Targeting Globo H with a Novel Antibody-Drug Conjugate for Cancer Therapy

The study explores OBI-999, an antibody-drug conjugate (ADC) targeting a hexasaccharide called Globo H, which is highly present in various cancers and minimally in normal tissues, making it a promising candidate for cancer immunotherapy. OBI-999 combines a monoclonal antibody OBI-888 specific to Globo H with monomethyl auristatin E (MMAE), a synthetic antineoplastic agent.

The research methods involved assessing Globo H's presence in different human cancer cell lines and determining OBI-999's binding specificity and internalization capabilities using flow cytometry and confocal microscopy. The anti-tumor effectiveness of OBI-999 was examined in xenograft and patient-derived xenograft models, with pharmacokinetic parameters being evaluated in both normal and tumor-bearing mice.

Results indicated that OBI-999 selectively bound to cancer cell lines expressing Globo H, including those from breast, gastric, lung, and pancreatic cancers, and did not bind to non-expressing lines. The conjugate was found to internalize and reach endosomes and lysosomes within 2.5 to 5 hours, implying that MMAE is released in a lysosome-dependent manner. In vivo studies showed significant tumor growth inhibition in response to OBI-999 in a dose-dependent manner, with complete inhibition observed in pancreatic cancer models at higher doses. OBI-999 demonstrated similar serum stabilities to Adcetris across various species and accumulated at the tumor site over time, with the highest levels observed 168 hours post-treatment and significantly higher MMAE levels in tumor masses compared to other organs and serum.

The conclusion highlights that OBI-999's preclinical studies have shown its targeting specificity and anti-tumor efficacy in multiple Globo H positive cancer types and its prolonged retention at the tumor site, providing a foundation for its potential clinical use in targeted cytotoxic therapy for solid tumors.