Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases
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). H...
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2017
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oai:doaj.org-article:84b20be1cd2e48b4b4a92b1de12240c02021-12-02T12:31:45ZLong lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases10.1038/s41598-017-01087-72045-2322https://doaj.org/article/84b20be1cd2e48b4b4a92b1de12240c02017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01087-7https://doaj.org/toc/2045-2322Abstract 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.Taku FukuzawaZenjiro SampeiKenta HarayaYoshinao RuikeMeiri Shida-KawazoeYuichiro ShimizuSiok Wan GanMachiko IrieYoshinori TsuboiHitoshi TaiTetsushi SakiyamaAkihisa SakamotoShinya IshiiAtsuhiko MaedaYuki IwayanagiNorihito ShibaharaMitsuko ShibuyaGenki NakamuraTakeru NambuAkira HayasakaFuta MimotoYuu OkuraYuji HoriKiyoshi HabuManabu WadaTakaaki MiuraTatsuhiko TachibanaKiyofumi HondaHiroyuki TsunodaTakehisa KitazawaYoshiki KawabeTomoyuki IgawaKunihiro HattoriJunichi NezuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
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Medicine R Science Q Taku Fukuzawa Zenjiro Sampei Kenta Haraya Yoshinao Ruike Meiri Shida-Kawazoe Yuichiro Shimizu Siok Wan Gan Machiko Irie Yoshinori Tsuboi Hitoshi Tai Tetsushi Sakiyama Akihisa Sakamoto Shinya Ishii Atsuhiko Maeda Yuki Iwayanagi Norihito Shibahara Mitsuko Shibuya Genki Nakamura Takeru Nambu Akira Hayasaka Futa Mimoto Yuu Okura Yuji Hori Kiyoshi Habu Manabu Wada Takaaki Miura Tatsuhiko Tachibana Kiyofumi Honda Hiroyuki Tsunoda Takehisa Kitazawa Yoshiki Kawabe Tomoyuki Igawa Kunihiro Hattori Junichi Nezu Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| description |
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. |
| format |
article |
| author |
Taku Fukuzawa Zenjiro Sampei Kenta Haraya Yoshinao Ruike Meiri Shida-Kawazoe Yuichiro Shimizu Siok Wan Gan Machiko Irie Yoshinori Tsuboi Hitoshi Tai Tetsushi Sakiyama Akihisa Sakamoto Shinya Ishii Atsuhiko Maeda Yuki Iwayanagi Norihito Shibahara Mitsuko Shibuya Genki Nakamura Takeru Nambu Akira Hayasaka Futa Mimoto Yuu Okura Yuji Hori Kiyoshi Habu Manabu Wada Takaaki Miura Tatsuhiko Tachibana Kiyofumi Honda Hiroyuki Tsunoda Takehisa Kitazawa Yoshiki Kawabe Tomoyuki Igawa Kunihiro Hattori Junichi Nezu |
| author_facet |
Taku Fukuzawa Zenjiro Sampei Kenta Haraya Yoshinao Ruike Meiri Shida-Kawazoe Yuichiro Shimizu Siok Wan Gan Machiko Irie Yoshinori Tsuboi Hitoshi Tai Tetsushi Sakiyama Akihisa Sakamoto Shinya Ishii Atsuhiko Maeda Yuki Iwayanagi Norihito Shibahara Mitsuko Shibuya Genki Nakamura Takeru Nambu Akira Hayasaka Futa Mimoto Yuu Okura Yuji Hori Kiyoshi Habu Manabu Wada Takaaki Miura Tatsuhiko Tachibana Kiyofumi Honda Hiroyuki Tsunoda Takehisa Kitazawa Yoshiki Kawabe Tomoyuki Igawa Kunihiro Hattori Junichi Nezu |
| author_sort |
Taku Fukuzawa |
| title |
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| title_short |
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| title_full |
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| title_fullStr |
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| title_full_unstemmed |
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| title_sort |
long lasting neutralization of c5 by sky59, a novel recycling antibody, is a potential therapy for complement-mediated diseases |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/84b20be1cd2e48b4b4a92b1de12240c0 |
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