Chimeric antigen receptors against multiple HLA-G isoforms
The present invention relates to chimeric antigen receptors (CAR) against multiple but not all human leukocyte antigen (HLA-G) isoforms. More specifically, the invention concerns CARs that are specific for HLA-G β2M-free or β2M-associated immunosuppressive isoforms respectively.
1. A cell comprising 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 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
(ii) 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;
(b) a CD28 transmembrane domain; and
(c) an intracellular domain comprising a 4-1BB costimulatory signaling region and a CD3 zeta endodomain.
2. The cell of claim 1 , wherein the cell is a T cell, a B cell, a NK cell, a NKT cell, a monocyte cell or a dendritic cell.
3. The cell of claim 1 , wherein the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
4. The cell of claim 1 , wherein the antigen binding domain is a scFv.
5. The cell of claim 1 , wherein the antigen binding domain comprises SEQ ID NO: 31.
6. The cell of claim 1 , wherein the CAR further comprises a human IgG4 hinge domain connecting the antigen binding domain to the transmembrane domain.
7. The cell of claim 1 , wherein the CAR comprises SEQ ID NO:
32, SEQ ID NO: 33, or SEQ ID NO: 34.
8. The cell of claim 1 ,
wherein the CD28 transmembrane domain comprises SEQ ID NO: 20,
wherein the 4-1BB costimulatory signaling region comprises SEQ ID NO: 21, and
wherein the CD3 zeta endodomain comprises SEQ ID NO: 22.
9. The cell of claim 1 , wherein the intracellular domain further comprises a CD28 costimulatory domain.