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Antibody Repertoires of Four- and Five-Feature Translocus Mice Carrying Human Immunoglobulin Heavy Chain and and Light Chain Yeast Artificial Chromosomes¹

Ian C. Nicholson^2,*, Xiangang Zou^*, Andrei V. Popov^3,*, Graham P. Cook, Elaine M. Corps, Sally Humphries, Christine Ayling^*, Beatriz Goyenechea^*, Jian Xian^*, Michael J. Taussig, Michael S. Neuberger and Marianne Brüggemann^4,*

^* Laboratory of Developmental Immunology and Laboratory of Molecular Recognition, The Babraham Institute, Babraham, Cambridge, United Kingdom; and Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom

We have produced mice that carry the human Ig heavy (IgH) and both and light chain transloci in a background in which the endogenous IgH and loci have been inactivated. The B lymphocyte population in these translocus mice is restored to about one-third of normal levels, with preferential (3:1) expression of human over human . Human IgM is found in the serum at levels between 50 and 400 µg/ml and is elevated following immunization. This primary human Ab repertoire is sufficient to yield diverse Ag-specific responses as judged by analysis of mAbs. The use of D_H and J segments is similar to that seen in human B cells, with an analogous pattern of N nucleotide insertion. Maturation of the response is accompanied by somatic hypermutation, which is particularly effective in the light chain transloci. These mice therefore allow the production of Ag-specific repertoires of both IgM, and IgM, Abs and should prove useful for the production of human mAbs for clinical use.

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