Abstract 1893: OBI-992, a novel TROP2 targeting antibody-drug conjugate, displayed excellent antitumor efficacy in various animal models

Abstract Background: TROP2 is a validated therapeutic target for cancer treatment. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2 antibody linked with a topoisomerase 1 inhibitor payload, exatecan, through conjugation with an enzyme-cleavable linker. Upon binding to TROP2 on the surface of cancer cells, OBI-992 is internalized into the cell and trafficked to lysosomes where the linker is cleaved by cathepsin B, releasing the payload exatecan to kill the cancer cells. This study aims to evaluate the antitumor efficacy of OBI-992 in vitro and in vivo, including cell-based cytotoxicity, cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models. Methods: The cytotoxicity of OBI-992 was evaluated in cell lines with different levels of TROP2 expression. In vivo efficacy was evaluated using CDX and PDX models of various cancer types. Bystander killing effect of OBI-992 was examined in a xenograft model containing a premixture of TROP2 positive and TROP2 negative cancer cells. Moreover, the impact of overexpression of P-glycoprotein (Pgp) or breast cancer resistance protein (BCRP) on the antitumor efficacy of TROP-2 ADCs was evaluated. OBI-992 in combination with PARP inhibitors such as olaparib and talazoparib was examined for potential synergistic effects in a homologous recombination deficiency (HRD) xenograft model. Results: The cytotoxicity of OBI-992 was positively associated with the TROP2 RNA levels in different cell lines. In various CDX and PDX models, a single dose of OBI-992 at 3 or 10 mg/kg exhibited remarkable tumor growth inhibition. Notably, the antitumor efficacy of OBI-992 surpassed that of datopotamab deruxtecan (Dato-DXd) across different CDX and PDX models. OBI-992 demonstrated a bystander killing effect as OBI-992 was able to kill TROP2-negative xenografts in the presence of nearby TROP2-positive cells. OBI-992 showed superior efficacy to Dato-DXd in the CDX model overexpressing Pgp or BCRP. These findings suggest that OBI-992 was not affected by the Pgp- and BCRP-mediated multidrug resistance. In the HRD CDX model at suboptimal doses, combination of OBI-992 with olaparib or talazoparib displayed remarkable synergistic effects. Conclusions: OBI-992 exhibited excellent antitumor efficacy and outperformed the benchmark Dato-DXd in CDX and PDX models of various cancer types. A strong bystander killing effect indicated that OBI-992 will be effective for tumors with heterogenous expression of target antigen. OBI-992 retained its antitumor effect upon overexpression of Pgp and BCRP, suggesting that OBI-992 may overcome the multidrug resistance. Outstanding synergistic effect with the combination of OBI-992 with PARP inhibitors was observed. These results warrant further studies of OBI-992 in the clinical setting. Citation Format: Wan-Fen Li, Ming-Feng Chiang, Hao-Cheng Weng, Jhih-Jie Yang, Hsin-Shan Wu, Chun-Jung Lin, Ping-Tzu Chiu, Ming-Tain Lai. OBI-992, a novel TROP2 targeting antibody-drug conjugate, displayed excellent antitumor efficacy in various animal models 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 1893.