Chimeric antigen receptor
The present invention provides a chimeric antigen receptor (CAR) which binds a low density target antigen, which comprises a Fab antigen binding domain. The invention also relates to cells expressing such a CAR and their use in the treatment of disease.
1. A chimeric antigen receptor (CAR) which binds B cell maturation antigen (BCMA), wherein the CAR comprises a Fab antigen binding domain comprising the VH domain of SEQ ID NO: 29 and the VL domain of SEQ ID NO: 30.
2. A nucleic acid sequence which encodes a CAR according to claim 1 .
3. A nucleic acid construct which encodes a CAR according to claim 1 and has one of the following general structures:
VH-CH-spacer-TM-endo-coexpr-VL-CL;
VL-CL-coexpr-VH-CH-spacer-TM-endo;
VL-CL-spacer-TM-endo-coexpr-VH-CH; or
VH-CH-coexpr-VL-CL-spacer-TM-endo;
in which:
VH is a nucleic acid sequence encoding a heavy chain variable region;
CH is a nucleic acid sequence encoding a heavy chain constant region
spacer is a nucleic acid encoding a spacer;
TM is a nucleic acid sequence encoding a transmembrane domain;
endo is a nucleic acid sequence encoding an endodomain;
coexpr is a nucleic acid sequence enabling co-expression of the first and second polypeptides;
VL is a nucleic acid sequence encoding a light chain variable region; and
CL is a nucleic acid sequence encoding a light chain constant region.
4. A nucleic acid construct according to claim 3 which also encodes a second chimeric antigen receptor having a domain antibody (dAb), scFv or Fab antigen binding domain.
5. A nucleic acid construct according to claim 4 , wherein the second chimeric antigen receptor binds one of the following antigens: CD19, FcRL5 and TACI.
6. A vector which comprises a nucleic acid sequence according to claim 2 .
7. A cytolytic immune cell which expresses a CAR according to claim 1 .
8. A cytolytic immune cell which expresses a first CAR according to claim 1 , and a second CAR which binds one of the following antigens: CD19, FcRL5 and TACI.
9. A cell according to claim 7 , which also expresses a constitutively active cytokine receptor.
10. A method for making a cell according to claim 7 , which comprises the step of introducing a nucleic acid which expresses the CAR into a cell ex vivo.
11. A pharmaceutical composition which comprises a plurality of cells according to claim 7 , together with a pharmaceutically acceptable carrier, diluent or excipient.
12. A method for treating cancer which comprises the step of administering a pharmaceutical composition according to claim 11 to a subject.
13. A method according to claim 12 , wherein the cancer is multiple myeloma.
14. A method for making a cell according to claim 8 , which comprises the step of introducing into a cell ex vivo: (a) a first nucleic acid which expresses the first CAR and a second nucleic acid which expresses the second CAR, or (b) a nucleic acid which expresses both the first and the second CARs.