The Development of Novel Radioimmunoconjugates for the PET Imaging and Radioimmunotherapy of Cancer

Author

Samantha M. Sarrett, The Graduate Center, City University of New YorkFollow

Date of Degree

6-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Brian Zeglis

Committee Members

Thomas Reiner

Melissa Deri

Jill Bargonetti

Jennifer Shusterman

Subject Categories

Biochemistry | Medicinal-Pharmaceutical Chemistry | Radiochemistry

Keywords

radioimmunoconjugate, positron emission tomography, radioimmunotherapy, monoclonal antibody, radiopharmaceutical, nuclear medicine

Abstract

Antibodies have long played a vital role in nuclear medicine for both the diagnosis and therapy of various malignancies. The role and development of antibodies in nuclear medicine can be broadly separated into three different categories: 1) bioconjugation strategies, 2) immunoPET imaging, and 3) radioimmunotherapy. This dissertation will attempt to comprehensively cover each of these categories through a series of studies, protocols, and reviews. For the bioconjugation strategies, we will describe the development of a novel site-selective bioconjugation strategy using an innovative lysine-targeting reagent, PFP-bisN₃, to prepare [⁸⁹Zr]Zr-^SSKDFO-pertuzumab for visualizing HER2+ breast cancer. Further, we introduce a new mAb with a catalytic domain that allows for the site-selective bioconjugation of chelators to yield [¹⁷⁷Lu]Lu-CHX-A”-DTPA-PODS-HER2DVD for targeting HER2+ breast cancer. For immunoPET, several chapters of this dissertation are dedicated to discussing the development of a CD133- targeting monoclonal antibody — [⁸⁹Zr]Zr-DFO-aCD133 — majorly focusing on immunoPET imaging of small cell lung cancer in traditional and advanced tumor murine models. We have recently begun to explore the therapeutic efficacy of this immunoconjugate as well using the ¹⁷⁷Lu labeled derivative, [¹⁷⁷Lu]Lu-DTPA-A”-CHX-aCD133. As for radioimmunotherapy, we describe creating a HER2-targeting nanobody with a residualizing prosthetic group for radiohalogenation to eventually be used for therapy of HER2+ malignancies. And lastly, we report a protocol for harnessing the inverse electron demand Diels-Alder (IEDDA) click reaction for diagnostic and therapeutic pretargeting; an overall introduction to antibodies in nuclear medicine; and a review based on the role of click chemistry and its advances in recent years.

Recommended Citation

Sarrett, Samantha M., "The Development of Novel Radioimmunoconjugates for the PET Imaging and Radioimmunotherapy of Cancer" (2023). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/5271