Author ORCID Identifier

0000-0002-9756-8449

Date of Graduation

5-2024

Document Type

Dissertation (PhD)

Program Affiliation

Molecular and Translational Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Kendra Carmon

Committee Member

Qingyun Liu

Committee Member

Daniel Frigo

Committee Member

Pierre McCrea

Committee Member

Vihang Narkar

Abstract

Antibody-drug conjugates (ADCs) are a fast-growing class of molecularly targeted therapies with 13 currently approved and over a 100 in clinical trials. ADCs consist of a monoclonal antibody (mAb) conjugated to a potent cytotoxic payload to selectively target tumor antigens highly expressed on the cell surface. ADC development has been limited in colorectal cancer (CRC) by the lack of novel and effective therapeutic targets. Epiregulin (EREG), is an epidermal growth factor receptor (EGFR) ligand that is highly expressed in CRCs of different subtypes and mutational statuses with low expression in normal tissues. Here, we have characterized the role of EREG in CRC progression, generated and evaluated the first EREG-targeted ADC, and developed a novel bispecific Ab for future ADC development. Genetic ablation of EREG in a KRAS mutant CRC cell line resulted in a decrease in migration, invasion, and tumor growth. Further, we produced a highly specific EREG mAb, H231, that exhibited strong binding affinity, internalization, and tumor-specific uptake as determined by 89Zr-immunoPET and biodistribution studies. Our lead EREG ADC, H231 EGC-qDuoDM gluc, was developed via site-specific chemoemzymatic conjugation of H231 to a novel tripeptide linker attached to a modified duocarmycin payload. H231 EGC-qDuoDM gluc demonstrated minimal toxicity and significant antitumor efficacy in preclinical models of CRC. Future studies include further optimization of EREG-targeted ADCs or testing in combination with other therapies to ultimately eliminate tumors and prevent relapse.

Keywords

Epiregulin, EGFR, Antibody-Drug Conjugates, Monoclonal Antibodies, Colorectal Cancer

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