sofituzumab vedotin (RG 7458) / Roche, Pfizer - LARVOL DELTA

Cytotoxic activity and safety characterization of IMV-M™, a MUC16 × DR5 bispecific antibody. (PubMed, Antib Ther) - "A comparative analysis of three bispecific antibodies, IMV-M (sofituzumab × DR5), 11D10 × DR5, and fluor × DR5, sharing an identical IgG1-anti-DR5 scFv architecture, was performed. IMV-M showed no significant cytotoxicity toward hepatic cell lines, even in the presence of Fc-directed polyclonal antibodies or clinically relevant concentrations of soluble CA125. These findings suggest that IMV-M cytotoxic activity requires clustering on MUC16, that CA125 at clinically relevant concentrations does not mediate IMV-M neutralization, and that aggregate formation with secondary antibodies or soluble MUC16 does not induce off-target toxicity."

Journal • Oncology

Tumor-selective regression through MUC16-guided DR5 (TNFRSF10B) clustering by the bispecific anti-MUC16×anti-DR5 antibody IMV-M™ (AACR 2026) - "IMV-M also lacked cytotoxicity toward hepatic cell lines.MethodsThree bispecific antibodies sharing identical anti-DR5 arms were generated: Sofituzumab (h5A3)×Lexatumumab scFv, 11D10/DR5×Lexatumumab scFv, and (anti-fluorescein)×Lexatumumab scFv. These findings indicate a low risk of off-target hepatic toxicity, consistent with the benign safety profile of earlier anti-DR5 antibodies.ConclusionsEffective DR5 agonism by bispecific antibodies requires high-order receptor clustering. IMV-M achieves this through MUC16-mediated assembly of multiple antibody molecules on a single MUC16 molecule, enabling potent, tumor-selective apoptosis without hepatotoxicity."

Bispecific • Oncology • MUC16 • TNFRSF10B

Preclinical assessment of HWK-016, a next-generation, MUC16-targeting ADC with novel bioconjugation and linker-payload technology (AACR 2026) - "Early clinical trials of MUC16-targeted ADCs, DMUC5754A and DMUC4064A, showed promising efficacy but were limited by targeting an epitope within the shed extracellular domain (ECD) of MUC16, leading to off-target binding to circulating CA125, which created an antigen sink. In summary, HWK-016 is a highly potent, MUC16-targeted ADC directed to the MUC16 non-shed ECD to avoid circulating CA125 binding. A phase I dose-escalation study is planned to evaluate HWK-016 in patients with advanced malignant solid tumors."

ADC • IO biomarker • Preclinical • Lung Cancer • Oncology • Solid Tumor • MUC16 • MUC4

Therapeutic Applications and Target Strategies of Antibody-Drug Conjugates in Ovarian Cancer. (PubMed, Iran J Pharm Res) - "This review summarizes a range of ADCs targeting tumor-associated antigens in ovarian cancer, including mirvetuximab soravtansine (MIRV), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), sacituzumab tirumotecan (SKB-264), PF-06664178, anetumab ravtansine (BAY 94-9343), BMS-986148, DMOT4039A, RC88, lifastuzumab vedotin (DNIB0600A), upifitamab rilsodotin (ABBV-181), ZW220, DMUC4064A, and sofituzumab vedotin (DMUC5754A). The ADCs hold significant potential to reshape the treatment landscape for ovarian cancer by providing targeted therapeutic options. Further research is required to optimize patient selection, address resistance mechanisms, and improve safety profiles."

Journal • Review • Oncology • Ovarian Cancer • Solid Tumor • MUC4

Pharmacokinetics of a THIOMABTM antibody drug conjugate (TDC): DMUC4064A in a phase 1 study with platinum-resistant ovarian cancer (AACR 2017) - "Compared to the conventional anti-MUC16 ADC (DMUC5754A, DAR 3.5) at 2.4 mg/kg (MTD), the TDC DMUC4604A at 5.6 mg/kg demonstrates a greater than 3 fold slower acMMAE clearance1. In this ongoing study of DMUC4604A, nonlinear PK of acMMAE and tAb were observed over the dose range studied, and exposures of acMMAE and tAb were highly correlated. This is the first report of clinical PK data of a TDC demonstrating slower clearance compared to a conventional ADC format."

Clinical • P1 data • Biosimilar • Gynecologic Cancers • Oncology • Ovarian Cancer