Erratum: Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria

Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, Connecticut 06410, USA.
Nature Biotechnology (Impact Factor: 41.51). 12/2007; 25(11):1256-64. DOI: 10.1038/nbt1344
Source: PubMed


The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology. In the rare hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH), somatic mutations result in a deficiency of glycosylphosphatidylinositol-linked surface proteins, including the terminal complement inhibitor CD59, on hematopoietic stem cells. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery. Deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of PNH. A recently developed, humanized monoclonal antibody directed against complement component C5, eculizumab (Soliris; Alexion Pharmaceuticals Inc., Cheshire, CT, USA), blocks the proinflammatory and cytolytic effects of terminal complement activation. The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.

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Available from: Robert Brodsky, Aug 14, 2014
    • "This situation of relative under-regulation of complement renders PNH cells, but not healthy host tissue, susceptible to lysis by the AP. Therapy with eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody directed against terminal complement component C5, inhibits MAC formation and thus intravascular lysis (Rother et al., 2007) (Supplementary Fig. 1B). Despite the clear benefits of complete blockage of complement TP for PNH patients (Brodsky et al., 2008;Hillmen et al., 2006;Kelly et al., 2011), the high treatment cost, insufficient response in some patients and increased risk for meningococcal infections need to be considered. "
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    ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients. Novel C3-opsonin targeted complement inhibitors act earlier in the cascade, at the level of activated C3 and are engineered from parts of the natural complement regulator Factor H (FH) or complement receptor 2 (CR2). This inhibitor class comprises three variants of “miniFH” and the clinically developed “FH-CR2” fusion-protein (TT30). We show that the approach of FH-CR2 to target C3-opsonins was more efficient in preventing complement activation induced by foreign surfaces, whereas the miniFH variants were substantially more active in controlling complement on PNH erythrocytes. Subtle differences were noted in the ability of each version of miniFH to protect human PNH cells. Importantly, miniFH and FH-CR2 interfered only minimally with complement-mediated serum killing of bacteria when compared to untargeted inhibition of all complement pathways by eculizumab. Thus, the molecular design of each C3-opsonin targeted complement inhibitor determines its potency in respect to the nature of the activator/surface providing potential functionality in PNH.
    No preview · Article · Jan 2016 · Immunobiology
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    • "Eculizumab (Soliris®) is a monoclonal antibody that binds to C5 and prevents its cleavage into C5a and C5b, thereby completely blocking the formation of terminal complement complex (C5b-9). It is currently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS and has opened a new era in the treatment of these diseases [18] [19] [20] [21] [22] [23]. However, the optimal or individualized treatment schedule has not yet been established due to lack of reliable and easy routine tests to monitor the treatment. "
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    ABSTRACT: Complement C5 inhibitor eculizumab treatment in atypical hemolytic uremic syndrome is effective, but associated with high costs. Complement inhibition monitoring in these patients has not been standardized. In this study we evaluated novel functional assays for application in routine follow-up. We documented that the Wieslab® complement screen assay showed a sensitivity of 1-2% of C5 activity by adding purified C5 or normal human serum to a C5 deficient serum. All the patient samples obtained during the treatment course, were completely blocked for terminal complement pathway activity for up to four weeks after the eculizumab infusion. Levels of complexes between eculizumab and C5 were inversely correlated to the complement activity (p=0.01). Moreover, titrating serum from eculizumab-treated patients into normal serum revealed that eculizumab was present in excess up to four weeks after infusion. Thus, we demonstrate sensitive, reliable and easy-performed assays which can be used to design individual eculizumab dosage regimens.
    Full-text · Article · Sep 2015 · Clinical Immunology
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    • "We detected comparable avidities for mAb 1340, A233 and A235 with half maximal effective concentrations (EC50) of 0.16 nM, 0.07 nM and 0.1 nM, respectively. The described antibodies showed similar binding strengths as an established anti-complement mAb Eculizumab (anti-C5 mAb, 0.12 nM) and even a higher mAb-antigen interaction as the routinely used therapeutic mAb Bevacizumab (anti-VEGF, 0.8 nM) [52], [53]. In consideration of a broad affinity range from 1 pM to 1 nM of therapeutic antibodies the newly described mAb 1340 displays a high avidity towards properdin [54]. "
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    ABSTRACT: The complement system is an essential part of the innate immune system by acting as a first line of defense which is stabilized by properdin, the sole known positive regulator of the alternative complement pathway. Dysregulation of complement can promote a diversity of human inflammatory diseases which are treated by complement inhibitors. Here, we generated a novel blocking monoclonal antibody (mAb) against properdin and devised a new diagnostic assay for this important complement regulator. Mouse mAb 1340 specifically detected native properdin from human samples with high avidity. MAb 1340 inhibited specifically the alternative complement mediated cell lysis within a concentration range of 1-10 µg/mL. Thus, in vitro anti-properdin mAb 1340 was up to fifteen times more efficient in blocking the complement system as compared to anti-C5 or anti-Ba antibodies. Computer-assisted modelling suggested a three-dimensional binding epitope in a properdin-C3(H2O)-clusterin complex to be responsible for the inhibition. Recovery of properdin in a newly established sandwich ELISA using mAb 1340 was determined at 80-125% for blood sample dilutions above 1∶50. Reproducibility assays showed a variation below 25% at dilutions less than 1∶1,000. Systemic properdin concentrations of healthy controls and patients with age-related macular degeneration or rheumatic diseases were all in the range of 13-30 µg/mL and did not reveal significant differences. These initial results encourage further investigation into the functional role of properdin in the development, progression and treatment of diseases related to the alternative complement pathway. Thus, mAb 1340 represents a potent properdin inhibitor suitable for further research to understand the exact mechanisms how properdin activates the complement C3-convertase and to determine quantitative levels of properdin in biological samples.
    Full-text · Article · May 2014 · PLoS ONE
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