Abstract 5804: Preclinical evaluation of LCB84, a novel next-generation TROP2 directed ADC utilizing a cancer selective linker and an MMAE payload

Abstract LCB84 is an antibody-drug conjugate (ADC) that consists of an antibody targeting human trophoblast cell-surface antigen-2 (TROP2) linked to monomethyl auristatin E (MMAE) via a beta-glucuronidase cleavable linker with a drug-to-antibody ratio (DAR) of 4. LCB84 demonstrates tumor selective killing by multiple mechanisms, increasing both safety and efficacy in parallel. Firstly, the over-expression of TROP2 in many solid tumors allows for targeted delivery of MMAE by LCB84 to Trop2-positive tumor tissues. Secondly, the overexpression of beta-glucuronidase in the lysosome of most tumors facilitates the selective release of active payload within tumor cells compared to normal healthy tissues. Thirdly, the intrinsic selectivity of tubulin inhibitor payloads, such as MMAE, for proliferating cells provides additional protection for non-proliferating normal cells. MMAE is also cell-permeable in its free drug form and can lead to increased efficacy of LCB84 via a bystander effect, enabling activity in heterogenous tumors. LCB84 demonstrates superior efficacy in mouse tumor xenograft studies when compared to benchmark TROP2-targeting ADCs, including sacituzumab govitecan and datopotamab deruxtecan. LCB84 also shows an improved safety profile compared to these clinical benchmarks, as well as compared to traditional MMAE-bearing ADCs, in both in vitro and in vivo toxicity assessments. Additionally, LCB84 shows a stable preclinical pharmacokinetic profile with minimal loss of payload over time. The utilization of an ADC for target-mediated delivery, in combination with a stable beta-glucuronide trigger for selective payload release in tumors, allows for a superior preclinical therapeutic index which is expected to translate to a best-in-class ADC in the clinic. Citation Format: Stephen Slocum, Hyejung Kim, Chul-Woong Chung, Changsik Park. Preclinical evaluation of LCB84, a novel next-generation TROP2 directed ADC utilizing a cancer selective linker and an MMAE payload abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5804.