5jz7 | pdb_00005jz7
NGF IN COMPLEX WITH MEDI578 scFv
Structural highlights
Disease[NGF_HUMAN] Defects in NGF are the cause of hereditary sensory and autonomic neuropathy type 5 (HSAN5) [MIM:608654]. The hereditary sensory and autonomic neuropathies are a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable.[1] [2] [3] Function[NGF_HUMAN] Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades through those receptor tyrosine kinase to regulate neuronal proliferation, differentiation and survival. Publication Abstract from PubMedUncontrolled 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. Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.,Dobson CL, Devine PW, Phillips JJ, Higazi DR, Lloyd C, Popovic B, Arnold J, Buchanan A, Lewis A, Goodman J, van der Walle CF, Thornton P, Vinall L, Lowne D, Aagaard A, Olsson LL, Ridderstad Wollberg A, Welsh F, Karamanos TK, Pashley CL, Iadanza MG, Ranson NA, Ashcroft AE, Kippen AD, Vaughan TJ, Radford SE, Lowe DC Sci Rep. 2016 Dec 20;6:38644. doi: 10.1038/srep38644. PMID:27995962[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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