POS1062 THERAPEUTIC POTENTIAL OF IMVOTAMAB, A CD20-TARGETED BISPECIFIC IGM T CELL ENGAGER, FOR THE TREATMENT OF REFRACTORY AUTOIMMUNE DISEASE PATIENTS
Authors: R. Domingo-Gonzalez, I. Baribaud, M. Oyasu, K. Hart, K. Burns, S. Pandey, M. Leabman, G. Hernandez, A. Candia, S. Carroll, R. Kunder, B. Keyt, M. Kotturi, C. Brodmerkel, M. B. Harler
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> B cell depletion therapy (BCDT) with conventional IgG antibodies (e.g. rituximab) has been used to treat autoimmune (AI) disease for several decades. However, many patients do not achieve long term disease control or remission. Failure of these therapies to fully deplete tissue-resident B cells may result in persistent reservoirs of pathogenic clones that contribute to the ongoing generation of autoantibodies and disease activity. Bispecific IgM antibody T cell engagers (TCEs) are exciting drug candidates with the potential to deplete tissue-resident target cells more effectively through T cell-dependent cellular cytotoxicity (TDCC) and complement-dependent cytotoxicity compared to conventional BCDT mechanisms of action. Imvotamab (IGM-2323) is an engineered high-affinity, high avidity bispecific anti-CD20 IgM antibody TCE that has been evaluated for the treatment of non-Hodgkin's lymphoma (NHL). <h3>Objectives:</h3> 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. <h3>Methods:</h3> The ability of imvotamab and rituximab (anti-CD20 IgG1) to deplete B cells in the context of AI disease was assessed using an <i>ex vivo</i> cytotoxicity assay. Human peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with AI disease, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) were utilized. B cell killing, T cell activation status, and cytokine release were assessed. The <i>in vivo</i> activity of a surrogate cynomolgus monkey cross-reactive CD20xCD3 IgM bispecific TCE, IGM-2324, was evaluated for depletion of B cells in peripheral blood and tissues of cynomolgus monkeys. B cell depletion in blood was measured by flow cytometry and in tissues by immunohistochemistry (IHC). <h3>Results:</h3> <i>Ex vivo</i> 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 patient and healthy donor PBMCs, and greater complement-dependent cytotoxicity compared to rituximab. Importantly, no hyper-active responses were noted for T cell activation and cytokine release following treatment of PBMCs with imvotamab from healthy donors and AI patients. Additionally, a rituximab-resistant cell line, with significantly reduced CD20 expression levels, was killed more effectively by imvotamab than rituximab. Evaluation of tissue-resident B cells in cynomolgus monkeys following treatment with IGM-2324 resulted in significant reductions in peripheral and tissue-resident B cells. IGM-2324 treatment led to the depletion of not only high and moderate tissue-resident CD20-expressing B cells, but also B cells that expressed low levels of CD20. <h3>Conclusion:</h3> Our preclinical data show imvotamab effectively kills peripheral B cells isolated from AI patients. Moreover, in a non-human primate model, a CD20xCD3 IgM TCE can penetrate tissues to kill target cells <i>in vivo</i>. Clinical trials with imvotamab in AI patients are ongoing to evaluate the therapeutic benefit of this mechanism. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Racquel Domingo-Gonzalez IGM Biosciences, Inc, IGM Biosciences, Inc, Isabelle Baribaud IGM Biosciences, Inc, IGM Biosciences, Inc, Miho Oyasu IGM Biosciences, Inc, IGM Biosciences, Inc, Kevin Hart IGM Biosciences, Inc, IGM Biosciences, Keely Burns IGM Biosciences, Inc, IGM Biosciences, Sivani Pandey IGM Biosciences, Inc, IGM Biosciences, Inc, Maya Leabman IGM Biosciences, Inc., IGM Biosciences, Inc., Genevive Hernandez IGM Biosciences, Inc., IGM Biosciences, Inc., Albert Candia IGM Biosciences, Inc., IGM Biosciences, Inc., Stephen Carroll IGM Biosciences, Inc, IGM Biosciences, Rebecca Kunder IGM Biosciences, Inc, IGM Biosciences, Inc, Bruce Keyt IGM Biosciences, Inc, IGM Biosciences, Maya Kotturi IGM Biosciences, Inc, IGM Biosciences, Carrie Brodmerkel IGM Biosciences, Inc, IGM Biosciences, Mary Beth Harler IGM Biosciences, Inc, IGM Biosciences, Inc.