With the development of immunotherapy in recent years, therapeutic antibodies have become a major player combating cancer with the limitation of recognizing cell surface or secreted molecules. In contract, the human T cell receptor (TCR) recognizes its cognate peptide antigen when presented on human leukocyte antigen (HLA) molecules, and thus detects a broader range of targets including intracellular proteins. Here we established an innovative strategy of generating fully human TCR mimic (TCRm) antibodies that can recognize antigen with a higher specificity and affinity. Previously, Biocytogen established RenMabTM and RenLiteTM mice (RenMiceTM).these humanized immunoglobulin mouse models generate fully human antibodies that carry human Ig heavy chain and human kappa light chain variable domains. Here, HLA genes were introduced into RenMice to build tolerance towards HLA. When immunized with HLA-peptide complexes, these mice generate antibodies that specifically target the HLA-peptide complex, with no reactivity to HLA alone nor other peptide-HLA complexes. Compared to natural TCRs, these TCRm antibodies show higher affinity and specificity. Using optimized immunization methods and high-throughput screening, our antibody discovery platform generated fully human TCRm antibodies from HLA/RenMab and HLA/RenLite mice. Producing TCR-mimic binders with this unique TCRm technology can become a very powerful tool in the immunotherapy field.