Targeting BCMA with MEDI2228: A Promising Antibody-Drug Conjugate for Multiple Myeloma Therapy

Despite significant improvements in treatment, multiple myeloma (MM) is still incurable. The B-cell maturation antigen (BCMA) is a promising target for MM therapies due to its limited presence in normal plasma cells and widespread presence in myeloma cells. MEDI2228 is a new antibody-drug conjugate (ADC) that targets BCMA, consisting of a human antibody linked to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer through a cleavable linker. MEDI2228 is quickly internalized and directed to lysosomes, where it induces DNA damage and cell death. It showed high efficacy in 80% of MM cell lines tested, regardless of BCMA expression levels, and was effective against resistant cell models and in the presence of bone marrow stromal cells. In animal models, a single dose of MEDI2228 led to tumor shrinkage.

Serum levels of soluble BCMA (sBCMA) are higher in MM patients, which could interfere with antibody therapies. MEDI2228's antibody was selected for its low binding to sBCMA and high binding to membrane-bound BCMA, maintaining its cytotoxicity even with high levels of sBCMA present. Additionally, MEDI2228 can target and eliminate CD19+CD138- clonogenic cells found in the bone marrow of MM patients, which are similar to MM plasma cells and express BCMA. MEDI2228's ability to target both bulk plasma cells and quiescent clonogenic cells suggests it may provide a more enduring clinical response for MM, a genetically diverse disease. The disclosures indicate various affiliations with MedImmune and other pharmaceutical entities for several authors.