Use of T Cell Receptor-like Antibody Fragments for Imaging and Immunotherapy Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 22, 2019
Creator
  • Miller, Keith Russell
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • The cellular proteome, in both healthy and diseased cells, is presented on the cell membrane surface as peptides bound to the major histocompatibility complex (pMHC). During disease, the interaction of specific disease associated pMHC with T cell receptors (TCR) expressed on CD8+ cytotoxic T cells allows the priming and activation of the immune system. Thus, the immune system can actively identify and kill diseased cells by recognition of the pMHC on the diseased cells' surface. Sometimes non-disease associated pMHC are misidentified on healthy cells, which are attacked leading to autoimmune disease. The association of the pMHC molecule with infection, cancer, and autoimmunity has made the pMHC a valuable target for immunotherapeutic development. In order to identify disease-associated pMHC molecules, high affinity antibodies endowed with TCR-like specificity have been developed as a novel means to target tumor and virus-infected cells and for studying autoimmune disease. Our goal is to improve disease treatment by using TCR-like antibody fragments (Fabs) that mimic the specificity of a TCR to study cancer and autoimmune Type 1 Diabetes (T1D). Using our phage-displayed derived TCR-like Fabs, we show specific identification of both human tumors and beta cells in mice. Specifically, one Fab, fE75, binds to the human epidermal growth factor Receptor 2 peptide, E75, bound to the MHC called Human Leukocyte Antigen-A2 expressed on many human cancer cells. fE75 binding improved in vivo imaging of human tumors in a tumor mouse model. Translation of such technology into the clinic may revolutionize how cancer is monitored and treated. Another Fab, fIGRP, binds the islet-specific glucose-6-phosphatase catalytic subunit-related protein peptide (IGRP), restricted to the MHC, histocompatibility-2 Kd (H-2Kd). IGRP peptide-bound H-2Kd is expressed on beta cells in the nonobese diabetic mouse model. Using fIGRP, we show that the Fab specifically localizes to beta cells in mouse pancreas and can prevent activation of autoimmune T cells. Thus, TCR-like Fabs have the potential to protect against T1D onset and be developed for targeted therapies for beta cell recovery. The ability to generate TCR-like Fabs has vast potential for studying antigen presentation in cancer, viral infections, and autoimmunity and for targeted therapeutics.
Date of publication
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Collins, Edward
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
Language
Publisher
Parents:

This work has no parents.

Items