Overview of Nectin
Nectin, a cell adhesion molecule belonging to the Immunoglobulin (Ig) superfamily, is a homologue of poliovirus receptor (PVR/CD155). It also known as poliovirus receptor-associated protein Receptor Related Protein (PVRL). At present, five members of this family have been found, named respectively: Nectin-1, Nectin-2, Nectin-3, Nectin-4 and poliovirus receptor (PVR), among which PVR and Nectin-2 are part of α herpes virus receptor. Except for Nectin-4, there are 2-3 isoforms formed by different cutting methods, such as: Nectin-1 has α, β and δ in three forms, Nectin-2 has α and δ in two forms, Nectin-3 also has α, β and δ in three forms, of which α is the highest content in the tissue.
Nectins play an important role in cadherin-based intermediate junctions in epithelial cells and fibroblasts. It plays an important role in the formation of adhesion connections between epithelial and endothelial cells. In addition to its pleiotropic function in cell-cell adhesion, Nectin is involved in a range of biological processes, including viral entry and immune regulation. Many viruses use the same surface of immunoglobulin superfamily proteins to mediate homotypic and heterotypic interactions to facilitate viral orientation, attachment, and subsequent entry into target cells. In fact, Nectin-1 and Nectin-2 (also known as PVRL1 and PVRL2) can interact directly with herpes simplex virus glycoprotein D(gD), It was originally isolated as an invasive receptor for herpes simplex virus (HSV) HSV-1 and HSV-2.
Overview of Nectin-4
In 2001, it was first reported that a gene segment encoding Nectin-4 on human chromosome 1, which contains 149,475 base pairs and was later named AL162592. It has been confirmed that nine exons in this segment are involved in the coding. Northern blot technique showed that Nectin-4 was expressed in both placental tissue and tracheal tissue, and the expression of Nectin-4 was higher in placental tissue than in tracheal tissue, but not found in other adult tissues.
Nectin-4 is abnormally high expressed in bladder cancer, lung cancer, breast cancer and ovarian cancer and has been identified as a histological and serological marker of breast cancer. Except Nectin-4, all Nectin family members are widely expressed in epithelial, endothelial, hematopoietic, neuronal cells, fibroblasts and other cells of normal adult tissue. Among them, Nectin-1 and -2 are widely expressed in various tissues, Nectin-3 is mainly expressed in testis and placenta. Thus, Nectin-4 has been defined in various cancers as a tumor-associated antigen with cancer-promoting properties that play a key role in tumor biology.
Structure of Nectin-4
Nectin-4, also known as PVRL4, belongs to the Nectins family and is a transmembrane cell adhesion molecule (type I transmembrane protein) with a molecular mass of about 66kda. It is mainly encoded by the NECTIN4 gene located on 1q23.3. The Nectin family of membrane proteins, including Nectin-4, have the following characteristics:
- Extracellular structural region consisting of three conserved IG-like rings (one IGV ring and two IGC rings)
- A transmembrane domain
- Cytoplasmic domains containing AFadin-binding motifs.
Nectin-4 differs from other proteins in the Nectin family, with sequence homology ranging from 25% to 30%. Nectin-1, 2, and 3 are expressed in adult tissues, but Nectin-4 is mainly expressed in the embryonic period and declines in adult expression.
Nectin-4 signaling pathway
Although the role of Nectin-4 in tumor metabolism and angiogenesis is still unclear, it is involved in various processes of tumor development. In other words, Nectin-4 plays an important role in the tumor signaling pathway. Nectin-4 upregulation activates the PI3K/AKT pathway, which in turn activates the Rac1 signaling pathway in preclinical models of gallbladder and gastric cancer. Activated Rac1 promotes liposome formation at the edge of migrating cells and anchorage-independent growth through activation of β4/SHP-2/c-Src In addition, Nectin-4 also participates in the activation of the Wnt signaling pathway through the PI3K/AKT axis in breast cancer stem cells, thereby promoting the proliferation and metastasis of cancer cells. Nectin-4 also causes the proliferation of human breast ductal carcinoma cell line T47D.
Design of ADC targeting Nectin-4
The expression of Nectin-4 is limited in normal tissues and high in cancer cells, so it can be used as a target for ADC development. Enfortumab, an ADC that targets Nectin-4, has been developed to date. The antibody was mainly expressed by CHO cells. Enfortumab can destroy microtubules and induce cell apoptosis by linking fully human monoclonal antibodies and MMAE with cleavable linkers.
Prospect of Nectin-4
- Molecular probe
In order to eliminate the shortcomings and limitations of biopsy analysis in displaying and characterizing Nectin-4 expression and mapping Nectin-4 heterogeneity, radionuclide imaging is a new development direction. The application of Nectin-4 in cancer diagnosis and treatment, in addition to ADC, is also developing molecular probes and CAR-T therapies targeting Nectin-4.
- Oncolytic virus therapy
Nectin-4 is a powerful weapon in the treatment of cancer. In fact, the increase in clinical trials combining anti-Nectin-4 with other anti-tumor molecules indicates the strategic position of Nectin-4 in the tumorigenic pathway. The silencing of Nectin-4 reduces the proliferation of hemangiosarcoma and skin squamous cells, but increases the expression of cyclin D1, especially inducing the up-regulation or down-regulation of VEGFR2. Therefore, Nectin-4 may participate in the regulation of angiogenesis by up-regulating the expression of VEGFR2. This is closely related to the development of cancer. All in all, Nectin-4 is a promising target for tumor therapy.