Th110 - Therapeutic Potential of Imvotamab, a CD20-Targeted Bispecific IgM T Cell Engager, for the Treatment of Refractory Autoimmune Disease Patients

Isabelle Baribaud – IGM Biosciences, Inc.; Carrie Brodmerkel – IGM Biosciences, Inc.; Keely Burns – IGM Biosciences, Inc.; Albert Candia – IGM Biosciences, Inc.; Stephen Carroll – IGM Biosciences, Inc.; Mary Beth Harler – IGM Biosciences, Inc.; Kevin Hart – IGM Biosciences, Inc.; Genevive Hernandez – IGM Biosciences, Inc.; Bruce Keyt – IGM Biosciences, Inc.; Maya Kotturi – IGM Biosciences, Inc.; Rebecca Kunder – IGM Biosciences, Inc.; Maya Leabman – IGM Biosciences, Inc.; Miho Oyasu – IGM Biosciences, Inc.; Sivani Pandey – IGM Biosciences, Inc.

Abstract Text: B cell depletion therapy with conventional IgGs has been used to treat autoimmune (AI) disease. However, these IgG-based therapies can fail to fully deplete tissue-resident B cells and many patients do not achieve long term disease control. Bispecific IgM antibody T cell engagers (TCEs) offer the potential to deplete tissue-resident target cells. Imvotamab (IGM-2323) is an engineered bispecific anti-CD20 IgM TCE that has been evaluated for the treatment of non-Hodgkin’s lymphoma (NHL). Given the promising durable response and safety profile in NHL, we evaluated imvotamab for depletion of peripheral and tissue-resident B cells in preclinical models of AI disease.

Ex vivo cytotoxicity assays using human peripheral blood mononuclear cells (PBMCs) or serum from healthy donors and AI patients showed imvotamab induced potent killing of B cells from both AI patients and healthy donor PBMCs, and greater complement-dependent cytotoxicity compared to rituximab. No hyper-active responses were noted for T cell activation and cytokine release following treatment of imvotamab with healthy and AI patient PBMCs. Additionally, a rituximab-resistant cell line, with significantly reduced CD20 expression levels, was killed more effectively by imvotamab than rituximab. Using a surrogate cynomolgus monkey cross-reactive CD20xCD3 IgM TCE, IGM-2324, peripheral and tissue-resident B cell were depleted in vivo, including low CD20-expressing B cells.

Our preclinical data show imvotamab effectively kills peripheral B cells from AI patients. Moreover, a CD20xCD3 IgM TCE can penetrate tissues to kill target cells in vivo. Clinical trials with imvotamab in AI patients are ongoing to evaluate the therapeutic benefit of this mechanism.