The common challenges of bispecific therapeutic antibody discovery are immunogenicity and chain mispairing issues. Biocytogen’s RenLiteTM immunoglobulin humanized mouse is designed not only to overcome these two issues, but also to provide a full human heavy chain repertoire diversity. RenLiteTM mouse carries full human heavy chain VDJ loci and a fixed common human light chain VJ gene. The derived antibodies share the same light chain with different heavy chain variable domains. This technology dramatically simplifies the following heavy and light chain pairing process. Antibodies generated by RenLiteTM mice underwent natural selection, differentiation, and affinity maturation in vivo utilizing a human heavy chain repertoire, the potential of immunogenicity is minimized. RenLiteTM mice show robust immune response comparable to wild-type mice and RenLiteTM mice derived antibodies show a wide range of binding affinity including subnanomolar binding. RenLiteTM antibodies also showed strong in vivo efficacy against tumor growth in xenograft mouse models. In summary, RenLiteTM mouse is a powerful tool for advancing current bispecific or multispecific antibody discovery.