Enhanced Anti-Myeloma Activity of GSK2857916: Targeting BCMA with a Novel Fc-Engineered ADC

The study explores the effectiveness of a novel antibody-drug conjugate (ADC), J6M0-mcMMAF (GSK2857916), targeting B cell maturation antigen (BCMA) in human multiple myeloma (MM). The humanized ADC exhibits binding to all CD138+ MM cell lines and patient cells, indicating BCMA's universal presence on myeloma cells. Quantitative RT-PCR reveals a significant increase in BCMA mRNA in CD138+ cells from MM patients compared to healthy individuals. J6M0-mcMMAF effectively inhibits cell growth and triggers apoptosis in MM cell lines and patient cells, regardless of drug sensitivity. The ADC induces cell death specifically in CD138+ MM cells without affecting CD138- cells, minimizing harm to surrounding BCMA-negative cells. It also blocks MM cell colony formation and does not impact the viability of BCMA-negative cells, demonstrating its specificity for BCMA-positive MM cells. The ADC enhances Fc-receptor binding due to afucosylation, improving antibody-dependent cellular cytotoxicity (ADCC) potency and MM cell lysis. This effect is more pronounced in autologous settings. Lenalidomide treatment of PBMC effector cells further enhances ADCC induced by J6M0-mcMMAF. In vivo studies in murine models show complete tumor elimination and extended survival with J6M0-mcMMAF treatment. The ADC also recruits macrophages to mediate phagocytosis of MM cells. The research suggests J6M0-mcMMAF as a promising immunotherapeutic agent for MM. The disclosures section mentions various consultancy and employment relationships with pharmaceutical companies for several authors.