5b71
Crystal structure of complement C5 in complex with SKY59Crystal structure of complement C5 in complex with SKY59
Structural highlights
DiseaseCO5_HUMAN Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:609536. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele (PubMed:15995705). FunctionCO5_HUMAN Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis). Publication Abstract from PubMedDysregulation of the complement system is linked to the pathogenesis of a variety of hematological disorders. Eculizumab, an anti-complement C5 monoclonal antibody, is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). However, because of high levels of C5 in plasma, eculizumab has to be administered biweekly by intravenous infusion. By applying recycling technology through pH-dependent binding to C5, we generated a novel humanized antibody against C5, SKY59, which has long-lasting neutralization of C5. In cynomolgus monkeys, SKY59 suppressed C5 function and complement activity for a significantly longer duration compared to a conventional antibody. Furthermore, epitope mapping by X-ray crystal structure analysis showed that a histidine cluster located on C5 is crucial for the pH-dependent interaction with SKY59. This indicates that the recycling effect of SKY59 is driven by a novel mechanism of interaction with its antigen and is distinct from other known pH-dependent antibodies. Finally, SKY59 showed neutralizing effect on C5 variant p.Arg885His, while eculizumab does not inhibit complement activity in patients carrying this mutation. Collectively, these results suggest that SKY59 is a promising new anti-C5 agent for patients with PNH and other complement-mediated disorders. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.,Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H, Sakiyama T, Sakamoto A, Ishii S, Maeda A, Iwayanagi Y, Shibahara N, Shibuya M, Nakamura G, Nambu T, Hayasaka A, Mimoto F, Okura Y, Hori Y, Habu K, Wada M, Miura T, Tachibana T, Honda K, Tsunoda H, Kitazawa T, Kawabe Y, Igawa T, Hattori K, Nezu J Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7. PMID:28439081[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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