40P - STOPIN: A new approach to solve the hematological toxicity of antibody-drug conjugates (ADC) with soft topoisomerase inhibitor

Background

Camptothecins are effective agents that selectively target topoisomerase I and are widely used as payload in ADC. Myelosuppression is the most common toxicity of camptothecins and ADC. Clinical experience suggests ADC toxicities are primarily driven by payload in a target-independent mechanism. Thus, we hypothesized that a “soft drug” design of camptothecin would result in a set of new payloads that possess potent anti-tumor activities and reduced toxicity. ADCs built from such soft topoisomerase inhibitors may exhibit improved safety to overcome these dose-limiting toxicities.

Methods

Camptothecin was structurally modified to maintain potent in vitro cytotoxicity, and meanwhile, minimize its exposure in circulation to reduce toxicity. We next constituted a Her2 ADC (T-PL1), which was composed of Trastuzumab conjugated to new payload PL1 at a DAR ratio of 8, with the same linker as DS-8201 (T-DXd). PL1 and T-PL1 were evaluated in multiple preclinical studies using standard methodology, in comparison with Dxd and DS-8201.

Results

In vitro studies demonstrated that new camptothecin PL1 had comparable cytotoxicity to Dxd across a panel of tumor cell lines. A rat pharmacokinetic study demonstrated that PL1 was quickly cleared from circulation resulting in low systemic exposure. In a 3-week intermittent toxicity study in rat, Dxd treatment at 3 mg/kg resulted in reduction of lymphocyte, neutrophil, platelet, and white blood cell counts. In contrast, PL1 treatment at 10 mg/kg had no effect on these hematological indices. Its ADC T-PL1 possessed comparable anti-tumor activities to DS-8201, moreover, it also exhibited robust tumor suppression in CDX models. Importantly, in a rat toxicity study, DS-8201 treatment at 60 mg/kg caused decreases in lymphocyte and white blood cell counts, while T-PL1 outperformed it and showed no trend of hematological toxicity at the same dosage.

Conclusions

The STOPIN design not only generated a new camptothecin with great potency and reduced hematological toxicity, but also provided a new ADC exhibiting excellent anti-tumor efficacy and improved safety as compared to DS-8201. This unique feature may provide a new approach to widen the ADC therapeutic window. Further preclinical evaluation of STOPIN-based ADC candidates is underway.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Shanghai MicuRx Pharmaceutical Co., Ltd.

Funding

Shanghai MicuRx Pharmaceutical Co., Ltd.

Disclosure

X. Wang, H. Yang, Y. Li, L. Wang, S. Liu: Financial Interests, Personal, Full or part-time Employment: MicuRx.