Exploiting the Heavy Chain Glycans for the Improvement of Radioimmunoconjugates

Author

Cindy Rodriguez, The Graduate Center, City University of New YorkFollow

Date of Degree

9-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Brian M. Zeglis

Committee Members

Melissa Deri

Frida Kleiman

Stylianos Bournazos

Subject Categories

Amino Acids, Peptides, and Proteins | Biochemistry | Biological Factors | Inorganic Chemicals | Oncology | Radiation Medicine

Keywords

imaging, therapy, antibody, radiochemistry, receptors, bioconjugation

Abstract

Radiolabeled antibodies have become indispensable tools in nuclear medicine. However, the natural roles of antibodies within the immune system mean that they have several intrinsic limitations as a platform for radiopharmaceuticals. A handful of recent preclinical studies suggest that binding by FcR and particularly FcyRI can affect the pharmacokinetic profiles of 89Zr-labeled radioimmunoconjugates. Fc receptors (FcR) are responsible for many of the interactions between immunoglobulins (IgG) and immune cells. In biomedicine, this interplay is critical to the activity of several types of immunotherapeutics; however, relatively little is known about how FcRs affect the in vivo performance of radiolabeled antibodies. Antibodies have long played a pivotal role in nuclear medicine for both the diagnosis and therapy of various malignancies, especially targeting cancer with immunoPET and radioimmunotherapy (RIT). Thus improvement upon the development and in vivo behavior of radioimmunoconjugates is a continuous clinical need.

This dissertation will attempt to comprehensively cover four main topics – (i) recent advances in antibody engineering for applications in immunoPET/SPECT, and RIT; (ii) evaluating the interplay of FcR with wild-type and aglycosylated variants of 89Zr-radiolabeled radioimmunoconjugates in various murine models of cancer; (iii) developing a site-specific bioconjugation strategy for the construction of 89Zr-radiolabeled radioimmunoconjugates for immunoPET of A33-expressing colorectal cancer and fluorescently labeled peptides for ɑvβ3- expressing glioblastoma ; and (iv) evaluating a novel 89Zr/177Lu-theranostic agent for the immunoPET and RIT of CD133-expressing small cell lung cancer.

Recommended Citation

Rodriguez, Cindy, "Exploiting the Heavy Chain Glycans for the Improvement of Radioimmunoconjugates" (2024). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/6065