Only ten new anticancer drugs targeting Nectin-4 are under clinical research in the world. What are the prospects?

Role of Nectin-4 in tumors

Urothelial carcinoma is a malignant tumor originating from the urinary bladder urothelium. It is one of the most common malignant tumors of the urinary system, accounting for more than 90% of bladder cancers.

In 2020, there were 516,000 new cases of urothelial carcinoma in the world, including about 77,000 new cases in China. By 2025, the number of new cases of urothelial cancer is expected to reach 586,000 globally (about 91,000 in China).

Chemotherapy is the main treatment for bladder cancer.

According to the National Health Commission Guidelines for the Diagnosis and treatment of Bladder Cancer (2022 edition), platinum-based combined chemotherapy is the most important and basic treatment for patients with metastatic bladder urothelial carcinoma.

Anti-pd-l1 checkpoint inhibitor immunotherapy is available for patients who do not respond to platinum-based therapy, but the average immune checkpoint inhibitor response rate is only about 20% and patients do not have access to supportive care.

Therefore, there is an urgent need for new and more effective therapies to treat urothelial carcinoma.

Tumor antigens are expressed on the surface of tumor cells and are potential targets for innovative drug development.

One of these antigens is tumor-associated Nectin-4, a member of the nectin family of the immunoglobulin superfamily, which is overexpressed in most urothelial carcinomas.

Two variants of Nectin-4 have been reported. Nectins have three domains:

Cell region, consisting of three conserved Ig-like rings (one IgV ring and two IgC rings)

Transmembrane domain

Cytoplasmic domain, containing an afadin binding module

Studies have shown that Nectin-4 is associated with the promotion of cancer cell proliferation and metastasis through the activation of Rac small G protein in WNT-β-catenin and PI3K-AKT signaling pathways.

Nectin-4 also interacts with the tyrosine kinase receptor ERBB2 to promote its activation, thereby stimulating the PI3K-AKT signaling pathway.

However, overexpression of nectin-4 by itself is not sufficient to demonstrate its importance for pathogenicity, and direct evidence for ectin-4 as a cancer driver gene is still lacking.

Although nectin-4 has been shown to be a prognostic marker for various cancers, its clinical efficacy needs to be further demonstrated and may be supplemented with other outcome predictors to provide sufficient accuracy and utility in the clinic.

There are only ten in clinical development worldwide

Antibody-conjugates (ADCs) are a class of drugs designed to target antigens on the surface of cells. As a tumor surface antigen, Nectin-4 is theoretically an effective target for ADC drug design.

Enfortumab vedotin is an ADC targeting nectin-4.

It is composed of human anti-Nectin-4 antibody and cytotoxic microtubule destructor monomethyl auristatin E (MMAE). After injection into human body, the drug was enriched at the tumor site by antibody-antigen binding.

Subsequently, proteases hydrolyze the linker between the antibody and the payload MMAE, releasing the MMAE, which disrupts microtubules and induces apoptosis 14.

In 2019, Enfortumab vedotin (Padcev) was approved by the FDA for the treatment of locally advanced and metastatic urothelial carcinoma, becoming the first and only approved ADC targeting nectin-4.

In February 2020, the combination of enfortumab vedotin and pembrolizumab was granted breakthrough therapy designation by the FDA as a first-line treatment for patients with locally advanced or metastatic urothelial cancer eligible for cisplatin. In 2020, Padcev generated more than $200 million in sales.

The challenge of targeting Nectin-4

Nectin-4 is primarily used as a binding platform for ADC-class drug Enfortumab vedotin to deliver payload MMAE and destroy nectin-4 expressing cancer cells.

It has been suggested that tumor shrinkage is due to toxin delivery rather than anti-Nectin-4 antibody, for example, anti-Nectin-4 antibody AGS-22M6 without payload has no intrinsic antitumor activity in vitro or in vivo.

Therefore, the design of drugs targeting Nectin-4 needs to be fully aware of this. Is it to directly act on nectin-4 or use this as a platform to design ADCs?

Targeting nectin-4 was the first breakthrough in bladder cancer treatment primarily because nectin-4 is overexpressed in almost all bladder cancers.

But nectin-4 is also present in normal tissues, and that's one reason Enfortumab vedotin is toxic. Further optimization of ADCs, including the use of engineered antibodies, novel linkers, ligation methods, and payloads, is required to reduce targeting toxicity.

Although ADCs are potent anticancer agents, resistance to ADCs can develop. Because the resistance mechanisms are adapted to the specific properties and interactions of the three ADC components, namely antibodies, linkers, and payloads, adequate preclinical experiments are needed to understand the causes of overall resistance in ADCs to improve the long-term therapeutic efficacy of ADCs.

Conclusion

The tumor-associated antigen nectin-4 is selectively overexpressed in urothelial carcinoma and other cancer types and represents a viable anticancer therapeutic target for ADCs, although its actual role in tumorigenesis is less significant.

Enfortumab vedotin is the first FDA-approved nectin-4 directed ADC and demonstrates that targeting nectin-4 for cancer therapy is feasible.

As ADC technology matures, it is believed that more targeted drugs will be developed in the future.

References:

1. Research Report on East Asia Foresea Securities

2.Nature Reviews Urology volume 18,pages93 -- 103(2021)