Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Strategies to inhibit beta common receptor mediated signalling using small molecules and monoclonal antibodies. (#174)

Urmi Dhagat 1 2 , Steffi K Cheung Tung Shing 1 2 , Tracy L Nero 1 2 , Winnie L Kan 3 , Timothy R Hercus 3 , Sophie E Broughton 1 2 , Timothy P Hughes 4 , Con Panousis 5 , Catherine M Owczarek 5 , Angel F Lopez 3 , Michael W Parker 1 2
  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, Melbourne, Victoria, Australia
  2. Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, Australia
  3. The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Victoria, Australia
  4. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  5. Research and Development, CSL Limited, Bio21 Molecular Science and Biotechnology Institute, Melbourne, Victoria, Australia

The cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 share a common receptor known as the beta common (bc, CD131) receptor. These cytokines activate downstream signalling pathways via a receptor complex incorporating a cytokine-specific alpha receptor and the bc receptor. In addition to their role in steady state haematopoiesis these cytokines have also been identified as critical mediators of the pathogenesis of inflammatory diseases such as rheumatoid arthritis, nasal polyposis, chronic hyperplastic sinusitis and asthma. However, other than steroids, there are no therapeutic agents that specifically and effectively target inflammation mediated by all three of these cytokines. We have identified two key ‘Sites’ on the cytokine receptor complex that can be targeted to inhibit βc receptor mediated signalling. Here we present data on the development of small molecules and a monoclonal antibody that specifically target the interface between the βc receptor and the cytokine (referred to as Site 2) to block downstream signalling. The second site of interest is called Site 4, this site is formed when two hexameric ternary complexes (2 cytokine:2 alpha receptor:1 βc homodimer) further assemble to form a dodecameric signalling complex. Here we report the binding epitope of a first monoclonal antibody with a Site 4 epitope within the βc receptor, using X-ray crystallography.