5B71

Crystal structure of complement C5 in complex with SKY59

Summary for 5B71

• Entry DOI: 10.2210/pdb5b71/pdb
• Descriptor: SKY59 Fab light chain, SKY59 Fab heavy chain, Complement C5 beta chain, ... (4 entities in total)
• Functional Keywords: ph-dependent, recycling antibody, immune system, complement c5, fab, complex
• Biological source: Homo sapiens; More
• Cellular location: Secreted: P01031
• Total number of polymer chains: 6
• Total formula weight: 119495.17

Authors

Irie, M.,Shimizu, Y.,Sampei, Z.,Fukuzawa, T. (deposition date: 2016-06-03, release date: 2017-05-03, Last modification date: 2024-10-23)

Primary citation

Fukuzawa, T.,Sampei, Z.,Haraya, K.,Ruike, Y.,Shida-Kawazoe, M.,Shimizu, Y.,Gan, S.W.,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.
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.
Sci Rep, 7:1080-1080, 2017

PubMed Abstract: Dysregulation 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.

PubMed: 28439081
DOI: 10.1038/s41598-017-01087-7

Experimental method

X-RAY DIFFRACTION (2.11 Å)