Bcma binding molecules and methods of use thereof

Abstract

The invention provides antibodies, antigen binding fragments thereof, chimeric antigen receptors (CARs), and engineered T cell receptors, polynucleotides encoding the same, and in vitro cells comprising the same. The polynucleotides, polypeptides, and in vitro cells described herein can be used in an engineered CAR T cell therapy for the treatment of a patient suffering from a cancer. In one embodiment, the polynucleotides, polypeptides, and in vitro cells described herein can be used for the treatment of multiple myeloma.

What is claimed is: 
     
         1 . A polypeptide comprising an antigen binding molecule that specifically binds to B-cell maturation antigen (BCMA), wherein the antigen binding molecule comprises a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 399; a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 400; a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 401; a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 404; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 405; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 406. 
     
     
         2 . The polypeptide of  claim 1 , wherein the antigen binding molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 398; and a VL comprising the amino acid sequence of SEQ ID NO: 403. 
     
     
         3 . The polypeptide of  claim 1 , wherein the antigen binding molecule is selected from the group consisting of scFv, Fab, Fab′, Fv, F(ab′)2, and any combination thereof. 
     
     
         4 . The polypeptide of  claim 3 , wherein the antigen binding molecule comprises an scFv and the VH and the VL are connected by a linker. 
     
     
         5 . The polypeptide of  claim 4 , wherein the linker comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 174. 
     
     
         6 . The polypeptide of  claim 1 , wherein the polypeptide is a chimeric antigen receptor (CAR) or a T cell receptor (TCR). 
     
     
         7 . The polypeptide of  claim 6 , wherein the CAR or TCR further comprises a transmembrane domain. 
     
     
         8 . The polypeptide of  claim 7 , wherein the transmembrane domain is a transmembrane domain of CD28, 4-1BB, CD8 alpha, CD4, CD19, CD3 epsilon, CD45, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, an alpha chain of a T cell receptor, a beta chain of a T cell receptor, a zeta chain of a T cell receptor, or any combination thereof. 
     
     
         9 . The polypeptide of  claim 7 , wherein the CAR further comprises a hinge region between the transmembrane domain and the antigen binding molecule, wherein the hinge region is of IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, CD28, or CD8 alpha. 
     
     
         10 . The polypeptide of  claim 6 , wherein the CAR or TCR further comprises a costimulatory region, wherein the costimulatory region is a signaling region of CD28, OX-40, 4-1BB, CD2, CD7, CD27, CD30, CD40, PD-1, ICOS, LFA-1, CD11α, CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276, LIGHT, NKG2C, Ig alpha, DAP-10, Fc gamma receptor, MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules, activating NK cell receptors, BTLA, a Toll ligand receptor, B7-H3, CDS, GITR, BAFFR, HVEM, KIRDS2, SLAMF7, NKp80, NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, TNFR2, TRANCE, DNAM1, SLAMF4, CD84, CD96, CEACAM1, CRTAM, Ly9, CD160, PSGL1, CD100, CD69, SLAMF6, SLAM, BLAME, SELPLG, LTBR, LAT, GADS, SLP-76, PAG, CD19a, a ligand that specifically binds with CD83, or any combination thereof. 
     
     
         11 . The polypeptide of  claim 6 , wherein the CAR or TCR further comprises an activation domain. 
     
     
         12 . The polypeptide of  claim 11 , wherein the activation domain is a CD3 zeta domain. 
     
     
         13 . One or more polynucleotide(s) encoding the polypeptide of  claim 1 . 
     
     
         14 . A cell comprising the polypeptide(s) of  claim 13 . 
     
     
         15 . The cell of  claim 14 , which is a tumor-infiltrating lymphocyte (TIL), autologous T cell, engineered autologous T cell (eACT), or an allogeneic T cell. 
     
     
         16 . A composition comprising the cell of  claim 14  and a carrier. 
     
     
         17 . A method of preparing a transduced cell, comprising introducing the one or more polynucleotide(s) of  claim 13  into a cell. 
     
     
         18 . A method for inducing immunity against a tumor in a subject in need thereof, comprising administering to the subject the polypeptide of  claim 1  or a cell expressing the polypeptide. 
     
     
         19 . A method for treating a cancer in a subject in need thereof, comprising administering to the subject the polypeptide of  claim 1  or a cell expressing the polypeptide. 
     
     
         20 . The method of  claim 19 , wherein the cancer is multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell lymphoma, one or more of B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CIVIL), 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, myelodysplasia and myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliferative disorder, asymptomatic myeloma, smoldering multiple myeloma, indolent myeloma, monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas, plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, multiple plasmacytoma, systemic amyloid light chain amyloidosis, POEMS syndrome, or a combination thereof.