MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab

Elhadad, Sonia; Chapin, John; Copertino, Dennis C.; Besien, Koen van; Ahamed, Jasimuddin; Laurence, Jeffrey

doi:10.1111/cei.13497

Cited by 47 publications

(44 citation statements)

References 29 publications

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“…SARS-CoV-2 may directly activate the LP of complement through binding to MBL via its glycoprotein envelope spikes, as has been documented for SARS-CoV [ 9 ], and suggested by the demonstration by our group of CoV-2 envelope spike protein binding to MASP2 [ 4 ]. Multiple positive feedback loops involving complement receptor-mediated inflammatory cytokine release and interactions among leukocytes, platelets, and endothelial cells have been documented in a variety of pathologic settings [ 18 ]. Significant deposits of complement components C5b-9, C4d, and MASP2 in the pulmonary, renal, and cutaneous microvasculature of SARS-CoV-2-infected patients [ 4 , 7 ], accompanied by microthrombosis, are consistent with systemic activation of complement and related pathology.…”

Section: Discussionmentioning

confidence: 99%

Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19

Laurence

Mulvey

Seshadri

et al. 2020

Clinical Immunology

111

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Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO 2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.

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Section: Discussionmentioning

confidence: 99%

Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19

Laurence

Mulvey

Seshadri

et al. 2020

Clinical Immunology

111

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“…An in vitro study has shown that inhibition of MASP2 by narsoplimab can reduce thrombotic microangiopathy (TMA) plasma-mediated human microvascular endothelial cell injury. 67 …”

Section: Antibody Therapeutics Undergoing First Regulatory Review In mentioning

confidence: 99%

Antibodies to watch in 2021

Kaplon

Reichert²

2021

mAbs

265

205

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In this 12 th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.

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“…60 More recent observations report that inhibition of mannose-binding lectin-associated serine protease (MASP2), the effector enzyme of LP, may be beneficial in conditions such as thrombotic microangiopathy (TMA) post allogeneic hematopoietic stem cell transplantation (alloHSCT). 61 In general, all these proposed mechanisms share in common the dominant role of complement activationespecially through the AP pathway -in the pathophysiology of SCD. Some studies revealed elevated biomarkers of complement activation in both steady state and crisis of SCD patients or mouse models.…”

Section: Underlying Mechanisms Of Complement Activation In Scd For Thmentioning

confidence: 99%

“… 60 More recent observations report that inhibition of mannose‐binding lectin-associated serine protease (MASP2), the effector enzyme of LP, may be beneficial in conditions such as thrombotic microangiopathy (TMA) post allogeneic hematopoietic stem cell transplantation (alloHSCT). 61 …”

Section: Underlying Mechanisms Of Complement Activation In Scd For Thmentioning

confidence: 99%

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Varelas

Tampaki

Sakellari

et al. 2021

JBM

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Sickle cell disease (SCD) is a widely spread inherited hemoglobinopathy that includes a group of congenital hemolytic anemias, all characterized by the predominance of sickle hemoglobin (HbS). Its features are anemia, predisposal to bacterial infections and complications such as vaso-occlusive crisis (VOC) or delayed hemolytic transfusion reaction (DHTR), which lead to increased rate of morbidity and mortality even in the era of hydroxyurea. The interaction between sickle cells, neutrophils, platelets or endothelial cells in small vessels results in hemolysis and has been considered the disease's main pathophysiological mechanism. Complement activation has been reported in small cohorts of SCD patients, but the governing mechanism has not been fully elucidated. This will be important to predict the patient group that would benefit from complement inhibition. Until now, eculizumab-mediated complement inhibition has shown beneficial effects in DHTR, with limited reports in patients with VOC. In the meantime, several innovative agents are under clinical development Our state-of-the-art review summarizes current data on 1) complement activation in SCD both in steady state and crisis, 2) underlying mechanisms of complement over-activation for the clinician in the context of SCD, 3) actions of hydroxyurea and new therapeutic approaches including indirect involvement in complement activation, and 4) novel paradigms in complement inhibition.

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MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab

Cited by 47 publications

References 29 publications

Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19

Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19

Antibodies to watch in 2021

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

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