Novel Complement Modulators for Paroxysmal Nocturnal Hemoglobinuria: Peptide and Protein Inhibitors of C3 Convertase Prevent Both Surface C3 Deposition and Subsequent Hemolysis of Affected Erythrocytes in Vitro

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 #370

Antonio M. Risitano, Patrizia Ricci, Caterina Pascariello, Maddalena Raia, Christoph Q Schmidt, Yingxue Li, Edimara S Reis, Michela Sica, Rosario Notaro, Luigi Del Vecchio, Fabrizio Pane, Daniel Ricklin, and John D Lambris

Some patients with PNH will have only a partial response to eculizumab, in that they will still be anemic and dependent upon transfusions. In some cases this will be because eculizumab only partially blocks the complement proteins. It turns out that there are two key complement proteins, C3 and C5, that control whether complement gets turned on. C3 gets turned on first, and C5 gets turned on later. Eventually a pore is formed in the surface of the red cell from patients with PNH which causes the cell to break open. Eculizumab keeps C5 in a permanently turned off state and this prevents the pore from forming, which prevents the cell from breaking open in the circulation. However, the C3 protein can still get turned on and can coat the surface of the red cell in such a way that the red cell will get destroyed in the spleen. This is known as extravascular hemolysis.

This study by a group in Italy examined two artificial proteins that might keep the C3 protein permanently turned off. This study examined the effect of Cp30 and mini-FH to see if these might someday be helpful to patients with PNH. These proteins have not yet been given to people. Researchers in this study took red cells from patients with PNH and looked to see the effect of these two proteins on the breakdown of red cells in the test tube. This study demonstrated that both of these proteins have the potential to turn off hemolysis, at least in the test tube. Because they both work at an early stage in the complement system, these compounds might prevent both types of hemolysis (breakdown in the blood vessels and extravascular hemolysis) and might be more effective than eculizumab at protecting the red cells in patients with PNH. On the other hand, since complement has the job of preventing infections, it is possible that a more intense blockade of complement might also lead to more infections than are seen with eculizumab. With the obvious exception of the meningococcemia infection, eculizumab does not seem to increase the chance of most infections, and this has yet to be seen with these newer anti-complement drugs.

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