Compositions comprising TL1A-Ig fusion protein for the regulation of T regulatory cells, and methods for their use

• US 9,603,925 B2
• Filed: 02/20/2014
• Issued: 03/28/2017
• Est. Priority Date: 01/09/2013
• Status: Expired

• Current Assignee: University of Miami
• Original Assignee: University of Miami
• Inventors: Podack, Eckhard R., Schreiber, Taylor H., Khan, Samia Q.
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US14/185,295
• Publication Number:
  US 20140286897A1
• Time in Patent Office: 1,132 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/52 : Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 14/55 : IL-2
• CPC Class Codes: C07K 16/246 : IL-2
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

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

1. A composition comprising (i) 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 Tumor Necrosis Factor Receptor Superfamily, Member 25 (TNFRSF25);

and (b) a second polypeptide comprising an immunoglobulin (Ig) polypeptide; and

(ii) one or both of an effective amount of interleukin (IL)-2 and an effective amount of an mTOR inhibitor.

2. The composition of claim 1, wherein, when administered to a human in need thereof, the composition reduces the frequency of naive CD4 T cells in the human.

3. The composition of claim 1, wherein the first polypeptide comprises

(a) the 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.

4. The composition of claim 1, wherein the fusion protein is a homomultimer, and wherein the homomultimer is a dimer of trimers.

5. The composition of claim 1, wherein the Ig polypeptide comprises one or more of a hinge region, a CH2 domain, and a CH3 domain of an IgG polypeptide.

6. The composition claim 1, wherein the Ig polypeptide comprises

(a) the 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.

7. The composition of claim 1, wherein the fusion protein comprises

(a) the 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.

8. The composition of claim 1, wherein the in vivo efficacy of the composition is higher than the in vivo efficacy of the first polypeptide when it is not coupled with an Ig polypeptide.

9. The composition of claim 1, wherein the effective amount of IL-2 is an amount that, in combination with the TL1A-Ig fusion protein, is sufficient to achieve a synergistic effect on the expansion of Treg cells when administered to a subject.

10. The composition of claim 1, wherein the effective amount of IL-2 is a dose of IL-2 that would induce suboptimal, or fail to induce, expansion of Treg cells if administered alone to a human patient.

11. The composition of claim 10, wherein the dose of IL-2 is less than 1 million units per square meter per day.

12. The composition of claim 11, wherein the dose of IL-2 is an amount in the range of about 30,000 to about 300,000 units per square meter per day.

13. The composition of claim 12, wherein the dose of IL-2 is about 300,000 units per square meter per day.

14. The composition of claim 12, wherein the dose of IL-2 is about 30,000 units per square meter per day.

15. The composition of claim 1, wherein the mTOR inhibitor is selected from the group consisting of rapamycin (sirolimus), CI-779, everolimus ABT-578, tacrolimus, AP-23675, BEZ-235, OSI-027, QLT-0447, ABI-009, BC-210, salirasib, TAFA-93, deforolimus (AP-23573), temsirolimus, 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol (PP242), AP-23841, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (CCI779), 40-epi-(tetrazolyl)-rapamycin (ABT578), biolimus-7, biolimus-9, and AP23464.

16. The composition of claim 15, wherein the mTOR inhibitor is rapamycin.

17. The composition of claim 16, wherein the effective amount of rapamycin is a dosage between about 25 μ

g/kg and about 500 μ

g/kg.

18. The composition of claim 1, wherein the composition comprises the fusion protein and the IL-2.

19. The composition of claim 1, wherein the composition comprises the fusion protein and the mTOR inhibitor.