Abstract 1549: Preclinical characterization of GQ1010, a next generation Trop2 ADC with the best-in-class potential against diverse Trop2+ solid tumors

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Abstract Background: While Trop2-targeting antibody-drug conjugates (ADC) have demonstrated meaningful clinical response for the treatment of solid tumors, these ADCs still exhibit significant safety issues that limit the full potential of Trop2 ADCs. GQ1010 was developed based on the intelligent Ligase-Dependent Conjugation (iLDC) technology platform of GeneQuantum to enhance the therapeutic window of Trop2 ADC by utilizing a stable linker and a next generation camptothecin analogue. Here we report that GQ1010 demonstrates superior anti-tumor activities against benchmark Trop2 ADCs while maintaining excellent safety profiles, and a potential for a larger therapeutic window, supporting further clinical investigation of GQ1010 in patient with diverse tumors. Method: To characterize GQ1010 in vitro, assays for target binding affinity, internalization, cell cycle, apoptosis, bystander killing, and in vitro cytotoxicity were used. A series of xenograft (CDX) models were used for in vivo efficacy evaluation. Ex vivo plasma stability study was performed to determine the linker stability by monitoring drug-antibody ratio (DAR) change and the payload shedding. In addition, in vivo payload distribution study was performed using a xenograft model. Toxicity study was performed in monkey, and clinical observation, body weight, food consumption, clinical pathology (hematology, coagulation, serum chemistry), and pathology were evaluated. Results: GQ1010 demonstrated more potent in vitro cytotoxicity than DS1062 in diverse Trop2+ cancer cell lines tested. GQ1010 also exhibited superior bystander killing than DS1062. GQ1010 further demonstrated strong in vivo antitumor activities in different CDX models including TNBC, gastric, head and neck (H&N) and pancreatic cancer, and the efficacies were better than DS1062 and Trodelvy®, consistent with the in vitro data. Ex vivo plasma stability data confirmed GQ1010 contains highly stable linker with a minimal DAR reduction and payload shedding, indicating expanded therapeutic window than the benchmark ADCs. Free payload distribution analysis in NCI-N87 model showed high target-specific payload delivery and ~90X payload enrichment in tumor than in plasma, confirming minimal shedding of the payload from GQ1010 during circulation in vivo. In the monkey toxicity study, GQ1010 demonstrated excellent safety without signal of interstitial lung disease (ILD) up to 80 mg/kg dosing. Conclusion: GQ1010 consistently demonstrate superior linker stability, in vitro and in vivo efficacies than DS1062 and Trodelvy®, while maintaining excellent safety. These data suggest GQ1010 has the potential as the next generation Trop2 ADC that can address the critical unmet needs for diverse cancer patients. Citation Format: Yajun Sun, Mingyu Hu, Cao Lv, Yu Si, Xiao Liu, Xinju Gao, Dong Yang, Guangming Chen, Boyu Zhong, Tony Zhang, Lili Shi, Gang Qin, Paul H. Song. Preclinical characterization of GQ1010, a next generation Trop2 ADC with the best-in-class potential against diverse Trop2+ solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1549.