Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma

Abstract

B-cell maturation antigen (BCMA, also termed TNFRSF17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells (PC). GSK2857916 (or J6M0-MMAF) is a BCMA-specific antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a protease-resistant linker. To evaluate the clinical potential of this agent, tumour cells from seventy multiple myeloma (MM) patients were assessed for BCMA expression by immunohistochemistry and flow cytometry. All patients tested expressed BCMA, at varying levels, and both surface and intracellular expression were observed. BCMA expression is maintained through relapse, extramedullary spread and in residual disease post therapy. BCMA levels may also be prognostically useful as higher levels of BCMA were associated with poorer outcomes, even taking into account genetic risk. We observed rapid internalization of surface BCMA and newly expressed protein by 1 h, suggesting a mechanism for J6M0-MMAF activity even with low surface antigen. J6M0-MMAF mediated cytotoxicity of MM cells varied with dose and antigen levels, with clonogenic progenitors killed at lower doses than mature cells. In comparison, J6M0-MMAF killing of primary CD138(+) myeloma cells occurred with slower kinetics. Our observations support BCMA to be a promising therapeutic target in MM for novel therapies such as J6M0-MMAF.

Effective Targeting of Multiple B-Cell Maturation Antigen–Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells

“…These investigators reported that all patient samples tested were BCMA+ and found a mean of 1,085 BCMA molecules per MM cell (range 349-4,268). 41 These values are well in the range of the reactivity of the anti-BCMA CAR T cells in this study, which it was demonstrated recognized BCMA+ cell lines that expressed as little as 222 BCMA molecules per cell (Table 1 and Fig. 4).…”

“…38,39 BCMAtargeting antibody drug conjugates (ADC), bispecific BCMA/CD3 antibodies, and BCMA-targeted CAR T cells have all been reported to have anti-MM cell reactivity. 23,26,40,41 Recently, in a study of anti-BCMA bi-specific antibodies, Lee et al used ABCbead quantitation methods to determine BCMA receptor density on 39 MM patient samples. These investigators reported that all patient samples tested were BCMA+ and found a mean of 1,085 BCMA molecules per MM cell (range 349-4,268).…”

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

“…Lee et al [25] • BM aspirates collected from pts with ND or RRMM, assessed for BCMA expression by FC…”

“…BCMA is highly expressed on malignant PCs collected from patients with MM compared with normal bone marrow mononuclear cells (BMMCs) from healthy donors, and several studies have assessed whether BCMA has value as a marker for diagnosis, prognosis, and/or as a predictor of treatment response (Table 1) [7,[23][24][25][26][27][28]. In contrast with CD138, BCMA is readily identified in delayed and frozen MM samples [22].…”

Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

“…Toward the goal of dual-antigen targeting for MM, a CAR incorporating a truncated "a proliferation-inducing ligand" (dAPRIL) as the ligand-binding domain had previously been reported to interact with both BCMA and another MM marker, the transmembrane activator and CAML interactor (TACI) 13 . However, TACI, like BCMA, exhibits heterogeneous expression in MM, and MM cells lacking expression of both antigens have been previously identified [14][15][16] . In contrast, CS1 (also known as SLAMF7 or CD319) is highly expressed on multiple types of MM and has been found on 90-97% of patient MM samples 17,18 , and an anti-CS1 CAR-T cell therapy 19 is currently being tested in the clinic (NCT03710421).…”