JPWO2020097321A5 - - Google Patents
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- JPWO2020097321A5 JPWO2020097321A5 JP2021524369A JP2021524369A JPWO2020097321A5 JP WO2020097321 A5 JPWO2020097321 A5 JP WO2020097321A5 JP 2021524369 A JP2021524369 A JP 2021524369A JP 2021524369 A JP2021524369 A JP 2021524369A JP WO2020097321 A5 JPWO2020097321 A5 JP WO2020097321A5
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- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 32
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 32
- 208000007465 Giant Cell Arteritis Diseases 0.000 claims description 24
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- 102000016355 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Human genes 0.000 claims description 4
- 108010092372 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Proteins 0.000 claims description 4
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- 102100019516 JAK2 Human genes 0.000 claims description 2
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- 210000001847 Jaw Anatomy 0.000 claims description 2
- 210000002540 Macrophages Anatomy 0.000 claims description 2
- 229950007708 Namilumab Drugs 0.000 claims description 2
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 2
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- 229960004618 prednisone Drugs 0.000 claims description 2
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Description
上記の全ての実施形態は、本発明の全ての態様に適用可能であることは、理解されるべきである。
特定の実施形態では、例えば、以下が提供される：
（項目１）
巨細胞性動脈炎（ＧＣＡ）を治療する方法であって、治療を必要とする対象に、顆粒球－マクロファージコロニー刺激因子（ＧＭ－ＣＳＦ）拮抗薬を含む組成物を投与することを含む、方法。
（項目２）
前記ＧＭ－ＣＳＦ拮抗薬が、ＧＭ－ＣＳＦ受容体拮抗薬である、項目１に記載の方法。
（項目３）
前記ＧＭ－ＣＳＦ受容体拮抗薬が、ヒトＧＭ－ＣＳＦＲαに特異的な抗体である、項目２に記載の方法。
（項目４）
前記抗ＧＭ－ＣＳＦＲα抗体が、マブリリムマブである、項目３に記載の方法。
（項目５）
前記ＧＭ－ＣＳＦ拮抗薬が、ＧＭ－ＣＳＦに特異的な抗体である、項目１に記載の方法。
（項目６）
前記抗ＧＭ－ＣＳＦ抗体が、ナミルマブ、オチリマブ、ギムシルマブ、レンジルマブ、またはＴＪＭ－２である、項目５に記載の方法。
（項目７）
前記対象が、５０～８５歳である、項目１～６のいずれか一項に記載の方法。
（項目８）
前記巨細胞性動脈炎が、新規発症の疾患である、項目１に記載の方法。
（項目９）
前記巨細胞性動脈炎が、再発性疾患である、項目１に記載の方法。
（項目１０）
前記巨細胞性動脈炎が、難治性疾患である、項目１に記載の方法。
（項目１１）
コルチコステロイドを、それを必要とする対象に併用投与することをさらに含む、項目１～１０のいずれかに記載の方法。
（項目１２）
前記併用投与されたコルチコステロイドの用量が、前記ＧＭ－ＣＳＦ拮抗薬を用いた前記治療の過程にわたって減らされる、項目１～１１のいずれかに記載の方法。
（項目１３）
前記治療が、ＧＣＡに関連する前記疾患症状の少なくとも一つの予防、低減または改善をもたらす、項目１に記載の方法。
（項目１４）
前記治療が、ＧＣＡに関連する症状の排除をもたらす、項目１３に記載の方法。
（項目１５）
前記治療が、動脈炎症を低減し、および／またはＧＣＡ病変に関連する遺伝子の発現を低減する、項目１３または１４に記載の方法。
（項目１６）
ＧＣＡ病変に関連する遺伝子の前記発現の低減は、ＧＭ－ＣＳＦ、ＧＭ－ＣＳＦＲα、ＪＡＫ２、ＩＬ－６、ＣＤ８３、ＰＵ．１、ＨＬＡ－ＤＲＡ、ＣＤ３Ｅ、ＴＮＦα、ＩＬ－１β、またはそれらの組み合わせから選択されるタンパク質および／またはメッセンジャーＲＮＡ（ｍＲＮＡ）の発現の低減をもたらす、項目１５に記載の方法。
（項目１７）
前記治療が、浸潤したマクロファージの低減もしくは除去、血管外膜におけるＴ細胞の低減、側頭動脈の栄養血管におけるＧＭ－ＣＳＦＲα発現の低減、炎症性浸潤の密度の低減、および／または血管壁リモデリングの低減もしくは安定化をもたらす、項目１３～１６のいずれか一項に記載の方法。
（項目１８）
前記治療が、前記動脈壁におけるＧＭ－ＣＳＦまたはＩＮＦ－γ陽性の細胞の低減をもたらす、項目１３～１７のいずれか一項に記載の方法。
（項目１９）
前記治療が、ＧＣＡを有さない対象に匹敵する遺伝子発現レベルに戻す、項目１３～１８のいずれか一項に記載の方法。
（項目２０）
前記治療が、インターフェロンシグナル伝達、ＩＬ－６シグナル伝達、および／またはＧＭ－ＣＳＦシグナル伝達に関連する遺伝子の遺伝子発現レベルを元に戻す、項目１９に記載の方法。
（項目２１）
前記治療が、ＩＮＦ－γ、ＩＮＦ－αＲ１、ＩＮＦ－γＲ１、ＩＮＦ－γＲ２、ＩＦＩ３０、ＩＦＩ３５、ＰＲＫＣＤ、Ｂ２Ｍ、ＩＦＮＡＲ１、ＣＩＩＴＡ、ＰＴＰＮ２、ＰＴＰＮ１１、ＩＲＦ１、ＩＦＲ５、ＩＲＦ８、ＧＢＰ１、ＧＢＰ５、ＳＴＡＴ１、ＳＴＡＴ２、ＦＣγＲ１Ａ／Ｂ、ＩＣＡＭ１、ＶＣＡＭ１、ＴＹＫ２、ＣＤ４４、ＩＰ６Ｋ２、ＤＤＸ５８、ＰＴＰＮ６、またはそれらの組み合わせから選択されるインターフェロンシグナル伝達に関連する遺伝子の遺伝子発現レベルを元に戻す、項目２０に記載の方法。
（項目２２）
前記治療が、ＰＴＰＮ１１、ＴＹＫ２、ＳＴＡＴ１、ＩＬ－１１ＲＡ 、ＩＬ－６、またはそれらの組み合わせから選択されるＩＬ－６シグナル伝達に関連する遺伝子の遺伝子発現レベルを元に戻す、項目２０に記載の方法。
（項目２３）
前記治療が、ＩＬ－２ＲＢ、ＩＬ－２ＲＧ、ＧＭ－ＣＳＦＲα、ＪＡＫ３、ＳＴＡＴ５Ａ、ＳＹＫ、ＰＴＰＮ１１、ＨＣＫ、ＦＹＮ、ＩＮＰＰ５Ｄ、ＢＬＮＫ、ＰＴＰＮ６、またはそれらの組み合わせから選択されるＧＭ－ＣＳＦシグナル伝達に関連する遺伝子の遺伝子発現レベルを元に戻す、項目２０に記載の方法。
（項目２４）
巨細胞性動脈炎に関連する前記疾患症状の前記少なくとも一つが、発熱、疲労、体重減少、頭痛、側頭の圧痛、および顎の不規則運動；一過性単眼視力喪失（ＴＭＶＬ）および前部虚血性視神経症（ＡＩＯＮ）、大動脈瘤および脈管炎を含む、項目１～２３のいずれかに記載の方法。
（項目２５）
前記対象が、前記組成物の投与前に血清炎症マーカーＣＲＰ≧１ｍｇ／ｄＬを有する、項目１に記載の方法。
（項目２６）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物が、１５０ｍｇの用量で投与される、項目１に記載の方法。
（項目２７）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物が、２週間に１回投与される、項目１に記載の方法。
（項目２８）
マブリリムマブが、静脈内投与または皮下投与によって投与される、項目４に記載の方法。
（項目２９）
前記対象が、追加の治療剤と併用投与される、項目１～２８のいずれか一項に記載の方法。
（項目３０）
前記追加の治療剤が、コルチコステロイドである、項目２９に記載の方法。
（項目３１）
前記コルチコステロイドがプレドニゾンである、項目３０に記載の方法。
（項目３２）
前記追加の治療剤が、２６週間にわたって減らされる、併用投与されるコルチコステロイドである、項目１１または１２に記載の方法。
（項目３３）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物の投与が、血清炎症マーカーＣＲＰを＜１ｍｇ／ｄＬに低減する、項目１～３２のいずれか一項に記載の方法。
（項目３４）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物の投与が、ＥＳＲ≦３０ｍｍ／時に低減する、項目１～３３のいずれか一項に記載の方法。
（項目３５）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物の投与が、ＧＣＡに関連する症状の持続的寛解をもたらす、項目１～３４のいずれか一項に記載の方法。
（項目３６）
前記寛解が、併用投与されるコルチコステロイドの低減と共に持続する、項目３５に記載の方法。
（項目３７）
前記持続的寛解が、実質的にコルチコステロイドを含まない、項目３６に記載の方法。
（項目３８）
前記持続的寛解が、コルチコステロイドを含まない、項目３７に記載の方法。
（項目３９）
ＧＭ－ＣＳＦ拮抗薬を含む前記組成物の投与が、２６週間の持続的寛解を達成している患者をもたらす、項目１～３８のいずれか一項に記載の方法。
（項目４０）
前記抗ＧＭ－ＣＳＦＲα抗体が、配列番号６によって定義される軽鎖相補性決定領域１（ＬＣＤＲ１）、配列番号７によって定義される軽鎖相補性決定領域２（ＬＣＤＲ２）、および配列番号８によって定義される軽鎖相補性決定領域３（ＬＣＤＲ３）、ならびに配列番号３によって定義される重鎖相補性決定領域１（ＨＣＤＲ１）、配列番号４によって定義される重鎖相補性決定領域２（ＨＣＤＲ２）、および配列番号５によって定義される重鎖相補性決定領域３（ＨＣＤＲ３）を含む、項目３に記載の方法。
It should be understood that all embodiments described above are applicable to all aspects of the invention.
In certain embodiments, for example, the following are provided:
(Item 1)
A method of treating giant cell arteritis (GCA) comprising administering to a subject in need thereof a composition comprising a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist. .
(Item 2)
The method of item 1, wherein the GM-CSF antagonist is a GM-CSF receptor antagonist.
(Item 3)
3. The method of item 2, wherein the GM-CSF receptor antagonist is an antibody specific to human GM-CSFRα.
(Item 4)
4. The method of item 3, wherein the anti-GM-CSFRα antibody is mavrilimumab.
(Item 5)
2. The method of item 1, wherein the GM-CSF antagonist is an antibody specific for GM-CSF.
(Item 6)
6. The method of item 5, wherein the anti-GM-CSF antibody is namilumab, otilimab, gimucirumab, lendolumab, or TJM-2.
(Item 7)
7. The method of any one of items 1-6, wherein the subject is 50-85 years old.
(Item 8)
2. The method of item 1, wherein said giant cell arteritis is a new-onset disease.
(Item 9)
The method of item 1, wherein said giant cell arteritis is a recurrent disease.
(Item 10)
2. The method of item 1, wherein the giant cell arteritis is an intractable disease.
(Item 11)
11. The method of any of items 1-10, further comprising co-administering a corticosteroid to the subject in need thereof.
(Item 12)
12. The method of any of items 1-11, wherein the dose of said co-administered corticosteroid is reduced over the course of said treatment with said GM-CSF antagonist.
(Item 13)
2. The method of item 1, wherein said treatment results in prevention, reduction or amelioration of at least one of said disease symptoms associated with GCA.
(Item 14)
14. The method of item 13, wherein said treatment results in elimination of symptoms associated with GCA.
(Item 15)
15. The method of items 13 or 14, wherein said treatment reduces arterial inflammation and/or reduces expression of genes associated with GCA lesions.
(Item 16)
The reduction in said expression of genes associated with GCA lesions is GM-CSF, GM-CSFRα, JAK2, IL-6, CD83, PU. 16. A method according to item 15, which results in reduced expression of a protein and/or messenger RNA (mRNA) selected from 1, HLA-DRA, CD3E, TNFα, IL-1β, or combinations thereof.
(Item 17)
said treatment reduces or eliminates infiltrated macrophages, reduces T cells in the adventitia, reduces GM-CSFRα expression in feeding vessels of the temporal artery, reduces density of inflammatory infiltrates, and/or vessel wall remodeling 17. The method of any one of items 13-16, which results in a reduction or stabilization of the
(Item 18)
18. The method of any one of items 13-17, wherein said treatment results in a reduction of GM-CSF or INF-γ positive cells in said artery wall.
(Item 19)
19. The method of any one of items 13-18, wherein said treatment restores gene expression levels comparable to subjects without GCA.
(Item 20)
20. The method of item 19, wherein said treatment restores gene expression levels of genes associated with interferon signaling, IL-6 signaling and/or GM-CSF signaling.
(Item 21)
wherein said treatment is INF-γ, INF-αR1, INF-γR1, INF-γR2, IFI30, IFI35, PRKCD, B2M, IFNAR1, CIITA, PTPN2, PTPN11, IRF1, IFR5, IRF8, GBP1, GBP5, STAT1, STAT2, 21. The method of item 20, wherein the gene expression level of a gene associated with interferon signaling selected from FCγR1A/B, ICAM1, VCAM1, TYK2, CD44, IP6K2, DDX58, PTPN6, or combinations thereof.
(Item 22)
21. The method of item 20, wherein said treatment restores gene expression levels of genes associated with IL-6 signaling selected from PTPN11, TYK2, STAT1, IL-11RA, IL-6, or combinations thereof. .
(Item 23)
said treatment is associated with GM-CSF signaling selected from IL-2RB, IL-2RG, GM-CSFRα, JAK3, STAT5A, SYK, PTPN11, HCK, FYN, INPP5D, BLNK, PTPN6, or combinations thereof 21. The method of item 20, wherein the gene expression level of the gene is restored.
(Item 24)
said at least one of said disease symptoms associated with giant cell arteritis is fever, fatigue, weight loss, headache, temporal tenderness, and irregular jaw movements; transient monocular vision loss (TMVL) and anterior 24. The method of any of items 1-23, including ischemic optic neuropathy (AION), aortic aneurysm and vasculitis.
(Item 25)
The method of item 1, wherein the subject has a serum inflammatory marker CRP > 1 mg/dL prior to administration of the composition.
(Item 26)
The method of item 1, wherein said composition comprising a GM-CSF antagonist is administered at a dose of 150 mg.
(Item 27)
The method of item 1, wherein said composition comprising a GM-CSF antagonist is administered once every two weeks.
(Item 28)
5. The method of item 4, wherein mavrilimumab is administered intravenously or subcutaneously.
(Item 29)
29. The method of any one of items 1-28, wherein said subject is co-administered with an additional therapeutic agent.
(Item 30)
30. The method of item 29, wherein said additional therapeutic agent is a corticosteroid.
(Item 31)
31. The method of item 30, wherein said corticosteroid is prednisone.
(Item 32)
13. The method of item 11 or 12, wherein said additional therapeutic agent is a co-administered corticosteroid tapered over 26 weeks.
(Item 33)
33. The method of any one of items 1-32, wherein administration of said composition comprising a GM-CSF antagonist reduces the serum inflammatory marker CRP to <1 mg/dL.
(Item 34)
34. The method of any one of items 1-33, wherein administration of said composition comprising a GM-CSF antagonist reduces ESR≦30 mm/h.
(Item 35)
35. The method of any one of items 1-34, wherein administration of said composition comprising a GM-CSF antagonist results in sustained remission of symptoms associated with GCA.
(Item 36)
36. The method of item 35, wherein said remission is sustained with reduction in co-administered corticosteroids.
(Item 37)
37. The method of item 36, wherein said sustained remission is substantially free of corticosteroids.
(Item 38)
38. The method of item 37, wherein said sustained remission does not include corticosteroids.
(Item 39)
39. The method of any one of items 1-38, wherein administration of said composition comprising a GM-CSF antagonist results in the patient achieving sustained remission for 26 weeks.
(Item 40)
wherein said anti-GM-CSFRα antibody is defined by light chain complementarity determining region 1 (LCDR1) defined by SEQ ID NO:6, light chain complementarity determining region 2 (LCDR2) defined by SEQ ID NO:7, and SEQ ID NO:8 and heavy chain complementarity determining region 1 (HCDR1) defined by SEQ ID NO: 3, heavy chain complementarity determining region 2 (HCDR2) defined by SEQ ID NO: 4, and heavy chain complementarity determining region 3 (HCDR3) defined by SEQ ID NO:5.
Claims (40)
Applications Claiming Priority (11)
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| US201862758127P | 2018-11-09 | 2018-11-09 | |
| US62/758,127 | 2018-11-09 | ||
| US201862782194P | 2018-12-19 | 2018-12-19 | |
| US62/782,194 | 2018-12-19 | ||
| US201962797813P | 2019-01-28 | 2019-01-28 | |
| US62/797,813 | 2019-01-28 | ||
| PCT/US2019/044231 WO2020096664A1 (en) | 2018-11-09 | 2019-07-30 | Treatment for giant cell arteritis |
| USPCT/US2019/044231 | 2019-07-30 | ||
| US201962883378P | 2019-08-06 | 2019-08-06 | |
| US62/883,378 | 2019-08-06 | ||
| PCT/US2019/060255 WO2020097321A1 (en) | 2018-11-09 | 2019-11-07 | Treatment for giant cell arteritis |
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| JP2022512943A JP2022512943A (en) | 2022-02-07 |
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| JP (1) | JP2022512943A (en) |
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| AU2006249062B2 (en) | 2005-05-18 | 2012-12-20 | Morphosys Ag | Anti-GM-CSF antibodies and uses therefor |
| JP4943044B2 (en) | 2005-07-20 | 2012-05-30 | リンテック株式会社 | Adhesive sheet |
| SI1999152T1 (en) * | 2006-03-27 | 2013-02-28 | Medimmune Limited | Binding member for gm-csf receptor |
| CN102459340A (en) * | 2009-04-23 | 2012-05-16 | 特罗科隆科学有限公司 | Granulocyte-macrophage colony-stimulating factor (gm-csf) neutralizing antibodies |
| EP2729498A1 (en) * | 2011-07-06 | 2014-05-14 | MorphoSys AG | Therapeutic combinations of anti -cd20 and anti - gm - csf antibodies and uses thereof |
| JP6239517B2 (en) | 2011-10-10 | 2017-11-29 | メディミューン リミテッド | Treatment of rheumatoid arthritis |
| JP2017515828A (en) | 2014-05-19 | 2017-06-15 | メディミューン リミテッド | Treatment for rheumatoid arthritis |
| CA2977321A1 (en) * | 2015-04-29 | 2016-11-03 | Institute For Research In Biomedicine | Ultra-potent neutralization of cytokines by multispecific antibodies and uses thereof |
| GB201519331D0 (en) | 2015-11-02 | 2015-12-16 | Glaxosmithkline Ip Dev Ltd | Treatment paradigm |
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