Targeting BCMA with Fc-Optimized ADC: A Promising Therapeutic Approach for Multiple Myeloma

The study explores the anti-cancer potential of an antibody-drug conjugate (ADC) named J6M0-mcMMAF (GSK2857916), which targets the B cell maturation antigen (BCMA) found on cancerous plasma cells in multiple myeloma (MM). This humanized ADC, connected by an unbreakable link and lacking fucose, was found to bind to all CD138-expressing MM cell lines and patient cells, indicating BCMA's universal presence on myeloma cells. The expression of BCMA mRNA was notably higher in CD138+ cells from MM patients compared to healthy individuals. J6M0-mcMMAF was effective in inhibiting cell growth and triggering apoptosis in both drug-sensitive and resistant MM cell lines and patient cells, while an isotype control ADC had no impact on MM cell viability.

The ADC specifically targeted CD138-positive patient MM cells without affecting CD138-negative cells, thus minimizing damage to nearby BCMA-negative cells. It also completely stopped the formation of MM cell colonies by inducing cell cycle arrest and apoptosis, without impacting the viability of BCMA-negative cells like NK cells, peripheral blood mononuclear cells (PBMCs), and bone marrow stromal cells (BMSCs). The ADC's Fc-receptor binding was enhanced due to the absence of fucose, which significantly improved its ability to induce antibody-dependent cellular cytotoxicity (ADCC) and maximum MM cell lysis in patients.

The in vivo effectiveness of J6M0-mcMMAF was tested in mice with MM xenograft models. Treatment at a dosage of 4 mg/kg completely removed tumors and kept the mice tumor-free for up to 100 days. In a bone marrow dissemination model, the ADC eradicated detectable tumors after two doses, leading to extended survival without weight loss in the mice. Even though less effective than J6M0-mcMMAF, J6M0 also prolonged survival and reduced tumor burden, suggesting the involvement of macrophage-mediated phagocytosis. J6M0-mcMMAF was shown to attract macrophages and facilitate the phagocytosis of MM cells.

Overall, the research indicates that J6M0-mcMMAF is a promising immunotherapeutic agent for MM, capable of inducing both direct and indirect killing of tumor cells in vitro and in vivo.