Abstract 2181: A novel CXCR4 antagonist strongly mobilizes hematopoietic stem cells in vivo

Abstract

Abstract Introduction: The transplantation of hematopoietic stem cells (HSCs) has been the standard of care for the treatment of chemotherapy sensitive relapsed acute leukemia. HSCs mainly reside in the bone marrow with only few HSCs circulating in the peripheral blood (PB), due to homing effect mediated by the interaction of chemokine receptor CXCR4 expressed on HSCs with chemotactic ligand SDF-1α rich in the bone marrow. It is clinically desirable to enhance the number of HSCs in the PB for collection during the transplantation procedure. Since SDF-1α/CXCR4 axis and interaction mediates the homing and retention of HSCs in the bone marrow, our laboratory has recently discovered and developed a novel small molecule, HFX51116, that is capable of binding CXCR4 and blocking its interaction with SDF-1α, raising the possibility that this compound can be used for releasing HSCs from the bone marrow to the PB useful for the transplantation of HSCs. Method and Results: In vitro, there was almost no toxicity of HFX51116 at high concentrations in bone marrow stromal cells that were originally extracted from rats. In addition, HFX51116 was stable in rat serum. In vivo, we tested the short-term and long-term mobilization efficacy of HFX51116. For the short-term efficacy study, we determined the dynamic change of efficacy at different times and doses of HFX51116 in HSC mobilization assays. Furthermore, different strains of mice, such as C57/BL6, C3H/HEJ and DBA/2, were sensitive to HFX51116. HFX51116, when used in combination with G-CSF, had higher efficacy than G-CSF alone. For the long-term repopulation study, we employed the CD45.1/CD45.2 competitive assay to demonstrate that the HSCs mobilized by G-CSF and HFX51116 had the repopulation ability when compared with the bone marrow cells. Conclusion: Our studies have demonstrated high HSC mobilization efficacy of HFX51116 in vivo and the promise of this new lead compound for further preclinical and clinical studies. Citation Format: Xiao Fang, Qian Meng, Xiong Fang, Yujia Mao, Yan Xu, Jing An, Ziwei Huang. A novel CXCR4 antagonist strongly mobilizes hematopoietic stem cells in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2181.