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Abstract
LN005 is a peptide–drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer.
As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species.
The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).
The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans.
This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs.
Acknowledgments
This research was sponsored by Shanghai Whittlong Pharmaceutical Institute, and was partially financially supported by a grant from the National Key R&D Program of China (2022YFF1202600), Key Technologies R&D Program of Guangdong Province (2023B1111030004) and the National Natural Science Foundation of China (No. 82104276, No. 82104275).
Author contributions
Yali Yuan: experiment conduction, original draft writing, data collection. Weiqiang Wang: study design, project coordination, manuscript review and editing. Jing Luo: project sponsor, writing - review. Chongzhuang Tang, Yuandong Zheng: research design, data analysis. Jinghua Yu: manuscript review & editing. Honghong Xu: project sponsor. Mingshe Zhu, Taijun Hang, Hao Wang, Xingxing Diao: study design, technical support, manuscript review and editing.
Disclosure statement
Jing Luo is currently an employee at Shanghai Whittlong Pharmaceutical Institute. Other authors declare no competing interests.