A New Target in ADC: Nectin-4

Recently, the application for clinical trail of Mabwell's ADC drug (9MW2821) targeting Nectin-4 has been accepted by NMPA. It is the first time that domestic enterprise enters the IND stage with the same target drug. It is reported that good effect has been achieved on the preclinical pharmacology and toxicology, and the drug has showed good anti-cancer effect on various animal tumor models.

Nectin-4 (Nectin cell adhesion molecule 4) is a type I membrane protein. It shows overexpression in many tumor cells, such as urothelial carcinoma, breast cancer, pancreatic cancer, triple negative breast cancer and bladder cancer. Nectin-4 can promote the proliferation, differentiation, migration and invasion of tumor cells by activating PI3K/Akt pathway. Therefore, taking Nectin-4 as therapeutic target might become an effective strategy for the treatment of high-expressed cancer of Nectin-4.

In fact, the Food and Drug Administration (FDA) accelerated the approval of enfortumab vedotin (trade name: Padcev) in 2019, which is used for the treatment of locally advanced or metastatic urothelial carcinoma. Padcev is a first-in-class antibody-drug conjugate (ADC) with Nectin-4 as its target, which conjugates anti-Nectin-4 monoclonal antibody with microtubule disruptor MMAE (monomethyl auristatin E).

The reason why FDA accelerated the approval of Padcev is that it shows good therapeutic effect on the patients with metastatic urothelial carcinoma in need of multi-line treatment. The primary outcome indicators are objective response rate (ORR) and duration of response: ORR is 44% (95% CI: 35.1, 53.2), complete and partial remission rates are 12% and 32% respectively; It is estimated that the median duration of response is 7.6 months (95% CI: 6.3). For patients with metastatic urothelial carcinoma who have failed to respond to treatment schemes such as PD-1/PD-L1 inhibitor and neoadjuvant chemotherapy, the successful R&D of Padcev has brought innovative treatment options. Padcev is currently in Phase II/III clinical trials for bladder cancer and other tumors, so as to expand its clinical indications.

Mabwell's 9MW2821 is a new ADC drug targeting Nectin-4 developed based on ADC drug development platform and automated high-throughput hybridoma antibody molecular discovery platform. 9MW2821 has a uniform structure and is easy to be industrialized. It has good medicinal properties in vitro, metabolic properties in vivo and preliminary safety, and has good anti-tumor effects in various animal tumor models. Its clinical value will be reveled in the next clinical trial.

ADC (antibody-drug conjugate) plays an increasingly significant role and shows its great potential in the field of cancer. Hospital supply companies have done a lot to ADC. Most ADC contains a type of cytotoxic drug that binds with a monoclonal antibody (mAb) against a specific tumor-associated antigen. ADC is one of the innovative racetracks with high barriers. It has strong protection effect and great potential. With the continuous iteration and maturity of ADC technology, the curative effect and acting force of ADC drugs have been continuously improved. At present, it has achieved excellent therapeutic effect in clinical trials, showing its advantages in posterior treatment and filling the indications that are still vacant. At the same time, it is expected to push forward the front line and replace some existing therapies. There is great market potential.

Nectin-4 has great potential and has become the target of ADC differentiated layout.

Driven by the development of antibody drugs, the progress and iteration of ADC technology, the R&D of ADC drugs has developed rapidly. At present, there are 10 kinds of ADC drugs on the market, and a total of 6 ADC drugs have been approved for the market in recent two years, exceeding the total number of drugs approved in the previous 17 years in one fell swoop, among which there are many drugs with far-reaching influence. Some analysts predict that the global ADC drug market capacity will reach USD10 billion in 2026 and exceed USD15 billion by 2030.

Looking back at the ADC market, however, the research targets are highly concentrated, mainly focusing on Her2, EGFR, TROP2, etc. Tumor is chosen to be the main indication, accounting for more than 90% of all ADC drugs, and breast cancer is the most popular one, followed by non-small cell lung cancer. The layout of ADC market in China also shows a similar trend. The targets are mainly concentrated in the popular targets of Trop-2, ROR1, BCMA and EGFR, and their indications are also concentrated in the tumor field.

The huge potential of ADC market will attract more enterprises. However, facing highly concentrated targets, indications and differentiated layout, many ADC R&D enterprises have fiercely struggled for seizing opportunities to find suitable drug targets. Although PADCEV, an ADC drug targeting Nectin-4, has been approved for marketing in America, there are few reports on ADC drugs targeting Nectin-4 in China at present. Nectin-4, as a popular target of ADC, has great potential for subsequent development.

Reference:

1.https://www.nature.com/articles/d41573-021-00054-2；

2.Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma；

3.Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4.

About  the Author:    

Yefenghong

Ye  Fenghong, a medical editor specializing in oncology at a healthcare internet  company, has conducted in-depth research on the pathogenesis and clinical  treatment of lung cancer and breast cancer. She has previously been involved  in the design and synthesis of anti-tumor drugs and has some experience in  computer-aided drug design. She is currently devoted to introducing  cutting-edge cancer treatment drugs to a wide range of readers, aiming to  help more people avoid cancer pain and embrace good health.