Araris Biotech AG announced on April 17 that it will acquire ARS Pharmaceutical's Nectin-4 antibody. Araris Biotech intends to use the acquired Nectin-4 antibody to develop differentiated Nectin-4 ADCs using its proprietary linker technology. According to Araris Biotech, its linker technology can improve the efficacy and tolerability of ADC drugs, significantly reduce the on-target off-tumor of Nectin-4 ADCs, and develop Nectin-4 ADCs with better therapeutic indices.

Ideal antitumor drug target: Nectin-4

Nectin-4 (poliovirus receptor 4) is a Ca2+ independent immunoglobulin-like protein, categorizing to the Nectin family of Ig superfamily proteins. There are Nectin-1, Nectin-2, Nectin-3 and Nectin-4 in the family, and their functions are to form physical connections between adjacent cells and participate in the intercellular communication and migration. 

Nectin-4 is a type I transmembrane protein that is mainly expressed in embryonic and placental tissues, and its expression is significantly decreased in adulthood. Generally speaking, the expression level of Nectin-4 is very low in healthy adult tissues, but it is specifically highly expressed in a variety of tumors, such as Urothelial Carcinoma, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, and gastric cancer. It promotes the tumor proliferation and migration by activating the PI3K/Akt pathway. These characteristics make Nectin-4 an ideal antitumor drug target. 

However, there is only one Nectin-4 ADC approved for marketing in the current, i.e. Seattle Genetics and Astellas Pharma Inc.'s Padcev (Enfortumab vedotin, EV), which is a coupling of a monoclonal antibody targeting Nectin-4 and microtubule-destroying cytotoxic drug MMAE. When the Nectin-4 antibody component in Padcev binds to Nectin-4 on the cell membrane, Padcev is absorbed into cells and linkers are dissolved by the lysosome. The released MMAE binds to microtubules, disrupting microtubule assembly and driving cell cycle arrest and apoptosis. 

In December 2019, Padcev received accelerated FDA approval for adult patients with locally advanced or metastatic urothelial carcinoma who have previously received a PD-(L)1 inhibitor and have received a platinum-containing chemotherapy regimen as part of neoadjuvant/adjuvant treatment or in the treatment of locally advanced or metastatic disease. The approval is based on EV-101 and EV-201 studies. 

EV-101 results show that among 112 patients with metastatic urothelial carcinoma treated with Padcev, the overall response rate (ORR) is 43%, the median duration of response (DOR) is 7.4 months, and the median overall survival (OS) is 12.3 months.

EV-201 results show that in 125 patients with metastatic urothelial carcinoma who have previously received platinum-based chemotherapy and immune checkpoint inhibitor (ICI) treatment, ORR is 44%, with 12% achieving complete response (CR), and the median DOR is 7.6 months. Among 89 patients with metastatic urothelial carcinoma treated only with ICI, ORR is 52% at a median follow-up of 13.4 months, with 20% achieving CR. 

In July 2021, Padcev was approved by the FDA for use in patients with relapsed or refractory advanced/metastatic urothelial carcinoma who have previously received PD-1/PD-L1 and platinum-containing chemotherapy. In December 2022, the FDA accepted a Supplemental Biologic License Application (sBLA) for Padcev in combination with Keytruda in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy. 

The clinical researches of applying Padcev in advanced solid tumors such as breast cancer, NSCLC, gastroesophageal cancer, and head and neck cancer are also conducted. An analysis published in Nature Reviews Drug Discovery predicted that the sales volume of Padcev could reach US$3.5 billion by 2026, making it a blockbuster ADC product. 

Competition in China

The broad-spectrum anticancer activity and market potential of Padcev enable Nectin-4 targets to attract the attention of pharmaceutical companies. Currently, 13 ADC drugs targeting Nectin-4 are under research worldwide. 9MW2821 of China Mabwell, BAT8007 of Bio-Thera and SYS6002 of CSPC Pharmaceutical Group Co., Ltd. are in clinical stages of Phase I and II, SKB410 of Kelun Pharmaceutical has been approved for clinical treatment, and the others are in the preclinical research stage. 

9MW2821 is an ADC drug targeting Nectin-4 developed by Mabwell. It is a combination of innovative antibody molecules, novel linkers, and novel payloads. After injection, 9MW2921 can bind to the antigens on the surface of tumor cells and enter into them. Through specific enzymatic hydrolysis, small molecules can be released to precisely kill tumors. 9MW2821 is homogeneous in structure, and it is easy to be industrialized. There is a good antitumor effect in a variety of animal tumor models. 

On April 5, Mabwell announced the results of Phase II clinical research of 9MW2821. Twelve urothelial carcinoma patients who completed at least one tumor evaluation had an ORR of 50% and a DCR of 100% at the recommended dose for Phase II clinical research (RP2D). Six cervical cancer patients who completed at least one tumor evaluation had an ORR of 50% and a DCR of 100%. At present, the company is actively promoting the research of 9MW2821 in urothelial carcinoma, cervical cancer, prostate cancer, HER2-negative breast cancer and NSCLC. 

BAT8007, a Nectin-4 ADC drug developed by Bio-Thera with its self-developed ADC platform, is composed of recombinant human Nectin-4 antibody and toxic small molecule topoisomerase I inhibitors via shear linkers. The high antitumor activity of BAT8007 and the strong bystander effect of toxin small molecules can effectively overcome the heterogeneity of tumor tissues.

In September 2022, BAT8007 received implied approval for clinical trials in China to be developed for the treatment of advanced solid tumors. On March 13, Bio-Thera announced that it had completed its first patient dosing of BAT8007. 

SYS6002 is a Nectin-4 ADC developed by CSPC Pharmaceutical Group Co., Ltd. with a proprietary enzyme-catalyzed site-specific antibody coupling technology. It can target mitotic inhibitor MMAE into Nectin-4 expressed tumor cells, and it has uniform DAR distribution and good safety. 

In February 2023, CSPC Pharmaceutical Group Co., Ltd announced that its subsidiary, Megalith Biopharmaceutical, had entered into an exclusive licensing agreement with Corbus Pharmaceuticals, Inc. on the development and commercialization of SYS6002. Corbus Pharmaceuticals will pay an upfront payment of US$7.5 million, a development and regulatory milestone amount of US$130 million, a sales milestone amount of US$555 million, and a percentage of sales dividends to acquire the rights and interests of SYS6002 in the US, the EU, the UK, Canada, Australia, etc. 

Kelun Pharmaceutical's SKB410 received the NMPA clinical trial notification in February this year to be developed for the treatment of advanced solid tumors. Kelun Pharmaceutical has licensed nine ADC projects to MSD on three separate occasions, and there is a speculation that SKB410 may be one of them. 

Due to the expression level difference in tumor and normal tissues, Nectin-4 becomes a promising target in the R&D of ADC drugs. At present, this is still a field with an uncertain future, and we will continue to pay attention to who will rank the top in China. 

References

1. Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): a potential target for cancer therapy. Eur J Pharmacol. 2021;911:174516. doi:10.1016/j.ejphar.2021.174516；

2. National Medical Products Administration. Retrieved Sep 23, 2022, from 

   https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d；

3. 1. BT8009; a Nectin-4 targeting Bicycle? Toxin Conjugate for treatment of solid tumors DOI: 10.1158/1535-7163.MCT-21-0875.

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.