Antitumor Potential and Safety of IMAB027-vcMMAE: A Targeted Antibody-Drug Conjugate for Claudin 6-Positive Cancers

The study focuses on the characterization of an antibody-drug conjugate (ADC) targeting Claudin 6 (CLDN6), a protein with limited expression in normal tissues but overexpressed in certain cancers. IMAB027, a monoclonal antibody (mAb) against CLDN6, has been conjugated with monomethyl auristatin E (MMAE), a potent cytotoxic agent, to enhance the delivery of the drug directly to tumor cells.

The research methods included assessing the internalization of IMAB027 in CLDN6-positive ovarian (OC) and testicular cancer (TC) cell lines using various assays. The binding and cytotoxic effects of the ADC, IMAB027–vcMMAE, were evaluated through flow cytometry and metabolic assays, with additional tests for apoptosis and the induction of cell death mechanisms. The in vivo antitumor activity and safety of the ADC were tested using xenograft mouse models with human OC cells.

Results showed that IMAB027–vcMMAE effectively bound to and was internalized by CLDN6-expressing cells, leading to a significant reduction in cell viability with low nanomolar EC50 values. The ADC induced apoptosis in a dose-dependent manner and maintained the ability to cause cell death through antibody-dependent and complement-dependent cytotoxicity. Notably, a bystander effect was observed in cocultures, where CLDN6-negative cells also experienced cell death. In vivo, a single dose of IMAB027–vcMMAE demonstrated significant antitumor effects, and repeated dosing was well tolerated without adverse effects.

The study concludes that IMAB027–vcMMAE is a specific and potent ADC against CLDN6, capable of inducing strong antitumor responses both in vitro and in vivo. It also suggests that the ADC may be effective against tumors with low or heterogeneous CLDN6 expression, potentially due to the bystander effect.

The research was presented at the American Association for Cancer Research Annual Meeting in 2018, with authors Özlem Türeci, Maria Kreuzberg, and others contributing to the findings.