Abstract LB138: A novel dual-TOP1i ADC targeting NaPi2b designed for high efficacy and tolerability

Abstract The Araris site-specific and one-step linker conjugation technology aims at generating stable, safe and highly potent ADCs without the need for antibody engineering prior to payload conjugation. Here we show data on a novel, multi-warhead anti-NaPi2b ADC armed with two different Topoisomerase-1 inhibitors (TOP1i) as payloads engineered for optimal efficacy and tolerability. The multi-warhead ADC was designed to maximize tumor-specific activity while balancing Exatecan toxicity by combining bystander-active Exatecan with a bystander-reduced Exatecan derivative that accumulates in cancer cells to enhance potency and reduce excessive bystander-mediated toxicities.The rat cross-reactive ADC shows excellent efficacy in multiple CDX and PDX models and importantly, is well tolerated with an HNSTD of higher than 90 mg/kg in a repeat-dose rat tolerability study.This ADC is highly homogeneous with a well-defined drug-to-antibody ratio (DAR) of 4 (2+2) and shows high stability under stressed conditions. In in vitro cytotoxicity assays on various NaPi2b expressing cell lines, the ADC demonstrated nM-potency, similar to other previously reported NaPi2b ADCs but being much less toxic to target-negative tumor or healthy cells and superior to Exatecan-only ADCs with full bystander capability. Moreover, our ADC showed excellent stability in mouse, rat and human sera without any sign of linker-payload deconjugation or linker cleavage. This ADC was stable in circulation as shown in pharmacokinetic studies in mouse and rat, demonstrating an exposure profile comparable to the unmodified parent antibody. Strikingly, the Araris ADC led to very high anti-tumor activity when administered as a single dose in a OVCAR-3 xenograft model as well as in PDX models of different origins and target expression levels at doses of 3 mg/kg and less. The bystander-optimized ADC also outperformed a pure, site-specifically defined DAR4-Exatecan ADC. Despite being highly efficacious, only mild and payload-specific toxicities were observed in rats resulting in a HNSTD of higher than 90mg/kg. Most importantly, the multi-warhead ADC did not induce unexpected toxicities and no findings in the lung. We here show promising efficacy and tolerability results on a noveldual-TOP1i ADC with optimized Exatecan bystander activity to maximize efficacy and manage Exatecan toxicity. We believe that this approach, in combination with a stable payload attachment at low DAR and an excellent exposure may help to develop ADCs with improved therapeutic indices for various solid tumor indications with the potential to become a best-in-class ADC. Citation Format: Isabella Attinger-Toller, Philipp Probst, Romain Bertrand, Emma Renard, Lia Kallenberger, Ramona Stark, Patrick Maurhofer, Dragan Grabulovski, Bernd Schlereth, Philipp R. Spycher. A novel dual-TOP1i ADC targeting NaPi2b designed for high efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB138.