Abstract 2871: Comparative anti-tumoral efficacy of endoglin-targeting ADCs harbouring different payloads for the treatment of gastric cancer

Endoglin (CD105), a TGFb-RII co-factor, overexpressed in tumor microvasculature and endothelial-derived CAFs, has been extensively validated as a therapeutic target for cancer treatment. Endoglin-targeting ADCs have been developed in this work, using a human IgG1 antibody, OMTX003, conjugated to different microtubule inhibitors such as eribulin (OMTX603-3) or MMAE (OMTX103), with DAR values between 4 and 8. Target binding was maintained within subnanomolar values for each ADC, similar to the unconjugated antibody. Internalization was efficient, with 75% intracellular localization within 60 minutes, regardless of the conjugated payload. In vitro activity in Endoglin-expressing HT1080 cells was target- and concentration-dependent, with IC50 values of 6 and 95.5pM, respectively. ADCs were tested for their in vivo anti-tumor efficacy in a gastric cancer PDX murine model. Complete tumor regression was observed. No re-growth occurred up to 40 days after treatment end, showing the lack of resistance to treatment. ADCs were well tolerated with no weight loss. These encouraging results are postulating these anti-ENG ADCs for further development. Citation Format: Isabel Egaña, Patricia González-Callejo, Alvaro González, Cristina Ferrer, Roland Kontermann, Oliver Seifer, Klaus Pfizenmaier, Myriam Fabre. Comparative anti-tumoral efficacy of endoglin-targeting ADCs harbouring different payloads for the treatment of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2871.