Dosing has begun in a Phase 1 clinical study evaluating BAT8007, an antibody-drug conjugate (ADC) that targets Nectin-4 being developed by Guangzhou, China-based Bio-Thera Solutions.

The multi-center, open-label Phase 1 clinical study in patients with advanced solid tumors aims to evaluate the safety and tolerability of BAT8007. Key objectives of the study are to determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to evaluate the pharmacokinetics and preliminary efficacy in patients with advanced solid tumors.

BAT8007 is an antibody-drug conjugate (ADC) targeting Nectin-4 designed for the treatment of solid tumors. The investigational agent targets Nectin-4.[1]

Nectin-4, a poliovirus receptor-related-4 (pvrl-4) encoded protein, belongs to the nectin subfamily of  immunoglobulin-like protein that participate in Ca(2+)-independent cell-cell adhesion. 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]

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In recent years, researchers have found that Nectin-4 is especially over-expressed in various malignant solid tumors, including urothelial carcinoma, breast cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer, esophageal cancer and head and neck cancer.[1]

Over-expression of Nectin-4 has also been associated with various aspects of tumor progression, including proliferation, angiogenesis, epithelial to mesenchymal transition, metastasis, DNA repair, tumor relapse, poor prognosis in several types of cancer.

Nectin-4 has high expression levels in a normal embryo and fetal tissues, while those expression levels decline in adulthood and has limited distribution in healthy tissues.

High expression levels of Nectin-4 in tumors is associated with poor prognosis for patients.

Today, enfortumab vedotin (Padcev®; Astellas Pharma US/Seagen) is the only Nectin-4-directed antibody drug conjugate (ADC) approved by the U.S. Food and Drug Administration.  The FDA approved enfortumab vedotin in 2019 for the treatment of patients with locally advanced or metastatic uroepithelial cancer (la/mUC) who have received prior PD-1/L1 inhibitors and platinum-based chemotherapy.  With only approved drug for the treatment of solid tumors and is a target of high interest for new drug discovery, there remains a major unmet medical need.

The investigational agent was developed by using Bio-Thera’s proprietary ADC linker-payload that includes a cleavable but systemically stable linker, a small molecule topoisomerase I inhibitor and high DAR.

The small molecule topoisomerase I inhibitor payload carried by BAT8007 has a strong cell membrane penetration ability. Consequently, when targeted cancer cells are killed, the payload has shown to be released and kill nearby cancer cells, producing a bystander effect, which has the potential to overcome the heterogeneity of the tumor. BAT8007 has demonstrated high anti-tumor activity, good stability, and safety in both in vitro and in vivo pharmacological studies.

Bio-Thera Solutions is developing four other ADCs based on its proprietary linker-payload, including ADCs targeting FRα (BAT8006), B7H3 (BAT8009), HER2 (BAT8010), and TROP2 (BAT8008). All of the ADCs in Bio-Thera’s pipeline are currently in early-stage clinical studies.

Clinical trials
Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of BAT8009 –NCT05405621
Evaluate the Safety, Tolerability and Pharmacokinetic Characteristics of BAT8008 for Injection – NCT05620017

Highlights of prescribing information
Enfortumab vedotin (Padcev®; Astellas Pharma US/Seagen) [Prescribing Information]

[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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