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Human IgG Monoclonal Anti-_IIb3-Binding Fragments Derived from Immunized Donors Using Phage Display¹

Marie-Josée Jacobin^*, Jeanny Laroche-Traineau^*, Melvyn Little^2,, Armin Keller^3,, Karlheinz Peter, Martin Welschof^3,, Alan Nurden^* and Gisèle Clofent-Sanchez^4,*

^* Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5533, Hopital Cardiologique, Pessac, France; German Cancer Research Center, Recombinant Ab Group, Heidelberg, Germany; and Department of Cardiology, University of Freiburg, Freiburg, Germany

Previous studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have relied on serum analysis and have shown the frequent development of Abs directed against the _IIb3 integrin. However, little is known about the molecular diversity of the humoral immune response to _IIb3 due to the paucity of mAbs issuing from these pathologies. We have isolated human IgG anti-_IIb3 binding fragments using combinatorial libraries of single-chain IgG created from the B cells of a GT and an AITP patient, both with serum Abs. Ab screening was performed using activated platelets or activated _IIb3-expressing Chinese hamster ovary cells. Sequencing of selected phage Abs showed that a broad selection of genes from virtually all V gene families had been used, indicating the diversity of the immune response. About one-half of the V_H and V_L segments of our IgG anti-_IIb3 fragments displayed extensive hypermutations in the complementarity-determining region, supporting the idea that an Ag-driven immune response was occurring in both patients. The H chain complementarity-determining region 3 analysis of phage Abs revealed motifs other than the well-known RGD and KQAGDV integrin-binding sequences. To our knowledge, our study is the first to illustrate multiple human IgG anti-_IIb3 reactivities and structural variations linked to the anti-platelet human immune response. Human _IIb3 Abs preferentially directed against the activated form of the integrin were further characterized because platelet _IIb3 inhibitors are potential therapeutic reagents for treating acute coronary syndromes. Currently available _IIb3 antagonists do not specifically recognize the activated form of the integrin.

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