AACR 2020: Evaluating anti-IL-2Ra in vivo efficacy on humanized knock-in mice
Interleukin-2 receptor alpha chain (also called as CD25) is a 55 kD glycoprotein, also known as IL-2Ra, Ly-43, p55, or Tac. It is expressed on activated T and B cells, thymocyte subset, pre-B cells, and T regulatory cells. IL-2Ra and IL-2Rβ (CD122), together with the common gamma chain (IL2Rg)(CD132), form the high affinity signaling IL-2 receptor. Its afﬁnity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of IL-2Ra on the surface of many different haematological tumor cells is now well established and, apart from its prognostic signiﬁcance, IL-2Ra may be present on leukemic stem cells and enable oncogenic signaling pathways in leukemic cells. Additionally, high IL-2Ra expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumors and autoimmune disease. The relative clinical safety and efﬁcacy of administering anti- IL-2Ra radioimmunoconjugates and immunotoxins in various haematological tumor indications has been established and clinical trials of a novel IL-2Ra-directed antibody drug conjugate are underway.
Biocytogen has generated IL-2Ra humanized mouse for both in vitro functional validation of signaling pathway and in vivo efficacy evaluation of IL-2Ra antibodies. The targeting strategy is that the genomic DNA covering exons 2~6 of mouse IL-2Ra gene which encode the extracellular domain are replaced by the counterpart of human IL-2Ra genomic DNA covering exons 2~6. Human IL-2Ra is mainly detectable on the T cells in spleen of the IL-2Ra humanized mice. The humanized mice are highly similar to the wild-type mice in basal leukocyte subpopulations, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. STAT-5 phosphorylation induced by mouse IL2 protein is blocked by anti-human IL-2Ra antibodies, suggesting that the functional pathways in IL-2Ra humanized mice work well. The colon cancer model established in IL-2Ra humanized mice is undergoing, anti-human IL-2Ra antibodies showed good efficacy in inhibiting tumor growth.
Taken together, IL-2Ra humanized mice are a useful tool for in vivo efficacy evaluation of human IL-2Ra antibodies that can be advanced to human clinical trials.