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Background: GQ1001 was developed to overcome the current limitation of existing HER2 ADCs by using the next generation site-specific conjugation and a stable linker technology, coined the intelligent ligase-dependent conjugation (iLDC) technology. iLDC provides a robust platform for the generation of ADC with high homogeneity and excellent stability. Our data show that GQ1001 is highly homogeneous with strong anti-tumor potency, more importantly, markedly enhanced linker stability and reduced off-target toxicity, and points to a safer HER2 ADC with a larger therapeutic window in human. Methods: In vitro and in vivo anticancer efficacy and the mechanism of action (MOA) of GQ1001 were assessed using several HER2+ cancer cell lines and animal models. Ex vivo linker stability was assessed by incubating GQ1001 with the plasma from different species. Pharmacokinetics in cynomolgus monkeys and safety profiles in rats and monkeys were evaluated. Results: GQ1001 was generated by conjugating trastuzumab to DM1 via an unique open-ring containing linker and the enzyme-based site-specific conjugation technology that significantly increases the stability of GQ1001. Optimal physiochemical property of GQ1001was demonstrated from the long-term stability study in liquid formulation. GQ1001 demonstrated similar in vitro anti-cancer activities to T-DM1 in HER2+ tumor cells. However, T-DM1 showed significant non-specific cytotoxicity in HER2- cells while GQ1001 didn’t. In animal studies, GQ1001 induced a robust dose-dependent tumor growth inhibition in multiple HER2-positive CDX and PDX models. From the combo treatment studies, GQ1001 showed synergistic anti-tumor response when combined with HER2-targeting tyrosine kinase inhibitors TKIs and chemotherapeutic agents in multiple HER2-positive models, including those resistant to anti-HER2 TKIs and/or mAbs. In ex vivo plasma stability assay, the DM1-shedding ratio of GQ1001 in human plasma was ~1/100th of that of T-DM1. This supreme linker stability was confirmed by the favorable pharmacokinetics in monkey with extremely low free DM1 exposure in circulation at a significantly lower level than T-DM1. The highest non-severely toxic dose HNSTD of GQ1001 in monkey was 45 mg/kg without any signs of peripheral neuropathy and interstitial lung disease, suggesting GQ1001 will demonstrate excellent tolerance in human. Consistent with this preclinical data, GQ1001 demonstrated superior tolerability profile in heavily pretreated HER2-positive advanced solid tumors patients in a global, open labeled multicenter phase Ia trial. Conclusions: GQ1001 is a unique HER2-targeting ADC that exhibits markedly-enhanced linker stability and safety profiles. Judging from preclinical data, GQ1001 demonstrates the potential to treat HER2-positive cancer patients, alone or in combination, who have progressed on previous HER2-targeting therapeutics with reduced toxicity. Citation Format: Lei Huang, Lili Shi, Yajun Sun, Cao Lv, Chengcheng Gong, Chong Liu, Jun Yang, Lu Jiang, Jinduo Yuan, Xuesong Li, Mingyu Hu, Xinju Gao, Yu Si, Hui Yang, Yan Shi, Bo Yang, Paul H. Song, Gang Qin, Biyun Wang. GQ1001 is a next generation HER2-targeting ADC with excellent druggability, safety and potency [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 2702.