Nectin-4, a cell adhesion molecule typically expressed at low levels in normal tissues, has become a focal point in oncology due to its elevated presence in certain cancers. Overexpression of Nectin-4 is linked to tumor growth, invasion, and progression, making it a prime candidate for targeted cancer therapies. LY4052031 and LY4101174, are novel antibody-drug conjugates (ADC) that deliver a cytotoxic payload directly to Nectin-4-expressing cells.

LY4052031 and LY4101174 are currently being evaluated in a Phase 1a/1b clinical trial. The trial involves dose-escalation and dose-optimization phases to determine the drug’s safety, tolerability, and pharmacokinetics. Once the optimal dose is established, researchers will assess its efficacy and safety across various tumor types and patient groups. This study aims to shed light these drugs potential as precise and effective treatments for Nectin-4-positive cancers, including metastatic castration resistant prostate cancer (mCRPC).

Preclinical research underscores very promising resulta. The ADC combines a fully human monoclonal anti-Nectin-4 antibody with a novel topoisomerase I inhibitor payload. This approach not only ensures specificity and selectivity but also offers a distinct mechanism of action compared to existing ADC therapies, potentially reducing resistance and altering the toxicity profile. In vitro, they demonstrated potent cytotoxicity and a notable bystander effect, effectively targeting both high and low Nectin-4-expressing cells. In vivo xenograft studies showed significant tumor growth inhibition, highlighting its therapeutic potential.

Cinical trial 1.

Clinical trial 2.