Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with...

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Death Receptor 5 (DR5) is a promising cancer therapy target due to its expression in many cancers and ability to induce apoptosis.
• Existing anti-DR5 IgG antibodies show limited efficacy, potentially due to insufficient receptor crosslinking.

Purpose of the Study:

• To evaluate the efficacy and safety of IGM-8444, a multivalent agonistic IgM antibody targeting DR5.
• To assess IGM-8444's potential as a monotherapy and in combination with chemotherapy or BCL-2 inhibitors for cancer treatment.

Main Methods:

• Engineered a multivalent agonistic IgM antibody (IGM-8444) with 10 binding sites for DR5.
• Assessed IGM-8444's binding avidity, in vitro cytotoxicity against cancer cell lines and primary hepatocytes, and in vivo efficacy in xenograft tumor models.
• Investigated synergistic effects when combined with chemotherapy or ABT-199 (BCL-2 inhibitor).

Main Results:

• IGM-8444 demonstrated potent DR5 multimerization, leading to efficient cancer cell apoptosis.
• It showed broad in vitro cytotoxicity against solid and hematologic cancer cell lines with no observed hepatotoxicity.
• In vivo studies revealed IGM-8444 monotherapy inhibited tumor growth, with significant regression in a gastric PDX model, and synergistic effects when combined with chemotherapy or ABT-199.

Conclusions:

• IGM-8444 is a potent DR5-targeting agent with a favorable safety profile, demonstrating efficacy in preclinical cancer models.
• The data support the clinical development of IGM-8444 for solid and hematologic malignancies, both as a standalone treatment and in combination therapies.