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Nucleic Acids Research, 1994, Vol. 22, No. 8 1389-1393
© 1994

MOLECULAR BIOLOGY

Antibodies generated from human immunoglobulin miniloci in transgenic mice

Simon D. Wagner, Gareth T. Williams, Tammy Larson, Michael S. Neuberger*, Daisuke Kitamura1,+, Klaus Rajewsky1, Jian Xian2 and Marianne Bruggemann2

Medical Research Council Laboratory of Molecular Biology Hills Road, Cambridge CB2 2QH, UK 1Institute for Genetics, University of Cologne Weyertal 121, D-5000 Cologne 41, Germany 2AFRC Babraham Institute Babraham, Cambridge CB2 4AT, UK

*To whom correspondence should be addressed

Received January 31, 1994. Revised March 16, 1994. Accepted March 16, 1994.

One approach to the production of human monoclonal antibodies focusses on the creation of transgenic mice bearing human immunoglobulin gene miniloci. Whilst such loci undergo lymphold-speclfic gene rearrangement, only a small proportion of mouse B cells express the human immunoglobulin chains; the miniloci thus contribute poorly to serum immunoglobulin. Attributing this poor performance to competition between the transgenic and endogenous immunoglobulin loci, we crossed mice bearing a human immunoglobulin heavy-chain (HulgH) mlnllocus with animals that had been rendered B cell-deficient by disruption of their endogenous heavy-chain locus. The results were dramatic: the human minilocus rescued B cell differentiation such that effectively all B cells now expressed human £ chains. The concentration of antibody in the mouse serum recognised by anti-human £ increased to a concentration about one sixth that in human serum. The HulgH antibodies are heterogenous with diversity being generated by both combinatorial and junctional processes. Following antigen challenge, specific antibody is elicited but at low titre.

+Present address: Medical Institute of Bioregulation, Kyushu University, 812 Japan


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