Abstract 6747: A next generation ADC: AR153, pH-dependent anti-B7H3 MMAE

Abstract Antibody-drug conjugates (ADCs) demonstrate significant anti-cancer efficacy, but their therapeutic index (TI) can be restricted due to toxicity in normal tissues. To address this limitation, pH-dependent antibodies have emerged as a promising solution. These antibodies exhibit weak binding to their target under physiologically neutral pH conditions but show strong binding in the acidic environment of the tumor microenvironment (TME), improving tumor selectivity and reducing off-target toxicity, thereby increasing the TI of ADCs. B7-H3, a member of the B7 family, is overexpressed in various solid tumors, making it a promising therapeutic target for ADC development. We screened a recombinant human antibody library (Ymax-ABL) and identified pH-dependent antibodies against B7-H3. We developed a pH-dependent anti-B7-H3 antibody (pH-B7-H3 Ab) that shows strong binding under acidic conditions such as TME, and reduced binding under neutral pH, as seen in healthy tissues. We generated ADCs by conjugating a pH-independent anti-B7-H3 antibody (Non-pH-B7-H3 Ab) and the pH-B7-H3 Ab with GGFG-Dxd and vc-PAB-MMAE, achieving drug-to-antibody ratios (DAR) of 3.8, 3.8, 3.5 and 3.9, respectively. Comparative studies revealed that pH-B7-H3-MMAE exhibited lower cytotoxicity than Non-pH-B7-H3-MMAE under neutral pH conditions typical of normal tissues. However, under acidic conditions (pH 6.0), both ADCs displayed comparable cytotoxicity. Additionally, in a B7-H3-expressing CDX model, ADCs demonstrated similar anti-cancer efficacy. Notably, pH-B7-H3 Ab exhibited superior penetration into tumor tissues compared to Non-pH-B7-H3 Ab, highlighting its potential to improve therapeutic outcomes by selectively targeting tumor cells while minimizing harm to normal tissues. Citation Format: wonhwa kang. A next generation ADC: AR153, pH-dependent anti-B7H3 MMAE [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 6747.