Nectin-4: a Key Target in the IgSF Family, Boosting Clinical Drug Research in Various Tumors!

1. What is Nectin-4?

1.1 The Structure of Nectin-4

Nectin-4 is an immunoglobulin-like molecule belonging to the Nectin family, which also includes NECTIN-1, NECTIN-2, and NECTIN-3. As poliovirus receptor-associated protein PVRL4, Nectin-4 binds to the poliovirus receptor (PVR/CD155). With a molecular weight of approximately 55.5 kDa and consisting of 510 amino acids, Nectin-4 features a distinct three-domain structure: an N-terminal signal peptide that guides its synthesis and localization; three immunoglobulin-like extracellular domains that mediate cell surface recognition and adhesion; a transmembrane region connecting the extracellular domains to the intracellular environment; and an intracellular domain with an afadin-binding motif, allowing specific interaction with the afadin protein. This structure promotes cell-to-cell adhesion, impacts cytoskeletal organization, and affects signal transduction (Figure 1) ^[1-2].

Figure 1. The structure of Nectin-4 ^[1]

1.2 The Expression and Function of Nectin-4

Nectin-4 is essential for cell-to-cell adhesion, utilizing its three immunoglobulin (Ig)-like domains to support cell adhesion, signal transduction, and interactions with the cytoskeleton. It is mainly found in embryonic and placental tissues, with low levels in adults. Recent studies suggest Nectin-4 could be a TIGIT ligand, and antibodies against it enhance tumor cell killing. It also serves as a receptor for certain viruses, providing a method to target and destroy tumors expressing Nectin-4. Abnormal Nectin-4 expression may drive tumor growth and metastasis, highlighting its potential as an anticancer target ^[3-4].

2. Nectin-4 Related Signaling Mechanism

2.1 Nectin-4-Related Cellular Molecular Mechanisms

Nectin-4 plays a key role in tumor development by regulating the PI3K/AKT signaling pathway. Under hypoxic conditions, soluble Nectin-4 binds to integrin β4 on endothelial cells, activating Src, PI3K, Akt, and eNOS, which promotes angiogenesis. In breast cancer, Nectin-4, along with ERBB2, activates the PI3K/AKT pathway to enhance DNA synthesis and supports cell proliferation and metastasis through the Wnt/β-catenin signaling. It also drives osteosarcoma development via the PI3K/AKT/NF-κB pathway and accelerates gastric and gallbladder cancers by activating Rac1 (Figure 2) ^[5].

Nectin-4 is crucial in tumor development, influencing various processes by regulating the PI3K/AKT pathway. In hypoxic conditions, soluble Nectin-4 binds to integrin β4 on endothelial cells, activating molecules like Src, PI3K, and Akt, which promotes angiogenesis. For instance, in breast cancer, Nectin-4 and ERBB2 jointly activate the PI3K/AKT pathway, aiding DNA synthesis and cancer cell proliferation. Additionally, Nectin-4 can activate the PI3K/AKT/NF-κB pathway in osteosarcoma and Rac1 in gastric and gallbladder cancers (Figure 2) ^[5].

Nectin-4 influences multiple signaling pathways beyond the PI3K/AKT pathway. It interacts with prolactin receptors through the JAK2-STAT5a pathway, significantly impacting prostate cancer growth. In breast cancer, Nectin-4 enhances p95-ErbB2-triggered JAK-STAT3 signaling, regulating the SOX2 to promote cell proliferation. Additionally, Nectin-4, regulated by the CXCR4/CXCL12-LYVE-1 axis, facilitates tumor-associated lymphangiogenesis and lymphatic metastasis. It also affects intercellular adhesion, remodels the actin cytoskeleton, and triggers EMT process, contributing to tumor spread to distant organs. These findings highlight Nectin-4's broad role in tumor biology and suggest new targets and strategies for cancer treatment ^[6-8].

Figure 2. Nectin-4 participates in multiple tumor processes by regulating PI3K/AKT signaling pathway ^[5]

2.2 Nectin-4 Related Drug Research Mechanisms

The first ADC drug targeting Nectin-4, Enfortumab Vedotin-ejfv (EV), has been approved for treating urothelial carcinoma. EV is a microtubule-inhibiting agent linked to anti-Nectin-4 monoclonal antibody (AGS-22M6) by a protease-sensitive linker MMAE. When EV binds to Nectin-4 on cancer cell surfaces, it triggers endocytosis, allowing the EV-Nectin-4 complex to enter the cell. Inside the cell, the complex is partially hydrolyzed by enzymes and transported to lysosomes, where it is fully decomposed under acidic conditions, releasing MMAE. MMAE inhibits microtubule polymerization, leading to halted cell division and subsequent apoptosis. In preclinical studies, EV significantly reduced tumor growth in mouse models of human breast, lung, and pancreatic cancers, advancing Nectin-4 targeted drugs into clinical trials (Figure 3) ^[5].

Figure 3. The mechanism of the Nectin-4-targeted drugs in tumors ^[5]

3. Nectin-4 and Diseases Research

Nectin-4 has recently drawn attention due to its abnormal overexpression in various cancers, including thyroid, esophageal, gastric, gallbladder, breast, skin, and colorectal cancers. ADCs targeting Nectin-4 have been FDA-approved for urothelial carcinoma, highlighting its role as a key biomarker and promising research target in cancer ^[9].

3.1 Nectin-4 in Digestive System Cancers Research

In colorectal cancer, it serves as a critical biomarker, promotes angiogenesis via integrin β1, impacts prognosis negatively, and is linked to resistance to 5-fluorouracil (5-FU) ^[10]. Gene silencing studies suggest that lowering Nectin-4 expression may be a potential treatment for colorectal cancer. In esophageal cancer, high Nectin-4 levels are associated with shorter survival and increased cell activity and migration ^[11]. For gastric cancer, Nectin-4 expression correlates with TNM stages ^[12]. In gallbladder carcinoma, Nectin-4 promotes tumor growth and metastasis by activating Rac1 ^[13].

3.2 Nectin-4 in Reproductive System Cancers Research

In cervical cancer, it may contribute to the resistance mechanism against 5-FU in metastatic tumors and is involved in processes like angiogenesis and DNA repair ^[14]. In ovarian cancer, high Nectin-4 expression correlates with disease progression and spheroid formation, which negatively impacts the efficacy of chemotherapy ^[15]. Furthermore, in respiratory cancers such as lung cancer, elevated Nectin-4 levels are associated with reduced survival, increased tumor invasiveness, and higher metastatic potential, underscoring its potential as an early diagnostic marker and a target for therapeutic intervention ^[16].

3.3 Nectin-4 in Urinary System or Other Cancers Research

In urinary system tumors, particularly urothelial carcinoma, high Nectin-4 expression is strongly linked to poor prognostic factors, including increased cancer mortality, lymphovascular invasion, and high-grade tumors ^[17]. Additionally, Nectin-4 is associated with several other cancers, such as breast cancer ^[18], liver cancer ^[19], head and neck cancer [20], thyroid cancer ^[20], melanoma ^[22], and skin squamous cell carcinoma ^[23]. It serves as a serum marker in breast cancer, a biomarker in skin squamous cell carcinoma, and plays a role in regulating the AKT/PI3K signaling pathway in melanoma. These observations highlight Nectin-4's central role in cancer research and its potential as a target for treatment strategies.

4. The Clinical Research Prospect of Nectin-4

Currently, only Padcev (Enfortumab Vedotin) has FDA approval for treating locally advanced or metastatic urothelial carcinoma. This approval confirms Nectin-4 as a viable drug target with significant clinical potential. While Padcev demonstrates the promise of Nectin-4 in urothelial cancer, ongoing research suggests its relevance in various other cancers. Many investigational Nectin-4-targeted drugs are advancing through preclinical and early clinical stages. To facilitate the development of these drugs, increased R&D investment and process optimization are essential. Major pharmaceutical companies focus on later-stage trials, while smaller biotech firms handle early research. Future clinical trials are expected to bring more Nectin-4-targeted drugs to Phase II/III, accelerating their development and market entry.

5. CUSABIO Nectin-4 Recombinant Proteins and Antibodies for Research Use

To assist pharmaceutical companies in their clinical research of Nectin-4 in digestive system cancer, reproductive system cancer, and urinary system cancer, etc. CUSABIO launched Nectin-4 active protein product (Code: CSB-MP822274HU), helping you in the research on the mechanism of Nectin-4 or its potential clinical value.

CUSABIO protein Nectin-4

Recombinant Human Nectin-4 (NECTIN4), partial (Active) Code: CSB-MP822274HU

Purity ≥ 95% by SDS

Purity was greater than 95% as determined by SDS-PAGE.

Activity Verified by a Functional ELISA

Immobilized NECTIN4 at 2 μg/ml can bind anti-NECTIN4 antibody (CSB-RA822274A0HU)