JP4502580B2 - 敗血症の治療または予防のためのil−18阻害剤の使用 - Google Patents
敗血症の治療または予防のためのil−18阻害剤の使用 Download PDFInfo
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Description
同義のアミノ酸の好ましい群
アミノ酸 同義の群
Ser Ser、Thr、Gly、Asn
Arg Arg、Gln、Lys、Glu、His
Leu Ile、Phe、Tyr、Met、Val、Leu
Pro Gly、Ala、Thr、Pro
Thr Pro、Ser、Ala、Gly、His、Gln、Thr
Ala Gly、Thr、Pro、Ala
Val Met、Tyr、Phe、Ile、Leu、Val
Gly Ala、Thr、Pro、Ser、Gly
Ile Met、Tyr、Phe、Val、Leu、Ile
Phe Trp、Met、Tyr、Ile、Val、Leu、Phe
Tyr Trp、Met、Phe、Ile、Val、Leu、Tyr
Cys Ser、Thr、Cys
His Glu、Lys、Gln、Thr、Arg、His
Gln Glu、Lys、Asn、His、Thr、Arg、Gln
Asn Gln、Asp、Ser、Asn
Lys Glu、Gln、His、Arg、Lys
Asp Glu、Asn、Asp
Glu Asp、Lys、Asn、Gln、His、Arg、Glu
Met Phe、Ile、Val、Leu、Met
Trp Trp
同義のアミノ酸のより好ましい群
アミノ酸 同義の群
Ser Ser
Arg His、Lys、Arg
Leu Leu、Ile、Phe、Met
Pro Ala、Pro
Thr Thr
Ala Pro、Ala
Val Val、Met、Ile
Gly Gly
Ile Ile、Met、Phe、Val、Leu
Phe Met、Tyr、Ile、Leu、Phe
Tyr Phe、Tyr
Cys Cys、Ser
His His、Gln、Arg
Gln Glu、Gln、His
Asn Asp、Asn
Lys Lys、Arg
Asp Asp、Asn
Glu Glu、Gln
Met Met、Phe、Ile、Val、Leu
Trp Trp
同義のアミノ酸の最も好ましい群
アミノ酸 同義の群
Ser Ser
Arg Arg
Leu Leu、Ile、Met
Pro Pro
Thr Thr
Ala Ala
Val Val
Gly Gly
Ile Ile、Met、Leu
Phe Phe
Tyr Tyr
Cys Cys、Ser
His His
Gln Gln
Asn Asn
Lys Lys
Asp Asp
Glu Glu
Met Met、Ile、Leu
Trp Met
健常な個体および疾患の個体における特定の循環サイトカインおよびそれらの天然の阻害剤の測定は、疾患の進行および重篤性に対するそれらの関与に関する情報を提供する。背景の節で述べたように、敗血症の主要な媒介物質の1つがIFN−γである。IL−18はINF−γの共誘導剤であるので、IL−18およびその天然の阻害剤(IL−18BPスプライス改変体a)のレベルを、特異的なELISAを用いることによって、敗血症患者においてモニタし、そして健常な被験者において見出されたレベルと比較した(実施例3)。
107人の健常な供与者におけるIL−18の平均レベルは、ECLアッセイによって測定されたように64±17pg/mlであった(Pomerantz et al. 2001)。関連タンパク質による干渉について、ECLアッセイで試験した。proIL−18は交差反応したが、成熟IL−1βまたはproIL−1βの存在によっては影響されなかったことが見出された。したがって、本研究におけるヒト血清試料において検出された成熟IL−18の20%という高い値は、proIL−18であり得る。IL−18のECLアッセイは、160ng/ml以下の濃度のIL−18BPaによって影響されなかった。
Kd=[LR]/[L遊離][R遊離]
L遊離=L全−LR
R遊離=R全−LR
L全=64+17pg/ml(平均レベル)、R全=2.15±0.15ng/ml(平均)およびKd=0.4nMを代入することによって、健常な被験者においては、約51.2pg/mlのIL−18(全ての約80%)が、遊離形態であったことを見出した。
IL−18のレベルおよびIL−18BPaのレベルを、入院(admission)の際直ちに、および入院(hospitalisation)中に採取した42人の敗血症患者由来の192の血清試料において試験した。IL−18およびIL−18BPaの両方のレベルは、健常な被験者と比較すると、敗血症患者において顕著に上昇し(図2A)、そして値の広い分布が観察された(図2B)。さらに、これらのレベルは、入院日における、これらの患者においては均一に高く、健常な個体と比較して、IL−18のレベルは、22倍の上昇を示し(1.5±0.4ng/ml対0.064±0.17ng/ml)、そしてIL−18BPaのレベルは、13倍の上昇を示した(28.6±4.5対2.15±0.15ng/ml、図2A)。これらの血清におけるクレアチニンレベルとIL−18またはIL−18BPaのいずれかの濃度との間に、統計的に有意な相関性は観察され得なかった(APACHE IIスコアによって評価、Knaus et al. 1993)。このことは、これらの患者におけるIL−18レベルおよびIL−18BPaレベルの向上が、腎臓疾患のためではなかったことを示唆する。
背景の節において記載したように、グラム陽性細菌Staphylococcus epidermidisが敗血症の原因であることは公知である。サイトカイン(たとえば、IL−1、IFN−γおよびTNF−α)の誘導は、この病因の重要な媒介物質である。IL−18は、IFN−γの共誘導剤であるので、Staphylococcus epidermidis IFN−γ誘導に対するその阻害の効果を試験した。IL−18阻害剤として使用されるIL−18BPaは、CHO細胞において産生された組換えヒスチジンタグ種(version)であった。
ELISAは、以下の2つの抗IL−18BPa抗体:マウスMab 582.10(実施例4に記載されるMab 582のサブクローン(捕獲抗体))およびウサギポリクローナル抗体(検出用)からなる(実施例4)。マイクロタイター96ウェルELISAプレート(Maxisorb;Nunc A/S,Roskilde,Denmark)を、抗IL−18BPa MAb No.582.10(PBS中MAb 582のサブクローン4μg/ml)で、4℃で一晩被覆した。このプレートを、0.05%Tween20を含むPBS(洗浄溶液)で洗浄し、そして水で1:10に希釈したBSAストック溶液(KPL,Geithersburg,MD)でブロック(2時間、37℃)した。BSAストック溶液を、全ての試験試料および検出抗体の希釈のために水(希釈液)で1:15に希釈した。血清試料を、水で少なくとも1:5に希釈し、そして、100μlアリコートをウェルに添加した。高純度のrIL−18BPa(CHOにおいて産生され、実施例4、表1に示されるIL−18BPに特異的なプロテインG精製したMab N430を用いて免疫アフィニティにより精製した)を、7連続2倍希釈液によって希釈し(4〜0.062ng/ml)、そして標準曲線を作成するために各ELISAプレートに添加した。このプレートを、37℃で2時間インキュベートし、そして洗浄溶液で3回洗浄した。ウサギ抗IL−18BPa血清(1:5000希釈、100μl/ウェル)を添加し、そしてそのプレートをさらに37℃で2時間インキュベートした。そのプレートを3回洗浄し、ヤギ抗ウサギ西洋ワサビペルオキシダーゼの結合体(HRP,Jackson ImmunoResearch Labs,PBS中1:10,000、100pl/ウェル)を添加し、そしてそのプレートを37℃で1時間インキュベートした。このプレートを3回洗浄し、そして、OPDペルオキシダーゼ基質(o−フェニレンジアミンジヒドロクロライド錠剤、Sigma)の添加により室温で30分間発光させた。この反応を3N HCl(100μl)により停止し、そして492nmの吸収をELISAリーダーにより測定した。ODを、IL−18BPa濃度の関数としてプロットし、そして直線性が、0.12〜2.00ng/ml IL−18BPaの範囲で観察された(図6)。
ポリクローナル抗体を産生させるために、rIL−18BPa−His6を、ウサギに注射した。
MAb番号 IRIA1 sRIA2
(cpm) (cpm)
148 23912 7941
297 1652 6483
369 316 12762
430 6887 3254
433 1009 15300
460 3199 4326
485 400 13010
582 15000 17897
601 1046 1928
1ヤギ抗マウス抗体で被覆されたプレートおよび125I IL−18BPa
で検出されたハイブリドーマ
2尿IL−18BPで被覆されたプレートおよび125Iヤギ抗マウス抗体で
検出されたハイブリドーマ
逆放射免疫アッセイ(IRIA)
PVCマイクロタイタープレート(Dynatech Laboratories,Alexandria.VA)を、アフィニティ精製したヤギ抗マウスF(ab)2抗体(10μg/ml、100μl/ウェル;Jackson ImmunoResearch Labs)で、4℃で一晩、被覆した。ついで、このプレートを、0.05% Tween20を含むPBS(洗浄溶液)で2回洗浄し、そしてBSA(洗浄溶液中0.5%)で、37℃で2時間ブロックした。ハイブリドーマ培養上清(100μl/ウェル)を添加し、そしてこのプレートを、室温で2時間インキュベートした。このプレートを3回洗浄し、125I−rIL−18BPa−His6(100μl中105cpm)を各ウェルに添加し、そしてこのプレートを、22℃で5時間インキュベートした。ついで、このプレートを3回洗浄し、そして各ウェルをガンマカウンタにおいてカウントした。陰性対照よりも少なくとも5倍高い結合放射活性を示したハイブリドーマ産生上清を、陽性とした。
rIL−18BPa(5μg/ml)を捕獲抗原として使用し、そして125I−ヤギ抗マウス抗体(100μl、105cpm)を検出のために使用した。ブロッキングおよび洗浄を前記のように行った。陽性クローンをさらに、濃縮ヒト尿から単離したIL−18BPを認識する能力についてsRIAによってスクリーニングした(Novick et al. 1999)。マイクロタイタープレートを、リガンドアフィニティ精製尿IL−18BP(1μg/ml)で被覆し、前記のとおりブロックおよび洗浄をした。ハイブリドーマ上清(100μl)を添加し、そして検出を、125I−ヤギ抗マウス抗体(100μl中105cpm)で行った。
マイクロタイタープレートを、尿IL−18BP(0.5μg/ml)またはrIL−18BPa(5μg/ml)のいずれかで被覆し、sRIAにおけるようにブロックおよび洗浄した。組換えヒトIL−18(50μl)を、最終濃度1.5μg/mlまで添加し(室温で15分)、その後、ハイブリドーマ上清(50μl)を添加した。検出を、125I−ヤギ抗マウス抗体(100μl中105cpm、室温で2時間)で行った。
TNFαおよびIL−1βは、敗血症中の心機能不全に関係している。IL−18は、TNFαおよびIL−1βの産生を媒介することが公知である前炎症性サイトカインであるので、LPS誘導心機能不全におけるIL−18の濃度を試験した。
前記実施例におけるIL−18含量の上昇は、LPSによって誘導された心機能不全において見出された。したがって、LPS誘導心筋機能不全に対するIL−18の中和の効果を評価した。
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Claims (9)
- IL−18阻害剤を含む敗血症関連心機能不全の治療および/または予防剤であって、該阻害剤がIL−18に対する抗体およびIL−18BPaまたはIL−18BPcであるIL−18結合タンパク質から選択される治療および/または予防剤。
- 前記IL−18結合タンパク質が、PEG結合されている請求項1記載の治療および/または予防剤。
- 前記IL−18阻害剤が、キメラ抗体、ヒト化抗体およびヒト抗体から選択される抗IL−18特異的抗体である請求項1記載の治療および/または予防剤。
- TNFRIもしくはTNFRIIの可溶性部分またはIL1−Raをさらに含む請求項1、2または3記載の治療および/または予防剤。
- 同時投与、連続投与または個別投与用の請求項4記載の治療および/または予防剤。
- IL−18阻害剤のコード配列を含む発現ベクターを含む敗血症関連心機能不全の治療および/または予防剤であって、該阻害剤がIL−18に対する抗体およびIL−18BPaまたはIL−18BPcであるIL−18結合タンパク質から選択される治療および/または予防剤。
- 遺伝子治療のための請求項6記載の治療および/または予防剤。
- 前記ベクターが、さらにプロモーターまたはエンハンサーである調節配列を含む請求項6記載の治療および/または予防剤。
- IL−18阻害剤を産生するように遺伝的に改変されている細胞を含む敗血症関連心機能不全の治療および/または予防剤であって、該阻害剤がIL−18に対する抗体およびIL−18BPaまたはIL−18BPcであるIL−18結合タンパク質から選択される治療および/または予防剤。
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CN109954131B (zh) * | 2017-12-14 | 2023-05-02 | 深圳市中科艾深医药有限公司 | 一种肿瘤坏死因子相关凋亡诱导配体拮抗剂作为脓毒血症治疗药物的应用 |
CN111012899A (zh) * | 2020-01-08 | 2020-04-17 | 重庆医科大学 | Il-38的新用途 |
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US4847325A (en) * | 1988-01-20 | 1989-07-11 | Cetus Corporation | Conjugation of polymer to colony stimulating factor-1 |
WO1991008231A1 (en) * | 1989-11-29 | 1991-06-13 | Brigham And Women's Hospital | [Ala IL-8]77 AS A LEUKOCYTE ADHESION INHIBITOR |
US5536637A (en) * | 1993-04-07 | 1996-07-16 | Genetics Institute, Inc. | Method of screening for cDNA encoding novel secreted mammalian proteins in yeast |
KR20000049050A (ko) * | 1996-10-11 | 2000-07-25 | 로즈 암스트롱, 크리스틴 에이. 트러트웨인 | 술폰아미드 치환된 아스파르트산 인터루킨-1β 전환 효소 억제제 |
BR9810409A (pt) * | 1997-03-18 | 2000-08-22 | Basf Ag | Métodos e composições para a modulação de responsividade a corticosteróides |
US6054487A (en) * | 1997-03-18 | 2000-04-25 | Basf Aktiengesellschaft | Methods and compositions for modulating responsiveness to corticosteroids |
IL121860A0 (en) * | 1997-08-14 | 1998-02-22 | Yeda Res & Dev | Interleukin-18 binding proteins their preparation and use |
CA2276216A1 (en) * | 1998-06-24 | 1999-12-24 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | An artificial peptide capable of neutralizing the biological activity of interleukin-18 |
TW201305214A (zh) * | 2000-02-10 | 2013-02-01 | Abbott Gmbh & Co Kg | 與人類間白素-18結合之抗體,及其製法及用途 |
KR20020086540A (ko) * | 2000-02-21 | 2002-11-18 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Il-18 저해물질의 용도 |
WO2002032374A2 (en) * | 2000-10-18 | 2002-04-25 | Immunex Corporation | Methods for treating il-18 mediated disorders |
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2002
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ATE451930T1 (de) | 2010-01-15 |
HK1066723A1 (en) | 2005-04-01 |
IL158866A (en) | 2011-01-31 |
MXPA03010575A (es) | 2005-03-07 |
EP1425028A2 (en) | 2004-06-09 |
UA85531C2 (uk) | 2009-02-10 |
WO2002092008A2 (en) | 2002-11-21 |
CN1529611A (zh) | 2004-09-15 |
JP2004531546A (ja) | 2004-10-14 |
EA009125B1 (ru) | 2007-10-26 |
DK1425028T3 (da) | 2010-03-01 |
CA2446942C (en) | 2010-07-20 |
CN100556450C (zh) | 2009-11-04 |
BR0210904A (pt) | 2005-08-16 |
KR20040045400A (ko) | 2004-06-01 |
IL158866A0 (en) | 2004-05-12 |
EP1425028A4 (en) | 2006-03-01 |
SI1425028T1 (sl) | 2010-02-26 |
DE60234778D1 (de) | 2010-01-28 |
US20030008822A1 (en) | 2003-01-09 |
EP1425028B1 (en) | 2009-12-16 |
PT1425028E (pt) | 2010-01-06 |
CY1109713T1 (el) | 2014-08-13 |
KR100877033B1 (ko) | 2009-01-07 |
ES2334773T3 (es) | 2010-03-16 |
WO2002092008A3 (en) | 2004-04-08 |
EA200301248A1 (ru) | 2005-06-30 |
CA2446942A1 (en) | 2002-11-21 |
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