• Jun-Ichi Nishimura and Yuzuru Kanakura.
• Osaka University Graduate School of Medicine, Department of Hematology and Oncology.
• Rinsho Ketsueki. 2015 Feb 1;56(2):103-10.

AbstractThis review is a commentary on an article entitled "Genetic variants in C5 and poor response to eculizumab" (N Engl J Med. 2014; 370: 632-639). The molecular basis for the poor response to eculizumab in Japanese patients is unclear. Of 345 Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH) who received eculizumab, 11 showed a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654 G>A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among patients with PNH (3.2%) was similar to that in healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. Non-mutant and mutant C5 both caused hemolysis in vitro, but only non-mutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to non-mutant and mutant C5 was completely blocked by N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. The functional capacity of the C5 polymorphism p.Arg885His, together with its failure to undergo blockade by eculizumab, accounts for the poor response to this agent in patients who carry this mutation.

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