BCMA CHIMERIC ANTIGEN RECEPTORS
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
1 . A polynucleotide encoding a chimeric antigen receptor (CAR) comprising: a humanized anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment thereof that binds one or more epitopes of a human BCMA polypeptide; a hinge and a transmembrane domain that reduce antigen independent cytokine release of the CAR; one or more intracellular co-stimulatory domains; and a primary signaling domain.
2 . The polynucleotide of claim 1 , wherein the humanized anti-BCMA antibody or antigen binding fragment that binds the human BCMA polypeptide;
(a) is selected from the group consisting of: a Camel Ig, Ig NAR, Fab fragments, Fab′ fragments, F(ab)′2 fragments, F(ab)′3 fragments, Fv, single chain Fv antibody (“scFv”), bis-scFv, (scFv)2, minibody, diabody, triabody, tetrabody, disulfide stabilized Fv protein (“dsFv”), a single-domain antibody (sdAb, Nanobody), preferably an scFv; and/or
b) comprises one or more CDRs as set forth in any one of SEQ ID NOs: 4-6; and/or
c) comprises one or more CDRs as set forth in any one of SEQ ID NOs: 1-3; and/or
d) comprises a variable light chain sequence as set forth in any one of SEQ ID NOs: 7-9, optionally wherein the variable light chain sequence comprises CDR sequences set forth in SEQ ID NOs: 1-3; and/or
e) comprises a variable heavy chain sequence as set forth in any one of SEQ ID NOs: 10-14, optionally wherein the variable heavy chain sequence comprises the CDR sequences set forth in SEQ ID NOs: 4-6.
3 . The polynucleotide of claim 1 , wherein the one or more co-stimulatory signaling domains are from a co-stimulatory molecule selected from the group consisting of: CARD11, CD2, CD7CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD137 (4-1BB), CD150 (CLAMF1), CD152 (CTLA-4), CD223 (LAG3), CD270 (HVEM), CD273 (PD-L2), CD274 (PD-L1), CD278 (ICOS), DAP10, LAT, NKD2C, SLP76, TRIM, and ZAP70.
4 . The polynucleotide of claim 1 , wherein the one or more co-stimulatory signaling domains are from a co-stimulatory molecule selected from the group consisting of: CD8, CD134, and CD137.
5 . The polynucleotide of claim 1 , wherein the CAR further comprises a signal peptide selected from the group consisting of: an IgG1 heavy chain signal polypeptide, a CD8α signal polypeptide, and a human GM-CSF receptor alpha signal polypeptide.
6 . The polynucleotide of claim 1 , wherein the hinge and transmembrane domain comprises a CTLA-4 hinge and transmembrane domain.
7 . The polynucleotide of claim 1 , wherein the hinge and transmembrane domain comprises a PD-1 hinge and transmembrane domain.
8 . The polynucleotide of claim 1 , wherein the polynucleotide sequence is set forth in SEQ ID NO: 70.
9 . The polynucleotide of claim 1 , wherein the polynucleotide sequence is set forth in SEQ ID NO: 72.
10 . A vector comprising the polynucleotide of claim 1 .
11 . The vector of claim 10 , wherein the vector is an expression vector, an episomal vector, a viral vector, a retroviral vector, or a lentiviral vector.
12 . The vector of claim 11 , wherein the lentiviral vector is selected from the group consisting essentially of: human immunodeficiency virus 1 (HIV-1); human immunodeficiency virus 2 (HIV-2), visna-maedi virus (VMV); caprine arthritis-encephalitis virus (CAEV); equine infectious anemia virus (EIAV); feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV).
13 . The vector of claim 11 , wherein the vector comprises a left (5′) retroviral LTR, a Psi (Ψ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a retroviral export element; a promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) retroviral LTR.
14 . An immune effector cell comprising the polynucleotide of claim 1 .
15 . The immune effector cell of claim 14 , wherein the immune effector cell is selected from the group consisting of: a T lymphocyte, a natural killer (NK) cell, and a natural killer T (NKT) cell.
16 . A composition comprising the immune effector cell of claim 14 and a physiologically acceptable excipient.
17 . A method of treating a B cell related condition in a subject in need thereof comprising administering to the subject a therapeutically effect amount of a composition comprising an immune effector cell comprising the polynucleotide of claim 1 .
18 . A chimeric antigen receptor (CAR) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 73, wherein the CAR comprises a variable light chain comprising the CDR sequences set forth in SEQ ID NOs: 1-3 and a variable heavy chain comprising the CDR sequences set forth in SEQ ID NOs: 4-6, and wherein the CDR sequences bind human B cell maturation antigen (BCMA).
19 . A method of reducing antigen-independent cytokine release by a cell comprising a a chimeric antigen receptor (CAR), wherein the CAR comprises: a humanized anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment thereof that binds one or more epitopes of a human BCMA polypeptide; a hinge and a transmembrane domain selected from (i) a CTLA-4 hinge and CTLA-4 transmembrane domain and (ii) a PD-1 hinge and PD-1 transmembrane domain; one or more intracellular co-stimulatory domains; and a primary signaling domain.
20 . The method of claim 19 , wherein the reduced antigen-independent cytokine release by the cell is relative to a cell comprising a CAR comprising a hinge and transmembrane domain that is not (i) a CTLA-4 hinge and CTLA-4 transmembrane domain or (ii) a PD-1 hinge and PD-1 transmembrane domain.