JP2016513666A - 組織メタロプロテイナーゼ阻害物質3型(timp−3)の変異体、組成物、及び方法 - Google Patents
組織メタロプロテイナーゼ阻害物質3型(timp−3)の変異体、組成物、及び方法 Download PDFInfo
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Abstract
Description
本願は、2013年3月14日出願の米国仮特許出願第61/782,613号;2013年3月15日出願の米国仮特許出願第61/798,160号;2013年3月18日出願の米国仮特許出願第61/802,988号;及び2014年2月17日出願の米国仮特許出願第61/940,673号の利益を主張し、これらの文献はその全体が参照により本明細書に援用される。
本願は、電子フォーマットの配列表と一緒に提出されている。この配列表は、2014年3月11日作成のA−1827WOPCT_SL31314という表題のファイルとして提供されており、サイズが306KBである。その配列表に関する電子フォーマットの情報は、その全体が参照により本明細書に援用される。
当分野で既知のいずれの発現系をも用いて本発明の組換えポリペプチドを作製することができる。一般に、宿主細胞は、所望のTIMP−3ポリペプチド(TIMP−3突然変異タンパク質または変異体を含む)をコードするDNAを含む組換え発現ベクターにより形質転換される。用いることのできる宿主細胞としては、原核生物、酵母菌またはより高等な真核生物細胞がある。原核生物としては、グラム陰性菌またはグラム陽性菌、例えば、大腸菌または桿菌が挙げられる。より高等な真核生物細胞としては、昆虫細胞及び哺乳動物起源の樹立細胞株が挙げられる。適切な哺乳動物の宿主細胞株の例としては、サル腎臓由来細胞のCOS−7株(ATCC CRL 1651)(Gluzman et al.,1981,Cell 23:175)、L細胞、293細胞、C127細胞、3T3細胞(ATCC CCL 163)、チャイニーズハムスター卵巣(CHO)細胞、HeLa細胞、BHK(ATCC CRL 10)細胞株、及びMcMahan et al.,1991,EMBO J.10:2821に記載されるようなアフリカミドリザル腎臓由来細胞株CVI(ATCC CCL 70)に由来するCVI/EBNA細胞株が挙げられる。細菌、真菌、酵母菌、及び哺乳動物の細胞宿主と使用するのに適切なクローニング及び発現ベクターが、Pouwels et al.(Cloning Vectors:A Laboratory Manual,Elsevier,New York,1985)に記載される。
TIMP−3ポリペプチド、変異体、突然変異タンパク質、または誘導体は、例えば、アッセイにおいて用いることができ、あるいは、それらはより多いレベルのTIMP−3活性が望まれるいずれかの状態(即ち、TIMP−3によって阻害されるか阻害され得るマトリクスメタロプロテアーゼ(MMP)及び/または他のプロテイナーゼが原因的または増悪的働きをする状態)の治療でも用いることができ、それとしては、以下に限定されないが、炎症性状態、骨関節炎、及び過剰もしくは不適切なMMP活性が起こる他の状態(例えば、心筋虚血、再潅流傷害、及び鬱血性心不全への進行途中)が挙げられる。炎症性状態としては、喘息、慢性閉塞性肺疾患(COPD)、及び特発性肺線維症(IPF)、炎症性腸疾患(例えば、潰瘍性大腸炎、クローン病、及びセリアック病)、乾癬、ウイルス性心筋炎を含む心筋炎、アテローム性動脈硬化症に関連した炎症、並びに、関節リウマチ、乾癬性関節炎及び同種のものを含む関節炎の状態が挙げられる。
また、本発明に包含されるのは、有効量の本発明のポリペプチド産生物(即ち、TIMP−3ポリペプチド、変異体、突然変異タンパク質、または誘導体)を、TIMP−3治療法(即ち、TIMP−3の内在レベルを増やすことまたは内因性TIMP−3の活性を増大することが有用である状態)に有用な薬剤的に許容できる希釈剤、保存剤、可溶化剤、乳化剤、アジュバント、及び/または担体とともに含む医薬組成物である。かかる組成物としては、様々な緩衝液含有量(例えば、トリスHCl、酢酸塩、リン酸塩)、pH、及びイオン強度の希釈剤;洗浄剤及び可溶化剤などの添加剤(例えば、トウィーン80、ポリソルベート80)、抗酸化剤(例えば、アスコルビン酸、メタ重亜硫酸ナトリウム)、保存剤(例えば、チメルソル(Thimersol)、ベンジルアルコール)及び充填物質(例えば、ラクトース、マンニトール);タンパク質へポリエチレングリコールなどのポリマーを共有結合的に付加したもの(上に考察の通りであり、例えば、米国特許第4,179,337号を参照されたく、なお、この文献は参照により本明細書に援用される);ポリ乳酸、ポリグリコール酸などのポリマー化合物の粒子状調製物またはリポソームに材料を組み込んだもの、が挙げられる。かかる組成物は、TIMP−3結合タンパク質の物理的状態、安定性、生体内放出速度、及び生体内排除速度に影響を与えることができる。例えば、Remington’s Pharmaceutical Sciences,18th Ed.(1990,Mack Publishing Co.,Easton,PA 18042)1435−1712ページを参照されたく、なお、この文献は参照により本明細書に援用される。
この実施例は、哺乳動物の発現系での発現に対してTIMP−3の1つ以上の突然変異の作用があればそれを決定するために用いられる方法を説明する。この実施例は、一般的なベクター及び宿主細胞系について記載しており、多くのベクター及び宿主細胞系は当分野で既知であり、本明細書に記載されており、組換えタンパク質の発現に対してTIMP−3配列中の特定の突然変異の作用がもしあればその決定に適切である。
この実施例は、TIMP−3の1つ以上の突然変異がヘパリン非依存性の増加を引き起こしたかどうかを決定するのに用いられる方法を記載する。細胞は、先に記載された通り形質転換またはトランスフェクトし、ヘパリンの存在または不存在下で培養する。ヘパリンを種々の量で加えて、ヘパリン依存性の程度が半定量的に分かるようにすることができる。次いで、種々の条件下で発現されるTIMP−3タンパク質、突然変異タンパク質、または変異体の量を決定し、ヘパリンが細胞外マトリクスからのTIMP−3タンパク質、突然変異タンパク質、もしくは変異体の放出に必要とされるか否か、または、必要とされる量もしくはヘパリンが低減されるか否かに特定の突然変異がいくらかでも作用を及ぼすかどうかを決定する比較を行う。
この実施例は、蛍光分析を用いてMMP活性を測定するMMP阻害アッセイについて記載し、他の方法は当分野で既知である。例えば、消光されたMMPサブタイプ5−FAM/QXL520蛍光共鳴エネルギー転移(FRET)ペプチド基質を活性化MMPサブタイプまたはサブタイプ特異的触媒領域によって切断すると、蛍光シグナルが増加する。いくつかの種々のMMPに対するFRETペプチドが、例えば、Anaspec,Fremont,CAから市販される。本明細書で使用される場合、TIMP−3タンパク質とは、天然TIMP−3またはTIMP−3突然変異タンパク質、変異体、もしくは誘導体であってもよく、試験されるタンパク質は試験分子と称される。
分子生物学の標準的な技術を用いて、TIMP−3の多くの突然変異タンパク質をコードする核酸を調製し、実質的に先に記載した通りに哺乳動物の細胞中に発現させた。コードされたTIMP−3突然変異タンパク質の発現に対する突然変異の作用を評価した。作製された突然変異のリストは次のものを含む:
G115T、N118D;K45E、K49S;K45E、K49E;K45E、T63E;K45E、Q80E;T63E、H78E;K45E、T63E、H78E;T63E、H78E、Q80E;K45E、T63E、H78E、Q80E;T63E、H78D;T63E、T74E、H78E;T63E、T74E、H78D;L51T、T74E、H78D;T74E、H78E、Q80E;T74E、H78D、Q80E;R43T、T74E、H78D、Q80E;R43E、T74E、H78D、Q80E;R43N、K45T;K45N、V47T;K49N、L51T;K65N、M67T;K75N、P77T;R43N、K45T、K49N、L51T;K45N、V47T、K49N、L51T;R43N、K45T、T63E、T74E、H78E;K45N、V47T、T63E、T74E、H78E;K49N、L51T、T63E、T74E、H78E;K45E、K49N、L51T、T63E;R43T、K49N、L51T、T74E、H78D;R43N、K45T、T74E、H78E;K49N、L51T、T74E、H78E;R43N、K45T、K49N、L51T、T74E、H78E;Q32N、A34T;S38D、D39T;R43N、K45T;V47N、K49T;K49N、L51T;K50N、V52T;L51N、K53T;F57N;P56N、G58T;T63N、K65T;P56N、G58T、T63N、K65T;M67N、M69T;H78N、Q80T;T84N、A86T;K94N、E96T;E96N、N98T;V97N、K99T;K99N、Q101T;T105N、R107T;D110N、K112T;E122N、W124T;R123N、D125T;Q126N;T128N;Q131N、K133T;R132N G134T;R138N、H140T;R138T;H140N、G142T;K142T;K146N、K148T;T158N、K160T;T166N、M168T;M168N;G173T;HS179N、H181T;H181N、A183T;R186N、K188T;R196N、W198T;P200N、D202T;P201N、K203T;D202N;A208Y;A208V;K45S、F57N;K49S、F57N;K68S、F57N;K133S、F57N;K45S、K133S、F57N;及びK49S、K68S、F57N。
この表は、哺乳動物の細胞中に実際に発現した多くのTIMP−3突然変異タンパク質で得られた、発現とMMP阻害の結果をまとめている。「哺乳動物での発現対WT」について、データは、発現が野生型(即ち、天然)TIMP−3のそれと実質的に同じであったことを示す「+」;発現が野生型TIMP−3で観察されたそれの2〜4倍に増加したことを示す「++」;発現が野生型TIMP−3の4倍より多くに増加したことを示す「+++」、として記録されている。酵素阻害を示す列の記号「−−−」は、かかる試験がなされなかったことを示す。野生型TIMP−3に対して観察した発現との比較で発現の倍数的増加を例証する発現レベルの増加を、ウエスタンブロットもしくはSDS−PAGE Coomassie染色ゲルを用いて定性的に決定するか、抗TIMP−3抗体(かかる抗体は、例えば、EMD Millipore,Billerica,MA:AbCam(登録商標),Cambridge,MA、もしくはR&D Systems,Minneapolis,MNから市販される)を用いてTIMP−3を捉えるForteBio Octet(登録商標)の読み取りで測定される発現力価の測定を通して定性的に決定する。
この実施例は、蛍光活性化細胞選別器(FACS)分析によって、TIMP−3タンパク質のHTB−94(商標)細胞(米国菌培養収集所(the American Type Culture Collection),Manassas,VAより市販される軟骨細胞株)に結合する能力を評価するアッセイについて記載する。HTB−94細胞を、HTB−94培地(10%ウシ胎児血清[FBS]及び2mM Lグルタミンを含有する高グルコースDMEM)中、5%CO2下37℃で培養する。細胞は、染色6〜12週間前に、標準細胞培養フラスコ中2.5×104細胞/mlの細胞密度で播種しておき、トリプシン処理によってフラスコから除去した後3〜4日ごとに継代培養する。FACS染色約16時間前に、HTB−94細胞をウェルあたり100,000細胞にて標準組織培養12ウェルプレートで2ml体積HTB94培地に播種し、5%CO2下37℃でインキュベートする。細胞は染色前に80〜90%コンフルエントである。
T、R138T、G173T、R186Q、K188Q;K45S、P56N、G58T、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q;K45S、P56N、G58T、D110N、K112T、R138T、K188E;K45S、P56N、G58T、K94N、E96T、D110N、K112T、K188E;K45S、P56N、G58T、D110N、K112T、R138T、R186N、K188T;K45S、P56N、G58T、K94N、E96T、D110N、K112T、R186N、K188T;K45S、P56N、G58T、D110N、K112T、R138T、R186Q、K188Q;K45S、P56N、G58T、K94N、E96T、D110N、K112T、R186Q、K188Q;K45E、P56N、G58T、K94N、E96T、D110N、K112T、R138T、G173T;K45E、P56N、G58T、K94N、E96T、R138T、G173T;K45S、P56N、G58T、K94N、E96T、D110N、K112T、R138T、G173T;K45S、P56N、G58T、K94N、E96T、R138T、G173T;K45N、V47T、P56N、G58T、H78N、Q80T、Q126N、R186Q、K188Q;K45N、V47T、P56N、G58T、H78N、Q80T、K94N、E96T、Q126N、;K45N、V47T、P56N、G58T、H78N、Q80T、Q126N、R138T;K45N、V47T、P56N、G58T、H78N、Q80T、R138T、R186Q、K188Q;K45N、V47T、P56N、G58T、H78N、Q80T、K94N、E96T、D110N、K112T、R186Q、K188Q;K45E、P56N、G58T、Q126N、R138T、R186Q、K188Q;K45N、V47T、P56N、G58T、Q126N、R138T、R186Q、K188Q;K45N、V47T、P56N、G58T、H78N、Q80T、R186Q、K188Q;K45S、P56N、G58T、H78N、Q80T、Q126N、R138T、R186Q、K188Q;K45S、P56N、G58T、H78N、Q80T、K94N、E96T、R138T、R186Q、K188Q;K45N、V47T、P56N、G58T、K94N、E96T、D110N、K112T、R186Q、K188Q;K45S、P56N、G58T、H78N、Q80T、K94N、E96T、R138T;K45N、V47T、P56N、G58T、K94N、E96T、D110N、K112T、R186Q;及びK45N、V47T、P56N、G58T、K94N、E96T、D110N、K112T、K188Qが挙げられる。これらの突然変異タンパク質は、本明細書に記載の通りに作製し試験することができる。
Claims (19)
- 配列番号2に示されるTIMP−3の成熟領域に対してアミノ酸配列が少なくとも95%同一である成熟領域を有し、少なくとも1つの突然変異を有し、前記突然変異がK45E;K45N;K45S;V47T;K49N;K49E;K49S;K50N;L51T;L51N;V52T;K53T;P56N;F57N;G58T;T63E;T63N;K65T;K65N;M67T;K68S;T74E;K75N;P77T;H78D;H78E;H78N;Q80E;Q80T;K94N;E96T;E96N;V97N;N98T;K99T;D110N;K112T;Q126N;K133S;R138T;R138N;H140T;T158N;K160T;T166N;M168T;G173T;H181N;A183T;R186N;R186Q、R186E、K188T;K188Q、K188E、P201N;K203T;I205F、I205Y、A208G、A208V、及びA208Yからなる群より選択される、単離されたTIMP−3突然変異タンパク質。
- 配列番号2に示されるTIMP−3の成熟領域に対してアミノ酸配列が少なくとも95%同一の成熟領域を有し、突然変異F57N及び少なくとも1つのさらなる突然変異を有し、前記突然変異はTIMP−3の1つ以上のK残基での置換である、単離されたTIMP−3突然変異タンパク質。
- 前記さらなる突然変異が前記アミノ酸配列中にN結合型グリコシル化部位を導入する、請求項2に記載のTIMP−3突然変異タンパク質。
- 配列番号2に示されるTIMP−3の成熟領域に対してアミノ酸配列が少なくとも90%同一の成熟領域を有し、前記突然変異タンパク質が、少なくとも1つのN結合型グリコシル化部位を前記アミノ酸配列の中に導入する少なくとも1つの突然変異を有する、単離されたTIMP−3突然変異タンパク質。
- 2、3、4、5、または6のN結合型グリコシル化部位が導入された、請求項4に記載のTIMP−3突然変異タンパク質。
- 前記N結合型グリコシル化部位が、アミノ酸48〜54を含む領域;アミノ酸93〜100を含む領域;アミノ酸121〜125を含む領域;アミノ酸143〜152を含む領域;アミノ酸156〜164を含む領域;アミノ酸183〜191を含む領域;及びその組合せからなる群より選択される前記TIMP−3アミノ酸配列の領域で導入される、請求項3に記載のTIMP−3突然変異タンパク質。
- 2、3、4、5または6(以上)のN結合型グリコシル化部位が導入される、請求項6に記載のTIMP−3突然変異タンパク質。
- 配列番号2に示されるTIMP−3の成熟領域に対してアミノ酸配列が少なくとも95%同一の成熟領域を有する単離されたTIMP−3突然変異タンパク質であって、前記突然変異タンパク質が
(a)TIMP−1、TIMP−2またはTIMP−4の電荷表面を模する、TIMP−3表面に露出した正電荷パッチの特性に変化を引き起こす、前記TIMP−3電荷パッチにおける1つ以上の突然変異;
(b)タンパク質切断の受けやすさを低減する1つ以上の突然変異;
(c)前記TIMP−3突然変異タンパク質とスカベンジャー受容体LRP−1の相互作用の低下を引き起こす1つ以上の突然変異;
(d)前記TIMP−3突然変異タンパク質のヘパリンまたは細胞外マトリクス成分の相互作用の低下を引き起こす1つ以上の突然変異;
(e)前記天然TIMP−3配列への1つ以上のシステイニル残基の追加;
(f)薬物動態学的及び/または薬力学的特性の向上;
(g)少なくとも1つのN結合型グリコシル化部位を導入する1つ以上の突然変異;及び
(h)(a)〜(g)に示される前記突然変異の組合せ、
からなる群より選択される少なくとも1つの突然変異を有する、前記単離されたTIMP−3突然変異タンパク質。 - i. K45E、K49S;(配列番号5)
ii. K45E、K49E;(配列番号6)
iii. K45E、T63E;(配列番号7)
iv. K45E、Q80E;(配列番号8)
v. K45E、T63E、H78E;(配列番号10)
vi. T63E、H78E、Q80E;(配列番号11)
vii. K45E、T63E、H78E、Q80E;(配列番号12)
viii. T63E、T74E、H78E;(配列番号13)
ix. T63E、T74E、H78D;(配列番号14)
x. L51T、T74E、H78D;(配列番号53)
xi. T74E、H78E、Q80E;(配列番号16)
xii. T74E、H78D、Q80E;(配列番号17)
xiii. K45N、V47T;(配列番号26)
xiv. K65N、M67T;(配列番号37)
xv. K45N、V47T、T63E、T74E、H78E;(配列番号18)
xvi. K49N、L51T、T63E、T74E、H78E;(配列番号19)
xvii. K45E、K49N、L51T、T63E;(配列番号20)
xviii. K49N、L51T、T74E、H78E;(配列番号21)
xix. K49N、L51T;(配列番号27)
xx. K50N、V52T;(配列番号30)
xxi. L51N、K53T;(配列番号54)
xxii. F57N;(配列番号33)
xxiii. P56N、G58T;(配列番号31)
xxiv. T63N、K65T;(配列番号36)
xxv. P56N、G58T、T63N、K65T;(配列番号32)
xxvi. K75N、P77T;(配列番号38)
xxvii. H78N、Q80T;(配列番号39)
xxviii. K94N、E96T;(配列番号40)
xxix. E96N、N98T;(配列番号41)
xxx. V97N、K99T;(配列番号42)
xxxi. D110N、K112T;(配列番号43)
xxxii. Q126N;(配列番号44)
xxxiii. R138N、H140T;(配列番号46)
xxxiv. R138T;(配列番号45)
xxxv. T158N、K160T;(配列番号47)
xxxvi. T166N、M168T;(配列番号48)
xxxvii. G173T;(配列番号49)
xxxviii. H181N、A183T;(配列番号50)
xxxix. R186N、K188T;(配列番号51)
xl. P201N、K203T;(配列番号52)
xli. A208Y;(配列番号55)
xlii. A208V;(配列番号56)
xliii. K45S、F57N;(配列番号23)
xliv. K49S、F57N;(配列番号28)
xlv. K68S、F57N;(配列番号34)
xlvi. K133S、F57N;(配列番号35)
xlvii. K45S、K133S、F57N;(配列番号24)
xlviii. K49S、K68S、F57N(配列番号29)
xlix. K45S、F57N、I205F、A208G(配列番号57)
l. K45S、F57N、A208G(配列番号58)
li. K45S、F57N、I205Y(配列番号59)
lii. K45S、F57N、I205Y、A208G(配列番号60)
liii. K45N、V47T、F57N、K75N、P77T、K94N、E96T、R138T、G173T(配列番号61)
liv. K45N、V47T、F57N、K94N、E96T、R138T、G173T(配列番号62):
lv. K45N、V47T、K50N、V52T、F57N、V97N、K99T(配列番号63)
lvi. K45S、K50N、V52T、F57N、V97N、K99T、R186N、K188T(配列番号64)
lvii. K45S、F57N、K94N、E96T、D110N、K112T、R138T、G173T(配列番号65)
lviii. K45S、F57N、T63N、K65T、K94N、E96T、G173T(配列番号66)
lix. K45N、V47T、K50N、V52T、F57N、V97N、K99T、R138T、R186N、K188T(配列番号67)
lx. K45S、F57N、T63N、K65T、K94N、E96T、Q126N、R138T(配列番号68)
lxi. K45N、V47T、K50N、V52T、F57N、V97N、K99T、R186N、K188T(配列番号69)
lxii. K45N、V47T、K50N、V52T、V97N、K99T、R138T、R186N、K188T(配列番号70)
lxiii. K45S、F57N、H78N、Q80T、K94N、E96T、R138T、G173T(配列番号71)
lxiv. K45S、F57N、K75N、P77T、K94N、E96T、R138T、G173T(配列番号72)
lxv. K45N、V47T、K50N、V52T、V97N、K99T、G173T、R186N、K188T(配列番号73)
lxvi. K45E、F57N、Q126N、R138T、G173T(配列番号74)
lxvii. K45S、F57N、T63N、K65T、K94N、E96T、R138T、G173T(配列番号75)
lxviii. K45S、K50N、V52T、F57N、V97N、K99T、R138T、R186N、K188T(配列番号76)
lxix. K45S. K50N、V52T、F57N、V97N、K99T、G173T、R186N、K188T(配列番号77)
lxx. K45N、V47T、F57N、K94N、E96T、G173T、R186N、K188T(配列番号78)
lxxi. K45N、V47T、F57N、K94N、E96T、D110N、K112T、R186N、K188T(配列番号79)
lxxii. K45N、V47T、F57N、V97N、K99T、R138T、G173T(配列番号80)
lxxiii. K45N、V47T、F57N、K99E G173T、R186N、K188T(配列番号81)
lxxiv. K45E、K49E、F57N、K94N、E96T、D110N、K112T、G173T、R186N、K188T(配列番号82)
lxxv. K50N、V52T、K94N、E96T、R138T、G173T(配列番号83)
lxxvi. K45E、K50N、V52T、K94N、E96T、D110N、K112T、R138T、G173T(配列番号84)
lxxvii. K50N、V52T、K94N、E96T、R138T、G173T、R186N、K188T(配列番号85)
lxxviii. K45E、F57N、T63N、K65T、K94N、E96T、G173T、R186N、K188T(配列番号86)
lxxix. K45N、V47T、F57N、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q(配列番号87)
lxxx. K45S F57N K94N、E96T R138T G173T(配列番号88)
lxxxi. K45E F57N K94N、E96T R138T G173T(配列番号89)
lxxxii. K45E F57N K94N、E96T D110N、K112T R138T G173T(配列番号90)
lxxxiii. K45E F57N K94N、E96T R138T G173T R186Q、K188Q(配列番号91)
lxxxiv. K45E F57N K94N、E96T R138T G173T R186E(配列番号92)
lxxxv. K45E F57N K94N、E96T R138T G173T K188E(配列番号93)
lxxxvi. K45E F57N K94N、E96T R138T G173T R186N、K188T(配列番号94)
lxxxvii. K45E K50N、V52T K94N、E96T D110N、K112T R138T G173T(配列番号95)
lxxxviii. K45E K50N、V52T K94N、E96T R138T G173T K188E(配列番号96)
lxxxix. K50N、V52T F57N K94N、E96T R138T G173T(配列番号97)
xc. K50N、V52T F57N K94N、E96T D110N、K112T R138T(配列番号98)、及び
xci. K45E F57N K94N、E96T D110N、K112T R138T(配列番号99)
からなる群より選択される、請求項8に記載のTIMP−3突然変異タンパク質。 - K49E、K50E、K53E、K99E、R186Q、K188Q;K49S、K50N/V52T、K53E、V97N/K99T、R186N/K188T;K50N/V52T、V97N/K99T、R186N/K188T;K49E、K53E、K188Q;K50N/V52T、R186N/K188T;K50N/V52T、F57N、R186N/K188T;K45S、K50N/V52T、F57N、R186N/K188T;K50N/V52T、F57N、T63N/K65T、R186N/K188T;K45S、K50N/V52T、F57N R186N/K188T;K45S、K49S、K50N/V52T、F57N R186N/K188T;K49S、K50N/V52T、F57N、V97N/K99T、R186N/K188T;K45S、K50N/V52T、F57N、V97N/K99T、R186N/K188T;K45S、F57N、D110N、K112T;K45S、F57N、H78N、Q80T、D110N、K112T;K45S、F57N、H78N、Q80T、D110N、K112T、Q126N;K45S、F57N、H78N、Q80T、K94N、E96T Q126N;K45S、F57N、H78N、Q80T、Q126N、G173T;K45S、F57N、T63N、K65T;K45S、F57N、T63N、K65T、K94N、E96T;K45S、F57N、T63N、K65T、R138T、G173T;K45N、V47T、F57N、T63N、K65T、R138T、G173T;K45S、F57N、T63N、K65T、K94N、E96T、R138T;K45N、V47T、F57N、T63N、K65T、K94N、E96T、R138T;K45S、F57N、Q126N、R138T、G173T;P56N、G58T、T63N、K65T、K94N、E96T、Q126N、G173T;P56N、G58T、T63N、K65T、D110N、K112T、Q126N、G173T;K49S、K50N、V52T、K53E、V97N、K99T、R186N、K188T;K50N、V52T、V97N、K99T、R186N、K188T;K49E、K53E、K188Q;K50N、V52T、R186N、K188T;K50N、V52T、F57N、R186N、K188T;K45S、K50N、V52T、F57N、R186N、K188T;K50N、V52T、F57N、T63N、K65T、R186N、K188T;K45S、K50N、V52T、F57N R186N、K188T;K45S、K49S、K50N、V52T、F57N R186N、K188T;K49S、K50N、V52T、F57N、V97N、K99T、R186N、K188T;K45S、K50N、V52T、F57N、V97N、K99T、R186N、K188T;K45E、K50N、V52T、D110N、K112T、R138T、G173T、K188E;K45E、F57N、D110N、K112T、R138T、G173T、K188E;K45E、K50N、V52T、K94N、E96T、D110N、K112T、G173T、K188E;K45E、F57N、K94N、E96T、D110N、K112T、G173T、K188E;K45E、K50N、V52T、D110N、K112T、R138T、G173T、R186N、K188T;K45E、F57N、D110N、K112T、R138T、G173T、R186N、K188T;K45E、K50N、V52T、K94N、E96T、D110N、K112T、G173T、R186N、K188T;K45E、F57N、K94N、E96T、D110N、K112T、G173T、R186N、K188T;K45E、K50N、V52T、D110N、K112T、R138T、G173T、R186Q、K188Q;K45E、F57N、D110N、K112T、R138T、G173T、R186Q、K188Q;K45E、K50N、V52T、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q;K45E、F57N、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q;K45E、K50N、V52T、D110N、K112T、R138T、K188E;K45E、F57N、D110N、K112T、R138T、K188E;K45E、K50N、V52T、K94N、E96T、D110N、K112T、K188E;K45E、F57N、K94N、E96T、D110N、K112T、K188E;K45E、K50N、V52T、D110N、K112T、R138T、R186N、K188T;K45E、F57N、D110N、K112T、R138T、R186N、K188T;K45E、K50N、V52T、K94N、E96T、D110N、K112T、R186N、K188T;K45E、F57N、K94N、E96T、D110N、K112T、R186N、K188T;K45E、K50N、V52T、D110N、K112T、R138T、R186Q、K188Q;K45E、F57N、D110N、K112T、R138T、R186Q、K188Q;K45E、K50N、V52T、K94N、E96T、D110N、K112T、R186Q、K188Q;K45E、F57N、K94N、E96T、D110N、K112T、R186Q、K188Q;K50N、V52T、D110N、K112T、R138T、G173T、K188E;K45S、F57N、D110N、K112T、R138T、G173T、K188E;K50N、V52T、K94N、E96T、D110N、K112T、G173T、K188E;K45S、F57N、K94N、E96T、D110N、K112T、G173T、K188E;K50N、V52T、D110N、K112T、R138T、G173T、R186N、K188T;K45S、F57N、D110N、K112T、R138T、G173T、R186N、K188T;K50N、V52T、K94N、E96T、D110N、K112T、G173T、R186N、K188T;K45S、F57N、K94N、E96T、D110N、K112T、G173T、R186N、K188T;K50N、V52T、D110N、K112T、R138T、G173T、R186Q、K188Q;K45S、F57N、D110N、K112T、R138T、G173T、R186Q、K188Q;K50N、V52T、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q;K45S、F57N、K94N、E96T、D110N、K112T、G173T、R186Q、K188Q;K50N、V52T、D110N、K112T、R138T、K188E;K45S、F57N、D110N、K112T、R138T、K188E;K50N、V52T、K94N、E96T、D110N、K112T、K188E;K45S、F57N、K94N、E96T、D110N、K112T、K188E;K50N、V52T、D110N、K112T、R138T、R186N、K188T;K45S、F57N、D110N、K112T、R138T、R186N、K188T;K50N、V52T、K94N、E96T、D110N、K112T、R186N、K188T;K45S、F57N、K94N、E96T、D110N、K112T、R186N、K188T;K50N、V52T、D110N、K112T、R138T、R186Q、K188Q;K45S、F57N、D110N、K112T、R138T、R186Q、K188Q;K50N、V52T、K94N、E96T、D110N、K112T、R186Q、K188Q;K45S、F57N、K94N、E96T、D110N、K112T、R186Q、K188Q;K50N、V52T、K94N、E96T、D110N、K112T、R138T、G173T;K50N、V52T、K94N、E96T、R138T、G173T;K45E、F57N、K94N、E96T、D110N、K112T、R138T、G173T;K45E、F57N、K94N、E96T、R138T、G173T;K45S、F57N、K94N、E96T、D110N、K112T、R138T、G173T;K45S、F57N、K94N、E96T、R138T、G173T;K45N、V47T、、H78N、Q80T、Q126N、R186Q、K188Q;K45N、V47T、F57N、H78N、Q80T、Q126N、R186Q、K188Q;K45N、V47T、F57N、H78N、Q80T、K94N、E96T、Q126N、;K45N、V47T、F57N、H78N、Q80T、Q126N、R138T;K45N、V47T、F57N、H78N、Q80T、R138T、R186Q、K188Q;K45N、V47T、F57N、H78N、Q80T、K94N、E96T、D110N、K112T、R186Q、K188Q;K50N、V52T、K94N、E96T、H78N、Q80T、R138T;K50N、V52T、K94N、E96T、H78N、Q80T、R138T、R186Q、K188Q;K45E、F57N、Q126N、R138T、R186Q、K188Q;K45N、V47T、F57N、Q126N、R138T、R186Q、K188Q;K45N、V47T、F57N、H78N、Q80T、R186Q、K188Q;K45S、F57N、H78N、Q80T、Q126N、R138T、R186Q、K188Q;K45S、F57N、H78N、Q80T、K94N、E96T、R138T、R186Q、K188Q;K50N、V52T、K94N、E96T、H78N、Q80T、R138T、;K45N、V47T、F57N、K94N、E96T、D110N、K112T、R186Q、K188Q;及びK45S、F57N、H78N、Q80T、K94N、E96T、R138T;K45N、V47T、F57N、K94N、E96T
からなる群より選択される、請求項8に記載のTIMP−3突然変異タンパク質。 - 請求項1〜10のいずれか一項に記載のTIMP−3突然変異タンパク質をコードする、単離された核酸。
- 請求項11に記載の単離された核酸を含む発現ベクター。
- 請求項12に記載の発現ベクターにより形質転換またはトランスフェクトされた、単離された宿主細胞。
- 組換えTIMP−3突然変異タンパク質の産生方法であって、請求項13に記載の形質転換またはトランスフェクトされた宿主細胞を前記TIMP−3突然変異タンパク質の発現を促進する条件下で培養することと、前記TIMP−3突然変異タンパク質を回収することとを含む、前記方法。
- 請求項1〜10のいずれか一項に記載のTIMP−3突然変異タンパク質と、生理学的に許容できる希釈剤、賦形剤、または担体とを含む組成物。
- TIMP−3によって阻害されるか阻害され得るマトリクスメタロプロテアーゼ(MMP)及び/または他のプロテイナーゼが原因的または増悪的働きをする状態の治療方法であって、前記状態を治療するのに十分な量の請求項15の組成物をかかる状態に罹った個人に投与することを含む、前記方法。
- 前記状態が、炎症性状態、骨関節炎、心筋虚血、再潅流傷害、及び、鬱血性心不全への進行からなる群より選択される、請求項16に記載の方法。
- 前記状態が、喘息、慢性閉塞性肺疾患(COPD)、及び特発性肺線維症(IPF)、炎症性腸疾患(例えば、潰瘍性大腸炎、クローン病、及びセリアック病)、乾癬、ウイルス性心筋炎を含む心筋炎、アテローム性動脈硬化症に関連した炎症、並びに、関節リウマチ及び乾癬性関節炎を含む関節炎状態からなる群より選択される、請求項16に記載の方法。
- 前記状態が、栄養障害型表皮水疱症、骨関節炎、偽痛風、若年性関節リウマチを含む関節リウマチ、強直性脊椎炎、歯周病、角膜潰瘍、表皮潰瘍、胃潰瘍を含む潰瘍、手術後の創傷治癒、再狭窄、肺気腫、骨パジェット病、骨粗鬆症、強皮症、褥瘡などの骨または組織の圧迫萎縮、真珠腫、創傷治癒異常、少関節性リウマチ様関節炎、多関節性リウマチ様関節炎、全身性発症関節リウマチ、強直性脊椎炎、腸疾患性関節炎、反応性関節炎、ライター症候群、SEA症候群(血清陰性、腱付着部症、関節症症候群)、皮膚筋炎、乾癬性関節炎、強皮症、全身性エリテマトーデス、脈管炎、マイオリティス(myolitis)、ポリマイオリティス(polymyolitis)、ダーマトマイオリティス(dermatomyolitis)、骨関節炎、結節性多発動脈炎、ウェゲナー肉芽腫症、動脈炎、リウマチ性多発筋痛症、サルコイドーシス、硬化症、原発性胆汁性硬化症、硬化性胆管炎、シェーグレン症候群、乾癬、尋常性乾癬、滴状乾癬、倒置乾癬、膿疱性乾癬、乾癬性紅皮症、皮膚炎、アトピー性皮膚炎、アテローム性動脈硬化症、ループス、スチル病、全身性エリテマトーデス(SLE)、重症筋無力症、炎症性腸疾患、潰瘍性大腸炎、クローン病、セリアック病(非熱帯性スプルー)、血清反応陰性関節症に関連した腸疾患、顕微鏡的大腸炎またはコラーゲン形成大腸炎、好酸球性胃腸炎、または直腸結腸切除及び回腸肛門吻合の後に起こる嚢炎、膵炎、インスリン依存性糖尿病、乳腺炎、胆嚢炎、胆管炎、胆管周囲炎、多発性硬化症(MS)、喘息(外因性喘息及び内因性喘息、並びに、関連する気道の慢性炎症性状態または応答性亢進、を含む)、慢性閉塞性肺疾患(COPD、即ち、慢性気管支炎、肺気腫)、急性呼吸器疾患症候群(ARDS)、呼吸促迫症候群、嚢胞性線維症、肺高血圧症、肺血管収縮、急性肺傷害、アレルギー性気管支肺アスペルギルス症、過敏性肺炎、好酸球性肺炎、気管支炎、アレルギー性気管支炎気管支拡張症、結核、過敏性肺炎、職業性喘息、喘息様障害、サルコイド、反応性気道疾患(または機能不全)症候群、綿肺、間質性肺疾患、好酸球増加症候群、鼻炎、副鼻腔炎、及び肺寄生虫症、ウイルス誘発性状態に関連した気道過敏(例えば、呼吸器多核体ウイルス(RSV)、パラインフルエンザウイルス(PIV)、ライノウイルス(RV)、及びアデノウイルス)、ギラン・バレー疾患、グレーブス病、アジソン病、レイノー現象、自己免疫性肝炎、移植片対宿主病(GVHD)、脳虚血、外傷性脳損傷、多発性硬化症、神経障害、ミオパチー、脊髄損傷、及び筋萎縮性側索硬化症(ALS)からなる群より選択される、請求項16に記載の方法。
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