Abstract LB124: Targeting NaPi2b with a novel dual TOP1i ADC that shows excellent biophysical properties and high efficacy in vivo

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 generated an anti-NaPi2b ADC with two different Topoisomerase-1 inhibitors (TOP1i) as payloads that shows excellent efficacy vs anti-NaPi2b ADCs that were unsuccessful in clinical trials due to low therapeutic indices (TI), preventing administration at therapeutically active doses. The Araris ADC was designed to combine two features in one ADC to maximize tumor-specific activity by using two different TOP1i payloads: one potent TOP1i that is able to exert bystander activity to address tumor heterogeneity and low-target expression and one exatecan derivative (DAR2) that accumulates in cells (low bystander activity) to achieve greater potency. This novel ADC is characterized by a well-defined drug-to-antibody ratio (DAR) of 4 (DAR2+2), high homogeneity and purity and shows high stability under stressed conditions. In in vitro assays on various target-positive cell lines with different NaPi2b expression levels, the Araris ADC demonstrated nM-potency in cell cytotoxicity assays, similar to the clinical NaPi2b ADCs lifastuzumab vedotin and upifitamab rilsodotin but being much less toxic to target-negative cells. Moreover, this ADC showed excellent stability in mouse and human sera, exemplified by the absence of payload deconjugation or linker cleavage. Most importantly, the ADC was extremely stable in circulation as shown in pharmacokinetic studies in rodents, demonstrating an exposure profile comparable to the unmodified parent antibody. Strikingly, in a high-expressing OVCAR-3 xenograft model, the Araris ADC administered as a single dose at 9 mg/kg on day 0 led to very high anti-tumor activity, essentially leading to tumor eradication and a long lasting anti-tumor response in all treated animals. We here show first encouraging results on a novel concept of combining TOP1i payloads that have two different features in one ADC to maximize efficacy and tolerability. We believe that this concept in combination with a stable payload attachment at low DAR and an excellent exposure may help to develop ADCs with an improved therapeutic index for various solid tumor indications. The initial results indicate that this ADC may overcome the limitations of current clinical programs against NaPi2b and has the potential to be a first-in-class ADC. Citation Format: Isabella Attinger-Toller, Philipp Probst, Lia Kallenberger, Emma Renard, Romain Bertrand, Rachael Fay, Roger Santimaria, Patrick Maurhofer, Dragan Grabulovski, Bernd Schlereth, Philipp Rene Spycher. Targeting NaPi2b with a novel dual TOP1i ADC that shows excellent biophysical properties and high efficacy in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB124.