Abstract Intratumoral heterogeneity and interpatient tumor heterogeneity have been recognized as hurdles for efficacious cancer treatments and may result in short duration of response and resistance to classical chemotherapies. It has been shown that combinations of chemotherapy drugs with an independent mode-of-action (MoA) controls tumor growth and enhances survival in both, hematological and solid tumors. In the past years, antibody-drug conjugates (ADCs) have successfully been included in cancer treatment paradigms. Recently, there has been a growing interest in dual-payload ADCs (dpADCs), i.e. ADCs consisting of two payloads conjugated to a tumor targeting antibody, for developing more efficacious ADCs. Similar to combining chemotherapy drugs, combining two payloads with independent MoA in one ADC might be an attractive strategy to address interpatient and intratumoral heterogeneity and increase response rate, duration of response, overall survival and overcome resistance. These payloads may act on (1) different cellular pathways (complementary MoA), (2) the same cellular pathway, or (3) the payloads may have a different pharmacokinetic profile, and by this dpADCs may enhance anti-tumor activity. Previously, we have shown that the native glycan of monoclonal antibodies is a privileged site for attachment of cytotoxic payloads1 (GlycoConnect© technology), while the therapeutic index is further elevated by a highly polar spacer technology (HydraSpace©)2. Here we show that GlycoConnect© technology can readily be extended to generation of dpADCs. We have developed a modular method enabling generation of dpADCs with tailored payload ratios. In vitro and in vivo studies will be presented showcasing these GlycoConnect© dpADCs combining payloads with different MoAs. 1Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14, doi: 10.1080/19420862.2022.2078466. 2Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012. Citation Format: Remon van Geel, Lieke Kraaijvanger, Mick Verhagen, Nick Burgers, Marie Nassiet, Margarida Espadinha, Elias Post, Sander van Berkel, Floris van Delft, Marcel Scheepstra, Anette Sommer. GlycoConnect© ADC toolbox expansion with dual payload ADC (dpADC) technology 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 1699.
Geel et al. (2026) studied this question.