US2016200817A1PendingUtilityA1

Methods Of Identifying Anti-Inflammatory Compounds

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Assignee: UNIV ROCKEFELLERPriority: Apr 22, 2008Filed: Sep 11, 2015Published: Jul 14, 2016
Est. expiryApr 22, 2028(~1.8 yrs left)· nominal 20-yr term from priority
Inventors:Jeffrey V. RavetchRobert M. Anthony
A61P 7/06A61P 37/06A61P 43/00A61P 7/00A61P 37/00A61P 25/28A61P 25/16A61P 29/00A61P 25/00A61K 2039/505G01N 2800/24G01N 33/6893G01N 33/566C07K 2317/41G01N 2333/4724A61P 17/06G01N 2333/7056A61P 17/00C07K 16/2851G01N 2500/00A61P 1/04C07K 2317/75G01N 33/5023G01N 33/564
50
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Claims

Abstract

A mammalian C-type lectin receptor type is identified which is shown to bind IgG antibodies or Fc fragments, thus inducing IVIG-related reversal of inflammation associated with various immune disorders. The identification of a DC-SIGN receptor type which interacts with IgG to promote a biological response reducing inflammation associated with immune disorders provides for methods of screening and selecting compounds which may be useful in treating various immune disorders by acting to modulate a DC-SIGN (+) cell to signal a second effector macrophage, causing an increase in expression of the FcγRIIB receptor and in turn inhibiting a cellular-mediated inflammatory response.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of identifying a test compound useful to activate or suppress anti-inflammatory activity associated with IgG autoantibody-mediated inflammation, which comprises:
 (a) combining a test compound in the presence of a DC-SIGN receptor type protein; and,   (b) measuring and comparing the effect of the test compound in the presence of the DC-SIGN receptor type protein, as compared to an appropriate control.   
     
     
         2 . The method of  claim 1  wherein the DC-SIGN receptor type protein is selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         3 . The method of  claim 1  wherein step a) is carried out in the presence of Ca ++ . 
     
     
         4 . The method of  claim 1  wherein the wherein the DC-SIGN receptor type protein is provided as a DC-SIGN (+)  cell. 
     
     
         5 . The method of  claim 4  wherein the DC-SIGN receptor type protein is selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         6 . The method of  claim 4  wherein the DC-SIGN (+)  cell is provided as cultured cells transfected with a nucleic acid molecule recombinantly encoding a lectin domain selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         7 . The method of  claim 1  wherein step a) is carried out in a cell-free environment. 
     
     
         8 . The method of  claim 7  wherein the DC-SIGN receptor type protein is selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         9 . The method of  claim 4  wherein step a) is carried out in the presence of Ca ++ . 
     
     
         10 . A method of identifying a test compound useful to activate or suppress anti-inflammatory activity associated with IgG autoantibody-mediated inflammation, which comprises:
 (a) providing DC-SIGN (+)  cells;   (b) exposing the DC-SIGN w  cells to a test compound; and,   (c) measuring the increase or decrease in a cellular component within the DC-SIGN (+)  cells as compared to DC-SIGN(−) cells or DC-SIGN (+)  cells not exposed to the test compound, wherein an increase or decrease of the cellular component is know to be related to modulation of a DC-SIGN receptor type.   
     
     
         11 . The method of  claim 10  wherein the DC-SIGN (+)  cell is provided as cultured cells transfected with a nucleic acid molecule recombinantly encoding a lectin domain selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         12 . The method of  claim 10  wherein step a) is carried out in the presence of Ca ++ . 
     
     
         13 . A method of identifying a test compound useful to activate or suppress anti-inflammatory activity associated with IgG autoantibody-mediated inflammation, which comprises:
 a) providing an amino acid sequence comprising a DC-SIGN receptor type or fragment containing at least a lectin domain;   b) contacting the receptor or fragment of step a) with the test compound; and,   c) measuring the extent of binding of the test compound to the lectin domain.   
     
     
         14 . The method of  claim 13  wherein the DC-SIGN receptor type protein is selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         15 . The method of  claim 13  wherein step b) is carried out in a cell-free environment. 
     
     
         16 . The method of  claim 13  wherein the DC-SIGN receptor type protein is selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         17 . The method of  claim 13  wherein step b) is carried out in the presence of Ca ++ . 
     
     
         18 . A method of identifying a test compound useful to activate or suppress anti-inflammatory activity associated with IgG autoantibody-mediated inflammation, which comprises:
 a) providing a first amino acid sequence comprising a lectin domain of a DC-SIGN receptor type;   b) contacting the lectin domain of step a) with a control antibody or variant thereof;   c) measuring the extent of binding of the control antibody to the lectin domain so as to determine a baseline binding value;   d) providing a second amino acid sequence comprising a lectin domain of a DC-SIGN receptor type;   e) contacting the lectin domain of step d) with the test compound;   f) measuring the extent of binding of the test compound to the lectin domain; and,   g) comparing the baseline binding value of step c) with the extent of binding of the test compound measured in step f).   
     
     
         19 . The method of  claim 18  wherein step b) and step e) are carried out in a cell-free environment. 
     
     
         20 . The method of  claim 19  wherein the control antibody is an IgG antibody comprising a carbohydrate chain wherein a galactose moiety is attached to a terminal sialic acid moiety via α 2,6 sialylation. 
     
     
         21 . The method of  claim 19  wherein the control antibody or variant is an Fc fragment comprising a carbohydrate chain wherein a galactose moiety is attached to a terminal sialic acid moiety via α 2,6 sialylation. 
     
     
         22 . The method of  claim 20  wherein step e) comprises contacting the ligand binding domain with the test compound and the Fc fragment. 
     
     
         23 . The method of  claim 17  wherein the amino acid sequences of step a) and step d) are provided by cultured cells expressing a lectin domain selected from the group consisting of SIGN-R, DC-SIGN and DC-SIGNR. 
     
     
         24 . The method of  claim 18  wherein step b) and step e) are carried out in the presence of Ca ++ . 
     
     
         25 . A method of treating an immune disorder which comprises administering to a patient a compound that binds to and activates a DC-SIGN receptor type or a member of the signal transduction pathway thereof and mediates anti-inflammatory activity associated with the immune disorder, with the proviso that the compound is not IVIG. 
     
     
         26 . The method of  claim 25  wherein the DC-SIGN receptor type is human DC-SIGN receptor. 
     
     
         27 . The method of  claim 26  wherein the immune disorder is selected from the group of immune disorders consisting of immune thrombocytopenia, autoimmune hemolytic anemia, systemic lupus erythematosus, Kawsaki's disease, sclerodema, rheumatoid arthritis, chronic inflammatory demyelinating polyneuropathy, phemigus, Crohn's disease, ulcerative colitis, psoriasis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease or conditions associated with autoantibody mediated inflammation. 
     
     
         28 . A method of treating an anti-inflammatory disease, which comprises administering to a patient a compound that binds to and activates a DC-SIGN receptor type or a member of the signal transduction pathway thereof and mediates anti-inflammatory activity associated with the anti-inflammatory disease, with the proviso that the compound is not IVIG. 
     
     
         29 . A pharmaceutical composition comprising:
 (a) a compound that binds to and activates a DC-SIGN receptor type, resulting in a promotion of anti-inflammatory activity associated with an immune disorder; and   (b) at least one pharmaceutically acceptable excipient, where the composition is formulated to achieve a certain result.   
     
     
         30 . The pharmaceutical composition of  claim 28  wherein the compound is an antibody. 
     
     
         31 . The pharmaceutical composition of  claim 28  wherein the compound is an Fc fragment. 
     
     
         32 . The pharmaceutical composition of  claim 28  wherein the compound is an Fc fragment comprising a carbohydrate chain wherein a galactose moiety is attached to a terminal sialic acid moiety via α 2,6 sialylation.

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