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

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biochemistry

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2023

Author dc:creator

• Sarrett, Samantha M

Advisor dc:contributor.advisor

• Brian Zeglis

Committee members dc:contributor.committeemember

• Thomas Reiner
• Melissa Deri
• Jill Bargonetti
• Jennifer Shusterman

• Biochemistry
• Medicinal-Pharmaceutical Chemistry
• Radiochemistry
• radioimmunoconjugate
• positron emission tomography
• radioimmunotherapy
• monoclonal antibody
• radiopharmaceutical
• nuclear medicine

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/5271

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-6366