American Association for Cancer Research
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Figure S4 from Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199

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posted on 2023-10-04, 15:20 authored by Beatrice T. Wang, Tasnim Kothambawala, Ling Wang, Thomas J. Matthew, Susan E. Calhoun, Avneesh K. Saini, Maya F. Kotturi, Genevive Hernandez, Eric W. Humke, Marvin S. Peterson, Angus M. Sinclair, Bruce A. Keyt

Figure S4 shows DR5 expression in tumor xenografts and comparison of IGM-8444 and anti-DR5 IgG in vivo

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IGM Biosciences Inc

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ARTICLE ABSTRACT

Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.

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    Molecular Cancer Therapeutics

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