JP5981964B2 - インターロイキン13結合タンパク質 - Google Patents
インターロイキン13結合タンパク質 Download PDFInfo
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- JP5981964B2 JP5981964B2 JP2014146943A JP2014146943A JP5981964B2 JP 5981964 B2 JP5981964 B2 JP 5981964B2 JP 2014146943 A JP2014146943 A JP 2014146943A JP 2014146943 A JP2014146943 A JP 2014146943A JP 5981964 B2 JP5981964 B2 JP 5981964B2
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Description
本願は、2006年9月8日に出願された米国仮特許出願第60/843,249号の優先権の利益を主張するものである。
本願の内容は、Protein Design Labs, Inc.とAbbott Laboratoriesによって、また、両者間で2005年12月14日に締結された共同研究契約に属し、IL−13に対する組換え操作された抗体を対象とする。
本発明は、IL−13結合タンパク質に関する。本発明の結合タンパク質としては、ヒトIL−13に結合可能な抗体、抗原結合性部分、及び他の抗原結合タンパク質が挙げられるが、これらだけに限定されない。さらに、本発明は、IL−13結合タンパク質を製造及び使用する方法を提供する。
X1は、T、D、G又はSであり、
X2はSであり、
X3はDであり、
X4は、M、S、Y、L又はHであり、
X5は、G、W、Y、A、S又はNであり、
X6は、V、I又はMであり、
X7は、D、H、S、Y、N又はGである。)、
CDR−H2. X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−X12−X13−X14−X15−X16−X17(配列番号65)(式中、
X1は、M、E、H、R、S、G又はLであり、
X2は、Iであり、又は存在せず、
X3は、H、Y、A、D、S又はWであり、
X4は、P、S、W又はGであり、
X5は、S、G、E又はDであり、
X6は、D、G、S、E又はNであり、
X7は、S、Y又はGであり、
X8は、E、N、Y、V又はRであり、
X9は、T、I又はKであり、
X10は、R、Y、I、D又はAであり、
X11は、L、Y、D又はFであり、
X12は、N、P、S又はDであり、
X13は、Q、E、D、P又はSであり、
X14は、K、M、S、T、A又はVであり、
X15は、F、L、V又はMであり、
X16は、K、R又はQであり、
X17は、D、G又はSである。)、
CDR−H3. X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−X12−X13−X14(配列番号66)(式中、
X1は、W、T、G、Y、D又はIであり、
X2は、R、A、S、G又はVであり、
X3は、T、F、Y又はSであり、
X4は、S、T又はYであり、
X5は、Y、F又はGであり、
X6は、F又はYであり、
X7は、S、Y、I又はFであり、
X8は、D、L、Y又はPであり、
X9はYであり、
X10はGであり、
X11は、Y、A、P又はEであり、
X12は、F、M、S、L又はIであり、
X13は、D、V、N又はKであり、
X14は、Y又はFである。)、
CDR−L1. X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−X12−X13−X14−X15 X16−X17(配列番号67)(式中、
X1は、K又はRであり、
X2は、S又はAであり、
X3は、S又はTであり、
X4は、Q、K又はIであり、
X5は、N、S、T、G又はEであり、
X6は、L、T又はSであり、
X7は、L、Q又はVであり、
X8は、Y、N、H、D又はTであり、
X9は、S、I又はTであり、
X10は、S、D、N、H又はYであり、
X11は、N又はGであり、
X12はQであり、
X13は、K、F、N、E又はSであり、
X14は、N、T又はSであり、
X15は、Y又はFであり、
X16は、L、A又はMであり、
X17は、A、D、E、H又はNである。)、
CDR−L2. X1−X2−X3−X4−X5−X6−X7(配列番号68)(式中、
X1は、L、S、K、T、W又はYであり、
X2は、V、T又はAであり、
X3は、S又はNであり、
X4は、N、K、T、M又はRであり、
X5は、R、K又はLであり、
X6は、F、D、E、H、P又はAであり、
X7は、S、R又はPである。)、及び
CDR−L3. X1−X2−X3−X4−X5−X6−X7−X8−X9(配列番号69)(式中、
X1は、F、W、Q又はAであり、
X2は、Q又はLであり、
X3は、H、G、Y、W又はNであり、
X4は、N、S、T、L又はYであり、
X5は、Y、T、S、E又はHであり、
X6は、L、V、F、Y、N、G、P又はDであり、
X7は、P又はHであり、
X8は、L、F、Y、W又はRであり、
X9は、T又はVである。)
配列番号32の残基50−66、
配列番号32の残基99−105、
配列番号33の残基24−39、
配列番号33の残基55−61、
配列番号33の残基94−102、
配列番号34の残基31−35、
配列番号34の残基50−66、
配列番号34の残基99−105、
配列番号35の残基24−39、
配列番号35の残基55−61、
配列番号35の残基94−102、
配列番号36の残基31−35、
配列番号36の残基50−66、
配列番号36の残基99−109、
配列番号37の残基24−39、
配列番号37の残基55−61、
配列番号37の残基94−102、
配列番号38の残基31−35、
配列番号38の残基50−66、
配列番号38の残基99−109、
配列番号39の残基31−35、
配列番号39の残基50−66、
配列番号39の残基99−112、
配列番号40の残基24−39、
配列番号40の残基55−61、
配列番号40の残基94−102、
配列番号41の残基31−35、
配列番号41の残基50−66、
配列番号41の残基99−112、
配列番号42の残基31−35、
配列番号42の残基50−66、
配列番号42の残基99−100、
配列番号43の残基24−39、
配列番号43の残基55−61、
配列番号43の残基94−102、
配列番号44の残基31−35、
配列番号44の残基50−65、
配列番号44の残基98−106、
配列番号45の残基24−40、
配列番号45の残基56−62、
配列番号45の残基95−103、
配列番号46の残基31−37、
配列番号46の残基52−67、
配列番号46の残基100−112、
配列番号47の残基24−34、
配列番号47の残基50−56、
配列番号47の残基89−97、
配列番号48の残基31−37、
配列番号48の残基52−67、
配列番号48の残基100−112、
配列番号49の残基24−34、
配列番号49の残基50−56、
配列番号49の残基89−97、
配列番号50の残基31−37、
配列番号50の残基52−67、
配列番号50の残基100−112、
配列番号51の残基24−34、
配列番号51の残基50−56、
配列番号51の残基89−97、
配列番号52の残基31−35、
配列番号52の残基50−66、
配列番号52の残基99−107、
配列番号53の残基23−36、
配列番号53の残基52−58、
配列番号53の残基91−99、
配列番号54の残基31−35、
配列番号54の残基50−65、
配列番号54の残基98−107、
配列番号55の残基24−38、
配列番号55の残基54−60、
配列番号55の残基93−101、
配列番号56の残基31−35、
配列番号56の残基50−65、
配列番号56の残基98−107、
配列番号57の残基24−38、
配列番号57の残基54−60、
配列番号57の残基93−101、
配列番号58の残基31−35、
配列番号58の残基50−65、
配列番号58の残基98−107、
配列番号59の残基24−38、
配列番号59の残基54−60、
配列番号59の残基93−101、
配列番号60の残基31−35、
配列番号60の残基50−65、
配列番号60の残基98−107、
配列番号61の残基24−38、
配列番号61の残基54−60、
配列番号61の残基93−101、
配列番号62の残基31−35、
配列番号62の残基50−65、
配列番号62の残基98−107、
配列番号63の残基24−38、
配列番号63の残基54−60、及び
配列番号63の残基93−101
VH 9C11 CDRセットとVL 9C11 CDRセット、
VH 21D9 CDRセットとVL 21D9 CDRセット、
VH 22D10 CDRセットとVL 22D10 CDRセット、
VH 5F1 CDRセットとVL 5F1 CDRセット、
VH 5G1 CDRセットとVL 5G1 CDRセット、
VH 3H7 CDRセットとVL 3H7 CDRセット、
VH 14B2 CDRセットとVL 14B2 CDRセット、
VH 13C5 CDRセットとVL 13C5 CDRセット、
VH 29G5 CDRセットとVL 29G5 CDRセット、
VH 33C3 CDRセットとVL 33C3 CDRセット、
VH 4A8 CDRセットとVL 4A8 CDRセット、
VH 1B6 CDRセットとVL 1B6 CDRセット、
VH 3E5 CDRセットとVL 3E5 CDRセット、
VH 6C8 CDRセットとVL 6C8 CDRセット、
VH 5D3 CDRセットとVL 5D3 CDRセット、及び
VH 8B6 CDRセットとVL 8B6 CDRセット
配列番号7
配列番号8
配列番号9
配列番号10
配列番号11
配列番号12
配列番号13
配列番号14
配列番号15
配列番号16
配列番号17
配列番号18
配列番号19
配列番号20
配列番号21
配列番号22
配列番号23
配列番号24
配列番号25
配列番号26
配列番号27
配列番号28
配列番号29
配列番号30及び
配列番号31
配列番号71
配列番号72
配列番号73
配列番号74
配列番号75
配列番号76
配列番号77
配列番号78
配列番号79
配列番号80
配列番号81
配列番号82
配列番号83
配列番号84
配列番号85
配列番号92
配列番号93及び
配列番号94
配列番号72と配列番号73、
配列番号74と配列番号75、
配列番号76と配列番号77、
配列番号78と配列番号79、
配列番号80と配列番号81、
配列番号82と配列番号83、
配列番号84と配列番号85
配列番号80と配列番号92、
配列番号80と配列番号93及び
配列番号80と配列番号94
炎、赤芽球ろう、原発性副腎不全、再発性視神経脊髄炎、再狭窄、リウマチ性心疾患、SAPHO(滑膜炎、アクネ、膿ほう症、骨過形成及び骨髄炎)、強皮症、続発性アミロイドーシス、ショック肺、強膜炎、坐骨神経症、続発性副腎不全、シリコーン関連結合組織病、スネドン−ウィルキンソン皮膚疾患、強直性脊椎炎(spondilitis ankylosans)、スティーブンス ジョンソン症候群(SJS)、全身性炎症反応症候群、側頭動脈炎、トキソプラズマ性網膜炎、中毒性表皮壊死症、横断性脊髄炎、TRAPS(腫よう壊死因子受容体、1型アレルギー反応、II型糖尿病、じんま疹、通常型間質性肺炎(UIP)、血管炎、春季カタル、ウイルス性網膜炎、フォークト−小柳−原田症候群(VKH症候群)、しん出型黄斑変性症、並びに創傷治癒からなる群から選択される障害の治療に有用である。
本発明は、IL−13に結合するヒトIL−13結合タンパク質、特に抗IL−13抗体又はその抗原結合性部分に関する。本発明の種々の態様は、抗体及び抗体断片、その薬剤組成物、並びにかかる抗体及び断片を製造するための核酸、組換え発現ベクター及び宿主細胞に関する。本発明の抗体を使用して、ヒトIL−13を検出し、インビトロ又は生体内でヒトIL−13活性を阻害し、また、遺伝子発現を調整する各方法も本発明に包含される。
本発明の一態様は、高親和性、低オフ速度及び高中和能でIL−13に結合する単離ネズミモノクローナル抗体又はその抗原結合性部分を提供する。本発明の第2の態様は、IL−13に結合するキメラ抗体を提供する。本発明の第3の態様は、IL−13に結合するヒト化抗体又はその抗原結合性部分を提供する。好ましくは、抗体又はその一部は単離抗体である。好ましくは、本発明の抗体は、1種類及び/又は複数種類のヒト抗IL−13抗体を中和している。
本発明の抗体は、当分野で公知の幾つかの技術のいずれかによって作製することができる。
モノクローナル抗体は、ハイブリドーマ、組換え及びファージディスプレイ技術又はこれらの組合せの使用を含めて、当分野で公知の多種多様な技術を用いて調製することができる。例えば、モノクローナル抗体は、当分野で公知の技術、及び、例えば、Harlow et al., Antibodies: A Laboratory Manual, (Gold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T−Cell Hybridomas 563−681 (Elsevier, N.Y., 1981)に教示された技術を含めたハイブリドーマ技術を用いて製造することができる(前記参考文献を参照によりその全体を本明細書に組み入れる。)。本明細書では「モノクローナル抗体」という用語は、ハイブリドーマ技術によって製造された抗体に限定されない。「モノクローナル抗体」という用語は、任意の真核生物、原核生物又はファージクローンを含めて、単一クローンに由来する抗体を指し、モノクローナル抗体が製造される方法ではない。
本発明の別の一態様においては、組換え抗体は、米国特許第5,627,052号、国際公開第92/02551号及びBabcock, J.S. et al.(1996) Proc. Natl. Acad. Sci. USA 93:7843−7848に記載のように、選択リンパ球抗体(selected lymphocyte antibody)方法(SLAM)と当分野で称される手順によって、単一の単離リンパ球から生成される。この方法においては、目的抗体を分泌する単細胞、例えば、セクション1に記載の免疫動物のいずれか1種類に由来するリンパ球を、抗原特異的溶血斑形成法によってスクリーニングする。抗原特異的溶血斑形成法では、抗原IL−13、IL−13のサブユニット、又はその断片を、ビオチンなどのリンカーを用いてヒツジ赤血球に連結し、それを使用して、IL−13に対して特異性を有する抗体を分泌する単細胞を特定する。目的とする抗体分泌細胞を特定した後、重鎖及び軽鎖可変領域cDNAを逆転写酵素PCRによって細胞から取り戻し、次いで、これらの可変領域を、適切な免疫グロブリン定常領域(例えば、ヒト定常領域)に関連して、COS、CHO細胞などのほ乳動物宿主細胞中で発現させることができる。次いで、生体内で選択されたリンパ球に由来する、増幅された免疫グロブリン配列を移入した宿主細胞を、更なる分析にかけ、例えば、移入細胞をパニングしてIL−13に対する抗体を発現する細胞を単離することによって、インビトロで選択することができる。増幅された免疫グロブリン配列は、国際公開第97/29131号及び国際公開第00/56772号に記載の方法などのインビトロ親和性成熟方法などによって、インビトロで更に操作することができる。
本発明の別の一実施形態においては、抗体は、ヒト免疫グロブリン遺伝子座の一部又は全部を含む非ヒト動物をIL−13抗原で免疫することによって製造される。好ましい一実施形態においては、非ヒト動物は、ヒト免疫グロブリン遺伝子座の大きい断片を含むマウス系統であって、マウス抗体産生が欠乏している操作されたマウス系統である、XENOMOUSEトランスジェニックマウスである。例えば、Green et al. Nature Genetics 7: 13−21(1994)並びに米国特許第5,916,771号、同5,939,598号、同5,985,615号、同5,998,209号、同6,075,181号、同6,091,001号、同6,114,598号及び同6,130,364号を参照されたい。1991年7月25日に公開された国際公開第91/10741号、1994年2月3日に公開された国際公開第94/02602号、共に1996年10月31日に公開された国際公開第96/34096号及び同96/33735号、1998年4月23日に公開された国際公開第98/16654号、1998年6月11日に公開された国際公開第98/24893号、1998年11月12日に公開された国際公開第98/50433号、1999年9月10日に公開された国際公開第99/45031号、1999年10月21日に公開された国際公開第99/53049号、2000年2月24日に公開された国際公開第00 09560号、及び2000年6月29日に公開された国際公開第00/037504号も参照されたい。XENOMOUSEトランスジェニックマウスは、完全ヒト抗体の成体様ヒトレパートリーを産生し、抗原特異的ヒトMabを生成する。XENOMOUSEトランスジェニックマウスは、ヒト重鎖遺伝子座及びx軽鎖遺伝子座のメガベースサイズの生殖系列構造(germline configuration)YAC断片の導入によって、ヒト抗体レパートリーの約80%を含む。その開示を参照により本明細書に組み入れる、Mendez et al., Nature Genetics 15:146−156(1997)、Green and Jakobovits J. Exp. Med. 188:483−495(1998)を参照されたい。
抗体ライブラリーをスクリーニングして、所望の結合特異性を有する抗体を特定するインビトロ方法によって、本発明の抗体を作製することもできる。組換え抗体ライブラリーのかかるスクリーニング方法は、当分野で周知であり、例えば、その各々の内容を参照により本明細書に組み入れる、Ladner他、米国特許第5,223,409号;Kang他、国際公開第92/18619号;Dower他、国際公開第91/17271号;Winter他、国際公開第92/20791号;Markland他、国際公開第92/15679号;Breitling他、国際公開第93/01288号;McCafferty他、国際公開第92/01047号;Garrard他、国際公開第92/09690号;Fuchs et al. (1991) Bio/Technology 9:1370−1372; Hay et al. (1992) Hum Antibod Hybridomas 3:81−85; Huse et al. (1989) Science 246:1275−1281; McCafferty et al., Nature (1990) 348:552−554; Griffiths et al. (1993) EMBO J 12:725−734; Hawkins et al. (1992) J Mol Biol 226:889−896; Clackson et al. (1991) Nature 352:624−628; Gram et al. (1992) PNAS 89:3576−3580; Garrad et al. (1991) Bio/Technology 9:1373−1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133−4137、並びにBarbas et al. (1991) PNAS 88:7978−7982、米国特許出願公開第20030186374号及び国際公開第97/29131号記載の方法が挙げられる。
本発明の抗体は、当分野で公知の幾つかの技術のいずれかによって製造することができる。例えば、重鎖及び軽鎖をコードする発現ベクターを宿主細胞に標準技術によって移入した、宿主細胞からの発現。「移入」という用語の様々な形態は、外来DNAを原核生物又は真核生物宿主細胞に導入するのに一般に使用される多種多様な技術、例えば、電気穿孔法、リン酸カルシウム沈殿、DEAE−デキストラン移入などを包含するものとする。原核生物宿主細胞でも真核生物宿主細胞でも本発明の抗体を発現することは可能であるが、真核細胞における抗体の発現が好ましく、ほ乳動物宿主細胞における抗体の発現が最も好ましい。というのは、かかる真核細胞(特にほ乳動物細胞)は、適切に折りたたまれた免疫学的に活性な抗体を組み立て、分泌する可能性が原核細胞よりも高いからである。
表5は、本発明の好ましい抗hIL−13抗体のVH及びVL領域のアミノ酸配列リストである。
キメラ抗体は、ネズミモノクローナル抗体に由来する可変領域とヒト免疫グロブリン定常領域とを有する抗体など、抗体の異なる部分が異なる動物種に由来する分子である。キメラ抗体を製造する方法は、当分野で公知であり、実施例2.1で詳細に考察する。例えば、参照によりその全体を本明細書に組み入れる、Morrison, Science 229:1202(1985); Oi et al., BioTechniques 4:214(1986); Gillies et al., (1989) J. Immunol. Methods 125:191−202、米国特許第5,807,715号、同4,816,567号及び同4,816,397号を参照されたい。また、適切な抗原特異性のマウス抗体分子由来の遺伝子を適切な生物活性のヒト抗体分子由来の遺伝子と一緒にスプライシングすることによって「キメラ抗体」を製造するために開発された技術(参照によりその全体を本明細書に組み入れる、Morrison et al., 1984, Proc. Natl. Acad. Sci. 81:851−855; Neuberger et al., 1984, Nature 312:604−608; Takeda et al., 1985, Nature 314:452−454)を使用することができる。
ヒト化抗体は、非ヒト種由来の1個以上の相補性決定領域(CDR)とヒト免疫グロブリン分子由来のフレームワーク領域とを有する所望の抗原に結合する、非ヒト種抗体由来の抗体分子である。公知のヒトIg配列は、例えば、参照によりその全体を本明細書に組み入れる、www.ncbi.nlm.nih.gov/entrez−/query.fcgi; www.atcc.org/phage/hdb.html; www.sciquest.com/; www.abcam.com/; www.antibodyresource.com/onlinecomp.html; www.public.iastate.edu/.about.pedro/research_tools.html; www.mgen.uniheidelberg.de/SD/IT/IT.html; www.whfreeman.com/immunology/CH−05/kuby05.htm; www.library.thinkquest.org/12429/Immune/Antibody.html; www.hhmi.org/grants/lectures/1996/vlab/; www.path.cam.ac.uk/.about.mrc7/m−ikeimages.html; www.antibodyresource.com/; mcb.harvard.edu/BioLinks/Immunology.html.www.immunologylink.com/; pathbox.wustl.edu/.about.hcenter/index.−html; www.biotech.ufl.edu/.about.hcl/; www.pebio.com/pa/340913/340913.html−; www.nal.usda.gov/awic/pubs/antibody/; www.m.ehime−u.acjp/.about.yasuhito−/Elisa.html; www.biodesign.com/table.asp; www.icnet.uk/axp/facs/davies/lin−ks.html; www.biotech.ufl.edu/.about.fccl/protocol.html; www.isac−net.org/sites_geo.html; aximtl.imt.unimarburg.de/.about.rek/AEP−Start.html; baserv.uci.kun.nl/.about.jraats/linksl.html; www.recab.uni−hd.de/immuno.bme.nwu.edu/; www.mrc−cpe.cam.ac.uk/imt−doc/public/INTRO.html; www.ibt.unam.mx/vir/V_mice.html; imgt.cnusc.fr:8104/; www.biochem.ucl.ac.uk/.about.martin/abs/index.html; antibody.bath.ac.uk/; abgen.cvm.tamu.edu/lab/wwwabgen.html; www.unizh.ch/.about.honegger/AHOseminar/Slide01.html; www.cryst.bbk.ac.uk/.about.ubcg07s/; www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.htm; www.path.cam.ac.uk/.about.mrc7/humanisation/TAHHP.html; www.ibt.unam.mx/vir/structure/stat_aim.html; www.biosci.missouri.edu/smithgp/index.html; www.cryst.bioc.cam.ac.uk/.abo−ut.fmolina/Web−pages/Pept/spottech.html; www.jerini.de/fr roducts.htm; www.patents.ibm.com/ibm.html.Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health(1983)に開示されている。かかる移入された配列を使用して、当分野で公知のように、免疫原性を低下させることができ、又は結合、親和性、オン速度、オフ速度、結合活性、特異性、半減期、若しくは任意の他の適切な特性を低減、増強若しくは改変することができる。
好ましくは、本発明の抗IL−13抗体は、例えば、当分野で公知の幾つかのインビトロ及び生体内アッセイのいずれか一つによって評価して、IL−13活性を低下させる、又は中和する、高い能力を示す(例えば、実施例1.1.C参照)。例えば、これらの抗体は、A−549細胞によるTARCのIL−13誘導性産生を、少なくとも約10−8M、約10−9M又は約10−10Mの範囲のIC50値で中和する。
ヒトIL−13に結合するその能力を考慮に入れると、本発明の抗ヒトIL−13抗体又はその一部は、酵素結合免疫吸着検定法(ELISA)、放射性免疫測定法(RIA)、組織免疫組織化学などの従来の免疫測定法を用いて、(例えば、血清、血しょうなどの生物試料中の)ヒトIL−13を検出するのに使用することができる。本発明は、生物試料を本発明の抗体又は抗体部分と接触させること、及びヒトIL−13に結合した抗体(又は抗体部分)又は結合していない抗体(又は抗体部分)を検出し、それによって生物試料中のヒトIL−13を検出することを含む、生物試料中のヒトIL−13を検出する方法を提供する。検出可能な物質で抗体を直接的又は間接的に標識して、結合した又は結合していない抗体の検出を容易にする。適切な検出可能物質としては、種々の酵素、補欠分子族、蛍光材料、発光材料、放射性材料などが挙げられる。適切な酵素の例としては、西洋ワサビペルオキシダーゼ、アルカリホスファターゼ、β−ガラクトシダーゼ又はアセチルコリンエステラーゼが挙げられる。適切な補欠分子族複合体の例としては、ストレプトアビジン/ビオチン及びアビジン/ビオチンが挙げられる。適切な蛍光材料の例としては、ウンベリフェロン、フルオレセイン、フルオレセインイソチオシアナート、ローダミン、ジクロロトリアジニルアミンフルオレセイン、ダンシルクロリド又はフィコエリトリンが挙げられる。発光材料の例としてはルミノールが挙げられる。適切な放射性材料の例としては、3H、14C、35S、90Y、99Tc、111In、125I、131I、177Lu、166Ho又は153Smが挙げられる。
本発明は、本発明の抗体又はその抗原結合性部分と薬学的に許容される担体とを含む薬剤組成物も提供する。本発明の抗体を含む薬剤組成物は、これらだけに限定されないが、障害の診断、検出若しくは監視、障害若しくはその1つ以上の症候の予防、治療、管理若しくは改善及び/又は研究に使用される。特定の一実施形態においては、これらの組成物は、本発明の1種類以上の抗体を含む。別の一実施形態においては、この薬剤組成物は、本発明の1種類以上の抗体と、IL−13活性が有害である障害を治療するための本発明の抗体以外の1種類以上の予防薬又は治療薬とを含む。好ましくは、障害又はその1つ以上の症候の予防、治療、管理又は改善に有用であることが知られている又は使用されてきた又は現在使用されている、予防薬又は治療薬。これらの実施形態によれば、組成物は、担体、希釈剤又は賦形剤を更に含み得る。
抗ヒトIL−13モノクローナル抗体の生成及び単離
(実施例1.1)
抗ヒトIL−13抗体を特定するアッセイ
別段の記載がない限り、実施例1を通して、以下のアッセイによって、抗ヒトIL−13抗体を特定し、特徴づけた。
ELISA
ヒトIL−13に結合する抗体をスクリーニングする酵素結合免疫吸着検定法を以下のように実施した。
BIACORE技術による親和性測定
BIACOREアッセイ(Biacore, Inc、Piscataway、NJ)は、オン、オフ速度定数の動力学的測定によって抗体の親和性を測定する。抗体と組換え精製ヒトIL−13又は組換え精製ヒトIL−13変種(R110Q)との結合を、ランニングHBS−EP(10mM HEPES[pH7.4]、150mM NaCl、3mM EDTA及び0.005%界面活性剤P20)を用いたBiacore(登録商標)3000装置(Biacore(登録商標)AB、Uppsala、Sweden)を用いて、表面プラズモン共鳴測定によって25℃で求めた。すべての化学物質をBiacore(登録商標)AB(Uppsala、Sweden)又は本明細書に記載の別の供給源から得た。10mM酢酸ナトリウム(pH4.5)で希釈されたヤギ抗マウスIgG(Fcγ)断片特異的ポリクローナル抗体(Pierce Biotechnology Inc、Rockford、IL)約5000RUを、標準アミンカップリングキットを製造者の指示及び手順に従って用いて、25μg/mlでCM5研究等級バイオセンサーチップ全体に直接固定した。バイオセンサー表面の未反応部分をエタノールアミンでブロックした。フローセル2及び4における改変カルボキシメチルデキストラン表面を反応表面として用いた。フローセル1及び3におけるヤギ抗マウスIgGを含まない非改変カルボキシメチルデキストランを基準表面として用いた。動力学的分析のために、1:1ラングミュア結合モデルから誘導された速度式を、Biaevaluation 4.0.1ソフトウェアを用いて(全体的一致(global fit)分析によって)全8回の注射の会合及び解離段階に同時にあてはめた。ヤギ抗マウスIgG特異的反応表面全体で捕捉するために、精製抗体をHEPES緩衝食塩水で希釈した。リガンドとして捕捉するマウス抗体(25μg/ml)を反応基質の上に流量5μl/minで注入した。会合及び解離速度定数Kon(単位M−1s−1)及びKoff(単位s−1)を連続流量25μl/minで求めた。速度定数は、10−200nMの範囲の10個の異なる抗原濃度で動力学的結合測定によって導出された。次いで、マウス抗体と組換え精製ヒトIL−13又は組換え精製ヒトIL−13との反応の平衡解離定数(単位M)を、動力学的速度定数から式KD=Koff/konによって計算した。結合を時間の関数として記録し、動力学的速度定数を計算する。このアッセイでは、106M−1s−1と高いオン速度及び10−6s−1と低いオン速度を測定することができる。
抗ヒトIL−13抗体の機能活性
本発明の抗ヒトIL−13抗体の機能活性を調べるために、抗体のIL−13活性阻害能力を測定する以下のアッセイに抗体を使用した。
A−549バイオアッセイ
A−549細胞によるTARC(CCL−17)のヒトIL−13誘導性産生を抑制する抗ヒトIL−13抗体の能力を以下のように分析した。1日目にA−549細胞を96ウェルプレート(2E5細胞/ウェル)の(10%FBSを含む)RPMI増殖培地に蒔いた。2日目に、400ng/ml rhTNF(100μl/ウェル)を含む新しいRPMI増殖培地で培地を置換した。一方、種々の濃度の免疫マウス血清、ネズミハイブリドーマ上清又は精製抗ヒトIL−13抗体を、10ng/ml組換え精製ヒトIL−13又はIL−13変種と一緒に、マイクロタイタープレート(U底、96ウェル、Costar)中のRPMI完全培地100μL中で37℃で1時間前温置した。次いで、抗体と組換え精製ヒトIL−13の混合物を、TNFで処理したA−549細胞に添加し(100μl/ウェル)、最終体積を200μl/ウェルとし(最終IL−13及びTNF濃度は、それぞれ5ng/ml及び200ng/mlであった。)、37℃で18時間温置した。温置後、無細胞上清150μLを各ウェルから抜き取り、産生されたヒトTARCのレベルをヒトTARC ELISA(R&D Systems Cat#DDN00)によって測定した。
抗ヒトIL−13モノクローナル抗体の生成
抗ヒトIL−13マウスモノクローナル抗体を以下のように得た。
ヒトIL−13抗原によるマウスの免疫化
1日目に、完全フロイントアジュバント又はImmunoeasyアジュバント(Qiagen、Valencia、CA)と混合された組換え精製ヒトIL−13変種(Peprotech)20マイクログラムを5匹の6−8週齢Balb/C、5匹のC57B/6マウス、及び5匹のAJマウスに皮下注射した。24、38及び49日目に、不完全フロイントアジュバント又はImmunoeasyアジュバントと混合された組換え精製ヒトIL−13変種20マイクログラムを同じマウスに皮下注射した。84、112又は144日目に、マウスに組換え精製ヒトIL−13変種1ugを静脈内注射した。
ハイブリドーマの作製
実施例1.2.Aに記載の免疫マウスから得られたひ細胞を、Kohler, G. and Milstein 1975, Nature, 256:495に記載の確立された方法に従ってSP2/O−Ag−14細胞と5:1の比で融合して、ハイブリドーマを作製した。融合生成物を、96ウェルプレート中のアザセリン及びヒポキサンチンを含む選択培地に2.5×106ひ臓細胞/ウェルの密度で蒔いた。融合から7から10日後、巨視的なハイブリドーマコロニーが観察された。ハイブリドーマコロニーを含む各ウェルの上清を、(実施例1.1.Aに記載のように)IL−13変種に対する抗体の存在についてELISAによって試験した。次いで、IL−13変種特異的活性を示す上清を、(実施例1.1.Cに記載のように)IL−13変種及びIL−13野生型を中和する能力についてTARCのA−549バイオアッセイによって試験した。
抗ヒトIL−13モノクローナル抗体の特定及び特性分析
実施例1.2.B及び1.2.Cに従って作製した、IL−13変種に結合する抗体を産生するハイブリドーマ、及びIL−13変種に特異的に結合可能な抗体を産生するハイブリドーマ、特にA−549バイオアッセイにおいて5nM又は5nM未満のIC50値を有する抗体を産生するハイブリドーマを限界希釈によってスケールアップし、クローン化した。
ネズミモノクローナル抗ヒトIL−13抗体の種特異性
17種類の上記モノクローナル抗体がネズミIL−13を認識するかどうかを判定するために、ELISAプレートを5ug/mlヤギ抗マウスIgG、Fc断片特異抗体(Pierce # 31170、Rockland、IL)で被覆することによって間接的ELISAを準備した。ネズミ抗ヒトIL−13 mAbを、0.1%BSAを含むPBS中で0.1から100ng/mlの範囲の種々の濃度で調製した。各抗体希釈物50ulを被覆ELISAプレートに添加し、室温で1時間温置した。0.05%Tween−20を含むPBSでウェルを3回洗浄した。組換えビオチン化マウスIL−13(R&D Systems)を0.1%BSAを含むPBSで0.1ug/mlに希釈した。50uL/ウェルを添加し、プレートを室温で1時間温置した。0.05%Tween−20を含むPBSでウェルを3回洗浄した。ストレプトアビジンHRP(Pierce # 21126、Rockland、IL.)を0.1%BSAを含むPBSで1:20000希釈した。50mL/ウェルを添加し、プレートを室温で1時間温置した。0.05%Tween−20を含むPBSでプレートを3回洗浄した。TMB溶液(Sigma # T0440、St. Louis、MO.)50マイクロリットルを各ウェルに添加し、室温で10分間温置した。1N硫酸を添加して反応を停止した。プレートを波長450nmで分光光度的に読み取った。間接的ELISAの結果によれば、mAb 3H7はmIL−13に結合することができた。その後のバイオアッセイにおいて、3H7は、mIL−13によって刺激されるTARC産生を2.4nMのIC50で用量依存的に阻害できることが判明した。Biacore分析によっても、mIL−13に対して3H7が12nMのKDで陽性結合することが実証された。表8の他のmAbはすべて、マウスIL−13に対して陽性結合を示さなかった。
ネズミモノクローナル抗ヒトIL−13抗体は、IL−13受容体(IL−13Rα1及びIL−13Rα2)に対するIL−13の結合を阻止する。
各ネズミ抗ヒトIL−13 mAbの可変領域のアミノ酸配列の決定
各アミノ酸配列を決定するために、約10×106個のハイブリドーマ細胞を遠心分離によって単離し、処理して、Trizol(Gibco BRL/Invitrogen、Carlsbad、CA.)を製造者の指示に従って用いて全RNAを単離した。SuperScript First−Strand Synthesis System(Invitrogen、Carlsbad、CA)を製造者の指示に従って用いて、全RNAを第1鎖DNA合成に供した。オリゴ(dT)を用いて、第1鎖合成を準備して(prime)、ポリ(A)+RNAを選択した。次いで、ネズミ免疫グロブリン可変領域の増幅用に設計されたプライマー(Ig−Primer Sets、Novagen、Madison、WI)を用いたPCRによって、第1鎖cDNA産物を増幅した。PCR産物をアガロースゲル上で分離し、切り出し、精製し、次いでTOPO Cloningキットを用いてpCR2.1−TOPOベクター(Invitrogen、Carlsbad、CA)にサブクローニングし、TOP10 chemically competent E. coli(Invitrogen、Carlsbad、CA)に転換した。形質転換体のコロニーPCRを実施して、挿入断片を含むクローンを特定した。QIAprep Miniprepキット(Qiagen、Valencia、CA)を用いて、挿入断片を含むクローンからプラスミドDNAを単離した。プラスミド中の挿入断片を、M13フォワードプライマー及びM13リバースプライマー(Fermentas Life Sciences、Hanover MD)を用いて、両方の鎖上で配列決定して、可変重鎖又は可変軽鎖DNA配列を決定した。実施例1.2.Cに記載した17種類のモノクローナル抗体の可変重鎖及び可変軽鎖配列を表5に示す。
組換え抗ヒトIL−13抗体
(実施例2.1)
組換えキメラ抗ヒトIL−13抗体の構築及び発現
ネズミ抗ヒトIL−13モノクローナル抗体5G1、13C5、9C11、21D9及び3H7の重鎖定常領域をコードするDNAを、細菌中で相同組換えによって、2つのヒンジ領域アミノ酸変異を含むヒトIgG1定常領域をコードするcDNA断片で置換した。これらの変異は、234位(EU付番)におけるロイシンからアラニンへの変化、及び235位におけるロイシンからアラニンへの変化である(Lund et al., 1991, J. Immunol., 147:2657)。これらの抗体の各々の軽鎖定常領域をヒトカッパ定常領域で置換した。pBOS発現プラスミドに連結されたキメラ重鎖及び軽鎖cDNAの同時形質移入によって、完全長キメラ抗体をCOS細胞中で一過性に発現させた(Mizushima and Nagata, Nucleic Acids Research 1990, Vol 18, pg 5322)。組換えキメラ抗体を含む細胞上清を、Protein A Sepharoseクロマトグラフィーによって精製し、結合した抗体を、酸緩衝剤を添加して溶出させた。抗体を中和し、PBSで透析した。
ヒト化抗ヒトIL−13抗体の構築及び発現
(実施例2.2.1)
ヒト抗体フレームワークの選択
(表3に記載の)各ネズミ可変重鎖及び可変軽鎖遺伝子配列を、Vector NTIソフトウェアを用いて、(http://www.ncbi.nlm.nih.gov/igblast/retrieveig.htmlのNCBI Ig Blastウェブサイトから得られた)44個のヒト免疫グロブリン生殖系列可変重鎖、又は46個の生殖系列可変軽鎖配列に対して別々に整列させた。
ヒト化抗体の構築
コンピューターで構築された上記ヒト化抗体を、オリゴヌクレオチドを用いて新規に構築した。各可変領域cDNAの場合、各60−80ヌクレオチドの6個のオリゴヌクレオチドを、各オリゴヌクレオチドの5’及び/又は3’末端において互いに20ヌクレオチド重複するように設計した。アニーリング反応においては、全6個のオリゴを組み合わせ、沸騰させ、dNTPの存在下でアニールした。次いで、DNAポリメラーゼI、Large(クレノー)断片(New England Biolabs #M0210、Beverley、MA.)を添加して、重複オリゴヌクレオチド間の約40bpの間隙を埋めた。次いで、改変pBOSベクター中のマルチクローニング部位に相補的である突出配列を含む2個の最外側プライマーを用いてPCRを実施して、可変領域遺伝子全体を増幅した(Mizushima, S. and Nagata, S., (1990) Nucleic acids Research Vol 18, No.17))。各cDNAの組立てから誘導されるPCR産物をアガロースゲル上で分離し、予測される可変領域cDNAサイズに対応するバンドを切り出し、精製した。細菌中で相同組換えによって、2つのヒンジ領域アミノ酸変異を含むヒトIgG1定常領域をコードするcDNA断片に、可変重鎖領域をインフレームで挿入した。これらの変異は、234位(EU付番)におけるロイシンからアラニンへの変化、及び235位におけるロイシンからアラニンへの変化である(Lund et al., 1991, J. Immunol., 147:2657)。可変軽鎖領域を、相同組換えによって、ヒトカッパ定常領域と一緒にインフレームで挿入した。細菌コロニーを単離し、プラスミドDNAを抽出し、cDNA挿入断片全体の配列を決定した。各抗体に対応する正確なヒト化重鎖及び軽鎖をCOS細胞に同時移入して、完全長ヒト化抗ヒトIL−13抗体を一過性に産生した。13C5の場合、13C5重鎖にグラフトしたcDNA及び13C5軽鎖にグラフトしたcDNAを含むpBOSベクターをCOS細胞に同時移入した。組換えキメラ抗体を含む細胞上清を、Protein A Sepharoseクロマトグラフィーによって精製し、結合した抗体を、酸緩衝剤を添加して溶出させた。抗体を中和し、PBSで透析した。幾つかのヒト化抗体を表10に示す。
ヒト化抗IL−13抗体の特性分析
本発明者らは、IL−13Rα1とIL−13Rα2の両方に対するIL−13の結合を阻止する単離モノクローナル抗体を有する。ELISAに基づく受容体結合アッセイと細胞表面の125I標識IL−13結合アッセイの両方によって、ネズミバージョンとヒト化バージョン(すなわち13C5.5)の両方の13C5は、両方の受容体に対するIL−13の結合を有効に阻止できることが実証された。25C8及び33C3を含めて、13C5と同じ系列の抗体も、両方の受容体に対するIL−13の結合を阻止することができた。
ヒト化抗IL−13抗体は、IL−13受容体に対するIL−13の結合を阻止する。
IL−13上の特異的エピトープへの抗IL−13抗体の結合
抗IL−13 mAb 13C5、13C5.5、9C11及び5G1が結合するヒトIL−13上のエピトープの地図を、エピトープ切除技術、続いて質量分析法(MS)によるペプチド分析を用いて作成した。エピトープ切除においては、タンパク質をまず固定化mAbに結合させ、次いでタンパク質分解酵素で消化した。タンパク質上のエピトープ領域をMS及びMS/MSを用いて決定して、エピトープ含有ペプチドを特定した。CNBr活性化Sepharoseビーズ(Amersham Biosciences、10mg/反応)を0.1M HCl 500uLに懸濁させ、15分間平衡にした。ビーズを小型反応カラム(USB Corporation)に移し、0.1M HCl、続いて0.1M NaHCO3カップリング緩衝剤で洗浄した。mAb(100ug)を懸濁液に添加し、ゆっくり回転させながら室温で2時間温置した。共有結合したmAbを有するビーズをpH約8.0の0.1M Tris−HCl緩衝剤で洗浄した。pH約8.0の0.1M Tris−HCl緩衝剤と一緒に2時間温置することによって、CNBr Sepharoseビーズ上の未反応基をブロックした。pHの異なる2種類の緩衝剤、すなわち、1)pH約4.0の0.1M酢酸Na、0.5M NaCl緩衝剤、及び2)pH約8.0の0.1M Tris−HCl、0.5M NaCl緩衝剤で連続洗浄して、脱離したmAbを除去した。ビーズをPBS 約0.14M NaCl、2.7mM KCl、4.3mM Na2HPO4、1.5mM KH2PO4、pH7.2中で平衡にし、IL−13と一緒に、又はIL−13なしで、室温で2時間温置した。ビーズをpH約7.2のPBSで洗浄後、一定分量の懸濁液をMALDI−TOF分析用に取り出した。
IL−13と複合化された抗IL−13の結晶化
13C5.5のFab部分は、ヒトIL−13と複合体を形成し、複合体の結晶は、以下のように生成した。
13C5.5 Fab断片の調製及び精製
13C5.5 Fab断片を調製するために、Ultrafree−15 Biomax 10kDa分子量カットオフ(MWCO)遠心ろ過装置(Millipore)を用いて、0.15M PBS緩衝剤中の13C5.5 IgGを2mg/mlにまず濃縮した。パパインゲルスラリー(Pierce)を予洗し、緩衝剤A(20mM Na2HPO4、10mM EDTA、20mMシステイン)を体積比1:1で用いて、2−3Xで充填した。次いで、濃縮抗体を50%パパインゲルスラリーと混合し、激しく振とうしながら37℃で24時間温置した。抗体/スラリー混合物を遠心分離し(Beckman 6KR)、PBSであらかじめ平衡にしたSuperdex 75に上清を充填した。主要なピークが溶出し、タンパク質をプールした。25mL Protein A Sepharose 4 Fast Flowアフィニティーカラム(Amersham Pharmacia)をPBS 100mLで洗浄して準備した。プールした抗体断片をアフィニティーカラム(流量2mL/min)にかけた。(280nmのUV吸光度によってモニターされた)13C5.5 Fab断片を含む画分をフロースルー(flow−thru)に収集した。(280nmのUV吸光度によって測定して)0.3mg/mLよりも高い13C5.5 Fab断片濃度を含む画分をプールし、−80℃で凍結させた。試料純度をSDS−PAGEによって評価した。
IL−13/13C5.5 Fab複合体の調製
組換えヒトIL−13をほ乳動物発現系で発現させ、続いて当分野で周知の技術を用いて精製した。組換えヒトIL−13と13C5.5 Fabタンパク質をモル比1:1で混合し、4℃で1時間温置した。複合体試料を、あらかじめ平衡にした(20mM Tris pH7.5、150mM NaCl)Superdex 200カラムに0.5ml/minで充填した。複合体をプールし、Ultrafree−15 Biomax 10kDa分子量カットオフ(MWCO)遠心ろ過装置(Millipore)を用いて24mg/mLに濃縮し、−80℃で凍結させた。試料純度をSDS−PAGEによって評価した。
IL−13/13C5.5 Fab複合体の結晶化
凍結したIL−13/13C5.5複合体貯蔵物(約24mg/mL)を氷上で解凍した。複合体(1.0μL)を貯蔵溶液(1.75M硫酸アンモニウム、100mM MES pH6.5、10mM CaCl2)1.0μLと混合した。生成した液滴を貯蔵器上のシッティングドロップウェル(CrysChemシッティングドロッププレート)中で約18℃で混合した。ダイアモンド状結晶が1週間以内に出現した。
IL−13/13C5.5 Fab複合体結晶の凍結保護及び急速冷却
IL−13/13C5.5 Fab複合体の結晶を母液+20%グリセリン中で繊維ループを用いて収集した。続いて、結晶を液体窒素に投げ込むことによって急速冷却した。
IL−13/13C5.5 Fab複合体のX線回折データ収集
IL−13/13C5.5 Fab結晶からのX線回折データを、米国イリノイ州アルゴンヌのAdvanced Photon SourceにおけるIMCAビームラインにおいて収集した。データ収集中、Oxford Cryosystems Cryostream冷却器を用いて、結晶を温度100Kに維持した。合計180フレームを1.0°の振動範囲で収集した。データをHKL2000プログラムスイート(Otwinowski and Minor, 1997)によって処理した。結晶方位を決定した後、データをDENZOによって積分し、SCALEPACKによってスケーリング及びマージングを行い、絶対目盛り上に配置し、TRUNCATEによって構造因子振幅に換算した(French and Wilson, 1978)。フリーR因子(Rfree)を計算するために、特有反射(unique reflection)の5パーセントを「フリー」セットに無作為に割り当てた(Brunger, 1992)。反射の残りの95%は、R因子(R)を計算するための「作用(working)」セットを構成した。X線回折データを表16に要約する。以下は、結晶形の指標付け(indexing)である:(1)IL−13/13C5.5 Fab:空間群P2(1)2(1)2(1)、a=163.578Å、b=163.318Å、c=228.627Å、α=90.0°、β=90.0°、γ=90.0°。表17に、データセットのX線回折統計を示す。
IL−13/13C5.5 Fab複合体結晶構造の分子置換解析及び精密化
最尤分子置換解析をプログラムPHASERによって求めた(Read, 2001)。合計6種類の13C5.5モノマーを空間群P2(1)2(1)2(1)において分解能3.0Åで解析した。検索モデルは、既報のFabの結晶構造であった(Protein Data Bank登録1BJ1; Muller et al. 1998)。座標を分子置換解析に基づいて作成した。
IL−13/13C5.5 Fab複合体構造
ヒトIL−13と複数の13C5.5 CDRの間で、広範な接触が認められる。抗体−抗原界面において埋められた表面積は1415.50Å2である。接触は、重要な水素結合、及び界面を安定化する疎水的相互作用で構成される。界面接触の大部分を構成する2個の最小配列セグメントは、IL−13らせんA及びD上にある(IL−13の構造については、参照により本明細書に組み入れる米国特許出願公開第2003−0013851号A1を参照されたい。)。これらの接触は、CDRのL1とL3及びH2とH3を連結する。上記に基づいて、エピトープ13C5.5結合範囲は、配列番号1のSer26−Asn38、Lys123−Arg130によって規定される局所(topographical)領域を含む。より好ましくは、エピトープ13C5.5結合範囲は、配列番号1のArg30−Asn38、Lys123−Arg127によって規定される局所領域を含む。
ヒト化IL−13抗体の生体内での有効性
抗hIL−13抗体の生体内での有効性を以下のように評価した。
ヒトIL−13誘発性ぜん息モデルにおけるヒト化IL−13抗体の生体内での有効性
抗hIL−13抗体5G1、13C5及び13C5.5の有効性を、マウスのヒトIL−13誘発性ぜん息モデルにおいて試験した。マウスに組換えヒトIL−13を無菌PBS 50μl中1μgの用量で、微小噴霧器を用い、気管の開口を可視化するげっ歯類用喉頭鏡を用いて、気管に送達して、投与した。合計2回のIL−13を試験1及び2日目に投与し、気道過敏性(AHR; Hoymann, H.G.; J Pharmacol Toxicol Methods. 2007 Jan−Feb;55(1):16−26)、粘液、酸性ほ乳動物キチナーゼ(AMCase, Donnelly LE, Barnes PJ., 1: Trends Pharmacol Sci. 2004 Oct;25(10):509−11)、並びに胸腺及び活性化調整ケモカイン(thymus and activation regulated chemokine)(TARC; Bisset LR, Schmid−Grendelmeier P., Curr Opin Pulm Med. 2005 Jan;11(1):35−42)を気管支肺胞洗浄液中で最終投与から24時間後に測定した。抗体用量100、300及び1000μgを、最初のIL−13投与の1日前に腹腔内注射によって投与した。結果を表19に要約する。IL−13Rα1とIL−13Rα2のどちらに対してもIL−13の結合を阻止しない5G1抗体は、このインビボモデルにおいてIL−13生理活性を中和することができず、5G1で処理した動物において検出されたAHR、AMCase及びMuc5acのレベルは、PBSで処理した対照動物と類似した。これに対し、α1とα2の両方の受容体に対する結合を阻止する13C5抗体は、すべてのパラメータを軽減するのに有効であった。IL−13で処理すると、気道抵抗が3.6cm H2O/ml/secから5.7cm H2O/ml/secに増加した。13C5(1000μg)で処理すると、気道抵抗は4.3cm H2O/ml/secに低下した。muc5acレベルによって測定される粘液分泌過多は、356.5単位から最大211Uに低下し、40%の低下に相当する抗体処理であった。同様に、AMCaseレベルは、202Uから68Uに低下し、66%の低下に相当し、TARCレベルで見られる低下と類似していた(n=10、p<.05、すべての用量)。組換えヒト化抗体13C5.5は、このモデルにおいて類似の結果を示した。IL−13は、30μg/mlメタコリン投与後の気道抵抗を3.9から5.5cm H2O/ml/secに増加させた。抗体13C5.5は、用量100、300及び1000μgにおいて気道抵抗をそれぞれ4.1、4.45及び4.3cm H2O/ml/secに抑制した。muc5acレベルによって測定される粘液分泌過多は、IL−13処理によって抗体処理用量100、300及び1000μgにおいて247Uからそれぞれ154、30.2及び11.1Uに低下した。これは、この抗体による粘液産生の38、88及び96%抑制を表す。IL−13処理は、抗体処理(用量100、300及び1000μg)によって、14、24及び68%抑制を示す113、98及び55Uに低下した130U AMCase活性を誘導した。これらのデータによれば、IL−13Rα1とα2の両方に対するIL−13の結合を阻止する13C5及び組換えヒト化抗体13C5.5は、AHR、粘液、及び肺におけるAMCase産生のIL−13誘導性反応を中和することができるのに対して、α1及びα2受容体に対するIL−13の結合を阻止しない抗体は、これらの生物学的反応のいずれを阻止するのにも有効ではない。
**p<0.05、ANOVA、ボンフェローニ
***p<0.01、ANOVA、ボンフェローニ
別の試験では、抗hIL−13抗体BAK502G9、MJ2−7及び13C5.5の有効性を、マウスのヒトIL−13誘発性ぜん息モデルにおいて比較した。マウスに組換えヒトIL−13を無菌PBS 50μl中1μgの用量で、軽い鎮静状態で鼻腔内送達して、投与した。合計2回のIL−13を試験1及び2日目に投与し、気道過敏性、粘液、及びAMCaseを気管支肺胞洗浄液中で最終投与から24時間後に測定した。抗体用量1000μgを、最初のIL−13投与の1日前に腹腔内注射によって投与した。試験結果を表20に要約する。IL−13α1とα2受容体の両方に対するIL−13の結合を阻止する13C5.5抗体は、すべてのパラメータを有意に低下させるのに有効であった。IL−13処理は、30mg/mlメタコリン投与後の気道抵抗を4.2cm H2O/ml/secから7.2cm H2O/ml/secに増加させた。13C5.5(1000μg)で処理すると、気道抵抗は4.6cm H2O/ml/secに86.8%低下した。muc5acレベルによって測定される粘液分泌過多は、768.2単位から412.9Uに低下し、58.8%の低下に相当する抗体処理であった。同様に、AMCaseレベルは316.5Uから147Uに低下し、52%の低下に相当した(n=10、p<.001)。IL−13Rα1に対するIL−13の結合を阻止するが、IL−13Rα2に対するIL−13の結合を有効に阻止しない、BAK502G9とMJ2−7の両方の抗体は、このモデルにおいて類似したIL−13誘導性AHR中和能力を示した。抗体BAK502G9及びMJ2−7は、気道抵抗を7.2からそれぞれ5.96cm H2O/ml/sec及び5.93cm H2O/ml/secに抑制し、AHRの42%及び41.5%の低下しか示さなかった。muc5acレベルによって測定される粘液分泌過多は、IL−13処理によって抗体用量1000μgにおいて、BAK502G9又はMJ2−7抗体それぞれ768.2Uから627.8及び380Uに低下し、23%及び64%の抑制に相当した。BAK502G9抗体は、AMCaseを抑制する効果が13C5.5又はMJ2−7抗体よりも低かった。IL−13処理は、BAK502G9又はMJ2−7抗体処理(用量1000μg)によって、それぞれ8%及び45%抑制を示す279及び169Uに低下する316.5U AMCase活性を誘導した。これらのデータによれば、IL−13Rα1とα2の両方に対するIL−13の結合を阻止する組換えヒト化抗体13C5.5は、AHR、粘液、及び肺におけるAMCase産生のIL−13誘導性反応を中和するのに極めて有効であるのに対して、IL−13 α2受容体に対するIL−13の結合をより低親和性でしか阻止しない抗体は、ぜん息の一因になるこれらの生物学的反応を阻止するのにさほど有効ではない。
OVA誘発性ぜん息マウスモデルにおけるIL−13抗体の生体内での有効性
(特に、IL−13Rα2に関する)受容体遮断性がmAbの生体内での有効性に影響を及ぼすかどうかをぜん息マウスモデルにおいて判定するために、mIL−13Rα1/Fc及びmIL−13Rα2/Fcタンパク質(R&D Systems)を用いた受容体結合ELISAによって測定して異なる受容体遮断性を示すラット抗マウスIL−13抗体のパネルを作製した(表21参照)。抗hIL−13 mAb 3H7は、マウスIL−13と交差反応するので、その抗mIL−13特性も表21に示した。マウスIL−13に対する抗体の結合親和性を組換えマウスIL−13(R&D Systems)に対するBIACOREアッセイによって測定し、マウスIL−13に対する抗体の効力(IC50)を組換えマウスIL−13に対するA−549バイオアッセイによって求めた。51D9及び48D3の可変ドメイン配列を表22に示す。
Claims (46)
- 抗原結合ドメインを含む結合タンパク質であり、前記結合タンパク質はIL−13に結合可能であり、前記抗原結合ドメインが、6個のCDR:CDR−H1、CDR−H2、CDR−H3、CDR−L1、CDR−L2及びCDR−L3を含み、ここで、前記6個のCDRは下記CDR(a)から(f)のセットから選択される、結合タンパク質:
(a)CDR-H1はS−S−W−I−H(配列番号32の残基31−35)であり、
CDR-H2はM−I−H−P−S−D−S−E−T−R−L−N−Q−K−F−K−D(配列番号32の残基50−66)であり、
CDR-H3はT−A−T−D−F−D−Y(配列番号32の残基99−105)であり、
CDR-L1はK−S−T−K−S−L−L−N−S−D−G−F−T−Y−L−D(配列番号33の残基24−39)であり、
CDR-L2はL−V−S−N−R−F−S(配列番号33の残基55-61)であり、及び
CDR-L3はF−Q−H−N−Y−L−P−L−T(配列番号33の残基94−102)である;
(b)CDR−H1はT−S−D−M−G−V−D(配列番号46の残基31−37)であり、
CDR−H2はH−I−W−W−D−D−V−K−R−Y−N−P−A−L−K−S(配列番号46の残基52−67)であり、
CDR−H3はT−V−S−S−G−Y−I−Y−Y−A−M−D−Y(配列番号46の残基100−112)であり、
CDR−L1はR−A−S−Q−D−I−R−N−Y−L−N(配列番号47の残基24−34)であり、
CDR−L2はY−T−S−K−L−H−S(配列番号47の残基50−56)であり、及び
CDR−L3はQ−Q−G−N−T−L−P−L−T(配列番号47の残基89−97)である;
(c)CDR−H1はT−S−D−L−G−V−G(配列番号50の残基31−37)であり、
CDR−H2はH−I−W−W−D−D−V−K−R−Y−N−P−A−L−K−S(配列番号50の残基52−67)であり、
CDR−H3はI−G−S−S−G−Y−I−Y−Y−E−M−D−Y(配列番号50の残基100−112)であり、
CDR−L1はR−A−S−Q−D−I−R−N−Y−L−N(配列番号51の残基24−34)であり、
CDR−L2はY−T−S−R−L−H−S(配列番号51の残基50−56)であり、及び
CDR−L3はQ−Q−G−N−T−L−P−L−T(配列番号51の残基89−97)である;
(d)CDR−H1はT−S−D−M−G−V−D(配列番号80の残基31−37)であり、
CDR−H2はH−I−W−W−D−D−V−K−R−Y−N−P−A−L−K−S(配列番号80の残基52−67)であり、
CDR−H3はT−V−S−S−G−Y−I−Y−Y−A−M−D−Y(配列番号80の残基100−112)であり、
CDR−L1はR−A−S−Q−D−I−R−N−Y−L−N(配列番号92の残基24−34)であり、
CDR−L2はY−T−S−M−K−P−R(配列番号92の残基50−56)であり、及び
CDR−L3はQ−Q−G−N−T−L−P−L−T(配列番号92の残基89−97)である;
(e)CDR−H1はT−S−D−M−G−V−D(配列番号80の残基31−37)であり、
CDR−H2はH−I−W−W−D−D−V−K−R−Y−N−P−A−L−K−S(配列番号80の残基52−67)であり、
CDR−H3はT−V−S−S−G−Y−I−Y−Y−A−M−D−Y(配列番号80の残基100−112)であり、
CDR−L1はR−A−S−Q−D−I−R−N−Y−L−N(配列番号93の残基24−34)であり、
CDR−L2はY−T−S−K−L−H−S(配列番号93の残基50−56)であり、及び
CDR−L3はQ−Q−G−L−T−P−P−L−T(配列番号93の残基89−97)である;又は
(f)CDR−H1はT−S−D−M−G−V−D(配列番号80の残基31−37)であり、
CDR−H2はH−I−W−W−D−D−V−K−R−Y−N−P−A−L−K−S(配列番号80の残基52−67)であり、
CDR−H3はT−V−S−S−G−Y−I−Y−Y−A−M−D−Y(配列番号80の残基100−112)であり、
CDR−L1はR−A−S−Q−D−I−R−N−Y−L−N(配列番号94の残基24−34)であり、
CDR−L2はY−T−S−M−K−P−R(配列番号94の残基50−56)であり、及び
CDR−L3はQ−Q−G−L−T−P−P−L−T(配列番号94の残基89−97)である。 - さらにヒト受容体フレームワークを含む、請求項1に記載の結合タンパク質。
- 前記ヒト受容体フレームワークが、以下からなる群から選択されるアミノ酸配列を含む、請求項2に記載の結合タンパク質:
配列番号6
配列番号7
配列番号8
配列番号9
配列番号10
配列番号11
配列番号12
配列番号13
配列番号14
配列番号15
配列番号16
配列番号17
配列番号18
配列番号19
配列番号20
配列番号21
配列番号22
配列番号23
配列番号24
配列番号25
配列番号26
配列番号27
配列番号28
配列番号29
配列番号30及び
配列番号31。 - 前記ヒト受容体フレームワークが、重要な残基における少なくとも1個のフレームワーク領域アミノ酸置換を含み、前記重要な残基が、
CDRに隣接する残基、
グリコシル化部位残基、
希少残基、
ヒトIL−13と相互作用可能な残基、
CDRと相互作用可能な残基、
正準(canonical)残基、
重鎖可変領域と軽鎖可変領域の接触残基、
バーニア(Vernier)ゾーン内の残基、及び
Chothiaによって定義された可変重鎖CDR1とKabatによって定義された第1の重鎖フレームワークとの重複領域中の残基
からなる群から選択される、請求項3に記載の結合タンパク質。 - 重要な残基が、2L、15L、22L、41L、42L、44L、49L、50L、51L、62L、71L、73L、10H、44H、46H、48H、67H、68H、70H、72H、74H、76H、83H、84H、86H、87H及び97Hからなる群から選択される、請求項4に記載の結合タンパク質。
- 前記結合タンパク質が、
配列番号32
配列番号33
配列番号46
配列番号47
配列番号50
配列番号51
配列番号76
配列番号77
配列番号78
配列番号79
配列番号80
配列番号81
配列番号92
配列番号93及び
配列番号94
からなる群から選択されるアミノ酸配列を有する少なくとも1個の可変ドメインを含む、請求項1に記載の結合タンパク質。 - 前記結合タンパク質が2個の可変ドメインを含み、前記2個の可変ドメインが、
配列番号32と配列番号33、
配列番号46と配列番号47、
配列番号50と配列番号51、
配列番号76と配列番号77、
配列番号78と配列番号79、
配列番号80と配列番号81、
配列番号80と配列番号92、
配列番号80と配列番号93及び
配列番号80と配列番号94
からなる群から選択されるアミノ酸配列を有する、請求項6に記載の結合タンパク質。 - 前記可変ドメインが配列番号80と配列番号81のアミノ酸配列を有する、請求項7に記載の結合タンパク質。
- 前記結合タンパク質が、ヒトIL−13(配列番号1)、及び配列番号1の位置130のアルギニン残基がグルタミン残基で置換されているヒトIL−13変種からなる群より選択される標的に結合し得る、請求項1、7及び8のいずれか一項に記載の結合タンパク質。
- 前記結合タンパク質がIL−13の生物学的機能を調節可能又は中和可能である、請求項1に記載の結合タンパク質。
- 前記結合タンパク質が、表面プラズモン共鳴によって測定して、少なくとも102M−1s−1の前記IL−13標的に対するオン速度定数(Kon)を有する;又は
前記結合タンパク質が、表面プラズモン共鳴によって測定して、10−3s−1以下の前記標的に対するオフ速度定数(Koff)を有する;又は
前記結合タンパク質が、10−7M以下の前記標的に対する解離定数(KD)を有する、請求項1に記載の結合タンパク質。 - 請求項1に記載の結合タンパク質を含む抗体構築物であって、リンカーポリペプチド又は免疫グロブリン定常ドメインを更に含む、抗体構築物。
- 前記結合タンパク質が、
免疫グロブリン分子、
モノクローナル抗体、
キメラ抗体、
CDRグラフト抗体、
ヒト化抗体、
Fab、
Fab’、
F(ab’)2、
Fv、
ジスルフィド結合Fv、
scFv、
ダイアボディ
多重特異性抗体、
二重特異性(dual specific)抗体及び
二重特異性(bispecific)抗体
からなる群から選択される、請求項12に記載の抗体構築物。 - 前記結合タンパク質が、
ヒトIgM定常ドメイン、
ヒトIgG1定常ドメイン、
ヒトIgG2定常ドメイン、
ヒトIgG3定常ドメイン、
ヒトIgG4定常ドメイン、
ヒトIgE定常ドメイン及び
ヒトIgA定常ドメイン
からなる群から選択される重鎖免疫グロブリン定常ドメインを含む、請求項12に記載の抗体構築物。 - 請求項12に記載の抗体構築物を含む抗体複合体であって、免疫接着(immunoadhension)分子、造影剤、治療薬及び細胞毒性薬からなる群から選択される薬剤を更に含む、抗体複合体。
- 前記結合タンパク質が、結晶化結合タンパク質である、請求項1に記載の結合タンパク質。
- 前記抗体構築物が、結晶化抗体構築物である、請求項12に記載の抗体構築物。
- 前記抗体複合体が、結晶化抗体複合体である、請求項15に記載の抗体複合体。
- 請求項1に記載の結合タンパク質のアミノ酸配列、請求項12に記載の抗体構築物のアミノ酸配列、又は請求項15に記載の抗体複合体のアミノ酸配列をコードする単離核酸。
- 請求項19に記載の単離核酸を含むベクター。
- 前記ベクターが、pcDNA、pTT、pTT3、pEFBOS、pBV、pJV及びpBJからなる群から選択される、請求項20に記載のベクター。
- 請求項20に記載のベクターを含む、宿主細胞。
- 前記宿主細胞が真核細胞又は原核細胞である、請求項22に記載の宿主細胞。
- 前記真核細胞が、原生生物細胞、動物細胞、植物細胞及び真菌細胞からなる群から選択される、請求項23に記載の宿主細胞。
- 前記動物細胞が、ほ乳動物細胞、トリ細胞及び昆虫細胞からなる群から選択される動物細胞である、請求項24に記載の宿主細胞。
- 前記宿主細胞が、CHO細胞、COS細胞又は酵母細胞からなる群より選択される、請求項23に記載の宿主細胞。
- 請求項22に記載の宿主細胞を、IL−13に結合可能な結合タンパク質の製造に十分な条件下で、培地中で培養することを含む、IL−13に結合可能なタンパク質を製造する方法。
- 請求項27に記載の方法によって製造されたタンパク質。
- (a)請求項16に記載の結晶化結合タンパク質、請求項17に記載の結晶化抗体構築物又は請求項18に記載の結晶化抗体複合体、及び成分とを含む製剤、ならびに
(b)少なくとも1種類の重合体担体
を含む、結合タンパク質の放出用組成物であって、前記成分が、アルブミン、スクロース、トレハロース、ラクチトール、ゼラチン、ヒドロキシプロピル−β−シクロデキストリン、メトキシポリエチレングリコール及びポリエチレングリコールからなる群から選択される、組成物。 - 前記重合体担体が、ポリアクリル酸、ポリシアノアクリラート、ポリアミノ酸、ポリ無水物、ポリデプシペプチド、ポリエステル、ポリ乳酸、ポリ(乳酸−co−グリコール酸)又はPLGA、ポリb−ヒドロキシブチラート、ポリカプロラクトン、ポリジオキサノン;ポリエチレングリコール、ポリ(ヒドロキシプロピル)メタクリルアミド、ポリ(オルガノ)ホスファゼン、ポリオルトエステル、ポリビニルアルコール、ポリビニルピロリドン、無水マレイン酸−アルキルビニルエーテルコポリマー、Pluronicポリオール、アルブミン、アルギナート、セルロース及びセルロース誘導体、コラーゲン、フィブリン、ゼラチン、ヒアルロン酸、オリゴ糖、グリコサミノグリカン(glycaminoglycan)、硫酸化多糖、これらの混合物及びコポリマーからなる群の1種類以上から選択されるポリマーである、請求項29に記載の組成物。
- 哺乳動物を治療しIL−13活性を低下させるための、請求項29に記載の組成物。
- IL−13活性が有害である障害に罹患したヒト対象におけるヒトIL−13活性を低下させる使用のための、請求項1から11及び16のいずれか一項に記載の結合タンパク質、請求項12から14及び17のいずれか一項に記載の抗体構築物、又は請求項15及び18のいずれかに記載の抗体複合体を含む、薬剤組成物。
- 前記障害が、呼吸器障害;ぜん息;アレルギー性及び非アレルギー性ぜん息;感染によるぜん息;呼吸器合胞体ウイルス(RSV)感染によるぜん息;慢性閉塞性肺疾患(COPD);気道炎症を伴う他の症状;好酸球増加症;線維症及び過剰粘液産生;嚢胞性線維症;肺線維症;アトピー性障害;アトピー性皮膚炎;じんま疹;湿疹;アレルギー性鼻炎;及びアレルギー性胃腸炎;皮膚の炎症性及び/又は自己免疫性症状;胃腸器官の炎症性及び/又は自己免疫性症状;炎症性腸疾患(IBD);潰よう性大腸炎;クローン病;肝臓の炎症性及び/又は自己免疫性症状;肝硬変;肝線維症;B及び/又はC型肝炎ウイルスによって引き起こされる肝線維症;強皮症;腫よう又は癌;肝細胞癌;グリア芽細胞腫;リンパ腫;ホジキンリンパ腫;ウイルス感染;(例えば、HTLV−1による)HTLV−1感染;1型防御免疫応答(protective type 1 immune response)の発現抑制並びにワクチン接種中の1型防御免疫応答の発現抑制からなる群から選択される、請求項32に記載の薬剤組成物。
- 第2の薬剤を更に含む請求項32に記載の薬剤組成物であって、前記抗体、抗体構築物、抗体複合体が第2の薬剤の投与前、投与と同時、又は投与後に投与され、前記第2の薬剤が、吸入ステロイド;ベータ作動物質;短時間作用性又は長時間作用性ベータ作動物質;ロイコトリエン又はロイコトリエン受容体の拮抗物質;ADVAIR;IgE阻害剤;抗IgE抗体;XOLAIR;ホスホジエステラーゼ阻害薬;PDE4阻害剤;キサンチン;抗コリン作用薬;肥満細胞安定剤;クロモリン;IL−4阻害剤;IL−5阻害剤;エオタキシン/CCR3阻害剤;ヒスタミン又はH1、H2、H3及びH4を含めたその受容体の拮抗物質;プロスタグランジンD又はその受容体DP1及びCRTH2の拮抗物質;TNF拮抗物質;TNF受容体の可溶性断片;ENBREL;TNF酵素拮抗物質;TNF変換酵素(TACE)阻害剤;ムスカリン受容体拮抗物質;TGFベータ拮抗物質;インターフェロンガンマ;ピルフェニドン;化学療法剤、メトトレキサート;レフルノミド;シロリムス(ラパマイシン)又はその類似体、CCI−779;COX2又はcPLA2阻害剤;NSAID;免疫調節物質;p38阻害剤;TPL−2、MK−2及びNFkB阻害剤;ブデノシド(budenoside);上皮成長因子;コルチコステロイド;シクロスポリン;スルファサラジン;アミノサリチル酸;6−メルカプトプリン;アザチオプリン;メトロニダゾール;リポキシゲナーゼ阻害剤;メサラミン;オルサラジン;バルサラジド;抗酸化剤;トロンボキサン阻害剤;IL−1受容体拮抗物質;抗IL−1β抗体;抗IL−6抗体;成長因子;エラスターゼ阻害剤;ピリジニル−イミダゾール化合物;TNF、LT、IL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、IL−14、IL−15、IL−16、IL−17、IL−18、IL−19、IL−20、IL−21、IL−22、IL−23、IL−24、IL−25、IL−26、IL−27、IL−28、IL−29、IL−30、IL−31、IL−32、IL−33、EMAP−II、GM−CSF、FGF又はPDGFの抗体又は作動物質;CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、CD90又はこれらのリガンドの抗体;FK506;ラパマイシン;ミコフェノール酸モフェチル;イブプロフェン;プレドニゾロン;ホスホジエステラーゼ阻害薬;アデノシン作動物質;抗血栓薬;補体阻害剤;アドレナリン作動薬;IRAK、NIK、IKK、p38又はMAPキナーゼ阻害剤;IL−1β変換酵素阻害剤;TNFα変換酵素阻害剤;T細胞シグナル伝達阻害剤;メタロプロテイナーゼ阻害剤;6−メルカプトプリン;アンジオテンシン変換酵素阻害薬;可溶性サイトカイン受容体;可溶性p55 TNF受容体;可溶性p75 TNF受容体;sIL−1RI;sIL−1RII;sIL−6R;抗炎症性サイトカイン;IL−4;IL−10;IL−11並びにTGFβからなる群から選択される、薬剤組成物。
- 請求項1に記載の結合タンパク質であって、前記結合タンパク質は単離抗体又はその抗原結合性フラグメントであり、前記抗体又はその抗原結合性フラグメントは、
ヒトIL−13に結合し、細胞表面に基づく受容体結合アッセイにおいて、1.5×10−8から1×10−8M、1×10−8から1×10−9M、10−9から10−10M、及び10−10から10−11Mからなる群から選択されるIC50で、又はELISAに基づく受容体結合アッセイにおいて、1.8×10−8から1×10−8M、1×10−8から1×10−9M、10−9から10−10M、及び10−10から10−11Mからなる群から選択されるIC50で、IL−13α2受容体に対する前記IL−13の結合を阻止する、
又は
a)105M−1s−1から106M−1s−1、又は106M−1s−1から107M−1s−1のオン速度定数(kon)、
b)表面プラズモン共鳴によって測定して、10−4s−1から10−5s−1、又は10−5s−1から10−6s−1のオフ速度定数(koff)、及び
c)1.5×10−10から1×10−10M、又は10−10から10−11Mの解離定数(KD)
からなる群から選択される結合特性でIL−13に結合する、結合タンパク質。 - ヒトIL−13に結合し、ヒトIL−13誘発性ぜん息モデルにおいてAHRを少なくとも50%抑制する、請求項35に記載の単離抗体又はその抗原結合性フラグメント。
- 前記抗体又はその抗原結合性フラグメントが、6.68×105M−1s−1、7.86×105M−1s−1、8.35×105M−1s−1、8.69×105M−1s−1、9.15×105M−1s−1、1.26×106M−1s−1、1.7×106M−1s−1及び2.51×106M−1s−1からなる群から選択されるIL−13に対するオン速度定数(kon)を有する、
前記抗体又はその抗原結合性フラグメントが、表面プラズモン共鳴によって測定して、1.23×10−4s−1、1.76×10−4s−1、4.74×10−4s−1、1.91×10−5s−1、2.14×10−5s−1、3.82×10−5s−1、8.81×10−5s−1及び9.65×10−5s−1からなる群から選択されるIL−13に対するオフ速度定数(Koff)を有する、又は
前記抗体又はその抗原結合性フラグメントが、1.05×10−10M、7.10×10−10M、1×10−11M、2.20×10−11M、2.72×10−11M、4.17×10−11M、5.68×10−11M、7.01x10−11M、7.10×10−11M及び9.79×10−11Mからなる群から選択されるIL−13に対する解離定数(KD)を有する、請求項35に記載の抗体又はその抗原結合性フラグメント。 - 抗体又はその抗原結合性フラグメントであって、
配列番号80と配列番号81のアミノ酸配列を有する2つの可変ドメイン;
第234位におけるロイシンからアラニンへの変異及び第235位におけるロイシンからアラニンへの変異を含むヒンジ領域を含むヒトIgG1重鎖定常領域;並びに
ヒトκ軽鎖定常領域を含み、
IL−13に結合し、IL−13Rα1及びIL−13Rα2へのIL−13の結合を阻害する、抗体又はその抗原結合性フラグメント。 - 請求項1から11及び16のいずれか一項に記載の結合タンパク質及び薬学的に許容される担体を含む薬剤組成物。
- 請求項35から37のいずれか一項に記載の抗体又はその抗体結合性フラグメント、及び薬学的に許容される担体を含む薬剤組成物。
- 請求項38に記載の抗体又はその抗原結合性フラグメント、及び薬学的に許容される担体を含む薬剤組成物。
- 請求項38に記載の抗体又はその抗原結合性フラグメントを含む、IL−13活性が有害である障害の治療において使用するための薬剤組成物であって、前記障害が、ぜん息、好酸球増加症、アトピー性皮膚炎、じんま疹、又はアレルギー性鼻炎である薬剤組成物。
- IL−13活性が有害である障害の治療において使用するための請求項41に記載の薬剤組成物であって、前記障害が、ぜん息、好酸球増加症、アトピー性皮膚炎、じんま疹、又はアレルギー性鼻炎である薬剤組成物。
- 前記薬学的に許容される担体が、前記結合タンパク質の吸収又は分散の増大に有用であるアジュバントとして機能する、請求項39、40又は41に記載の薬剤組成物。
- IL−13活性が有害である障害を治療するための少なくとも1種類の追加の治療薬を更に含む、請求項39から43のいずれか一項に記載の薬剤組成物。
- 前記追加の薬剤が、治療薬、造影剤、細胞毒性薬、血管新生阻害剤;キナーゼ阻害剤;同時刺激分子遮断薬;接着分子遮断薬;抗サイトカイン抗体又はその機能的断片;メトトレキサート;シクロスポリン;ラパマイシン;FK506;検出可能な標識又はレポーター;TNF拮抗物質;抗リウマチ薬;筋弛緩薬、麻薬、非ステロイド抗炎症薬(NSAID)、鎮痛薬、麻酔薬、鎮静薬、局所麻酔薬、神経筋遮断薬、抗菌剤、乾せん治療薬、コルチコステロイド、タンパク質同化ステロイド、エリスロポイエチン、免疫化、免疫グロブリン、免疫抑制剤、成長ホルモン、ホルモン補充薬、放射性医薬品、抗うつ薬、抗精神病薬、刺激薬、ぜん息治療薬、ベータ作動物質、吸入ステロイド、経口ステロイド、エピネフリン又は類似体、サイトカイン及びサイトカイン拮抗物質からなる群から選択される、請求項39から43のいずれか一項に記載の薬剤組成物。
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