Compositions comprising TL1A-Ig fusion protein for the regulation of T regulatory cells, and methods for their use
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-039/395
C07K-014/52
C07K-014/525
A61K-031/436
A61K-038/20
C07K-014/55
A61K-047/48
A61K-031/7088
C07K-016/24
출원번호
US-0185295
(2014-02-20)
등록번호
US-9468677
(2016-10-18)
발명자
/ 주소
Podack, Eckhard R.
Schreiber, Taylor H.
Khan, Samia Q.
출원인 / 주소
University of Miami
대리인 / 주소
Fish & Richardson P.C.
인용정보
피인용 횟수 :
0인용 특허 :
58
초록▼
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 interleu
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).
대표청구항▼
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
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 μg/kg and about 500 μg/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.
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