BCMA-TARGETED CHIMERIC ANTIGEN RECEPTORS
The present disclosure provides BCMA-targeted chimeric antigen receptors (CARs) as well as preparation methods and applications thereof. The CARs of the present disclosure targets BCMA-positive cells, and can be used for treating BCMA-positive B-cell lymphoma, multiple myeloma and plasma cell leukemia.
1 . A chimeric antigen receptor (CAR), comprising: an anti-BCMA antigen-binding region which comprises a light chain variable region (V L ) and a heavy chain variable region (V H ), V L comprising three complementarity determining regions (CDRs), LCDR1, LCDR2 and LCDR3, V H comprising three CDRs, HCDR1, HCDR2 and HCDR3,
(a) wherein LCDR1, LCDR2 and LCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, respectively, wherein HCDR1, HCDR2 and HCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, respectively;
(b) wherein LCDR1, LCDR2 and LCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, respectively, wherein HCDR1, HCDR2 and HCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, respectively; or
(c) wherein LCDR1, LCDR2 and LCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, respectively, wherein HCDR1, HCDR2 and HCDR3 have amino acid sequences about 80% to about 100% identical to the amino acid sequences set forth in SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, respectively.
2 . The CAR of claim 1 , wherein V L is located at the N-terminus of V H .
3 . The CAR of claim 1 , wherein V L and V H have amino acid sequences about 80% to about 100% identical to amino acid sequences set forth in (a) SEQ ID NO: 1 and SEQ ID NO: 2, respectively; (a) SEQ ID NO: 3 and SEQ ID NO: 4, respectively; or (a) SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
4 . The CAR of claim 1 , wherein the anti-BCMA antigen-binding region is a single-chain variable fragment (scFv) that specifically binds BCMA.
5 . The CAR of claim 1 , wherein the CAR further comprises one or more of the following:
(a) a signal peptide,
(b) a hinge region,
(c) a transmembrane domain,
(d) a co-stimulatory region, and
(e) a cytoplasmic signaling domain.
6 . The CAR of claim 5 , wherein the co-stimulatory region comprises a co-stimulatory region of 4-1BB (CD137), CD28, OX40, CD2, CD7, CD27, CD30, CD40, CD70, CD134, PD1, Dap10, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), NKG2D, GITR, TLR2, or combinations thereof.
7 . The CAR of claim 5 , wherein the cytoplasmic signaling domain comprises a cytoplasmic signaling domain of CD3 ζ.
8 . The CAR of claim 5 , wherein the hinge region comprises a hinge region of CD8, CD28, CD137, Ig4, or combinations thereof.
9 . The CAR of claim 5 , wherein the transmembrane domain comprises a transmembrane domain of CD8, CD28, CD3c, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, or combinations thereof.
10 . An immune cell expressing the CAR of claim 1 .
11 . The immune cell of claim 10 , wherein the immune cell is a T cell or a natural killer (NK) cell.
12 . A nucleic acid encoding the CAR of claim 1 .
13 . A vector comprising the nucleic acid of claim 12 .
14 . A method of treating cancer, the method comprising administering the immune cell of claim 10 to a subject in need thereof.
15 . The method of claim 14 , wherein the cancer is a hematologic cancer.
16 . The method of claim 14 , wherein the cancer is a plasma-cell malignancy.
17 . The method of claim 14 , wherein the cancer is a BCMA-positive malignancy.
18 . The method of claim 14 , wherein the cancer is multiple myeloma (MM), or plasma cell leukemia.
19 . The method of claim 14 , wherein the immune cell is administered by infusion, injection, transfusion, implantation, and/or transplantation.
20 . The method of claim 14 , wherein the immune cell is administered intravenously, subcutaneously, intradermally, intranodally, intratumorally, intramedullary, intramuscularly, or intraperitoneally.
21 . (canceled)
22 . The method of claim 14 , wherein the immune cell is allogeneic or autologous.
23 . The method of claim 14 , wherein the subject is a human.
24 - 33 . (canceled)
34 . The CAR of claim 1 , comprising an amino acid sequence about 80% to about 100% identical to the amino acid sequence set forth in SEQ ID NO: 59, SEQ ID NO: 61, or SEQ ID NO: 63.