title: Genetic variants in C5 and poor response to eculizumab.
abstract: BACKGROUND
  Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
  
  
  METHODS
  We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
  
  
  RESULTS
  Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
  
  
  CONCLUSIONS
  The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).
authors: From Osaka University Graduate School of Medicine (J.N., M.Y., H.S., Y.K.) and World Premier International Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Suita (T.K.), Medical Research Institute and Hard Tissue Genome Research Center, Tokyo Medical and Dental University (S.H., J.I.), Tokyo Medical University (K.O.), and Alexion Pharma (M.H.), Tokyo, Tokai University School of Medicine, Isehara (K.A.), Fukushima Medical University, Fukushima (H.N., T.S.), Ichinomiya Municipal Hospital, Ichinomiya (K.K.), Hamanomachi Hospital, Fukuoka (T.E.), Yamaguchi Grand Medical Center, Hofu (T.T.), Niigata University Medical and Dental Hospital, Niigata (M.M.), Japanese Red Cross Takayama Hospital, Takayama (T.M.), and Iwate Prefectual Central Hospital, Morioka (Y.W.) - all in Japan; University of Buenos Aires, Buenos Aires (A.L.B., A.L.); and Alexion Pharmaceuticals, Cheshire, CT (L.L., K.J., P.T.).
authors: Jun-ichi
authors: J
authors: Nishimura
authors: Masaki
authors: M
authors: Yamamoto
authors: Shin
authors: S
authors: Hayashi
authors: Kazuma
authors: K
authors: Ohyashiki
authors: Kiyoshi
authors: K
authors: Ando
authors: Andres L
authors: AL
authors: Brodsky
authors: Hideyoshi
authors: H
authors: Noji
authors: Kunio
authors: K
authors: Kitamura
authors: Tetsuya
authors: T
authors: Eto
authors: Toru
authors: T
authors: Takahashi
authors: Masayoshi
authors: M
authors: Masuko
authors: Takuro
authors: T
authors: Matsumoto
authors: Yuji
authors: Y
authors: Wano
authors: Tsutomu
authors: T
authors: Shichishima
authors: Hirohiko
authors: H
authors: Shibayama
authors: Masakazu
authors: M
authors: Hase
authors: Lan
authors: L
authors: Li
authors: Krista
authors: K
authors: Johnson
authors: Alberto
authors: A
authors: Lazarowski
authors: Paul
authors: P
authors: Tamburini
authors: Johji
authors: J
authors: Inazawa
authors: Taroh
authors: T
authors: Kinoshita
authors: Yuzuru
authors: Y
authors: Kanakura
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D003182:Complement C5 / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007564:Japan; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; C481642:eculizumab