Target-responsive subcellular catabolism analysis for early-stage antibody–drug conjugates screening and assessment

Acta Pharmaceutica Sinica B

Jiali Liu¹  Hui Ye²  Xiaofang Zhang²  Yazhong Liu²  Fang Zhou²  Guangji Wang²  Jingwei Zhang²  Hua Sang² 

[1] Department of Pharmacy, the Affiliated Hospital of Nantong University, Nantong 226001, China;Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;

关键词: ADC;    Target-responsive subcellular catabolism (TARSC);    T-DM1;    Therapeutic efficacy;    Screening;    Biosimilarity;   

DOI  :  

来源: DOAJ

【 摘 要 】

Events including antibody‒antigen affinity, internalization, trafficking and lysosomal proteolysis combinatorially determine the efficiency of antibody–drug conjugate (ADC) catabolism and hence the toxicity. Nevertheless, an approach that conveniently identifies proteins requisite for payload release and the ensuing toxicity for mechanistic studies and quality assessment is lacking. Considering the plethora of ADC candidates under development, we developed a target-responsive subcellular catabolism (TARSC) approach that examines ADC catabolism and probes changes in response to targeted interferences of proteins of interest. We firstly applied TARSC to study the commercial T-DM1 and the biosimilar. We recorded unequivocal catabolic behaviors regardless of the absence and presence of the targeted interferences. Their negligible differences in TARSC profiles agreed with their undifferentiated anti-tumoral efficacy according to further in vitro viability and in vivo tumor growth assays, highlighting TARSC analysis as a useful tool for biosimilarity assessment and functional dissection of proteins requisite for ADC catabolism. Additionally, we employed TARSC to investigate the catabolic behavior of a new trastuzumab–toxin conjugate. Collectively, TARSC can not only characterize ADC catabolism at (sub)cellular level but also comprehensively determine which protein targets affect payload release and therapeutic outcomes. Future use of TARSC is thus anticipated in early-stage screening, quality assessment and mechanistic investigations of ADCs.

【 授权许可】

Unknown