Production of humanized antibodies in transgenic animals

A method of making a transgenic vector comprising a humanized Immunoglobulin (Ig) locus capable of producing a functional repertoire of humanized antibodies in a non-human animal generating antibody diversity primarily through gene conversion and/or hypermutation, comprising:

• (i) obtaining a DNA fragment comprising an Ig locus or a portion therefor from said non-human animal, which comprises at least two V gene segments, at least one J gene segment and at least one constant region gene segment, and non-coding sequences;
• and
• (ii) integrating by homologous recombination at least one functional human V gene segment encoding a human V region amino acid sequence, into said DNA fragment of step (i) to produce a humanized Ig locus,
• wherein the V gene segments present are separated only by non-coding, non-human sequences derived from said non-human animal that generates antibody diversity primarily through gene conversion and/or hypermutation, and at least one of the functional V gene segments encoding a human V region amino acid sequence is placed downstream of the other V gene segments, and
• wherein said Ig gene segments are juxtaposed in an unrearranged, partially rearranged or fully rearranged configuration, as to permit gene rearrangement and gene conversion of said humanized Ig locus and the production of a functional repertoire of humanized antibodies with V region amino acid sequences encoded by more than one V region gene segment, in said non-human animal.