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1. Paroxysmal nocturnal hemoglobinuria (PNH) patients with poor response to eculizumab were found to have a mutation in complement protein C5.
2. When tested in vitro, the mutant C5 protein did not bind eculizumab, suggesting that the mechanism for resistance in these patients is protein-drug binding disruption caused by the C5 mutation.
Evidence Rating Level: 2 (Good)
Study Rundown: PNH causes intravascular hemolysis and stems from a deficiency in complement regulatory proteins. The monoclonal antibody eculizumab targets complement protein C5 and inhibits the formation of the cytolytic pore C5b-9 thereby greatly reducing the complement-mediated hemolysis seen in PNH patients. While more than 99% of patients have good response to eculizumab, a specific subset of patients in Japan do not. The authors of this study sought to identify the cause of this. They identified a mutation in the C5 gene that appears to disrupt the binding of eculizumab to C5 and therefore its ability to inhibit hemolysis in patients with PNH. The in vitro binding studies suggested that the mechanism of resistance among these patients is due to a change in the C5 binding site of eculizumab. The authors then demonstrated the prevalence of these mutations in sample pools in different populations, but they were relatively small sample sizes. This study provides solid evidence clarifying the mechanism for poor response to eculizumab in patients with PNH.
Click to read the study in NEJM
Relevant Reading: Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial
Study Author, Dr. Jun-ichi Nishimura, MD, PhD, talks to 2 Minute Medicine: Assistant Professor, Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
“Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement–mediated hemolysis associated with PNH. We identified a C5 polymorphism (c.2654G→A) in Japanese patients with PNH that prevents binding and blockade by eculizumab, while retaining the functional capacity of the mutant C5 to cause hemolysis. Therefore, the polymorphism in the target protein might be important to consider in patients with a poor response to the antibody-based treatments for various diseases.”
In-Depth [genetic analysis study]: This study aimed to identify the molecular basis for the poor response to eculizumab found in a particular subset of Japanese PNH patients. The authors collected blood samples from a total of 12 patients (11 Japanese and 1 Argentinian of Asian ancestry) who had poor response to eculizumab and 8 controls (7 patients with good response to eculizumab and 1 healthy patient). They sequenced the C5 gene for all patients enrolled in the study and identified a missense mutation in exon 21 (c.2654G->A) which produced the polymorphis p.Arg885His. This same mutation was identified in all 11 Japanese patients who had poor response to eculizumab, and in none of the controls. The Argentinian patient had a different mutation: c.2653->T that produced p.Arg885Cys. An in vitro study was then performed that demonstrated that eculizumab did not bind the mutant C5 protein. However, the monoclonal antibody N19-8, that binds a different site on C5, bound both.
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