Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria |
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| Institution: | 1. Division of Biodiagnostic Sciences and Technologies, INRASTES, National Center for Scientific Research “Demokritos”, Athens, Greece;2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;3. Amyndas Pharmaceuticals, Glyfada, Athens, Greece;4. Hematology and Bone Marrow Transplant Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy;1. Division of Hematologic Malignancies, Department of Oncology, The Bunting and Blaustein Cancer Research Building, 1650 Orleans Street, Room 3M87, Baltimore, MD 21287-0013, USA;2. Division of Hematology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, MD 21205, USA;1. University of California San Francisco, San Francisco, CA, United States;2. Southern California Liver Centers, Coronado, CA, United States;3. University of Maryland School of Medicine, Baltimore, MD, United States;4. Tulane University School of Medicine, New Orleans, LA, United States;5. Department of Medicine, University of Minnesota, Minneapolis, MN, United States;6. University of Southern California, Los Angeles, CA, United States;7. Mayo Clinic Hospital, Phoenix, AZ, United States;8. Eisai Corporation of North America, Woodcliff Lake, NJ, United States;9. Eisai Ltd, Hatfield, UK |
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| Abstract: | Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH. These emerging clinical needs have sparked a true resurgence of complement therapeutics that offer the promise of even more effective, disease-tailored therapies for PNH. Here, we review the current state of complement therapeutics with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH. We also discuss the relative advantages and benefits offered by each complement-targeting approach, including translational considerations that might leverage a more comprehensive clinical intervention for PNH. |
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| Keywords: | Complement therapeutics PNH C3 inhibitors Extravascular hemolysis Compstatins Clinical trials |
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