PVRL4

Official Full Name

nectin cell adhesion molecule 4

Organism

Homo sapiens

GeneID

81607

Background

This gene encodes a member of the nectin family. The encoded protein contains two immunoglobulin-like (Ig-like) C2-type domains and one Ig-like V-type domain. It is involved in cell adhesion through trans-homophilic and -heterophilic interactions. It is a single-pass type I membrane protein. The soluble form is produced by proteolytic cleavage at the cell surface by the metalloproteinase ADAM17/TACE. The secreted form is found in both breast tumor cell lines and breast tumor patients. Mutations in this gene are the cause of ectodermal dysplasia-syndactyly syndrome type 1, an autosomal recessive disorder. Alternatively spliced transcript variants have been found but the full-length nature of the variant has not been determined.[provided by RefSeq, Jan 2011]

Synonyms

NECTIN4; LNIR; PRR4; EDSS1; PVRL4; nectin-4;

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Detailed Information

The NECTIN4 (Nectin Cell Adhesion Molecule 4) gene is located on the long arm of human chromosome 1 at 1q23.3. It encodes a type I transmembrane glycoprotein with a molecular weight of approximately 66 kDa, belonging to the immunoglobulin superfamily of adhesion molecules. The protein structure includes three characteristic domains: an extracellular region composed of three immunoglobulin (Ig)-like domains (an N-terminal IgV domain and two C-terminal IgC2 domains), a single transmembrane domain, and a cytoplasmic tail that contains an afadin-binding motif. This configuration enables NECTIN4 to mediate intercellular adhesion through either homophilic or heterophilic trans-interactions. The IgV domain is responsible for binding to other nectin family members, while the IgC2 domains stabilize the adhesion junctions.

Under physiological conditions, NECTIN4 expression is developmentally regulated. It is broadly expressed in embryonic and fetal tissues, where it plays roles in morphogenesis, but is restricted in adult normal tissues, being mainly found in epithelial structures such as the skin, esophagus, and bladder.

Figure 1. Nectin 4/PVRL4 is normally expressed in the adherens junctions between adjacent epithelial cells. (Noyce RS, et al., 2012)

A key feature of NECTIN4 is its susceptibility to proteolytic cleavage by the metalloprotease ADAM17/TACE near the membrane in the transmembrane region. This releases a ~40 kDa soluble extracellular domain (sNECTIN4). The cleavage process is significantly enhanced in the tumor microenvironment, leading to elevated levels of sNECTIN4 in the serum of patients with various cancers. Studies have shown that sNECTIN4 can serve not only as a diagnostic biomarker but also as a pro-angiogenic factor—stimulating endothelial cell proliferation and migration through the integrin β4–Src–PI3K–Akt–iNOS signaling axis, thus supporting tumor vascularization. Additionally, sNECTIN4 can activate the PI3K/AKT/NF-κB pathway by downregulating miR-520c-3p, promoting metastasis—a mechanism validated in osteosarcoma models.

In normal physiology, NECTIN4 contributes to intercellular communication via multiple mechanisms. It binds afadin, recruiting tight junction proteins such as ZO-1 to promote epithelial cell–cell adhesion, and cooperates with claudins and occludins to maintain cell polarity and barrier function. During neurodevelopment, NECTIN4 is involved in synapse formation and regulates neuronal signal transmission. Notably, unlike NECTIN1, NECTIN4 does not serve as an entry receptor for α-herpesviruses, making it a safe antiviral therapeutic target.

Oncological Significance and Mechanisms

The mechanisms by which NECTIN4 promotes tumor progression are multifaceted. At the cellular level, NECTIN4 activates the PI3K/AKT signaling pathway to enhance tumor cell proliferation and survival. In bladder cancer cell lines, NECTIN4 monoclonal antibodies suppress AKT phosphorylation, inducing G2/M arrest and apoptosis. In breast cancer models, NECTIN4 forms complexes with HER2, synergistically activating prosurvival signaling. Regarding invasion and metastasis, NECTIN4 facilitates epithelial-mesenchymal transition (EMT) by upregulating MMP9 and SNAIL1, thereby increasing migratory capacity.

Of particular importance, NECTIN4 plays a central role in angiogenesis and lymphangiogenesis. The soluble NECTIN4 domain interacts with endothelial integrin β4, activating the Src–PI3K–Akt–iNOS pathway to stimulate neovascularization. Simultaneously, it promotes lymphatic vessel proliferation via VEGF-C–dependent mechanisms, creating conduits for tumor dissemination.

Clinical Translation and Drug Development

Enfortumab vedotin (trade name Padcev), the world's first NECTIN4-targeting ADC, was granted accelerated FDA approval in 2019, marking the beginning of NECTIN4-targeted therapy. Developed jointly by Astellas and Seagen, the drug combines a humanized anti-NECTIN4 antibody with the microtubule-disrupting agent monomethyl auristatin E (MMAE), linked via a cleavable mc-vc linker. In the pivotal Phase II EV-201 trial, patients with metastatic urothelial carcinoma previously treated with platinum and PD-1/PD-L1 inhibitors achieved an ORR of 44%, including a 12% complete response rate, with a median duration of response (DOR) of 7.6 months. Based on these results, in April 2023, the FDA approved Padcev in combination with pembrolizumab as a first-line treatment for locally advanced or metastatic urothelial carcinoma.

The success of Padcev has spurred a new wave of NECTIN4-targeted drug development. 9MW2821, developed by Mabwell Biotech, is the first NECTIN4 ADC to enter Phase III trials for cervical cancer. Using site-specific cysteine conjugation (DAR=4) and a novel cleavable linker for a new microtubule inhibitor, its Phase I/II data presented at ASCO 2024 showed promising results: among 53 patients with platinum-refractory recurrent/metastatic cervical cancer, ORR was 35.8%, disease control rate (DCR) 81.1%, median progression-free survival (PFS) 3.9 months, and 12-month overall survival rate 74.6%. In patients with strong NECTIN4 (3+) expression, ORR rose to 43.6%, highlighting the value of biomarker-guided therapy. Currently, three Phase III trials of 9MW2821 are underway, targeting cervical cancer, third-line urothelial carcinoma, and first-line therapy in combination with PD-1 inhibitors.

Table: Global Progress in NECTIN4-Targeted Drug Development

Drug Name	Developer	Payload Type	DAR	Development Stage	Indication(s)
Enfortumab vedotin (Padcev)	Astellas/Seagen	MMAE	3.8	Approved	Urothelial carcinoma
9MW2821	Mabwell Biotech	Microtubule inhibitor	4	Phase III	Cervical, urothelial cancer
LY4052031	Eli Lilly	Camp98 (TOP1i)	8	Phase I (terminated)	Solid tumors
ADRX-0706	Adcentrx	AP052 (tubulin inhibitor)	8	Phase Ia/Ib	Advanced solid tumors
IPH45	Innate Pharma	Topoisomerase I inhibitor	-	Phase I	Solid tumors
CNTY-107	Century Therapeutics	CAR γδ T cells	-	Preclinical	Solid tumors

Patent analysis points to future innovation directions. Chinese patent 202180087838 proposes targeting the VC1 bridge domain with antibodies that block NECTIN4-mediated cell–cell adhesion, disrupt tumor cell clustering, and enhance ADC tissue penetration. These antibodies bind the K197/S199 epitope, demonstrating threefold increased antitumor activity in vivo compared to enfortumab vedotin's IgV-targeting strategy. Another breakthrough involves the use of exatecan as a payload. When linked via cleavable connectors, it retains high efficacy even in tumors with high MDR expression, addressing chemotherapy resistance.

With ongoing research, the scope of NECTIN4-targeted therapy continues to expand. Beyond ADCs, bispecific antibodies, CAR-T therapies, and oncolytic viruses are under clinical development. Century Therapeutics' CNTY-107 is the first preclinical iPSC-derived NECTIN4 CAR γδ T cell therapy. Leveraging the innate properties of γδ T cells enables HLA-independent targeting of NECTIN4-positive tumors and offers a promising "off-the-shelf" solution for solid tumors, addressing the infiltration challenges of traditional CAR-T therapy.

References:

Klümper N, Eckstein M. Biomarkers of Response to Anti-NECTIN4 Antibody-Drug Conjugate Enfortumab Vedotin in Urothelial Cancer. Eur Urol Focus. 2024 Mar;10(2):224-226.
Wong JL, Rosenberg JE. Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma. Expert Opin Biol Ther. 2021 Jul;21(7):863-873.
Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol. 2021 Nov 15;911:174516.

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