Peptidic chimeric antigen receptor t cell switches and uses thereof

Abstract

Disclosed herein are chimeric antigen receptor effector cells (CAR-ECs) and CAR-EC switches. The switchable CAR-ECs are generally T cells. The one or more chimeric antigen receptors may recognize a peptidic antigen on the CAR-EC switch. The CAR-ECs and switches may be used for the treatment of a condition in a subject in need thereof.

1 . A chimeric antigen receptor-effector cell switch comprising:
 a. a peptidic antigen that binds a chimeric antigen receptor on an effector cell; and   b. a targeting moiety that binds a cell surface molecule on a target cell.   
     
     
         2 .- 62 . (canceled) 
     
     
         63 . A method of treating a cancer in a subject comprising:
 a. administering to the subject a first chimeric antigen receptor-effector cell (CAR-EC) switch to a subject, wherein the first CAR-EC switch comprises:
 a. a first peptidic antigen that binds a chimeric antigen receptor on an effector cell; and 
 b. a first targeting moiety that binds a cell surface molecule on a target cell; and 
   b. administering a first chimeric antigen receptor-effector cell comprising a chimeric antigen receptor that binds to the peptidic antigen of the chimeric antigen receptor-effector cell switch.   
     
     
         64 . The method of  claim 63 , wherein the binding of the first peptidic antigen on the first CAR-EC switch to the first chimeric antigen receptor on an effector cell and the binding of the first targeting moiety on the first CAR-EC switch to the cell surface molecule on the target cell induces a CAR-EC-mediated immune response that is cytotoxic to the target cell. 
     
     
         65 . The method of  claim 63 , wherein the first CAR-EC switch comprises two peptidic antigens. 
     
     
         66 . The method of  claim 63 , wherein the first targeting moiety comprises a targeting peptide, an antibody, or an antigen binding fragment of an antibody. 
     
     
         67 . The method of  claim 66 , wherein the antibody or the antigen binding fragment of the antibody is selected from the group consisting of: an immunoglobulin, an Fc null immunoglobulin, a Fab, and antigen binding fragments thereof. 
     
     
         68 . The method of  claim 66 , wherein the first targeting moiety is selected from the group consisting of: an anti-EGFR antibody, an anti-Her2 antibody, an anti-EGFRvIII antibody, an anti-CD33 antibody, an anti-CLL-1 antibody, an anti-CEA antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-BCMA antibody, and an anti-CS1 antibody, and antigen binding fragments thereof. 
     
     
         69 . The method of  claim 67 , wherein the first targeting moiety is an anti-CD19 antibody or an antigen binding fragments thereof. 
     
     
         70 . The method of  claim 66 , wherein the first targeting antibody or the antigen binding fragment of the antibody comprises a light chain and a heavy chain pair, wherein the light chain and heavy chain are encoded by nucleic acid sequences comprising nucleic acid sequence pairs selected from the group consisting of: SEQ ID NOs: 8 and 9; SEQ ID NOs: 8 and 10; SEQ ID NOs: 11 and 12; SEQ ID NOs. 13 and 14; SEQ ID NOs: 15 and 16; SEQ ID NOs: 17 and 18; and SEQ ID NOs: 19 and 20. 
     
     
         71 . The method of  claim 66 , wherein the first targeting antibody or the antigen binding fragment of the antibody comprises a light chain and a heavy chain pair, wherein the light chain and heavy chain comprise amino acid sequence pairs selected from the group consisting of: SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs. 25 and 26; SEQ ID NOs: 27 and 28; SEQ ID NOs: 27 and 29; SEQ ID NOs: 30 and 29; SEQ ID NOs: 36 and 29; SEQ ID NOs: 31 and 28; SEQ ID NOs: 27 and 32; SEQ ID NOs: 27 and 33; SEQ ID NOs: 27 and 34; and SEQ ID NOs: 27 and 35. 
     
     
         72 . The method of  claim 66 , wherein the first peptidic antigen is fused to a region of the targeting antibody or antigen binding fragment of the antibody selected from the group consisting of: (i) an N terminus of a light chain; (ii) an N terminus of a heavy chain; (iii) both an N terminus of a light chain and an N terminus of a heavy chain; (iv) an N terminus of a VL domain of an IgG; (v) an N terminus of a VH domain of an IgG; (vi) an N terminus of a VL domain of a Fab; (vii) an N terminus of a VH domain of a Fab; (viii) an N terminus of a VL domain and a VH domain of an IgG; (ix) and an N terminus of a VL domain and a VH domain of a Fab. 
     
     
         73 . The method of  claim 69 , wherein the first peptidic antigen is fused to a region of the targeting antibody or antigen binding fragment of the antibody selected from the group consisting of: (i) an N terminus of a light chain; (ii) an N terminus of a heavy chain; (iii) both an N terminus of a light chain and an N terminus of a heavy chain; (iv) an N terminus of a VL domain of an IgG; (v) an N terminus of a VH domain of an IgG; (vi) an N terminus of a VL domain of a Fab; (vii) an N terminus of a VH domain of a Fab; (viii) an N terminus of a VL domain and a VH domain of an IgG; (ix) and an N terminus of a VL domain and a VH domain of a Fab. 
     
     
         74 . The method of  claim 63 , wherein the first CAR-EC switch comprises a linker that links the peptidic antigen and the targeting moiety. (New) The method of  claim 74  wherein (i) the linker comprises about 1 to about 20 amino acids; (ii) the linker comprises a sequence selected from SEQ ID NOs: 38-42; or (iii) the linker comprises about 1 to about 20 amino acids and the linker comprises a sequence selected from SEQ ID NOs: 38-42. 
     
     
         76 . The method of  claim 63 , wherein the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, pancreatic cancer, lung cancer, glioma, and glioblastoma. 
     
     
         77 . The method of  claim 63 , wherein the cell surface molecule is selected from the group consisting of: a tumor associated antigen; a cluster of differentiation protein; a receptor; an integral membrane protein and a glycoprotein. (New) The method of  claim 63 , wherein the first peptidic antigen comprises a length of between about 2 and about 10, about 10 and about 20, about 20 and about 30, about 30 and about 40, about 40 and about 50, about 50 and about 60, about 60 and about 70, about 70 and about 80, about 80 and about 90 amino acids, or about 2 and about 90 amino acids. 
     
     
         79 . The method of  claim 63 , further comprising administering one or more second CAR-EC switch to the subject, each second CAR-EC switch comprising:
 a. a peptidic antigen that binds a chimeric antigen receptor on an effector cell; and   b. a second targeting moiety that binds a cell surface molecule on a target cell;   wherein the second targeting moiety of each second CAR-EC switch differs from the first targeting moiety comprised on the first CAR-EC switch; and   wherein the peptidic antigen comprised on the second CAR-EC switch is optionally   (i) the same as the first peptidic antigen comprised on the first CAR-EC switch or   (ii) a second peptidic antigen that differs from the first peptidic antigen comprised on the first CAR-EC switch;   provided that if the second CAR-EC switch comprises a second peptidic antigen, the method further comprises administering a second chimeric antigen receptor-effector cell comprising a chimeric antigen receptor that binds to the second peptidic antigen of the second CAR-EC switch.   
     
     
         80 . The method of  claim 79 , wherein
 (i) the first targeting moiety comprises an anti-CD20 antibody or an antigen binding portion thereof and the second targeting moiety comprises an anti-CD19 antibody or an antigen binding portion thereof; or   (ii) the first targeting moiety comprises an anti-CD19 antibody or an antigen binding portion thereof and the second targeting moiety comprises an anti-CD20 antibody or an antigen binding portion thereof.   
     
     
         81 . The method of  claim 79 , wherein the second CAR-EC switch is administered to the subject after the first CAR-EC switch.