Deciphering the Anticancer Potential and Mechanistic Insights of OBI-888: A Humanized Anti-Globo H Antibody

The study focuses on OBI-888, a humanized monoclonal IgG1 antibody that targets the hexasaccharide Globo H, which is found in various cancers. The research aimed to investigate the mechanisms of action and in vivo effectiveness of OBI-888. Methods included assessing antibody-dependent cell-mediated cytotoxicity and phagocytosis, binding affinity to FcγRs, and complement-dependent cytotoxicity through ELISA-based assays. The anti-immunosuppressive effect was studied using a Jurkat/NFAT-luciferase reporter assay, and in vivo anti-tumor efficacy was measured in xenograft mouse models with GH-expressing tumors. Tumor cell GH expression was determined pre- and post-tumor excision using flow cytometry and immunohistochemistry, while lymphocyte populations in the tumor microenvironment were evaluated by IHC.

Results indicated that OBI-888 showed significant ADCC and ADCP activity with respective EC50 values of 4.68 and 29.15 μg/mL. It also displayed binding affinity to multiple FcγRs, including a low affinity genotype, and had an EC50 of 0.86 μg/mL for binding to C1q, crucial for CDC initiation. The addition of GH ceramide induced a dose-dependent immunosuppressive effect, which could be reversed by OBI-888 at a concentration of 8.7 μM. In various GH+ xenograft cancer models, OBI-888 led to tumor growth inhibition ranging from 30-85%. Immunohistochemistry revealed GH staining on immune cells in intra- and peri-tumor regions, and OBI-888 was found to reduce the M2 macrophage population.

The study concludes that OBI-888 has the potential to induce tumor lysis through ADCC, ADCP, and CDC, and its binding affinity to FcγRs, including a low affinity genotype, could benefit patients with such a genotype. The immunosuppressive effect of GH ceramide and the anti-immunosuppressive function of OBI-888 were highlighted. In vivo tumor growth inhibition and a decrease in the M2 population in GH+ xenograft models suggest a potential mechanism of action through immune modulation. The findings indicate that OBI-888 may have significant therapeutic potential for treating cancers expressing GH. A first-in-human clinical trial for OBI-888 has been initiated.