Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Mamoun M. Alhamadsheh

First Committee Member

Miki S. Park

Second Committee Member

Jessica Faridi

Third Committee Member

Wade Russu

Fourth Committee Member

Qinliang Zhao

Abstract

This project describes the development of a new antitumor therapeutic platform that combines the benefits of small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are popular cathepsin B cleavable ADC linkers. Due to its instability in mouse serum, translating efficacy data from mouse to human is more difficult. It has been reported that replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) improves ADC stability in mouse serum. The effect of the EVCit linker on the stability of SMDCs has not been reported so far. In a xenograft mouse model of prostate cancer, we found that incorporating the EVCit linker in PSMA-targeting SMDCs equipped with the transthyretin ligand AG10 resulted in conjugates with lower toxicity, extended half-life, and superior therapeutic efficacy compared to the standard metastatic castration-resistant prostate cancer (mCRPC) treatment option, docetaxel. This should improve the predictability of SMDC preclinical toxicity and efficacy data from mice.

Pages

91

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