CD79A chimeric antigen receptors
The invention provides improved compositions for adoptive cell therapies for cancers that express CD79A.
1. A chimeric antigen receptor (CAR) comprising:
a) an extracellular domain that comprises an anti-CD79A antibody or antigen binding fragment thereof that binds one or more epitopes of a human CD79A polypeptide, wherein the anti-CD79A antibody or antigen binding fragment thereof comprises a variable light chain sequence comprising complementarity-determining region (CDR) sequences CDRL1-CDRL3 set forth in SEQ ID NOs: 1-3, 9-11, or 17-19, and a variable heavy chain sequence comprising CDRH1-CDRH3 sequences set forth in SEQ ID NOs: 4-6, 12-14, or 20-22;
b) a transmembrane domain;
c) one or more intracellular co-stimulatory signaling domains; and
d) a primary signaling domain.
2. The CAR of claim 1 , wherein the anti-CD79A antibody or antigen binding fragment thereof that binds the human CD79A polypeptide is selected from the group consisting of: a Fab′ fragment, a F(ab′) 2 fragment, a bispecific Fab dimer (Fab2), a trispecific Fab trimer (Fab3), an Fv, an single chain Fv protein (“scFv”), a bis-scFv, (scFv) 2 , a minibody, a diabody, a triabody, a tetrabody, and a disulfide stabilized Fv protein (“dsFv”).
3. The CAR of claim 1 , wherein the anti-CD79A antibody or antigen binding fragment thereof that binds the human CD79A polypeptide is an scFv.
4. The CAR of claim 1 , wherein the anti-CD79A antibody or antigen binding fragment thereof comprises a variable light chain sequence as set forth in SEQ ID NO: 7, 15, or 23 and/or a variable heavy chain sequence as set forth in SEQ ID NO: 8, 16, or 24.
5. The CAR of claim 1 , wherein the transmembrane domain is:
a) isolated from a polypeptide selected from the group consisting of: alpha or beta chain of the T-cell receptor, CD3δ, CD3ε, CD3γ, CD3ζ, CD4, CD5, CD8a, CD9, CD16, CD22, CD27, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, CD152, CD154, and PD1;
b) isolated from a polypeptide selected from the group consisting of: CD8a, CD28, CD4, CD45, PD1, and CD152; or
c) isolated from CD8α.
6. The CAR of claim 1 , wherein the one or more intracellular co-stimulatory signaling domains:
a) are isolated from a co-stimulatory molecule selected from the group consisting of: TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD137 (4-1BB), CD278 (ICOS), DAP10, LAT, NKD2C, SLP76, TRIM, and ZAP70;
b) are isolated from a co-stimulatory molecule selected from the group consisting of: CD28, CD134, and CD137; or
c) is isolated from CD137.
7. The CAR of claim 1 , wherein the primary signaling domain is:
a) isolated from a polypeptide selected from the group consisting of: FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD3ζ, CD22, CD79a, CD79b, and CD66d; or
b) isolated from a CD3ζ.
8. The CAR of claim 1 , further comprising a hinge region polypeptide.
9. The CAR of claim 8 , wherein the hinge region polypeptide comprises a hinge region of CD8α.
10. A polypeptide comprising the CAR of claim 1 , wherein the polypeptide further comprises a signal peptide.
11. The CAR of claim 1 , comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 25 to 30.
12. A polynucleotide encoding a CAR of claim 1 or the sequence set forth in any one of SEQ ID NOs: 31-36.
13. A vector comprising the polynucleotide of claim 12 .
14. An immune effector cell comprising the vector of claim 13 .
15. A composition comprising the immune effector cell of claim 14 and a physiologically acceptable excipient.
16. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effect amount of the composition of claim 15 .
17. The method of claim 16 , wherein the cancer is a hematological malignancy.
18. The method of claim 16 , wherein the cancer is non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), multiple myeloma (MM), acute myeloid leukemia (AML), or chronic myeloid leukemia (CML).
19. The method of claim 18 , wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma, small lymphocytic lymphoma (SLL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).
20. The method of claim 18 , wherein the non-Hodgkin's lymphoma is diffuse large B cell lymphoma (DLBCL).