Recombinant Antibodies for Immunotherapy: Therapeutic Antibodies from XenoMouse Transgenic Mice

For close to two decades, realization of the promise of monoclonal antibody (mAb) technology for the generation of therapeutic “magic bullets” has been challenged primarily by limited efficacy and safety related to immunogenicity of mouse antibodies in human patients. Among the technologies developed to overcome these hurdles were transgenic mice genetically engineered with a “humanized” humoral immune system. One such transgenic technology, the XenoMouse, has succeeded in recapitulating the human antibody response in mice by introducing nearly the entire human immunoglobulin (Ig) loci into the germline of mice with inactivated mouse antibody machinery. XenoMouse strains have been used to generate a large array of high-affinity, potent, fully human antibodies directed to targets in multiple disease indications, many of which are advancing in clinical development. Full validation of the technology has been achieved with the recent regulatory approval of panitumumab, a fully human antibody directed against epidermal growth factor receptor, for the treatment of advanced colorectal cancer. The successful development of panitumumab, as the first antibody derived from human antibody transgenic mice, signifies an important milestone for XenoMouse and other human antibody transgenic technologies and points to their potential contributions for future therapeutics. RATIONALE FOR DEVELOPING HUMAN ANTIBODY-PRODUCING TRANSGENIC MICE The discovery of hybridoma technology in 1975 for the isolation of high-specificity and high-affinity mouse monoclonal antibodies (mAbs) opened the door to a new class of therapeutics with a potential to substantially impact both therapy and diagnosis of many human diseases.