The overall objective of this proposal is to develop a more effective therapeutic approach for the selective destruction of cancer cells. We propose to investigate the feasibility of combining the potential tumor specificity of monoclonal antibodies directed against tumor-associated antigens with the high linear energy transfer, short-range alpha radiations emitted in the decay of 211At. Astatine-211-labeled monoclonal antibodies offer the attractive possibility of matching the cellular specificity of an antibody with radiation of approximately cellular range. The antibody chosen for these studies is OC 125, a monoclonal antibody directed against a surface antigen present on human ovarian cancer cells. We have labeled OC 125 with I125, studied its interaction with human ovarian carcinoma cells in vitro and demonstrated selective uptake of I125 activity in human ovarian tumor implants in athymic mice.
The specific aims are: (1) to label OC 125 with At211 using an acylation reaction without decreasing its affinity for ovarian cancer cells; (2) to measure the radiotoxicity of At211-labeled OC 125 in ovarian cancer cell lines; (3) to measure the therapeutic efficacy of At211-labeled OC 125 administered intraperitoneally to mice with malignant ascites; (4) to study the effects of several factors including antibody dose and circulating antigen level on the pharmacokinetics of labeled OC 125 and F(ab')2 and Fab' fragments in nude mouse models of ovarian cancer; and (5) to study the therapeutic utility of At211-labeled OC 125 in nude mice bearing human ovarian tumor xenografts. Although the proposed studies are limited to the study of in vitro and in vivo model systems, it is important to bear in mind that if the proposed experiments are successful, treatment of ovarian cancer might be possible via intraperitoneal and/or intravenous administration of At211-labeled antibodies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042324-03
Application #
3183440
Study Section
Radiation Study Section (RAD)
Project Start
1985-09-01
Project End
1989-06-30
Budget Start
1987-09-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Duke University
Department
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
Choi, Jaeyeon; Vaidyanathan, Ganesan; Koumarianou, Eftychia et al. (2018) Astatine-211 labeled anti-HER2 5F7 single domain antibody fragment conjugates: radiolabeling and preliminary evaluation. Nucl Med Biol 56:10-20
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:
Pozzi, Oscar R; Zalutsky, Michael R (2017) Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for211At labeling at high activities and radiation doses of211At ?-particles. Nucl Med Biol 46:43-49
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
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
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

Showing the most recent 10 out of 156 publications