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To determine whether cancer patients have ever made antibodies with disease-fighting potential, we screened combinatorial antibody libraries from cancer patients for immunoglobulins that can identify metastatic tumor cells. This strategy yielded human antibodies specific for the activated conformation of the adhesion receptor integrin \u03b1v\u03b23 that is associated with a metastatic phenotype. In a remarkable example of convergent evolution, two of these antibodies were shown to contain the Arg-Gly-Asp integrin recognition motif of the natural ligand within the third complementarity-determining region of the heavy chain. These antibodies interfered with lung colonization by human breast cancer cells in a mouse model and inhibited existing metastatic disease. Our data imply that, at least at some time, these antibodies were part of a patient's surveillance system against metastatic cells, targeting the activated conformer of integrin \u03b1v\u03b23 and disrupting its functions. The ligand-mimetic nature of these antibodies, combined with specificity for a single receptor, is unique in the integrin\u2013ligand repertoire. The convergent evolution of critical sequences in antibodies and other ligands that bind to the same target means that the immune response has sufficient power to find a best chemical solution for the optimization of binding energy, even though antibodies evolve in real time, as compared with billions of years for the natural ligand.<\/jats:p>","DOI":"10.1073\/pnas.0407869101","type":"journal-article","created":{"date-parts":[[2004,11,24]],"date-time":"2004-11-24T20:24:43Z","timestamp":1101327883000},"page":"17210-17215","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":34,"title":["Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis"],"prefix":"10.1073","volume":"101","author":[{"given":"Brunhilde","family":"Felding-Habermann","sequence":"first","affiliation":[{"name":"Departments of Molecular and Experimental Medicine and Chemistry, The Scripps Research Institute and The Skaggs Institute of Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037; 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