The goal of this research proposal is to increase the clinical utility of labeled monoclonal antibodies (mAbs) for diagnostic and therapeutic nuclear medicine through the development of more effective approaches for labeling mAbs and mAb fragments with radioiodine nuclides and 211At. Iodine-131 is the most frequently used nuclide clinical radioimmunotherapy, but its usefulness has been compromised by in vivo dehalogenation of mAbs labeled via conventional procedures. Better mAb radioiodination methods also would facilitate the use of (123)I and SPECT, and 124I and PET, for lesion detection and dosimetry estimation. Astatine-211 emits alpha-particles that have a higher radiobiological effectiveness and shorter range than beta-particles and, for certain therapeutic applications, may be better matched to the characteristics of the tumor. In this continuation application, we propose to focus on radiohalogenation strategies for mAbs that are internalized rapidly into tumor cells after binding to antigen. This emphasis is in response to the emergence of the epidermal growth factor receptor variant III (EGFRvIII) as a tumor-specific target on gliomas, breast carcinomas and other tumors. EGFRvIII, a mutant receptor with a deletion in the BGFR extracellular domain is not found on normal tissues. Our hypothesis is that optimizing labeling methods for internalizing mAbs such as anti-EGFRvIII will enhance tumor retention and tumor-to-normal tissue ratios, thereby improving their clinical potential as diagnostic and therapeutic agents for tumors expressing EGFRvIII.
Our specific aims are: 1) To label anti-EGFRvIII mAbs and fragments with radioiodine nuclides and 211At using N-succinimidyl 5-iodo-3-pyridinecarboxylate and N- succinimidyl 5-[211At]astato-3-pyridinecarboxylate and evaluate their potential as diagnostic and therapeutic radiopharmaceuticals; 2) To investigate other strategies for labeling mAbs and fragments with radioiodine and 211At including use of alternate positively charged templates, D-amino acid linkers, and new approaches involving oligosaccharide conjugation; and 3) To investigate the nature of the high- and low-molecular weight labeled catabolites generated in tumor cells in vitro and tumor and normal tissues in vivo and use these data as a guide for developing improved methods for labeling mAbs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA042324-16
Application #
6350062
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Stone, Helen B
Project Start
1985-09-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
16
Fiscal Year
2001
Total Cost
$391,405
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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