At present, ADC targets mainly focus on HER2, TROP2 and Claudin18.2, while the research and development of Nectin-4 targets is relatively small, with only 10 pharmaceutical companies in the world working on it. To date, the only Nectin-4 ADC drug approved by the FDA is Enfortumab Vedotin (EV), which is approved for advanced and metastatic urothelial carcinoma. Nectin-4 is a well-verified oncology target, and its clinical potential needs to be further developed. The development of drugs targeting Nectin-4 has broad market prospects.
In recent years, the incidence of bladder cancer has remained high, and urothelial carcinoma is the most common type of bladder cancer. Nectin-4 exists on the surface of most urothelial cancer cells and is rarely expressed in normal tissues, so it can be used as a target for cancer development. The ADC drug targeting Nectin-4 - Enfortumab Vedotin (EV) has achieved ideal clinical efficacy, and is currently developing molecular probes targeting Nectin-4 and CAR-T therapy, and exploring related combination therapies. In the future, the exploration of the mechanism related to Nectin-4 and cancer occurrence is bound to be more and more in-depth.
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 NECTIN4 gene located on 1q23.3.
Nectin family membrane proteins, including Nectin-4, have the following characteristics:
(1) An extracellular structural region consisting of three conserved IG-like rings (one IGV ring and two IGC rings)
(2) A transmembrane domain
(3) Cytoplasmic domains containing afadin binding motifs.
Figure 1: (A) Schematic diagram of the Nectin protein family, (B)Nectin-4, and (C) Nectin-like molecules (Necls)
(Source: Subhajit Chatterjee, et,al,2021)
Nectin-4 is quite different from other proteins in the Nectin family, and the sequence homology is between 25% and 30%. Nectin-1, 2, and 3 are expressed in adult tissues, but Nectin-4 is mainly expressed in embryonic period, and its expression declines in adulthood.
Research Progress of Nectin-4 Targets
Nectin-4 (Nectin cell adhesion molecule 4) is a type I transmembrane cell adhesion molecule belonging to the Nectin family. A homolog formerly known as the poliovirus receptor (PVR/CD155) is also known as the poliovirus receptor associated (PRR) protein. During physiological development, Nectin-4 is specifically expressed during embryonic and fetal development and is very low expressed in adult tissues. It forms physical connections between neighboring cells and is essential for enabling intercellular communication, migration, and other important cellular processes.
Nectin-4 is overexpressed in a variety of tumor cells, and Nectin-4 is used as a marker for cancer recurrence and metastasis, which is associated with poor prognosis of a variety of cancers, including uroepithelial carcinoma, breast cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, hepatocellular carcinoma and bladder cancer. Nectin-4 can promote tumor cell proliferation and differentiation, angiogenesis, lymphangiogenesis and lymphatic metastasis through activation of PI3K/AKT pathway, playing an important role in the occurrence and metastasis of cancer. Nectin-4 is also an independent biomarker associated with poor overall survival in some cancer types. Due to its high specific expression in tumors, drug studies targeting this target have emerged.
Figure 2 Mechanism of action of Nectin-4
(Source: Wafa Bouleftour.et al,2023)
Padcev, the First Nectin-4 Targeting Drug
Compared with popular targets such as HER2, EGFR and Trop2, there are currently few targeted drugs targeting Nectin-4, and only one ADC product Padcev (Enfortumab Vedotin) is on the market in the world. Padcev is a "first-in-class" new drug jointly developed by Seagen and Astellas. Seagen is responsible for the ADC linking technology, and Astellas is responsible for the target identification. Seagen is a leading biotechnology company in the ADC field. Three of Seagen's four products currently on the market are ADCs. Padcev is the second ADC drug launched by the company.
Figure 3 Padcev
Source: Astellas Pharma
In December 2019, the FDA accelerated approval of Padcev for the treatment of locally advanced or metastatic uroepithelial carcinoma in patients treated with PD-1/PD-L1 inhibitors and platinum-based chemotherapy agents, based on the Phase II EV-201 trial results. The objective response rate of Padcev was 44% (55/125) compared with previous treatment.
In December 2020, Padcev, declared by Astellas, was approved for clinical use in China, and its indication is locally advanced or metastatic urothelial carcinoma.
In July 2021, Padcev was fully approved by the FDA, and the indications will be extended to patients with locally advanced or metastatic urothelial carcinoma who have received PD-1/PD-L1 inhibitor therapy and are not eligible for cisplatin therapy.
In April 2022, Padcev was approved for marketing in the European Union. In addition to Europe, Padcev is currently approved for marketing in Japan;
In April 2023, the FDA approved Padcev in combination with Keytruda, a PD-1 inhibitor called Perbolizumab, for first-line treatment of locally advanced or metastatic urothelial carcinoma.
The Padcev combination therapy has demonstrated its excellent clinical potential in combination with immune checkpoint inhibitors. In addition to the indications for urothelial cancer, Nectin-4 ADC may be expected to further expand the indications to breast cancer, pancreatic cancer, ovarian cancer, etc. in the future.
According to Seagen's financial report, since Padcev was approved for listing in 2021, its sales in that year reached $340 million, and its sales in 2022 was $451 million. The famous magazine Nature Drug Discovery predicts that Padcev's global sales are expected to reach $3.5 billion by 2026, the performance is second only to Enhertu.
Elevating Padcev therapy to first-line could add more than $1 billion in additional sales. According to Evaluate Pharma's forecast, Padcev sales are expected to reach $4.7 billion by 2028.
Nectin-4 and Cancer
It has been known that NECTIN-4 is abnormally expressed in a variety of cancers, including bladder cancer, breast cancer, lung cancer, pancreatic cancer and ovarian cancer. Serum Nectin-4 levels were significantly elevated in patients with non-small cell lung cancer or serous ovarian cancer. Therefore Nectin-4 can be used as a marker to monitor cancer recurrence and metastasis.
Preclinical models demonstrated that Nectin-4 exsits in cell membranes and cytoplasm. Recently, Nectin-4 expression has been found to be upregulated in some rare cancers, such as osteoma and hemangioma, and some papillary thyroid cancers, making Nectin-4 a promising target for cancer therapy.
However, overexpression of Nectin-4 does not indicate that nectin-4 is associated with cancer development. At present, the role of Nectin-4 in tumor metastasis and abnormal angiogenesis is unclear, and there is insufficient evidence to show that Nectin-4 is the driving gene of cancer, and other outcome factors may be needed to assist.
Angiogenesis and Lymphangiogenesis
After tumor cells proliferate, malignant cells often tend to spread through the angiogenesis or lymphangiogenesis pathway. Nectin-4 is then involved in tumor metastasis through the process of angiogenesis. PI3K and AKT also participate in the formation of new blood vessels through the soluble Nextin-4 extracellular domain, which interacts with endothelial integrin-β4 to promote angiogenesis through Src, PI3K, Akt, and iNOS(inducible nitric oxide synthase).
In angiosarcoma model in vitro, Src controls angiogenesis, and in osteosarcoma, Nectin-4 induces the expression of PI3K/AKT/NF-κB by down-regulating the expression of miR-520c-3p, thereby promoting the progression and metastasis of osteosarcoma, Nanoquinoline inhibits DNA repair and angiogenesis by regulating the inner and outer regions of Nextin-4.
In addition, Nectin-4 is involved in lymphangiogenesis, which is another pathway that promotes tumor metastasis through regulation. More mechanisms and regulatory drugs need to be further discovered.
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. Applications of Nectin-4 in cancer diagnosis and treatment include the development of molecular probes targeting Nectin-4 (as shown in below table) and CAR T therapy (NCT03932565) in addition to ADCs.
Nuclear medicine molecular probes targeting Nectin-4
The FDA has approved the combination of enfortomab vedotin and pembrolizumab as a first-line drug for the treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. The combination of enfortomab vedotin and other immunotherapies and drugs in the future is very worth looking forward to.
Oncolytic virotherapy is another innovative strategy in which Nectin-4 shows promise. Preclinical trials have shown that recombinant measles virus has antitumor effects on Nectin-4 positive colorectal cancer cells, pancreatic cancer cells, and triple-negative breast cancer cells, including cells that are ineffective to targeted therapy.
Nectin-4 is a powerful weapon in the treatment of cancer. Indeed, the increase in clinical trials combining anti-Nectin-4 with other anti-tumor molecules suggests Nectin-4's strategic role in tumorigenetic pathways. As mentioned above, Nectin-4 is involved in malignant cell proliferation. The silencing of Nectin-4 decreased the proliferation of hemangiosarcoma and cutaneous squamous cells, but increased the expression of cyclin D1 (cyclin D1), especially induced the up-regulation or down-regulation of VEGFR2. Therefore, Nectin-4 may be involved in the regulation of angiogenesis by up-regulation of VEGFR2 expression. This is closely related to the occurrence of cancer. All in all, Nectin-4 is a very promising target in tumor therapy.
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. Heath, E.I. and J.E. Rosenberg, The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nature Reviews. Urology, 2021. 18(2).
. Bouleftour, W., P. Sargos, and N. Magne, Nectin-4: a Tumor Cell Target and Status of Inhibitor Development. Current Oncology Reports, 2023. 25(3): p. 181-188.
. Takano, A., et al., Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Research, 2009. 69(16): p. 6694-6703.
. Zhang, Y., et al., Nectin-4 promotes gastric cancer progression via the PI3K/AKT signaling pathway. Human Pathology, 2018. 72: p. 107-116.
. Zhang, Y., et al., A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. Cancer Letters, 2016. 375(1): p. 179-189.
. Nectin-4-Directed Drugs for Solid Tumors
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. HER2 Targeted Therapies In Breast Cancer
. Claudin18.2 Targeted Therapies In Cancer