Treatment of cytokine release syndrome with gm-csf antagonists

Abstract

The present invention provides, among other things, a method of treating a subject with infection-induced hyperinflammation comprising administering to the subject a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of hyperinflammation. The present invention also provides, among other things, a method of inhibiting or reducing cytokine release syndrome (CRS) or acute respiratory distress syndrome (ARDS) in a subject comprising administering to the subject a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of CRS or ARDS.

1 . A method of treating a subject infected with a virus comprising administering to the subject a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of viral infection. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the virus is a coronavirus. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the subject develops a lung disease. 
     
     
         7 . (canceled) 
     
     
         8 . A method of inhibiting or reducing cytokine release syndrome (CRS) in a subject comprising administering to the subject a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of CRS. 
     
     
         9 - 11 . (canceled) 
     
     
         12 . The method of  claim 8 , wherein the one or more symptoms comprise hyperinflammation of lung tissue. 
     
     
         13 - 16 . (canceled) 
     
     
         17 . The method of  claim 8 , wherein the cytokine release syndrome (CRS) is associated with a virus infection. 
     
     
         18 . (canceled) 
     
     
         19 . A method of inhibiting or reducing acute respiratory distress syndrome (ARDS) in a subject comprising administering to the subject a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of ARDS. 
     
     
         20 - 23 . (canceled) 
     
     
         24 . The method of  claim 19 , wherein the ARDS is associated with a pulmonary infection. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 24 , wherein the infection is a viral infection. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the one or more symptoms are associated with SARS, MERS, or COVID-19. 
     
     
         31 . The method of  claim 30 , wherein the one more symptoms associated with COVID-19 are fever, cough, fatigue, coughing up sputum from the lungs, bone or joint pain, sore throat, headache, chills, nausea or vomiting, stuffy nose, or shortness of breath. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the subject has an elevated level of an inflammation marker. 
     
     
         36 - 48 . (canceled) 
     
     
         49 . The method of  claim 1 , wherein the step of administering comprises intravenous administration. 
     
     
         50 - 53 . (canceled) 
     
     
         54 . The method of  claim 1 , wherein the therapeutically effective dose is between 0.5 mg/kg and 10 mg/kg. 
     
     
         55 - 58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein a single administration of the GM-CSF antagonist is sufficient to improve, stabilize or reduce one or more symptoms for longer than seven days. 
     
     
         60 - 71 . (canceled) 
     
     
         72 . The method of  claim 1 , wherein the GM-CSF antagonist is a GM-CSF receptor alpha (GM-CSFRα) antagonist. 
     
     
         73 . (canceled) 
     
     
         74 . The method of  claim 72 , wherein the GM-CSFRα antagonist is a GM-CSFRα antibody or fragment thereof. 
     
     
         75 . The method of  claim 74 , wherein the GM-CSFRα antagonist is a GM-CSFRα antibody or fragment thereof that competes with an anti-GM-CSFRα antibody defined by a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2. 
     
     
         76 - 77 . (canceled) 
     
     
         78 . The method of  claim 74 , wherein the anti-GM-CSFRα antibody or a fragment thereof comprises a light chain complementary-determining region 1 (LCDR1) defined by SEQ ID NO: 6, a light chain complementary-determining region 2 (LCDR2) defined by SEQ ID NO: 7, and a light chain complementary-determining region 3 (LCDR3) defined by SEQ ID NO: 8; and a heavy chain complementary-determining region 1 (HCDR1) defined by SEQ ID NO: 3, a heavy chain complementary-determining region 2 (HCDR2) defined by SEQ ID NO: 4, and a heavy chain complementary-determining region 3 (HCDR3) defined by SEQ ID NO: 5. 
     
     
         79 - 90 . (canceled) 
     
     
         91 . The method of  claim 1 , wherein the administering the GM-CSF antagonist results in discharge from the hospital and/or weaning off from on-going medical care within 10 days. 
     
     
         92 - 99 . (canceled)