Enhanced Anti-Cancer mAbs: Targeting Oxidized MIF for Therapeutics and Diagnostics

The study focuses on the development and evaluation of second-generation monoclonal antibodies (mAbs) targeting oxidized Macrophage Migration Inhibitory Factor (oxMIF), a cytokine linked to tumor growth. The first-generation anti-oxMIF mAb showed safety and efficacy in a phase 1 trial. The new bioengineered mAbs, ON203 and ON102, were designed to enhance therapeutic and diagnostic capabilities, respectively. Methods included hydrophobicity and stability testing, as well as assessments of antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP). Tumor penetration was evaluated in mice, and pharmacokinetics and bioavailability were measured. Efficacy was determined using PC3 xenograft models.

The bioengineering process led to a significant reduction in hydrophobicity and improved stability for both mAbs, resulting in enhanced bioavailability and tumor accumulation. The mAbs did not induce unspecific cytokine release from peripheral blood mononuclear cells (PBMCs). ON203 demonstrated potent ADCC and ADCP activities, significantly outperforming the first-generation mAb. The improved efficacy of ON203 was evidenced by the inhibition of tumor growth in the xenograft model.

The conclusion highlights the potential of ON203 to offer superior efficacy over its predecessor, with Zr89-ON102 serving as a companion diagnostic tool for patient selection. The plan is to advance these mAbs for clinical application, with a strategy to combine ON203 with other immunotherapies or checkpoint inhibitors to expand treatment options for patients with solid tumors.