A Rare Genetic Polymorphism in C5 Confers Poor Response to the Anti-C5 Monoclonal Antibody Eculizumab by Nine Japanese Patients with PNH

Original Publication Date: 
Tuesday, January 1, 2013

Note: This review is based upon a presentation at the 2012 American Society of Hematology (ASH) Annual Meeting, December 7-10 in Atlanta, Georgia.The full abstract may be reviewed on the ASH Annual Meeting Web site. Search by entering the title in the search box. The abstract number is referenced to access the full report.

Oral Presentation
Abstract #3197 

Rafael Bejar, Kristen E. Stevenson, Petar Stojanov, J. Eric Zaneveld, Michal Bar-Natan, Bennett Caughey, Hui Wang, Guillermo Garcia-Manero, Hagop M. Kantarjian, Corey Cutler, Jerome Ritz, Kristian Cibulskis, Gad Getz, David P. Steensma, Richard M. Stone, Rui Chen, Donna S. Neuberg, and Benjamin L. Ebert

This study from Japan looked at a very rare group of patients with PNH—those who seem to have absolutely no benefit at all from eculizumab. Eculizumab binds to and inactivates the C5 complement protein and protects the red cell from the pore forming on its surface. This prevents breakdown of red blood cells that occurs in the circulation and turns very dark urine clear almost overnight—in almost all patients. However, in Japan, 3% of the patients have a slightly different version of the gene that encodes the C5 protein. These patients therefore have a C5 protein that escapes from the effect of eculizumab and causes a form of true eculizumab resistance. So far, this genetic variant has not been seen in patients of European or African ancestry. It will be interesting to see whether there are other countries in Asia where this variant is found. The authors show that there is another drug (under development) that is similar to eculizumab which is able to inactivate the C5 protein from these patients, offering hope that they too will be able to benefit from this strategy some day.

Reviewer Bio: