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Inflammation and immunology
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Christopher Bellamy, Stephen J. Jenkins, Henry J. McSorley, David A. Dorward, Timothy J. Kendall
The kinin system generates vasoactive peptides from a group of plasma protein kininogens. These kininogens are cleaved by enzymes called kallikreins, which are formed from the cleavage of prekallikrein by factor XIIa (activated Hageman factor) of the coagulation system. The resulting activation of the kinin cascade releases bradykinin, a potent vascular permeability agent. Bradykinin also causes vasodilatation and excites nerve endings, causing pain. The properties of bradykinin are therefore similar to those of histamine, but the rate of production of bradykinin is slower because of the multiple steps involved in activating the kinin proteolytic cascade. Other elements of the kinin cascade, in particular kallikrein, not only have chemotactic activity but also activate the complement component C5−C5a.
Monoclonal antibodies used for the management of hemataological disorders
Published in Expert Review of Hematology, 2022
Kanjaksha Ghosh, Kinjalka Ghosh
This humanized monoclonal antibody against complement component 5 (C5) has been very successfully used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) [46] and atypical hemolytic syndrome (aHUS) [47]. The antibody has also been used for or evaluated against other complement activation disorder like Neuromyelitis Optica [48]. Bacterial, i.e. Neisserial and Meningococcal meningitis is one of the important side effects of this therapy [49]; hence, all patients on this medication as chronic therapy must receive meningococcal vaccination. Other Neisserial infections also have been recorded as a complication of this therapy. Once started for PNH, this therapy should not be stopped suddenly as hyperhemolysis of complement sensitive red cells, which accumulated during the therapy may occur, in the absence of this complement inhibitor with attendant complications. Eculizumab needs to be injected frequently (Q2 weeks); however, another antibody Ravulizumab developed for the same purpose needs much less frequent administration (4–6 week interval) but needs a higher dosage.
Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Emerging Drugs, 2022
Camilla Frieri, Régis Peffault de Latour, Flore Sicre De Fontbrune
A phase III trial is now ongoing (NCT04469465) [96]. This is a randomized, double-blind, placebo-controlled, multiple-dose study in PNH patients who have clinically evident extravascular hemolysis on a C5 inhibitor (eculizumab or ravulizumab). The main objective of this study is to evaluate the efficacy of danicopan as an add-on therapy to a complement component 5 (C5) inhibitor. Participants will be randomized to receive danicopan or a placebo, in a 2:1 ratio for 12 weeks, in addition to their C5 inhibitor therapy. At Week 12, patients randomized to receive the placebo will be switched to danicopan, in addition to their C5 inhibitor, for an additional 12 weeks. Participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy.
Complement system network in cell physiology and in human diseases
Published in International Reviews of Immunology, 2021
Roberta Romano, Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Claudio Pignata
In general, patients affected with complement deficiencies presenting with severe and recurrent infections, despite adequate vaccinations, may benefit from antibiotic prophylactic regimens [4]. Complement targeted therapies have been proven useful in several clinical conditions. A humanized monoclonal antibody, Eculizumab, binding the terminal complement component C5 [51] has found widespread use in complement-associated diseases. In particular, it represents the gold standard treatment for Paroxysmal Nocturnal Hemoglobinura thanks to its ability to block C5 cleavage in C5a and C5b and, subsequently, the formation of Membrane Attack Complex. This compensates the absence of CD59 [66]. In atypical Hemolytic Uremic Syndrome with complement involvement, Eculizumab is used to determine a sufficient inhibition of Membrane Attack Complex to eventually prevent cell damage [51]. The effect of the therapy may be monitored through hemolytic or Enzyme-Immuno-Assays classical pathway and alternative pathway functional tests [57]. It must be mentioned that the inhibition of the terminal pathway may lead to a 1000-fold increase in meningococcal infections [50].