[The C5 gene polymorphism in patients with PNH]
Jun-Ichi Nishimura1, Yuzuru Kanakura
1Osaka University Graduate School of Medicine, Department of Hematology and Oncology.
Summary
A genetic variant in C5, p.Arg885His, explains poor response to eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) patients. This mutation prevents eculizumab binding, leading to continued hemolysis.
Area of Science:
- Genetics
- Immunology
- Pharmacology
Context:
- Eculizumab is a C5 complement inhibitor used to treat paroxysmal nocturnal hemoglobinuria (PNH).
- Some Japanese patients with PNH exhibit a poor response to eculizumab therapy.
- The underlying genetic or molecular basis for this treatment resistance is not fully understood.
Purpose:
- To investigate the molecular basis for poor response to eculizumab in Japanese patients with PNH.
- To identify specific genetic variants in the C5 complement protein associated with eculizumab resistance.
Summary:
- A heterozygous missense mutation in C5 (c.2654 G>A), predicting the p.Arg885His polymorphism, was identified in 11 out of 345 Japanese PNH patients showing a poor response to eculizumab.
- This C5 p.Arg885His polymorphism, found in both PNH patients and healthy individuals, did not bind to eculizumab, rendering the complement cascade susceptible to uncontrolled hemolysis.
- An alternative antibody, N19-8, targeting a different epitope on C5, effectively blocked hemolysis in vitro, suggesting a potential therapeutic alternative.
Impact:
- Identifies a specific C5 genetic variant (p.Arg885His) as the cause of eculizumab resistance in some PNH patients.
- Explains the mechanism of resistance: the mutation prevents eculizumab binding while C5 remains functional.
- Suggests potential for alternative complement-targeting therapies, like N19-8, for patients with this specific genetic profile.
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