2. Academic Validation
  3. Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

  • Sci Rep. 2016 Dec 20:6:38644. doi: 10.1038/srep38644.
Claire L Dobson 1,  Paul W A Devine 2 3,  Jonathan J Phillips 4,  Daniel R Higazi 1,  Christopher Lloyd 1,  Bojana Popovic 1,  Joanne Arnold 1,  Andrew Buchanan 1,  Arthur Lewis 1,  Joanne Goodman 1,  Christopher F van der Walle 1,  Peter Thornton 1,  Lisa Vinall 1,  David Lowne 1,  Anna Aagaard 5,  Lise-Lotte Olsson 5,  Anna Ridderstad Wollberg 5,  Fraser Welsh 1,  Theodoros K Karamanos 2 3,  Clare L Pashley 2 3,  Matthew G Iadanza 2 3,  Neil A Ranson 2 3,  Alison E Ashcroft 2 3,  Alistair D Kippen 1,  Tristan J Vaughan 1,  Sheena E Radford 2 3,  David C Lowe 1
Affiliations

Affiliations

  • 1 MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
  • 2 Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
  • 3 School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK.
  • 4 Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB2 3RA, UK.
  • 5 Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
PMID: 27995962 DOI: 10.1038/srep38644
Abstract

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the Amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins.

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