5JZ7

NGF IN COMPLEX WITH MEDI578 scFv

Summary for 5JZ7

• Entry DOI: 10.2210/pdb5jz7/pdb
• Descriptor: Beta-nerve growth factor, MEDI578 scFv, heavy chain, MEDI578 scFv, light chain (3 entities in total)
• Functional Keywords: antibody, complex, epitope, ngf, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P01138
• Total number of polymer chains: 12
• Total formula weight: 156350.41

Authors

Olsson, L.-L.,Aagaard, A. (deposition date: 2016-05-16, release date: 2017-01-11, Last modification date: 2024-11-13)

Primary citation

Dobson, C.L.,Devine, P.W.,Phillips, J.J.,Higazi, D.R.,Lloyd, C.,Popovic, B.,Arnold, J.,Buchanan, A.,Lewis, A.,Goodman, J.,van der Walle, C.F.,Thornton, P.,Vinall, L.,Lowne, D.,Aagaard, A.,Olsson, L.L.,Ridderstad Wollberg, A.,Welsh, F.,Karamanos, T.K.,Pashley, C.L.,Iadanza, M.G.,Ranson, N.A.,Ashcroft, A.E.,Kippen, A.D.,Vaughan, T.J.,Radford, S.E.,Lowe, D.C.
Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.
Sci Rep, 6:38644-38644, 2016

PubMed 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.

PubMed: 27995962
DOI: 10.1038/srep38644

Experimental method

X-RAY DIFFRACTION (3.4 Å)