Background/Purpose: 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). Given the preliminary clinical profile of imvotamab in NHL, which shows durable response rates and a favorable safety profile, we evaluated its potential to deplete peripheral and tissue-resident B cells in preclinical models of AI disease.

Methods: The ability of imvotamab, rituximab (anti-CD20 IgG1) and a bispecific CD20xCD3 IgG TCE to deplete B cells in the context of AI disease was assessed using an ex vivo TDCC assay. Human peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with AI disease, including SLE, RA, and multiple sclerosis (MS)were utilized. B cell killing, T cell activation status, and cytokine release were assessed. The in vivo 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).

Results: Imvotamab induced killing of B cells in PBMCs from both AI patients and healthy donors. The maximum killing of B cells and half maximal effective concentration (EC50) were comparable between imvotamab, rituximab, and the bispecific CD20xCD3 IgG TCE. Importantly, no hyper-active responses were noted for T cell activation and cytokine release following treatment of PBMCs with imvotamab or the bispecific IgG TCE from healthy volunteers and AI patients. 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.

Conclusion: Our preclinical data suggests that imvotamab can effectively target and kill peripheral B cells from AI patients. Moreover, a CD20xCD3 IgM bispecific TCE can penetrate tissues and mediate direct killing of CD20-expressing target cells in vivo. Clinical studies with imvotamab in patients with autoimmune diseases, including RA and SLE, are planned to evaluate the therapeutic benefit of this mechanism.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-potential-of-imvotamab-a-cd20-targeted-bispecific-igm-t-cell-engager-for-the-treatment-of-refractory-autoimmune-disease-patients/