Redirecting T-cell Activity with Anti-BCMA/Anti-CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia and Other B-cell Lymphomas

Abstract

T-cell redirecting bispecific antibodies hold high promise for treatment of proliferation, and cytotoxicity. This was independent of the level of BCMA B-cell malignancies. B-cell maturation antigen (BCMA) exhibits high ex- expression, but generally lower in mature B-cell malignancies compared pression on normal and malignant mature B cells including plasma cells, with multiple myeloma. Despite low BCMA levels, healthy donor T cells which can be enhanced by inhibition of γ-secretase. BCMA is considered a and CLL-derived T cells induced lysis of (autologous) CLL cells upon ad-validated target in multiple myeloma but whether mature B-cell lymphomas dition of teclistamab. These data show that BCMA is expressed on various can be targeted by the BCMAxCD3 T-cell redirector teclistamab is cur- B-cell malignancies and that lymphoma cell lines and primary CLL can be rently unknown. BCMA expression on B-cell non–Hodgkin lymphoma and targeted using teclistamab. Further studies to understand the determinants primary chronic lymphocytic leukemia (CLL) cells was assessed by flow cy- of response to teclistamab are required to identify which other diseases tometry and/or IHC. To assess teclistamab efficacy, cells were treated with might be suitable for teclistamab targeting. teclistamab in presence of effector cells with/without γ-secretase inhibition. Significance:Besides reported BCMA expression on multiple myeloma, BCMA could be detected on all tested mature B-cell malignancy cell lines, we demonstrate BCMA can be detected and enhanced using γ-secretase while expression levels varied per tumor type. γ-secretase inhibition uni- inhibition on cell lines and primary material of various B-cell malignanversally increased BCMA surface expression. These data were corroborated cies. Furthermore, using CLL we demonstrate that low BCMA-expressing in primary samples from patients with Waldenstrom’s macroglobulinemia, tumors can be targeted efficiently using the BCMAxCD3 DuoBody CLL, and diffuse large B-cell lymphoma. Functional studies with the B- teclistamab. cell lymphoma cell lines revealed teclistamab-mediated T-cell activation,