Abstract Targeting death receptor DR5 with agonist antibody could trigger extrinsic apoptosis via caspase activation in cancer cells while sparing normal tissues. Ozekibart (INBRX109), a tetra-valent anti-DR5 antibody, showed significant efficacy as a monotherapy in patients with advanced or metastatic, unresectable chondrosarcoma, with disease control rate (DCR) of 54%, (compared to 27.5% in the placebo group). Later in a study of advanced Ewing sarcoma, Ozekibart combined with irinotecan and temozolomide demonstrated improved clinical benefit with an ORR of 64% and a DCR of 92%. Encouraged with these results, we designed a DR5-targeting ADC with the aim to synergize the extrinsic apoptosis activity of DR5 engaging and superb cytotoxicity effect of Top-1 inhibitor. In this presentation we show systematic evaluation of this novel ADC including specific tumor cell engaging, anti-tumor efficacy, serum stability, and pharmacokinetics (PK) in target-humanized mice. First, the unique design of the tri-valent DR5-targeting antibody demonstrated superior activity over counterparts. Second,its resulting ADC form showed a robust tumor growth inhibition across diverse xenografts, potentially benefit from its dual mode of action design, surpassing clinically advanced control agents (INBRX109). Our ADC showed dose dependent in vivo antitumor activity without hook effect seen with agonist antibodies. Finally, this ADC showed better in vivo safety profile: lower on-target off-tumor apoptosis, longer half-life and better tolerability in comparison with that of INBRX109,suggesting a potentially wider therapeutic window. These results may support progression of this novel DR5-tageting ADC into clinical development as a potentially more potent and safer DR5-targeted therapy. Citation Format: Yang Wang, Lixia Cao, Cui Feng, Yifan Yang, Fangdun Jiang, Lixia Gu, Qi Zhang, Chen Li, Ming Zhou, Cancan Li, Wei Huang, Bonan Yan, Ziping Wei, Yuhong Zhou, . A DR5-targeting ADC exhibits superior anti-tumor activity and potentially better therapeutic window 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 2637.
Wang et al. (Fri,) studied this question.