MGC018: Advancing B7-H3-Targeted Therapy for Solid Cancers

The B7-H3 molecule, a part of the B7 immunomodulatory family, is often found in higher amounts in various solid tumors and is linked to more severe diseases and worse outcomes in different cancers. An antibody-drug conjugate (ADC) known as MGC018 has been developed to target B7-H3. It consists of a cleavable linker attached to a duocarmycin payload, specifically valine-citrulline-seco DUocarmycin hydroxyBenzamide Azaindole (vc-seco-DUBA), which is then linked to a humanized IgG1/kappa monoclonal antibody against B7-H3. The average drug-to-antibody ratio is approximately 2.7. Initial studies showed that MGC018 has a promising profile in preclinical testing, with strong interactions with tumor cells and associated blood vessels, limited effects on normal tissues, and significant cytotoxic and antitumor capabilities in various B7-H3-expressing cancer cell lines.

To further develop MGC018 for clinical use, more extensive preclinical studies were carried out. The ADC was created by Synthon Biopharmaceuticals B.V., and both single and repeated dose efficacy studies were performed in mice with human tumor grafts that express B7-H3. These studies aimed to understand the relationship between the maximum concentration of the drug, the exposure, and the anti-tumor effect, as well as to determine the minimum effective dose. Additionally, a toxicology study was conducted in cynomolgus monkeys, administering MGC018 at dosages of 1, 3, 6, and 10 mg/kg every three weeks for three doses.

The results showed that MGC018 had a specific and dose-dependent antitumor effect on B7-H3-positive tumor grafts from breast, lung, ovarian cancers, and melanoma. The antitumor activity was found to be driven by the total drug exposure rather than the peak concentration. MGC018 was well-tolerated in cynomolgus monkeys at all tested dosages, with the highest dose of 10 mg/kg being identified as the highest non-severely toxic dose.

In conclusion, MGC018, which is an ADC with a humanized monoclonal antibody targeting B7-H3 and linked to a potent DNA alkylating payload through a cleavable peptide linker, has shown a favorable preclinical profile. It has shown potent antitumor activity in vivo at clinically relevant doses and was well-tolerated in a relevant toxicology model. The findings suggest that MGC018 could be a potential ADC therapy for solid cancers that express B7-H3.