The present invention provides compounds and compositions for use in the treatment of cancer as part of a Chimeric Antigen Receptor T-cell (CAR-T) therapy. In particular, the present invention discloses IL-18 binding molecules such as, for example, the IL-18 binding protein (IL-18BP) for use in Chim
The present invention provides compounds and compositions for use in the treatment of cancer as part of a Chimeric Antigen Receptor T-cell (CAR-T) therapy. In particular, the present invention discloses IL-18 binding molecules such as, for example, the IL-18 binding protein (IL-18BP) for use in Chimeric Antigen Receptor T-cell (CAR-T) therapy as a modulator to avoid or minimize side effects.
대표청구항▼
1. An IL-18 binding molecule for use in a Chimeric Antigen Receptor T-cell (CAR-T) therapy of a patient diagnosed with a disease associated with expression of a tumor antigen to avoid or minimize side effects related to the CAR-T therapy. 2. The IL-18 binding molecule for use of claim 1 as a modulat
1. An IL-18 binding molecule for use in a Chimeric Antigen Receptor T-cell (CAR-T) therapy of a patient diagnosed with a disease associated with expression of a tumor antigen to avoid or minimize side effects related to the CAR-T therapy. 2. The IL-18 binding molecule for use of claim 1 as a modulator of IL-18 levels in the patient to avoid or minimize side effects related to the CAR-T therapy. 3. The IL-18 binding molecule for use of claim 2, wherein the IL-18 levels are levels of free IL-18. 4. The IL-18 binding molecule for use of any one of claims 1 to 3, wherein the IL-18 binding molecule inhibits IFN-gamma secretion. 5. The IL-18 binding molecule for use of any one of claims 1 to 4, wherein the IL-18 binding molecule inhibits IL-18 mediated stimulation of IFN-gamma secretion, that is further elevated by IL-12. 6. The IL-18 binding molecule for use of any one of claims 1 to 5, wherein the disease associated with expression of a tumor antigen is a proliferative disease, a precancerous condition, a cancer, and/or a non-cancer related indication associated with expression of the tumor antigen. 7. The IL-18 binding molecule for use of any one of claims 1 to 6, wherein the patient has cancer, particularly a hematological cancer or a solid tumor, particularly a tumor expressing tumor-associated antigens. 8. The IL-18 binding molecule for use of claim 7, wherein the cancer is a hematologic cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative condition, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia. 9. The IL-18 binding molecule for use of any one of claims 1 to 8, wherein a population of cells is used in the CAR-T therapy, which are engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. 10. The IL-18 binding molecule for use of claim 9, wherein the cells are further engineered to express IL-18. 11. The IL-18 binding molecule for use of any one of claims 1 to 10, wherein the side effects are due to an overshooting of the immune system and/or a cytokine release syndrome. 12. The IL-18 binding molecule for use of claim 11, wherein the side effects are selected from the group consisting of unremitting fever, hypotension, hypoxia (lung involvement), other end-organ damage and dysfunction including but not limited to liver and kidney, cytopenias, coagulopathy, hemophagocytosis and neurologic toxicities. 13. The IL-18 binding molecule for use of any one of claims 1 to 12, as a modulator of free IL-18 levels in the patient. 14. The IL-18 binding molecule for use of any one of claims 1 to 13 for decreasing the IL-18 levels, particularly the free IL-18 levels, in the patient. 15. The IL-18 binding molecule for use of any one of claims 1 to 14, wherein the patient is an animal, particularly a human. 16. The IL-18 binding molecule for use of any one of claims 1 to 15, which is an IL-18 binding protein (IL-18BP), including any functional equivalent or functional part thereof which retains the modulator activity. 17. The IL-18 binding molecule for use of any one of claims 1 to 15, which is an IL-18 binding antibody that specifically binds to free IL-18, but not to IL-18 bound in a complex, including any functional equivalent or functional part thereof which retains the modulator activity. 18. The IL-18 binding molecule for use of claim 16, which is a human IL-18BP (hIL-18 BP), preferably a recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional part thereof, which retains the modulator activity. 19. The IL-18 binding molecule for use of claim 18, wherein said human IL-18BP is selected from isoform a, b, c and d of human IL-18BP, particularly isoform a as in SEQ ID NO: 2, isoform b as in SEQ ID NO: 3, isoform c as in SEQ ID NO: 4 or isoform d as in SEQ ID NO: 5, including any functional equivalent or functional part of isoforms a, b, c and/or d, which retains the modulator activity. 20. The IL-18 binding molecule for use of claim 19, which is an IL-18BP as shown in SEQ ID NO: 2, including any functional equivalent or functional part thereof, which retains the modulator activity, preferably wherein the functional equivalent has a sequence identity of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% to the sequence depicted in SEQ ID NO: 2 and retains the modulator activity. 21. The IL-18 binding molecule for use of claim 20, wherein the functional equivalent or functional part thereof includes a mutein of IL-18BP, a fragment, a peptide, a functional derivative, a functional fragment, a fraction, a circularly permuted derivative, a fused protein comprising IL-18BP, an isoform or a salt thereof which retains the modulator activity. 22. A composition comprising the IL-18 binding molecule, particularly an IL-18 binding molecule of any one of claims 16 to 21, for use in a Chimeric Antigen Receptor T-cell (CAR-T) therapy of a patient, diagnosed with a disease associated with expression of a tumor antigen, to avoid or minimize side effects related to the CAR-T therapy, optionally wherein the composition comprises a pharmaceutically acceptable carrier and/or solvent and/or excipient. 23. The composition for use of claim 22, as a modulator of IL-18 levels in the patient to avoid or minimize side effects related to the CAR-T therapy. 24. The composition for use of claim 22 or 23, wherein the side effects are due to an overshooting of the immune system and/or a cytokine release syndrome. 25. The composition for use of any one of claims 22 to 24, wherein the disease is a proliferative disease, a precancerous condition, a cancer, and a non-cancer related indication associated with expression of the tumor antigen. 26. The composition for use of any one of claims 22 to 25, wherein the patient has cancer, particularly a hematological cancer or a solid tumor, particularly a tumor expressing tumor-associated antigens. 27. The composition for use of claim 26, wherein the cancer is a hematologic cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative condition, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia. 28. The composition for use of any one of claims 22 to 27, wherein the side effects are selected from the group consisting of unremitting fevers, hypotension, hypoxia (lung involvement), other end-organ damage and dysfunction including but not limited to liver and kidney, cytopenias, coagulopathy, hemophagocytosis and neurologic toxicities. 29. The composition for use of any one of claims 22 to 28 comprising (i) a population of cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, and(ii) an IL-18 binding molecule, particularly the IL-18 binding molecule of any one of claims 15 to 20. 30. The composition for use of claim 29, wherein the population of cells of (i) are further engineered to express IL-18. 31. The composition for use of any one of claims 22 to 30, wherein the IL-18 binding protein (IL-18BP) further comprises N-terminal and/or C-terminal deletion variants of IL-18BP. 32. The composition for use of any one of claims 22 to 31, wherein the patient is an animal, particularly a human. 33. The composition for use of any one of claims 22 to 32, comprising N-terminal and/or C-terminal deletion variants of IL-18BP in an amount of up to 40%, particularly up to 30%, particularly up to 20%, particularly up to 15%, particularly up to 10%, particularly up to 7.5%, particularly up to 5%, particularly up to 2.5%, particularly up to 1%, particularly up to 0.5%, particularly up to 0.25%, particularly up to 0.1%, particularly up to 0.05%, particularly up to 0.01%. 34. The composition for use of claim 31 or 33, wherein said deletion variants comprise deletions of between 1 and 5 amino acid residues at the C-terminal end of the IL-18BP and/or between 1 and 30 amino acid residues at the N-terminal end of the IL-18BP. 35. The composition for use of any one of claims 31 to 34, wherein said N-terminal and/or C-terminal deletion variants of IL-18BP are present in an amount of up to 40%, particularly in an amount of between 2% and 35%. 36. The IL-18 binding molecule of any one of claims 1 to 21 or the composition of any one of claims 22 to 35 for controlling and/or modulating, particularly decreasing, IL-18 levels, particularly free IL-18 levels, in the patient. 37. A method for modulating IL-18 levels in a patient under a Chimeric Antigen Receptor T-cell (CAR-T) therapy to avoid or minimize side effects, comprising administering to a patient in need thereof a therapeutically effective amount of an IL-18 binding molecule, particularly an IL-18 binding molecule according to any one of claims 16 to 21, or a therapeutically effective amount of a composition of any one of claims 22 to 35. 38. The method for use of claim 37, for modulating, particularly decreasing, IL-18 levels, particularly free IL-18 levels, in the patient. 39. The method for use of claim 37 or 38, wherein the patient has a disease associated with expression of a tumor antigen, e.g., a proliferative disease, a precancerous condition, a cancer, and a non-cancer related indication associated with expression of the tumor antigen. 40. The method for use of claim 39, wherein the patient has cancer, particularly a hematological cancer or a solid tumor, particularly a tumor expressing tumor-associated antigens. 41. The method for use of claim 40, wherein the cancer is a hematologic cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia. 42. The method for use of any one of claims 37 to 41, wherein the patient is an animal, particularly a human. 43. The method of any one of claims 37 to 42, wherein the CAR-T-cells and the IL-18 binding molecule or the composition, respectively, are administered to the patient concomitantly. 44. The method of any one of claims 37 to 42, wherein the CAR-T-cells and the IL-18 binding molecule or the composition, respectively, are administered to the patient sequentially. 45. The method of any one of claims 37 to 44, wherein the IL-18 binding molecule or the composition, respectively, is administered to the patient as an acute intervention during the CAR-T therapy. 46. The IL-18 binding molecule for use of claim 7 or the composition for use of claim 26 or the method of claim 40 wherein the cancer is a solid tumor, particularly selected from the group consisting of colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancer, combinations of said cancers, and metastatic lesions of said cancers. 47. The IL-18 binding molecule for use of any one of claim 1 to 21, 36 or 46 or the composition for use of any one of claim 22 to 35 or 46, or the method of any one of claims 37 to 46, wherein in a body fluid of the patient an abnormal level of free IL-18 has been determined, in particular wherein the level of free IL-18 exceeds the level of free IL-18 in body fluids of a healthy control subject, particularly by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, using an assay capable of detecting free IL-18 in body fluids, said assay comprising the IL-18 binding molecule as defined in any one of claims 16 to 21. 48. The IL-18 binding molecule for use, the composition for use or the method of claim 47, wherein the assay for quantifying the level of free IL-18 in the body fluid(s) comprises the following steps: a) bringing a sample of body fluid suspected to contain free IL-18 into contact with the IL-18 binding molecule as defined in any one of claims 16 to 21 as the capturing molecule for free IL-18;b) allowing the IL-18 binding molecule to bind to free IL-18; andc) detecting the binding of the IL-18 binding molecule and determining the amount of free IL-18 in the sample. 49. The IL-18 binding molecule for use, the composition for use or the method of any one of claim 47 or 48, wherein the body fluid is selected from the group consisting of broncho-alveolar lavage fluid (BALF) circulation fluids, secretion fluids, biopsy, and homogenized tissue, particularly serum, urine, tear, saliva, bile, sweat, exhalation or expiration, sputum, bronchoalveolar fluid, sebum, cellular, gland, mucosa and tissue secretion. 50. The IL-18 binding molecule for use of any one of claims 1 to 21, 36 or 46 to 49 or the composition for use of any one of claims 22 to 35 or 46 to 49, or the method of any one of claims 37 to 49, wherein the therapy of the patient further comprises the use of one or more check-point inhibitor(s). 51. The IL-18 binding molecule for use of claim 50 or the composition for use of claim 50, or the method of claim 50, wherein the check-point inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.