The trophoblast cell-surface antigen 2 (TROP2) is one of the many targetable gene mutations or marker proteins studied in cancer therapy. Based on ongoing research, it is considered an ideal candidate for targeted anti-cancer therapeutics, and several TROP2-targeted antibody-drug conjugates have been developed for clinical use.  In addition to these FDA approved ADCs, novel, investigational ADC targeting Trop2 are being developed.

Among new these investigational agent targeting TROP2 is GQ1010, a novel ADC being developed by Pyramid Biosciences in collaboration with their partners at GeneQuantum Healthcare (Suzhou) Co.

“TROP2 is a highly validated target in oncology, and TROP2-directed therapies are an important potential treatment option for a large number of cancers,” explained Brian Lestini, MD PhD, CEO of Pyramid Biosciences.

“However, despite the TROP2 agents currently approved or in development, there remains significant unmet need for therapies that improve efficacy while reducing the potential for serious toxicities and optimizing therapeutic index and combinability. Preclinical data demonstrates the potential for GQ1010’s unique ADC chemistry to provide a superior, best-in-class clinical profile and improve patient outcomes. Based on this preclinical data, we are excited to be moving GQ1010 into clinical development.”

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GQ1010 is based on the intelligent Ligase-Dependent Conjugation (iLDC) technology platform developed by GeneQuantum and enhance the therapeutic window of the TROP2 targeting ADC by utilizing a stable linker and a next generation camptothecin analogue.[3]

Data presented at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida, highlighted the preclinical efficacy and safety profile of GQ1010, a potential best-in-class antibody drug conjugate (ADC) targeting trophoblast cell surface antigen 2 (TROP2), across several in vitro and in vivo models. [3]

The poster presentation demonstrated the differentiating attributes of GQ1010.

The data from preclinical studies with GQ1010 were based on a series of xenograft models used for in vivo efficacy evaluation. In addition ex vivo plasma stability study were performed to determine the linker stability by monitoring drug-antibody ratio (DAR) change and the payload shedding, while in vivo payload distribution study were performed using a xenograft model.

Toxicity study were performed in monkey, and clinical observation, body weight, food consumption, clinical pathology (including hematology, coagulation, serum chemistry), and pathology were evaluated.

Specifically, in a mouse syngeneic MC38 colon cancer model, the combination of GQ1010 plus anti-PD-1 therapy showed compelling synergistic tumor growth inhibition, which was superior to datopotamab deruxtecan (DS-1062; Daiichi Sankyo) plus anti-PD-1. In this study, the GQ1010 combination reported 5 of 6 animals achieved a complete response, compared to zero of 6 animals with the DS-1062 combination.

GQ1010 showed more potent in vitro cytotoxicity and a superior bystander effect versus datopotamab deruxtecan, and increased in vivo tumor growth inhibition with GQ1010 monotherapy compared head-to-head with either DS-1062 or sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) across multiple cancer models.

Safety findings with GQ1010 in a non-human primate (NHP) study indicated a differentiated profile and highest non-severe toxic dose (HNSTD) of greater than 30 mg/kg, which may translate to a wider therapeutic window in human studies relative to more advanced TROP2 ADCs in development.

Plasma stability studies showed 98% retention of drug-to-antibody ratio (DAR) for GQ1010, attributable to its unique, irreversible cleavable linker chemistry.

“These preclinical findings are driven by GQ1010’s unique ADC design, which utilizes site-specific enzymatic conjugation technology and a novel linker-payload which confer potent cytotoxicity and better stability in the plasma,” noted Qin Gang, Ph.D., CEO of GeneQuantum Healthcare.

“The preclinical differentiation seen with GQ1010 provides further validation of the capabilities of the GeneQuantum platform to produce best-in-class bioconjugates, as was also observed in a Phase 1a study of the HER2-directed ADC, GQ1001,” Gang added.

Highlights of Prescribing Information
Sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences)[Prescribing Information]

Reference
[1] Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019 Mar 1;12:1781-1790. doi: 10.2147/OTT.S162447. PMID: 30881031; PMCID: PMC6402435.
[2] Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015 Mar;6(3-4):84-105. doi: 10.18632/genesandcancer.40. PMID: 26000093; PMCID: PMC4426947.
[3] Sun Y, Hu M, Lv C, Si Y, Liu X, Gao X, Yang D, Chen G, Zhong B, Zhang T, Shi L, Qin G, Song PH. 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.

Featured image: Featured Image: Attendees during the AACR 2016 Annual Meeting – April 19, 2016. Courtesy: © AACR/Scott Morgan 2016. Used with permission.

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