Year: 2026
Type: preprint
Abstract: Background IMV-M is a MUC16×DR5 bispecific antibody has demonstrated MUC16-selective anti-tumor activity. However, it remained unclear whether multiple binding of IMV-M on a single MUC16 molecule was required for IMV-M cytotoxicity, whether circulating CA125 could attenuate its efficacy or cause off-target toxicity, and whether anti-drug antibodies might induce IMV-M aggregation and related adverse effects. Methods 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. Sofituzumab binds to multiple epitopes on a single MUC16 molecule, whereas 11D10 binds a single MUC16 epitope, and fluor does not bind any human antigen. Antibody binding to shed and cell-surface MUC16 was evaluated by ELISA and flow cytometry. Cytotoxicity was assessed in a MUC16 + /DR5 + tumor cell line and MUC16 − /DR5 + hepatic cell lines. Additional studies examined the effects of soluble CA125 and Fc-directed polyclonal antibodies on IMV-M activity. Results IMV-M bound MUC16 to a markedly higher extent than the 11D10×DR5 comparator, consistent with its multivalent engagement, while binding of fluor×DR5 to MUC16 was negligent. Only IMV-M induced potent cytotoxicity in MUC16 + tumor cells, whereas 11D10×DR5 and fluor×DR5 control antibodies were inactive, demonstrating that multivalent clustering on MUC16 is required for apoptosis. 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. Conclusions These findings indicate 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.
Authors: Victor S. Goldmacher, Iosif M. Gershteyn
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7128720213