Abstract 4120: Depletion of tissue-resident B cells by a CD20xCD3 IgM bispecific T cell engager in cynomolgus monkeys demonstrates effective tissue penetration and potent target cell killing

Imvotamab (IGM-2323) is an engineered high-affinity, high-avidity bispecific anti-CD20 IgM antibody T cell engager (TCE) that is currently being studied as monotherapy in a Phase 1/2 clinical trial for relapsed/refractory non-Hodgkin’s lymphoma (NHL) (NCT04082936). Imvotamab offers a novel treatment strategy in NHL by depleting CD20-expressing tumor cells through multiple mechanisms, including the recruitment of T cells to kill tumor cells through T cell dependent cellular cytotoxicity, complement-dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation. We evaluated the activity of a surrogate cynomolgus monkey cross-reactive CD20xCD3 IgM bispecific TCE, IGM-2324, in depleting CD20-expressing B cells in peripheral blood and lymphoid tissues of cynomolgus monkeys in vivo. We hypothesized that the high affinity and valency of IGM-2324 would enable potent B cell killing in blood and tissues even when B cells express low levels of CD20. Cynomolgus monkeys were administered vehicle or IGM-2324 at 5 mg/kg or 25 mg/kg through intravenous infusion twice weekly for a total of four doses on days 1, 4, 7, and 10. B cell depletion in peripheral blood was assessed by measuring the frequency of CD19+ B cells through flow cytometry. Administration of IGM-2324 at 5 and 25 mg/kg resulted in a nearly complete depletion in peripheral CD19+ B cells at 8 hours post the 1st dose through 24 hours post the last dose on day 11. Depletion of tissue-resident B cells was evaluated in the spleen, mesenteric lymph node (MLN) and bone marrow (BM) of monkeys at 24 hours post the last dose of vehicle or IGM-2324 on day 11. Immunohistochemistry studies were conducted on the formalin-fixed paraffin-embedded lymphoid tissues by staining for CD19 and CD20 expression. The number and intensity of CD19 or CD20 positive B cells were determined by quantitative imaging analysis. Compared to vehicle-treated animals, significant dose-dependent reductions in both CD19 and CD20-expressing B cells were observed in spleen, MLN and BM following treatment with 5 and 25 mg/kg of IGM-2324. Most importantly, 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. Our preclinical data indicate that a CD20xCD3 IgM bispecific TCE can penetrate tissues and mediate direct killing of CD20-expressing target cells. B cell depletion in the periphery and tumors of relapsed/ref