Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes

We have produced mice that carry the human Ig heavy (IgH) and both kappa an d lambda light chain transloci in a background in which the endogenous IgH and kappa loci have been inactivated. The B lymphocyte population in these translocus mice is restored to about one-third of normal levels, with prefe rential (3:1) expression of human lambda over human kappa. Human IgM is fou nd in the serum at levels between 50 and 400 mu g/ml and is elevated follow ing immunization. This primary human Ab repertoire is sufficient to yield d iverse 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 accompanie d by somatic hypermutation, which is particularly effective in the light ch ain transloci, These mice therefore allow the production of Ag-specific rep ertoires of both IgM,kappa and IgM,lambda Abs and should prove useful for t he production of human mAbs for clinical use.