B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, such as antibody-drug conjugates (ADC), have achieved remarkable clinical response in patients with relapsed and refractory MM. BOC Sciences provides comprehensive ADC development services for BCMA targets and MM, including antibody modification, linker-cytotoxin synthesis, antibody-drug conjugation, and DAR characterization services. With unique expertise in chemical synthesis and biochemistry, we are confident to provide a one-stop ADC development service to meet your specific needs.
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B cell maturation antigen (BCMA) or CD269, also termed tumor necrosis factor receptor superfamily member 17 (TNFRS17), is a type III transmembrane protein without a signal-peptide and containing cysteine-rich extracellular domains. BCMA was first identified in the early 1990s. Expression of this 184-amino acid glycoprotein plays a major role in B-cell maturation and differentiation into plasma cells. In normal human tissues, both BCMA protein and mRNA are found almost exclusively on plasma cells and are selectively overexpressed during plasmacyte malignant transformation, promoting tumor cell growth, survival, and drug resistance. This consistent elevation and virtually sole confinement of BCMA on the surface of MM cells from both cell lines and patient samples has made BCMA a compelling target for drug discovery and development in MM.
Fig. 1. B cell maturation antigen (BCMA)-based immunotherapies with multiple mechanisms of action against MM cells. (Frontiers in immunology. 2018, 9: 1821).
Belantamab mafodotin (GSK2857916) is a humanized anti-BCMA IgG1 mAb conjugated to monomethyl auristatin F (MMAF, mafodotin) via a non-cleavable maleimidocaproyl (MC) linker. Mafodotin is released after complete proteolytic degradation of the whole mAb backbone as well as the linker by lysosomes. It then binds to tubulin and impedes microtubule assembly, leading to G2/M cell cycle arrest and subsequent cell apoptosis. Preclinical study discovered that GSK2857916 markedly inhibited BCMA+ MM cell growth in a dose- and time-dependent manner, with low bystander toxicity on surrounding BCMA-cells. It also rapidly eliminated MM cells in subcutaneous and systemic MM mouse models, leading to tumor-free duration up to 3.5 months. Another study of GSK2857916 demonstrated strong antibody-dependent cellular cytotoxicity (ADCC) activity which was further enhanced by lenalidomide.
BCMA Targeted Therapy in Multiple Myeloma (MM)
Multiple myeloma (MM) is a hematological cancer characterized by clonal plasma cell proliferation in the bone marrow along with high levels of monoclonal immunoglobulins in the blood and/or urine. Ranking behind non-Hodgkin’s lymphoma, MM is the second most common blood cancer and the 14th most prevalent cancer overall. Active MM, which is accompanied by a tetrad of symptoms, generally abbreviated CRAB-hypercalcemia, renal insufficiency, anemia, and bone lesions-often is preceded by an asymptomatic phase known as monoclonal gammopathy of undetermined significance (MGUS). Progression from MGUS to MM, which carries a risk of about 1% per year, may also include another asymptomatic state known as smoldering myeloma. The clinical development of BCMA-targeted ADCs suggests that this immunotherapy is well suited for the treatment of MM.
Fig. 2. Multiple myeloma (MM) cells.
ADC has high targeting selectivity and enhanced lethality in the field of tumor therapy. Therefore, it provides an ideal treatment for MM patients. The technical focus of BCMA targeted ADC for MM immunotherapy is to select antibody, payload and linker. BOC Sciences has the ability to synthesize highly effective toxins and toxin derivatives with different mechanisms for targets of interest to customers. In addition, we provide linker customization services to balance ADC drug stability and payload release efficiency by adjusting necessary linker parameters, so as to achieve appropriate and successful ADC drug development. Click here for more targeted ADC development services.