Abstract 4356: OBI-902, a novel TROP2 targeted antibody-drug conjugate via GlycOBI® platform, has favorable pharmacokinetics and sustained antitumor activities in challenging solid tumors

Abstract Trophoblast cell surface antigen 2 (TROP2) is overexpressed in a variety of solid tumors, including non-small cell lung cancer (NSCLC), pancreatic cancer (PC), gastric cancer (GC), and colorectal cancer (CRC), where high expression levels of TROP2 correlate with poor prognosis. OBI-902 is a novel site-specific antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 monoclonal antibody linked to a topoisomerase I (TOP1) inhibitor payload with drug-to-antibody ratio of 4 via OBI’s proprietary glycan conjugation platform (GlycOBI®) and dual-action enzymatic technology (EndoSymeOBI®). This unique linker-payload design is expected to enhance the ADC stability and improve the efficiency of payload delivery in tumors. This study aimed to evaluate the therapeutic potential of OBI-902 in challenging solid tumors. In vitro linker-payload stability was evaluated in human serum albumin via LC-MS. Pharmacokinetics (PK) was assessed in the serum and tumor of NSCLC xenograft mouse model. The antitumor activity studies of OBI-902 were conducted in NSCLC, PC, GC, and challenging CRC xenograft mouse models with Dato-DXd, SG, or MK-2870 as benchmarks. The antitumor activities were evaluated in both tumor volumes of 200-250 mm3 and 500-550 mm3 (large tumor burden). Survival was analyzed with the log-rank (Mantel-Cox) test with *p<0.05, **p<0.01. Humane endpoint: Tumor volume was larger than 1500 mm3. OBI-902 showed superior in vitro linker-payload stability than the Dato-DXd. In addition, OBI-902 exhibited favorable PK profiles with excellent ADC stability in circulation and efficient payload release in NSCLC xenograft model. The tumor-to-serum ratios of payload Cmax and AUC0-t were 33 and 86, respectively. OBI-902 achieved 4.2-fold higher intra-tumor payload exposure than that of MK-2870 at the same dosage. OBI-902 exhibited potent and durable antitumor activities. In the GC xenograft model, tumor volume reductions of OBI-902 were 3.6- to 6.2-fold better compared to benchmarks, by day 57. In the challenging CRC model, OBI-902 showed a sustained suppression of tumor growth by day 56 (329 ± 110 mm3) compared to benchmark ADCs which reached over 1000 mm3 before day 18. In the large-tumor NSCLC xenograft model, OBI-902 achieved superior antitumor activity, with 40% of treated mice surviving beyond day 70. In contrast, all mice treated with benchmarks were sacrificed early (tumor volume >1500 mm) at days between 29 and 42. Similarly, in the large-tumor PC xenograft model, OBI-902 prolonged survival beyond day 50, while all mice in the benchmark groups were sacrificed by day 28. OBI-902 can efficiently deliver payload to the site of action (tumor) to achieve desirable drug exposure and sustainable antitumor activities in various challenging solid tumors, pointing to its potential to be the best-in-class TROP2 ADC. Citation Format: Ren-Yu Hsu, Chi-Huan Lu, Chi-Sheng Shia, Hsin-Shan Wu, Lu-Tzu Chen, Jhih-Jie Yang, Jyy-Shiuan Tu, Hui-Wen Chang, Shih-Ni Wen, Ming-Tain Lai, Ya-Chi Chen. OBI-902, a novel TROP2 targeted antibody-drug conjugate via GlycOBI platform, has favorable pharmacokinetics and sustained antitumor activities in challenging solid tumors [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 4356.