2. Academic Validation
  3. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases

Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases

  • Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7.
Taku Fukuzawa 1,  Zenjiro Sampei 1,  Kenta Haraya 1,  Yoshinao Ruike 1,  Meiri Shida-Kawazoe 2,  Yuichiro Shimizu 1,  Siok Wan Gan 1,  Machiko Irie 3,  Yoshinori Tsuboi 2,  Hitoshi Tai 4,  Tetsushi Sakiyama 2,  Akihisa Sakamoto 2,  Shinya Ishii 2,  Atsuhiko Maeda 2,  Yuki Iwayanagi 3,  Norihito Shibahara 2,  Mitsuko Shibuya 2,  Genki Nakamura 2,  Takeru Nambu 2,  Akira Hayasaka 2,  Futa Mimoto 2,  Yuu Okura 1,  Yuji Hori 2,  Kiyoshi Habu 3,  Manabu Wada 3,  Takaaki Miura 3,  Tatsuhiko Tachibana 3,  Kiyofumi Honda 1,  Hiroyuki Tsunoda 3,  Takehisa Kitazawa 3,  Yoshiki Kawabe 2 3,  Tomoyuki Igawa 2,  Kunihiro Hattori 3,  Junichi Nezu 5
Affiliations

Affiliations

  • 1 Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #07-11 to 16, Synapse, 138623, Singapore.
  • 2 Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
  • 3 Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
  • 4 Chugai Research Institute for Medical Science, Inc., Gotemba, Shizuoka, Japan.
  • 5 Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #07-11 to 16, Synapse, 138623, Singapore. nezujyn@chugai-pharm.co.jp.
PMID: 28439081 DOI: 10.1038/s41598-017-01087-7
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.

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