combination can be administered together with an antigen of interest. Multispecific Binding Molecules In some embodiments, the HIF-2a inhibitor of the present disclosure is used in combination with a multispecific binding molecule (“MBM”). As used herein, the term “MBM” refers to a binding molecule that recognizes two or more different epitopes. Examples of MBMs include bispecific binding molecules (“BBMs”), which recognize two different epitopes, and trispecific binding molecules (“TBMs”), which recognize three different epitopes. The epitopes can be present on the same target or on different targets. The MBMs suitable for use or administration in combination with the HIF-2a inhibitors of the disclosure thus comprise at least two antigen binding domains (“ABDs”) that bind to different epitopes. The term “antigen-binding domain” or “ABD” as used herein refers to a portion of an MBM that has the ability to bind to an epitope non-covalently, reversibly and specifically. Generally, for treatment of cancer, the MBMs useful in combination with the HIF-2a inhibitors of the disclosure bind to at least one tumor-associated antigen (“TAA”). As used herein, the term “tumor-associated antigen” or “TAA” refers to a molecule (typically a protein, carbohydrate, lipid or some combination thereof) that is expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), and which is useful for the preferential targeting of a pharmacological agent to the cancer cell. A TAA is a marker that may be expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells. A TAA may also be a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1-fold overexpression, 2-fold overexpression, 3- fold overexpression or more in comparison to a normal cell. A TAA may be a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. Certain TAAs may be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of a normal cell. Accordingly, the term “TAA” encompasses antigens that are specific to cancer cells, sometimes known in the art as tumor-specific antigens (“TSAs”). Further, as used herein, the term “cancer” refers to a disease characterized by the uncontrolled (and often rapid) growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, leukemia, multiple myeloma, asymptomatic myeloma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. In some embodiments, the TAA is expressed on cancerous B cells. The term “cancerous B cell” refers to a B cell that is undergoing or has undergone uncontrolled proliferation. Examples of TAAs that can be targeted by the MBMs (e.g., BBMs or TBMs) useful in combination with the HIF-2a inhibitors of the disclosure include TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD44v6, B7H3, KIT, IL-13Ra2, IL-11Ra, PSCA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, MUC1, EGFR, EGFRvIII, NCAM, CAIX, LMP2, EphA2, fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, GD2, folate receptor alpha, folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TAARP, WT1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53 mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD19, CD20, CD30, ERBB2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, BCMA, gp100Tn, FAP, tyrosinase, EPCAM, CEA, Igf-I receptor, Cadherin17, CD32b, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, TACSTD2, and EphB2. In certain aspects, the TAAs are expressed on cancerous blood cells, e.g., cancerous B cells. Examples of TAAs expressed on cancerous B cells include, but are not limited to, CD19, CD20, CD22, CD123, BCMA, CD33, CLL1, CD138 (also known as Syndecan-1, SDC1), CS1, CD38, CD133, FLT3, CD52, TNFRSF13C (TNF Receptor Superfamily Member 13C, also referred to in the art as BAFFR: B-Cell-Activating Factor Receptor), TNFRSF13B (TNF Receptor Superfamily Member 13B, also referred to in the art as TACI: Transmembrane Activator And CAML Interactor), CXCR4 (C-X-C Motif Chemokine Receptor 4), PD-L1 (programmed death-ligand 1), LY9 (lymphocyte antigen 9, also referred to in the art as CD229), CD200, FCGR2B (Fc fragment of IgG receptor lib, also referred to in the art as CD32b), CD21, CD23, CD24, CD40L, CD72, CD79a, and CD79b. In addition to binding a TAA, MBMs useful in combination with the HIF-2a inhibitors of the disclosure can engage the immune system, for example a T cell or an NK cell. Engagement of T cells can be achieved through targeting CD3 or other component(s) of a TCR complex, for example TCR-α, TCR-β, or a TCR-α/β dimer. Exemplary ABDs that recognize CD3 or other components of the TCR complex are described in WO 2020/052692 and WO2019/104075 (for example see Sections 7.8.1, 7.8.2 and 7.8.3 of WO 2020/052692 and Section 6.5 of WO 2019/104075, incorporated by reference herein). The MBMs can further include an ABD that binds to CD2, for example as generally disclosed in WO 2019/104075. In some embodiments, CD2 can be targeted through the use of its ligand CD58 and CD2-binding portions thereof as ABDs, as described in Section 6.6.2 of WO 2019/104075, incorporated by reference herein. Engagement of NK cells can be achieved through targeting CD16, NKp46, NKG2D, NKp30, NKp44, NKp46, or a combination thereof, e.g., a combination of CD16 and NKp46. See, e.g., Hu et al., 2019, Front. Immunol. 10:1205, Gauthier et al., 2019, Cell 177(7):1701-1713. In some embodiments, the MBM is a BBM that binds to B cell maturation antigen, or BCMA, and a component of the TCR complex, preferably CD3. In other embodiments, the MBM is a TBM that binds to BCMA, a component of the TCR complex, preferably CD3, as well as either a second TAA or CD2 (e.g., through a CD58-based ABD, e.g., an ABD containing amino acids residues 30-123 of CD58). The expression of BCMA has been linked to a number of cancers, autoimmune disorders, and infectious diseases. Cancers with increased expression of BCMA include some hematological cancers, such as multiple myeloma, Hodgkin’s and non- Hodgkin’s lymphoma, various leukemias, and glioblastoma. WO 2019/229701 describes a number of MBMs that specifically bind to human BCMA as well as sequences of exemplary BCMA binding sequences that can be included in MBMs that bind to BCMA (see for example the BCMA binding sequences set disclosed in paragraph [0149] and Table 1 of WO 2019/229701, incorporated by reference herein). WO 2019/229701 also describes BBMs that are directed against BCMA and CD3 (see for example Section 7.3.3.1 of PCT WO 2019/229701, incorporated by reference herein). In other embodiments, the MBM is a BBM that binds CD19 and a component of the TCR complex, preferably CD3. In other embodiments, the MBM is a TBM that binds to CD19, a component of the TCR complex, preferably CD3, as well as either a second TAA or CD2 (e.g., through a CD58-based ABD, e.g., an ABD containing amino acids residues 30- 123 of CD58). A TBM that binds to CD19, CD3 and CD2 (e.g., through a CD58-based ABD, e.g., an ABD containing amino acids residues 30-123 of CD58) can have the general configuration depicted in Fig.1D of WO2019/104075, for example where X in Fig.1D is a CD19 ABD, X is a CD3 ABM and Z is a CD2 ABM, and more specifically the configurations shown in Figs.12A, 12B and 12C of WO2019/104075, all of which figures and accompanying text are incorporated by reference herein. CD19 is expressed during early pre-B cell development and remains until plasma cell differentiation. CD19 is expressed on both normal B cells and malignant B cells whose abnormal growth can lead to B-cell lymphomas. For example, CD19 is expressed on B-cell lineage malignancies, including, but not limited to non-Hodgkin’s lymphoma (B-NHL), chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Whilst a large number of MBMs that are being developed for cancer therapy typically include one or more ABDs directed against a TAA and one or more ABDs that are able to facilitate engagement of immune cells, MBMs useful in combination with the HIF-2a inhibitors of the disclosure need not engage immune cells such as T cells or NK cells. For example, MBMs can be used to inhibit the angiogenesis pathways, for example by targeting VEG-F and another antigen such as Delta-like Ligand 4 (DLL-4), a transmembrane ligand for the Notch receptor or angiopoietin 2 (ANG-2). Exemplary types of ABDs include antigen-binding fragments and portions of both immunoglobulin and non-immunoglobulin based scaffolds that retain the ability of binding an antigen non-covalently, reversibly and specifically. Thus, as used herein, the term “antigen-binding domain” encompasses antibody fragments that retain the ability of binding an antigen non-covalently, reversibly and specifically. Examples of binding fragments include, but are not limited to, single-chain Fvs (scFv), a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment which consists of a VH domain; and an isolated complementarity determining region (CDR). Thus, the term “antibody fragment” encompasses both proteolytic fragments of antibodies (e.g., Fab and F(ab)2 fragments) and engineered proteins comprising one or more portions of an antibody (e.g., an scFv). In addition to immunoglobulin-based ABDs, such Fab-, scFv- and other antibody fragment based ABDs such as those described above), the MBMs of the disclosure can also include non-immunoglobulin-based ABDs, or a combination of immunoglobulin and non- immunoglobulin based ABDs. Immunoglobulin-based ABDs that can be used are described in WO 2019/104075 and WO 2019/229701 (see for example Sections 7.2 and 7.3.1 of WO 2019/229701 and Section 6.2.1 of WO 2019/104075, incorporated by reference herein). Non-immunoglobulin-based ABDs, which include Kunitz domains, Adnexins, Affibodies, DARPins, Avimers, Anticalins, Lipocalins, fibronectins scaffolds, Affimers, and Fynomers, are described in WO 2019/104075 and WO 2019/229701 (see for example Section 7.4 of WO 2019/229701 and Section 6.3 of WO 2019/104075 and Fig.2 and Table 1 of Hober et al., 2019, Methods 154:143–152, incorporated by reference herein). For MBMs that target CD2, a suitable ABD is CD58 or a fragment thereof, as described in Section 6.6.2 of WO 2019/104075, incorporated by reference herein. BBMs comprise at least two ABDs but can also contain more than two ABDs. BBMs that contain only two ABDs and are considered bivalent, and a BBM can have three ABDs (i.e., is trivalent), four ABDs (i.e., is tetravalent), or more, provided that the BBM has at least one ABD that can bind one epitope and at least one ABD that can bind a different epitope. Exemplary bivalent, trivalent, and tetravalent BBM configurations are described in WO 2019/229701 (for example Figure 1 and Section 7.5 of WO 2019/229701 and Section 7.5 of WO 2019/229701, incorporated by reference herein). Although WO 2019/229701 relates to BCMA binding molecules, which can suitably be used in combination with the HIF-2a inhibitors of the disclosure, the BBM formats described therein are also applicable to any epitope / antigen pairing, for example any TAA and T cell receptor component pair or a TAA and NK cell activating receptor such as CD16, NKp46, NKG2D, NKp30, NKp44 or NKp46. Similarly, TBMs have at least three ABDs (i.e., a TBM is at least trivalent), but can also contain more than three ABDs. For example, a TBM can have four ABDs (i.e., is tetravalent), five ABDs (i.e., is pentavalent), or six ABDs (i.e., is hexavalent), provided that the TBM has at least one ABD that can bind one epitope, at least one ABD that can bind a second epitope, and at least one ABD that can bind a third epitope. Exemplary trivalent, tetravalent, pentavalent, and hexavalent TBM configurations are described in WO 2019/104075 and WO 2019/195535 (for example Figure 1 and Section 6.4 of WO 2019/104075 and Figure 1 and Section 7.4 of WO 2019/195535, incorporated by reference herein). Although WO 2019/104075 relates to TBMs that bind to CD2, CD3 (or another T cell receptor component) and a tumor-associated antigen (TAA) and WO 2019/195535 relates to TBMs that bind to CD3 (or another T cell receptor component) and two TAAs, both of which can suitably be used in combination with the HIF-2a inhibitors of the disclosure, the TBM formats described therein are also applicable to any combination of three epitopes or antigens. For example, a TBM can target a TAA and two NK cell activating receptors, for example any two of CD16, NKp46, NKG2D, NKp30, NKp44 or NKp46. In a particular embodiment, a TBM useful in combination with the HIF-2a inhibitors of the disclosure can target a TAA, CD16 and NKp46 (see, e.g., Gauthier et al., 2019, Cell 177(7):1701-1713). The ABDs of an MBM (or portions thereof) can be connected to each other, for example, by short peptide linkers or by an Fc domain. Methods of connecting ABDs to form an MBM are described in WO 2019/104075 and WO 2019/229701 (see for example Section 7.3.2 of WO 2019/229701 and Section 6.2.2 of WO 2019/104075, incorporated by reference herein). The MBMs can have an Fc region formed by the association of two Fc domains. The Fc domains can be homodimeric or heterodimeric. Exemplary heterodimerization strategies, which include knob-into-hole and polar bridge formats, are described in Table 2 and Section 6.3.1.5 of WO 2019/104075 and subsections thereof, incorporated by reference herein. The Fc region can have altered effector function. The term “effector function” refers to an activity of an antibody molecule that is mediated by binding through a domain of the antibody other than the antigen binding domain, usually mediated by binding of effector molecules. Effector function includes complement-mediated effector function, which is mediated by, for example, binding of the C1 component of the complement to the antibody. Activation of complement is important in the opsonization and lysis of cell pathogens. The activation of complement also stimulates the inflammatory response and may also be involved in autoimmune hypersensitivity. Effector function also includes Fc receptor (FcR)- mediated effector function, which may be triggered upon binding of the constant domain of an antibody to an Fc receptor (FcR). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody- coated target cells by killer cells (called antibody-dependent cell-mediated cytotoxicity, or ADCC), release of inflammatory mediators, placental transfer and control of immunoglobulin production. An effector function of an antibody may be altered by altering, e.g., enhancing or reducing, the affinity of the antibody for an effector molecule such as an Fc receptor or a complement component. Fc regions with altered effector function are described, for example, in Sections 6.3.1.1 through 6.3.1.5 of WO 2019/104075, incorporated by reference herein, and can include, for example altered binding to one or more Fc receptors such as FcRN, modified disulfide bond architecture, or altered glycosylation patterns as compared to a wild type Fc region. Additional MBM formats that can be used in combination with the HIF-2a inhibitors of the disclosure are disclosed, inter alia, in Fig.1 of Suurs et al., 2019, Pharmacology & Therapeutics 201:103–119, Fig.2 of Labrijn et al., 2019, Nat Rev Drug Discov.18(8):585- 608; Fig.4 of Krishnamurthy and Jimeno, 2018, Pharmacology and Therapeutics 185:122– 134; Fig.3 of Sedykh et al., 2018, Drug Design, Development and Therapy 12:195–208; Fig. 1 of Spiess et al., 2015, Molecular Immunology 67:95–106; Fig.2 of Brinkmann & Kontermann, 2017, mAbs, 9:2, 182-212; Fig.3 of Klein et al., 2016, mAbs, 8:6, 1010-1020;’ and Fig.2 of Klein et al., 2019, Methods 154:21–31, all of which figures and accompanying text are incorporated by reference herein. A number of MBMs have been developed or are in development for treatment of a variety of cancers and can be used in combination of the HIF-2a inhibitors of the disclosure. See, for example, Tables 1 and 2 of Labrijn et al., 2019, Nat Rev Drug Discov.18(8):585- 608; Tables 1 and 2 of Krishnamurthy and Jimeno, 2018, Pharmacology and Therapeutics 185:122–134; Fig.3 of Suurs et al., 2019, Pharmacology & Therapeutics 201:103–119; Table 1 of Weidle et al., 2014, Seminars in Oncology 41:653-660, Table I of Sedykh et al., 2018, Drug Design, Development and Therapy 12:195–208; Table 1 of Spiess et al., 2015, Molecular Immunology 67:95–106; Table 1 of Dahlen et al., 2018, Therapeutic Advances in Vaccines and Immunotherapy 6(1) 3–17; and Table 3 of Brinkmann & Kontermann, 2017, mAbs, 9(2):182-212, all such tables and figures and accompanying text incorporated by reference herein. Exemplary MBMs that can be used in combination with the HIF-2a inhibitors of the disclosure are set forth in the foregoing tables and figures as well as in Table 14 below. Table 14. Exemplary MBMs
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Accordingly, the molecules of the disclosure can be administered in combination with any MBM described [Table 14], for example to treat a cancer indicated for that MBM in [Table 14] above. In other embodiments, the MBM described in [Table 14] binds to BCMA, for example the AMG701, AMG701, CC-93269, JNJ-64007957, PF-06863135, or REGN5458. The molecules of the disclosure can be used in combination with any of the foregoing BCMA-targeting MBMs to treat hematologic cancers such as multiple myeloma, Hodgkin’s and non- Hodgkin’s lymphoma, various leukemias, and glioblastoma. In other embodiments, the MBM described in [Table 14] binds to CD19, for example the MBM is A-319, AMG562, Blinatumomab, MGD011, or OXS-1550. The molecules of the disclosure can be used in combination with any of the foregoing CD19-targeting MBMs to treat hematologic cancers such as non-Hodgkin’s lymphoma (B-NHL), chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Other Therapeutic Agents In another embodiment, the HIF-2a inhibitor of the present disclosure is used in combination with one or more of the therapeutic agents listed in Table 2156 or listed in the patent and patent applications cited in Table 15, to treat cancer. Each publication listed in Table 15 is herein incorporated by reference in its entirety, including all structural formulae therein. Table 15. Other Exemplary Therapeutic Agents
Figure imgf000129_0002
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0002
Specific Embodiments Embodiment 1: A pharmaceutical combination comprising a HIF2α inhibitor and one or more therapeutic agents. Embodiment 2: The pharmaceutical combination of embodiment 1, wherein the HIF2α inhibitor is a compound having the structure of formula (I):
Figure imgf000137_0001
Embodiment 3: The pharmaceutical combination of embodiment 1, wherein one or more therapeutic agents is a PD-1 inhibitor and optionally an A2aR antagonist. Embodiment 4: The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224. Embodiment 5: The pharmaceutical combination of embodiment 3, wherein the A2aR antagonist is selected from istradefylline, tozadenant, preladenant, vipadenan, taminadenant (PBF-509), ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER- 6947, VER-7835, CGS-15943, ZM-241,385, or MEDI9447. Embodiment 6: The pharmaceutical combination of embodiment 3, wherein the HIF2α inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are in 2 or 3 separate formulations. Embodiment 7: The pharmaceutical combination of embodiment 3, wherein the HIF2α inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are administered simultaneously or sequentially. Embodiment 8: The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is spartalizumab and the A2aR antagonist is taminadenant. Embodiment 9: The pharmaceutical combination of embodiment 3, wherein the PD-1 inhibitor is tislelizumab and the A2aR antagonist is taminadenant. Embodiment 10: A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of any one of embodiments 1-9. Embodiment 11: The method of embodiment 10, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma. Embodiment 12: The method of embodiment 11, wherein the cancer is renal cell carcinoma. Embodiment 13: The method of embodiment 10, wherein the cancer is a malignancy with one or more HIF stabilizing mutations. Embodiment 14. The method of embodiment 13, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations. Embodiment 15: The pharmaceutical combination of any one of embodiments 1-9, for use in the treatment of cancer. Embodiment 16: The pharmaceutical combination of any one of embodiment 1-9, for use in the manufacture of a medicament for the treatment of cancer. Embodiment 17: The pharmaceutical combination of embodiments 15 or 16, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma. Embodiment 18: The pharmaceutical combination of embodiment 17, wherein the cancer is renal cell carcinoma. Embodiment 19: The pharmaceutical combination of embodiments 15 or 16, wherein the cancer is a malignancy with one or more HIF stabilizing mutations. Embodiment 20: The pharmaceutical combination of embodiment 19, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations. Embodiment 21: Use of a pharmaceutical combination of any one of embodiments 1- 9 for the manufacture of a medicament for the treatment or prevention of cancer. Embodiment 22: Use of a pharmaceutical combination of any one of embodiments 1- 9 for the treatment or prevention of cancer. Embodiment 23: The use of embodiments 21 or 22, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma. Embodiment 24: The use of embodiment 23, wherein the cancer is renal cell carcinoma. Embodiment 25: The use of embodiment 21 or 22, wherein the cancer is a malignancy with one or more HIF stabilizing mutations. Embodiment 26: The use of embodiment 25, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations. In some embodiments, Compound I is administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg once daily. In some embodiments, Compound I is administered at a dose of about 50 mg to about 600 mg. In some embodiments, Compound I is administered at a dose of about 400 mg. In some embodiments, Compound I is administered once every four weeks. In some embodiments, Compound I is administered at a dose of about 50 mg every week. In some embodiments, Compound I is administered at a dose of about 600 mg every week. In some embodiments, Compound I is administered at a dose of about 100 mg every day. In some embodiments, Compound I is administered orally. In some embodiments, the HIF2α inhibitor is the fumarate salt of Compound I. In some embodiments, the PD-1 inhibitor comprises spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224. In some embodiments, the PD-1 inhibitor comprises spartalizumab. In some embodiments, the PD-1 inhibitor comprises tislelizumab. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg every three or four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD- 1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg every three weeks. In some embodiments, the PD- 1 inhibitor is administered at a dose of about 300 mg every three weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg every four weeks. In some embodiments, the PD-1 inhibitor is administered intravenously. In some embodiments, the PD-1 inhibitor is administered over a period of about 20 to about 40 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the A2aR antagonist is administered at a dose of about 80 mg, about 160 mg, or about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 80 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 160 mg twice daily. In some embodiments, the A2aR antagonist is administered at a dose about 240 mg twice daily. In some embodiments, the A2aR antagonist is administered orally. In an embodiment, Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 25 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 200 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 400 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 500 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 600 mg once weekly, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 80 mg twice daily. In an embodiment, Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 160 mg twice daily. In an embodiment, Compound I is administered at a dose of 12.5 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 25 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 50 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 75 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. In an embodiment, Compound I is administered at a dose of 100 mg once daily, spartalizumab is administered at a dose of 400 mg once every four weeks, and the taminadenant is administered at a dose of 240 mg twice daily. Pharmaceutical Compositions In another aspect, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, which includes HIF-2a inhibitor (e.g., a HIF-2a inhibitor described herein), in combination with a second therapeutic agent (e.g., a therapeutic agent described herein), formulated together with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g. by injection or infusion). The compositions of this disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions. In certain embodiments, the mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular). In an embodiment, the composition is administered by intravenous infusion or injection. In another embodiment, the composition is administered by intramuscular or subcutaneous injection. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion. Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high antibody concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. In some embodiments, a HIF-2a inhibitor (e.g., a HIF-2a inhibitor described herein), in combination with a second therapeutic agent (e.g., a therapeutic agent described herein), can be formulated into a formulation (e.g., a dose formulation or dosage form) suitable for administration (e.g., intravenous administration) to a subject as described herein. The therapeutic agents, e.g., inhibitors, antagonist or binding agents, can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In certain embodiments, the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. In certain embodiments, a therapeutic agent or compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer a compound of the disclosure by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. Therapeutic compositions can also be administered with medical devices known in the art. Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The pharmaceutical compositions of the disclosure may include a "therapeutically effective amount" or a "prophylactically effective amount" of a compound of the disclosure. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound is outweighed by the therapeutically beneficial effects. A "therapeutically effective dosage" preferably inhibits a measurable parameter, e.g., tumor growth rate by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit a measurable parameter, e.g., cancer, can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. Additional features or embodiments of the methods, compositions, dosage formulations, and kits described herein include one or more of the following. Further embodiments In another aspect, the disclosure features kits that may include a HIF-2a inhibitor and one or more additional agents in suitable packaging with written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer. In another aspect, the disclosure provides methods for further combination therapies in which, in addition to a HIF-2a inhibitor, one or more other therapeutic agents known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target proteins is used, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of the composition comprising a HIF-2a inhibitor as described herein with one or more of other HIF-2a inhibitors as described herein, chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, where desired, a synergistic or additive therapeutic effect. Additional therapeutic agents useful in the methods of the invention include any agent capable of modulating a target molecule, either directly or indirectly. Non-limiting examples of target molecules modulated by second agents include enzymes, enzyme substrates, products of transitions, antibodies, antigens, membrane proteins, nuclear proteins, cytosolic proteins, mitochondrial proteins, lysosomal proteins, scaffold proteins, lipid rafts, phosphoproteins, glycoproteins, membrane receptors, G-protein-coupled receptors, nuclear receptors, protein tyrosine kinases, protein serine/threonine kinases, phosphatases, proteases, hydrolases, lipases, phospholipases, ligases, reductases, oxidases, synthases, transcription factors, ion channels, RNA, DNA, RNAse, DNAse, phospholipids, sphingolipids, nuclear receptors, ion channel proteins, nucleotide-binding proteins, calcium-binding proteins, chaperones, DNA binding proteins, RNA binding proteins, scaffold proteins, tumor suppressors, cell cycle proteins, and hi stones. Additional therapeutic agents may target one or more signaling molecules including but not limited to the following: 4EPB-1, 5 -lipoxygenase, Al, Abl, Acetyl-CoAa Carboxylase, actin, adaptor/scaffold proteins, adenylyl cyclase receptors, adhesion molecules, AFT, Aktl, Akt2, Akt3, ALK, AMPKs, APC/C, ARaf, Arf-GAPs, Arfs, ASK, ASKl, asparagine hydroxylase FIH transferases, ATF2, ATF-2, ATM, ATP citrate lyase, ATR, Auroras, B cell adaptor for PI3- kinase (BCAP), Bad, Bak, Bax, Bcl-2, Bcl-B, Bcl-w, Bcl- XL, Bid, Bik, Bim, BLNK, Bmf, BMP receptors, Bok, BRAF, Btk, Bub, cadherins, CaMKs, Casein kinases, Caspase 2, Caspase 3, Caspase 6, Caspase 7, Caspase 8, Caspase 9, caspases, catenins, cathepsins, caveolins, Cbl, CBP/P300 family, CD45, CDC25 phosphatases, Cdc42, Cdk 1, Cdk 2, Cdk 4, Cdk 6, Cdk 7, Cdks, CENPs, Chkl, Chk2, CLKs, Cot, cRaf, CREB, Crk, CrkL, Csk, Cyclin A, Cyclin B, Cyclin D, Cyclin E, Dbl, deacetylases, DLK, DNA methyl transferases, DNA-PK, Dok, Dual Specificity phosphatases (DUSPs), E2Fs, eg5/KSP, Egr-1, eIF4E-binding protein, Elk, elongation factors, endosomal sorting complex required for transport (ESCRT) proteins, Eph receptors, Erks, esterases, Ets, Eyes absent (EYA) tyrosine phosphatases, Fas associated death domain (FADD), FGF receptors, Fgr, focal adhesion kinase (FAK), fodrin, Fos, FOXO, Fyn, GAD, Grb2, Grb2 associated binder (GAB), GSK3a, GSK3p, H- Ras, H3K27, Hdm, HER receptors, HIFs, histone acetylases, histone deacetylases, Histone H3K4 demethylases, FDV1GA, Hrk, Hsp27, Hsp70, Hsp90s, hydrolases, hydroxylases, IAPs, IGF receptors, IKKs, IL-2, IL-4, IL-6, IL-8, ILK, Immunoglobulin-like adhesion molecules, initiation factors, inositol phosphatases, interferon- alpha (IFN-alpha) integrins, interferon a, interferon β, IRAKs, Jakl, Jak2, Jak3, JHDM2A, Jnks, K- Ras, Kit receptor, KSR, LAR phosphatase, LAT, Lck, Lim kinase, LKB-1, Low molecular weight tyrosine phosphatase, Lyn, MAP kinase phosphatases (MKPs), MAPKAPKs, MARKs, Mcl-1, Mek 1, Mek 2, MEKKs, MELK, Met receptor, metabolic enzymes, metalloproteinases, MKK3/6, MKK4/7, MLKs, MNKs, molecular chaperones, Mos, mTOR, (e.g. everolimus) multi-drug resistance proteins, Myc, MyD88, myotubularins, MYST family, Myt 1, N- Ras, Nek, NFAT, NIK, nitric oxide synthase, Non receptor tyrosine phosphatases (NPRTPs), Noxa, nucleoside transporters, pl30CAS, pl4Arf, pl6, p21CIP, p27KIP, p38s, p53, p70S6 Kinase, p90Rsks, PAKs, paxillin, PDGF receptors, PDK1, P- Glycoprotein, phopsholipases, phosphoinositide kinases, PI3 -Kinase class 1, Piml, Pim2, Pim3, Pinl prolyl isomerase, PKAs, PKCs, PKR, PP1, PP2A, PP2B, PP2C, PP5, PRK, Prks, prolyl-hydroxylases PHD-1, prostaglandin synthases, pS6, PTEN, Puma, RABs, Rac, Ran, Ras-GAP, Rb, Receptor protein tyrosine phosphatases (RPTPs), Rel-A (p65-NFKB), Ret, RHEB, Rho, Rho-GAPs, RIP, RNA polymerase, ROCK 1, ROCK 2, SAPK/JNK 1,2,3, SCF ubiquitination ligase complex, selectins, separase, serine phosphatases, SGK1, SGK2, SGK3, She, SHIPs, SHPs, sirtuins, SLAP, Slingshot phosphatases (SSH), Smac, SMADs, small molecular weight GTPases, Sos, Spl, Src, SRFs, STAT1, STAT3, STAT4, STAT5, STAT6, suppressors of cytokine signaling (SOCs), Syk, T-bet, T-Cell leukemia family, TCFs, TGFP receptors, Tiam, ΊΊΕ1, TIE2, topoisomerases, Tpl, TRADD, TRAF2, Trk receptors, TSC1,2, tubulin, Tyk2, ubiquitin proteases, urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) system, UTX, Vav, VEGF receptors, vesicular protein sorting (Vsps), VHL, Weel, WT-1, WT-1, XIAP, Yes, ZAP70, and β-catenin. Preferred additional therapeutic agents may target one or more signaling molecules including but not limited to the following: 4EPB-1, Aktl, Akt2, Akt3, asparagine hydroxylase FIH transferases, Cdk 1, Cdk 2, Cdk 4, Cdk 6, Cdk 7, Cdks, E2Fs, eIF4E-binding protein, FGF receptors, FOXO, Grb2, Grb2 associated binder (GAB), GSK3a, GSK3p, Hdm, HER receptors, HIFs, histone acetylases, histone deacetylases, Histone H3K4 demethylases, Hsp27, Hsp70, Hsp90s, hydrolases, hydroxylases, IL-2, inositol phosphatases, interferon- alpha (IFN-alpha), Mek 1, Mek 2, Met receptor, mTOR (in particular everolimus), Myc, p53, p70S6 Kinase, p90Rsks, PDGF receptors, PDK1, phosphoinositide kinases, PI3 -Kinase class 1, prolyl-hydroxylases PHD-1, pS6, PTEN, RHEB, sirtuins, ΊΊΕ1, TIE2, TSC1,2, ubiquitin proteases, VEGF receptors, VHL, and β-catenin. In another aspect, this invention also relates to methods and pharmaceutical compositions for inhibiting abnormal cell growth in a mammal which comprises a therapeutically effective amount of a HIF-2a inhibitor in combination with an amount of an anti-cancer agent (e.g., a chemotherapeutic agent). Many chemotherapeutics are presently known in the art and can be used in combination with a HIF-2a inhibitor disclosed herein. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, immunotherapeutic agents (in particular Anti-PD1, Anti-PD-L1, Anti-LAG-3, Anti-TIM-3, GITR agonist, IL15/IL-15Ra complexes, TGf beta inhibitors, A2aR inhibitors, Anti-CD73, Anti-ENTPD2), proapoptotic agents, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Tykerb/Tyverb (lapatinib), Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include 2,2',2"-trichlorotriethylamine; 2-ethylhydrazide; aceglatone; aldophosphamide glycoside; alkyl sulfonates such as busulfan, improsulfan and piposulfan; alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); aminolevulinic acid; amsacrine; anti-adrenals such as aminoglutethimide, mitotane, trilostane; antibiotics such as anthracyclins, actinomycins and bleomycins including aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); arabinoside ("Ara-C"); aziridines such as benzodopa, carboquone, meturedopa, and uredopa; bestrabucil; bisantrene; capecitabine; cyclophosphamide; dacarbazine; defofamine; demecolcine; diaziquone; edatraxate; elfomithine; elliptinium acetate; esperamicins; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; etoglucid; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; folic acid replenisher such as frolinic acid; gacytosine; gallium nitrate; gemcitabine; hydroxyurea; lentinan; lonidamine; mannomustine; mitobronitol; mitoguazone; mitolactol; mitoxantrone; mopidamol; nitracrine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; oxazaphosphorines; pentostatin; phenamet; pipobroman; pirarubicin; podophyllinic acid; procarbazine; PSK.RTM.; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; razoxane; retinoic acid; sizofiran; spirogermanium; taxanes, e.g., paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); tenuazonic acid; thiotepa; triazenes; triaziquone; urethan; vindesine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum or platinum analogs and complexes such as cisplatin and carboplatin; anti -microtubule such as diterpenoids, including paclitaxel and docetaxel, or Vinca alkaloids including vinblastine, vincristine, vinflunine, vindesine, and vinorelbine; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase I and II inhibitors including camptothecins (e.g., camptothecin-11), topotecan, irinotecan, and epipodophyllotoxins; topoisomerase inhibitor RFS 2000; epothilone A or B; difluoromethylormthine (DMFO); histone deacetylase inhibitors; compounds which induce cell differentiation processes; gonadorelin agonists; methionine aminopeptidase inhibitors; compounds targeting/decreasing a protein or lipid kinase activity; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; anti-androgens; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMODAL®); Hsp90 inhibitors such as 17-AAG (17- allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 or PD0325901 from Pfizer, leucovorin, EDG binders, antileukemia compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, antiproliferative antibodies or other chemotherapeutic compounds. Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, and Velcade®. This invention further relates to a method for using the compounds or pharmaceutical composition in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, or implants, e.g., with corticosteroids, hormones, or used as radiosensitizers. One such approach may be, for example, radiation therapy in inhibiting abnormal cell growth or treating the proliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein. Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended without limitation to include exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non- limiting example, the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir- 192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres. Without being limited by any theory, the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation, which comprises administering to the mammal an amount of a HIF-2a inhibitor, which is effective in sensitizing abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. Further therapeutic agents that can be combined with a subject compound may be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety. In some embodiments, the compositions and methods further comprise administering, separately or simultaneously one or more additional agents (e.g.1, 2, 3, 4, 5, or more). Additional agents can include those useful in wound healing. Non-limiting examples of additional agents include antibiotics (e.g. Aminoglycosides, Cephalosporins, Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones, Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's, Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes (e.g. Testosterone), Cholestanes (e.g. Cholesterol), Cholic acids (e.g. Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g. Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcotic analgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol, Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone, Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine), chemotherapy (e.g. anticancer drugs such as but not limited to Altretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine, Dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin, Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone, Procarbazine, Streptozocin, Tamoxifen, Teniposide, Vinblastine, Vincristine), anti- inflammatory agents (e.g. 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; Decanoate; Deflazacort; Delatestryl; Depo-Testosterone; 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; Mesterolone; Methandrostenolone; Methenolone; Methenolone Acetate; Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Nandrolone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxandrolane; Oxaprozin; Oxyphenbutazone; Oxymetholone; 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; Stanozolol; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Testosterone; Testosterone Blends; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium), or anti-histaminic agents (e.g. Ethanolamines (like diphenhydrmine carbinoxamine), Ethylenediamine (like tripelennamine pyrilamine), Alkylamine (like chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine), other anti-histamines like astemizole, loratadine, fexofenadine, bropheniramine, clemastine, acetaminophen, pseudoephedrine, triprolidine). EXAMPLES The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Example 1: Non-clinical pharmacology Compound I anti-tumor activity has been assessed in VHL-deficient ccRCC cell lines- derived and patient-derived xenograft mouse models. 786-O and SKRCO-1 xenograft mouse models The effects of Compound I on ratio tumor volume in the 786-0 xenograft mouse model (A) and SKRCO-1 xenograft mouse model (B) are illustrated in Fig.1. In the case of 786-0 subcutaneous xenografts (A), female nude mice were treated with Compound I at 0.3, 1, 3, 10 and 30 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 34 days post tumor inoculation and lasted 20 days. Initial tumor volume at day 0 was approximately 280 mm3. For the SKRCO-1 subcutaneous xenografts (B), female nude mice were treated with Compound I at 1, 3 and 10 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 52 days post tumor inoculation and lasted 21 days. Initial tumor volume at day 0 was approximately 211 mm3. Values are mean ± SEM; sample size, (n=4-6 mice per group). *: p < 0.05 vs. vehicle controls (ANOVA on ranks and post hoc Tukey test). In both 786-0 (expressing HIF2α only) and SKRCO-1 (expressing HIF1α and HIF2α) ccRCC cell lines-derived xenograft mouse models, Compound I demonstrated dose- dependent efficacy which correlated with dose-dependent target genes modulation. Compound I achieved maximal attainable efficacy in both models tested (786-O: ~70% tumor regression; SKRCO-1: ~50% tumor regression) at doses of 10 mg/kg p.o. qd respectively. HKIX2207 tumor model The effects of Compound I on ratio tumor volume in HKIX2207 tumor models are illustrated in Fig.2. In panel A, female nude mice bearing HKIX2207 human primary ccRCC subcutaneous xenografts were treated with Compound I at 10 mg/kg p.o. qd and 30 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween80 0.5%). Treatments started 26 days post tumor inoculation and lasted 28 days. Values are mean ± SEM; sample size, (n=5 to 6 mice per group). Initial tumor volume at day 0 was approximately 268 mm3. Changes in body weight (%corr) represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals. Initial body weight at day 0 was 24-26 g. In panel B, female nude mice bearing HKIX2207 human primary ccRCC subcutaneous xenografts were treated with Compound I at 40 and 100 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 39 days post tumor inoculation and lasted 28 days. Values are mean ± SEM; sample size, (n=4 to 5 mice per group). Initial tumor volume at day 0 was approximately 260 mm3. Changes in body weight (%corr) represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals. Initial body weight at day 0 was 24-26 g. In HKIX2207 tumor model, Compound I demonstrated dose-dependent efficacy. Compound I achieved maximal attainable efficacy at doses of 40 mg/kg p.o. qd. HKIX2967 tumor model The effects of Compound I on ratio tumor volume in HKIX2967 tumor models are illustrated in Fig.3. In Panel A, female nude mice bearing HKIX2967 human primary ccRCC subcutaneous xenografts were treated with Compound I at 10 and 30 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 12 days post tumor inoculation and lasted 21 days. Values are mean ± SEM; sample size, (n=5 to 6 mice per group). Initial tumor volume at day 0 was approximately 278 mm3. Changes in body weight (%corr) represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals. Initial body weight at day 0 was 23-27 g. In Panel B, female nude mice bearing HKIX2967 human primary ccRCC subcutaneous xenografts were treated with Compound I at 40 and 100 mg/kg p.o. qd or vehicle control (10%EtOH + 30%PEG400 + 60%MC 0.5% / Tween800.5%). Treatments started 24 days post tumor inoculation and lasted 31 days. Values are mean ± SEM; sample size, (n=5 to 6 mice per group). Initial tumor volume at day 0 was approximately 276 mm3. Changes in body weight (%corr) represent the ratio between body weight at day x (corrected by subtraction of primary tumor weight) and body weight at day 0 (corrected by subtraction of primary tumor weight) expressed in percentage for each individual animals. Initial body weight at day 0 was 26-27 g. In HKIX2967 tumor model, Compound I also demonstrated dose-dependent efficacy. Compound I achieved maximal attainable efficacy at doses of 40 mg/kg p.o. qd. Overall, Compound I achieved maximal attainable efficacy in ccRCC tumor mouse models at doses with good tolerability. Example 2: A Phase I/Ib, open-label, multi-center study of Compound I as a single agent and in combination with Everolimus or IO agents in patients with advanced/relapsed ccRCC and other malignancies with HIF2α stabilizing mutations A first-in-human (FIH) study will be run to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of Compound I as a single agent and in combination with everolimus, or spartalizumab plus taminadenant in adult patients with advanced, relapsed clear cell renal cell carcinoma (ccRCC). The study will also explore the use of single agent Compound I in patients older than 12 years old with malignancies harboring a HIF2α stabilizing mutation. Primary objectives To characterize the safety and tolerability of Compound I as a single agent and in combination with everolimus, or spartalizumab plus taminadenant in patients with advanced ccRCC and HIF (hypoxia-inducible factor) stabilizing mutations. Endpoints for primary objectives ● Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory parameters, vital signs and electrocardiograms (ECGs) ● Tolerability: Dose interruptions, reductions and dose intensity for both dose escalation and expansion ● Escalation Only: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for Compound I as a single agent and in combinations Secondary objectives To assess the preliminary anti-tumor activity of Compound I as a single agent and in combination with everolimus, or spartalizumab and taminadenant. To characterize the PK of Compound I as a single agent and in combination with everolimus, or spartalizumab and taminadenant. Endpoints for secondary objectives ● Overall Response Rate (ORR), Best Overall Response (BOR), Progression Free Survival (PFS) (for RD only), Duration of Response (DOR) (for RD only), Disease Control Rate (DCR) per RECIST v1.1 ● Plasma concentration of Compound I and Taminadenant, whole blood concentration of Everolimus, serum concentration of Spartalizumab, and derived PK parameters for each analyte Exploratory objectives and endpoints
Figure imgf000158_0001
Figure imgf000159_0001
Study design This is a FIH, open-label, phase I/Ib, multi-center study consists of 3 dose escalation parts (Arms 1, 2 and 3), each followed by a dose expansion part. The study design is summarized in Fig.4. The first dose escalation part (Arm 1) will initially evaluate Compound I weekly (QW) dosing and may also include evaluation of daily (QD) dosing. The dose escalation part for groups receiving Compound I in combination with everolimus (Arm 2) or spartalizumab and taminadenant (Arm 3) will open after at least two dose levels of single agent Compound I have been evaluated and shows to satisfy Escalation with Overdose Control (EWOC). In addition, the dose and dosing frequency identified for Compound I single agent that satisfies EWOC at the time of start of combination will be used with the partners in the corresponding dose escalation arms of the study. For the first three subjects in each dose escalation part (Arm 1, Arm 2, and Arm 3), a staggered approach will be utilized for enrollment and will occur as follows: ● 1st patient dosed, wait at least 24 hours ● 2nd patient dosed, wait at least 24 hours ● 3rd patient dosed Once the optimal dose and dosing frequency is identified for Compound I as a single agent, the corresponding dose expansion arms will be opened in the single agent arm (Arm 1A and Arm 1B). Similarly, the dose expansion arms (Arm 2A and Arm 3A) for the combination therapies will be opened once the recommended dose (RD) for combination is identified in the escalation arms. The dose expansion part of Compound I single agent will include two treatment arms: Arm1A will enroll ccRCC patients and Arm1B will enroll patients with malignancies harboring HIF2α stabilizing mutations. Arm1B will enroll patients who are 12 years or older with refractory/relapsed malignancies and known mutations in at least one of the following genes as per local diagnostic test: VHL, FH, SDHx, EPAS1/HIF2A, ELOC/TCEB1. The expansion part of the combination therapies will enroll patients with ccRCC and include Arm2A (Compound I with everolimus) and Arm3A (Compound I with spartalizumab and taminadenant). Study Flow Screening period- Subjects will be evaluated against study inclusion and exclusion criteria discussed herein below. Treatment period- The treatment period commences on Day 1 of Cycle 1. For the purpose of scheduling and evaluations, a treatment cycle will consist of 28 days for patients. End of treatment period & Follow-up (FU) period-patients who discontinue treatment due to disease progression will be followed for safety evaluations 150 days after treatment discontinuation in Arm 3/3A and 30 days after treatment discontinuation in Arm 1/1A/1B and Arm 2/2A. Patients who discontinue treatment due to AE or any other reason other than disease progression will be followed for safety evaluations and tumor assessment until disease progression 150 days after treatment discontinuation in Arm 3/3A and 30 days after treatment discontinuation in Arm 1/1A/1B and Arm 2/2A. Rationale for study design The design of this study was chosen to characterize the safety and tolerability of Compound I as a single agent and in combinations with everolimus or spartalizumab and taminadenant in subjects with ccRCC. The MTD and/or a lower biologically active RD will be determined for Compound I as a single agent and in combinations. This design will also enable assessment of PK of Compound I and combination partners. The study will be guided by a Bayesian Hierarchical Logistic Regression Model (BHLRM). The BHLRM is a well-established method to estimate the MTD/RD in cancer subjects. The adaptive BHLRM will be guided by the escalation with overdose control (EWOC) principle to control the risk of DLT in future subjects on study. The use of Bayesian response adaptive models for small datasets has been accepted by EMEA (“Guideline on clinical trials in small populations”, February 1, 2007) and endorsed by numerous publications (Babb et al., “Cancer phase I clinical trials: efficient dose escalation with overdose control,” Stat Med.17(10):1103-20, 1998); (Neuenschwander et al.2008); (Neuenschwander et al.2010); (Neuenschwander et al.2014), and its development and appropriate use is one aspect of the FDA’s Critical Path Initiative. The decisions on new dose levels are made by the Investigators and Novartis study personnel in a dose escalation meeting based upon the review of subject tolerability and safety information (including the BHLRM/ summaries of DLT risk) along with PK, PD and preliminary activity information available at the time of the decision. Rationale for dose/regimen and duration of treatment This is the first trial that will evaluate Compound I in humans. The starting dose for Compound I , for subjects enrolled in this trial, is 50 mg weekly. Preclinical pharmacology and PK/PD data informed the selection of the starting dose. Preclinical safety data in 4-week GLP toxicology studies in rats (25 and 75 mg/kg/day or 200 mg/kg/wk) and dogs (10 mg/kg/day or 25 mg/kg/wk) provide support for a starting dose up to 25 mg daily or up to 120 mg weekly and provisional top doses of 100 mg daily or 600 mg weekly in humans. To ensure sufficient exposure margins, the dose escalation of Compound I in FIH as a single agent will start with 50 mg weekly. PK/PD data from mouse xenograft models indicate that pharmacological activity by inhibition of HIF2α is anticipated at the starting dose. If the t1/2 of Compound I is significantly shorter than the predicted values, there is an option to reduce-dosing frequency from weekly to daily. The provisional QD dose will start at 25 mg which is expected to be therapeutically active based on preclinical pharmacology data. The provisional QD doses will be adjusted based on emerging PK data. In the combination arms, the starting dose and dose regimen of Compound I will be determined based on the data from the single agent arm of the study and will be at least one dose level below the highest dose of single agent Compound I that also satisfies the EWOC at the time of starting the combo. In Arm 3, the starting dose for spartalizumab will be 400 mg i.v. every 4 weeks and the starting dose for taminadenant will be 80 mg twice daily based on previous clinical studies. Rationale for choice of combination drugs Clinical data suggests targeting HIF2α inhibition may be an effective therapeutic option in patients with advanced RCC, though the percentage of clinical responses reported on early clinical trials has been low (ORR 14% for PT2385, 24% for PT2977/MK-6482) with most of them being incomplete (Courtney KD et al 2018) (ESMO abstract). This is hypothesized to be, at least in part, secondary to an observed increase in HIF1α transcriptional activity. There is a strong interconnection between hypoxia response/HIFs and the adenosine pathway. Therefore, boosting the activity of the immune checkpoint inhibitor spartalizumab, with the A2aR antagonist taminadenant and the HIF2α inhibitor Compound I may complement the antitumor effects of this immunotherapy in addition to the direct anti-tumoral activity of Compound I in ccRCC. Study Population This study will be conducted in adult patients (age 18 or older) with a confirmed diagnosis of advanced, relapsed clear cell Renal Cell Carcinoma following standard of care treatment; with the exception of a single agent expansion group (Arm 1B) that will be conducted in patients 12 years of age or older with HIF stabilizing mutations as described below (inclusion criteria #4) with no available therapies of proven clinical benefit. The investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered treatment in the study. Key inclusion criteria For dose escalation and expansion arms on single agent (SA) and combinations, with the exception of Arm1B: 1. Male and female ≥ 18 years of age 2. Histologically confirmed and documented clear cell renal cell carcinoma (ccRCC). Disease must be measureable as determined by RECIST v1.1. 3. Patient with unresectable, locally advanced or metastatic ccRCC with documented disease progression following all standard of care therapy including PD-1/L1 checkpoint inhibitor and a VEGF targeted therapy as monotherapy or in combination. Escalation: No restriction on the number of prior treatments Expansion: Up to 3 prior lines of treatment for advanced/metastatic disease 4. ECOG performance status ≤ 1 For Arm 1B: 1. Male and female of age ≥ 12 years of age. 2. Histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes: ● Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease) ● Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma) ● Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome) ● Malignancies with EPAS1/HIF2A mutations ● Malignancies with ELOC/TCEB1 mutations 3. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. 4. For patients age ≥ 16 years: ECOG performance status ≤ 1; for patients age ≥ 12 and < 16 years: Lansky performance status ≥ 70. Key exclusion criteria 1. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids. Patients with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment prior to study entry and at doses ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment. 2. Known additional malignancy that is progressing or requires active treatment within the past 3 year(s). Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy. 3. Patients having out of range lab values during screening and before the first dose of study treatment. Out of range lab values are defined as: ● Absolute neutrophil count (ANC) <1.0 × 109/L ● Platelets <75 × 109/L ● Hemoglobin (Hgb) < 10g/dL ● Serum creatinine > 1.5 × ULN or creatinine clearance < 40mL/min using Cockcroft- Gault formula ● Total bilirubin > 1.5 × ULN , except for patients with Gilbert’s syndrome > 3.0 × ULN or direct bilirubin > 1.5 × ULN ● Aspartate aminotransferase (AST) > 3 × ULN ● Alanine aminotransferase (ALT) > 3 × ULN ● Serum electrolytes ≥ grade 2 despite adequate supplementation. 4. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes: a. ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment. b. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent. c. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C. d. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists. e. Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure. 5. Patient previously treated with a HIF2α inhibitor. Study treatment For this study, the term “investigational drug” and "study treatment" refers to Compound I, taminadenant and spartalizumab. All dosages prescribed and dispensed to patients and all dose changes during the study must be recorded on the Dosage Administration Record eCRF. Table 16: Dose and treatment schedule
Figure imgf000165_0002
Dose escalation guidelines Starting dose The starting dose for Compound I as single agent of 50 mg weekly (QW) is supported by 4-week GLP toxicology studies in rats and dogs that satisfies EWOC criteria. The starting dose for taminadenant in combination with Compound I and spartalizumab is 80 mg twice daily (BID), while spartalizumab is fixed at 400 mg Q4W intravenously. The starting doses for the combination arms must satisfy EWOC criteria. Provisional dose levels Table 17 describes the provisional starting dose and dose levels of Compound I with weekly dosing regimen that may be evaluated during the trial. Dose level -1 represents a dose that may be evaluated if higher doses are not well tolerated. The actual doses evaluated in the study may be different from those shown in the table, as clinical experience is used to elucidate the relationships between dose, systemic exposure, pharmacological activity and toxicity. Additional dose levels may be added during the study. Table 17. Provisional QW dose levels for Compound I (Scenario 1)
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Efficacy assessments ● Tumor assessment per RECIST v1.1. In Arm 3, iRECIST will also be utilized. Pharmacokinetic assessments ● Plasma concentration of Compound I and taminadenant (and its metabolite NJI765) serum concentration of spartalizumab and derived PK parameters. ● Exploratory analysis on the correlation of PK with PD, safety and efficacy. Key safety assessments ● Adverse event (AE) monitoring will be conducted on ongoing basis, with physical examinations, monitory of laboratory markers and other safety parameters (e.g. changes in ECG and EEG). ● Frequency, severity and seriousness of AEs, laboratory abnormalities will be evaluated. Other assessments ● Assessment in tumor of expression status of potential predictors of efficacy, pharmacodynamic markers, and potential predictive markers of response and mechanisms of resistance (HIF2α, HIF1α, CD8, PD-L1). ● PD effect in blood, proof of mechanism (modulation of EPO), assessment of cfDNA as surrogate for predictive PD, for mutational burden and resistance markers in tumor biopsy DNA Data analysis ● Study data will be analyzed and reported in a clinical study report (CSR) based on all patients’ data up to the time when all patients have completed the trial or discontinued from the study. ● Patients treated with the same dosing regimen (dose and dosing schedule) of Compound I as a single agent and in combination and indication will be pooled into a single treatment group (including patients from dose escalation and dose expansion parts) with the exception of Arm1B. Equivalents Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS 1. A pharmaceutical combination comprising a HIF2α inhibitor, a PD-1 inhibitor, and optionally an A2aR antagonist.
2. The pharmaceutical combination of claim 1, wherein the HIF2α inhibitor is a compound having the structure of formula (I):
Figure imgf000169_0001
3. The pharmaceutical combination of claim 1, wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, tislelizumab (BGB-A317), BGB-108, INCSHR1210, or AMP-224.
4. The pharmaceutical combination of claim 1, wherein the A2aR antagonist is selected from istradefylline, tozadenant, preladenant, vipadenan, taminadenant (PBF-509), ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER- 7835, CGS-15943, ZM-241,385, or MEDI9447.
5. The pharmaceutical combination of claim 1, wherein the HIF2α inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are in 2 or 3 separate formulations.
6. The pharmaceutical combination of claim 1, wherein the HIF2α inhibitor, the PD-1 inhibitor, and optionally the A2aR antagonist are administered simultaneously or sequentially.
7. The pharmaceutical combination of claim 1, wherein the PD-1 inhibitor is spartalizumab and the A2aR antagonist is taminadenant.
8. The pharmaceutical combination of claim 1, wherein the PD-1 inhibitor is tislelizumab and the A2aR antagonist is taminadenant.
9. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of any one of claims 1-8.
10. The method of claim 9, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
11. The method of claim 10, wherein the cancer is renal cell carcinoma.
12. The method of claim 9, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
13. The method of claim 12, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
14. The method according to any of the claims 9 to 13, wherein the HIF2α inhibitor is a compound having the structure of formula (I):
Figure imgf000171_0001
( ) that is administered orally at a dose of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, or about 600 mg every week.
15. The method according to any of the claims 9 to 13, wherein the HIF2α inhibitor is a compound having the structure of formula (I):
Figure imgf000171_0002
( ) that is administered orally at a dose of about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg once daily.
16. The method according to claim 14 or 15, wherein the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg.
17. The method according to claim 14 or 15, wherein the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg.
18. The method according to claim 14 or 15, wherein the PD-1 inhibitor is administered at a dose of about 200 mg, about 300 mg, about 400 mg, or about 500 mg.
19. The method according to claims 14 or 15, wherein the PD-1 inhibitor is administered once every three or four weeks.
20. The method according to claim 14 or 15, wherein the PD-1 inhibitor is administered intravenously.
21. The method according to any of claims 14 or 20, wherein the A2aR is administered orally at a dose of about 80 mg, about 160 mg, or about 240 mg twice daily.
22. The pharmaceutical combination of any one of claims 1-8, for use in the treatment of cancer.
23. The pharmaceutical combination of any one of claims 1-8, for use in the manufacture of a medicament for the treatment of cancer.
24. The pharmaceutical combination of claim 22 or 23, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
25. The pharmaceutical combination of claim 24, wherein the cancer is renal cell carcinoma.
26. The pharmaceutical combination of claim 22 or 23, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
27. The pharmaceutical combination of 26, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
28. Use of a pharmaceutical combination of any one of claims 1-8 for the manufacture of a medicament for the treatment or prevention of cancer.
29. Use of a pharmaceutical combination of any one of claims 1-8 for the treatment or prevention of cancer.
30. The use of claim 28 or 29, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, breast cancer, clear cell renal cell carcinoma (ccRCC), colorectal cancer, germ cell tumor, glioblastoma multiforme (GBM), glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, lung cancer, malignant glioma, ocular cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, or renal cell carcinoma.
31. The use of claim 30, wherein the cancer is renal cell carcinoma.
32. The use of claim 28 or 29, wherein the cancer is a malignancy with one or more HIF stabilizing mutations.
33. The use of claim 32, wherein the one or more HIF stabilizing mutations is selected from the group consisting of VHL mutations, FH mutations, SDHD mutations, SDHAF2 mutations, SDHC mutations, SDHB mutations, SDHA mutations, EPAS1/HIF2A mutations, or ELOC/TCEB1 mutations.
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