Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Brian M. Zeglis

Committee Members

Jason S. Lewis

Jill Bargonetti

Aneta Mieszawska

Subject Categories

Amino Acids, Peptides, and Proteins | Macromolecular Substances | Organic Chemicals | Other Chemicals and Drugs | Pharmaceutical Preparations | Therapeutics

Keywords

antibody, radioimmunoconjugate, bioconjugation, immuno-oncology

Abstract

The role of antibody-based molecular agents for diagnosis and therapy of cancer has expanded significantly over the past decades. However, most of these constructs are synthesized using traditional bioconjugation methods based on the random ligations between the molecular cargo and lysine residues within the protein. These non-specific approaches can create poorly defined conjugates with suboptimal immunoreactivity and in vivo performance while Site-specific approaches to antibody bioconjugation based on ligations between maleimides and free cysteine residues have long stood as attractive alternatives. Yet the inherent instability of the thiol-maleimide linkage has fueled the search for new, more stable thiol-reactive prosthetic groups. One particularly promising solution is the use of a novel bioconjugation reagent based on a phenyloxadiazolyl methyl sulfone (PODS) scaffold that selectively reacts with free cysteines to form more stable and well- defined immunoconjugates. The first four chapters of thesis focus on the development, optimization, and evaluation of PODS-based bioconjugation strategies for the generation of immuno- and radioimmunoconjugates with improved immunoreactivity. The fifth and final chapter describe the preparation of antibody-based gold(I)-compounds with significant cytotoxicity in HER2-positive breast cancer cells.

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