Improved Tumor Selectivity of Radiolabeled Peptides by Receptor and Antigen Dual Targeting in the Neurotensin Receptor Model
| Autor: | André Pèlegrin, Anne Gruaz-Guyon, Monique Dussaillant, William Rostène, Olivier Raguin, Jacques Barbet, Marc Hillairet de Boisferon, Cynthia Thiercelin |
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| Rok vydání: | 2002 |
| Předmět: |
Biomedical Engineering
Mice Nude Pharmaceutical Science Bioengineering Mice Carcinoembryonic antigen Antigen Antibody Specificity Antigens Neoplasm Cell surface receptor Neoplasms Antibodies Bispecific Tumor Cells Cultured Animals Humans Receptors Neurotensin Computer Simulation Tissue Distribution Neurotensin receptor Receptor Pretargeting Pharmacology biology Chemistry Indium Radioisotopes Organic Chemistry Pentetic Acid Radioimmunotherapy Molecular biology Peptide Fragments Tumor antigen Carcinoembryonic Antigen Kinetics Radioimmunodetection biology.protein Female Haptens Hapten Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 13:654-662 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc015585g |
| Popis: | Radiolabeled peptides are emerging tools for diagnosis and therapy of tumors overexpressing receptors. However, binding to receptors expressed by nontumor tissues may cause toxicity. The objective of this study was to specifically enhance the binding affinity of labeled peptides to tumor cells, as opposed to receptor-positive nontumor cells, to ensure targeting selectivity. This was achieved by the simultaneous binding of hapten-bearing peptides to their receptor and to a tumor-associated antigen, mediated by a bispecific antibody directed to the tumor antigen and to the hapten. Binding of labeled neurotensin analogues bearing the DTPA(indium) hapten (NT-DTPA( 1 1 1 In)) to human colorectal carcinoma cells (HT29), which express the neurotensin receptor (NTR1) and carcinoembryonic antigen (CEA), was studied in the presence of a bispecific antibody (BsmAb) directed to CEA and to DTPA-(indium). In vitro dual binding of NT-DTPA in the presence of BsmAb was about 6.5-fold higher than monovalent binding to NTR1 and 3.5-fold higher than the sum of the monovalent bindings to NTR1 or to CEA, suggesting cooperativity. Increased binding under bivalent conditions translated into increased internalization. In vivo pretargeting with BsmAb enhanced tumor uptake and tumor retention. Hapten bearing peptides binding simultaneously an overexpressed cell-surface receptor and a tumor antigen show increased selectivity to target tumor cells as compared to cells only expressing the cell surface receptor. Better resistance to enzymatic degradation and optimized administration protocols should further enhance in vivo targeting selectivity and may allow the development of radiopharmaceuticals labeled with isotopes suitable for radiotherapy such as 1 3 1 I or 9 0 Y. |
| Databáze: | OpenAIRE |
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