Abstract 1563: ADRX-0134 as a novel auristatin-based NaPi2b antibody-drug conjugate with widened therapeutic window

Abstract Sodium-dependent phosphate transport protein 2B (NaPi2b; SLC34A2) is overexpressed in a variety of cancers, including lung carcinomas, ovarian, and endometrial cancers with restricted normal tissue expression. Based on this differential expression profile, a proof-of-concept for an antibody-drug conjugate (ADC) approach utilizing NaPi2b was achieved with lifastuzumab vedotin and upifitamab rilsodotin. Both ADCs used auristatin tubulin inhibitor payloads but have been discontinued due to adverse toxicities driven by the linker-payload technologies, resulting in reduced drug exposures impacting efficacy. To overcome these limitations in therapeutic window, Adcentrx has developed ADRX-0134, a NaPi2b-targeting next-generation ADC with a drug-antibody ratio (DAR) of 8. ADRX-0134 is conjugated to a novel tubulin inhibitor payload AP052 with a proprietary cleavable linker utilizing Adcentrx’ proprietary i-Conjugation® technology, resulting in an ADC with refined biophysical features. The antibody of ADRX-0134 was selected based on its strong nanomolar and highly specific cell binding affinity and similar cross-reactivity to cynomolgus monkey and rodent orthologs. The ADC exhibits sub-nanomolar cytotoxic activity to NaPi2b-expressing tumor cells and has a very stable PK profile with minimal deconjugation. This translates to the observed strong efficacy and durable tumor regression in mouse models of ovarian, endometrial and non-small cell lung cancers with high as well as low/heterogenous NaPi2b expression. Most notably, ADRX-0134 achieved tumor regression in settings where deruxtecan- and vedotin-based NaPi2b ADCs were insufficient. Besides the improvement in efficacy, ADRX-0134 was highly tolerated in a repeat dose non-human primate study at up to 18 mg/kg, the highest tested dose. Here, the stable TK profile ensured minimal and recoverable hematology findings, an unchanged clinical chemistry profile and normal histology of lung, liver, GI and eye, which were key safety liabilities for other NaPi2b ADCs. In summary, ADRX-0134 exhibits excellent biophysical features with highly selective and increased efficacy in NaPi2b-expressing tumors, while being well-tolerated in cynomolgus monkeys at doses that are expected to provide a widened therapeutic window over first-generation NaPi2b ADCs. Citation Format: Andrew M. Hau, Kris Zhang, Maria Shahmoradgoli, Mario M.-C. Kuo, Dong Jun Lee, Anna Y. Wang, Peter P. Challita, Oscar Betancourt, Wes Sisson, Erin Nye, Monica Leung, Albert Goldson, Felipe Acosta, Alexander Chu-Kung, Hui Li, Sabine Rottmann, Pia M. Challita-Eid. ADRX-0134 as a novel auristatin-based NaPi2b antibody-drug conjugate with widened therapeutic window [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1563.