Poster Presentation 6th Australian Health and Medical Research Congress 2012

Development of integrin inhibitors as haemopoietic stem cell mobilisation agents (#382)

Benjamin Cao 1 , Zhen Zhang 1 , Jochen Grassinger 1 , Brenda Williams 1 , Songhui Li 1 , Paul G Savage 1 , David N Haylock 1 , Oliver E Hutt 1 , Susan K Nilsson 1
  1. CSIRO Materials Science and Engineering, Clayton, VIC, Australia

Haemopoietic stem cells (HSCs) are rare, multipotent populations of adult stem cells, which give rise to all blood cell types in the human body. HSCs maintain the HSC pool throughout life, an essential characteristic for their use in stem cell transplants following high dose chemotherapy in the treatment of cancers such as leukaemia and lymphoma. Peripheral blood (PB) stem cells are one of the most common sources of HSCs for transplants, however their extremely low numbers in steady state requires BM HSC mobilisation for successful harvests. Of the several adhesive microenvironment interactions known to retain HSCs within the BM, the integrin family of heterodimeric transmembrane proteins have been shown to be critical. In addition, these interactions have also been shown to be important in HSC engraftment following transplantation and as a consequence, the β1 integrins, α4β1 (very-late antigen-4; VLA-4) and α9β1 have been identified as potential therapeutic targets for HSC mobilisation. In an effort to understand the mechanism of integrin-mediated HSC mobilisation and facilitate the search for novel HSC mobilising agents, we synthesized a water soluble, fluorescent integrin antagonist, R-BC154, which has high affinities against both α4β1 (Kd = 19.4 nM) and α9β1 (Kd = 20.9 nM) integrins. This probe was successfully applied to in vivo binding assays, where R-BC154 was shown to bind preferentially to haemopoietic stem and progenitors (LSK) as well as enriched HSCs (SLAM) within mice BM. In addition, potent sub-nanomolar integrin inhibitors were identified as stem cell mobilisation agents, which were shown to give enhanced mobilisation yields when used in combination with either AMD3100 or G-CSF. Furthermore, we show that HSCs mobilised by integrin inhibitors can give rise to long-term multi-lineage haemopoietic reconstitution post-transplant.