Chimeric antigen receptors against multiple HLA-G isoforms

1. An anti-human leukocyte antigen G (HLA-G) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises:

(a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 5, a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 7; and

(b) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 8, a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 9 and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 10.

2. The antibody or antigen-binding fragment of claim 1 , wherein the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.

3. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment is humanized or chimeric.

4. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment is conjugated to a toxic agent.

5. The antigen-binding fragment of claim 1 , wherein the antigen-binding fragment is a scFv, a Fv, a Fab, a Fab′, or a F(ab′) 2 .

6. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 , and a pharmaceutically acceptable carrier.

7. A chimeric antigen receptor (CAR) comprising:

(a) an extracellular domain comprising an antigen binding domain that specifically binds to HLA-G, wherein the antigen binding domain comprises:

(i) a VH comprising a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 5, a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 7; and

(ii) a VL comprising a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 8, a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 9 and a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 10;

(b) a transmembrane domain; and

(c) an intracellular signaling domain.

8. The CAR of claim 7 , wherein the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.

9. The CAR of claim 7 , wherein the antigen binding domain is a scFv.

10. The CAR of claim 9 , wherein the antigen binding domain comprises SEQ ID NO: 31.

11. The CAR of claim 7 , wherein the transmembrane domain is a CD28 transmembrane domain; and wherein the intracellular signaling domain comprises a 4-1BB costimulatory signaling region and a CD3 zeta endodomain.

12. The CAR of claim 11 , wherein:

the CD28 transmembrane domain comprises SEQ ID NO: 20,

the 4-1BB costimulatory signaling region comprises SEQ ID NO: 21, and

the CD3 zeta endodomain comprises SEQ ID NO: 22.

13. The CAR of claim 11 , wherein the intracellular signaling domain further comprises a CD28 costimulatory domain.

14. The CAR of claim 7 , further comprising a hinge domain connecting the antigen binding domain to the transmembrane domain.

15. The CAR of claim 14 , wherein the hinge domain is (i) a human IgG4 hinge domain, (ii) a human IgG4 hinge domain and a CH3 human IgG4 domain, (iii) a mutated CH2 human IgG4 domain, a human IgG4 hinge domain and a CH3 human IgG4 hinge domain, (iv) a CD28 hinge or (v) a CD8a hinge domain.

16. The CAR of claim 7 , wherein the CAR comprises SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 or SEQ ID NO: 85.

17. A pharmaceutical composition comprising a cell comprising the CAR of claim 7 , and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , wherein the cell is a T cell, a B cell, a NK cell, a NKT cell, a monocyte cell or a dendritic cell.

19. A nucleic acid molecule encoding the CAR of claim 7 .

20. An expression vector comprising the nucleic acid molecule of claim 19 .