Abstract 1585: KH815, a novel dual-payload TROP2-directed antibody-drug conjugate, shows potent antitumor efficacy in pre-clinical tumor model

TROP2 (trophoblast cell surface antigen 2) is expressed at high levels in various human carcinomas and is associated with tumor differentiation and pathological aggression. Several antibody-drug conjugates (ADCs) targeting TROP2, such as sacituzumab govitecan and datopotamab deruxtecan, have shown promising anti-tumor activity in multiple solid tumors, particularly in breast cancer. However, their clinical application remains limited by inadequate efficacy, highlighting the unmet clinical need for improving the efficacy of single payload TROP2-targeting ADCs.This study presents the preclinical evaluation of a novel dual-payload TROP2-targeting ADC, KH815, composed of a humanized IgG1 antibody (hRS7) directed against TROP2 which is conjugated to a topoisomerase I inhibitor(TOP1i) and an RNA polymerase II inhibitor(RNA POL IIi). KH815 achieves an average drug-to-antibody ratio (DAR) of about 7.5 (4+3.5) using cysteine and glycoside antibody coupling technologies with an appropriate DAR, high SEC purity, homogeneous particle size distribution, and favorable thermal stability.The dual mechanism of KH815 enables the simultaneous inhibition of RNA synthesis and the induction of DNA double-strand breaks, resulting in a potent and synergistic anti-tumor effect both in vitro and in vivo xenograft mouse models in comparison to other TOP1i-TROP2-targeting ADCs. In both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models, KH815 exhibited dose-dependent tumor growth inhibition and demonstrated superior anti-tumor activity compared to the single-TOP1i ADC, at equivalent or even lower doses. Furthermore, KH815 has been shown to be more effective than TOP1i-ADC (sacituzumab govitecan and datopotamab deruxtecan) in tumor inhibition in a PDX model derived from Trodelvy pretreated patients and in a HCT-15 cell CDX model, which expresses P-gp protein, a pump that can extrude DXd. This provides additional evidence that KH815 has the potential to overcome resistance to TOP1i-ADCs. The non-GLP toxicity study in cynomolgus monkeys provided evidence of the favorable safety profile of KH815, the highest non-severely toxic dose (HNSTD) is 40 mg/kg/dose.In summary, KH815, an ADC with dual toxins and unique mechanisms of action, displayed superior anti-tumor effects, the ability to overcome drug resistance, and an acceptable safety profile in preclinical studies. These findings support the potential of KH815 as a promising advanced therapeutic candidate for tumors. Citation Format: Yonghao Zhao, Pengfei Ren, Menglong Guan, Jiao Tang, Lu Qi, Xinzou Fan, Shijun Yin, Gang Lei, Xiao Ke. KH815, a novel dual-payload TROP2-directed antibody-drug conjugate, shows potent antitumor efficacy in pre-clinical tumor model [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 1585.