Compositions and Methods for the Regulation of T Regulatory Cells Using TL1A-Ig Fusion Protein

Abstract

Compositions comprising TL1A-Ig fusion proteins and methods of their use, e.g., for the treatment of diseases and disorders associated with antigen-specific immune responses, are described. Also described are combination therapies that include the administration of a TNFRSF25 agonist and an interleukin (e.g., IL-2) and/or an mTOR inhibitor (e.g., rapamycin).

What is claimed is: 
     
         1 . An isolated or recombinant nucleic acid comprising a polynucleotide sequence which encodes a TL1A fusion protein, the fusion protein comprising: (a) a first polypeptide comprising an extracellular domain of a human TL1A polypeptide or a fragment thereof that specifically binds to Tumor Necrosis Factor Receptor Superfamily, Member 25 (TNFRSF25), and (b) a second polypeptide comprising an immunoglobulin (Ig) polypeptide; or a complementary polynucleotide sequence thereof. 
     
     
         2 . The nucleic acid of  claim 1 , wherein said nucleic acid encodes a monomeric fusion protein capable of forming a fusion protein homomultimer, wherein the homomultimer is a dimer of trimers. 
     
     
         3 . The nucleic acid of  claim 1 , wherein the nucleic acid encodes a polypeptide that, when administered to a human in need thereof, reduces the frequency of naive CD4 T cells in the human. 
     
     
         4 . The nucleic acid of  claim 1 , wherein the second polypeptide comprises one or more of a hinge region, a CH2 domain, and a CH3 domain of an IgG polypeptide. 
     
     
         5 . The nucleic acid of  claim 1 , wherein the second polypeptide comprises the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 14. 
     
     
         6 . The nucleic acid of  claim 1 , wherein the first polypeptide comprises:
 (a) an amino acid sequence of SEQ ID NO: 12, or   (b) an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 12.   
     
     
         7 . The nucleic acid of  claim 1 , wherein the nucleic acid encodes a fusion protein comprising SEQ ID NO: 12 and SEQ ID NO: 14. 
     
     
         8 . The nucleic acid of  claim 1 , wherein the nucleic acid encodes a fusion protein comprising SEQ ID NO: 16. 
     
     
         9 . The nucleic acid of  claim 1 , wherein the nucleic acid further comprises a nucleotide sequence that encodes a secretory or signal peptide operably linked to the fusion protein. 
     
     
         10 . A vector comprising the nucleic acid of  claim 1 . 
     
     
         11 . An isolated or recombinant host cell comprising the vector of  claim 10 . 
     
     
         12 . A method of producing a TL1A fusion protein, the method comprising: (a) introducing into a population of cells the nucleic acid of  claim 7 , wherein the nucleic acid is operatively linked to a regulatory sequence effective to produce the polypeptide encoded by the nucleic acid; and (b) culturing the cells in a culture medium to produce the polypeptide. 
     
     
         13 . The method of  claim 12 , further comprising: (c) isolating the polypeptide from the cells or culture medium. 
     
     
         14 . A composition comprising a human TL1A-Ig fusion protein, the fusion protein comprising (a) a first polypeptide comprising an extracellular domain of a human TL1A polypeptide or a fragment thereof that specifically binds to TNFRSF25; and (b) a second polypeptide comprising an Ig polypeptide. 
     
     
         15 . The composition of  claim 14 , wherein, when administered to a human in need thereof, the composition reduces the frequency of naive CD4 T cells in the human. 
     
     
         16 . The composition of  claim 14 , wherein the first polypeptide comprises:
 (a) an amino acid sequence of SEQ ID NO: 12, or   (b) an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 12.   
     
     
         17 . The composition of  claim 14 , wherein the fusion protein is a homomultimer, and wherein the homomultimer is a dimer of trimers. 
     
     
         18 . The composition of  claim 14 , wherein the Ig polypeptide comprises one or more of a hinge region, a CH2 domain, and a CH3 domain of an IgG polypeptide. 
     
     
         19 . The composition  claim 14 , wherein the Ig polypeptide comprises:
 (a) an amino acid sequence of SEQ ID NO: 14, or   (b) an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 14.   
     
     
         20 . The composition of  claim 14 , wherein the fusion protein comprises:
 (a) an amino acid sequence of SEQ ID NO: 16, or   (b) an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 16.   
     
     
         21 . The composition of  claim 14 , wherein the composition is characterized by enhanced in vivo efficacy compared to the first polypeptide when it is not coupled with an Ig polypeptide. 
     
     
         22 . A method of modulating an antigen-specific immune response in a human patient in need thereof, the method comprising: administering to the patient the composition according to  claim 14 , wherein the composition is administered in an amount that comprises a therapeutically effective amount of the fusion protein. 
     
     
         23 . The method of  claim 22 , wherein the patient in need thereof is a patient selected from the group consisting of a patient undergoing or about to undergo induction therapy in preparation for a solid organ or stem cell transplant, a patient who is a solid organ or stem cell transplant recipient and is undergoing or is about to undergo maintenance therapy, a patient who is a solid organ or stem cell transplant recipient, an allergic patient; a patient who is receiving or about to receive a vaccine, and a patient being treated or about to be treated with an immune checkpoint inhibitor. 
     
     
         24 . The method of  claim 22 , wherein the therapeutically effective amount of the fusion protein is in a range selected from the group consisting of 0.1-10 milligrams per kilogram of body weight per day (mg/kg/day), 0.5-5 mg/kg/day, and 1-2 mg/kg/day. 
     
     
         25 . A method of treating a disease or disorder associated with an antigen-specific immune response, or treating one or more symptoms of the disease or disorder, in a human patient in need thereof, the method comprising: administering to the patient the composition of  claim 14 , wherein the composition is administered in an amount that comprises a therapeutically effective amount of the fusion protein. 
     
     
         26 . The method of  claim 25 , wherein the therapeutically effective amount of the fusion protein is in a range selected from the group consisting of 0.1-10 milligrams per kilogram of body weight per day (mg/kg/day), 0.5-5 mg/kg/day, and 1-2 mg/kg/day. 
     
     
         27 . The method of  claim 25 , wherein the disease or disorder is selected from the group consisting of autoimmune disease or disorder, transplant rejection, graft-versus-host disease, inflammation, asthma, allergies, and chronic infection. 
     
     
         28 . The method of  claim 27 , wherein the disease or disorder is asthma. 
     
     
         29 . The method of  claim 22 , wherein the composition is administered to the patient in an amount that significantly increases proliferation of Treg cells in the patient following the administration. 
     
     
         30 . The method of  claim 22 , wherein the composition is administered to the patient in an amount that increases proliferation of Treg cells by at least two-fold in the patient following the administration. 
     
     
         31 . The method of  claim 22 , comprising multiple administrations of the composition to the patient. 
     
     
         32 . The method of  claim 22 , wherein the disease or disorder is an autoimmune disease selected from the group consisting of inflammatory bowel disease and rheumatoid arthritis. 
     
     
         33 . A method of reducing an adverse event associated with a therapy involving the administration of a TNFRSF25 agonist, wherein the method comprises administering to a patient in need thereof the composition according to  claim 14  in a physiologically acceptable carrier. 
     
     
         34 . The method of  claim 33 , wherein the adverse event is selected from the group consisting of development of one or more symptoms of inflammatory bowel disease, weight loss, rash, diarrhea, myalgias, decreased platelet counts, elevated liver enzyme levels, and death. 
     
     
         35 . The method of  claim 22 , wherein the composition is formulated as a pharmaceutical preparation. 
     
     
         36 . The method of  claim 25 , wherein the composition is formulated as a pharmaceutical preparation. 
     
     
         37 . The method of  claim 33 , wherein the composition is formulated as a pharmaceutical preparation.