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1.
PLoS Pathog ; 17(12): e1010175, 2021 12.
Article in English | MEDLINE | ID: covidwho-1592244

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Currently, as dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus envelope binds to the angiotensin converting enzyme 2 (ACE2) on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in-vivo SARS-CoV-2 infection better than ACE2-Ig. Mechanistically, we show that anti-spike antibody generation, ACE2 enzymatic activity, and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus titers. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Immunoglobulin Fc Fragments/metabolism , Immunoglobulin G/metabolism , Protein Domains , Recombinant Fusion Proteins/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites , Binding Sites, Antibody , COVID-19/prevention & control , Chlorocebus aethiops , Female , HEK293 Cells , Humans , Immunoglobulin Fc Fragments/therapeutic use , Immunoglobulin G/therapeutic use , Mice, Transgenic , Neutralization Tests , Protein Binding , Recombinant Fusion Proteins/therapeutic use , SARS-CoV-2/drug effects , Vero Cells
2.
Nat Med ; 27(7): 1262-1271, 2021 07.
Article in English | MEDLINE | ID: covidwho-1550325

ABSTRACT

Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1-2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1-2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1-F3 stage NASH, with an acceptable safety profile.


Subject(s)
Fibroblast Growth Factors/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Recombinant Fusion Proteins/therapeutic use , Body Mass Index , Double-Blind Method , Female , Humans , Liver/pathology , Liver Cirrhosis/drug therapy , Magnetic Resonance Imaging , Male , Middle Aged , Treatment Outcome
3.
Nature ; 599(7885): 465-470, 2021 11.
Article in English | MEDLINE | ID: covidwho-1428880

ABSTRACT

Monoclonal antibodies with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefits in cases of mild-to-moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these monoclonal antibodies and has limited efficacy in preventing disease complications or mortality among hospitalized patients with COVID-195. Here we report the development and evaluation of anti-SARS-CoV-2 monoclonal antibodies with optimized Fc domains that show superior potency for prevention or treatment of COVID-19. Using several animal disease models of COVID-196,7, we demonstrate that selective engagement of activating Fcγ receptors results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection against SARS-CoV-2 challenge and for treatment of pre-infected animals. Our results highlight the importance of Fcγ receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fcγ receptor engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function and improved clinical efficacy against COVID-19 disease.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , Immunoglobulin Fc Fragments/immunology , Immunoglobulin Fc Fragments/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Cricetinae , Disease Models, Animal , Female , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Fc Fragments/pharmacology , Immunoglobulin G/chemistry , Immunoglobulin G/immunology , Male , Mice , Pre-Exposure Prophylaxis , Receptors, IgG/chemistry , Receptors, IgG/immunology , Treatment Outcome
5.
Acta Haematol ; 144(3): 319-321, 2021.
Article in English | MEDLINE | ID: covidwho-802601

ABSTRACT

A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.


Subject(s)
COVID-19/diagnosis , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Blood Coagulation Tests , COVID-19/complications , COVID-19/virology , Hemophilia A/complications , Hemophilia A/pathology , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index
6.
MAbs ; 12(1): e1782600, 2020.
Article in English | MEDLINE | ID: covidwho-599156

ABSTRACT

While the potential therapeutic utility of angiotensin-converting enzyme 2 (ACE2) is well established, the clinical development of ACE2 drugs has been limited, likely due in part to the short half-life of the protein. In contrast, Ig-like ACE2 fusion proteins have exhibited greatly extended plasma half-life in vivo, and they have been shown to have a potent neutralization effect against SARS-CoV-2. Clinical investigation of Ig-like ACE2 fusion proteins as COVID-19 interventions is thus warranted.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Immunoglobulin Fc Fragments/therapeutic use , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Immunoglobulin Fc Fragments/adverse effects , Pandemics , Peptidyl-Dipeptidase A/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Recombinant Fusion Proteins/therapeutic use , SARS-CoV-2 , Treatment Outcome
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