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 ...
(All Rights Reserved)