Product and method for treatment of conditions associated with receptor-desensitization

Abstract

Particular members of the multisubunit immune recognition receptor (MIRR) family of receptors, specifically, the B cell antigen receptor (BCR), the pre-B cell receptor (pre-BCR), the pro-B cell receptor (pro-BCR), Ig Fc receptors (FcR), and NK receptors, can be physically uncoupled from their associated transducers. The invention describes regulatory compounds and methods for mimicking such dissociation/destabilization for the purposes of receptor desensitization and for treatment of conditions in which receptor desensitization or alternatively, enhanced or prolonged receptor sensitization, is desirable. Compounds and methods for enhancing or prolonging receptor sensitization are also disclosed, as are methods for identifying regulatory compounds suitable for use in the present methods.

1 . A method to desensitize an Ig Fc receptor, said method comprising: contacting an Ig Fc receptor, with a regulatory compound, wherein said receptor has a transducer component and an extracellular ligand binding component;
 wherein contact with said regulatory compound: (1) causes a dissociation of said extracellular ligand binding component from said transducer component when said components are associated with each other prior to contact with said compound; or (2) inhibits association of said extracellular ligand binding component with said transducer component when said components are dissociated from each other prior to contact with said compound.   
     
     
         2 - 49 . (canceled) 
     
     
         50 . The method of  claim 1 , wherein said regulatory compound binds to said transducer component. 
     
     
         51 . The method of  claim 1 , wherein said regulatory compound binds to said extracellular ligand binding component. 
     
     
         52 . The method of  claim 1 , wherein said regulatory compound inhibits association of said extracellular ligand binding component with said transducer component when said components are dissociated from each other. 
     
     
         53 . The method of  claim 52 , wherein said regulatory compound selectively binds to a portion of said transducer component that contacts a portion of said extracellular ligand binding component when said receptor is bound by its natural ligand, thereby inhibiting contact of said transducer component with said extracellular ligand binding component. 
     
     
         54 . The method of  claim 52 , wherein said regulatory compound selectively binds to a portion of said transducer component which contacts a portion of said extracellular ligand binding component, thereby inhibiting phosphorylation of said transducer component when the receptor is bound by its natural ligand. 
     
     
         55 . The method of  claim 1 , wherein said regulatory compound is selected from the group consisting of an antibody, a peptide and a mimetope thereof. 
     
     
         56 . The method of  claim 1 , wherein said regulatory compound is an antibody 
     
     
         57 . The method of  claim 56 , wherein said antibody is monovalent. 
     
     
         58 . The method of  claim 56 , wherein said antibody is divalent. 
     
     
         59 . The method of  claim 56 , wherein said antibody binds to said transducer component. 
     
     
         60 . The method of  claim 59 , wherein said transducer component is selected from the group consisting of FcRβ and FcRγ. 
     
     
         61 . The method of  claim 56 , wherein said antibody is a bi-specific antibody comprising:
 a. a first portion which binds to said receptor and: (1) causes a dissociation of said extracellular ligand binding component from said transducer component when said components are associated with each other prior to contact with said compound; or (2) inhibits association of said extracellular ligand binding component with said transducer component when said components are dissociated from each other prior to contact with said compound; and   b. a second portion which selectively binds to a cell surface molecule expressed by a cell which expresses said receptor.   
     
     
         62 . The method of  claim 61 , wherein said transducer component is selected from the group consisting of FcRβ and FcRγ. 
     
     
         63 . The method of  claim 61 , wherein said regulatory compound selectively binds to said transducer component and inhibits association of said extracellular ligand binding component with said transducer component. 
     
     
         64 . The method of  claim 1 , wherein said receptor is a human Ig Fc receptor selected from the group consisting of FcαRI, FcεRI, FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIb, and wherein said regulatory compound selectively binds to an extracellular ligand binding domain of said Fc receptor. 
     
     
         65 . The method of  claim 64 , wherein said receptor comprises an alpha chain receptor extracellular binding component. 
     
     
         66 . The method of  claim 64 , wherein said receptor comprises an α chain receptor extracellular ligand binding component and a transducer component comprising a β chain and/or γ chain. 
     
     
         67 . The method of  claim 64 , wherein said receptor is expressed by a cell selected from the group consisting of a macrophage, a dendritic cell, a neutrophil, a mast cell and a basophil. 
     
     
         68 . The method of  claim 64 , wherein said regulatory compound is administered to a patient that has a condition associated with inflammation. 
     
     
         69 . The method of  claim 68 , wherein said condition is associated with allergic inflammation. 
     
     
         70 . The method of  claim 1 , wherein said regulatory compound is administered to a patient that has an autoimmune disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, insulin dependent diabetes mellitis, multiple sclerosis, myasthenia gravis, Grave's disease, autoimmune hemolytic anemia, autoimmune thrombocytopenia purpura, Goodpasture's syndrome, pemphigus vulgaris, acute rheumatic fever, post-streptococcal glomerulonephritis, and polyarteritis nodosa. 
     
     
         71 . The method of  claim 1 , wherein said regulatory compound is administered to a patient by way of a therapeutic composition comprising a pharmaceutically acceptable carrier and said compound.