Polymeric immunoglobulin fusion proteins that target low-affinity fcγ receptors

Abstract

The present invention concerns a family of nucleic acids, polypeptides and cloning vectors which direct expression of fusion proteins that can mimic aggregated IgG (AIG) and immune complex function with respect to their interactions with FcγR and which allow for the inclusion and targeting of a second protein domain to cells expressing FcγR. This was accomplished by expressing multiple linear copies of the hinge and CH2 domains (HCH2) of human IgG1 fused to the framework region of human IgG1. Convenient restriction sites allow for the facile introduction of additional amino-terminal domains. Methods for treating patients using fusion proteins are also disclosed. The HCH2 polymers described here represent a new strategy in the design of recombinant proteins for the therapeutic targeting of FcγR in autoimmune disorders.

1 - 82 . (canceled) 
     
     
         83 . A polypeptide comprising
 a first region comprising a protein or portion thereof; and   a second region comprising more than one copy of at least a portion of an HCH2 region of a first IgG;   wherein the polypeptide targets cells expressing FcγR, binds to FcγR, the polypeptide binds complement components, or both.   
     
     
         84 . The polypeptide of  claim 83 , wherein the first region comprises at least a portion of a sequence from a Fab region of a human antibody or a humanized antibody, a CD8α, an HSA, or a transporter protein. 
     
     
         85 . The polypeptide of  claim 83 , further comprises a third region which comprises at least a portion of an HCH2 region of a second IgG. 
     
     
         86 . The polypeptide of  claim 83 , wherein the amino acid sequence comprises at least two sequences of IgG. 
     
     
         87 . The polypeptide of  claim 83 , wherein the first IgG is a human, rodent, cow, goat, sheep, horse, dog, cat, or pig IgG. 
     
     
         88 . The polypeptide of  claim 83 , comprising an amino acid sequence comprising a sequence of at least two from the group consisting of IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, and IgM. 
     
     
         89 . The polypeptide of  claim 83 , wherein the polypeptide targets or binds cells expressing one or more of FcγR, FcαR, FcεR, FcμR, FcδR, or FcRn. 
     
     
         90 . The polypeptide of  claim 83 , wherein the polypeptide is in a vaccine composition. 
     
     
         91 . The polypeptide of  claim 83 , wherein the second region comprises 2-10 copies of the hinge and CH2 regions of an IgG. 
     
     
         92 . A polypeptide comprising an antibody sequence and more than one copy of at least a portion of an HCH2 region of an IgG. 
     
     
         93 . A method for administering comprising
 administering the polypeptide of  claim 83  to at least one cell.   
     
     
         94 . The method of  claim 93 , further defined as a method of treating a mammal comprising administering the polypeptide to the mammal. 
     
     
         95 . The method of  claim 94 , wherein the mammal has an immune deficiency disorder, dermatomyositis-polymyositis, an infectious disease, autoimmune thyroiditis, interstitial cystitis, prostatitis, an inflammatory disease, an autoimmune disease, an allergic disease, a degenerative disease of the central nervous system, a disease of the platelets, a disease of the blood vessels, inflammatory neuropathy, a traumatic condition, rheumatoid arthritis, lupus, and/or asthma. 
     
     
         96 . The method of  claim 93 , further defined as a method of killing neoplastic cell comprising treating a neoplastic cell with the polypeptide. 
     
     
         97 . The method of  claim 93 , further defined as a method of killing a virally infected cell comprising treating a virally infected cell with the polypeptide. 
     
     
         98 . A method of delivering a therapeutic agent to a delivery site in a mammal comprising
 providing the therapeutic agent to the mammal;   
       wherein the therapeutic agent comprises a polypeptide of  claim 83  and the therapeutic agent is delivered to the delivery site. 
     
     
         99 . The method of  claim 98 , wherein the polypeptide further comprises a third region which comprises at least a portion of an HCH2 region of a second IgG. 
     
     
         100 . A method of preparing an immunological product comprising
 immunizing a mammal with an amount of an antigen and a polypeptide comprising a first region comprising a protein or portion thereof and a second region comprising more than one copy of at least a portion of an HCH2 region of a first IgG;   producing the immunological product in the mammal, wherein the immunological product is a T cell, a product produced by a T cell, a B cell, or an antibody produced by a B cell; and   recovering the immunological product from the mammal.   
     
     
         101 . The method of  claim 100 , wherein the first region comprises a portion of or all of an antibody. 
     
     
         102 . A nucleic acid that encodes for the polypeptide of  claim 83 .