Unique biological properties of catalytic domain directed human anti-CAIX antibodies discovered through phage-display technology

Autor: Kristen W. Brady, Wayne A. Marasco, Anuradha Yammanuru, Agnes Lo, Aimee St. Clair Tallarico, Chen Xu, Quan Karen Zhu, Akikazu Murakami, Natasha S. Barteneva
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Phage display
medicine.drug_class
Immunology
Oncology/Oncology Agents
lcsh:Medicine
Endosomes
Monoclonal antibody
Epitope
03 medical and health sciences
0302 clinical medicine
Antigen
Antigens
Neoplasm
Peptide Library
Catalytic Domain
medicine
Biomarkers
Tumor
Humans
Biotinylation
Peptide library
Carbonic Anhydrase IX
lcsh:Science
Biochemistry/Biomacromolecule-Ligand Interactions
Carcinoma
Renal Cell
030304 developmental biology
Oncology/Renal Cancer
Carbonic Anhydrases
0303 health sciences
Multidisciplinary
biology
Urology/Renal Cancer
lcsh:R
Antibodies
Monoclonal
Surface Plasmon Resonance
Molecular biology
Kidney Neoplasms
3. Good health
Kinetics
Epitope mapping
030220 oncology & carcinogenesis
biology.protein
lcsh:Q
Biotechnology/Bioengineering
Immunotherapy
Antibody
Epitope Mapping
Research Article
Signal Transduction
Zdroj: PLoS ONE, Vol 5, Iss 3, p e9625 (2010)
PLoS ONE
ISSN: 1932-6203
Popis: Carbonic anhydrase IX (CAIX, gene G250/MN-encoded transmembrane protein) is highly expressed in various human epithelial tumors such as renal clear cell carcinoma (RCC), but absent from the corresponding normal tissues. Besides the CA signal transduction activity, CAIX may serve as a biomarker in early stages of oncogenesis and also as a reliable marker of hypoxia, which is associated with tumor resistance to chemotherapy and radiotherapy. Although results from preclinical and clinical studies have shown CAIX as a promising target for detection and therapy for RCC, only a limited number of murine monoclonal antibodies (mAbs) and one humanized mAb are available for clinical testing and development. In this study, paramagnetic proteoliposomes of CAIX (CAIX-PMPLs) were constructed and used for anti-CAIX antibody selection from our 27 billion human single-chain antibody (scFv) phage display libraries. A panel of thirteen human scFvs that specifically recognize CAIX expressed on cell surface was identified, epitope mapped primarily to the CA domain, and affinity-binding constants (KD) determined. These human anti-CAIX mAbs are diverse in their functions including induction of surface CAIX internalization into endosomes and inhibition of the carbonic anhydrase activity, the latter being a unique feature that has not been previously reported for anti-CAIX antibodies. These human anti-CAIX antibodies are important reagents for development of new immunotherapies and diagnostic tools for RCC treatment as well as extending our knowledge on the basic structure-function relationships of the CAIX molecule.
Databáze: OpenAIRE
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