Anti-pad4 autoantibodies as clinical response biomarkers for the treatment of rheumatoid arthritis

Abstract

The present disclosure relates to the use of anti-PAD4 autoantibodies as a clinical biomarker for rheumatoid arthritis (RA) treatment. The disclosure further provides an assay to detect anti-PAD4 autoantibodies, assay kits for the detection of anti-PAD4 autoantibodies, as well as computer implemented diagnostic methods.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a rheumatoid arthritis patient comprising
 identifying the rheumatoid arthritis patient having anti-peptidylarginine deiminase 4 (anti-PAD4) autoantibody level below the lower limit of quantification (LLOQ) for an assay of 5000 U/ml; and   administering an antibody or antigen-binding fragment thereof that inhibits association between human granulocyte macrophage colony-stimulating factor receptor alpha (GM-CSFRα) and its ligand GM-CSF to the patient.   
     
     
         22 . The method of  claim 21 , wherein the antibody or antigen binding fragment thereof that inhibits association between GM-CSFRα and its ligand GM-CSF specifically binds to GM-CSFRα. 
     
     
         23 . The method of  claim 21 , wherein the antibody or antigen-binding fragment thereof that inhibits association between GM-CSFRα and its ligand GM-CSF comprises complementary determining regions having the amino acid sequence set forth in SEQ ID NOS: 6 to 11. 
     
     
         24 . The method of  claim 21 , wherein the antibody or antigen-binding fragment thereof that inhibits association between GM-CSFRα and its ligand GM-CSF comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 5. 
     
     
         25 . The method of  claim 21 , wherein the patient has been treated with one or more additional Disease-modifying antirheumatic drugs (DMARDs), either before, during, or after administration of an antibody or antigen-binding fragment thereof that inhibits association between GM-CSFRα and its ligand GM-CSF. 
     
     
         26 . The method  claim 21 , wherein the anti-PAD4 autoantibody level is detected in one or more of the patient's whole blood, blood serum, plasma, or synovial fluid. 
     
     
         27 . The method according to claim  6 , wherein the anti-PAD4 autoantibody level is detected in the patient's blood serum. 
     
     
         28 . The method of  claim 21 , further comprising a step of determining, submitting a sample taken from the patient for determination, or instructing a clinical laboratory to determine the expression level or activity of one or more additional biomarkers, or to determine at least one clinical status marker, or a combination thereof. 
     
     
         29 . The method of  claim 21 , wherein the antibody or antigen-binding fragment thereof that inhibits association between GM-CSFRα and its ligand GM-CSF is administered at a fixed dose. 
     
     
         30 . The method of  claim 21 , wherein the assay is an immunoassay, an agglutination assay, or a homogeneous assay. 
     
     
         31 . The method according to  claim 30 , wherein the assay is an immunoassay, and the immunoassay employs detectably labeled PAD4. 
     
     
         32 . The method according to  claim 31 , wherein the detectably labeled PAD4 is ruthenylated PAD4. 
     
     
         33 . The method of  claim 30 , wherein the immunoassay detects anti-PAD4-autoantibody bound to PAD4.