Publication Date:
2009-03-21
Description:
The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens. An affinity-improved version of bH1 inhibits both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. Such "two-in-one" antibodies challenge the monoclonal antibody paradigm of one binding site, one antigen. They could also provide new opportunities for antibody-based therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bostrom, Jenny -- Yu, Shang-Fan -- Kan, David -- Appleton, Brent A -- Lee, Chingwei V -- Billeci, Karen -- Man, Wenyan -- Peale, Franklin -- Ross, Sarajane -- Wiesmann, Christian -- Fuh, Germaine -- New York, N.Y. -- Science. 2009 Mar 20;323(5921):1610-4. doi: 10.1126/science.1165480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19299620" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies, Bispecific/chemistry/genetics/*immunology/therapeutic use
;
Antibodies, Monoclonal/chemistry/genetics/*immunology/therapeutic use
;
Antibodies, Monoclonal, Humanized
;
Antibody Affinity
;
Antibody Specificity
;
Binding Sites, Antibody/genetics
;
Cell Proliferation/drug effects
;
Complementarity Determining Regions/genetics/immunology
;
Crystallography, X-Ray
;
Epitopes/immunology/metabolism
;
Genetic Engineering
;
Humans
;
Mice
;
Models, Molecular
;
Mutagenesis
;
Neoplasms, Experimental/drug therapy
;
Protein Conformation
;
Protein Structure, Tertiary
;
Receptor, ErbB-2/chemistry/*immunology/metabolism
;
Thermodynamics
;
Trastuzumab
;
Vascular Endothelial Growth Factor A/chemistry/*immunology/metabolism
;
Xenograft Model Antitumor Assays
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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