Abstract 7179: OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile
Authors: Shia Chi-Sheng , Wen Shih-Ni , Hsu Ren-Yu , Tu Jyy-Shiuan , Chang Hui-Wen , Li Wan-Fen , Lai Ming-Tain 
Published: March 2024

Background: TROP2 targeting antibody-drug conjugates (ADC) have demonstrated promising clinical responses for the treatment of various solid tumors. However, these ADCs still exhibit serious safety issues, such as hematologic toxicities and interstitial lung disease. OBI-992, a novel TROP2 targeting ADC, which is derived from the conjugation of an anti-TROP2 antibody with a topoisomerase I inhibitor, exatecan, via an enzyme-cleavable linker. OBI-992 is designed to have high serum stability and broad therapeutic index. Herein, we describe the results from preclinical studies of OBI-992, including in vitro and in vivo stability, pharmacokinetics/pharmacodynamics (PK/PD) profile, and safety evaluation.

Material and Methods: To characterize OBI-992, the linker stability was evaluated by ex vivo serum stability and rat PK studies. PK/PD properties, including systemic and tumor exposures as well as receptor occupancy, were evaluated in a human lung cancer xenograft model. In vitro toxicity testing, including ADC toxicity on differentiating neutrophils and FcγR mediated toxicity, was evaluated using human monocyte THP-1 cells. A 6-week repeat dose toxicity study in cynomolgus monkeys was conducted to evaluate the safety and toxicokinetics of OBI-992.

Results: Ex vivo serum stability demonstrated that OBI-992 exhibited better linker stability than the benchmark datopotamab deruxtecan (Dato-DXd). In vivo PK evaluation in rats showed that OBI-992 had lower Cmax and AUC of free payload than Dato-DXd, indicating a better PK profile of OBI-992 in rats. A PK/PD study in tumor-bearing mice revealed that OBI-992 exhibited higher tumor exposure of free payload than Dato-DXd, resulting in a better antitumor efficacy. In addition, the antitumor effect positively correlated with percentage of receptor occupancy in a dose-dependent manner. In vitro cytotoxicity testing demonstrated that OBI-992 had lower toxicity in differentiating neutrophils and THP-1 cells compared to Dato-DXd, suggesting that OBI-992 may cause less off-target toxicity. Toxicokinetics of OBI-992 in cynomolgus monkeys revealed that the systemic exposure of ADC was similar to that of total antibody. Furthermore, the systemic exposure of ADC and total antibody were found to increase in a dose-proportional manner. Major toxicities in monkeys were target-related skin lesions. The highest non-severely toxic dose (HNSTD) was determined to be 60 mg/kg.

Conclusions: OBI-992 exhibits remarkable antitumor efficacy and a favorable safety profile, supporting further clinical development of OBI-992 in TROP2 positive cancers.

Citation Format: Chi-Sheng Shia, Shih-Ni Wen, Ren-Yu Hsu, Jyy-Shiuan Tu, Hui-Wen Chang, Wan-Fen Li, Ming-Tain Lai. OBI-992, a novel TROP2 targeting antibody drug conjugate demonstrates superior in vivo PK/PD properties and a favorable safety profile [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(6_Suppl):Abstract nr 7179.