Abstract
Antibody-drug conjugates (ADC) offer a targeted cancer treatment approach by delivering cytotoxic payloads directly to tumor cells. However, resistance mechanisms, poor tumor penetration, and off-target toxicity often limit clinical efficacy. Vartumab targets oncofetal chondroitin sulfate (ofCS), a pan-cancer target present on tumor cells and in the malignant stroma, with low expression in normal tissues. As part of transitioning Vartumab to clinical evaluation, two linker-payloads known to mediate bystander effects, valine-citrulline (vc)—monomethyl auristatin E (MMAE) and glycine-glycine-phenylalanine-glycine (ggfg)—Deruxtecan (DXd), were investigated for design of Vartumab ADCs. We show that the ADCs maintain specificity to ofCS proteoglycans, cancer cells, and tissue biopsies, exhibiting specific binding to a wide range of malignant and metastatic tissues. Biodistribution assessment of Vartumab ADCs in mice shows strong and specific tumor uptake, with minimal accumulation in other organs. Both ADCs induced bystander killing of antigen-negative cells in the presence of antigen-positive cells and displayed potent anti-tumor activities in a cell-derived xenograft melanoma model. Furthermore, we show that Vartumab conjugates with bystander-capable linker-payloads exhibit greater in vivo potency compared to those with payloads lacking significant bystander effect. Finally, toxicity assessment in rats indicates that the ADC-MMAE is well-tolerated upon repeated doses, with similar dose-limiting toxicities as reported for clinically approved MMAE-conjugated ADCs. Our data support further clinical development of Vartumab-based ADCs.
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Acknowledgements
The authors would like to acknowledge Chumpol Hueyploo, Sabrina Damiri, Julie Zeberg Salwin, Akiko Shirashi, Benjamin Jacobsen, Muhammad Tauseef Mukhtar, Raminta Jonauskaite, Yasmin Ibrahim, and Mikkel Snog Vestergård for excellent technical support. At the University of Copenhagen, Faculty of Health and Medical Sciences, we would like to thank the Core Facility for Flow Cytometry and Single Cell Analysis for assistance in flow cytometry experiments, the Histolab for preparing tissues blocks and slides for us, and the Core Facility for Integrated BioImaging for helping with image acquisition… We would also like to thank the Department of Cellular and Molecular Medicine for access to their MALDI-TOF instrument.
Funding
EEVC is supported by the Novo Nordisk Foundation (NNF) BRIDGE Translational Excellence Program grant (NNF23SA0087869). JM is supported by the NNF Project grant (NNF23OC0086106). MD is supported by the Terry Fox Research Institute New Frontier Program Project Grant (1109). ASa is supported by the NNF Tandem grant (NNF21OC0068192); NNF Distinguished Innovator grant (NNF22OC0076055).
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ASk, EVC, SC, RD, TG and ASa conceived and designed the study; ASk, EVC and ASa wrote the original manuscript draft; ASk and EVC prepared the main figures and supplementary figure files; HZO prepared Fig. 5g; ASk, EVC, SC, JM, RD, AMS, HZO and LD, performed the experiments; MD, TG and ASa supervised; ASk, EVC, SC, JM, RD, AMS, HZO, LD, TGT, MD, TG and ASa contributed to discussing the data, reviewing the manuscript and approved the final manuscript.
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ASa, MD, and TGT are shareholders of VAR2 Pharmaceuticals. The antibodies are subject to a patenting process owned by VAR2 Pharmaceuticals. The remaining authors declare no competing interests.
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Skafte, A., Vidal-Calvo, E.E., Choudhary, S. et al. Preclinical profiling of antibody drug conjugates targeting oncofetal chondroitin sulfate. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08420-x
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DOI: https://doi.org/10.1038/s41419-026-08420-x
