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Activated vitronectin as a target for anticancer therapy with human antibodies
- Source :
- Cancer Immunology, Immunotherapy. 53:799-808
- Publication Year :
- 2004
- Publisher :
- Springer Science and Business Media LLC, 2004.
-
Abstract
- The formation of a provisional extracellular matrix represents an important step during tumor growth and angiogenesis. Proteins that participate in this process become activated and undergo conformational changes that expose biologically active cryptic sites. Activated matrix proteins express epitopes not found on their native counterparts. We hypothesized that these epitopes may have a restricted tissue distribution, rendering them suitable targets for therapeutic human monoclonal antibodies (huMabs). In this study, we exploited phage antibody display technology and subtractive phage selection to generate human monoclonal antibody fragments that discriminate between the activated and native conformation of the extracellular matrix protein vitronectin. One of the selected antibody fragments, scFv VN18, was used to construct a fully human IgG/kappa monoclonal antibody with an affinity of 9.3 nM. In immunohistochemical analysis, scFv and huMab VN18 recognized activated vitronectin in tumor tissues, whereas hardly any activated vitronectin was detectable in normal tissues. Iodine 123-radiolabeled huMabVN18 was shown to target to Rous sarcoma virus-induced tumors in chickens, an animal model in which the epitope for huMab VN18 is exposed during tumor development. Our results establish activated vitronectin as a potential target for tumor therapy in humans.
- Subjects :
- Sarcoma, Avian
Cancer Research
Protein Conformation
Angiogenesis
medicine.drug_class
Immunology
Immunoglobulin Variable Region
Melanoma, Experimental
Mice, Nude
Enzyme-Linked Immunosorbent Assay
Monoclonal antibody
Epitope
Iodine Radioisotopes
Extracellular matrix
Mice
Peptide Library
medicine
Animals
Humans
Immunology and Allergy
Vitronectin
Immunoglobulin Fragments
Poultry Diseases
Mice, Inbred BALB C
Rous sarcoma virus
biology
Antibodies, Monoclonal
biology.organism_classification
Molecular biology
Peptide Fragments
Mice, Inbred C57BL
Avian Sarcoma Viruses
Radioimmunodetection
Oncology
Colonic Neoplasms
biology.protein
Immunohistochemistry
Binding Sites, Antibody
Antibody
Chickens
Epitope Mapping
Subjects
Details
- ISSN :
- 14320851 and 03407004
- Volume :
- 53
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology, Immunotherapy
- Accession number :
- edsair.doi.dedup.....edaafdcdd5e351b02d44bd695077c957