Introduction/Rationale: Chimeric antigen receptor (CAR) T cells targeting autoreactive memory B cells show promise in autoimmune disease, but long-lived plasma cells may also drive pathology. To achieve a more durable immune reset, we designed a novel OR-gated CAR T cell that utilizes a single chain variable fragment (scFv) targeting both memory B and plasma cells.
Methods: Antigen profiling of healthy donor blood and bone marrow samples identified B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI) as B cell restricted targets with low risk of target related toxicity. Despite low sequence homology, the extracellular domains of BCMA and TACI share structural similarity in their ligand-binding domains, enabling the development of cross-reactive antibodies.
Results: An antibody display library panned with TACI protein yielded antibodies binding to TACI or BCMA with varying affinities. CAR T cells engineered from select antibodies exhibit robust cytolytic function, proliferation, and cytokine production in response to BCMA- or TACI-expressing cell lines in vitro. BCMA/TACI CAR T cells effectively control a plasma-cell derived tumor cell line expressing both antigens in vivo. Furthermore, we demonstrate B cell depletion by BCMA/TACI CAR T cells using autoimmune patient samples.
Conclusion: In summary, we have generated potent CAR T cells expressing a novel, single scFv recognizing both BCMA and TACI that can be utilized to target plasma and memory B cells more widely for treatment of autoimmune diseases.
