Abstract 7168: PBI-410 (GQ1010), A novel Trop-2-targeted ADC demonstrates a favorable safety and toxicokinetic profile in multiple preclinical assessments
Authors: Sun Yajun , Reddy Vijayapal , Kulanthaivel Palaniappan , Feng Yanwen , Zhao Jie , Chi Zhiyan , Wang Junhao , Shi Lili , Qin Gang , Song Paul H. 
Published: March 2024

Introduction: Trop-2-targeting ADCs (Trop-2 ADC) have demonstrated notable clinical efficacy; however, safety concerns necessitate frequent dose adjustments or discontinuations. PBI-410 (GQ1010) is a next-generation TROP-2 ADC developed using GeneQuantum's Ligase-Dependent Conjugation (iLDC) technology, that integrates a highly stable linker and a novel camptothecin analogue payload, TopoIx. This study included comprehensive preclinical evaluations that demonstrated a favorable safety and TK profile and potential for broader therapeutic margin versus other Trop-2 ADCs approved or in development.

Methods: TopoIx underwent extensive Good Laboratory Practice toxicity assessments in Sprague-Dawley (SD) rats (payload alone) and as part of the intact ADC in Non-Human Primates. Rats were administered repeated intravenous infusions of 0.5, 1.25, and 2.5 mg/kg of H0011 once a week over 5 doses. The potential toxicity profile of PBI-410 was evaluated in cynomolgus monkeys via repeated intravenous infusions of 10, 30, and 60 mg/kg doses every 3 weeks for 3 doses, followed by a six-week recovery phase.

Results: TopoIx administration in SD rats exhibited good tolerance, with slight reductions in body weight gain and food consumption. Microscopic tissue changes resolved post-drug withdrawal, except for persistent findings in the sciatic nerve. Repeated doses of PBI-410 in cynomolgus monkeys were well-tolerated, primarily manifesting as skin pigmentation and associated microscopic alterations in specific tissues, such as eyes, esophagus, thymus, and lymph nodes typical for topoisomerase inhibitors. Importantly, these changes were reversible upon drug cessation. The HNSTD/NOAEL for PBI-410 was determined to be 60 mg/kg. This corresponds to mean Cmax of 1760 µg/mL and AUCinf of 235000 µg*hr/mL for ADC and for TopoIx mean Cmax of 16.4 ng/mL and AUCinf of 2610 ng*hr/mL. The lower exposure of TopoIx suggests minimum payload shedding in the systemic circulation. Notably, PBI-410 demonstrated a significantly enhanced safety profile compared to other Topo1-based Trop-2 ADCs, including an absence of hematopoietic and intestinal toxicities, and no pulmonary toxicity or interstitial lung disease (ILD) observed.

Conclusion: PBI-410 demonstrated a favorable and differentiated nonclinical safety profile and favorable TK relative to those reported to date for other Trop-2 ADCs in development. This profile, in addition to the potent anti-tumor response and synergistic activity in combination with anti-PD1 reported previously, position PBI-410 as a best-in-class potential Trop-2 ADC and partner of choice for anti-PD1 combination therapy. Additionally, TopoIx has displayed excellent properties among the TOP1 inhibitors, making it suitable for a broader therapeutic application based on exceptional potency while maintaining a favorable safety profile.

Citation Format: Yajun Sun, Vijayapal Reddy, Palaniappan Kulanthaivel, Yanwen Feng, Jie Zhao, Zhiyan Chi, Junhao Wang, Lili Shi, Gang Qin, Paul H. Song. PBI-410 (GQ1010), A novel Trop-2-targeted ADC demonstrates a favorable safety and toxicokinetic profile in multiple preclinical assessments [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(6_Suppl):Abstract nr 7168.