BACKGROUND

Multiple myeloma (MM) is an incurable plasma cell malignancy with significant morbidity and mortality. While proteasome inhibitors and immunomodulatory agents have improved rate and depth of responses, most patients will eventually relapse. Accordingly, there is an urgent medical need for more effective therapeutic strategies capable of eradicating minimal residual disease. Chimeric antigen receptors (CARs) combine an antibody domain directed against a surface antigen with signaling domains that induce T cell activation. CD229, a member of the SLAM (signaling lymphocyte activation molecule) family of proteins, is strongly expressed on both MM cell lines and primary MM cells, including chemotherapy-resistant CD19-138-pre-plasma cells. CD229 is physiologically expressed on T and B lymphocytes and natural killer (NK) cells but absent from myeloid cells, hematopoietic stem cells, and nonhematopoietic cells. Thus, a CD229-specific CAR T cell can be used to target MM cells.

BRIEF SUMMARY

Disclosed are chimeric antigen receptor (CAR) polypeptides comprising a CD229 antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

Disclosed are nucleic acid sequences capable of encoding a CAR polypeptide comprising a CD229 antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

Disclosed are antibodies or fragments thereof that bind to human CD229, wherein said antibody comprises a variable heavy chain comprising a sequence having at least 90% identity to a sequence set forth in SEQ ID NOs:16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; a variable light chain comprising a sequence having at least 90% identity to a sequence set forth in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45; or both.

Disclosed are nucleic acid sequences comprising a variable heavy chain comprising a sequence having at least 90% identity to a sequence set forth in SEQ ID NOs: 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, or 148; a variable light chain comprising a sequence having at least 90% identity a sequence set forth in SEQ ID NOs:149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, or 163; or both.

Disclosed are methods of treating multiple myeloma comprising administering an effective amount of a T cell genetically modified to express a CAR polypeptide comprising a CD229 antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

Disclosed are methods of detecting CD229 on a cell comprising administering a composition comprising an antibody or fragment thereof comprising a variable heavy chain comprising a sequence having at least 90% identity to a sequence set forth in SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; a variable light chain comprising a sequence having at least 90% identity to a sequence set forth in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45; or both to a sample and detecting the binding of the antibody or fragment thereof to CD229.

Disclosed are methods of killing CD229 positive cells comprising administering an effective amount of a T cell genetically modified to express a CAR polypeptide comprising a CD229 antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

Disclosed are methods of activating a T cell expressing a CAR polypeptide comprising a CD229 antigen binding domain, a transmembrane domain, and an intracellular signaling domain comprising culturing the T cell with a cell expressing CD229 and detecting the presence or absence of IFN-γ after culturing, wherein the presence of IFN-γ indicates the activation of the T cell.

Additional advantages of the disclosed method and compositions will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice of the disclosed method and compositions. The advantages of the disclosed method and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

