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PhD Studentship: Use of multicellular human liver models to investigate clearance of therapeutic antibodies.

University of Birmingham - Centre for Liver and Gastroenterology Research, Institute of Immunity and Immunotherapy, University of Birmingham

Qualification Type: PhD
Location: Birmingham
Funding for: UK Students, EU Students
Funding amount: £8,000 pa
Hours: Full Time
Placed On: 16th May 2019
Closes: 12th July 2019

We are seeking a flexible, ambitious PhD candidate with an interest in human liver biology and drug development who will engage in a multi-disciplinary research project. The project aims to improve the design of new humanized therapeutic antibodies to prevent clearance within the hepatic circulation. Cells of the hepatic reticuloendothelial system express receptors that can bind and internalise antibody in a non-specific manner or via target-mediated clearance. Thus, preclinical screening tools that recreate human biodistribution and clearance mechanisms are vital to de-risk the development process and allow for efficient and rational selection of candidate antibodies. This project is a partnership between an internationally recognised centre of excellence for the study of human liver biology and GSK, a science-led global healthcare company, who has proven experience in the design and utility of therapeutic antibodies. We have refined methodology for the isolation and culture of human hepatic endothelial1 and macrophage populations2, and have developed whole tissue based perfusion methodologies3 and assays that recreate blood flow over cultured cells4. These allow us to assess the likely binding and clearance of therapeutic antibody within the hepatic vasculature in healthy and diseased individuals. Thus, we are proposing to use isolated cell populations and whole liver perfusion technology to assess the clearance and cellular localisation of antibody. The project will provide opportunities for close collaboration between the academic and corporate sectors, with time spent performing research at GSK’s UK research Hub in Stevenage, and will provide experience and skills in cutting-edge interdisciplinary research. The candidate will have access to additional transferrable skills training and mentoring through the Graduate School in Birmingham. 

References

  1. Shetty, S., Lalor, P.F. & Adams, D.H. Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol (2018).
  2. Liaskou, E., et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57, 385-398 (2013).
  3. Wiggins, B.G., et al. In Vitro and Ex Vivo Models to Study T Cell Migration Through the Human Liver Parenchyma. Methods Mol Biol 1591, 195-214 (2017).
  4. Lalor, P.F., Herbert, J., Bicknell, R. & Adams, D.H. Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol 304, G469-478 (2013). 

Person Specification

The ideal applicant will have an undergraduate/masters degree in a biomedical or biochemical discipline and proven experience working with human biomaterials. Experience of liver biology and/or human cell culture and isolation is desirable, as is demonstrable experience of working as part of a multi-disciplinary team. They should have a commitment to research in human disease and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a biomedical discipline.

   
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