Methods for treating PSMA-expressing cancers

Abstract

This invention provides a combination for use in treating cancers that express prostate-specific membrane antigen (PSMA). [Solution] A combination comprising a PD-1 inhibitor, a CTLA-4 inhibitor, and a radiolabeled compound of formula Ia for use in treating PSMA-expressing cancer in the subject. JPEG2026049728000042.jpg45132 The aforementioned combination comprises one or more further anticancer agents, wherein the further anticancer agents are selected from octreotide, lanreotide, vapreotide, pasireotide, satreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under 35 U.S.C. § 119(e) of U.S. Provisional Application 62 / 977,932 filed February 18, 2020, and incorporates the entire disclosure thereof herein by reference.

[0002] Field of Invention The present invention relates to a method for treating prostate cancer and other cancers that express prostate-specific membrane antigen (PSMA), such as PSMA-expressing cancers and cancers that express PSMA in neovascular structures. In particular, the present invention provides a novel therapy based on a combination of a PSMA therapeutic agent, such as radiolabeled compound I disclosed herein, and an immuno-oncology (IO) therapeutic agent, wherein the IO therapeutic agent is selected from LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Background technology]

[0003] Background and Overview of the Invention The prostate gland is a male reproductive organ that functions to produce and store semen, which provides nutrients and fluids for the survival of sperm introduced into the vagina during reproduction. Like other tissues, the prostate can develop malignant (cancerous) or benign (non-cancerous) tumors. In fact, prostate cancer is one of the most common cancers in men in Western society and the second most common form of malignant tumor in American men. Current treatments for prostate cancer include hormone therapy, radiation therapy, surgery, chemotherapy, photodynamic therapy, and combination therapy. However, many of these treatments affect the quality of life of patients, especially men diagnosed with prostate cancer after the age of 50. For example, the use of hormone therapy is often accompanied by side effects such as osteoporosis and liver damage. Such side effects are more selective or specific to the tissue responsible for the diseased condition and should be mitigated by using treatments that avoid non-target tissues such as bone or liver.

[0004] Prostate-specific membrane antigen (PSMA) is a biomarker expressed in prostate cancer. PSMA can be overexpressed in malignant prostate tissue compared to other organs in the human body, such as the kidneys, proximal small intestine, and salivary glands. PSMA is also expressed in neovascular structures within many non-prostate solid tumors, including lung, colon, breast, kidney, liver, and pancreatic carcinomas, but not in normal vascular structures. PSMA expression in the brain is also minimal. PSMA is a type II cell surface membrane-bound glycoprotein with a molecular weight of approximately 110 kD, containing an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and a broad extracellular domain (amino acids 44-750). While the functions of the intracellular segment and transmembrane domain are currently considered trivial, the extracellular domain is involved in several different activities. For example, PSMA plays a role in the central nervous system, where it metabolizes N-acetyl-aspartylglutamate (NAAG) to glutamine and N-acetylaspartate. PSMA also plays a role in the proximal small intestine, removing gamma-linked glutamate from poly-gamma-glutamate folate and alpha-linked glutamate from peptides and small molecules. However, the specific function of PSMA in prostate cancer cells remains unclear.

[0005] PSMA is named primarily because of its high expression levels in prostate cancer cells compared to other tissues; however, its specific function in prostate cancer cells remains unclear. PSMA expression is highly restricted in normal tissues. It is present only in salivary gland tissue, kidney tissue, and a small number of cells in the small and large intestines. PSMA is overexpressed in malignant prostate tissue compared to other organs in the human body, such as the kidneys, proximal small intestine, and salivary glands. Higher PSMA expression is associated with higher malignancy, metastasis, and castration resistance. Tumor expression of PSMA in prostate cancer is typically 100 to 1,000 times higher than in normal tissue. Unlike many other membrane-bound proteins, PSMA undergoes rapid intracellular translocation in a manner similar to cell surface-bound receptors such as vitamin receptors. PSMA translocates via clathrin-coated pits and can then be recycled to the cell surface or go to lysosomes. Therefore, diagnostic agents, contrast agents, and therapeutic agents can target PSMA for delivery to PSMA-expressing cells, such as prostate cancer cells.

[0006] PSMA is also expressed in neovascularization in cancers other than prostate cancer, such as thyroid cancer, renal clear cell carcinoma, bladder transitional cell carcinoma, colon adenocarcinoma, neuroendocrine cancer, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer. These cancers represent a broad range of cancers with different histological subtypes, growth rates, and cell cycle times. In some cases, the cancer is embedded within normal tissue, which can alter radioresistance. Furthermore, hypoxic areas of large deposits also become radioresistant. These and other factors are known to result in various intrinsic responses to traditional external beam radiotherapy. [Overview of the project]

[0007] While the activity of PSMA on the cell surface of prostate cells is under investigation, PSMA has been shown to be a viable target for the selective and / or specific delivery of bioactive agents, including drug compounds, or combinations of bioactive agents, to such prostate cells. Some such drug compounds are formulated with formula I [ka] It is a compound or a salt thereof.

[0008] Compound I can be described as a small molecule that specifically binds to PSMA (prostate-specific membrane antigen) expressed on the surface of prostate cancer cells. Compound I is a pharmacophore ligand, glutamate-urea-lysine; chelator, DOTA( 177 Lu and 225 It can be characterized as consisting of a compound that can complex with Ac and a linker that connects the ligand and the chelator. Although not bound by theory, it is thought that urea-based pharmacophore ligands can bind drugs to PSMA at the disease site and allow for internal delivery. Furthermore, it is thought that binding of I-Lu or I-Ac can lead to internal delivery via endocytosis, which can provide sustained retention of the ligand and its bound radioactive cargo within cancer cells. When used here, the term "compound I" is used in the context of therapy, and it binds to a radionuclide.

[0009] The radioactive ligand therapy (RLT) used in the clinic is for thyroid cancer. 131 I and for bone metastasis treatment 223 Radium or 89 It contains alpha-emitting elements such as strontium.

[0010] 177 Lu has a half-life of 6.7 days. It travels undisorderly through tissues, moving approximately 20–80 cells or 0.5–2 mm, emitting 0.5 MeV energy consisting of negatively charged beta particles (electrons) that primarily cause base damage and single-strand disruption. At high doses, these lesions can interact to convert sublethal damage (SLD) or potentially lethal damage (PLD) into irreversible lethal damage. 177 Lu also emits 113kv and 208kV radiation, which can be used for contrast imaging.

[0011] 225The half-life of Ac is 9.9 days, and it emits 8.38 MeV energy alpha particles during imaging. Only a mere 0.5% of the energy is emitted as 142 Kv photons. Therefore, most of the radiation particles are positively charged and are approximately 8,000 times larger than beta particles. Furthermore, the energy from these particles deposits over a relatively short distance (2 - 3 cells). As a result, there is high-density and severe tissue damage in the form of double-strand breaks with multiple damage sites representing irreparable lethal damage. This is referred to as high linear energy transfer (LET) or densely ionizing ionization and delivers 3 - 7 times more absorbed dose than beta particles. The type of cell damage caused by any isotope ( 177 Lu or 225 Ac) is predicted to be different due to the differences in the characteristics of each projectile. 177 Lu provides radiation with a long path length and can thus effectively deliver radiation to adjacent cells. In particular, the predominance of single-strand breaks, especially in the presence of oxygen, provides an opportunity to repair sublethal damage (SLD) and / or potentially lethal damage (PLD), which are optimal conditions for normal tissue repair. Conversely, 225 Ac delivers extremely powerful, high LET radiation and has a much more limited potential to repair normal tissue. The radiobiological effectiveness of alpha radiation is at least 5 times that of beta irradiation, and the biological effect ratio (RBE) should be considered for the irradiation dose. 225 Ac treatment is more effective even in hypoxic tumor regions because the type of DNA damage caused does not require oxygen. 225 A potential drawback of Ac treatment is that due to the short path length, a large amount of damaging radiation may deposit only within a short distance of 2 - 4 cells.

[0012] Combinations of therapeutic agents based on combinations of PSMA therapeutic agents and cancer immunotherapy (I-O) therapeutic agents and methods of treating PSMA-expressing cancers are described herein.

[0013] Cancer immunotherapy (I-O) therapeutic agents can break established resistance to cancer and restore an effective cancer-specific immune response.

[0014] The internal radiation of tumor cells provided by the radiolabeled compounds I described herein, particularly compound Ia, can damage tumors, induce the release of tumor antigens, and thus allow the immune system to better visualize the tumor. IO therapy provides immune checkpoint blockade and therefore improves the immune anti-tumor T cell response. In this way, IO therapy can synergistically enhance the effects of internal radiation by radiolabeled compounds I, particularly compound Ia.

[0015] The present invention provides a novel combination of a PSMA therapeutic agent, for example, compound I, particularly compound Ia, and one or more cancer immunotherapy (IO) therapeutic agents for use in treating PSMA-expressing cancers in a subject, wherein the IO therapeutic agent is selected from the group consisting of LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. In one embodiment, the IO treatment agent is selected from the group consisting of spartalizumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, nivolumab, MK-3475, MPDL3280A, MEDI5736, ipilimumab, tremelimumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, and AMP-224. In one embodiment, the PSMA treatment agent is radiolabeled compound I.

[0016] The combination or method of the present invention may comprise one or more further anticancer agents.

[0017] In the combination or method of the present invention, the LAG-3 inhibitor may be selected from LAG525, BMS-986016, or TSR-033.

[0018] In the combination or method of the present invention, the TIM-3 inhibitor may be MBG453 or TSR-022.

[0019] In the combination or method of the present invention, the GITR agonist may be selected from GWN323, BMS-986156, MK-4166, MK-1248, TRX518, INCAGN1876, AMG228, or INBRX-110.

[0020] In the combination or method of the present invention, the TGF-β inhibitor may be XOMA089 or fresolimmab.

[0021] In the combination or method of the present invention, the IL-15 / IL-15RA complex may be selected from NIZ985, ATL-803, or CYP0150.

[0022] Further anticancer agents according to the present invention may be selected from octreotide, lanreotide, vapreotide, pasireotide, satreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib.

[0023] The present invention provides the following exemplary embodiments. It is recognized that each of the embodiments provided below can also be carried out using compound I or any other stereoisomer of compound I or any other stereoisomer of compound Ia, as described in the various embodiments.

[0024] 1. Radiolabeled formula Ia (compound Ia) for use in the treatment of PSMA-expressing cancers in the target population. [ka] A combination comprising a compound and one or more cancer immunotherapy (IO) agents, wherein the IO agent is selected from LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

[0025] 2. A method for treating PSMA-expressing cancer in a subject, wherein the subject is radiolabeled with formula Ia (compound Ia) [ka] A method comprising administering a combination of a compound and one or more cancer immunotherapy (IO) agents, wherein the IO agent is selected from LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

[0026] 3. A combination of item 1 or the method of item 2, wherein the radiolabeled compound Ia and the IO therapeutic agent are separate compositions and are administered separately to the subject.

[0027] 4. Any combination of item 1 or 3, or the method of item 2 or 3, wherein the LAG-3 inhibitor is selected from LAG525, BMS-986016, or TSR-033.

[0028] 5. Any combination of items 1 or 3-4, or any method of items 2-4, wherein the TIM-3 inhibitor is MBG453 or TSR-022.

[0029] 6. The GITR agonist is selected from GWN323, BMS-986156, MK-4166, MK-1248, TRX518, INCAGN1876, AMG228, or INBRX-110, in any combination of items 1 or 3-5, or in any method of items 2-5.

[0030] 7. Any combination of items 1 or 3-6, or any method of items 2-6, wherein the TGF-β inhibitor is XOMA089 or fresolimmab.

[0031] 8. Any combination of items 1 or 3-7, or any method of items 2-7, wherein the IL-15 / IL-15RA complex is selected from NIZ985, ATL-803, or CYP0150.

[0032] 9. Any combination of items 1 or 3-8, or any method of items 2-8, comprising one or more additional anticancer agents.

[0033] 10. A combination or method of item 9, wherein further anticancer agents are selected from octreotide, lanreotide, bapreotide, pasireotide, satreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib.

[0034] 11. PSMA-expressing cancer is prostate cancer, any combination of item 1 or 3-10, or any method of item 2-10.

[0035] 12. Any combination of item 1 or 3-10, or any method of item 2-10, wherein the PSMA-expressing cancer is selected from thyroid cancer, renal clear cell carcinoma, bladder transitional cell carcinoma, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

[0036] 13. A combination or method of item 12 wherein PSM is expressed in neovascular structures of cancer.

[0037] 14. Compound I 177 Lu and 225 A combination of items 1 or 3-13, or any method of items 2-13, for binding to a radionuclide selected from Ac.

[0038] 15. Compound I 177 A combination or method of item 14 that combines with Lu.

[0039] 16. Compound I 225 A combination or method of item 14 that combines with Ac.

[0040] 17. 177 Compound Ia and that bind to Lu 225A combination or method of item 14, wherein both compounds Ia that bind to Ac are administered to the target.

[0041] 18. A PD-1 inhibitor is administered, and the PD-1 inhibitor is not pembrolizumab, in any combination of items 1 or 3-16, or by any method of items 2-17.

[0042] 19. To be administered 177 The combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 2 GBq to approximately 13 GBq.

[0043] 20. To be administered 177 The combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 4 GBq to approximately 11 GBq.

[0044] 21. To be administered 177 The combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 5 GBq to approximately 10 GBq.

[0045] 22. To be administered 177 The combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 6 GBq to approximately 9 GBq.

[0046] 23. To be administered 177 A combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 6.5 GBq to approximately 8.5 GBq.

[0047] 24. To be administered 177 The combination or method of item 15 or 17, wherein the amount of compound Ia bound to Lu is approximately 7 GBq to approximately 8 GBq.

[0048] 25. To be administered 225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 1 MBq to approximately 6 MBq.

[0049] 26. To be administered225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 1 MBq to approximately 5 MBq.

[0050] 27. To be administered 225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 1 MBq to approximately 4 MBq.

[0051] 28. To be administered 225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 1 MBq to approximately 3 MBq.

[0052] 29. To be administered 225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 2 MBq to approximately 3 MBq.

[0053] 30. To be administered 225 A combination or method of item 16 or 17, wherein the amount of compound Ia bound to Ac is approximately 2 MBq.

[0054] 31. Any combination of items 1, 3-16 or 18-30 or any method of items 2-30, wherein the IO treatment agent is selected from spartalizumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, nivolumab, MK-3475, MPDL3280A, MEDI5736, ipilimumab, tremelimumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210 and AMP-224.

[0055] 32. Any combination of items 1, 3-16 or 18-30 or any method of items 2-30, wherein the IO treatment agent is selected from nivolumab, MK-3475, MPDL3280A, MEDI5736, ipilimumab and tremelimumab.

[0056] 33. Any combination of items 1, 3-16 or 18-31, or any method of item 2-30, wherein the IO treatment agent is nivolumab.

[0057] 34. Any combination of items 1, 3-16 or 18-31, or any method of item 2-30, wherein the IO treatment agent is ipilimumab.

[0058] 35. Any combination of items 1, 3-16 or 18-31, or any method of item 2-30, wherein the IO treatment agent is tremelimumab.

[0059] In some embodiments, the combinations described herein may provide beneficial anticancer effects, such as enhanced anticancer effects, reduced toxicity, and / or reduced side effects. For example, a second therapeutic agent such as a radiolabeled compound I, particularly compound Ia, and an IO therapeutic agent, for example, one or more or all of the further therapeutic agents, can be administered in low doses compared to monotherapy doses, as is necessary to achieve the same therapeutic effect. Thus, compositions and methods for treating proliferative disorders, including cancer, using the above combination therapies are disclosed.

[0060] In some embodiments, a method of treating a subject, for example, a subject having the cancer described herein, with the combination described herein includes the administration of the combination as part of a treatment regimen. In some embodiments, the treatment regimen includes one or more, for example, two, three, or four of the combinations described herein. In some embodiments, the treatment regimen is administered to the subject in at least one phase and optionally two phases, for example, a first phase and a second phase. In some embodiments, the first phase includes a dose escalation phase. In some embodiments, the first phase includes one or more dose escalation phases, for example, a first, second, or third dose escalation phase. In some embodiments, the dose escalation phase includes, for example, the administration of two, three, four, or more combinations of therapeutic agents described herein. In some embodiments, the second phase includes a dose expansion phase. In some embodiments, the dose expansion phase includes, for example, the administration of two, three, four, or more combinations of therapeutic agents described herein. In some embodiments, the dose expansion phase includes the same two, three, four, or more therapeutic agents as the dose escalation phase.

[0061] In one embodiment, the first dose escalation phase includes the administration of a combination of a radiolabeled compound I, a PSMA therapeutic agent such as compound Ia, and one or more further therapeutic agents such as the IO therapeutic agents described herein, where the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) of one or both therapeutic agents is determined. In one embodiment, prior to the first dose escalation phase, the subject may be administered one of the therapeutic agents to be administered in the first dose escalation phase as a monotherapy.

[0062] In one embodiment, the second dose escalation phase includes the administration of a combination of a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia, and one or more further therapeutic agents, such as two of the IO therapeutic agents described herein, where the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) of one, two, or all of the therapeutic agents is determined. In one embodiment, the second dose escalation phase begins after the completion of the first dose escalation phase. In one embodiment, the second dose escalation phase includes the administration of one or more of the therapeutic agents administered in the first dose escalation phase. In one embodiment, the second dose escalation phase is performed without performing the first dose escalation phase.

[0063] In one embodiment, the third dose escalation phase includes the administration of a combination of a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia, and one or more further therapeutic agents such as three of the IO therapeutic agents described herein, where the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) of one, two, three, or all of the therapeutic agents is determined. In one embodiment, the third dose escalation phase begins after the completion of the first or second dose escalation phase. In one embodiment, the third dose escalation phase includes the administration of one or more (e.g., all) of the therapeutic agents administered in the second dose escalation phase. In one embodiment, the third dose escalation phase includes the administration of one or more of the therapeutic agents administered in the first dose escalation phase. In one embodiment, the third dose escalation phase is performed without performing the first, second, or both dose escalation phases.

[0064] In one embodiment, the dose escalation phase begins after the completion of the first, second, or third dose escalation phase. In one embodiment, the dose escalation phase includes the administration of the combination administered during the dose escalation phase, e.g., the first, second, or third dose escalation phase. In one embodiment, a biopsy sample is obtained from the subject during the dose escalation phase. In one embodiment, the subject is treated for prostate cancer.

[0065] While not intended to be theoretically bound, in some embodiments, treatment regimens including dose escalation and dose expansion phases allow for the introduction of novel agents or regimens into combinations, rapid production of combinations, and / or evaluation of the safety and activity of acceptable combinations. [Modes for carrying out the invention]

[0066] Detailed description definition As used herein, the term "alkyl" may be branched as desired and may include carbon chains containing 1 to 4 carbon atoms, and may be referred to as "lower alkyls." Explanatory alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0067] When used here, the singular expression means that the subject is one or more than one (for example, at least one).

[0068] The term "or" is used to mean the term "and / or" and is interchangeable with it unless the context clearly indicates otherwise. However, the term "or" in a claim that is not in plural dependent form means only "or" and is not interchangeable with "and".

[0069] "Approximately" and "roughly" generally refer to the acceptable degree of error in a measured quantity, taking into account the nature or precision of the measurement. Examples of degrees of error include being within 20 percent (%) of a given value or range of values, typically within 10 percent, and more typically within 5 percent.

[0070] The term "therapeutic agent" encompasses all therapeutic agents described herein unless otherwise specified.

[0071] As used herein, the term “salt” refers to a salt with a counterion that may be used pharmaceutically. See, in general, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1–19. Preferred salts are those that are pharmacologically effective and suitable for contact with the target tissue without excessive toxicity, irritation, or allergic response. The compounds described herein may have a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and thus react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. Such salts include: (1) Acid addition salts that can be obtained by the reaction of a parent compound of a free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, or an organic acid such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid; or (2) When an acidic proton is present in the parent compound, it is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or a salt is formed by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimamine, or N-methylglucamine. Includes.

[0072] Salts are well known to those skilled in the art, and any such salt may be considered in connection with the embodiments described herein. Examples of salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, and hexin-1,6-diates. This includes salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0073] The terms “combination” or “in combination” are not intended to imply that the treatment or therapeutic agent must be formulated to be administered simultaneously and / or delivered together, but these delivery methods are within the scope of the delivery described herein. The therapeutic agent in a combination may be administered simultaneously with, before, or after one or more other further treatments or therapeutic agents. The therapeutic agents or treatments may be administered in any order. Generally, each therapeutic agent is administered in the dose and / or regimen determined for that therapeutic agent. It is further understood that the therapeutic agents used in this combination may be administered together in a single composition or separately in different compositions. In some embodiments, the therapeutic agent used in a combination is used at a level not exceeding that typically used individually. In some embodiments, the level of the therapeutic agent used in a combination may be lower than when used individually.

[0074] In one embodiment, the therapeutic agent is administered at a therapeutic dose or a dose that is less than the therapeutic dose when administered individually. In one embodiment, the concentration of the second therapeutic agent administered when administered in combination is lower than the dose at which the second therapeutic agent is therapeutically effective when administered individually. In one embodiment, the concentration of the first therapeutic agent administered in combination is lower than the dose at which the first therapeutic agent is therapeutically effective when administered individually. In one embodiment, in combination therapy, the concentration of the second therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. In one embodiment, in combination therapy, the concentration of the first therapeutic agent required to achieve inhibition, e.g., proliferation inhibition, is lower than the therapeutic dose of the first therapeutic agent as monotherapy, e.g., at least 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.

[0075] The terms “inhibition,” “inhibitor,” or “antagonist” include a reduction in a parameter of a molecule, such as an immune checkpoint inhibitor, e.g., activity. For example, inhibition of activity by at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more of the activity of a molecule, e.g., an inhibitory molecule, is included in this term. Therefore, inhibition does not have to be 100%.

[0076] A "fusion protein" and a "fusion polypeptide" are proteins or polypeptides having at least two parts covalently linked to each other, where each part is a polypeptide having different properties. These properties can be biological, such as in vitro or in vivo activity. They can also be simple chemical or physical properties, such as binding to a target molecule or catalysis of a reaction. The two parts may be linked directly by a single peptide bond or via a peptide linker, but are within a leading frame relative to each other.

[0077] The terms “activation,” “activator,” or “agonist” involve an increase in a parameter of a molecule, such as a co-stimulatory molecule, e.g., activity. For example, an increase of at least or about 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of activity, e.g., co-stimulatory activity, is included in this term.

[0078] The term "anti-cancer effect" refers to biological effects that can be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in the number of cancer cells, a reduction in the number of metastases, an extension of life expectancy, a reduction in cancer cell proliferation, a reduction in cancer cell survival, or an improvement in various physiological symptoms associated with the cancerous state. "Anti-cancer effect" can also be manifested by the ability of the therapeutic agents described herein (e.g., peptides, polynucleotides, cells, small molecules, and antibodies) to first prevent the development of cancer.

[0079] The term "antitumor effect" refers to a biological effect that can be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, or a reduction in tumor cell survival.

[0080] The term "cancer" refers to a disease characterized by the rapid and immature proliferation of abnormal cells, but may include benign cancers. In various embodiments, cancer cells may spread locally or to other parts of the body via the bloodstream and lymphatic system. In some embodiments, cancer is PSMA-expressing cancer; in other embodiments, PSMA may be expressed in the neovascularization of cancer. Examples of various cancers are described herein and include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, thyroid cancer, renal clear cell carcinoma, bladder transitional cell carcinoma, colon adenocarcinoma, neuroendocrine cancer, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, etc. In some embodiments, cancer is selected from the group consisting of glioma, carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, nasopharyngeal carcinoma, leukemia, adenocarcinoma, and myeloma. Other exemplary cancers include small cell lung cancer, bone cancer, head and neck cancer, hepatocellular carcinoma, cutaneous or intraocular melanoma, uterine cancer, gastric cancer, colon cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, gastric and esophageal cancer, endocrine cancer, parathyroid cancer, adrenal cancer, urethral cancer, penile cancer, ureteral cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, brainstem gliomas, pituitary adenomas, inflammatory myofibroblastic tumors, and combinations thereof.

[0081] The terms “tumor” and “cancer” are used interchangeably here, and both terms encompass tumors of solid and liquid nature, for example, generalized or circulating. When used here, the terms “cancer” or “tumor” include premalignant, as well as malignant cancers and tumors and benign cancers. When used here, the term “cancer” includes primary malignant cells or tumors (for example, cells that have not migrated to a location other than the original malignant tumor or tumor site in the subject body) and secondary malignant cells or tumors (for example, those resulting from metastasis, which is the migration of malignant cells or tumor cells to a secondary site different from the original tumor site).

[0082] As used herein, the terms “treatment” and “to treat” mean a reduction or improvement in the progression, severity and / or duration of a disorder, such as cancer, a proliferative disorder, or improvement in one or more symptoms of the disorder (e.g., one or more recognizable symptoms), resulting from the administration of one or more treatments or therapeutic agents. In specific embodiments, the terms “treatment” and “to treat” mean an improvement in at least one measurable physical parameter of a proliferative disorder, such as cancer, which is not necessarily recognizable by the patient, such as tumor growth. In other embodiments, the terms “treatment” and “to treat” mean inhibition of the progression of a proliferative disorder, such as cancer, by physical means, for example, by stabilization of recognizable symptoms, or by physiological means, for example, by stabilization of physical parameters, or both. In other embodiments, the terms “treatment” and “to treat” mean a reduction or stabilization of tumor size or cancer cell count.

[0083] In many of the embodiments described herein, the therapeutic agent administered as described herein in combination with a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia, may be an antibody or other polypeptide or a nucleic acid encoding such polypeptide. In some embodiments, the therapeutic agent described herein for use in combination with a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia, comprises a polypeptide and / or nucleic acid having the sequence specified herein or a sequence substantially identical or similar thereto, for example, a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence specified herein. In amino acid sequences, the term “substantially identical” as used herein means a first amino acid sequence containing a sufficient or minimum number of amino acid residues that are i) identical to or ii) conserved substitutions of aligned amino acid residues in the second amino acid sequence, such that the first and second amino acid sequences may have a common structural domain and / or common functional activity. For example, a control sequence, such as an amino acid sequence containing a common structural domain that is at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence provided herein, is substantially similar to the amino acid sequence provided herein.

[0084] In nucleotide sequences, the term "substantially identical" as used herein means a first nucleic acid sequence containing a sufficient or minimum number of nucleotides that are identical to the aligned nucleotides in the second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity or a common structural polypeptide domain or common functional polypeptide activity. For example, a control sequence, e.g., a nucleotide sequence having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence provided herein, is substantially identical to the nucleic acid sequence provided herein.

[0085] The term "functional variant" refers to a polypeptide that has a naturally occurring sequence or a substantially identical amino acid sequence to the sequence provided herein, is encoded by substantially identical nucleotide sequences, and can have one or more activities of the naturally occurring sequence or the sequence provided herein.

[0086] In various embodiments, the calculation of homology, sequence identity, or similarity between sequences (these terms are used interchangeably here) can be carried out as follows:

[0087] To determine the percentage identity of two amino acid sequences or two nucleic acid sequences, the sequences may be aligned for optimal comparison purposes (for example, gaps may be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In various embodiments, the length of the reference sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, or 60%, or at least 70%, 80%, 90%, or 100% of the length of the reference sequence. Then, amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions may be compared. If 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 (wherein used, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology").

[0088] Percent identity between two arrays is a function of the number of identical positions shared by the arrays, taking into account, for example, the number of gaps and the length of each gap, which was necessary to introduce for optimal alignment of the two arrays.

[0089] In one embodiment, the comparison of sequences and determination of percentage identity between two sequences can be achieved using a mathematical algorithm. In one embodiment, the percentage identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm, which is incorporated into the GAP program of the GCG software package (available at www.gcg.com), using a Blossum 62 matrix or PAM250 matrix and gap weights 16, 14, 12, 10, 8, 6 or 4 and length weights 1, 2, 3, 4, 5 or 6. In yet another embodiment, the percentage identity between two nucleotide sequences is determined using the GAP program of the GCG software package (available at www.gcg.com), using an NWSgapdna.CMP matrix and gap weights 40, 50, 60, 70 or 80 and length weights 1, 2, 3, 4, 5 or 6. In one embodiment, the set of parameters that can be used is a Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0090] In one explanatory embodiment, the percentage 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 is incorporated into the ALIGN program (version 2.0), using the PAM120 weighted residue table, gap length penalty 12, and gap penalty 4.

[0091] In one embodiment, the nucleic acid and amino acid sequences described herein can be used as "query sequences" 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) described in Altschul, et al. (1990) J. Mol. Biol. 215:403-10. In one embodiment, a BLAST nucleotide search can be performed in the NBLAST program with a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. In one embodiment, a BLAST amino acid sequence search can be performed in the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the amino acid sequences described herein. In one explanatory embodiment, to obtain gapped alignments for comparative purposes, Gapped BLAST can be used as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. In other embodiments, when using the BLAST and Gapped BLAST programs, the fault parameters of each program (e.g., XBLAST and NBLAST) may be used. See www.ncbi.nlm.nih.gov.

[0092] As used herein, the terms "hybridize under low stringency, medium stringency, high stringency, or very high stringency conditions" describe the conditions for hybridization and washing. Exemplary guidance for carrying out hybridization reactions can be found in the current protocol in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1–6.3.6, which is incorporated herein by reference. Aqueous and non-aqueous methods are described in that reference, and either may be used. The exemplary specific hybridization conditions described herein are as follows: 1) Low-stringency hybridization conditions involve washing twice with 6× sodium chloride / sodium citrate (SSC) at approximately 45°C, followed by 0.2× SSC and 0.1% SDS at at least 50°C (the washing temperature may be increased up to 55°C for low-stringency conditions); 2) Medium-stringency hybridization conditions involve washing once or twice with 6× SSC at approximately 45°C, followed by 0.2× SSC and 0.1% SDS at 60°C; 3) High-stringency hybridization conditions involve washing once or once with 6× SSC at approximately 45°C, followed by 0.2× SSC and 0.1% SDS at 65°C; and 4) Ultra-high-stringency hybridization conditions involve washing once or once with 0.5M sodium phosphate and 7% SDS at 65°C, followed by 0.2× SSC and 1% SDS at 65°C. In some embodiments, therapeutic agents for use in the combinations and methods described herein may have further conservative or non-essential amino acid substitutions that do not substantially affect the function of the therapeutic agents described herein.

[0093] The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that contain both amino and acid functional groups and can be included in polymers of naturally occurring amino acids. Examples of amino acids include naturally occurring amino acids; their analogs, derivatives, and congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both D- and L-optical isomers and peptide mimetic compounds.

[0094] A "conservative amino acid substitution" is the replacement of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains are defined in this art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), non-charged 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).

[0095] The terms “polypeptide,” “peptide,” and “protein” (if single-chain) are used interchangeably here to refer to amino acid polymers of any length. The polymers may be linear or branched, may contain modified amino acids, and may have non-amino acid molecules in between. The term also encompasses amino acid polymers modified by any other operation, such as disulfide bond formation, glucosylation, lipid addition, acetylation, phosphorylation, or conjugation with labeling components. In various embodiments, polypeptides may be isolated from natural sources, produced by recombinant techniques from eukaryotic or prokaryotic hosts, or be products of synthetic methods.

[0096] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence” and “polynucleotide” are interchangeable. These refer to polymeric forms of nucleotides of any length, such as deoxyribonucleotides or ribonucleotides or their analogues. In some embodiments, polynucleotides may be single-stranded or double-stranded, and if single-stranded, they may be coding or non-coding (antisense) strands. In various embodiments, polynucleotides may include modified nucleotides such as methylated nucleotides and nucleotide analogs, and nucleotide sequences may be further modified after polymerization, such as by the presence of non-nucleotide components and / or by conjugation with labeling components. In various embodiments, nucleic acids may be recombinant polynucleotides or polynucleotides of genomic, cDNA, semi-synthetic or synthetic origin, which are linked with other polynucleotides in non-natural or non-natural configurations.

[0097] The term "isolated," as used herein, refers to a substance removed from its original or natural environment (e.g., the natural environment, if it exists naturally). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated from some or all of the substances simultaneously present in the natural system by human intervention is isolated. Such a polynucleotide is part of a vector and / or such a polynucleotide or polypeptide is part of a composition, and such a vector or composition is still isolated if it is not part of the environment in which it is found naturally.

[0098] Various aspects of the present invention are described in further detail below. Further definitions are given throughout the specification.

[0099] antibody molecule In one embodiment, the combination described herein comprises a therapeutic agent which is an antibody molecule together with a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia, or the method described herein involves using such a therapeutic agent which is an antibody molecule together with a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia.

[0100] As used herein, the term “antibody molecule” refers to a protein containing at least one immunoglobulin variable domain sequence. The term “antibody molecule” includes, for example, full-length, mature antibodies and antigen-binding fragments of antibodies. For example, an antibody molecule may contain a heavy (H) chain variable domain sequence (hereinafter abbreviated as VH) and a light (L) chain variable domain sequence (hereinafter abbreviated as VL). In other examples, an antibody molecule may contain two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (e.g., scFv), single-variable domain antibodies, bispecific antibodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which can be produced by modification of the entire antibody or de novo-synthesized using recombinant DNA technology. In some embodiments, a functional antibody fragment retains the ability to selectively bind to each antigen or receptor. In various embodiments, antibodies and antibody fragments may be derived from any class and any subclass of antibodies (e.g., IgG1, IgG2, IgG3, and IgG4), including but not limited to IgG, IgA, IgM, IgD, and IgE, and may be monoclonal or polyclonal, human, humanized, CDR-transplanted, or in vitro-produced antibodies. In other embodiments, the antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. In other embodiments, the antibody may have a light chain selected from, for example, kappa or lambda.

[0101] Examples of antigen-binding fragments include (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide crosslinking at the hinge region; (iii) Fd fragments, which consist of VH and CH1 domains; (iv) Fv fragments, which consist of VL and VH domains of a single arm of an antibody; (v) bispecific antibody (dAb) fragments, which consist of a VH domain; (vi) camelid or camelid variable domains; (vii) single-stranded Fv (scFv) (see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) single-domain antibodies. In one embodiment, these antibody fragments can be obtained using conventional techniques known to those skilled in the art, and the fragments can be screened for usefulness in the same manner as intact antibodies.

[0102] The term "antibody" includes intact molecules and their functional fragments. In various embodiments, the constant region of an antibody may be modified, for example, mutated, to alter the properties of the antibody (e.g., for Fc receptor binding, antibody glucosylation, cysteine ​​residue count, or an increase or decrease of one or more effector cell functions or complement functions).

[0103] In one embodiment, the antibody molecule may also be a single-domain antibody. A single-domain antibody may include an antibody in which the complementarity-determining region is part of a single-domain polypeptide. Examples include, but are not limited to, heavy-chain antibodies, naturally occurring light-chain-deficient antibodies, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and non-antibody-derived single-domain scaffolds. A single-domain antibody may be any single-domain antibody known in the art or any future single-domain antibody. In various embodiments, a single-domain antibody may be derived from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cattle. According to another aspect of the invention, a single-domain antibody is a naturally occurring single-domain antibody known as a light-chain-deficient heavy-chain antibody. Such a single-domain antibody is disclosed, for example, in WO9404678. For clarity, this variable domain derived from a naturally occurring light-chain-deficient heavy-chain antibody is referred here to as VHH or nanobody to distinguish it from the conventional VH of four-chain immunoglobulins. Such VHH molecules may originate from antibodies produced in camelid species, such as camels, llamas, dromedaries, alpacas, and guanacos. Other non-camellid species may naturally produce heavy-chain antibodies lacking light chains; such VHHs are within the scope of this invention.

[0104] The VH and VL regions can be subdivided into highly variable regions called "complementarity determination regions" (CDRs), which contain scattered, more conserved regions called "framework regions" (FR or FW).

[0105] The scope of the framework region and CDR is strictly defined by several methods (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used in Oxford Molecular's AbM antibody modeling software. Generally, see, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

[0106] In this context, the terms "complementarity-determining region" and "CDR" refer to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. Generally, each heavy chain variable region has three CDRs (HCDR1, HCDR2, HCDR3) and each light chain variable region has three CDRs (LCDR1, LCDR2, LCDR3).

[0107] The precise amino acid sequence boundaries of a given CDR can be determined using one of several well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme) and Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme). When used here, CDRs defined by the “Chothia” numbering scheme are sometimes referred to as “hypervariable loops.”

[0108] For example, under Kabat, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under Chothia, the CDR amino acids of VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues of VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, the CDR consists of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH, and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.

[0109] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, a sequence may include all or part of the amino acid sequence of a naturally occurring variable domain. For example, a sequence may or may not include one, two, or more N-terminal or C-terminal amino acids, and may include other modifications that are compatible with the formation of a protein structure.

[0110] The term "antigen-binding site" refers to a portion of an antibody molecule that contains determinants that form an interface for binding to an antigen or its epitope. For proteins (or protein mimes), the antigen-binding site typically includes one or more loops (of at least four amino acids or amino acid mimes) that form an interface for binding to the antigen. Typically, the antigen-binding site of an antibody molecule includes at least one or two CDRs and / or hypervariable loops, or more typically, at least three, four, five, or six CDRs and / or hypervariable loops.

[0111] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to a preparation of an antibody molecule with a single-molecule composition. Monoclonal antibody compositions exhibit single-binding specificity and affinity for a particular epitope. Monoclonal antibodies can be manufactured by hybridoma technology or by non-hybridoma technology methods (e.g., recombinant methods).

[0112] An "effectively human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can be problematic in some situations, for example, if antibody molecules are repeatedly administered in the treatment of chronic or recurrent disease conditions. The HAMA response may render repeated antibody administration ineffective due to increased antibody clearance from serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and also due to the possibility of an allergic reaction (see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

[0113] In various embodiments, the antibody molecule may be a polyclonal or monoclonal antibody. In other embodiments, the antibody may be produced by recombinant methods, for example, by phage display or combinatorial methods.

[0114] Phage display and combinatorial methods for antibody production are known in the art (for example, all of which are incorporated herein by reference: Ladner et al. U.S. Patent 5,223,409; Kang et al. International Publication WO92 / 18619; Dower et al. International Publication WO91 / 17271; Winter et al. International Publication WO92 / 20791; Markland et al. International Publication WO92 / 15679; Breitling et al. International Publication WO93 / 01288; McCafferty et al. International Publication WO92 / 01047; Garrard et al. International Publication WO92 / 09690; Ladner et al. International Publication WO90 / 02809; Fuchs et al. (1991) Bio / Technology 9:1370-1372; Hay et al. (1992) Hum Antibod Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio / Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS (As described in 88:7978-7982).

[0115] In one embodiment, the antibody is either a fully human antibody (e.g., an antibody produced in a mouse genetically engineered to produce antibodies from human immunoglobulin sequences) or a non-human antibody, such as a rodent (mouse or rat), goat, primate (e.g., monkey), or camel antibody. In one embodiment, the non-human antibody is a rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

[0116] Human monoclonal antibodies can be produced using transgenic mice that carry human immunoglobulin genes, rather than using mouse strains. Splenocytes from these transgenic mice immunized with the target antigen can be used to produce hybridomas that secrete human mAbs with specific affinity for epitopes from human proteins (e.g., Wood et al. International Application WO91 / 00906, Kucherlapati et al. PCT Publication WO91 / 10741; Lonberg et al. International Application WO92 / 03918; Kay et al. International Application 92 / 03917; Lonberg, N. et al. 1994 Nature 368:856-859; Green, LL et al. 1994 Nature Genet. 7:13-21; Morrison, SL et al. 1994 Proc. Natl. Acad. Sci. USA 81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon et al. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

[0117] In one embodiment, the antibody may have a variable region or part thereof, e.g., a CDR, produced in a non-human organism, e.g., a rat or mouse. In another embodiment, chimeric, CDR-implanted, and humanized antibodies may be used. In yet another embodiment, an antibody produced in a non-human organism, e.g., a rat or mouse, and then modified, e.g., by modifying the variable framework or constant region to reduce its antigenicity in humans may be used.

[0118] Chimeric antibodies can be produced using recombinant DNA technology known in this field (Robinson et al., International Patent Publication PCT / US86 / 02269; Akira, et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., International Application WO86 / 01533; Cabilly et al., US Patent 4,816,567; Cabilly et al., European Patent Application 125,023; Better et al. (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al.). (See PNAS 84:214-218 (1987); Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

[0119] In one embodiment, a humanized or CDR-transplanted antibody may have at least one or two, but generally three, recipient CDRs (heavy and / or light immunoglobulin chains) replaced by donor CDRs. In various embodiments, the antibody may be replaced by at least a portion of non-human CDRs, or only a portion of the CDRs may be replaced by non-human CDRs. In one explanatory embodiment, the number of CDRs required for the humanized antibody to bind to the antigen may be replaced. In one embodiment, the donor may be a rodent antibody, e.g., a rat or mouse antibody, and the recipient may be a human framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is referred to as the “donor,” and the immunoglobulin providing the framework is referred to as the “acceptor.” In one embodiment, the donor immunoglobulin is non-human (e.g., rodent). In one exemplary embodiment, the acceptor framework is a naturally occurring (e.g., human) framework or consensus framework or an array of similarities, with approximately 85% or more, or approximately 90%, 95%, 96%, 97%, 98%, or 99% or more.

[0120] In this context, the term "consensus sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) within a family of related sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)). Within a family of proteins, each position in the consensus sequence is occupied by the most frequently occurring amino acid at that position within the family. If two amino acids occur with equal frequency, either may be included in the consensus sequence. "Consensus framework" refers to the framework region within a consensus immunoglobulin sequence.

[0121] Antibodies can be humanized by methods known in this field (see, for example, Morrison, SL, 1985, Science 229:1202-1207, by Oi et al., 1986, BioTechniques 4:214 and Queen et al. US5,585,089, US5,693,761 and US5,693,762, all of which are incorporated herein by reference).

[0122] Humanized or CDR-implanted antibodies can be produced by CDR implantation or CDR substitution, in which one, two, or all CDRs in the immunoglobulin chain can be replaced. See, for example, U.S. Patent 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter US5,225,539, all of which are expressly incorporated herein by reference. Winter describes a CDR implantation method that can be used to prepare humanized antibodies used in the combinations and methods described herein (UK Patent Application GB2188638A, filed March 26, 1987; Winter US5,225,539), all of which are expressly incorporated herein by reference.

[0123] Further, humanized antibodies in which specific amino acids are substituted, deleted, or added may be used. Criteria for selecting amino acids from a donor are described in columns 12-16 of US5,585,089, for example, the content of which is incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP519596A1, published December 23, 1992.

[0124] In one embodiment, the antibody molecule may be a single-chain antibody. In one embodiment, a single-chain antibody (scFV) may be manipulated (see, for example, Colcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). In another embodiment, a single-chain antibody may be dimerized or polymerized to produce a polyvalent antibody that is specific to various epitopes of the same target protein.

[0125] In yet another embodiment, the antibody molecule has a heavy chain constant region, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; or a heavy chain constant region selected from, for example, the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody molecule has a light chain constant region, selected from, for example, the (e.g., human) light chain constant regions of kappa or lambda. In another embodiment, the constant region may be modified, for example, mutated, to modify the properties of the antibody (e.g., Fc receptor binding, antibody glucosylation, cysteine ​​residue count, one or more increases or decreases in effector cell function and / or complement function). In one embodiment, the antibody has effector function and can immobilize complement. In another embodiment, the antibody does not recruit effector cells or immobilize complement. In another embodiment, the antibody has reduced or no ability to bind to the Fc receptor. For example, isotypes or subtypes, fragments or other variants that do not support binding to the Fc receptor, such as those in which the Fc receptor binding region is mutagenic or deleted.

[0126] Methods for modifying the constant region of an antibody are known in the art. In one embodiment, an antibody with modified function, such as modified affinity for an effector ligand like cellular FcR or the C1 component of complement, can be produced by replacing at least one amino acid residue in the constant region of the antibody with a different residue (see, for example, EP388,151A1, U.S. Patent 5,624,821 and U.S. Patent 5,648,260, all of which are incorporated herein by reference). Similar types of modifications can be used to reduce or eliminate these functions when applied to immunoglobulins of mouse or other species.

[0127] In one embodiment, an antibody molecule may be derivatized with or linked to another functional molecule (e.g., another peptide or protein). As used herein, the “derivativeized” antibody molecule is modified. Methods of derivatization include, but are not limited to, the addition of affinity ligands such as fluorescent moieties, radionucleotides, toxins, enzymes, or biotin. Therefore, antibody molecules used as therapeutic agents in conjunction with PSMA therapeutic agents such as the radiolabeled compound I described herein may include derivatized and other modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be functionally linked (chemically coupled, genetically fused, non-covalently associated, or otherwise) to one or more other molecules, such as other antibodies (e.g., bispecific antibodies), detectable agents, cytotoxic agents, drugs, and / or proteins or peptides (e.g., streptavidin core regions or polyhistidine tags) that can mediate the association of an antibody or antibody moiety with other molecules.

[0128] In one embodiment, a certain type of derivatized antibody molecule is produced by crosslinking two or more antibodies (of the same type or different types to, for example, create a bispecific antibody). Suitable crosslinkers include heterobifunctional or homobifunctional (e.g., disuccinimidyl suberate) having two distinctly reactive groups separated by a suitable spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimidyl). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

[0129] In various embodiments, antibody molecules may be conjugated with other molecules, typically labeling or therapeutic agents (e.g., cytotoxic or cell proliferation inhibitors) or moieties. Radioisotopes may be used in therapeutic applications. Radioisotopes that can bind to antibodies include, but are not limited to, α-, β-, or γ-emitters or β- and γ-emitters. Such radioisotopes include iodine ( 131 I or 125 I), Yttrium ( 90 Y), Lutetium ( 177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), Rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), Indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), Rhodium ( 188 Rh), sulfur (35S), carbon ( 14 C), tritium ( 3 H), chromium ( 51 Cr), chlorine ( 36 Cl), cobalt ( 57 Co or 58 Co), iron ( 59 Fe), selenium ( 75 Se) or gallium ( 67 This includes, but is not limited to, Ga. Radioactive isotopes useful as therapeutic agents include yttrium ( 90 Y), Lutetium (177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), Rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi) and rhodium ( 188 It contains Rh. For example, radioactive isotopes useful as labels for diagnostic use include iodine ( 131 I or 125 I), Indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), carbon ( 14 C) and tritium ( 3 H) or one or more of the therapeutic isotopes listed above.

[0130] In one embodiment, a radiolabeled antibody molecule and a method for labeling the same are provided. In one embodiment, a method for labeling an antibody molecule is disclosed. The method comprises contacting an antibody molecule with a chelating agent to produce a conjugated antibody. The conjugated antibody is radiolabeled with radioisotopes, for example, 111 indium, 90 yttrium, and 177 lutetium, to produce a labeled antibody molecule.

[0131] In one embodiment, as described above, antibody molecules can be conjugated into therapeutic agents. Therapeutically active radioisotopes have already been described. Examples of other therapeutic agents include Taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, meitansinoids, e.g., meitansinol (see U.S. Patent 5,208,020), CC-1065 (see U.S. Patents 5,475,092, 5,585,499, 5,846,545) and their analogues or homologues. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechloretamine, thiotepa chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozocin, mitomycin C and cis-dichlorodiamine platinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mitramycin and anthramycin (AMC)), and mitotic inhibitors (e.g., vincristine, vinblastine, taxol and maytansinoids).

[0132] multispecific antibody molecules In some embodiments, the antibody molecule used with the PSMA therapeutic agent described herein, particularly compound Ia, is a multispecific antibody molecule, for example, comprising multiple immunoglobulin variable domain sequences, where the multiple first immunoglobulin variable domain sequences have binding specificity to a first epitope, and the multiple second immunoglobulin variable domain sequences have binding specificity to a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or a subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In some embodiments, the multispecific antibody molecule comprises a third, fourth, or fifth immunoglobulin variable domain. In some embodiments, the multispecific antibody molecule is a two-specific antibody molecule, a three-specific antibody molecule, or a four-specific antibody molecule.

[0133] In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. The bispecific antibody has specificity for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence having binding specificity to a first epitope and a second immunoglobulin variable domain sequence having binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule includes a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity to a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule includes a semi-antibody having binding specificity to a first epitope and a semi-antibody having binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule includes a semi-antibody or a fragment thereof having binding specificity to a first epitope and a semi-antibody or a fragment thereof having binding specificity to a second epitope. In one embodiment, the bispecific antibody molecule includes an scFv or a fragment thereof having binding specificity to a first epitope and an scFv or a fragment thereof having binding specificity to a second epitope.

[0134] Protocols for producing bispecific or heterodimeric antibody molecules are known in the art; e.g., the “knob-in-hole” approach described in US5731168; e.g., electrostatic steering Fc pair formation described in WO09 / 089004, WO06 / 106905 and WO2010 / 129304; e.g., chain exchange operation domain (SEED) heterodimer formation described in WO07 / 110205; e.g., Fab arm exchange described in WO08 / 119353, WO2011 / 131746 and WO2013 / 060867 For example, a bi-antibody conjugate, e.g., by antibody crosslinking, to produce a bi-specific structure using heterobifunctionality having an amine-reactive group and a sulfhydryl-reactive group, as described in US4433059; for example, a bi-specific antibody determinant produced by the recombination of hemiantibodies (heavy-light chain pairs or Fabs) from different antibodies via a cycle of reduction and oxidation of disulfide bonds between two heavy chains, as described in US4444878; for example, a trifunctional antibody, e.g., three Fabs crosslinked via sulfhydryl-reactive groups, as described in US5273743 Fragments; for example, pairs of scFv crosslinked via a C-terminal tail through a disulfide or amine-reactive chemical crosslink, such as the biosynthetic binding protein described in US5534254; for example, bifunctional antibodies described in US5582996, such as Fab fragments with different binding specificities, dimerized via leucine zippers (e.g., c-fos and c-jun) with a replaced constant domain; for example, bispecific and oligospecific monovalent and oligovalent receptors described in US5591828, such as one antibody VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region and the VH region of the other antibody, which typically has a light chain; for example, the bispecific DNA-antibody conjugate described in US5635602, e.g., crosslinking of an antibody or Fab fragment via a DNA double-strand fragment; for example, the bispecific fusion protein described in US5637481, e.g., an expression construct comprising two scFvs and a hydrophilic helical peptide linker and a complete constant region between them; for example, the one described in US5837242,Polyvalent and multispecific binding proteins, for example, dimers of polypeptides having a first domain with a binding region for the Ig heavy chain variable region and a second domain with a binding region for the Ig light chain variable region, generally referred to as bispecific antibodies (which form bispecific, trispecific, or tetraspecific molecules; higher-order structures are also disclosed); for example, as described in US5837821, which can dimerize to form bispecific / polyvalent molecules. Mini-body constructs having linked VL and VH chains further connected to a peptide spacer to the antibody hinge region and CH3 region; VH and VL domains linked in either direction by a short peptide linker (e.g., 5 or 10 amino acids) or without any linker, capable of dimerizing to form bispecific bispecific antibodies; trimers and tetramers, e.g., as described in US5844094; strings of VH domains (or VL domains in family members) linked by peptide bonds with a crosslinkable group at the C-terminus further linked to a VL domain, e.g., as described in US5864019; and single-chain linked polypeptides, e.g., as described in US5869620, in which both VH and VL domains linked via a peptide linker are combined into a multivalent structure via non-covalent or chemical crosslinking, and both scFV or bispecific antibody type forms are used to form, e.g., homodivalent, heterodivalent, trivalent and tetravalent structures. Further examples of polyspecific and bispecific molecules and methods for producing them include, for example, US5910573, US5932448, US5959083, US5989830, US6005079, US6239259, US6294353, US6333396, US6476198, US6511663, US6670453, US6743896, US6809185, US6833441, US7129330, US71 83076, US7521056, US7527787, US7534866, US7612181, US2002 / 004587A1, US2002 / 076406A1, US2002 / 103345A1, U S2003 / 207346A1, US2003 / 211078A1, US2004 / 219643A1, US2004 / 220388A1, US2004 / 242847A1, US2005 / 003403A1,US2005 / 004352A1, US2005 / 069552A1, US2005 / 079170A1, US2005 / 100543A1, US2005 / 136049A1, US2005 / 136051A1, US2005 / 1 63782A1, US2005 / 266425A1, US2006 / 083747A1, US2006 / 120960A1, US2006 / 204493A1, US2006 / 263367A1, US2007 / 004909A1, U S2007 / 087381A1, US2007 / 128150A1, US2007 / 141049A1, US2007 / 154901A1, US2007 / 274985A1, US2008 / 050370A1, US2008 / 069 820A1, US2008 / 152645A1, US2008 / 171855A1, US2008 / 241884A1, US2008 / 254512A1, US2008 / 260738A1, US2009 / 130106A1, US2 009 / 148905A1, US2009 / 155275A1, US2009 / 162359A1, US2009 / 162360A1, US2009 / 175851A1, US2009 / 175867A1, US2009 / 2328 11A1, US2009 / 234105A1, US2009 / 263392A1, US2009 / 274649A1, EP346087A2, WO00 / 06605A2, WO02 / 072635A2, WO04 / 081051A1, This can be seen in 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, and WO99 / 64460A1. The contents of the above-cited applications are incorporated herein by reference as a whole.

[0135] In one aspect, isolated nucleic acid molecules encoding antibody molecules for producing the antibodies described herein, their vectors, and host cells are provided. The nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA.

[0136] Cancer immunotherapy drugs Selected PD-1 inhibitors In various embodiments, IO agents may be used in conjunction with PSMA therapeutic agents such as the radiolabeled compound I described herein, particularly compound Ia. Any of the IO agents described below in this section titled "Cancer Immunotherapy Agents" may be used for cancer treatment in conjunction with PSMA therapeutic agents such as the radiolabeled compound I described herein, particularly compound Ia. For example, PD-1 inhibitors may be used. Programmed death 1 (PD-1) protein is an inhibitory member of the CD28 / CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). Two ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified and shown to downregulate T cell activation by binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43). PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9).

[0137] PD-1 is known as an immunosuppressive protein that downregulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745). The interaction between PD-1 and PD-L1 can act as an immune checkpoint, potentially leading to, for example, tumor-infiltrating lymphopenia, decreased T-cell receptor-mediated proliferation, and / or immune evasion by cancer cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immunosuppression can be reversed by inhibiting the local interaction between PD-1 and PD-L1 or PD-L2; when the interaction between PD-1 and PD-L2 is similarly blocked, the effect is additive (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).

[0138] In one embodiment, the combination or method described herein includes an IO therapeutic agent such as a PD-1 inhibitor. In one embodiment, the IO treatment agent is selected from PDR001 (Novartis), pembrolizumab (Merck & Co), pidilizumab (CureTech), durvalumab, atezolizumab, avelumab, nivolumab (Bristol-Myers Squibb Company), MK-3475, MPDL3280A, MEDI5736, ipilimumab (Bristol-Myers Squibb Company), tremelimumab, MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). In one embodiment, the IO treatment agent is a PD-1 inhibitor, and the PD-1 inhibitor is PDR001, also known as spartalizumab. In another embodiment, the PD-1 inhibitor is not pembrolizumab.

[0139] 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 such as that described in US2015 / 0210769, published July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” which is incorporated herein by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule is spartalizumab (PDR001).

[0140] In one embodiment, the anti-PD-1 antibody molecule includes at least one, two, three, four, five, or six complementarity-determining regions (CDRs) (or collectively, all CDRs) encoded by heavy and light chain variable regions containing the amino acid sequences shown in Table 1 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1) or by the nucleotide sequences shown in Table 1. In one embodiment, the CDRs are defined by Kabat (e.g., as shown in Table 1). In one embodiment, the CDRs are defined by Chothia (e.g., as shown in Table 1). In one embodiment, the CDRs are defined by a combined Kabat and Chothia CDR definition (e.g., as shown in Table 1). In one embodiment, the combination of Kabat and Chothia CDRs of VH CDR1 contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more CDRs (or all CDRs collectively) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 1 or encoded by the nucleotide sequences shown in Table 1.

[0141] In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 501, the VHCDR2 amino acid sequence of SEQ ID NO: 502, and the VHCDR3 amino acid sequence of SEQ ID NO: 503, as disclosed in Table 1; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 510, the VLCDR2 amino acid sequence of SEQ ID NO: 511, and the VLCDR3 amino acid sequence of SEQ ID NO: 512.

[0142] In one embodiment, the antibody molecule comprises VH, which includes VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526, as disclosed in Table 1; and VL, which includes VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531.

[0143] In one embodiment, the anti-PD-1 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 506 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule includes VL containing the amino acid sequence of SEQ ID NO: 520 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule includes VL containing the amino acid sequence of SEQ ID NO: 516 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 516. In one embodiment, the anti-PD-1 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 506 and VL containing the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 506 and VL containing the amino acid sequence of SEQ ID NO: 516.

[0144] In one embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 507 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 507. In another embodiment, the antibody molecule includes VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 521 or 517. In yet another embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 507 and VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.

[0145] In one embodiment, the anti-PD-1 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 508 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 508. In another embodiment, the anti-PD-1 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 522 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 522. In yet another embodiment, the anti-PD-1 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 518 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 518. In yet another embodiment, the anti-PD-1 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 508 and a light chain containing the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 508 and a light chain containing the amino acid sequence of SEQ ID NO: 518.

[0146] In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 509. In another embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 523 or 519. In yet another embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.

[0147] The antibody molecules described herein may be prepared by the vectors, host cells, and methods described in US2015 / 0210769, which are incorporated herein by reference in their entirety.

[0148] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0149] In one embodiment, the PD-1 inhibitor is administered in a dose of approximately 200 mg to approximately 500 mg (e.g., approximately 300 mg to approximately 400 mg). In one embodiment, the PD-1 inhibitor is administered once every three weeks. In one embodiment, the PD-1 inhibitor is administered once every four weeks. In another embodiment, the PD-1 inhibitor is administered in a dose of approximately 200 mg to approximately 400 mg (e.g., approximately 300 mg) once every three weeks. In yet another embodiment, the PD-1 inhibitor is administered in a dose of approximately 300 mg to approximately 500 mg (e.g., approximately 400 mg) once every four weeks.

[0150] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and a TGF-β inhibitor, e.g., NIS793. In one embodiment, the combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer.

[0151] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and a TLR7 agonist, e.g., LHC165. In one embodiment, the combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer. In one embodiment, the TLR7 agonist, e.g., LHC165, is administered by intratumor injection.

[0152] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and an adenosine receptor antagonist, e.g., PBF509 (NIR178). In one embodiment, the combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer.

[0153] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and a porcupine inhibitor, e.g., WNT974. In one embodiment, the combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer.

[0154] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and an A2aR antagonist, e.g., PBF509 (NIR178). In one embodiment, this combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer. While not intended to be bound by theory, it is considered that a combination or method comprising a PD-1 inhibitor, e.g., PDR001, and an A2aR antagonist, e.g., PBF509 (NIR178), may result in increased efficacy against the anti-PD-1 inhibitor. In one embodiment, the combination of a PD-1 inhibitor, e.g., PDR001, and an A2aR antagonist, e.g., PBF509 (NIR178), results in regression of prostate tumors.

[0155] In one embodiment, the combination or method comprises a PD-1 inhibitor, e.g., PDR001, and a PD-L1 inhibitor, e.g., FAZ053. In one embodiment, the combination is administered to a subject in a therapeutically effective dose, for example, for the treatment of prostate cancer.

[0156] Other exemplary PD-1 inhibitors In one embodiment, the anti-PD-1 antibody molecule is pembrolizumab (Merck & Co), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or Keytruda®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US8,354,509 and WO2009 / 114335, which are incorporated herein by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises, for example, one or more CDR sequences of pembrolizumab disclosed in Table 2 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence. In another embodiment, the PD-1 inhibitor is not pembrolizumab.

[0157] In one embodiment, the anti-PD-1 antibody molecule is pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, US7,695,715, US7,332,582 and US8,686,119, which are incorporated herein by reference as a whole. In one embodiment, the anti-PD-1 antibody molecule comprises, for example, one or more CDR sequences of pidilizumab disclosed in Table 2 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0158] In one embodiment, the anti-PD-1 antibody molecule is durvalumab.

[0159] In one embodiment, the anti-PD-1 antibody molecule is atezolizumab.

[0160] In one embodiment, the anti-PD-1 antibody molecule is avelumab.

[0161] 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 US9,205,148 and WO2012 / 145493, which are incorporated herein by reference as a whole. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences of MEDI0680 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0162] In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences of REGN2810 (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0163] 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 CDR sequences of PF-06801591 (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0164] In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences of BGB-A317 or BGB-108 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0165] 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 CDR sequences of INCSHR1210 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0166] In one embodiment, the anti-PD-1 antibody molecule is TSR-042(Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences of TSR-042 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0167] Furthermore, known anti-PD-1 antibodies include, for example, those described in WO2015 / 112800, WO2016 / 092419, WO2015 / 085847, WO2014 / 179664, WO2014 / 194302, WO2014 / 209804, WO2015 / 200119, US8,735,553, US7,488,802, US8,927,697, US8,993,731 and US9,102,727, which are incorporated herein by reference as a whole.

[0168] In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding with one of the anti-PD-1 antibodies described herein and / or binds to the same epitope of PD-1.

[0169] In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, as described in US8,907,053, for example, which is incorporated herein by reference in whole. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin containing an extracellular or PD-1 binding moiety of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg(Amplimmune), disclosed in WO2010 / 027827 and WO2011 / 066342, for example, which are incorporated herein by reference in whole).

[0170] In another embodiment, the IO treatment agent is ipilimumab (Bristol-Myers Squibb Company). In yet another embodiment, the PD-1 inhibitor is nivolumab (Bristol-Myers Squibb Company). In one embodiment, nivolumab is administered intravenously at a dose of approximately 3 mg / kg every 2-3 weeks for an initial period of 2 years. Subsequently, maintenance therapy every 12 weeks may be applied after the initial treatment. It should be understood that these drug regimens vary depending on the patient's response to treatment and are at the discretion of the treating physician. In another embodiment, the dose of ipilimumab for the treatment of unresectable or metastatic melanoma is 3 mg / kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses. In another embodiment, the PD-1 inhibitor is selected from MK-3475, MPDL3280A, MEDI5736, and tremelimumab. In other embodiments, the IO treatment agent is ipilimumab (Bristol-Myers Squibb Company) and the PSMA treatment agent is radiolabeled compound I, particularly compound Ia. In yet another embodiment, the PD-1 inhibitor is nivolumab (Bristol-Myers Squibb Company) and the PSMA treatment agent is radiolabeled compound I, particularly compound Ia. In yet another embodiment, the PD-1 inhibitor is tremelimumab and the PSMA treatment agent is radiolabeled compound I, particularly compound Ia.

[0171] [Table 2]

[0172] Further combination therapy In one embodiment, the combination or method comprises a PD-1 inhibitor (e.g., PDR001) and an mTOR inhibitor, e.g., RAD001 (also known as everolimus). In one embodiment, the combination comprises PDR001 and an mTOR inhibitor, e.g., RAD001. In one embodiment, the combination comprises PDR001 and RAD001. In one embodiment, the mTOR inhibitor, e.g., RAD001, is administered once weekly in a dose of at least 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In one embodiment, the mTOR inhibitor, e.g., RAD001, is administered once weekly in a dose of 10 mg. In one embodiment, the mTOR inhibitor, e.g., RAD001, is administered once weekly in a dose of 5 mg. In one embodiment, an mTOR inhibitor, such as RAD001, is administered once daily in a dose of at least 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In another embodiment, an mTOR inhibitor, such as RAD001, is administered once daily in a dose of 0.5 mg. In yet another embodiment, the combination is administered to a subject in a therapeutically effective dose for the treatment of cancer, such as the cancer described herein, such as prostate cancer.

[0173] LAG-3 inhibitors In one embodiment, the combination or method described herein includes a LAG-3 inhibitor. In one embodiment, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).

[0174] 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 disclosed in US2015 / 0259420, published September 17, 2015, entitled "Antibody Molecules to LAG-3 and Uses Thereof," which is incorporated herein by reference in its entirety.

[0175] In one embodiment, the anti-LAG-3 antibody molecule includes at least one, two, three, four, five, or six complementarity-determining regions (CDRs) (or collectively, all CDRs) encoded by heavy and light chain variable regions containing the amino acid sequences shown in Table 5 (e.g., from the heavy and light chain variable region sequences of BAP050-Clonel I or BAP050-Clone J disclosed in Table 5) or by the nucleotide sequences shown in Table 5. In one embodiment, the CDRs are defined by Kabat (e.g., as shown in Table 5). In one embodiment, the CDRs are defined by Chothia (e.g., as shown in Table 5). In one embodiment, the CDRs are defined by a combined Kabat and Chothia CDR definition (e.g., as shown in Table 5). In one embodiment, the combination of Kabat and Chothia CDRs for VH CDR1 includes the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more CDRs (or all CDRs collectively) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 5 or encoded by the nucleotide sequences shown in Table 5.

[0176] In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703, as disclosed in Table 5; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712.

[0177] In one embodiment, the anti-LAG-3 antibody molecule comprises VH, which includes VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 740 or 741, as disclosed in Table 5; and VL, which includes VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751. In one embodiment, the anti-LAG-3 antibody molecule comprises VH, which includes VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 760 or 741, as disclosed in Table 5; and VL, which includes VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751.

[0178] In one embodiment, the anti-LAG-3 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 706 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 706. In another embodiment, the anti-LAG-3 antibody molecule includes VL containing the amino acid sequence of SEQ ID NO: 718 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 718. In yet another embodiment, the anti-LAG-3 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 724 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule includes a VL containing the amino acid sequence of SEQ ID NO: 730 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule includes a VH containing the amino acid sequence of SEQ ID NO: 706 and a VL containing the amino acid sequence of SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule includes a VH containing the amino acid sequence of SEQ ID NO: 724 and a VL containing the amino acid sequence of SEQ ID NO: 730.

[0179] In one embodiment, the antibody molecule contains VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 707 or 708. In one embodiment, the antibody molecule contains VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule contains VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 725 or 726. In one embodiment, the antibody molecule includes a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 731 or 732. In another embodiment, the antibody molecule includes a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In yet another embodiment, the antibody molecule includes a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

[0180] In one embodiment, the anti-LAG-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 709 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 709. In another embodiment, the anti-LAG-3 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 721 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 721. In yet another embodiment, the anti-LAG-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 727 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 733 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 733. In another embodiment, the anti-LAG-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO: 721. In yet another embodiment, the anti-LAG-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 727 and a light chain containing the amino acid sequence of SEQ ID NO: 733.

[0181] In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 716 or 717. In one embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 728 or 729. In one embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 734 or 735. In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

[0182] The antibody molecules described herein may be prepared by vectors, host cells, and methods described in US2015 / 0259420, which are incorporated herein by reference in their entirety.

[0183] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0184] In one embodiment, the LAG-3 inhibitor (e.g., the anti-LAG-3 antibody molecule described herein) is administered in doses of approximately 300 to 1000 mg, for example, approximately 300 mg to 500 mg, approximately 400 mg to 800 mg, or approximately 700 mg to 900 mg. In one embodiment, the LAG-3 inhibitor is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In one embodiment, the LAG-3 inhibitor is administered once every three weeks. In one embodiment, the LAG-3 inhibitor is administered once every four weeks. In another embodiment, the LAG-3 inhibitor is administered in doses of approximately 300 mg to 500 mg (e.g., approximately 400 mg) once every three weeks. In yet another embodiment, the LAG-3 inhibitor is administered in doses of approximately 700 mg to 900 mg (e.g., approximately 800 mg) once every four weeks. In yet another embodiment, the LAG-3 inhibitor is administered in doses of approximately 400 mg to approximately 800 mg (e.g., approximately 600 mg) once every four weeks.

[0185] In one embodiment, the composition or method comprises a LAG-3 inhibitor, e.g., the LAG-3 inhibitor described herein, and a PD-1 inhibitor, e.g., the PD-1 inhibitor described herein. In one embodiment, the combination of the LAG-3 inhibitor and the PD-1 inhibitor is administered in a therapeutically effective dose to a subject with a solid tumor, e.g., prostate cancer. While not intended to be theoretically bound, the combination comprising the LAG-3 inhibitor and the PD-1 inhibitor is thought to have increased activity compared to the administration of the PD-1 inhibitor alone.

[0186] In one embodiment, the composition or method comprises a LAG-3 inhibitor, e.g., the LAG-3 inhibitor described herein, a GITR agonist, e.g., the GITR agonist described herein, and a PD-1 inhibitor, e.g., the PD-1 inhibitor described herein. In one embodiment, the combination of the LAG-3 inhibitor, GITR agonist, and PD-1 inhibitor is administered in a therapeutically effective dose to a subject with a solid tumor, e.g., prostate cancer. In one embodiment, the combination comprising the LAG-3 inhibitor, GITR agonist, and PD-1 inhibitor may result in increased IL-2 production.

[0187] Other exemplary LAG-3 inhibitors In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO2015 / 116539 and US9,505,839, which are incorporated herein by reference as a whole. In one embodiment, the anti-LAG-3 antibody molecule comprises, for example, one or more (or collectively all) CDR sequences of BMS-986016, heavy chain or light chain variable region sequences, or heavy chain or light chain sequences, as disclosed in Table 6.

[0188] 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 CDR sequences of TSR-033 (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0189] 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 WO2008 / 132601 and US9,244,059, which are incorporated herein by reference as a whole. In one embodiment, the anti-LAG-3 antibody molecule comprises, for example, one or more CDR sequences of IMP731 (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence, as disclosed in Table 6. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences of GSK2831781 (or collectively all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0190] 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 (or collectively all) CDR sequences of IMP761, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0191] Further known anti-LAG-3 antibodies include, for example, those described in WO2008 / 132601, WO2010 / 019570, WO2014 / 140180, WO2015 / 116539, WO2015 / 200119, WO2016 / 028672, US9,244,059, and US9,505,839, which are incorporated herein by reference in their entirety.

[0192] In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding to one of the anti-LAG-3 antibodies described herein and / or binds to the same epitope of LAG-3.

[0193] In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), as disclosed in WO2009 / 044273, which is incorporated herein by reference in its entirety.

[0194] [Table 4]

[0195] TIM-3 inhibitor In one embodiment, the combination or method described herein includes a TIM-3 inhibitor. While not intended to be theoretically bound, TIM-3 is thought to correlate with tumor bone marrow signature in The Cancer Genome Atlas (TCGA) database, and the most abundant TIM-3 in normal peripheral blood mononuclear cells (PBMCs) is found in bone marrow cells. TIM-3 is expressed in multiple bone marrow subsets in human PBMCs, including but not limited to monocytes, macrophages, and dendritic cells.

[0196] Tumor purity estimation is performed on several TCGA tumor samples (e.g., adrenocortical carcinoma (ACC), urothelial carcinoma of the bladder (BLCA), invasive breast carcinoma (BRCA), cervical squamous cell carcinoma and cervical adenocarcinoma (CESC), colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), renal chromophobe cell carcinoma (KICH), renal clear cell carcinoma (KIRC), renal papillary cell carcinoma (KIRP), and low-grade brain glioma). TIM-3 expression correlates well with (LGG), hepatocellular carcinoma of the liver (LIHC), adenocarcinoma of the lung (LUAD), squamous cell carcinoma of the lung (LUSC), serous cystadenocarcinoma of the ovary (OV), adenocarcinoma of the prostate (PRAD), adenocarcinoma of the rectum (READ), cutaneous melanoma (SKCM), thyroid cancer (THCA), endometrial carcinoma of the uterus (UCEC), and carcinosarcoma of the uterus (UCS), suggesting that TIM-3 expression in tumor samples originates from tumor invasion.

[0197] In one embodiment, the combination or method is used to treat kidney cancer (e.g., clear cell carcinoma of the kidney (KIRC) or papillary cell carcinoma of the kidney (KIRP)). In another embodiment, the combination is used to treat brain tumors (e.g., low-grade glioma of the brain (LGG) or glioblastoma multiforme (GBM)). In one embodiment, the combination is used to treat mesothelioma (MESO). In another embodiment, the combination is used to treat sarcoma (SARC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), lung squamous cell carcinoma (LUSC), or prostate cancer.

[0198] While not intended to be theoretically bound, in some embodiments, it is understood that cancers that can be effectively treated by the combinations or methods described herein can be identified by determining the patient fraction in each sign above the 75th percentile across the TCGA through clustering of signs by immunosignature.

[0199] In one embodiment, T cell gene signature includes the expression of one or more (e.g., all) of the following: CD2, CD247, CD3D, CD3E, CD3G, CD8A, CD8B, CXCR6, GZMK, PYHIN1, SH2D1A, SIRPG, or TRAT1.

[0200] In one embodiment, the bone marrow gene signature includes the expression of one or more (e.g., all) of SIGLEC1, MSR1, LILRB4, ITGAM, or CD163.

[0201] In one embodiment, TIM-3 gene signature includes the expression of one or more (e.g., all) of HAVCR2, ADGRG1, PIK3AP1, CCL3, CCL4, PRF1, CD8A, NKG7, or KLRK1.

[0202] While not intended to be theoretically bound, in some embodiments, a TIM-3 inhibitor, e.g., MBG453, may have a synergistic effect with a PD-1 inhibitor, e.g., PDR001, in mixed lymphocyte reaction (MLR) assays. In some embodiments, inhibition of PD-L1 and TIM-3 may result in tumor reduction and survival in mouse models of cancer. In some embodiments, inhibition of PD-L1 and LAG-3 may result in tumor reduction and survival in mouse models of cancer.

[0203] In one embodiment, the method or combination is used to treat cancers having high levels of expression of TIM-3 and one or more bone marrow signature genes (e.g., one or more genes expressed in macrophages). In one embodiment, cancers with high levels of TIM-3 and bone marrow signature gene expression are selected from sarcoma (SARC), mesothelioma (MESO), brain tumors (e.g., glioblastoma (GBM)), kidney cancer (e.g., renal papillary cell carcinoma (KIRP)), or prostate cancer. In another embodiment, the combination or method is used to treat cancers having high levels of expression of TIM-3 and one or more T cell signature genes (e.g., one or more genes expressed in dendritic cells and / or T cells). In one embodiment, cancers with high levels of TIM-3 and T cell signature gene expression are selected from kidney cancer (e.g., renal clear cell carcinoma (KIRC)), lung cancer (e.g., lung adenocarcinoma (LUAD)), pancreatic adenocarcinoma (PAAD), prostate cancer, or testicular cancer (e.g., testicular germ cell tumor (TGCT)).

[0204] While not intended to be theoretically bound, in some embodiments, cancers that can be effectively treated by combinations or methods targeting two, three, or more of the targets described herein through clustering of signs by immunosignature can be identified, for example, by determining a patient fraction of more than 75 percent for both or all of the targets.

[0205] In one embodiment, the combination or method is used for, for example, kidney cancer (e.g., papillary cell carcinoma of the kidney (KIRC) or papillary cell carcinoma of the kidney (KIRP)), mesothelioma (MESO), lung cancer (e.g., adenocarcinoma of the lung (LUAD) or squamous cell carcinoma of the lung (LUSC)), sarcoma (SARC), testicular cancer (e.g., germ cell tumor of the testis (TGCT)), prostate cancer, pancreatic cancer (e.g., adenocarcinoma of the pancreas (PAAD)), cervical cancer (e.g., squamous cell carcinoma of the cervix and adenocarcinoma of the cervix (CE)). To treat cancers selected from SC), head and neck cancers (e.g., head and neck squamous cell carcinoma (HNSC)), bladder cancers (e.g., urothelial carcinoma of the bladder (BLCA)), gastric cancers (e.g., gastric adenocarcinoma (STAD)), skin cancers (e.g., cutaneous melanoma (SKCM)), breast cancers (e.g., invasive breast cancer (BRCA)), or bile duct cancers (CHOL), the treatment includes a TIM-3 inhibitor (e.g., a TIM-3 inhibitor as described herein) and a PD-1 inhibitor (e.g., a PD-1 inhibitor as described herein).

[0206] In one embodiment, a combination or method comprises a TIM-3 inhibitor (e.g., a TIM-3 inhibitor described herein) and a LAG-3 inhibitor (e.g., a LAG-3 inhibitor described herein) to treat cancers selected from, for example, renal cancer (e.g., papillary cell carcinoma of the kidney (KIRC)), mesothelioma (MESO), lung cancer (e.g., adenocarcinoma of the lung (LUAD) or squamous cell carcinoma of the lung (LUSC)), sarcoma (SARC), testicular cancer (e.g., germ cell tumor of the testis (TGCT)), cervical cancer (e.g., squamous cell carcinoma of the cervix and adenocarcinoma of the cervix (CESC)), ovarian cancer (OV), head and neck cancer (e.g., squamous cell carcinoma of the head and neck (HNSC)), gastric cancer (e.g., adenocarcinoma of the stomach (STAD)), bladder cancer (e.g., urothelial carcinoma of the bladder (BLCA)), breast cancer (e.g., invasive breast cancer (BRCA)), prostate cancer, or skin cancer (e.g., cutaneous melanoma (SKCM)).

[0207] In one embodiment, the combination or method may be used for, for example, kidney cancer (e.g., papillary cell carcinoma of the kidney (KIRC)), lung cancer (e.g., adenocarcinoma of the lung (LUAD) or squamous cell carcinoma of the lung (LUSC)), mesothelioma (MESO), testicular cancer (e.g., germ cell tumor of the testis (TGCT)), sarcoma (SARC), cervical cancer (e.g., squamous cell carcinoma of the cervix and adenocarcinoma of the cervix (CESC)), head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSC)), stomach cancer (e.g. For example, to treat cancers selected from gastric adenocarcinoma (STAD), ovarian cancer (OV), bladder cancer (e.g., urothelial carcinoma of the bladder (BLCA)), breast cancer (e.g., invasive breast cancer (BRCA)), prostate cancer, or skin cancer (e.g., cutaneous melanoma (SKCM)), the treatment includes a TIM-3 inhibitor (e.g., a TIM-3 inhibitor as described herein), a PD-1 inhibitor (e.g., a PD-1 inhibitor as described herein), and a LAG-3 inhibitor (e.g., a LAG-3 inhibitor as described herein).

[0208] In one embodiment, a combination or method comprises, for example, a TIM-3 inhibitor (e.g., a TIM-3 inhibitor as described herein), a PD-1 inhibitor (e.g., a PD-1 inhibitor as described herein), and a c-MET inhibitor (e.g., a c-MET inhibitor as described herein) to treat a cancer selected from, for example, renal cancer (e.g., renal papillary cell carcinoma (KIRC)), lung cancer (e.g., lung adenocarcinoma (LUAD)), prostate cancer, or mesothelioma (MESO).

[0209] In one embodiment, the TIM-3 inhibitor is MBG453 (Novartis) or TSR-022 (Tesaro). In one embodiment, the TIM-3 inhibitor is MBG453.

[0210] 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 disclosed in US2015 / 0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” which is incorporated herein by reference in its entirety.

[0211] In one embodiment, the anti-TIM-3 antibody molecule includes at least one, two, three, four, five, or six complementarity-determining regions (CDRs) (or collectively, all CDRs) encoded by heavy and light chain variable regions containing the amino acid sequences shown in Table 7 (e.g., the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 7) or by the nucleotide sequences shown in Table 7. In one embodiment, the CDRs are defined according to the Kabat definition (e.g., as shown in Table 7). In one embodiment, the CDRs are defined according to the Chothia definition (e.g., as shown in Table 7). In one embodiment, one or more CDRs (or collectively, all CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions compared to the amino acid sequences shown in Table 7 or encoded by the nucleotide sequences shown in Table 7.

[0212] In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 801, the VHCDR2 amino acid sequence of SEQ ID NO: 802, and the VHCDR3 amino acid sequence of SEQ ID NO: 803, as disclosed in Table 7; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 810, the VLCDR2 amino acid sequence of SEQ ID NO: 811, and the VLCDR3 amino acid sequence of SEQ ID NO: 812. In another embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 801, the VHCDR2 amino acid sequence of SEQ ID NO: 820, and the VHCDR3 amino acid sequence of SEQ ID NO: 803, as disclosed in Table 7; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 810, the VLCDR2 amino acid sequence of SEQ ID NO: 811, and the VLCDR3 amino acid sequence of SEQ ID NO: 812.

[0213] In one embodiment, the anti-TIM-3 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 806 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 806. In another embodiment, the anti-TIM-3 antibody molecule includes VL containing the amino acid sequence of SEQ ID NO: 816 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 816. In another embodiment, the anti-TIM-3 antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 822 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 822. In one embodiment, the anti-TIM-3 antibody molecule includes a VL containing the amino acid sequence of SEQ ID NO: 826 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 826. In one embodiment, the anti-TIM-3 antibody molecule includes a VH containing the amino acid sequence of SEQ ID NO: 806 and a VL containing the amino acid sequence of SEQ ID NO: 816. In one embodiment, the anti-TIM-3 antibody molecule includes a VH containing the amino acid sequence of SEQ ID NO: 822 and a VL containing the amino acid sequence of SEQ ID NO: 826.

[0214] In one embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 807 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 807. In one embodiment, the antibody molecule includes VL encoded by the nucleotide sequence of SEQ ID NO: 817 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 817. In one embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 823 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 823. In one embodiment, the antibody molecule includes VL encoded by the nucleotide sequence of SEQ ID NO: 827 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 827. In one embodiment, the antibody molecule comprises VH encoded by the nucleotide sequence of SEQ ID NO: 807 and VL encoded by the nucleotide sequence of SEQ ID NO: 817. In another embodiment, the antibody molecule comprises VH encoded by the nucleotide sequence of SEQ ID NO: 823 and VL encoded by the nucleotide sequence of SEQ ID NO: 827.

[0215] In one embodiment, the anti-TIM-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 808 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 808. In another embodiment, the anti-TIM-3 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 818 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 818. In yet another embodiment, the anti-TIM-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 824 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 824. In one embodiment, the anti-TIM-3 antibody molecule includes a light chain containing the amino acid sequence of SEQ ID NO: 828 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 828. In another embodiment, the anti-TIM-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 808 and a light chain containing the amino acid sequence of SEQ ID NO: 818. In yet another embodiment, the anti-TIM-3 antibody molecule includes a heavy chain containing the amino acid sequence of SEQ ID NO: 824 and a light chain containing the amino acid sequence of SEQ ID NO: 828.

[0216] In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 809. In one embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 819 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 819. In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 825. In one embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 829 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 829. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 819. In another embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 829.

[0217] The antibody molecules described herein may be prepared by the vectors, host cells, and methods described in US2015 / 0218274, which are incorporated herein by reference in their entirety.

[0218] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0219] In certain embodiments, the TIM-3 inhibitor is administered at a dosage of about 50 mg to about 100 mg, about 200 mg to about 250 mg, about 500 mg to about 1000 mg or about 1000 mg to about 1500 mg. In certain embodiments, the TIM-3 inhibitor is administered once every four weeks. In other embodiments, the TIM-3 inhibitor is administered at a dosage of about 50 mg to about 100 mg once every four weeks. In other embodiments, the TIM-3 inhibitor is administered at a dosage of about 200 mg to about 250 mg once every four weeks. In other embodiments, the TIM-3 inhibitor is administered at a dosage of about 500 mg to about 1000 mg once every four weeks. In other embodiments, the TIM-3 inhibitor is administered at a dosage of about 1000 mg to about 1500 mg once every four weeks.

[0220] Other exemplary TIM-3 inhibitors In certain embodiments, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In certain embodiments, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences of TSR-022 (or collectively all of the CDR sequences), the heavy or light chain variable region sequences or the heavy or light chain sequences. In certain embodiments, the anti-TIM-3 antibody molecule comprises, for example, one or more of the CDR sequences of APE5137 or APE5121 (or collectively all of the CDR sequences), the heavy or light chain variable region sequences or the heavy or light chain sequences, as disclosed in Table 8. APE5137, APE5121 and other anti-TIM-3 antibodies are disclosed in WO2016 / 161270, which is hereby incorporated by reference in its entirety into this specification.

[0221] In certain embodiments, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. In certain embodiments, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy or light chain variable region sequences or the F38-2E2 sequences of the heavy or light chain.

[0222] Additional known anti-TIM-3 antibodies include, for example, those described in WO2016 / 111947, WO2016 / 071448, WO2016 / 144803, US8,552,156, US8,841,418 and US9,163,087, which are incorporated herein by reference in their entirety.

[0223] In certain embodiments, the anti-TIM-3 antibody is an antibody that competes for binding with one of the anti-TIM-3 antibodies described herein and / or binds to the same epitope of TIM-3.

[0224]

Table 6

[0225] GITR agonist Glucocorticoid-induced TNFR-related protein (GITR) is a member of the tumor necrosis factor superfamily (TNFRSF). GITR expression is constitutively detected in mouse and human CD4+CD25+ regulatory T cells and can be further increased upon activation. In contrast, effector CD4+CD25− T cells and CD8+CD25− T cells have low to undetectable levels of GITR expression and are rapidly upregulated after T cell receptor activation. GITR expression is also detected in activated NK cells, dendritic cells and macrophages. The signaling pathways downstream of GITR have been shown to be involved in the MAPK and canonical NFκB pathways. Various TRAF family members are involved as signaling intermediates downstream of GITR (Nocentini et al. (2005) Eur. J. Immunol. 35:1016-1022).

[0226] GITR-mediated cell activation is thought to perform several functions, including, but is not limited to, co-stimulation to enhance proliferation and effector function, inhibition of regulatory T cell suppression, and protection from activation-induced cell death, depending on cell type and microenvironment (Shevach and Stephens (2006) Nat. Rev. Immunol. 6:613-618). Agonist monoclonal antibodies against mouse GITR effectively induce tumor-specific immunity and eradicate established tumors in a mouse syngeneic tumor model (Ko et al. (2005) J. Exp. Med. 202:885-891).

[0227] In one embodiment, the combination or method described herein includes a GITR agonist. In one embodiment, the GITR agonist is selected from GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte / Agenus), AMG228 (Amgen), or INBRX-110 (Inhibrx).

[0228] Exemplary GITR agonist In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule described in WO2016 / 057846, published on April 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy,” which is incorporated herein by reference in its entirety.

[0229] In one embodiment, the anti-GITR antibody molecule includes at least one, two, three, four, five, or six complementarity-determining regions (CDRs) (or collectively, all CDRs) encoded by heavy and light chain variable regions containing the amino acid sequences shown in Table 9 (e.g., the heavy and light chain variable region sequences of MAB7 disclosed in Table 9) or by the nucleotide sequences shown in Table 9. In one embodiment, the CDRs are defined according to the Kabat definition (e.g., as shown in Table 9). In one embodiment, the CDRs are defined according to the Chothia definition (e.g., as shown in Table 9). In one embodiment, one or more CDRs (or collectively, all CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions compared to the amino acid sequences shown in Table 9 or encoded by the nucleotide sequences shown in Table 9.

[0230] In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 909, the VHCDR2 amino acid sequence of SEQ ID NO: 911, and the VHCDR3 amino acid sequence of SEQ ID NO: 913, as disclosed in Table 9; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 914, the VLCDR2 amino acid sequence of SEQ ID NO: 916, and the VLCDR3 amino acid sequence of SEQ ID NO: 918.

[0231] In one embodiment, the anti-GITR antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 901 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 901. In another embodiment, the anti-GITR antibody molecule includes VL containing the amino acid sequence of SEQ ID NO: 902 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 902. In yet another embodiment, the anti-GITR antibody molecule includes VH containing the amino acid sequence of SEQ ID NO: 901 and VL containing the amino acid sequence of SEQ ID NO: 902.

[0232] In one embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 905 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 905. In another embodiment, the antibody molecule includes VL encoded by the nucleotide sequence of SEQ ID NO: 906 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 906. In yet another embodiment, the antibody molecule includes VH encoded by the nucleotide sequence of SEQ ID NO: 905 and VL encoded by the nucleotide sequence of SEQ ID NO: 906.

[0233] In one embodiment, the anti-GITR antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 903 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 903. In another embodiment, the anti-GITR antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 904 or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 904. In yet another embodiment, the anti-GITR antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 903 and a light chain containing the amino acid sequence of SEQ ID NO: 904.

[0234] In one embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 907. In another embodiment, the antibody molecule includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 908 or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 908. In yet another embodiment, the antibody molecule includes a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 908.

[0235] The antibody molecules described herein can be produced by the vectors, host cells and methods described in WO2016 / 057846, which are incorporated herein by reference in their entirety.

[0236] [Table 7-1] [Table 7-2] [Table 7-3]

[0237] <> In certain embodiments, the GITR agonist is administered at a dose of about 2 mg to about 600 mg (e.g., about 5 mg to about 500 mg). In certain embodiments, the GITR agonist is administered once a week. In other embodiments, the GITR agonist is administered once every three weeks. In other embodiments, the GITR agonist is administered once every six weeks.

[0238] In certain embodiments, the GITR agonist is administered at a dose of about 2 mg to about 10 mg (e.g., about 5 mg), about 5 mg to about 20 mg (e.g., about 10 mg), about 20 mg to about 40 mg (e.g., about 30 mg), about 50 mg to about 100 mg (e.g., about 60 mg), about 100 mg to about 200 mg (e.g., about 150 mg), about 200 mg to about 400 mg (e.g., about 300 mg) or about 400 mg to about 600 mg (e.g., about

[0239] In certain embodiments, the GITR agonist is administered at a dose of about 2 mg to about 10 mg (e.g., about 5 mg), about 5 mg to about 20 mg (e.g., about 10 mg), about 20 mg to about 40 mg (e.g., about 30 mg), about 50 mg to about 100 mg (e.g., about 60 mg), about 100 mg to about 200 mg (e.g., about 150 mg), about 200 mg to about 400 mg (e.g., about 300 mg) or about 400 mg to about 600 mg (e.g., about 500 mg), once every three weeks.

[0240] In one embodiment, the GITR agonist is administered in doses of approximately 2 mg to approximately 10 mg (e.g., approximately 5 mg), approximately 5 mg to approximately 20 mg (e.g., approximately 10 mg), approximately 20 mg to approximately 40 mg (e.g., approximately 30 mg), approximately 50 mg to approximately 100 mg (e.g., approximately 60 mg), approximately 100 mg to approximately 200 mg (e.g., approximately 150 mg), approximately 200 mg to approximately 400 mg (e.g., approximately 300 mg), or approximately 400 mg to approximately 600 mg (e.g., approximately 500 mg), once every 6 weeks.

[0241] In one embodiment, the GITR agonist is administered three times over a 3-week period, followed by a 9-week rest period. In another embodiment, the GITR agonist is administered four times over a 12-week period, followed by a 9-week rest period. In yet another embodiment, the GITR agonist is administered four times over a 21-week or 24-week period, followed by a 9-week rest period.

[0242] 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, for example, in US9,228,016 and WO2016 / 196792, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises, for example, one or more (or collectively all) CDR sequences of BMS-986156, heavy chain or light chain variable region sequences, or heavy chain or light chain sequences, as disclosed in Table 10.

[0243] 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, for example, in US8,709,424, WO2011 / 028683, WO2015 / 026684 and Mahne et al. Cancer Res. 2017; 77(5):1108-1118, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all) CDR sequences of MK-4166 or MK-1248, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0244] In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, for example, in US7,812,135, US8,388,967, US9,028,823, WO2006 / 105021 and Ponte J et al. (2010) Clinical Immunology; 135:S96, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all) CDR sequences of TRX518, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0245] In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte / Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US2015 / 0368349 and WO2015 / 184099, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences of INCAGN1876 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0246] In one embodiment, the anti-GITR antibody molecule is AMG228 (Amgen). AMG228 and other anti-GITR antibodies are disclosed, for example, in US9,464,139 and WO2015 / 031667, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences of AMG228 (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0247] In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US2017 / 0022284 and WO2017 / 015623, which are incorporated herein by reference in their entirety. In one embodiment, the GITR agonist comprises one or more (or all collectively) CDR sequences of INBRX-110, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0248] In one embodiment, the GITR agonist (e.g., fusion protein) is MEDI 1873 (Medimmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, for example, in US2017 / 0073386, WO2017 / 025610 and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract nr 561, which are incorporated herein by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of the IgG Fc domain, functional multimerization domain, and receptor-binding domain of the glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873.

[0249] In one embodiment, the anti-GITR antibody molecule is the anti-GITR antibody molecule disclosed in WO2013 / 039954, which is incorporated herein by reference in its entirety. In another embodiment, the anti-GITR antibody molecule is the anti-GITR antibody molecule disclosed in US2014 / 0072566, which is incorporated herein by reference in its entirety.

[0250] Further known GITR agonists (e.g., anti-GITR antibodies) include, for example, those described in WO2016 / 054638, which are incorporated herein by reference in their entirety.

[0251] In one embodiment, an anti-GITR antibody is an antibody that competes for binding with one of the anti-GITR antibodies described herein and / or binds to the same epitope of GITR.

[0252] In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In another embodiment, the GITR agonist is an immunoadhesin-binding fragment (e.g., an immunoadhesin-binding fragment containing the extracellular or GITR-binding portion of GITRL) fused to a constant region (e.g., the Fc region of an immunoglobulin sequence).

[0253] [Table 8]

[0254] TGF-β inhibitors In one embodiment, the combination or method described herein includes a transforming growth factor beta (also known as TGF-β, TGFβ, TGFb, or TGF-beta, and used herein interchangeably) inhibitor for use in combination with any of the IO agents described herein, similar to the above combination or method, in a PSMA therapeutic agent such as radiolabeled compound I described herein.

[0255] TGF-β belongs to a large family of structurally related cytokines, including, for example, bone morphogenetic proteins (BMPs), growth and differentiation factors, activins, and inhibins. In one embodiment, the TGF-β inhibitors described herein can bind to and / or inhibit one or more isoforms of TGF-β (e.g., one, two, or all of TGF-β1, TGF-β2, or TGF-β3).

[0256] Under normal conditions, TGF-β maintains homeostasis and restricts the proliferation of epithelial, endothelial, neuronal, and hematopoietic cell lineages, for example, by inducing antiproliferative and apoptotic responses. Canonical and non-canonical signaling pathways are involved in the cellular response to TGF-β. Activation of the TGF-β / Smad canonical pathway can mediate the antiproliferative effect of TGF-β. Non-canonical TGF-β pathways can activate further intracellular pathways, such as mitogen-active protein kinase (MAPK), phosphatidylinositol 3 kinase / protein kinase B, and 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), and thus regulate epithelial-mesenchymal transition (EMT) and / or cell motility.

[0257] Modifications of the TGF-β signaling pathway are associated with human diseases, such as cancer, cardiovascular disease, fibrosis, reproductive disorders, and wound healing. While not intended to be theoretically bound, in some embodiments, the role of TGF-β in cancer is thought to depend on the disease context (e.g., tumor stage and genetic alterations) and / or cellular context. For example, in the later stages of cancer, TGF-β can modulate cancer-related processes, for instance, by promoting tumor growth (e.g., EMT induction), blocking antitumor immune responses, increasing tumor-associated fibrosis, or enhancing angiogenesis (Wakefield and Hill Nat Rev Cancer. 2013; 13(5):328-41). In some embodiments, combinations or methods comprising the TGF-β inhibitors described herein are used to treat cancer in the later stages, metastatic, or advanced stages.

[0258] Preclinical evidence indicates that TGF-β plays a crucial 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 downregulate the host immune response through several mechanisms, e.g., a shift in the T helper balance towards the Th2 immunophenotype; inhibition of antitumor Th1 type responses and M1 macrophages; suppression of cytotoxic CD8+ T lymphocyte (CTL), NK lymphocyte, and dendritic cell function, and production of CD4+CD25+ T regulatory cells; or enhancement of the protumor activity of M2 macrophages mediated by the secretion of immunosuppressive cytokines (e.g., IL10 or VEGF), pro-inflammatory cytokines (e.g., IL6, TNFα, or IL1), and the production of genotoxic reactive oxygen species (ROS) (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).

[0259] In one embodiment, the TGF-β inhibitor is used in combination with a PSMA therapeutic agent such as radiolabeled compound I and further with one or more (e.g., two, three, four, or all) of PD-1 inhibitors and LAG-3 inhibitors, GITR agonists, c-MET inhibitors, IDO inhibitors, or A2aR antagonists. In one embodiment, the combination or method is used to treat pancreatic cancer, colorectal cancer, gastric cancer, prostate cancer, or melanoma (e.g., refractory melanoma). In one embodiment, the TGF-β inhibitor is selected from fresolimmab or XOMA089.

[0260] Exemplary TGF-β inhibitors In one embodiment, the TGF-β inhibitor includes compounds disclosed in XOMA089 or in International Patent Application Publication WO2012 / 167143, which are incorporated herein by reference in their entirety.

[0261] XOMA089 is also known as XPA.42.089. XOMA089 is a fully human monoclonal antibody that specifically binds to and neutralizes TGF-beta 1 and 2 ligands.

[0262] The heavy chain variable region of XOMA089 has the amino acid sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLVTVSS (SEQ ID NO: 240) (disclosed as SEQ ID NO: 6 in WO2012 / 167143). The light chain variable region of XOMA089 has the amino acid sequence SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO: 241) (disclosed as SEQ ID NO: 8 in WO2012 / 167143).

[0263] XOMA089 binds to human TGF-β isoforms with high affinity. Generally, XOMA089 binds to TGF-β1 and TGF-β2 with high affinity and to TGF-β3 with less affinity. In the Biacore assay, the K of XOMA089 to human TGF-β D The concentrations are 14.6 pM to TGF-β1, 67.3 pM to TGF-β2, and 948 pM to TGF-β3. Considering the high affinity binding to all three TGF-β isoforms, in one embodiment, XOMA089 is expected to bind to TGF-β1, 2, and 3 at the doses of XOMA089 described herein. XOMA089 cross-reacts with rodent and cynomolgus monkey TGF-β and exhibits functional activity in vitro and in vivo, making rodents and cynomolgus monkeys suitable species for toxicity testing.

[0264] While not intended to be theoretically bound, in one embodiment, resistance to PD-1 immunotherapy is thought to be associated with the presence of transcriptional signatures, including genes linking TGF-β signaling and TGF-β-dependent processes, such as wound healing or angiogenesis (Hugo et al. Cell. 2016; 165(1):35-44). In one embodiment, TGF-β blockade expands the therapeutic range of therapies that inhibit the PD-1 / PD-L1 axis. TGF-β inhibitors may influence the clinical benefits of PD-1 immunotherapy, for example, by modulating factors affecting the tumor microenvironment, such as vascularization, fibrosis, or effector T cell recruitment (Yang et al. Trends Immunol. 2010; 31(6):220-7; Wakefield and Hill Nat Rev Cancer. 2013; 13(5):328-41; Truty and Urrutia Pancreatology. 2007; 7(5-6):423-35).

[0265] While not intended to be constrained by theory, in certain embodiments, it is conceivable that some elements of the antitumor immune cycle expressing PD-1 and TGF-β receptors, or both, may propagate non-redundant cellular signaling. For example, in a mouse model of autotopic prostate cancer, the use of either dominant-negative morphology of TGFBRII or suppression of TGF-β production in T cells delayed tumor growth (Donkor et al. Immunity. 2011; 35(1):123-34; Diener et al. Lab Invest. 2009; 89(2):142-51). Studies in transgenic adenocarcinoma (TRAMP) mice of the mouse prostate showed that blocking TGF-β signaling in adoptive T cells increased persistence and antitumor activity (Chou et al. J Immunol. 2012; 189(8):3936-46). The antitumor activity of transplanted T cells may decrease over time, partly due to upregulation of PD-1 in tumor-infiltrating lymphocytes, supporting the PD-1 and TGF-β inhibitory combinations described herein. The use of neutralizing antibodies against PD-1 or TGF-β may also affect Tregs, considering the high expression levels of PD-1 and the response to TGF-β stimulation (Riella et al. Am J Transplant. 2012; 12(10):2575-87), supporting the PD-1 and TGF-β inhibitory combinations for treating cancer, for example, by enhancing the regulation of Treg differentiation and function.

[0266] While not intended to be constrained by theory, it is conceivable that cancer can use TGF-β to evade immune surveillance to promote tumor growth and metastatic progression. For example, in some advanced cancers, high levels of TGF-β are associated with tumor aggressiveness and poor prognosis, and the TGF-β pathway can promote one or more of cancer cell motility, aggression, EMT, or stem cell phenotypes. Immune regulation mediated by cancer cells and leukocyte populations (e.g., via diverse cell expression or secretion molecules, e.g., IL-10 or TGF-β) may limit the response to checkpoint inhibitors as monotherapy in some patients. In one embodiment, combined inhibition of TGF-β and checkpoint inhibitors (e.g., PD-1 inhibitors described herein) is used to treat cancers that do not respond or respond poorly to checkpoint inhibitor (e.g., anti-PD-1) monotherapy, such as pancreatic cancer or colorectal cancer (e.g., microsatellite-stable colorectal cancer (MSS-CRC)). In other embodiments, combined inhibition of TGF-β and checkpoint inhibitors (e.g., PD-1 inhibitors described herein) is used to treat cancers exhibiting high levels of effector T cell infiltration, such as lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), liver cancer (e.g., hepatocellular carcinoma), prostate cancer, or kidney cancer (e.g., clear cell renal cell carcinoma). In some embodiments, combinations of TGF-β inhibitors and PD-1 inhibitors may produce synergistic effects.

[0267] In one embodiment, the TGF-β inhibitor (e.g., XOMA089) is administered in doses of 0.1 mg / kg to 20 mg / kg, for example, 0.1 mg / kg to 15 mg / kg, 0.1 mg / kg to 12 mg / kg, 0.3 mg / kg to 6 mg / kg, 1 mg / kg to 3 mg / kg, 0.1 mg / kg to 1 mg / kg, 0.1 mg / kg to 0.5 mg / kg, 0.1 mg / kg to 0.3 mg / kg, and 0.3 mg / kg. The dosage is g / kg to 3 mg / kg, 0.3 mg / kg to 1 mg / kg, 3 mg / kg to 6 mg / kg, or 6 mg / kg to 12 mg / kg, for example, approximately 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, 12 mg / kg, or 15 mg / kg, for example, administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0268] In one embodiment, the TGF-β inhibitor (e.g., XOMA089) is administered in doses of 0.1 mg / kg to 15 mg / kg (e.g., 0.3 mg / kg to 12 mg / kg or 1 mg / kg to 6 mg, e.g., approximately 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, 12 mg / kg or 15 mg / kg), for example, once every three weeks. For example, the TGF-β inhibitor (e.g., XOMA089) may be administered in doses of 0.1 mg / kg to 1 mg / kg (e.g., 0.1 mg / kg to 1 mg / kg, e.g., 0.3 mg / kg), for example, once every three weeks. In one embodiment, the TGF-β inhibitor (e.g., XOMA089) is administered intravenously.

[0269] In one embodiment, the TGF-β inhibitor is administered in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and with a PSMA therapeutic agent such as radiolabeled compound I described herein.

[0270] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered intravenously, for example, in doses of 0.1 mg / kg to 15 mg / kg (e.g., 0.3 mg / kg to 12 mg / kg or 1 mg / kg to 6 mg, e.g., about 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, 12 mg / kg or 15 mg / kg), for example, once every three weeks, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered intravenously, for example, in doses of 50 mg to 500 mg (e.g., doses of 100 mg to 400 mg, e.g., about 100 mg, 200 mg, 300 mg or 400 mg), for example, once every three weeks or once every four weeks, for example, by intravenous infusion. In one embodiment, a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered in doses of 100 mg to 300 mg (e.g., doses of approximately 100 mg, 200 mg, or 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0271] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of approximately 0.1 mg / kg or 0.3 mg / kg, for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of approximately 100 mg, for example, once every three weeks, for example, by intravenous infusion. In another embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of approximately 0.3 mg / kg, for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of approximately 100 mg or 300 mg, for example, once every three weeks, for example, by intravenous infusion. In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered, for example, by intravenous infusion, at doses of approximately 1 mg / kg, 3 mg / kg, 6 mg / kg, 12 mg / kg, or 15 mg / kg, for example, once every three weeks, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered, for example, by intravenous infusion, at doses of approximately 300 mg, for example, once every three weeks.

[0272] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 0.1 mg to 0.2 mg (e.g., about 0.1 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 50 mg to 200 mg (e.g., about 100 mg), for example, once every three weeks, for example, by intravenous infusion.

[0273] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 0.2 mg to 0.5 mg (e.g., about 0.3 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 50 mg to 200 mg (e.g., about 100 mg), for example, once every three weeks, for example, by intravenous infusion.

[0274] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 0.2 mg to 0.5 mg (e.g., about 0.3 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0275] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 0.5 mg to 2 mg (e.g., about 1 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0276] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 2 mg to 5 mg (e.g., about 3 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0277] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 5 mg to 10 mg (e.g., about 6 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0278] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 10 mg to 15 mg (e.g., about 12 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0279] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered at a dose of 10 mg to 20 mg (e.g., about 15 mg / kg), for example, once every three weeks, for example, by intravenous infusion, and a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is administered at a dose of 200 mg to 400 mg (e.g., about 300 mg), for example, once every three weeks, for example, by intravenous infusion.

[0280] In one embodiment, a TGF-β inhibitor (e.g., XOMA089) is administered before the administration of a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule). In another embodiment, the TGF-β inhibitor (e.g., XOMA089) is administered after the administration of a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule). In one embodiment, the TGF-β inhibitor (e.g., XOMA089) and the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) are administered separately with an interval of at least 30 minutes (e.g., at least 1 hour, 1.5 hours, or 2 hours) between the two administrations.

[0281] In one embodiment, the combination or method comprises one or more of the following: a PD-1 inhibitor (e.g., a PD-1 inhibitor as disclosed herein), a TGF-β inhibitor (e.g., a TGF-β inhibitor as disclosed herein), a MEK inhibitor (e.g., a MEK inhibitor as disclosed herein), an IL-1β inhibitor (e.g., an IL-1b inhibitor as disclosed herein), or an A2aR antagonist (e.g., an A2aR antagonist as disclosed herein), together with a PSMA therapeutic agent such as radiolabeled compound I disclosed herein. While not intended to be theoretically bound, in one embodiment, TGFβ is thought to promote immunosuppression by Treg subsets in CRC and pancreatic cancer. In one embodiment, the combination or method comprising one or more of the following: a PD-1 inhibitor, a TGF-β inhibitor, a MEK inhibitor, an IL-1b inhibitor, or an A2aR antagonist, together with a PSMA therapeutic agent such as radiolabeled compound I disclosed herein, is administered, for example, in a therapeutically effective dose to a subject having CRC or pancreatic cancer or prostate cancer.

[0282] In some embodiments, a combination or method comprising a PD-1 inhibitor (e.g., the PD-1 inhibitor described herein) and a TGF-β inhibitor (e.g., the TGF-β inhibitor described herein) together with a PSMA therapeutic agent such as the radiolabeled compound I disclosed herein may show improved efficacy in controlling tumor growth in a mouse MC38 CRC model compared to either agent alone. While not intended to be theoretically bound, in some embodiments, a TGF-β inhibitor combined with a PD-1 inhibitor is thought to improve, for example, increase the efficacy of the PD-1 inhibitor. In some embodiments, a combination or method comprising a PD-1 inhibitor (e.g., the PD-1 inhibitor described herein) and a TGF-β inhibitor (e.g., the TGF-β inhibitor described herein) administered to a subject having CRC may result in improved, for example, increased efficacy of the PD-1 inhibitor.

[0283] Other exemplary TGF-β inhibitors In one embodiment, the TGF-β inhibitor includes fresolimmab (CAS Registry Number: 948564-73-6). Fresolimmab is also known as GC1008. Fresolimmab is a human monoclonal antibody that binds to and inhibits TGF-beta isoforms 1, 2, and 3.

[0284] The heavy chain of fresolimmab is QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDIANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPS It has the amino acid sequence CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 238).

[0285] The light chain of fresolimmab has the amino acid sequence ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 239).

[0286] Fresolimmab is disclosed, for example, in International Patent Application Publication WO2006 / 086469 and U.S. Patents 8,383,780 and 8,591,901, which are incorporated herein by reference in their entirety.

[0287] IL-15 / IL-15Ra complex In some embodiments, the combination or method described herein includes 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). In some embodiments, the IL-15 / IL-15RA complex is NIZ985. While not intended to be theoretically bound, in some embodiments, IL-15 is thought to enhance, for example, natural killer cells to eliminate, for example, lethal pancreatic cancer cells. In some embodiments, for example, in an animal model of colorectal cancer, the response, for example, to the combination or method described herein, for example, the combination or method including the IL-15 / IL-15Ra complex, is associated with natural killer cell infiltration.

[0288] Exemplary IL-15 / IL-15Ra complex In one embodiment, the IL-15 / IL-15Ra complex comprises human IL-15 complexed with human IL-15Ra in a soluble form. In one embodiment, the complex may comprise IL-15 covalently or non-covalently bound to IL-15Ra in a soluble form. In one embodiment, human IL-15 is non-covalently bound to IL-15Ra in a soluble form. In another embodiment, as described in WO2014 / 066527, which is incorporated herein by reference in its entirety, the human IL-15 of the composition comprises the amino acid sequence of SEQ ID NO: 1001 in Table 11, and the human IL-15Ra in a soluble form comprises the acid sequence of SEQ ID NO: 1002 in Table 11. The molecules described herein may be produced by the vectors, host cells, and methods described in WO2007 / 084342, which is incorporated herein by reference in its entirety.

[0289] [Table 9]

[0290] While not intended to be theoretically bound, in microsatellite-stable CRCs with low T-cell infiltration, IL-15 is thought to promote, for example, increase T-cell priming (see, e.g., Lou, KJ SciBX 7(16); 10.1038 / SCIBX.2014.449). In one embodiment, a combination or method comprises one or more of the following: a PD-1 inhibitor (e.g., a PD-1 inhibitor as disclosed herein), an IL-15 / IL15RA complex (e.g., an IL-15 / IL15RA complex as disclosed herein), and a MEK inhibitor (e.g., a MEK inhibitor as disclosed herein), an IL-1b inhibitor (e.g., an IL-1b inhibitor as disclosed herein), or an A2aR antagonist (e.g., an A2aR antagonist as disclosed herein), together with a PSMA therapeutic agent such as radiolabeled compound I disclosed herein. In one embodiment, the combination or method promotes, for example, increases T-cell priming. While not intended to be theoretically bound, it is further conceivable that IL-15 may induce NK cell infiltration. In one embodiment, a response to a PSMA therapeutic agent such as one or more PD-1 inhibitors, IL-15 / IL-15RA complexes and MEK inhibitors, IL-1b inhibitors, or A2Ar antagonists and the radiolabeled compound I disclosed herein may result in NK cell infiltration.

[0291] Other exemplary IL-15 / IL-15Ra complex 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 disclosed in WO2008 / 143794, which is incorporated herein by reference in its entirety. In one embodiment, the IL-15 / IL-15Ra Fc fusion protein comprises the sequence disclosed in Table 12.

[0292] In one embodiment, the IL-15 / IL-15Ra complex includes IL-15 (CYP0150, Cytune) fused to the sushi domain of IL-15Ra. The sushi domain of IL-15Ra refers to a domain that begins at the first cysteine ​​residue after the signal peptide of IL-15Ra and ends at the fourth cysteine ​​residue after the signal peptide. Complexes of IL-15 fused to the sushi domain of IL-15Ra are disclosed in WO2007 / 04606 and WO2012 / 175222, which are incorporated herein by reference in their entirety. In one embodiment, the IL-15 / IL-15Ra sushi domain fusion includes the sequences disclosed in Table 12.

[0293] [Table 10]

[0294] PSMA treatment The combinations described herein include a PSMA therapeutic agent, such as a radiolabeled compound I, and one or more further therapeutic agents, which may be administered to a patient for the treatment of cancer. The further therapeutic agent may be any of the therapeutic agents described herein, comprising one or more of the above-mentioned IO agents. In one embodiment, the PSMA therapeutic agent is a compound of formula I or a salt thereof, wherein the compound is radiolabeled. [ka]

[0295] Any form of Compound I described herein is intended to represent the compound and variants of its structural formula. For example, the formulas described herein are intended to include racemates or one or more enantiomers, diastereomers, or geometric isomers or mixtures thereof. Furthermore, any of the formulas described herein are intended to represent salts, hydrates, or solvates or mixtures thereof of such compounds. For example, symbols [ka] Compounds represented by a structural formula containing the symbol [ka] The carbon atom marked with the symbol includes both stereoisomers and is specifically bonded. [ka] but [ka] It is recognized that it is included in the meaning of. For example, one stereoisomer of compound I that is included within the range of the above general formula is compound I shown below: [ka] This includes salts, hydrates, or solvates of such compounds.

[0296] In some embodiments of the combinations for use or method described herein, where the PSMA therapeutic agent is radiolabeled compound I, particularly compound Ia, 177 Lu and 225 It can bind to a radionuclide selected from Ac. In one embodiment, 177 A radiolabeled compound I, particularly compound Ia, bound to Lu, is administered. 225 A radiolabeled compound I, particularly compound Ia, bound to Ac, is administered. 177 Radiolabeled compound I bonded to Lu, particularly compound Ia and 225 Radiolabeled compound I, particularly compound Ia, bound to Ac, is administered. PSMA therapeutic agents such as radiolabeled compound I, particularly compound Ia, may be administered in a non-enteral form. In one embodiment, the non-enteral form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.

[0297] 177In various embodiments in which radiolabeled compound I, particularly compound Ia, bonded to Lu, is administered, the amount administered is about 2 GBq to about 13 GBq, about 4 GBq to about 11 GBq, about 5 GBq to about 10 GBq, about 6 GBq to about 9 GBq, about 6.5 GBq to about 8.5 GBq, or about 7 GBq to about 8 GBq. In various embodiments, the amount administered is about 2 GBq, about 3 GBq, about 4 GBq, about 5 GBq, about 6 GBq, about 7 GBq, about 8 GBq, about 9 GBq, about 10 GBq, or about 7.4 GBq. In one embodiment, 177 The total amount of radiolabeled compound I, particularly compound Ia, bonded to Lu is in the range of approximately 15 GBq to approximately 200 GBq, approximately 25 GBq to approximately 185 GBq, approximately 35 GBq to approximately 150 GBq, approximately 40 GBq to approximately 100 GBq, approximately 40 GBq to approximately 90 GBq, approximately 40 GBq to approximately 80 GBq, approximately 40 GBq to approximately 70 GBq, approximately 40 GBq to approximately 60 GBq, approximately 40 GBq to approximately 50 GBq, and approximately 42 GBq to approximately 58 GBq. In other embodiments, 177 The total amount of radiolabeled compound I, particularly compound Ia, bound to Lu is approximately 20 GBq, 30 GBq, 40 GBq, 41 GBq, 42 GBq, 43 GBq, 44 GBq, 45 GBq, 46 GBq, 47 GBq, 48 GBq, 49 GBq, 50 GBq, 60 GBq, or 70 GBq. In one embodiment, the maximum duration of the treatment in question is approximately 19 to 23 months.

[0298] 225 In one embodiment, when a radiolabeled compound I bound to Ac, particularly compound Ia, is administered, the administered amount is approximately 1 MBq to 20 MBq, 4 MBq to 14 MBq, 5 MBq to 10 MBq, 6 MBq to 8 MBq, 1 MBq to 10 MBq, 1 MBq to 9 MBq, 1 MBq to 8 MBq, 1 MBq to 7 MBq, 1 MBq to 6 MBq, 1 MBq to 5 MBq, 1 MBq to 4 MBq, 1 MBq to 3 MBq, or 2 MBq to 3 MBq. In another embodiment, the administered amount is approximately 1 MBq, 2 MBq, 2.5 MBq, 3 MBq, 4 MBq, 5 MBq, 6 MBq, 7 MBq, 8 MBq, 9 MBq, or 10 MBq.

[0299] In other embodiments, the combinations and methods described herein further include contrast enhancement of PSMA expression by cancer. In some embodiments, the contrast enhancement step is performed before administration of a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia. In other embodiments, the contrast enhancement step is performed after administration of a PSMA therapeutic agent such as radiolabeled compound I, particularly compound Ia. In various embodiments, the contrast enhancement method is selected from the group consisting of SPECT contrast, positron emission tomography contrast, IHC, and FISH. In some embodiments, contrast enhancement is performed by SPECT contrast.

[0300] Further anticancer drugs In some cases, a pharmaceutical aqueous solution of a PSMA therapeutic agent, such as radiolabeled compound I, is combined with other therapeutic agents such as other anticancer agents, anti-allergic agents, anti-nausea agents (or antiemetic agents), analgesics, cytoprotective agents, and combinations thereof.

[0301] In various embodiments, chemotherapeutic agents considered for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Milleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), and carmustine (BiCNU®). ), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Citoxane® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (Depoty®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), que Daunorubicin liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepsid®), fludarabine phosphate (Fludarabine®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®) Trademarks)), Idarubicin (Idamycin®), Ifosfamide (IFEX®), Irinotecan (Camptosar®), L-asparaginase (ELSPAR®), Leucovorin calcium, Melphalan (Alkeran®), 6-Mercaptopurine (Purinesol®), Methotrexate (Folex®), Mitoxantrone (Novantrone®), Mylotarg, Paclitaxel (Taxol®), Nab-Paclitaxel (Abraxane®) (登録商標)It contains, Phoenix (yttrium 90 / MX-DTPA), pentostatin, polyfeprosan 20 and carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0302] In other embodiments, anticancer agents that can be combined with PSMA therapeutic agents such as the radiolabeled compound I described herein include: Tyrosine kinase inhibitors: Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1H-indazole-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, ABT) Also known as 869 and available from Genentech); sunitinib malate (Sutent®); bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazine-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in US Patent 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); zactima (ZD6474); and imatinib or imatinib mesylate (Gleevec® and Gleevec®).

[0303] Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (Avastin®), axitinib (Inlyta®); brivanib alanine ester (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indole-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); cediranib (AZD2171, CAS 288383-20-1); valgatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Teratinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); Tibozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Batalanib 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-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, listed in PCT Publication WO02 / 066470); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Linifanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Restaurtinib (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]triazine-5-yl)methyl)piperidine-3-ol (BMS690514); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrole-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); and Aflibercept (Eylea®), sulfatinib, sulfatinib.

[0304] Platelet-derived growth factor (PDGF) receptor inhibitors: Imatinib (Gleevec®); Linifanib (N-[4-(3-amino-1H-indazole-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Pazopanib (Votrient®); Axitinib (Inlyta®); Sorafenib (Nexavar®); Valgatef (BIBF1120, CAS 928326-83-4); Teratinib (BAY57-9352, CAS 332012-40-5); Batalanib dihydrochloride (PTK787, CAS 212141-51-0); and motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication WO02 / 066470).

[0305] Fibroblast growth factor receptor (FGFR) inhibitors: Brivanib alanine ester (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indole-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yloxy)propan-2-yl)2-aminopropanoate); Valgatef (BIBF1120, CAS 928326-83-4); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethyl-piperazine-1-yl)-phenylamino]-pyrimidine-4-yl}-1-methylurea (BGJ398, CAS 872511-34-7); danucertib (PHA-739358); and N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine-7-yl]-N'-(1,1-dimethylethyl)-urea (PD173074, CAS 219580-11-7). Sulfatinib, sulfatinib.

[0306] Aurora kinase inhibitors: Danucertib (PHA-739358); N-[4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide (ZM447439, CAS 331771-20-1); 4-(2-amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidineamine (CYC116, CAS 693228-63-6); Tozacertib (VX680 or MK-0457, CAS 639089-54-6); Alicertib (MLN8237); (N-{2-[6-(4-cyclobutylamino-5-trifluoromethylpyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-yl]-2-oxo-ethyl}acetamide) (PF-03814735); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); senicertib (R-763); valacertib (AZD1152); and N-cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1H-benzimidazole-2-yl]-1H-pyrazole-4-yl]-urea (AT9283).

[0307] Cyclin-dependent kinase (CDK) inhibitors: Aloysin A; Arbocidib (also known as flavopyridol or HMR-1275, described in 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-clomenone and US Patent 5,621,002); Crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00, CAS 920113-03-7); Indislam (E7070); Roscovitine (CYC202); 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one, hydrochloride (PD0332991); Dinacyclib (SCH727965); N-[5-[[(5-tert-butyloxazole-2-yl)methyl]thio]thiazole-2-yl]piperidine-4-carboxamide (BMS 387032, CAS 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazole-2-yl)-1H-indazole-5-yl]-N-ethyl-4-methyl-3-pyridinemethamine (AG-024322, CAS 837364-57-5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidine-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H-imidazole-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidineamine (AZD5438, CAS 602306-29-6); palbociclib (PD-0332991);and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY 10000394), ribocyclib.

[0308] Checkpoint kinase (CHK) inhibitors: 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl-1H-pyrazole-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidine-7-amine (SCH900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidine-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]octo-3-yl)amino]-3-(1H-benzimidazole-2-yl)-6-chloroquinoline-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isogranulatimide, debromohimenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyradinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutylisothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindro[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazosin-1,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A(YGRKKRRQRRRLYRSPAMPENL) and CBP501((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and (αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazole-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl]-cyclohexaneacetamide(PF-0477736).

[0309] 3-Phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitors: 7-2-amino-N-[4-[5-(2-phenantrenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]phenyl]acetamide (OSU-03012, CAS 742112-33-0); pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[2-(1H-imidazole-4-yl)-ethylamino]-pyrimidine-2-ylamino}phenyl)amide (BX912, CAS 702674-56-4); and 4-dodecyl-N-1,3,4-thiadiazole-2-ylbenzenesulfonamide (PHT-427, CAS 1191951-57-1).

[0310] Protein kinase C (PKC) activators: bryostatin I (bryo-1) and sotrastaurin (AEB071).

[0311] B-RAF inhibitors: Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951, CAS 475108-18-0); Vemurafenib (Zelboraf®, PLX-4032, CAS 918504-65-1); 5-[1-(2-hydroxyethyl)-3-(pyridine-4-yl)-1H-pyrazole-4-yl]-2,3-dihydroinden-1-oneoxime (GDC-0879, CAS 905281-76-7); 5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazole-4-yl]-2,3-dihydro-1H-indene-1-one oxime (GSK2118436 or SB590885); (+ / -)-methyl(5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-1-yl)-1H-benzimidazole-2-yl)carbamate (also known as XL-281 and BMS908662) and N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX4720).

[0312] C-RAF inhibitors: sorafenib (Nexavar®); 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide (ZM336372, CAS 208260-29-1); and 3-(1-cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628, CAS 1007871-84-2).

[0313] Human granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim (Newpogen®); sunitinib malate (Sutent®); pegfilgrastim (Neulasta®); and quizartinib (AC220, CAS 950769-58-1).

[0314] RET inhibitors: sunitinib malate (Sutent®); vandetanib (Caprelsa®); motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication WO02 / 066470); sorafenib (BAY 43-9006); regorafenib (BAY73-4506, CAS 755037-03-7); and danucertib (PHA-739358).

[0315] FMS-like tyrosine kinase 3 (FLT3) inhibitors or CD135: sunitinib malate (Sutent®); quizartinib (AC220, CAS 950769-58-1); N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-imidazo[1,2-b]pyridazine-6-amine sulfate (SGI-1776, CAS 1173928-26-1); and bargatef (BIBF1120, CAS 928326-83-4).

[0316] c-kit inhibitors: Pazopanib (Votrient®); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication WO02 / 066470); Masitinib (Masivet®); Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951, CAS 475108-18-0); Batalanib dihydrochloride (PTK787, CAS 212141-51-0); Teratinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Axitinib (Inlyta®); Dasatinib (BMS-345825); and Sorafenib (Nexavar®).

[0317] Bcr / Abl kinase inhibitors: Imatinib (Gleevec®); Nilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danucertib (PHA-739358), AT9283 (CAS 1133385-83-7); Salakatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imine-9-yl]-2-oxoethyl]acetamide (PF-03814735, CAS 942487-16-3).

[0318] IGF-1R inhibitors: Lincitinib (OSI-906); [7-[trans-3-[(azetidine-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine (AEW541, CAS 475488-34-7); [5-(3-benzyloxyphenyl)-7-[trans-3-[(pyrroridine-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-propanedinitrile (thyrophostin AG1024, CAS 65678-07-1); 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methyl-5-(4-morpholinyl)-1H-benzimidazole-2-yl]-2(1H)-pyridinone (BMS536924, CAS 468740-43-4); 4-[2-[4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1,2-dihydro-2-oxo-3-pyridinyl]-7-methyl-1H-benzimidazole-5-yl]-1-piperazinepropanenitrile (BMS554417, CAS 468741-42-6); (2S)-1-[4-[(5-cyclopropyl-1H-pyrazole-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazine-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methyl-2-pyrroridinecarboxamide (BMS754807, CAS 1001350-96-4); picropodophyllotoxin (AXL1717); and nordihydroguaiaretinic acid.

[0319] IGF-1R antibodies: Phyditumumab (CP751871); Sixtumumab (IMC-A12); Ganitumumab (AMG-479); Lobatumumab (SCH-717454); Darotuzumab (MK0646); R1507 (available from Roche); BIIB022 (available from Biogen); and MEDI-573 (available from Medimmune).

[0320] MET inhibitors: 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-methoxyquinoline-4-yloxy)pyridine-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG) 458); Crizotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-dihydro-1H-indole-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrole-2-yl}methylene)-1,3-dihydro-2H-indole-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrole-2-yl} Methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholine-4-ylpropyl)-1H-pyrrole-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazole-4-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(quinoline-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-yl]-1H-pyrazole-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-yl]sulfamide (MK2461, CAS 917879-39-1);6-[[6-(1-methyl-1H-pyrazole-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-pyrrole-2-yl]methylene]-1,3-dihydro-2H-indole-2-one (PHA665752, CAS 477575-56-7).

[0321] Epidermal growth factor receptor (EGFR) inhibitors: 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®) Standard)); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-5-yl)methyl)piperidine-3-ol (BMS690514); canertinib dihydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidine-4-amine (AEE788, CAS 497839-62-0); Mbritinib (TAK165); Peritinib (EKB569); Afatinib (BIBW2992); Neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazole-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yl]carbamic acid, (3S)-3-morpholinyl methyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrole-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidine-6-yl]phenol (PKI166, CAS 187724-61-4).

[0322] EGFR antibodies: cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); trastuzumab (Herceptin®); nimotuzumab (hR3); zaltumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0323] mTOR inhibitors: Temsirolimus (Torisel®); Ridaforolimus (formerly 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[30.3.1.0 4,9 ]Hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, described in PCT Publication WO03 / 064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholine-4-yl]pyrido[2,3-d]pyrimidine-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-d]pyrimidine-7(8H)-one (PF04691502, CAS 1013101-36-4); N 2-[1,4-Dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine-, intramolecular salt (SF1126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide (also known as XL765, SAR245409); and (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indole-2-yl)imidazo[1,5-f][1,2,4]triazine-7-yl)cyclohexanecarboxylic acid (OSI-027).

[0324] Mitogen - Active Protein Kinase (MEK) Inhibitor: XL-518 (also known as GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); Selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, AZD6244 or ARRY Also known as 142886, described in PCT Publication WO2003077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, described in PCT Publication WO2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901, described in PCT Publication WO2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126, described in US Patent 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, listed in PCT Publication 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, listed in PCT Publication WO2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059, Biaffin GmbH & Co.Available from KG, Germany); 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); Trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80); 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).

[0325] Alkylating agents: Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodar®); Dactinomycin (also known as Actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolicin, and phenylalanine mustard, Alkeran®); Altoretamine (also known as Hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Milleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphatidyl Mido (Citoxane® and Neosar®); Dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednummustine; Procarbazine (Matulane®); Mechloretamine (also known as nitrogen mustard, mustine, and mechloroetamine hydrochloride, Mustargen®); Streptozosin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA, and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxane®, Neosar®, Procytox®, Revimmune®); and Bendamustine HCl (Treanda®).

[0326] Aromatase inhibitors: exemestane (Aromasin®); letrozole (Femara®); and anastrozole (Arimidex®).

[0327] Topoisomerase I inhibitors: irinotecan (Camptosar®); topotecan hydrochloride (Hycamtin®); and 7-ethyl-10-hydroxycampotecin (SN38).

[0328] Topoisomerase II inhibitors: etoposide (VP-16 and etoposide phosphate, Toposar®, Bepsid® and Etopophos®); teniposide (VM-26, Vamon®); and tafluposide.

[0329] DNA synthesis inhibitors: Capecitabine (Xeloda®); gemcitabine hydrochloride (Gemzar®); nelarabine ((2R,3S,4R,5R)-2-(2-amino-6-methoxypurine-9-yl)-5-(hydroxymethyl)oxolan-3,4-diol, Alanone® and Atriance®); and sapacitabine (1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4-(palmitoylamino)pyrimidine-2(1H)-one).

[0330] Folic acid antagonists or antifolic acid agents: Trimethrexate glucuronide (Neutrexin®); pyritrexime isethionate (BW201U); pemetrexed (LY231514); larcitrexed (Tomudex®); and methotrexate (Rheumatrex®, Trexal®).

[0331] Immunomodulators: aftuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimide (CC4047); and IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2, and interferon-γ, CAS 951209-71-5, available from IRX Therapeutics).

[0332] G protein-coupled somatostatin receptor inhibitors: Octreotide (also known as octreotide acetate, Sandostatin® and Sandostatin LAR®); Lanreotide acetate (CAS 127984-74-1); Seglitide (MK678); Vapreotide acetate (Sanvar®); and Cyclo(D-Trp-Lys-Abu-Phe-MeAla-Tyr) (BIM23027).

[0333] Interleukin-11 and synthetic interleukin-11 (IL-11): Oprelbequin (Neumega®).

[0334] Erythropoietin and synthetic erythropoietin: Erythropoietin (Epogen® and Procrit®); darbepoetin alpha (Aranesp®); peginesatide (Hematide®); and EPO (Micera®) covalently linked to polyethylene glycol.

[0335] Histone deacetylase (HDAC) inhibitors: Vorinostat (Zolinza®); Romidepsin (Istodax®); Trichostatin A (TSA); Oxamfratin; Vorinostat (Zolinza®, suberoylanilide hydroxamic acid); Pyroxamide (siberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η- [Oxo-2-oxyranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxyranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl](Cyl-2);Cyclo[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxyranoctanoyl-D-prolyl](HC-toxin);Cyclo[(αS,2S)- [α-amino-η-oxo-2-oxiranoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl](WF-3161); Chlamidosin ((S)-cyclic (2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiranoctanoyl); Apicidine (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl); Romid Psin (Istodax®, FR-901228); 4-phenylbutyrate; spircostatin A; milproin (valproic acid); entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); and depdecin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienitol).

[0336] Biological reaction modifiers include therapies such as interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines (for treatment and prevention), gene therapy, and nonspecific immunomodulators. Interferon alpha (Intron®, Roferson®-A); interferon beta; interferon gamma; interleukin-2 (IL-2 or aldesleukin, Proleukin®); filgrastim (Newpogen®); salglamostim (Leukine®); erythropoietin (epoetin); interleukin-11 (oprelbequin); imiquimod (Aldara®); lenalidomide (Revlimid®); rituximab (Rituxan®); trastuzumab (Herceptin®); Calmette-Guélain bacillus (theraCys® and TICE® BCG); levamisol (Ergamisol®); and denileukin difutitox (Ontak®).

[0337] Plant alkaloids: Paclitaxel (Taxol and Onxal TM ); Paclitaxel protein binding (Abraxane®); Vinblastine (Vinblastine sulfate, also known as vincaloicoblastine and VLB, Alkaban-AQ® and Velban®); Vincristine (Vincristine sulfate, also known as LCR and VCR, Oncovin® and Vincasar Pfs®); and Vinorelbine (Navelbine®).

[0338] Taxane antineoplastic agents: Paclitaxel (Taxol®); Docetaxel (Taxotere®); Cabazitaxel (Jevtana®, 1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytaxa-11-ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2- Hydroxy-3-phenylpropanoate; and larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotaxa-11-en-2-ylbenzoate).

[0339] Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, described in US Patent 4,261,989); Letaspimycin (IPI504), GaPETespib (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethylpyridine-2-ylmethyl)-9H-purine-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-indazole-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5422 or PF04929113, CAS 908115-27-5); and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

[0340] Thrombopoietin (TpoR) agonists: eltrombopag (SB497115, Promacta® and Revolade®); and romiprostim (Nplate®).

[0341] Demethylating agents: 5-azacitidine (Vidaza®); and decitabine (Dacogen®).

[0342] Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, Proleukin®); Interleukin-11 (also known as oprelbekin, Neumega®); and alpha-interferon alpha (also known as IFN-alpha, Intron® A and Roferon-A®).

[0343] 17. α-hydroxylase / C17,20-lyase (CYP17A1) inhibitor: abiraterone acetate (Zyitga®).

[0344] Miscellaneous cytotoxic agents: arsenic trioxide (Trisenox®); asparaginase (L-asparaginase, also known as Erwinia L-asparaginase, Elspar® and Kidrolase®); and asparaginase Erwinia Chrysanthemi (Erwinaze®).

[0345] CC chemokine receptor 4 (CCR4) antibody: mogamulizumab (Poteligent®) CD20 antibodies: rituximab (Rituxan® and Mabcela®); and tositumomab (Bexal®); and ofatumumab (Arzera®).

[0346] CD20 antibody drug conjugates: ibritumomab tiuxetan (Zevalin®); and tositumomab, CD22 antibody drug conjugate: Inotuzumab ozogamicin (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.) CD30 mAb-cytotoxin conjugate: brentuximab vedotin (Adcetrix®); CD33 antibody drug conjugate: gemtuzumab ozogamicin (Mylotarg®), CD40 antibody: Dasetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.) CD52 antibody: Alemtuzumab (Campus®), Anti-CS1 antibody: elotuzumab (HuLuc63, CAS No. 915296-00-3) CTLA-4 antibodies: tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as tisilimumb, CP-675,206); and ipilimumab (a CTLA-4 antibody, known as MDX-010, CAS No. 477202-00-9).

[0347] TPH inhibitor: telototristat PARP (poly-ADP-ribose polymerase) inhibitors: olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zeluja), talazoparib, veliparib. In one embodiment, the therapeutic agent administered in addition to a PSMA therapeutic agent such as radiolabeled compound I disclosed herein is not olaparib.

[0348] In one embodiment, the present invention provides a combination or combination therapy of a PSMA therapeutic agent such as radiolabeled compound I and one or more therapeutic agents selected from the group consisting of octreotide, lanreotide, vapreotide, pasireotide, satreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, pazopanib, and olaparib. In one embodiment, the therapeutic agent administered in addition to the PSMA therapeutic agent such as radiolabeled compound I disclosed herein is not olaparib.

[0349] Methods of treating cancer In one embodiment, the present invention relates to an in vivo treatment of a target using a combination of a PSMA therapy, such as radiolabeled compound I disclosed herein, and a therapeutic agent disclosed herein, or a composition or formulation containing such combination, to inhibit or reduce the growth of cancerous tumors.

[0350] In one embodiment, PSMA treatments such as PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL-15 / IL15RA conjugates, and radiolabeled compound I disclosed herein are administered or used according to the administration regimens disclosed herein.

[0351] In one embodiment, the combination disclosed herein is suitable for in vivo cancer treatment. For example, the combination may be used to inhibit the growth of cancerous tumors. The combination may also be used in combination with one or more standard treatments (e.g., for cancer or infectious disorders), vaccines (e.g., therapeutic cancer vaccines), cell therapy, radiotherapy, surgery, or any other therapeutic agent or modality to treat the disorder herein. For example, the combination may be administered with the antigen of interest to achieve antigen-specific enhancement of immunity. In one embodiment, the combinations disclosed herein may be administered in any order or simultaneously.

[0352] In other embodiments, methods are provided for treating a subject, for example, a hyperproliferative condition or disorder (e.g., cancer) in the subject, such as a solid tumor, hematological malignancy, soft tissue tumor, or metastatic lesion. The method includes administering to the subject, for example, a combination or composition or formulation containing at least two or more or at least three (e.g., four or more) of the therapeutic agents disclosed herein, according to a dosage regimen disclosed herein.

[0353] As used herein, the term “cancer” means all types of cancerous growth or carcinogenic processes, metastatic tissue, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or invasive stage. Examples of cancerous disorders include, but are not limited to, solid tumors, hematological malignancies, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignant tumors of various organ systems, such as those affecting the liver, lungs, breasts, lymphatic system, thyroid, colon, neuroendocrine system, digestive system (e.g., colon), genitourinary system (e.g., kidneys, urothelium, bladder cells), prostate, CNS (e.g., brain, nerve, or glial cells), skin (e.g., melanoma), pancreas, and pharynx, e.g., sarcomas and carcinomas (including adenocarcinoma and squamous cell carcinoma). Adenocarcinoma includes malignant tumors such as most colon cancers, rectal cancers, renal cell carcinomas, liver cancers, non-small cell lung cancers, small intestine cancers, and esophageal cancers. Squamous cell carcinoma includes, for example, malignant tumors of the lungs, esophagus, skin, head and neck region, oral cavity, anus, and cervix. Metastatic lesions of the above cancers can also be treated or prevented using the methods, combinations, and compositions of the present invention.

[0354] As used herein, the term "subject" is intended to include both humans and non-human animals.

[0355] In one embodiment, the combination therapy described herein comprises a composition of the present invention co-formulated and / or co-administered with one or more further therapeutic agents, such as one or more anticancer agents, cytotoxic or cell proliferation inhibitors, hormonal treatments, vaccines and / or other immunotherapies. In other embodiments, the combination is further administered or used in combination with other therapeutic modalities, including surgery, radiation, cryosurgery and / or hyperthermia. In one embodiment, such combination therapy can take advantage of therapeutic agents administered at lower doses and thus avoid the potential toxicity or complications associated with various monotherapies.

[0356] In one embodiment, when administered as a combination, a PSMA therapeutic agent or further therapeutic agent, such as radiolabeled compound I, may be administered individually, for example, in an amount or dose higher, lower, or the same as each agent used as a monotherapy. In one embodiment, the amount or dose administered of the PSMA therapeutic agent or further therapeutic agent, such as radiolabeled compound I, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dose administered of each agent used as a monotherapy. In another embodiment, the amount or dose of the PSMA therapeutic agent or further therapeutic agent, such as radiolabeled compound I, that produces the desired effect (e.g., cancer treatment) is low (e.g., at least 20%, at least 30%, at least 40%, or at least 50%).

[0357] Pharmaceutical composition In other embodiments, the present invention provides compositions, e.g., pharmaceutically acceptable compositions, comprising one or more, e.g., two, three, four, five, six, seven, eight or more, of the PSMA therapeutic agents or further therapeutic agents described herein, such as radiolabeled compound I, either alone or together with a pharmaceutically acceptable carrier. **Polarity of use herein** includes any and all physiologically compatible solvents, dispersion media, isotonic and absorption retardants, etc. In some embodiments, the carrier may be suitable for intravenous, intramuscular, subcutaneous, non-enteral, rectal, spinal, or epithelial administration (e.g., by injection or infusion).

[0358] The compositions described herein may be in a variety of forms. Various embodiments include, for example, solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liquid, semi-solid and solid dosage forms such as liposomes and suppositories. The form depends on the intended method of administration and therapeutic application. In some embodiments, the composition is in the form of an injectable or infusible solution. In some embodiments, the method of administration is non-enteral (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular). In some embodiments, the composition is administered by intravenous infusion or injection. In other embodiments, the composition is administered by intramuscular or subcutaneous injection.

[0359] As used herein, the terms “non-enteral administration” and “administer non-enterally” mean methods of administration other than enteral and local administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intrathecal, epidural, and intrasternal injections and infusions.

[0360] In some embodiments, the therapeutic composition must be sterile and stable under manufacturing and storage conditions. In various embodiments, the composition may be formulated as a solution, microemulsion, dispersion, liposome, or other regular structure. In some embodiments, the composition is suitable for high antibody concentrations. A sterile injection solution may be prepared by incorporating the required amount of the active compound into a suitable solvent containing, as needed, one or a combination of the components listed above, followed by filtration sterilization. In some embodiments, a dispersion is prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other necessary components from those listed above. For sterile powders for preparing sterile injection solutions, suitable preparation methods are vacuum drying and freeze-drying, which yield a powder of the active component and any further desired components from a pre-sterilically filtered solution. In some embodiments, the proper fluidity of the solution may be maintained, for example, by the use of a coating such as lecithin, in the case of a dispersion by maintaining the required particle size, and by the use of a surfactant. In other embodiments, long-term absorption of the injection composition may be achieved by adding absorption-delaying agents, such as monostearate and gelatin, to the composition.

[0361] In one embodiment, a PSMA therapeutic agent such as radiolabeled compound I, or a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, GITR agonist, TGF-β inhibitor, IL-15 / IL-15RA conjugate, or any combination thereof, can be formulated into a formulation (e.g., a single-dose formulation or dosage form) suitable for administration (e.g., intravenous administration) to the subjects described herein.

[0362] In one embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) or composition described herein can be formulated into a formulation (e.g., a single-dose formulation or dosage form) suitable for administration to the subjects described herein (e.g., intravenous administration).

[0363] In one embodiment, the formulation is a drug formulation. In another embodiment, the formulation is a lyophilized formulation, for example, lyophilized or dried from a drug formulation. In another embodiment, the formulation is a reconstituted formulation, for example, reconstituted from a lyophilized formulation. In another embodiment, the formulation is a liquid formulation. In one embodiment, the formulation (e.g., a drug formulation) comprises a PSMA therapeutic agent such as radiolabeled compound I, or a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, GITR agonist, TGF-β inhibitor, IL-15 / IL-15RA complex, or any combination thereof.

[0364] In one embodiment, the formulation is a drug formulation. In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a buffer.

[0365] In one embodiment, the formulation (e.g., drug formulation) contains a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 10-50 mg / mL, for example, 15-50 mg / mL, 20-45 mg / mL, 25-40 mg / mL, 30-35 mg / mL, 25-35 mg / mL, or 30-40 mg / mL, for example, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 33.3 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL. In another embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 30-35 mg / mL, for example, 33.3 mg / mL.

[0366] In one embodiment, the formulation (e.g., a drug formulation) includes a buffer containing histidine (e.g., a histidine buffer). In one embodiment, the buffer (e.g., a histidine buffer) is present at concentrations of 1 mM to 20 mM, for example, 2 mM to 15 mM, 3 mM to 10 mM, 4 mM to 9 mM, 5 mM to 8 mM, or 6 mM to 7 mM, for example, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 6.7 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM. In one embodiment, the buffer (e.g., a histidine buffer) is present at a concentration of 6 mM to 7 mM, for example, 6.7 mM. In other embodiments, the buffer (e.g., histidine buffer) has a pH of 4 to 7, for example, 5 to 6, for example, 5, 5.5, or 6. In one embodiment, the buffer (e.g., histidine buffer) has a pH of 5 to 6, for example, 5.5. In one embodiment, the buffer contains histidine at a concentration of 6 mM to 7 mM (e.g., 6.7 mM) and has a pH of 5 to 6 (e.g., 5.5).

[0367] In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 30-35 mg / mL, for example, 33.3 mg / mL; and a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5).

[0368] In one embodiment, the formulation (e.g., a drug formulation) further contains a carbohydrate. In one embodiment, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at concentrations of 50 mM to 150 mM, for example, 25 mM to 150 mM, 50 mM to 100 mM, 60 mM to 90 mM, 70 mM to 80 mM, or 70 mM to 75 mM, for example, 25 mM, 50 mM, 60 mM, 70 mM, 73.3 mM, 80 mM, 90 mM, 100 mM, or 150 mM. In one embodiment, the formulation contains a carbohydrate or sucrose present at a concentration of 70 mM to 75 mM, for example, 73.3 mM.

[0369] In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 30-35 mg / mL, for example, 33.3 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); and a carbohydrate or sucrose present at a concentration of 70 mM-75 mM, for example, 73.3 mM.

[0370] In one embodiment, the formulation is a drug formulation. In one embodiment, the formulation (e.g., a drug formulation) comprises a PSMA therapeutic agent such as radiolabeled compound I, or a PD-1 inhibitor or PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a GITR agonist, a TGF-β inhibitor, an IL-15 / IL-15RA conjugate or any combination thereof, and a buffer.

[0371] In one embodiment, the formulation (e.g., a drug formulation) further comprises a surfactant. In one embodiment, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.005% to 0.025% (w / w), for example, 0.0075% to 0.02% or 0.01% to 0.015% (w / w), for example, 0.005%, 0.0075%, 0.01%, 0.013%, 0.015%, or 0.02% (w / w). In one embodiment, the formulation comprises the surfactant or polysorbate 20 present at a concentration of 0.01% to 0.015%, for example, 0.013% (w / w).

[0372] In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 30-35 mg / mL, for example, 33.3 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); and a surfactant or polysorbate 20 present at a concentration of 0.01%-0.015%, for example, 0.013% (w / w).

[0373] In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 30-35 mg / mL, for example, 33.3 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); a carbohydrate or sucrose present at a concentration of 70 mM-75 mM, for example, 73.3 mM; and a surfactant or polysorbate 20 present at a concentration of 0.01%-0.015%, for example, 0.013% (w / w).

[0374] In one embodiment, the formulation (e.g., a drug formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 33.3 mg / mL; a buffer containing histidine at a concentration of 6.7 mM and having a pH of 5.5; sucrose present at a concentration of 73.3 mM; and polysorbate 20 present at a concentration of 0.013% (w / w).

[0375] In one embodiment, the formulation is a lyophilized formulation. In one embodiment, the lyophilized formulation is a lyophilized formulation obtained by lyophilizing the drug formulation described herein. For example, 2-5 mL, 3-4 mL, or 3.6 mL of the drug formulation described herein is filled into a container (e.g., a vial) and lyophilized.

[0376] In one embodiment, the formulation is a reconstituted formulation. For example, a reconstituted formulation may be manufactured by dissolving a lyophilized formulation in a diluent and dispersing the drug in the reconstituted formulation. In one embodiment, the lyophilized formulation is reconstituted with 0.5 mL to 2 mL, for example, 1 mL of sterile water for injection or buffer solution. In another embodiment, the lyophilized formulation is reconstituted with 1 mL of sterile water for injection, for example, in clinical practice.

[0377] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a PSMA therapeutic agent such as radiolabeled compound I, or a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, GITR agonist, SERD, CDK4 / 6 inhibitor, CXCR2 inhibitor, CSF-1 / 1R conjugate, c-MET inhibitor, TGF-β inhibitor, A2aR antagonist, IDO inhibitor, MEK inhibitor, IL-15 / IL-15RA complex, IL-1β inhibitor, or any combination thereof, and a buffer.

[0378] In one embodiment, the formulation (e.g., the reconstituted formulation) contains a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20 mg / mL to 200 mg / mL, for example, 50 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, or 90 mg / mL to 110 mg / mL, for example, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / mL. In one embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) is present at a concentration of 80 to 120 mg / mL, for example, 100 mg / mL.

[0379] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a buffer containing histidine (e.g., a histidine buffer). In one embodiment, the buffer (e.g., a histidine buffer) is present at concentrations of 5 mM to 100 mM, e.g., 10 mM to 50 mM, 15 mM to 25 mM, e.g., 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In one embodiment, the buffer (e.g., a histidine buffer) is present at concentrations of 15 mM to 25 mM, e.g., 20 mM. In another embodiment, the buffer (e.g., a histidine buffer) has a pH of 4 to 7, e.g., 5 to 6, e.g., 5, 5.5, or 6. In one embodiment, the buffer (e.g., a histidine buffer) has a pH of 5 to 6, e.g., 5.5. In one embodiment, the buffer contains histidine at a concentration of 15 mM to 25 mM (e.g., 20 mM) and has a pH of 5 to 6 (e.g., 5.5).

[0380] In one embodiment, the formulation (e.g., the reconstituted formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 80-120 mg / mL, for example, 100 mg / mL; and a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5).

[0381] In one embodiment, the formulation (e.g., a reconstituted formulation) further comprises a carbohydrate. In one embodiment, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at a concentration of 100 mM to 500 mM, for example, 150 mM to 400 mM, 175 mM to 300 mM, or 200 mM to 250 mM, for example, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, or 300 mM. In one embodiment, the formulation comprises a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example, 220 mM.

[0382] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 80–120 mg / mL, e.g., 100 mg / mL; a buffer containing histidine at a concentration of 6 mM–7 mM (e.g., 6.7 mM) and having a pH of 5–6 (e.g., 5.5); and a carbohydrate or sucrose present at a concentration of 200 mM–250 mM, e.g., 220 mM.

[0383] In one embodiment, the formulation (e.g., a reconstituted formulation) further comprises a surfactant. In one embodiment, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.01% to 0.1% (w / w), for example, 0.02% to 0.08%, 0.025% to 0.06%, or 0.03% to 0.05% (w / w), for example, 0.01%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In one embodiment, the formulation comprises surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example, 0.04% (w / w).

[0384] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 80-120 mg / mL, for example, 100 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, for example, 0.04% (w / w).

[0385] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, e.g., 0.04% (w / w).

[0386] In one embodiment, the formulation (e.g., a reconstituted formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 100 mg / mL; a buffer containing histidine at a concentration of 6.7 mM and having a pH of 5.5; sucrose present at a concentration of 220 mM; and polysorbate 20 present at a concentration of 0.04% (w / w).

[0387] In one embodiment, the formulation is reconstituted so that at least 1 mL (e.g., at least 1.5 mL, 2 mL, 2.5 mL, or 3 mL) of the reconstituted formulation is extractable from a container (e.g., vial) containing the reconstituted formulation. In one embodiment, the formulation is reconstituted and / or extracted from the container (e.g., vial) in clinical practice. In one embodiment, the formulation (e.g., the reconstituted formulation) is infused into an infusion bag before infusion to the patient is initiated, for example, within 1 hour (e.g., within 45 minutes, 30 minutes, or 15 minutes).

[0388] In one embodiment, the formulation is a liquid formulation. In one embodiment, the liquid formulation is prepared by diluting the drug formulation described herein. For example, the drug formulation may be diluted with a solution containing, for example, 10-30 mg / mL (e.g., 25 mg / mL) of one or more additives (e.g., concentrated additives). In one embodiment, the solution contains one, two or all of histidine, sucrose, or polysorbate 20. In one embodiment, the solution contains the same additives as the drug formulation. The additives include, but are not limited to, amino acids (e.g., histidine), carbohydrates (e.g., sucrose), or surfactants (e.g., polysorbate 20). In one embodiment, the liquid formulation is not a reconstituted lyophilized formulation. In another embodiment, the liquid formulation is a reconstituted lyophilized formulation. In one embodiment, the formulation is stored as a liquid. In another embodiment, the formulation is prepared as a liquid and then dried before storage, for example, by lyophilization or spray drying.

[0389] In one embodiment, the formulation (e.g., liquid formulation) contains a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 5 mg / mL to 50 mg / mL, for example, 10 mg / mL to 40 mg / mL, 15 mg / mL to 35 mg / mL, or 20 mg / mL to 30 mg / mL, for example, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL. In another embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20 to 30 mg / mL, for example, 25 mg / mL.

[0390] In one embodiment, the formulation (e.g., a liquid formulation) contains a buffer (e.g., a histidine buffer) containing histidine. In one embodiment, the buffer (e.g., a histidine buffer) is present at a concentration of 5 mM to 100 mM, for example, 10 mM to 50 mM, 15 mM to 25 mM, for example, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM. In one embodiment, the buffer (e.g., a histidine buffer) is present at a concentration of 15 mM to 25 mM, for example, 20 mM. In another embodiment, the buffer (e.g., a histidine buffer) has a pH of 4 to 7, for example, 5 to 6, for example, 5, 5.5, or 6. In one embodiment, the buffer (e.g., a histidine buffer) has a pH of 5 to 6, for example, 5.5. In one embodiment, the buffer contains histidine at a concentration of 15 mM to 25 mM (e.g., 20 mM) and has a pH of 5 to 6 (e.g., 5.5).

[0391] In one embodiment, the formulation (e.g., a liquid formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20-30 mg / mL, for example, 25 mg / mL; and a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5).

[0392] In one embodiment, the formulation (e.g., a liquid formulation) further contains a carbohydrate. In one embodiment, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at a concentration of 100 mM to 500 mM, for example, 150 mM to 400 mM, 175 mM to 300 mM, or 200 mM to 250 mM, for example, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, or 300 mM. In one embodiment, the formulation contains a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example, 220 mM.

[0393] In one embodiment, the formulation (e.g., a liquid formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20-30 mg / mL, for example, 25 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); and a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, for example, 220 mM.

[0394] In one embodiment, the formulation (e.g., a liquid formulation) further comprises a surfactant. In one embodiment, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.01% to 0.1% (w / w), for example, 0.02% to 0.08%, 0.025% to 0.06%, or 0.03% to 0.05% (w / w), for example, 0.01%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In one embodiment, the formulation comprises surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example, 0.04% (w / w).

[0395] In one embodiment, the formulation (e.g., a liquid formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20-30 mg / mL, for example, 25 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, for example, 0.04% (w / w).

[0396] In one embodiment, the formulation (e.g., liquid formulation d) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 20-30 mg / mL, e.g., 25 mg / mL; a buffer containing histidine at a concentration of 6 mM-7 mM (e.g., 6.7 mM) and having a pH of 5-6 (e.g., 5.5); a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, e.g., 0.04% (w / w).

[0397] In one embodiment, the formulation (e.g., a liquid formulation) comprises a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 25 mg / mL; a buffer containing histidine at a concentration of 6.7 mM and having a pH of 5.5; sucrose present at a concentration of 220 mM; and polysorbate 20 present at a concentration of 0.04% (w / w).

[0398] In one embodiment, each container (e.g., vial) is filled with 1 mL to 10 mL (e.g., 2 mL to 8 mL, 3 mL to 7 mL, or 4 mL to 5 mL, e.g., 3 mL, 4 mL, 4.3 mL, 4.5 mL, 5 mL, or 6 mL) of the liquid formulation. In another embodiment, the liquid formulation is filled into the container (e.g., vial) such that at least 2 mL (e.g., at least 3 mL, at least 4 mL, or at least 5 mL) of the liquid formulation can be extracted per container (e.g., vial). In one embodiment, the liquid formulation is diluted from the drug formulation and / or extracted from the container (e.g., vial) at the clinical site. In one embodiment, the formulation (e.g., liquid formulation) is infused into an infusion bag before infusion to the patient is initiated, for example, within 1 hour (e.g., within 45 minutes, 30 minutes, or 15 minutes).

[0399] The formulations described herein can be stored in a container. A container used for any of the formulations described herein may include, for example, a vial and, optionally, a stopper, a cap, or both. In one embodiment, the vial is a glass vial, e.g., a 6R white glass vial. In another embodiment, the stopper is a rubber stopper, e.g., a gray rubber stopper. In another embodiment, the cap is a flip-off cap, e.g., an aluminum flip-off cap. In one embodiment, the container includes a 6R white glass vial, a gray rubber stopper, and an aluminum flip-off cap. In one embodiment, the container (e.g., vial) is a single-use container. In one embodiment, a drug substance in the container (e.g., vial) is present in an amount of 50 mg to 150 mg, e.g., 80 mg to 120 mg, 90 mg to 110 mg, 100 mg to 120 mg, 100 mg to 110 mg, 110 mg to 120 mg, or 110 mg to 130 mg.

[0400] Other exemplary buffers that may be used in the formulations described herein include, but are not limited to, arginine buffer, citrate buffer, or phosphate buffer. Other exemplary carbohydrates that may be used in the formulations described herein include, but are not limited to, trehalose, mannitol, sorbitol, or combinations thereof. The formulations described herein also include isotonic agents, such as sodium chloride, and / or stabilizers, such as amino acids (e.g., glycine, arginine, methionine, or combinations thereof).

[0401] Therapeutic agents, such as PSMA therapeutic agents, inhibitors, antagonists, or conjugates, including radiolabeled compound I, can be administered in a variety of methods known in the art, but for many treatments, the appropriate route / method of administration is intravenous injection or infusion. For example, PSMA therapeutic agents such as radiolabeled compound I or other therapeutic agents are administered at rates exceeding 20 mg / min, e.g., 20–40 mg / min and typically above 40 mg / min, at approximately 35–440 mg / m². 2 Typically, approximately 70-310 mg / m² 2and more typically, about 110 - 130 mg / m 2 can be administered by intravenous infusion to reach a dose of. In certain embodiments, a PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agents are administered by intravenous infusion at a rate of less than 10 mg / min or 5 mg / min or less to reach a dose of about 1 - 100 mg / m 2 , about 5 - 50 mg / m 2 , about 7 - 25 mg / m 2 or about 10 mg / m 2 . As will be appreciated by those skilled in the art, the route and / or method of administration will vary depending on the desired result. In certain embodiments, the active compound can be prepared with a carrier that protects the compound against rapid release, such as a controlled release formulation including implants, transdermal patches, and microencapsulation delivery systems. In various embodiments, biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods of preparing such formulations are generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0402] In one embodiment, a PSMA therapeutic agent, such as radiolabeled compound I, or other therapeutic agents may be administered orally, for example, using an inert diluent or an absorbable edible carrier. In another embodiment, any of the therapeutic agents described herein (and optionally other components) may be filled into hard or soft-shelled gelatin capsules, compressed into tablets, or directly incorporated into the target diet. For oral therapeutic administration, the therapeutic agent may be incorporated and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc., along with additives. In one embodiment, to administer the therapeutic agent of the present invention by means other than enteral administration, it may be necessary to coat the therapeutic agent with a substance that prevents its inactivation or to co-administer it. In another embodiment, the therapeutic composition may also be administered by pharmaceutical devices known in the art.

[0403] The administration regimen may be adjusted to provide the optimal desired response (e.g., therapeutic response). For example, a single bolus may be administered, divided doses may be administered over time, or the dose may be gradually reduced or increased depending on the urgency of the treatment situation. In some embodiments, the non-enteral composition may be formulated into dose unit forms for ease of administration and uniformity of dosage. As used herein, a dose unit form means a physically separated unit suitable as a unit dose for the subject to be treated; each unit may contain a predetermined amount of the active compound calculated to produce the desired therapeutic effect, along with the necessary pharmaceutical carrier. In various embodiments, the specifications of the dose unit forms of the present invention are indicated and directly depend on (a) the specific characteristics of the active compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the field of mixtures of such active compounds for the treatment of the subject.

[0404] An exemplary, non-limiting range of therapeutic or prophylactic effective doses of the therapeutic agent is 0.1–30 mg / kg or 1–25 mg / kg. Dosages and treatment regimens may be determined by those skilled in the art. In some embodiments, the therapeutic agent is administered by injection (e.g., subcutaneously or intravenously) in doses of about 1–40 mg / kg, e.g., 1–30 mg / kg, e.g., about 5–25 mg / kg, about 10–20 mg / kg, about 1–5 mg / kg, 1–10 mg / kg, 5–15 mg / kg, 10–20 mg / kg, 15–25 mg / kg, or about 3 mg / kg. The dosing schedule may vary, for example, once a week to every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutic agent is administered in doses of about 10–20 mg / kg every other week.

[0405] As another example, the non-limiting range of the therapeutic or prophylactic effective dose of the therapeutic agent described herein is 200–500 mg or 300–400 mg / kg. In one embodiment, the therapeutic agent is administered by injection (e.g., subcutaneously or intravenously) in doses of approximately 200–500 mg, for example, approximately 250–450 mg, approximately 300–400 mg, approximately 250–350 mg, approximately 350–450 mg, or approximately 300 mg or approximately 400 mg (e.g., a constant dose). The dosing schedule (e.g., a constant dosing schedule) may vary, for example, once a week, every two weeks, three weeks, four weeks, five weeks, or six weeks. In one embodiment, the therapeutic agent is administered in doses of approximately 300–400 mg once every three weeks or once every four weeks. In one embodiment, the therapeutic agent is administered in doses of approximately 300 mg once every three weeks. In one embodiment, the therapeutic agent is administered in doses of approximately 400 mg once every four weeks. In another embodiment, the therapeutic agent is administered in doses of approximately 300 mg once every four weeks. In yet another embodiment, the therapeutic agent is administered in doses of approximately 400 mg once every three weeks. While not intended to be theoretically bound, in some embodiments, constant or fixed dosing may be beneficial to the patient, for example, for preserving the drug supply and reducing dispensing errors.

[0406] In one embodiment, the clearance (CL) of the therapeutic agent is approximately 6–16 mL / hour, for example, approximately 7–15 mL / hour, approximately 8–14 mL / hour, approximately 9–12 mL / hour, or approximately 10–11 mL / hour, for example, approximately 8.9 mL / hour, 10.9 mL / hour, or 13.2 mL / hour.

[0407] In one embodiment, the body weight index of the therapeutic agent to CL is approximately 0.4 to 0.7, approximately 0.5 to 0.6, or 0.7 or less, for example, 0.6 or less, or approximately 0.54.

[0408] In one embodiment, the steady-state volume of distribution (Vss) of the therapeutic agent is approximately 5–10V, for example, approximately 6–9V, approximately 7–8V, or approximately 6.5–7.5V, for example, approximately 7.2V.

[0409] In one embodiment, the half-life of the therapeutic agent is approximately 10 to 30 days, for example, approximately 15 to 25 days, approximately 17 to 22 days, approximately 19 to 24 days, or approximately 18 to 22 days, for example, approximately 20 days.

[0410] In one embodiment, the Cmin of the therapeutic agent (e.g., for a patient weighing 80 kg) is at least about 0.4 μg / mL, for example, at least about 3.6 μg / mL, for example, about 20–50 μg / mL, for example, about 22–42 μg / mL, about 26–47 μg / mL, about 22–26 μg / mL, about 42–47 μg / mL, about 25–35 μg / mL, about 32–38 μg / mL, for example, about 31 μg / mL or about 35 μg / mL. In one embodiment, Cmin is determined for a patient who received the therapeutic agent in a dose of about 400 mg once every four weeks. In another embodiment, Cmin is determined for a patient who received the therapeutic agent in a dose of about 300 mg once every three weeks. In one embodiment, Cmin is determined based on IL-2 changes in an SEB exovivo assay, for example, to determine the EC of the therapeutic agent. 50At least about 50 times higher, e.g., at least about 60 times, 65 times, 70 times, 75 times, 80 times, 85 times, 90 times, 95 times or 100 times, e.g., at least about 77 times higher. In other embodiments, Cmin is determined, e.g., based on the change in IL-2 in the SEB ex vivo assay, and the EC of the therapeutic agent 90 is at least 5 times higher, e.g., at least 6 times, 7 times, 8 times, 9 times or 10 times, e.g., at least about 8.6 times higher.

[0411] A PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agents can be administered by intravenous infusion to reach a dose of greater than 20 mg / min, e.g., 20 - 40 mg / min and typically 40 mg / min or more, about 35 - 440 mg / m 2 , typically about 70 - 310 mg / m 2 and more typically, about 110 - 130 mg / m 2 In certain embodiments, an infusion rate of about 110 - 130 mg / m 2 achieves a level of about 3 mg / kg. In other embodiments, a PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agents can be administered by intravenous infusion to reach a dose of less than 10 mg / min, e.g., at a rate of 10 mg / min or less, about 1 - 100 mg / m 2 , e.g., about 5 - 50 mg / m 2 , about 7 - 25 mg / m 2 or about 10 mg / m 2 It should be noted that the dosage values can vary depending on the type and severity of the condition to be alleviated. For any particular subject, the specific dosing regimen should be adjusted by the professional judgment of the person administering or supervising the administration of the composition, and it is also understood that the dosage ranges shown herein are merely exemplary and are not intended to limit the scope or practice of the compositions of the present application.

[0412] The pharmaceutical composition of the present invention may contain a "therapeutic effective dose" or "preventive effective dose" of a PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agents. "Therapeutic effective dose" refers to an effective amount in the dosage and duration required to achieve the desired therapeutic outcome. The therapeutic effective dose of a PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agents may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agent to induce the desired response in the individual. The therapeutic effective dose is also such that the therapeutic benefits outweigh any toxic or adverse effects of the PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agent. A "therapeutic effective dose" can inhibit measurable parameters, such as tumor growth rate, by at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to an untreated subject. Measurable parameters of a PSMA therapeutic agent such as radiolabeled compound I or other therapeutic agent, such as the ability to inhibit cancer, can be evaluated in animal model systems that predict efficacy in human tumors. Alternatively, this property of the composition can be evaluated by testing the in vitro inhibitory capacity of a PSMA therapeutic agent, such as radiolabeled compound I, or other therapeutic agents, by assays known to those skilled in the art.

[0413] "Prophylactic effective dose" refers to the effective amount of dosage and duration required to achieve the desired preventive outcome. Typically, since prophylactic doses are used for pre-disease or early-stage conditions, the prophylactic effective dose is less than the therapeutic effective dose.

[0414] kit The therapeutic combinations disclosed herein may be provided in kits. In some embodiments, the therapeutics are provided in vials or containers. Where appropriate, the therapeutics may be in liquid or dry (e.g., lyophilized) form. In some embodiments, a kit may contain one or more (e.g., one, two, three, four, five, or all) therapeutics of the therapeutic combination disclosed herein. In some embodiments, the kit may further contain a pharmaceutically acceptable diluent. In various embodiments, the therapeutics may be provided in the kit in the same or separate formulations (e.g., as a mixture or in separate containers). A kit may contain a fixed amount of therapeutics providing one or more doses. If a fixed amount for multiple doses is provided, the doses may be uniform or variable. For example, variable dosing regimens may be increased or decreased as appropriate. In some embodiments, the doses of multiple therapeutics in the combination may be independently uniform or variable. In further embodiments, the kit may include one or more other elements, including instructions for use; other agents, e.g., labels or agents or radioprotective compositions effective for chelating or otherwise coupling the therapeutic agent to the label; devices or other materials for preparing the therapeutic agent for administration; pharmaceutically acceptable carriers; and devices or other materials for administering the agent to a subject.

[0415] Inclusion by citation All publications, patents, and accession numbers listed herein are incorporated herein by reference in the same manner that each individual publication or patent is specifically and individually incorporated herein by reference.

[0416] Equal portions While specific embodiments of the subject matter of the invention are described, the above specification is descriptive and not limiting. Many variations of the invention will become apparent to those skilled in the art through this specification and the accompanying claims. The full scope of the invention should be determined by considering the claims and specification, along with such variations and the full scope of equivalents. [Examples]

[0417] Radiolabeled compound I can be prepared by the method described in WO2015055318, which is incorporated herein by reference for the preparation of radiolabeled compound I, particularly compound Ia. The preparation of radiolabeled compound Ia is abbreviated below.

[0418] Example 1: Synthesis of Compound Ia The glutamyl isocyanate was produced in situ by adding a mixture of 3 mmol of bis(tert-butyl) L-glutamate hydrochloride and 1.5 mL of N-ethyldiisopropylamine (DIPEA) in 200 mL of dry CH2CI2 to 1 mL of dry CH2CI2 solution of 1 mmol of triphosgene over 4 hours at 0°C. After stirring the reaction mixture at 25°C for 1 hour, 0.5 mmol of resin immobilization (2-chloro-trityl resin) 4 mL of DCM solution of ε-allyloxycarbonyl protected lysine was added, and the mixture was reacted for 16 hours with gentle stirring. The resin was filtered off, and the allyloxy protecting group was removed by using a 4 mL CH2CI2 solution of 30 mg of tetrakis(triphenyl)palladium(0) and 400 pL of morpholine for 3 hours. The coupling of Fmoc-3-(2-naphthyl)-L-alanine and trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid was carried out stepwise using 2 mmol of Fmoc protective acid, 1.96 mmol of HBTU, and 2 mmol of N-ethyldiisopropylamine in a final volume of 4 mL of DMF. After activation with 3.95 equivalents of HBTU and DIPEA for 2 hours, 4 equivalents of tris(t-bu)-DOTA (Chematech) were reacted with the resin packing for 3 hours in a final volume of 3 mL of DMF. The product was cleaved from the resin in a 2 mL mixture of trifluoroacetic acid, triisopropylsilane, and water (95:2.5:2.5). Purification was performed using RP-HPLC, and the purified product was analyzed by analytical RP-HPLC and MALDI-MS.

[0419] Example 2: Radiolabeling of compound Ia 177 Lu label: 177Lu (approximately 100 MBq) was mixed with 200 μI of 0.4 M sodium acetate buffer containing Chelex (pH=5). A 1 mM solution of compound I in 10 μI of 10% DMSO aqueous solution, 2 μI of saturated ascorbic acid solution, and 40 μI of [unclear text] were also mixed. 177 The solution containing Lu was mixed and stirred at 95°C for 10 minutes. Labeling was confirmed by radio-HPLC (within 5 minutes using an aqueous solution of 0-100% ACN, Monolith column).

Claims

1. Radiolabeled compound Ia (compound Ia) for use in the treatment of PSMA-expressing cancers in the target population. 【Chemistry 1】 A combination comprising the compound and one or more cancer immunotherapy (I-O) agents, wherein the I-O agent is selected from LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL-15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

2. A method for treating PSMA-expressing cancer in a subject, wherein the subject is radiolabeled with formula Ia (compound Ia) 【Chemistry 2】 A method comprising administering a combination of a compound and one or more cancer immunotherapy (I-O) agents, wherein the I-O agent is selected from LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL-15 / IL-15RA complexes, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

3. The combination of claim 1 or the method of claim 2, wherein the radiolabeled compound Ia and the I-O therapeutic agent are separate compositions and are administered separately to the subject.

4. A combination of any one of claims 1 or 3 or the method of claim 2 or 3, wherein the LAG-3 inhibitor is selected from LAG525, BMS-986016, or TSR-033.

5. A combination of any of claims 1, 3, or 4, or any of claims 2 to 4, wherein the TIM-3 inhibitor is MBG453 or TSR-022.

6. A combination of any of claims 1 or 3 to 5, or any method of any of claims 2 to 5, wherein the GITR agonist is selected from GWN323, BMS-986156, MK-4166, MK-1248, TRX518, INCAGN1876, AMG228, or INBRX-110.

7. A combination of any of claims 1 or 3 to 6, or any method of any of claims 2 to 6, wherein the TGF-β inhibitor is XOMA089 or fresolimmab.

8. A combination of any of claims 1 or 3 to 7, or any of claims 2 to 7, wherein the IL-15 / IL-15RA complex is selected from NIZ985, ATL-803, or CYP0150.

9. A combination of any of claims 1 or 3 to 8, or a method of any of claims 2 to 8, comprising one or more further anticancer agents.

10. The combination or method of claim 9, wherein the additional anticancer agent is selected from octreotide, lanreotide, vapreotide, pasireotide, satreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib.

11. A combination of any one of claims 1 or 3 to 10, or any one of claims 2 to 10, wherein the PSMA-expressing cancer is prostate cancer.

12. Any combination of claim 1 or 3 to 10, or any method of claim 2 to 10, wherein the PSMA-expressing cancer is selected from thyroid cancer, renal clear cell carcinoma, bladder transitional cell carcinoma, colon adenocarcinoma, neuroendocrine cancer, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and breast cancer.

13. The combination or method of claim 12, wherein PSM is expressed in the neovascular structures of cancer.

14. Compound Ia １７７ Lu and ２２５ A combination of any of claims 1 or 3 to 13, or a method of any of claims 2 to 13, for binding to a radionuclide selected from Ac.

15. Compound Ia １７７ A combination or method of claim 14, which is coupled to Lu.

16. Compound Ia ２２５ A combination or method of claim 14, which is coupled to Ac.

17. １７７ Compound Ia and that bind to Lu ２２５ The combination or method of claim 14, wherein both compounds Ia that bind to Ac are administered to the target.

18. A combination of any of claims 1 or 3 to 16, or any of claims 2 to 17, wherein a PD-1 inhibitor is administered, and the PD-1 inhibitor is not pembrolizumab.

19. Administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia bound to Lu is about 2 GBq to about 13 GBq.

20. Administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia bound to Lu is about 4 GBq to about 11 GBq.

21. To be administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia that binds to Lu is from about 5 GBq to about 10 GBq.

22. Administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia bound to Lu is about 6 GBq to about 9 GBq.

23. Administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia bound to Lu is about 6.5 GBq to about 8.5 GBq.

24. Administered １７７ The combination or method of claim 15 or 17, wherein the amount of compound Ia bound to Lu is about 7 GBq to about 8 GBq.

25. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 1 MBq to about 6 MBq.

26. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 1 MBq to about 5 MBq.

27. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 1 MBq to about 4 MBq.

28. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 1 MBq to about 3 MBq.

29. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 2 MBq to about 3 MBq.

30. Administered ２２５ The combination or method of claim 16 or 17, wherein the amount of compound Ia bound to Ac is about 2 MBq.

31. A combination of any of claims 1, 3 to 16 or 18 to 30 or any method of claims 2 to 30, wherein the I-O treatment agent is selected from spartalizumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, nivolumab, MK-3475, MPDL3280A, MEDI5736, ipilimumab, tremelimumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210 and AMP-224.

32. A combination of any of claims 1, 3-16 or 18-30 or any method of any of claims 2-30, wherein the I-O therapeutic agent is selected from nivolumab, MK-3475, MPDL3280A, MEDI5736, ipilimumab and tremelimumab.

33. A combination of any of claims 1, 3 to 16 or 18 to 31, or any method of any of claims 2 to 30, wherein the I-O therapeutic agent is nivolumab.

34. A combination of any of claims 1, 3 to 16 or 18 to 31, or any method of any of claims 2 to 30, wherein the I-O therapeutic agent is ipilimumab.

35. A combination of any of claims 1, 3 to 16 or 18 to 31 or any of claims 2 to 30, wherein the I-O therapeutic agent is tremelimumab.

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