1. Academic Validation
  2. 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

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

  • Mol Cancer Ther. 2021 Dec;20(12):2483-2494. doi: 10.1158/1535-7163.MCT-20-1132.
Beatrice T Wang 1 Tasnim Kothambawala  # 1 Ling Wang  # 1 Thomas J Matthew  # 1 Susan E Calhoun 1 Avneesh K Saini 1 Maya F Kotturi 1 Genevive Hernandez 1 Eric W Humke 1 Marvin S Peterson 1 Angus M Sinclair 1 Bruce A Keyt 2
Affiliations

Affiliations

  • 1 IGM Biosciences Inc., Mountain View, California.
  • 2 IGM Biosciences Inc., Mountain View, California. bkeyt@igmbio.com.
  • # Contributed equally.
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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