The Hu-M? CIEA NOG Mouse?: A Preclinical Platform to Test the Efficacy and Safety of Novel Therapeutics

摘要

The systematic production and generation of "humanized" mice is critical for the commercialization and utilization of this novel animal model in industry and for large-scale applications. The Hu-M? CIEA NOG mouse? is generated by injection of human hematopoietic CD34+ progenitor cells into the CIEA NOG (NOD/SCID/IL2R gamma null) mouse?. These mice develop a functional human immune system and can be used as a preclinical platform to test the efficacy and safety of novel therapeutics including those for human restricted pathogens. HuMurine has generated over 300 Hu-M? CIEA NOG mice? by using CD34+ human hematopoietic progenitor cells (HPCs) purified from human fetal liver, and >80% of mice injected intrahepatically as new born mice develop humanization levels of >30%, as determined by the ratio of human lymphocytes [huCD45+ / (huCD45+ + muCD45+)] in the peripheral blood. Similar to humanization profiles displayed in humanized NSG mice, Hu-M? CIEA NOG mice? (Hu-M? mice) display human T cells (CD4+, CD8+), B cells (CD 19+), as well as lower levels of human NK cells (CD56+) and macrophages (CD14+) as determined by flow cytometric analysis of peripheral blood. Additionally we have found evidence of human B and T cell development in the bone marrow and spleen of Hu-M? mice. Key B (immature, na?ve, mature) and T cell subsets (CD45RA, CD45RO) were identified and characterized within the human lymphocytic population in these organs. This provides evidence that the Hu-M? mouse can support human B and T lymphopoiesis and can be used as a platform to test immunotherapies that involve or are directed against B or T cell subsets. Since immunotoxicity is a major life-threatening side effect of novel immunotherapies, as evidenced from the TGN1412 trials, preclinical animal models that can quickly and economically screen INDs for potential immunotoxicity would greatly improve the ability to select compounds with decreased off-target toxicities. Hu-M? mice can be successfully implemented for detecting and quantifying immunotoxicity induction during an immunotherapy regiment including those triggered by mAbs in vivo.