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Diabetes 52:2689-2695, 2003
© 2003 by the American Diabetes Association, Inc.

Recombinant Fabs of Human Monoclonal Antibodies Specific to the Middle Epitope of GAD65 Inhibit Type 1 Diabetes–Specific GAD65Abs

Carolyn J. Padoa1,2, J. Paul Banga3, Anne-Marie Madec4, Manfred Ziegler5, Michael Schlosser6, Eva Ortqvist7, Ingrid Kockum8, Jerry Palmer1, Olov Rolandsson9, Katherine A. Binder1, Jefferson Foote10, Dong Luo1, and Christiane S. Hampe1

1 Department of Medicine, University of Washington, Seattle, Washington
2 Department of Chemical Pathology, University of the Witwatersrand & National Health Laboratory Services, Johannesburg, South Africa
3 Division of Medicine, Guy’s, Kings and St. Thomas’ School of Medicine, London, U.K
4 Institut National de la Santé et de la Recherche Médicale, Laennec Faculty of Medicine, University of Lyon, Lyon, France
5 Institute of Diabetes "Gerhardt Katsch," Karlsburg, Germany
6 Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Karlsburg, Germany
7 Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
8 Department of Molecular Medicine, Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
9 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
10 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington

Autoantibodies to the 65-kDa isoform of GAD (GAD65Abs) are associated with type 1 diabetes development, but the conformational nature of the GAD65Ab epitopes complicates the evaluation of disease risk. Six GAD65-specific recombinant Fabs (rFabs) were cloned from monoclonal antibodies b96.11, DP-C, DP-A, DPD, 144, and 221–442. The binding of GAD65Abs in 61 type 1 diabetic patients to GAD65 was analyzed by competitive radioimmunoassays with the six rFabs to ascertain disease-specific GAD65Ab binding specificities. The median binding was reduced significantly by rFab b96.11 (72%) (P < 0.0001), DP-A (84%) (P < 0.0001), DP-C (84%) (P < 0.0001), 221–442 (79%) (P < 0.0001), and DP-D (80%) (P < 0.0001). The competition pattern in type 1 diabetic patients differed from that in GAD65Ab-positive late autoimmune diabetes in adults (LADA) patients (n = 44), first-degree relatives (n = 38), and healthy individuals (n = 14). Whereas 87 and 72% of the type 1 diabetic sera were competed by rFab b96.11 and DP-C, respectively, only 34 and 26% of LADA patients, 18 and 25% of first-degree relatives, and 7 and 28% of healthy individuals showed competition (P < 0.0001). These findings support the view that type 1 diabetes is associated with disease- and epitope-specific GAD65Abs and supports the notion that the middle epitope is disease associated. These GAD65-specific rFabs should prove useful in predicting type 1 diabetes and in the study of conformational GAD65Ab epitopes.

Address correspondence and reprint requests to Dr. Christiane S. Hampe, Department of Medicine, Box 357710, University of Washington, Seattle, WA 98195. E-mail: champe{at}u.washington.edu


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