# US 2014/0193410 A1 · Compositions and Methods for the Regulation of T Regulatory Cells Using TL1A-Ig Fusion Protein > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0193410 A1 - Document ID: US20140193410A1 - Status: Published application - Kind: A1 - Application number: 14/151,497 - Filed: 2014-01-09 - Published: 2014-07-10 - Earliest claimed: 2013-01-09 - Assignees: University of Miami - Applicants: University of Miami - Inventors: Eckhard R. Podack; Taylor H. Schreiber; Samia Q. Khan - Web page: https://patentgrep.com/patent/US20140193410A1 ## CPC - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin - A61K 31/7088: Compounds having three or more nucleosides or nucleotides - A61K 38/20: Interleukins [IL] - A61K 38/2013: {IL-2} - A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum - A61K 39/39541: {against normal tissues, cells} - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 1/12: Antidiarrhoeals - A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 11/00: Drugs for disorders of the respiratory system - A61P 17/00: Drugs for dermatological disorders - A61P 21/00: Drugs for disorders of the muscular or neuromuscular system - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - A61P 37/00: Drugs for immunological or allergic disorders - A61P 37/02: Immunomodulators - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 14/55: IL-2 - C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95} - C07K 14/52: Cytokines; Lymphokines; Interferons - C07K 16/246: {IL-2} - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## 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). ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) 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. ### Claim 4 (depends on 1) 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. ### Claim 5 (depends on 1) 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. ### Claim 6 (depends on 1) 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. ### Claim 7 (depends on 1) The nucleic acid of claim 1, wherein the nucleic acid encodes a fusion protein comprising SEQ ID NO: 12 and SEQ ID NO: 14. ### Claim 8 (depends on 1) The nucleic acid of claim 1, wherein the nucleic acid encodes a fusion protein comprising SEQ ID NO: 16. ### Claim 9 (depends on 1) 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. ### Claim 10 (depends on 1) A vector comprising the nucleic acid of claim 1. ### Claim 11 (depends on 10) An isolated or recombinant host cell comprising the vector of claim 10. ### Claim 12 (depends on 7) 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. ### Claim 13 (depends on 12) The method of claim 12, further comprising: (c) isolating the polypeptide from the cells or culture medium. ### Claim 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. ### Claim 15 (depends on 14) 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. ### Claim 16 (depends on 14) 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. ### Claim 17 (depends on 14) The composition of claim 14, wherein the fusion protein is a homomultimer, and wherein the homomultimer is a dimer of trimers. ### Claim 18 (depends on 14) 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. ### Claim 19 (depends on 14) 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. ### Claim 20 (depends on 14) 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. ### Claim 21 (depends on 14) 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. ### Claim 22 (depends on 14) 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. ### Claim 23 (depends on 22) 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. ### Claim 24 (depends on 22) 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. ### Claim 25 (depends on 14) 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. ### Claim 26 (depends on 25) 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. ### Claim 27 (depends on 25) 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. ### Claim 28 (depends on 27) The method of claim 27, wherein the disease or disorder is asthma. ### Claim 29 (depends on 22) 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. ### Claim 30 (depends on 22) 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. ### Claim 31 (depends on 22) The method of claim 22, comprising multiple administrations of the composition to the patient. ### Claim 32 (depends on 22) 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. ### Claim 33 (depends on 14) 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. ### Claim 34 (depends on 33) 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. ### Claim 35 (depends on 22) The method of claim 22, wherein the composition is formulated as a pharmaceutical preparation. ### Claim 36 (depends on 25) The method of claim 25, wherein the composition is formulated as a pharmaceutical preparation. ### Claim 37 (depends on 33) The method of claim 33, wherein the composition is formulated as a pharmaceutical preparation.