Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis

Abstract

Combinatorial antibody libraries have the potential to display the entire immunological record of an individual, allowing one to detect and recover any antibody ever made, irrespective of whether it is currently being produced. We have termed this the ''fossil record'' of an individual's antibody response. To determine whether cancer patients have ever made antibodies with diseasefighting 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 ␣v␤3 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 ␣v␤3 and disrupting its functions. The ligand-mimetic nature of these antibodies, combined with specificity for a single receptor, is unique in the integrin-ligand 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. convergent evolution ͉ human antibodies ͉ integrin ␣v␤3 C ombinatorial antibody libraries allow the cloning of the entire immunological repertoire of an individual (1, 2). One advantage of this method is that, in principle, it allows the resurrection of any antibody that an individual has ever made, irrespective of whether the antibody is currently being produced. We have referred to this feature of combinatorial antibody libraries as the ''fossil record'' of an individual's immunological history (3).In cancer, the successful establishment of a tumor in the host does not necessarily mean that there was a failure to produce antitumor antibodies. Tumor establishment also could be due to the fact that the growth rate of the malignant cells outstripped the ability of the immune response to deal with the tumor mass or that the target antigen has been modulated. Over the years, these ideas have been generally termed "immune surveillance", but there has been no simple way to test this concept. Insofar as we can now clone the fossil record, we can study whether patients with cancer have made antibodies with specificities unique to cancer cells and whether such antibodies can influence the outcome of the host-tumor encounter.To test these ideas, we took advantage of studies in our laboratory that...

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