Rare diseases Xagena

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Paroxysmal nocturnal hemoglobinuria: genetic variants in C5 and poor response to Eculizumab

Eculizumab ( Soliris ) 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.

Researchers have assessed the sequences of the gene encoding C5 in patients with paroxysmal nocturnal hemoglobinuria who had either a good or poor response to Eculizumab.
They also evaluated the functional properties of C5 as it was encoded in these patients.

Of 345 Japanese patients with paroxysmal nocturnal hemoglobinuria 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 paroxysmal nocturnal hemoglobinuria ( 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.

In conclusion, 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. ( Xagena )

Nishimura J et al, N Engl J Med 2014; 370:632-639