Session Information
Date: Sunday, November 17, 2024
Title: SLE – Treatment Poster II
Session Type: Poster Session B
Session Time: 10:30AM-12:30PM
Background/Purpose: B cell depletion therapy (BCDT) with conventional IgG mAbs has been employed for the treatment of autoimmune (AI) disease for ~20 years; however, many patients do not achieve long term disease control or remission. Failure to respond to BCDT (e.g. rituximab) has been associated with an inability to deplete B cell subsets that are important in autoimmune pathophysiology, including low-expressing CD20+ B cells that are the precursors to autoantibody-producing plasmablasts and plasma cells. Bispecific IgM antibody T cell engagers (TCEs) offer the potential to deplete low target expressing cells more effectively than conventional effector function IgG antibodies through T cell-dependent cellular cytotoxicity (TDCC) and complement-dependent cytotoxicity (CDC). Imvotamab (IGM-2323) is an engineered high-affinity, high avidity bispecific anti-CD20 IgM antibody TCE. Given the 10:1 ratio of CD20 binding to T cell engagement, we evaluated the potential avidity advantage of imvotamab in depleting low-expressing CD20+ B cells as compared to conventional IgGs.
Methods: The affinity of imvotamab and its corresponding bivalent anti-CD20 IgG antibody to recombinant human CD20 protein was measured by surface plasmon resonance. The ability of imvotamab to deplete low-expressing CD20+ B cells in the context of AI disease was assessed using an ex vivo cytotoxicity assay, and compared to rituximab, an approved treatment for several autoimmune diseases including RA. Human peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with AI disease, including SLE and RA, were utilized as a source of B cell subsets with a range of CD20 expression levels. Finally, the killing of a low-expressing CD20+ B cell line by imvotamab was compared to rituximab and evaluated in an ex vivo TDCC assay with human PBMCs as effector cells.
Results: Imvotamab bound to human CD20 with an apparent 40-fold higher binding affinity (KD) and ~40-fold slower off-rate (kdis) than the bivalent anti-CD20 IgG. Imvotamab induced killing of B cells across a broad range of CD20 expression levels in PBMCs from both AI patients and healthy donors. Importantly, imvotamab induced significantly more potent and maximal depletion of low-expressing CD20+ B cell subsets, including switched memory B cells and activated memory B cells, compared to rituximab. Using a low expressing CD20+ B cell line, imvotamab induced more effective killing compared to conventional IgG mAbs, including rituximab.
Conclusion: Imvotamab was substantially more effective than rituximab in killing low expressing CD20+ B cells, including switched memory and activated memory B cells from patients with autoimmune disease. Results using a low expressing CD20+ cell line further substantiate this finding, supporting the potential for improved killing of key pathogenic B cell subsets by imvotamab over rituximab. Imvotamab is currently being evaluated in phase 1b clinical trials with severe SLE (NCT# NCT06041568) and moderate to severe RA (NCT# NCT06087406).
To cite this abstract in AMA style:
Domingo-Gonzalez R, Baribaud I, Tyagi S, Hart K, Eberwine R, Sinclair A, Candia A, Keyt B, Elloso M, Kotturi M, Harler M. Imvotamab, a CD20-Targeted Bispecific IgM T Cell Engager, Effectively Depletes Low-Expressing CD20+ B Cells in Preclinical Models of Autoimmune Disease [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/imvotamab-a-cd20-targeted-bispecific-igm-t-cell-engager-effectively-depletes-low-expressing-cd20-b-cells-in-preclinical-models-of-autoimmune-disease/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/imvotamab-a-cd20-targeted-bispecific-igm-t-cell-engager-effectively-depletes-low-expressing-cd20-b-cells-in-preclinical-models-of-autoimmune-disease/