Anti-tcr antibody molecules and uses thereof

Abstract

The disclosure provides antibody molecules that bind to TCR Vβ regions and multispecific molecules comprising said antibody molecules. Additionally, disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, pharmaceutical compositions comprising aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

What is claimed is: 
     
         1 . A method of expanding T cells that expresses a T cell receptor beta variable region (TCRβV) in a T cell population, the method comprising:
 contacting the T cell population with a composition comprising a multispecific molecule, wherein the multispecific molecule comprises a first domain that binds to a first target molecule and a second domain that binds to a second target molecule, 
 wherein the first target molecule is a TCRβV and the second target molecule is a target molecule on a target cell that is different from the first target molecule, and 
 wherein the first domain contacts the TCRβV of a T cell receptor (TCR) expressed by the T cells in the T cell population, thereby expanding the T cells in the T cell population. 
 
     
     
         2 . The method of  claim 1 , wherein the T cell population is an in vivo T cell population. 
     
     
         3 . The method of  claim 1 , wherein the second domain comprises a tumor-targeting domain, a cytokine molecule, or a stromal modifying domain. 
     
     
         4 . The method of  claim 1 , wherein the multispecific molecule comprises at least two non-contiguous polypeptide chains,
 wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first member of a dimerization module, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second member of the dimerization module, wherein the first polypeptide chain and the second polypeptide chain form a complex via the first member of the dimerization module and the second member of the dimerization module.   
     
     
         5 . The method of  claim 4 , wherein the first polypeptide chain comprises the first domain and the second polypeptide chain comprises the second domain, wherein:
 (i) the first polypeptide chain comprises the first domain linked to the first member of the dimerization module, and the second polypeptide chain comprises the second domain linked to the second member of the dimerization module;   (ii) the first polypeptide chain comprises a first portion of the first domain linked to the first member of the dimerization module, and the second polypeptide chain comprises a first portion of the second domain linked to the second member of the dimerization module; wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the first domain and a fourth polypeptide chain comprising a second portion of the second domain;   (iii) the first polypeptide chain comprises a first portion of the first domain linked to the first member of the dimerization module, and the second polypeptide chain comprises the second domain linked to the second member of the dimerization module; wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the first domain; or   (iv) the first polypeptide chain comprises the first domain linked to the first member of the dimerization module, and the second polypeptide chain comprises a first portion of the second domain linked to the second member of the dimerization module; wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the second domain.   
     
     
         6 . The method of  claim 5 , wherein the multispecific molecule further comprises a linker between the first domain and the first member of the dimerization module, a linker between the second domain and the second member of the dimerization module, a linker between the first portion of the first domain and the first member of the dimerization module, a linker between the first portion of the second domain and the second member of the dimerization module, a linker between the first member of the dimerization module and the second domain, a linker between the first member of the dimerization module and the first portion of the second domain or a combination thereof, wherein the linker is selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non helical linker. 
     
     
         7 . The method of  claim 4 , wherein the first polypeptide chain comprises the first domain and the second domain, wherein the first polypeptide chain comprises:
 (i) the first domain linked to the first member of the dimerization module linked to the second domain;   (ii) a first portion of the first domain linked to the first member of the dimerization module linked to a first portion of the second domain, wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the first domain and a fourth polypeptide chain comprising a second portion of the second domain;   (iii) a first portion of the first domain linked to the first member of the dimerization module linked to the second domain, wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the first domain; or   (iv) the first domain linked to the first member of the dimerization module linked to a first portion of the second domain, wherein the at least two non-contiguous polypeptide chains comprises a third polypeptide chain comprising a second portion of the second domain.   
     
     
         8 . The method of  claim 7 , wherein the multispecific molecule further comprises a linker between the first domain and the first member of the dimerization module, a linker between the second domain and the second member of the dimerization module, a linker between the first portion of the first domain and the first member of the dimerization module, a linker between the first portion of the second domain and the second member of the dimerization module, a linker between the first member of the dimerization module and the second domain, a linker between the first member of the dimerization module and the first portion of the second domain or a combination thereof,
 wherein the linker is selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non helical linker.   
     
     
         9 . The method of  claim 1 , wherein the multispecific molecule comprises a polypeptide sequence comprising:
 (i) the first domain linked to the second domain;   (ii) a first portion of the first domain linked to a first portion of the second domain, wherein the polypeptide sequence further comprises a second portion of the first domain and a second portion of the second domain;   (iii) a first portion of the first domain linked to the second domain, wherein the polypeptide sequence further comprises a second portion of the first domain; or   (iv) the first domain linked to a first portion of the second domain, wherein the polypeptide sequence further comprises a second portion of the second domain.   
     
     
         10 . The method of  claim 9 , wherein the polypeptide sequence further comprises a linker between the first domain and the second domain, a linker between the first portion of the first domain and the first portion of the second domain, a linker between the first portion of the first domain and the second domain, a linker between the first domain and the first portion of the second domain, or a combination thereof,
 wherein the linker is selected from a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.   
     
     
         11 . The method of  claim 1 , wherein the TCRβV is TCRβV1, TCRβV2, TCRβV3, TCRβV4, TCRβV5, TCRβV6, TCRβV7, TCRβV8, TCRβV9, TCRβV10, TCRβV11, TCRβV12, TCRβV19, TCRβV20, TCRβV21, TCRβV23, TCRβV24, TCRβV25, TCRβV26, TCRβV27, TCRβV28, TCRβV29 or TCRβV30. 
     
     
         12 . The method of  claim 1 , wherein the TCRβV is TCRβV2, TCRβV4-1, TCRβV4-2, TCRβV5-1, TCRβV5-5, TCRβV5-6, TCRβV6, TCRβV6-5, TCRβV6-6, TCRβV6-9, TCRβV7-2, TCRβV7-3, TCRβV7-8, TCRβV7-9, TCRβV9, TCRβV10-1, TCRβV10-2, TCRβV10-3, TCRβV11-2, TCRβV12-3, TCRβV12-4, TCRβV12-5, TCRβV19, TCRβV20-1, TCRβV21, TCRβV24-1, TCRβV25-1 or TCRβV28. 
     
     
         13 . The method of  claim 1 , wherein the TCRβV is TCRβV2, TCRβV3-1, TCRβV4-1, TCRβV4-2, TCRβ3V5-1, TCRβV5-4, TCRβV5-5, TCRβV5-6, TCRβV6-1, TCRβV6-5, TCRβV6-6, TCRβV7-3, TCRβV7-6, TCRβV7-8, TCRβV9, TCRβV11-2, TCRβV19, TCRβV20-1, TCRβV24-1, TCRβV27, TCRβV28, TCRβV29-1 or TCRβV30. 
     
     
         14 . The method of  claim 1 , wherein second target molecule is selected from the group consisting of BCMA, FcRH5, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD99, CD123, FcRH5, CLEC12, CD179A, SLAMF7, or NY-ESO1, PDL1, CD47, gangloside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2/neu, Telomerase, SAP-1, Survivin, NY-ESO-1/LAGE-1, PRAME, SSX-2, Melan-A/MART-1, Gp100/pme117, Tyrosinase, TRP-1/-2, MC1R, b-catenin, BRCA1/2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, b-catenin, CDK4, CDC27, a actinin-4, TRP1/gp75, TRP2, gp100, Melan-A/MART1, gangliosides, WT1, EphA3, Epidermal growth factor receptor (EGFR), MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, Folate receptor alpha, L1-CAM, CAIX, gpA33, GD3, GM2, VEGFR, Intergrin, a carbohydrates, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C and tenascin W. 
     
     
         15 . The method of  claim 1 , wherein the second domain is an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. 
     
     
         16 . The method of  claim 15 , wherein the second domain is a T cell engager and wherein the second target molecule is a TCRβV other than the TCRβV to which the first domain binds. 
     
     
         17 . The method of  claim 15 , wherein the second target molecule is not a TCRβV. 
     
     
         18 . The method of  claim 15 , wherein the second target molecule is CD19. 
     
     
         19 . The method of  claim 15 , wherein the second target molecule is CD3. 
     
     
         20 . The method of  claim 15 , wherein the second target molecule is CD123. 
     
     
         21 . The method of  claim 3 , wherein the second domain comprises a tumor-targeting domain and the second target molecule is a cancer antigen. 
     
     
         22 . The method of  claim 21 , wherein the cancer antigen is a hematological cancer antigen, a solid tumor antigen, a metastatic cancer antigen, a soft tissue tumor antigen, a cancer antigen of a metastatic lesion or a stromal antigen. 
     
     
         23 . The method of  claim 22 , wherein the cancer antigen is:
 (i) the solid tumor antigen, wherein the solid tumor is pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, or liver cancer; or   (ii) the hematological cancer antigen, wherein the hematological cancer is a B-cell malignancy or a T cell malignancy.   
     
     
         24 . The method of  claim 22 , wherein the cancer antigen is the hematological cancer antigen and the B-cell malignancy or the T cell malignancy is Hodgkin's lymphoma, Non-Hodgkin's lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, or acute lymphocytic leukemia. 
     
     
         25 . The method of  claim 23 , wherein the cancer antigen is the hematological cancer antigen and the B-cell malignancy is Hodgkin's lymphoma, wherein the Non-Hodgkin's lymphoma is B cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, or hairy cell leukemia. 
     
     
         26 . The method of  claim 3 , wherein the second domain comprises a cytokine molecule selected from the group consisting of interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), interferon gamma and functional fragments or variants thereof. 
     
     
         27 . The method of  claim 1 , wherein binding of the first domain to the TCRβV and binding of the second molecule to the target molecule promotes the T cells to kill cancer cells. 
     
     
         28 . The method of  claim 1 , wherein the target cell is a T cell. 
     
     
         29 . The method of  claim 1 , wherein the target cell is a non-cancer cell. 
     
     
         30 . The method of  claim 1 , wherein the method expands T cells in vivo.