Abstract 1723: Application of clinical stage GlycoConnect® technology to bispecific antibodies yields improved bispecific ADCs in comparison to randomly conjugated bsADCs

Abstract Several bispecific antibodies (bsAbs), with the ability to bind selectively and in a concerted fashion to two tumor associated antigens (TAAs) or in the form of a biparatopic antibody, have meanwhile been approved for cancer therapy. Another increasingly successful modality for anti-cancer therapy are antibody-drug conjugates (ADCs). Although typically based on random conjugation to cysteine or lysine residues, we have shown that the native glycan of monoclonal antibodies is a privileged site for attachment of cytotoxic payloads1, while the therapeutic index is further enhanced by a highly polar spacer technology (HydraSpace®)2. Complemented by a broad choice of payloads with various modes-of-action (toxSYN® platform), these technologies have jointly been applied in multiple clinical ADC programs with the most advanced now in phase 3. As multiple different bsAb formats have been introduced and are currently in clinical trials3 we wanted to understand how GlycoConnect® conjugation technology would work in context of different bsAb formats to create site-specific ADCs with defined DAR. To this end, GlycoConnect® bispecific ADCs (bsADCs) were generated with high yield and purity and the successful application of the GlycoConnect® technology was demonstrated for several different bsAb formats. In addition, we will show the advantages of GlycoConnect® conjugation in generating bsADCs compared to random cysteine conjugation. GlycoConnect® bsADCs are more homogeneous than randomly conjugated bsADCs, have improved stability and provide for compelling antitumor activity in in vivo cancer xenograft models. 1 (a) van Geel et al. Bioconj. Chem. 2015, 26, 2233-2242. (b) Wijdeven et al. MAbs 2022, DOI: 10.1080/19420862.2022.2078466. 2 Verkade et al. Antibodies 2018, 7, 12, doi:10.3390/antib7010012. 3 Herrera et al. Trends in Cancer 2024, 10, 10, doi.org/10.1016/j.trecan.2024.07.002. Citation Format: Lianne Lelieveldt, Nazli Hilal Turkmen, Kinneret Rozales, Maya Wadmany, Anna Kaliakatsou, Floris van Delft, Anette Sommer. Application of clinical stage GlycoConnect® technology to bispecific antibodies yields improved bispecific ADCs in comparison to randomly conjugated bsADCs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1723.