Production and selection of antigen-specific fully human monoclonal antibodies from mice engineered with human Ig loci

Abstract The ability to produce highly specific fully human monoclonal antibodies to human antigens has potential significant applications to human therapy. This review describes the creation of novel mouse strains engineered to produce a diverse repertoire of fully human antibodies in the absence of mouse antibodies. These mouse strains have been generated by introducing megabase-sized human immunoglobulin loci, containing the majority of the human antibody gene repertoire, in nearly germline configuration, into mice deficient in mouse antibody production. The mice produce high levels of human IgMκ and IgGκ antibodies with a diverse adult-like repertoire. Upon immunization with multiple human antigens the mice generate high affinity, antigen-specific fully human monoclonal antibodies with neutralization activity. Comparison of these mice to other strains containing limited human antibody gene repertoire underscores the importance of the large number of variable genes for faithful reproduction of functional and diverse human antibody response in mice.