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The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPα inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFκB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect.

Novel therapeutics are needed for the effective treatment of acute myeloid leukemia (AML), as standard chemotherapeutics are poorly tolerated and ~50% of patients relapse primarily due to the incomplete elimination of leukemia stem cells (LSCs). CD123, the IL-3Rα chain, is highly expressed on leukemic blasts, LSCs, and is further increased in patients with poor prognostic factors. Bispecific T-cell engager (TCE) antibodies and CAR-T cells targeting CD123 have shown promising clinical efficacy in AML patients, but cytokine release syndrome limits their therapeutic window and remains a major safety concern. IGM-2537 is a novel pentameric IgM bispecific TCE antibody engineered with ten anti-CD123 binding sites, and an anti-CD3ε single chain Fv domain fused to the joining chain to engage T-cells. Here, we report the functional characterization of IGM-2537 using in vitro, ex vivo and in vivo anti-tumor efficacy studies with preliminary safety evaluation of this novel class of IgM TCE. IGM-2537 bound with high selectivity, affinity and avidity to CD123 through an epitope distinct from IL-3. In vitro, IGM-2537 co-engaged with both CD123 and CD3 to induce potent T-cell activation and T-cell mediated cytotoxicity of AML cell lines. Though IGM-2537 demonstrated comparable maximal killing activity to a comparator IgG TCE, IGM-2537 demonstrated minimal cytokine release. In ex vivo patient-derived AML or normal bone marrow colony formation assays, IGM-2537 eliminated AML colony forming cells at physiologically relevant effector/target (E/T) ratios but spared normal progenitors. In addition, IGM-2537 potently depleted CD123+ basophils and plasmacytoid dendritic cells (pDC) in normal human peripheral blood mononuclear cells. In vivo, IGM-2537 completely inhibited tumor growth in the AML xenograft tumor model, MV4-11 in humanized NSGdKO mice at doses as low as 1 mg/kg. To further evaluate the potency and safety of the CD123xCD3 IgM bispecific TCE format in vivo, a cynomolgus cross-reactive CD123xCD3 IgM bispecific TCE was evaluated for tolerability and pharmacodynamic responses in cynomolgus monkeys. All animals tolerated this bispecific IgM TCE well at doses up to 10 mg/kg (the maximal dose level evaluated), a dose 100-fold greater than published doses of a comparator IgG TCE. Complete depletion of CD123+ basophils and substantial reductions of pDCs were seen in blood and bone marrow with minimal to no cytokine induction. In summary, IGM-2537 demonstrated potent in vitro and in vivo T-cell mediated cytotoxicity of AML cell lines with minimal cytokine induction. These preclinical data further support the clinical development of IGM-2537 for the treatment of AML and more broadly substantiate the use of IgM antibodies as a framework for TCEs to provide an improved therapeutic window for T-cell redirected therapeutics. Citation Format: Gene Li, Ling Wang, Poonam Yakkundi, Paul Hinton, Deepal Pandya, Keerthana Sekar, Rodine Rosete, Zhongde Ye, Nardeen Hanna, Maya F. Kotturi, Liz Bogaert, Jiyoung Hong, Christina Tsai, Thomas Manley, Bruce A. Keyt, Angus M. Sinclair, Liqin Liu. Novel CD123xCD3 bispecific IgM antibody, IGM-2537, potently induces T-cell mediated cytotoxicity of acute myeloid leukemia cells with minimal cytokine release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2933.