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