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 #
5R37CA042324-15
Application #
6149948
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Stone, Helen B
Project Start
1985-09-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
15
Fiscal Year
2000
Total Cost
$382,764
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
Zhou, Zhengyuan; Chitneni, Satish K; Devoogdt, Nick et al. (2018) Fluorine-18 labeling of an anti-HER2 VHH using a residualizing prosthetic group via a strain-promoted click reaction: Chemistry and preliminary evaluation. Bioorg Med Chem 26:1939-1949
Pruszynski, Marek; Kang, Choong Mo; Koumarianou, Eftychia et al. (2018) d-Amino Acid Peptide Residualizing Agents for Protein Radioiodination: Effect of Aspartate for Glutamate Substitution. Molecules 23:
Raghavan, Raghu; Howell, Roger W; Zalutsky, Michael R (2017) A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers. Biomed Phys Eng Express 3:
Zhou, Zhengyuan; Vaidyanathan, Ganesan; McDougald, Darryl et al. (2017) Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation. Mol Imaging Biol 19:867-877
D'Huyvetter, Matthias; De Vos, Jens; Xavier, Catarina et al. (2017) 131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment. Clin Cancer Res 23:6616-6628
Vaidyanathan, Ganesan; McDougald, Darryl; Choi, Jaeyeon et al. (2016) N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules. Org Biomol Chem 14:1261-71
Vaidyanathan, Ganesan; McDougald, Darryl; Choi, Jaeyeon et al. (2016) Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET. J Nucl Med 57:967-73
Vaidyanathan, Ganesan; McDougald, Darryl; Koumarianou, Eftychia et al. (2015) Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG. Nucl Med Biol 42:673-84
Pruszy?ski, Marek; ?yczko, Monika; Bilewicz, Aleksander et al. (2015) Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals. Nucl Med Biol 42:439-445
Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan et al. (2015) D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination. Nucl Med Biol 42:19-27

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