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

@article{Rother2007DiscoveryAD,
  title={Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria},
  author={Russell P. Rother and Scott A. Rollins and Christopher F. Mojcik and Robert A. Brodsky and Leonard Bell},
  journal={Nature Biotechnology},
  year={2007},
  volume={25},
  pages={1256-1264}
}
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… 
Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
  • E. Wong, D. Kavanagh
  • Biology, Medicine
    Translational research : the journal of laboratory and clinical medicine
  • 2015
Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria.
Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria.
TLDR
Investigation of the effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system found they are excellent, and potentially cost-effective, candidates for further clinical investigation.
Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going
  • A. Risitano
  • Biology, Medicine
    Translational medicine @ UniSa
  • 2014
TLDR
Anti-complement treatment allowed transfusion independence in at least half of PNH patients receiving eculizumab, with adequate control of all hemolysis-associated symptoms even in almost all remaining patients, and the risk of thromboembolic events seems substantially reduced on eculizer treatment, apparently resulting in improved survival.
Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria.
TLDR
The current state of complement therapeutics is reviewed with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH, including translational considerations that might leverage a more comprehensive clinical intervention for PNH.
Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies.
  • A. Risitano
  • Biology, Medicine
    Advances in experimental medicine and biology
  • 2013
TLDR
The first complement inhibitor eculizumab, a humanized anti-C5 monoclonal antibody, has been proven safe and effective for the treatment of PNH patients and renewed the interest for the development of novel complement inhibitors which aim to modulate early phases of complement activation, more specifically at the level of C3 activation.
Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist’s Opinion
TLDR
New promising perspectives derive from complement inhibitors and iron chelators, as well as more invasive treatments such as immunoadsorption or the use of dedicated hemodialysis filters in the presence of AKI.
...
...

References

SHOWING 1-10 OF 103 REFERENCES
Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria.
TLDR
Eculizumab, administered at 900 mg every 12 to 14 days, was sufficient to completely and consistently block complement activity in all patients, and the close relationship between sustained terminal complement inhibition, hemolysis, and symptoms was demonstrated.
Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.
TLDR
This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.
Inhibition of terminal complement: a novel therapeutic approach for the treatment of systemic lupus erythematosus
TLDR
Monoclonal antibodies that specifically inhibit terminal complement activation while preserving the critical functions of the early complement cascade have now been developed.
Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement.
TLDR
It is established that a functional recombinant transmembrane form of CD59 can be expressed on the surface of GPI-anchoring deficient PNH cells and suggested that retroviral gene therapy with this molecule could provide a treatment for PNH patients.
Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria.
TLDR
Results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH.
Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.
TLDR
It is shown that Ab's or peptides that block C5a-C5a receptor interactions prevent pregnancy complications and the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS are identified.
Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6.
TLDR
The inhibition by anti-C6 indicates that Muscle weakness and electrophysiologic abnormalities associated with EAMG are dependent on the complement MAC, and that muscle weakness results from tissue injury in addition to loss of muscle membrane and AChR.
Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.
TLDR
Using flow cytometric analysis of granulocytes, it is identified cells that have the PNH phenotype, and PNH red blood cells also were identified, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH.
Paroxysmal nocturnal haemoglobinuria.
Paroxysmal nocturnal haemoglobinuria (PNH) is a unique disorder in which many of the patient’s red cells have an abnormal susceptibility to activated complement. This results from the presence of a
...
...