JP2020505318A - 肥満及び摂食障害の治療 - Google Patents
肥満及び摂食障害の治療 Download PDFInfo
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Abstract
Description
本出願は、2016年12月6日出願の「肥満及び摂食障害の治療」と標題されたオーストラリア特許仮出願第2016905018号による優先権を請求し、その内容は、その全体で参照によって本明細書に援用される。
次の出願又は刊行物が、本出願で参照され、それらの内容は全体で、参照によって本明細書に援用される:
Amirah E-E A et al., Expert Opin Drug Deliv 12(12):1923-1941 (2015);
国際特許出願PCT/GB1996/001094(WO96/034885)、標題「Biologically active peptide fragments of OB protein」;
国際特許出願PCT/AU1996/000386(WO97/000958)、標題「Novel TGF-b like cytokine」;
国際特許出願PCT/US2009/001231(WO2009/108340)、標題「Leptin agonist and methods of use」;
国際特許出願PCT/US2013/023465(WO2013/113008)、標題「Growth differentiation factor 15 (GDF-15) polypeptides」;
国際特許出願PCT/EP2015/063596(WO2015/197446)、標題「MIC-1 fusion proteins and uses thereof」;
国際特許出願PCT/EP2017/050695(WO2017/121865)、標題「MIC-1 receptor and uses thereof」;
国際特許出願PCT/EP2017/062583(WO2017/202936)、標題「MIC-1 compounds and use thereof」、及び
米国特許第5,225,539号、標題「Recombinant altered antibodies and methods of making altered antibodies」。
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップを含む方法に関する。
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を含む医薬組成物に関する。
前記対象が低い、正常な、又は高い血清中レプチンレベルを有するかどうかを決定するステップと、
低い又は正常な血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップ、又は
高い血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤を投与するステップ
とを含む方法に関する。
(i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
を投与するステップを含む方法に関する。
(i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
を含む医薬組成物に関する。
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップを含む方法に関する。
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
の使用に関する。
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を含む医薬組成物に関する。
前記対象が低い、正常又は高い血清中レプチンレベルを有するかどうかを決定するステップと、
低い又は正常な血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップ、又は
高い血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤を投与するステップとを含む方法に関する。
低い又は正常な血清中レプチンレベルを有すると決定された対象において、体重(例えば、体重減少の達成)及び/又は食欲を制御するための、
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
の使用、さらには
高い血清中レプチンレベルを有すると決定された対象において、体重及び/又は食欲を制御するための、
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤の使用に関する。
(i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
を投与するステップを含む方法に関する。
(i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
の使用に関する。
(i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
を含む医薬組成物に関する。
[実施例]
CHOWを給餌されているか、又は12週間の高脂肪食(HFD)から食事性肥満(DIO)を有する10匹の雄の22週齢C57BL6マウスからなる群を使用して、研究を行った。マウスに、浸透圧ミニポンプ(例えば、Alzet(登録商標)モデル2002;Durect Corporation社製、Cupertino、CA、米国)を介して、ビヒクル(CHOWc又はDIOc)又は以前に記載された方法(Johnen H et al., Nat Med 13:1333-1340 (2007))に従って生産された組換えマウスMIC−1(0.5μg/gBW/日;CHOWm又はDIOm)のいずれかを注入した。MIC−1は、食物摂取の減少と付随して、持続的体重減少を誘導し(図1A及びB)、これは、HFD(14%)マウスでは、CHOW給餌マウス(7%;図1A)においてよりも、かなり低い定常状態血清中MIC−1レベルを有するにも関わらず(それぞれ6.3+/−0.8ng/ml vs 10.7+/−1.3ng/ml;p<0.01)、比例して約2倍高かったことが見出された。標準的な二重エネルギーX線吸収測定法(DEXA,dual-energy X-ray adsorptiometry)によって測定されたとおり、研究過程にわたって、DIOmマウスは、体脂肪量及び除脂肪量の両方を失ったCHOWmマウスと比較して、体脂肪量のかなりの量を失ったが、除脂肪量はほとんど失わなかった(図1C及びD)。さらに、DIOmマウスの鼠径脂肪組織は、マクロファージマーカーF4/80のかなり低い正規化qPCR発現を示し(10.3+/−1.9 vs 73.2+/−10.5;p<0.05)、これは、代謝表現型を改善すると予測される(Li Z et al., J Neurochem 95:361-376 (2005))マクロファージ脂肪浸潤の減少を示している。
飼料給餌11週齢C57BL6マウスを使用し、それに、(標準浸透圧ミニポンプを使用して)ビヒクル、組換えマウスMIC−1(0.5μg/体重g/24時間)、レプチン(0.5μg/体重g/24時間)、又はMIC−1+レプチン(MIC−1 0.5μg/体重g+レプチン0.5μg/体重g/24時間)のいずれかを6日間にわたって連続注入して、研究を行った。レプチンは、Creative Biomart社(Shirley、NY、米国)から供給された組換えマウスレプチンであった。
ビヒクル、マウスレプチン(0.5μg/g/日)及び組換えマウスMIC−1(0.5μg/g/日)を二成分組み合わせで、普通食を給餌されている雄のマウス及び高脂肪食で24週間後に肥満に(食事性肥満(DIO)を有するマウス)、かつレプチン抵抗性にした雄のマウスに注入した。結果が、図3A及び3Bに示されている。マウスに、MIC−1及びレプチンの組み合わせを注入した場合に、体重減少の最大レベルが見出された。HFDマウスで、MIC−1及びレプチンの組み合わせで観察された体重減少の程度が特に顕著であった。
食事性肥満(DIO)を有するマウス及び普通食給餌マウスにおいて、1群当たり7匹のマウスを用いて、MIC−1とレプチンとの間の相互作用を実証及び特性決定するために、さらなる実験を行った。使用した方法は、実施例1〜3に関して記載したものと同様であり、及び/又は以前に記載されたとおりであった(Tsai VW et al., Int J Obes (Lond) doi: 10.1038/ijo.2017.258 (2017))。各マウスに、2つの浸透圧ミニポンプ(Alzet model 2002;Durect Corporation社製)を移植した。一方のポンプはビヒクル又はMIC−1(最小培地で成長させたP.パストリス(P.pastoris)から発現及び分泌され、3ステップ手順で高度に精製され、次いで、凍結乾燥され、使用まで−80℃で貯蔵された、使用時点で、4mM HCL中で再構成され、次いで、PBSビヒクル中で適切な濃度に希釈されたマウスMIC−1の組換え成熟ドメイン)のいずれかを含有し、第2のポンプは、ビヒクル又はレプチン(大腸菌(E.coli)で産生され、147aaからなり、16.1kDaの分子量を有する単一の非グリコシル化ポリペプチド鎖としての組換えマウスレプチン)のいずれかを含有した。ビヒクル又はMIC−1は、ミニポンプを介して、0.5μg/gBW/日で、実験期間にわたって注入した一方で、ビヒクル又はレプチンは、0.2μg/gBW/日で実験期間にわたって注入した。体重(BW)を最初の13日間にわたってモニターし、その間、マウスは大部分、平静であった。全体脂肪量及び除脂肪量を処置中に、二重エネルギーX線吸収測定法(DEXA;Lunar PIXImus2マウスデンシトメータ;GE Healthcare社製、Waukesha、WI、米国)を使用して測定した。マウスの行動を実質的に中断させるDEXA及び食物摂取測定などの調査は、15から19日目の間に行い、その期間は、体重をモニターしなかった。正常な肝臓及びDIOからの肝臓に対する効果を、固定され、切片化され、ヘマトキシリン及びエオシンで染色された解剖肝臓からの組織を用いて調査した。標準的な糖負荷試験(GTT,glucose tolerance tests)及びインスリン感受性試験(ITT,insulin sensitivity tests)も、処置マウスで行った(14日目)。
Ob/Obマウスは、レプチンの変異不活性型を有し、したがって、これらのマウスは、機能的に不活性なレプチン経路を有し、このことが、普通食餌で重篤で急速に進行する肥満及びその結果につながる。しかしながら、そのマウスはなお、インタクトなレプチン受容体及びシグナル伝達経路を有し、したがって、それらの内因性変異レプチンには応答しないにも関わらず、レプチンの投与には応答することができる。ここでは、正常なレプチンの背景レベルの上昇を伴うことなく(DIOマウスで起こるものを参照されたい)、肥満モデルにおいて、MIC−1とレプチンとの間の相互作用をさらに調査するために、このマウスを実験で使用した。この実験で使用した方法は、実施例1〜3に関連して記載したとおり、及び/又は以前に記載されたとおり(Tsai VW et al., Int J Obes (Lond) doi: 10.1038/ijo.2017.258 (2017))であった。
先行する実施例、特に実施例4で観察された結果は、過剰発現したMIC−1の食欲不振/悪液質誘導活性が、レプチン経路を阻害することによって低下し得ることを示唆した。この研究では、マウスに、レプチンアンタゴニスト(マウススーパーレプチンアンタゴニスト(SMLA,mouse super leptin antagonist);Protein Laboratories Rehevot Ltd社製、Rehevot、イスラエル)を連続注入によって投与した。SMLAは、レプチン受容体について高い親和性を有するが、レプチン受容体を活性化させることはなく、したがって、レプチン作用のドミナントネガティブ競合阻害物質として作用する変異型マウスレプチン分子である(Shpilman M et al., J Biol Chem 286:4429-4442 (2011))。マウスに、2つの浸透圧ミニポンプを皮下移植した。一方のミニポンプは、MIC−1又はビヒクル(0.5μg/gBW/日)を注入し、他方はSMLA又はビヒクル(1.5μg/gBW/日)を注入した。使用方法は、実施例1〜3に関連して記載されたとおり、及び/又は以前に記載されたとおり(Tsai VW et al., Int J Obes (Lond) doi: 10.1038/ijo.2017.258 (2017))である。
1. Bootcov MR et al., Proc Natl Acad Sci USA 94:11514-11519 (1997)
2. Breit SN and MR Bootcov, International Patent Application No PCT/AU96/00386 (WO 97/00958)
3. Fairlie WD et al., Gene 254:67-76 (2000)
4. Moore AG et al., J Clin Endocrinol Metab 85:4781-4788 (2000)
5. Fairlie WD et al., Biochem 40:65-73 (2001)
6. Breit SN et al., International Patent Application No PCT/AU01/00456 (WO 01/81928)
7. Fairlie WD et al., J Leukocyte Biol 65:2-5 (1999)
8. Brown DA et al., Lancet 359:2159-2163 (2002)
9. Koniaris LG. J Gastrointest Surg 2003 7(7):901-905 (2003)
10. Welsh JB and GM Hampton, Cancer Res 61:5974-5978 (2001)
11. Buckhaults P et al., Cancer Res 61:6996-7001 (2001)
12. Welsh JB et al., Proc Natl Acad Sci USA 100:3410-3415 (2003)
13. Brown DA et al., Biotechniques 33(1):118-20, 122, 124 passim (2002)
14. Koopmann J et al., Clin Cancer Res 10(7):2386-2392 (2004)
15. Brown DA et al., Clin Cancer Res 9:2642-2650 (2003)
16. Tsai VWW et al., Int J Obes (Lond) 40(2):193-7 (2016)
17. Breit SN et al., Growth Factors 29:187-195 (2011)
18. Johnen H et al., Cardiovasc Pathol 21:499-505 (2012)
19. Kempf T et al., Circ Res 98:351-360 (2006)
20. Wang X et al., Aging (Albany NY) 6:690-704 (2014)
21. Johnen H et al., Nat Med 13:1333-1340 (2007)
22. Breit SN, International Patent Application No PCT/AU2005/000525 (WO 2005/099746)
23. Vigano ALL et al., Cancer Res 73 Suppl1, Abstract nr 4650 (2103)
24. Lu ZH et al., Asian Pac J Cancer Prev 15:6047-6052 (2014)
25. Kempf T et al., J Am Coll Cardiol 50:1054-1060 (2007)
26. Macia L et al., PLoS One 7, e34868 (2012)
27. Chrysovergis K et al., Int J Obes (Lond) 38(12):1555-1564 (2014)
28. Hong JH et al., Diabetes Metab J 38:472-479 (2014)
29. Tsai VW et al., PLoS One 8, e55174 (2013)
30. Mullican SE et al., Nat Med 23(10):1150-1157 (2017)
31. Vayghan HJ et al., IRJABS 4(10):3099-3103 (2013)
32. Jacquet D et al., Int J Obesity 25:491-495 (2001)
33. Obesity: preventing and managing the global epidemic. Report of a WHO consultation, World Health Organ Tech Rep Ser 894:i-xii, 1-253 (2000)
34. Bluher S et al., J Invest Med 57(7):784-788 (2009)
35. Stamatiadis DN et al., Clin Endocrinol 60(4):434-441 (2004)
36. Gonzalez LC et al., Neuroendocrinology 70(3):213-220 (1999)
37. Iikuni N et al., Curr Immunol Rev 4(2): 70-79 (2008)
38. Tesitore L et al., Int J Mol Med 5(4):421-426 (2000)
39. Kempf T et al., Eur J Endocrinol 167:671-678 (2012)
40. Carstensen M et al., Eur J Endocrinol 162:913-917 (2010)
41. Dostalova I et al., Eur J Endocrinol 161:397-404 (2009)
42. Herder C et al., Diabetes Obes Metab 15 Suppl 3, 39-50 (2013)
43. Patricia G et al., US Patent No 6,777,388
44. Pluckthun A., Bio/Technology 9:545-551 (1991)
45. Hudson PJ and C Souriau., Nat Med 9(1): 129-134 (2003)
46. Lonberg N., Curr Opin Immunol 20:450-459 (2008)
47. Kashmiri SVS et al. Methods 36(1): 25-34 (2005)
48. Marvin JS and HB Lowman. Phage Display in Biotechnology and Drug Discovery (2015)
49. Bowers PM et al., J Biol Chem 288(11):7688-7696 (2013)
50. Nejati-Koshki K et al., Asian Pac J Cancer Prev 14(11):6595-6599 (2014)
51. Zhang F et al., Nature 387:206-209 (1997)
52. Kovalsky I et al., Diabetes Obes Metab 12:393-402 (2010)
53. Zabeau L et al., Biol Chem 395(5):499-514 (2014)
54. Iversen PO et al., Blood 100:4123-4128 (2002)
55. De Rosa V et al., J Clin Invest 116:447-455 (2006)
56. Amirah E-E A et al., Expert Opin Drug Deliv 12(12):1923-1941 (2015)
57. Bender TS et al., Neuroscience 303:569-576 (2015)
58. Hanson LR et al., Drug Deliv 19(3):149-154 (2012)
59. Ashima RS., J Clin Invest 118(7):2380-2383 (2008)
60. Considine RV et al., New Engl J Med 334:292-295 (1996)
61. Al Maskari MY and AA Alnaqdy., Sultan Qaboos Univ Med J 6(2):27-31 (2006)
62. Vassilev LT et al., Science 303(5659):844-848 (2004)
63. Baek SJ et al., Molec Pharm 67(2):356-364 (2005)
64. Baek, SJ et al., Mol Pharmacol 59:901-908 (2001)
65. Brown, DA et al., Cancer Epidemiol Biomarkers Prev 21:337-346 (2012)
66. Matheny M et al., J Endocrinol 222(1):27-41 (2014)
67. Ioffe E et al., Proc Natl Acad Sci U S A 95:11852-11857 (1998)
68. Maffei M et al., Nat Med 1(11):1155-1161(1995)
69. Yang L et al., Nat Med 23(10):1158-1166 (2017)
70. Emmerson PJ et al., Nat Med 23(10):1215-1219 (2017)
71. Tsai VW et al., Int J Obes (Lond) doi: 10.1038/ijo.2017.258 (2017)
72. Li Z et al., J Neurochem 95:361-376 (2005)
73. Tsai VW et al., Int J Obes (Lond) doi: 10.1038/ijo.2017.258 (2017)
74. Shpilman M et al., J Biol Chem 286:4429-4442 (2011)
Claims (24)
- 対象において体重及び/又は食欲を制御する方法であって、前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップを含む、前記方法。 - 対象において体重減少を達成するために行う、請求項1に記載の方法。
- 対象が過体重又は肥満の対象である、請求項1又は2に記載の方法。
- 対象が、食事性肥満(DIO)を有する対象である、請求項3に記載の方法。
- 対象が、2型糖尿病(T2D)、非アルコール性脂肪性肝炎(NASH)に罹患している、及び/又はインスリン抵抗性を示す、請求項3に記載の方法。
- 対象において、2型糖尿病(T2D)及び/又はT2Dの1若しくは2以上の合併症、肥満又は過体重(例えば、非アルコール性脂肪性肝炎(NASH)又はグルコース不耐性)を治療又は予防する方法であって、前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップを含む、前記方法。 - 対象が、比較的低い血清中レプチンレベルを有する過体重又は肥満の対象である、請求項3〜5のいずれかに記載の方法。
- 対象に、MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤を、レプチン及び/又はレプチンアゴニストを含む第2の薬剤と同時に投与する、請求項1〜7のいずれかに記載の方法。
- MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤と、レプチン及び/又はレプチンアゴニストを含む第2の薬剤とを組み合わせて単一の医薬組成物として投与する、請求項8に記載の方法。
- 第1の薬剤が、組換えMIC−1又は合成MIC−1を含む、請求項1〜9のいずれかに記載の方法。
- 第1の薬剤が、活性なMIC−1断片を含む、請求項1〜9のいずれかに記載の方法。
- 第2の薬剤が、組換えレプチン又は合成レプチンを含む、請求項1〜11のいずれかに記載の方法。
- 第2の薬剤が、活性なレプチン断片を含む、請求項1〜11のいずれかに記載の方法。
- (i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を含む医薬組成物。 - 対象において体重及び/又は食欲を制御する方法であって、
前記対象が低い、正常な、又は高い血清中レプチンレベルを有するかどうかを決定するステップと、
低い又は正常な血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤、並びに
(ii)レプチン及び/又はレプチンアゴニストを含む第2の薬剤
を投与するステップ、又は
高い血清中レプチンレベルを有すると決定された前記対象に、有効量の
(i)MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤を投与するステップ
とを含む、前記方法。 - 第1及び第2の容器を含むキットであって、前記第1の容器が、MIC−1、MIC−1アゴニスト及び/又はMIC−1誘導剤を含む第1の薬剤を含有し、前記第2の容器が、レプチン及び/又はレプチンアゴニストを含む第2の薬剤を含有し、請求項1〜13及び15のいずれかに記載の方法において前記キットを使用するための指示書と共に包装されていてもよい、前記キット。
- 対象において体重及び/又は食欲を増加させる方法であって、前記対象に、有効量の
(iii)MIC−1阻害剤、及び
(iv)レプチン阻害剤
を投与するステップを含む、前記方法。 - 体重及び/又は食欲の増加を達成するために行う、請求項17に記載の方法。
- 対象が食欲不振又は悪液質に罹患している、請求項17又は18に記載の方法。
- 対象が、進行がんに罹患している悪液質の対象である、請求項17又は18に記載の方法。
- MIC−1阻害剤がアンタゴニスト抗MIC−1抗体又はそのMIC−1結合断片を含む、請求項17〜20のいずれかに記載の方法。
- レプチン阻害剤がアンタゴニスト抗レプチン抗体又はそのレプチン結合断片を含む、請求項17〜20のいずれかに記載の方法。
- (i)MIC−1阻害剤、及び
(ii)レプチン阻害剤
を含む医薬組成物。 - 第1及び第2の容器を含むキットであって、前記第1の容器がMIC−1阻害剤を含有し、前記第2の容器がレプチン阻害剤を含有し、請求項17〜22のいずれかに記載の方法において前記キットを使用するための指示書と共に包装されていてもよい、前記キット。
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EP0833912B1 (en) | 1995-06-22 | 2009-02-25 | St Vincent's Hospital Sydney Limited | Novel tgf-beta like cytokine |
ATE368471T1 (de) * | 1996-06-04 | 2007-08-15 | Scripps Research Inst | Diagnostische und therapeutische verfahren in zusammenhang mit der regulation der energiemobilisation durch ob-protein und ob- antikörper |
AU2008310310A1 (en) * | 2007-10-09 | 2009-04-16 | St Vincent's Hospital Sydney Limited | A method of treating cachexia with the removal or inactivation of macrophage inhibitory cytokine-1 |
US8470772B2 (en) | 2008-02-27 | 2013-06-25 | Temple University—Of the Commonwealth System of Higher Education | Leptin agonist and methods of use |
WO2011057331A1 (en) * | 2009-11-11 | 2011-05-19 | Monash University | A method for treating obesity |
MX343729B (es) * | 2011-04-08 | 2016-11-18 | Amgen Inc | Factor de diferenciación de crecimiento 15 (gdf-15) y composiciones del mismo para usarse en el tratamiento o mejoramiento de trastornos metabólicos. |
EP3683228A3 (en) | 2012-01-26 | 2020-07-29 | Amgen Inc. | Growth differentiation factor 15 (gdf-15) polypeptides |
KR102208861B1 (ko) * | 2012-12-21 | 2021-01-27 | 아베오 파마슈티컬즈, 인크. | 항-gdf15 항체 |
PL3122775T3 (pl) * | 2014-03-26 | 2020-05-18 | Julius-Maximilians-Universität Würzburg | Przeciwciała monoklonalne przeciwko czynnikowi wzrostu i różnicowania 15 (gdf-15) oraz ich zastosowanie do leczenia kacheksji nowotworowej i nowotworu |
EP3157947A1 (en) * | 2014-06-23 | 2017-04-26 | Novartis AG | Hsa-gdf-15 fusion polypeptide and use thereof |
RU2017101436A (ru) | 2014-06-24 | 2018-07-24 | Ново Нордиск А/С | Mic-1 слитные белки и их применение |
US20170306008A1 (en) * | 2014-09-25 | 2017-10-26 | Aveo Pharmaceuticals, Inc. | Methods of reversing cachexia and prolonging survival comprising administering a gdf15 modulator and an anti-cancer agent |
EP3701969A1 (en) * | 2014-10-31 | 2020-09-02 | NGM Biopharmaceuticals, Inc. | Compositions and methods of use for treating metabolic disorders |
WO2017121865A1 (en) | 2016-01-15 | 2017-07-20 | Novo Nordisk A/S | Mic-1 receptor and uses thereof |
CA3025251A1 (en) | 2016-05-24 | 2017-11-30 | Novo Nordisk A/S | Mic-1 compounds and uses thereof |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007532586A (ja) * | 2004-04-13 | 2007-11-15 | セントビンセンツ ホスピタル シドニー リミテッド | 食欲を調節する方法 |
JP2010536717A (ja) * | 2007-08-16 | 2010-12-02 | セントビンセンツ ホスピタル シドニー リミテッド | マクロファージ阻害性サイトカイン(mic−1)活性を調節するための作用物質及び方法 |
JP2013524807A (ja) * | 2010-04-22 | 2013-06-20 | イッサム リサーチ ディベロプメント カンパニー オブ ザ ヘブリュー ユニバーシティ オブ エルサレム リミテッド | 高親和性レプチン及びレプチンアンタゴニスト |
Non-Patent Citations (1)
Title |
---|
OBESITY, vol. 24, no. 7, JPN6021048084, 25 May 2016 (2016-05-25), pages 1454 - 1463, ISSN: 0004731509 * |
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EP3551214B1 (en) | 2024-03-13 |
CN110072541B (zh) | 2023-05-02 |
AU2017371382A1 (en) | 2019-06-13 |
US20200069774A1 (en) | 2020-03-05 |
CN110072541A (zh) | 2019-07-30 |
EP3551214A1 (en) | 2019-10-16 |
EP3551214A4 (en) | 2020-07-01 |
JP7134960B2 (ja) | 2022-09-12 |
CA3045700A1 (en) | 2018-06-14 |
WO2018102854A1 (en) | 2018-06-14 |
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