Novel Therapeutic Approaches Targeting MDSC in Myelodysplastic Syndrome
Technical Report,01 Sep 2016,31 Aug 2017
H. Lee Moffitt Cancer Center and Research Institute Tampa United States
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Development of targeted MDS therapies has been challenged by a limited insight of molecular mechanisms of disease pathogenesis and therefore, current therapeutic approaches remain highly empiric largely ignoring the role of the inflammatory bone marrow BM microenvironment. We identified S100A9 as a mediator of myeloid derived suppressor cell MDSC activation and as the native ligand to CD33, which is highly expressed in MDS. Therefore, our goals are to develop novel therapeutic strategies that inactivate MDSC to improve survival of HSPC and allow us to provide the basis for more effective, biologically rational MDS therapeutics. Based on our initial hypothesis of hematopoietic improvement through the targeting of the S100A9-CD33 pathway, this funding year we were able show that our proposed approaches can inactivate MDSC in vitro. This is achieved through the development of a specific S100A9 trap, the CD33-chimeric human IgG1 molecule CD33-fusion. We demonstrated that CD33-fusion is able to neutralize soluble S100A9 and suppresses S100A9 induced pro-inflammatory cytokine production as well as improve hematopoiesis. This focused translational research represents the base to develop novel treatments for MDS providing a unique opportunity for success with potential for enormous clinical impact.
- Medicine and Medical Research