Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond

Blood ◽  
2021 ◽  
Author(s):  
Eleni Gavriilaki ◽  
Régis Peffault de Latour ◽  
Antonio Maria Risitano
Keyword(s):  
Complement Activation ◽  
Lectin Pathway ◽  
Prototype Model ◽  
Complement Inhibition ◽  
Hematologic Diseases ◽  
Classical Complement Pathway ◽  
Complement Inhibitors ◽  
Hemolytic Transfusion Reaction ◽  
Personalized Approach ◽  
Long Acting

Complement is an elaborate system of the innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototype model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan have been also now approved with PNH. Novel agents, such as factor B and factor D inhibitors, are under study with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug needs to be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease (CAD), primarily with the C1s inhibitor of the classical complement pathway, sutimlimab, but also with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, are investigated in transplant-associated thrombotic microangiopathy (TA-TMA). With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction (DHTR) or immune thrombocytopenia (ITP), might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases focusing on: a) complement biology for the clinician, b) complement activation and therapeutic inhibition in prototypical complement-mediated hematologic diseases, c) hematologic entities under investigation for complement inhibition, and d) other complement-related disorders of potential interest to hematologists.

scholarly journals Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

2020 ◽  
Vol 117 (40) ◽  
pp. 25018-25025 ◽  
Author(s):  
Jan C. Holter ◽  
Soeren E. Pischke ◽  
Eline de Boer ◽  
Andreas Lind ◽  
Synne Jenum ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Failure ◽  
Complement Activation ◽  
Blood Donors ◽  
Innate Immune ◽  
Lectin Pathway ◽  
Complement Inhibitors ◽  
Activation Products ◽  
The Complement System ◽  
Recognition Molecule

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

scholarly journals Halting targeted and collateral damage to red blood cells by the complement system

2021 ◽  
Author(s):  
M. Jalink ◽  
E. C. W. de Boer ◽  
D. Evers ◽  
M. Q. Havinga ◽  
J. M. I. Vos ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Complement System ◽  
Blood Cells ◽  
Defense Mechanism ◽  
Standard Of Care ◽  
Complement Protein ◽  
Complement Inhibition ◽  
Complement Inhibitors ◽  
The Complement System ◽  
Patient Burden

AbstractThe complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

scholarly journals Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

2020 ◽  
Author(s):  
Ting Gao ◽  
Mingdong Hu ◽  
Xiaopeng Zhang ◽  
Hongzhen Li ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Lung Injury ◽  
Complement Activation ◽  
Suppressive Effect ◽  
Lectin Pathway ◽  
Highly Pathogenic ◽  
N Protein ◽  
Promising Target

AbstractAn excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo. Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.One Sentence SummaryThe lectin pathway of complement activation is a promising target for the treatment of highly pathogenic coronavirus induced pneumonia.

scholarly journals Proteins of the Lectin Pathway of complement activation at the site of injury in subarachnoid hemorrhage compared with peripheral blood

2020 ◽  
Vol 10 (8) ◽  
Author(s):  
Thorkil Anker‐Møller ◽  
Anne‐Mette Hvas ◽  
Niels Sunde ◽  
Steffen Thiel ◽  
Anne Troldborg
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Complement Activation ◽  
Peripheral Blood ◽  
Lectin Pathway

scholarly journals Extracellular Vesicle-Induced Classical Complement Activation Leads to Retinal Endothelial Cell Damage via MAC Deposition

2020 ◽  
Vol 21 (5) ◽  
pp. 1693 ◽  
Author(s):  
Chao Huang ◽  
Kiera P. Fisher ◽  
Sandra S. Hammer ◽  
Julia V. Busik
Keyword(s):  
Extracellular Vesicles ◽  
Complement Activation ◽  
Cell Damage ◽  
Membrane Attack Complex ◽  
Extracellular Vesicle ◽  
Rat Plasma ◽  
Classical Complement Pathway ◽  
Endothelium Damage ◽  
Classical Complement

Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in DR through activation of the complement system. However, the mechanism through which extracellular vesicle-induced complement activation contributes to retinal vascular cytolytic damage in DR is not well understood. In this study, we demonstrate that IgG-laden extracellular vesicles in rat plasma activate the classical complement pathway, and in vitro Streptozotocin (STZ)-induced rat diabetic plasma results in MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Moreover, removal of the plasma extracellular vesicles reduced the MAC deposition and abrogated cytolytic damage seen in HRECs. Together, the results of this study demonstrate that complement activation by IgG-laden extracellular vesicles in plasma could lead to MAC deposition and contribute to endothelium damage and progression of DR.

scholarly journals Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 Patients

2020 ◽  
Vol 120 (12) ◽  
pp. 1720-1724 ◽  
Author(s):  
Michael Hultström ◽  
Robert Frithiof ◽  
Oskar Eriksson ◽  
Barbro Persson ◽  
Miklos Lipcsey ◽  
...  
Keyword(s):  
Critically Ill ◽  
Complement Activation ◽  
Tertiary Hospital ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
Strongly Correlated ◽  
Increased Risk ◽  
Mannose Binding ◽  
Patients At Risk ◽  
Binding Lectin

AbstractThe ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients (n = 65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

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