The Center for Drug Evaluation (CDE) of China National Medical Products Administration has approved the investigational new drug application (IND) for 9MW2821, an anti-Nectin-4 ADC drug candidate, being developed by Shanghai Mabwell. A phase I study to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary effectiveness in patients with advanced solid tumors started earlier this month.
Mabwell’s 9MW2821 is a Nectin-4 targeted ADC developed by world-class ADC drug development platform and automated high-throughput antibody discovery platform of Mabwell. This drug candidate has achieved site-specific modification based on the ADC conjugate technology jointly developed by Mabwell and Shanghai Institute of Materia Medica.
Nectin-4, a poliovirus receptor-related-4 (pvrl-4) encoded protein, is a Ca2+ independent immunoglobulin-like protein. Along with other Nectins (Nectin-1, -2, and -3), it is primarily involved in cell-cell adhesion. However, in contrast to other Nectins, Nectin-4 is specifically enriched in the embryonic and placental tissues but its expression significantly declines in adult life. [1]
Nectin-4 is especially overexpressed and served as a tumor-associated inducer in various malignant tumors including breast, lung, colorectal, pancreatic, ovarian cancers etc. This over-expression is generally associated with various aspects of tumor progression like proliferation, angiogenesis, epithelial to mesenchymal transition, metastasis, DNA repair, tumor relapse, poor prognosis in several types of cancer. [1]
Clinical trials
The clinical trials will be conducted for solid tumors including urothelial carcinoma, breast cancer, lung cancer. This is China’s first drug candidate that has been approved to clinical study among its domestic counterparts using the same target. And it will be the second Nectin-4 targeted ADC drug candidate approved to initiate clinical studies in the world.
The investigational ADC is categorized as a Class I innovative drug and is being developed using Mabwell’s novel platform and automated high-throughput antibody discovery platform. The site-specific ADC is created by using a novel conjugate technology which is jointly developed by Mabwell and Shanghai Institute of Materia Medica. The investigational agent boasts the advantages of homogenous structure, high purity, and being easy production. It has also demonstrated favorable druggability properties in binding affinity, endocytosis, preliminary in vivo and in vitro pharmacodynamic activities, drug metabolism properties, and preliminary safety.
Results from preclinical pharmacological and toxicological studies showed that this drug candidate has favorable anti-tumor effects in a variety of animal tumor models. In addition, its safety in cynomolgus monkeys and rats indicated a superior safety margin, which indicates its potential in future trials.
Nectin-4 targeting ADCs
Mabwell’s 9MW2821 is one of 8 Nectin-4 targeted ADCs in clinical development. Other investigational agents include Silverback’s SBT6290, a selective TLR8 agonist conjugated to a Nectin4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells and BT8009 a bicyclic peptide toxin conjugate being developed by Bicycle Therapeutics.
Enfortumab vedotin (Padcev™; Astellas Pharma/Seagen) is currently the only Nectin-4-directed antibody and microtubule inhibitor conjugate.
Highlights of prescribing information
Enfortumab vedotin (Padcev™; Astellas Pharma/Seagen)(Prescribing Information)
Reference
[1] Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol. 2021 Nov 15;911:174516. doi: 10.1016/j.ejphar.2021.174516. Epub 2021 Sep 20. PMID: 34547246.
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