vedotinbased

Vedotin-based refers to a subset of antibody-drug conjugates (ADCs) in which the cytotoxic payload is monomethyl auristatin E (MMAE) linked to a monoclonal antibody via a valine-citrulline (vc) dipeptide linker. This design enables targeted delivery of MMAE to cancer cells that express a specific antigen, with the vc linker designed to release MMAE upon internalization and lysosomal processing. The resulting localized exposure aims to maximize antitumor activity while limiting systemic toxicity, though side effects and resistance can occur.

Mechanism of action involves antibody binding to a tumor-associated antigen, internalization of the ADC, and enzymatic cleavage of the vc linker in the lysosome to release MMAE. The released MMAE disrupts tubulin polymerization, impairs microtubule dynamics, and induces cell cycle arrest and apoptosis. Some bystander killing of neighboring tumor cells can occur if MMAE diffuses from the target cell.

Representative vedotin-based ADCs include brentuximab vedotin (anti-CD30) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma; enfortumab vedotin (anti-nectin-4) for locally advanced or metastatic urothelial cancer; polatuzumab vedotin (anti-CD79b) used with rituximab and chemotherapy for certain B-cell lymphomas; and tisotumab vedotin (anti-tissue factor) for cervical cancer. These agents have varying regulatory statuses, with several approved in the United States and Europe and others in ongoing development or additional indications.

Safety considerations include peripheral neuropathy, fatigue, nausea, and hematologic effects; tisotumab vedotin can cause ocular toxicity. Ongoing research aims to expand indications, optimize linker design, and address resistance mechanisms such as antigen loss and alterations in internalization or drug efflux.