Enhanced T-Cell Engagement and Cytokine Control with High-Avidity IgM Bispecific Antibody IGM-2323

Researchers have created a unique bispecific antibody platform that harnesses the high avidity of IgM antibodies and combines it with the high affinity and specificity of IgG antibodies. This is achieved by integrating the matured binding domains of IgG onto the multimeric structure of an IgM antibody and attaching a CD3 binding single chain Fv domain to the J-chain. The engineered IgM T cell bispecific antibody exhibits strong binding to specific targets while minimizing T cell over-stimulation. A specific bispecific IgM antibody, IGM-2323, has shown over 1000-fold increased avidity for binding CD20 antigen and demonstrates more than 100-fold higher potency in mediating complement-dependent cytotoxicity (CDC) compared to its IgG counterpart. Additionally, IGM-2323 displays potent T cell-dependent cytotoxicity against low CD20-expressing cells and rituximab-resistant cell variants. It also significantly reduces cytokine release both in vitro and in vivo, offering a safer and more effective alternative to IgG-based bispecifics. In vivo studies in humanized NSG mice and cynomolgus monkeys have shown complete B cell depletion at low doses, with durable depletion in spleen and lymphoid tissues and no observable adverse effects. A transient increase in circulating IL-6 was noted post-infusion, with minimal increases in TNF-alpha and IFN-gamma levels. These findings suggest the broad applicability of the IgM-based bispecific antibody format, with a Phase I clinical trial for IGM-2323 underway for patients with relapsed/refractory Non-Hodgkin's Lymphoma. The study's authors are affiliated with IGM Biosciences, indicating potential conflicts of interest.