Overcoming multidrug resistance in gastrointestinal cancers with a CDH17-targeted ADC conjugated to a DNA topoisomerase inhibitor.

Cadherin 17 (CDH17) has emerged as a promising target for gastrointestinal (GI) cancers, which are often complicated by multidrug resistance (MDR) and recurrence. In this study, we developed 7MW4911, a CDH17-targeted antibody-drug conjugate (ADC) that incorporates a topoisomerase inhibitor MF-6 (Topi MF-6) payload linked via a cleavable linker, designed specifically to address MDR in GI cancers. 7MW4911 exhibited high specificity for CDH17-expressing cancer cells and potent cytotoxicity in vitro.

Structural and Functional Characterization of Disulfide Bond Isomers of Therapeutic Immunoglobulin G2 Antibody.

Human immunoglobulin G2 (IgG2) is a crucial therapeutic monoclonal antibody (mAb). IgG2 possesses a unique short hinge region characterized by four pairs of interheavy chain disulfide bonds, generating multiple disulfide-bonded isomers, including IgG2-A, IgG2-B, and the intermediate IgG2-A/B. Despite their biological relevance, the characterization of isomers has primarily focused on IgG2-A and IgG2-B, with IgG2-A/B overlooked.

Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate.

We designed and developed 9MW2821, an anti-Nectin-4 antibody-drug conjugate (ADC) with an enzymatically cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) as the payload. Four bioanalytical assays for total antibodies, conjugated antibodies, conjugated payload, and free payload were then developed and validated for the comprehensive evaluation of the multiple drug forms of 9MW2821. Specific sandwich enzyme-linked immunosorbent assays were used to quantify total antibodies and conjugated antibody, showing good drug-to-antibody ratio (DAR) tolerance.

A HER2-targeted antibody-novel DNA topoisomerase I inhibitor conjugate induces durable adaptive antitumor immunity by activating dendritic cells.

We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory.

Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers.

Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody-drug conjugate (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV.