Nectin cell adhesion molecule 4 (Nectin-4) (Nectin-4)

Nectin cell adhesion molecule 4 (Nectin-4) is a type I transmembrane protein and a member of the immunoglobulin superfamily that mediates Ca2+-independent cell-cell adhesion [4, 8]. While its expression is high during embryonic development and in placental tissues, it is minimally present in healthy adult tissues, such as the skin and bladder [6, 8]. In contrast, Nectin-4 is significantly overexpressed in various malignancies, including urothelial, breast, lung, and ovarian cancers, where it promotes tumor cell proliferation, migration, and angiogenesis through pathways like PI3K/AKT [5, 8, 11]. It also serves as a ligand for the inhibitory immune checkpoint TIGIT and can act as a receptor for viral entry [4, 6]. Due to its differential expression between tumor and normal tissues, Nectin-4 has become a validated therapeutic target, most notably for antibody-drug conjugates (ADCs) [1, 11]. The FDA-approved ADC enfortumab vedotin targets Nectin-4 to deliver a cytotoxic payload directly to cancer cells, leading to cell death [2, 6]. Therapeutic challenges include on-target toxicities like skin rash and payload-related adverse events such as peripheral neuropathy [6, 9].

Other names

PVRL4Poliovirus receptor-related 4LNIRPRR4Nectin-4

Antibody-drug conjugate (ADC) binding to the extracellular domain of Nectin-4, followed by internalization and release of a cytotoxic payload (e.g., monomethyl auristatin E) to induce apoptosis [1, 2, 6].