Abstract

The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.

Highlights

  • Eculizumab remains the first and only inhibitor of the complement system used in clinical practice

  • It targets the terminal complement pathway and leaves the proximal complement pathways intact. It was approved by the United States Food and Drug Administration and the European Medicines Agency in 2007 for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and in 2011 for the treatment of atypical haemolytic uraemic syndrome

  • The results provided safety and efficacy data that supported the feasibility of using an antibody therapeutically for sustained blockade of C5

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Summary

Introduction

Eculizumab remains the first and only inhibitor of the complement system used in clinical practice. Through an understanding of these pathogenic mechanisms, including the importance of the terminal pathway common to both PNH and aHUS, there have been benefits from the use of the complement inhibitor eculizumab. Underlying haemolysis and the development of anaemia in PNH is the absence of two GPI-anchored complement regulatory proteins CD55 and CD59 from erythrocytes.

Results
Conclusion

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