JP2015157840A - Tfpi−2の変異体クニッツドメインiに関連した方法および組成物 - Google Patents
Tfpi−2の変異体クニッツドメインiに関連した方法および組成物 Download PDFInfo
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Abstract
Description
本発明は、NIH助成金HL−70369、HL64119およびHL−36365の下で、政府によって支援されて行われた。それゆえ、米国政府は、本発明において一定の権利を有し得る。
線維素溶解に主に関与する作用物質は、活性型プラスミノーゲンであるプラスミンである。多くの物質は、プラスミノーゲンを活性化でき、例として、活性型ハゲマン因子、ストレプトキナーゼ、ウロキナーゼ(uPA)、組織プラスミノーゲン活性化因子(tPA)およびプラズマカリクレイン(pKA)が挙げられる。pKAは、ウロキナーゼの酵素前駆体形態の活性化因子でもあり、直接型プラスミノーゲン活性化因子でもある。
血栓性合併症、腎臓毒性、BPTIの場合は、免疫原性の可能性故に、これらの薬剤は、慎重に使用され、通常「最後の手段」(PUTT89)として温存される。抗線溶剤の3種すべては、標的特異性および親和性を欠き、特徴付けされていない代謝経路を通って組織および器官と相互に作用する。親和性が低いために必要な大量投与、特異性の欠如による副作用ならびに免疫応答の可能性および器官/組織毒性は、出血を防ぐようにまたは常用の術後の療法として輸血治療を回避または減らすようにこれらの抗線溶剤を予防的に使用することへの妨げを増やす。従って、安全な抗線溶剤が必要とされている。
本明細書において具体化され、広く記載されるように、本発明の目的(1つ以上)によると、本発明は一様態において、1種以上の変異を有する配列番号1を含むポリペプチドに関する。たとえば、本明細書において、1種以上の以下の置換を有する配列番号1を提供する:ロイシンは、17位(BPTI番号付け)においてアルギニンまたはリジンに変わる;チロシンは、46位においてグルタミン酸に変わる;チロシンは、11位においてトレオニンに変わる;アスパラギン酸は、10位においてチロシンまたはグルタミン酸に変わる;アラニンは、16位においてメチオニンに変わる;アラニンは、16位においてグリシンに変わる;アラニンは、16位においてセリンに変わる。
(項目1)
1種以上のアミノ酸変異を有する配列番号1を含むポリペプチドであって、第1の変異が、BPTI番号付けシステムを使用して17位でのロイシンからアルギニンまたはリジンへの置換を含む、ポリペプチド。
(項目2)
前記ポリペプチドが第2の変異を含み、該第2の変異が、46位でのチロシンからグルタミン酸への置換を含む、項目1に記載のポリペプチド。
(項目3)
前記ポリペプチドが第2の変異を含み、前記第2の変異が、11位でのチロシンからトレオニンへの置換を含む、項目1に記載のポリペプチド。
(項目4)
前記ポリペプチドが第2の変異を含み、前記第2の変異が、10位でのアスパラギン酸からチロシンへの置換を含む、項目1に記載のポリペプチド。
(項目5)
前記ポリペプチドが第2の変異を含み、前記第2の変異が、10位でのアスパラギン酸からグルタミン酸への置換を含む、項目1に記載のポリペプチド。
(項目6)
前記ポリペプチドが第2の変異を含み、前記第2の変異が、16位でのアラニンからメチオニン、グリシンまたはセリンへの置換を含む、項目1に記載のポリペプチド。
(項目7)
前記アミノ酸変異が、46位でのチロシンからグルタミン酸への置換、11位でのチロシンからトレオニンへの置換、16位でのアラニンからメチオニン、グリシン、またはセリンへの置換、および10位でのアスパラギン酸からチロシンまたはグルタミン酸への置換からなる群より選択される1種以上の変異を含む、項目1に記載のポリペプチド。
(項目8)
項目1〜7のいずれか1項に記載のポリペプチドを含む、組成物。
(項目9)
項目1〜7のいずれか1項に記載のポリペプチドをコードする、核酸。
(項目10)
項目1〜7のいずれか1項に記載のポリペプチドの有効量をプラスミンと接触させることを含む、少なくとも1種のプラスミン活性を阻害する方法。
(項目11)
項目1〜7のいずれか1項に記載のポリペプチドの有効量を対象へ投与することを含む、プラスミン活性の阻害を必要としている対象を処置する方法。
(項目12)
前記対象が血管形成を有する、項目11に記載の方法。
(項目13)
前記対象が腫瘍形成を有する、項目11に記載の方法。
(項目14)
前記対象が骨再形成を受けている、項目11に記載の方法。
(項目15)
前記対象が血友病を有する、項目11に記載の方法。
(項目16)
前記対象が整形外科手術を受けている、項目11に記載の方法。
(項目17)
前記対象が冠動脈バイパス移植(CABG)を受けている、項目11に記載の方法。
(項目18)
前記対象が全身性炎症反応症候群(SIRS)である、項目11に記載の方法。
(項目19)
項目1に記載のポリペプチドの有効量を対象へ投与することを含む、関節リウマチの治療をする必要とする対象において、それを治療する方法。
(項目20)
KD1変異体と一緒でのプラスミンの結晶構造をモデリングすること;
該プラスミンと該KD1変異体との間の相互作用を決定すること;
ステップbの結果に基づいて、該KD1変異体がプラスミン阻害剤であるかどうかを決定すること;
を含む、プラスミン阻害剤を同定する方法。
(項目21)
項目9に記載の核酸の有効量を対象へ投与することを含む、プラスミンの阻害を必要とする対象においてプラスミンを阻害する方法。
(項目22)
リガンドが前記ポリペプチドに結合している、項目1〜7のいずれか1項に記載のポリペプチド。
(項目23)
項目9に記載の核酸を含む、トランスジェニック動物。
(項目24)
前記ポリペプチドが、TFPI−2の野生型クニッツドメインと比較して低減した抗凝固活性を有する、項目11〜21のいずれか1項に記載の方法。
さらに、本明細書において開示する有効量の核酸を対象へ投与することを含む、プラスミンの阻害を必要とする対象においてプラスミンを阻害する方法を開示する。
本発明は、本発明の好ましい実施形態の以下の詳細な説明およびそこに含まれる実施例、ならびに図面およびそれらについて前述したものと同様に以下に説明するものを参照することにより容易に理解されるであろう。
文脈上他の意味に解すべき場合を除き、本明細書および添付の請求の範囲で使用される単数形「1つの、ある(a)」、「1つの、ある(an)」および「この、その(the)」は、複数形指示対象を含む。従って、たとえば、「1つの小分子」に関しては、1以上の小分子の混合物を含むなどである。
ウシ膵臓トリプシン阻害剤(BPTI)は、クニッツ型セリンプロテアーゼ阻害剤である。それはプラスミンを阻害し、開心術で使用され、術前出血と血液製剤の投与を最低限に抑えるため整形外科手術において推奨されている(1−5)。近年、プラスミノーゲン/プラスミン系はまた、骨再形成および吸収(11−15)および腫瘍形成(Tumorogenesis)および血管形成(8、16、17)と同様に関節リウマチ(6−10)の発生に関与している。
水および緩衝化媒体を包含する。非経口ビヒクルは、塩化ナトリウム溶液、リンガーデキストロース、デキストロースおよび塩化ナトリウム、乳酸加リンガーまたは固定油を含む。静脈内ビヒクルは、流動食および栄養補充液、電解質補給物(リンガーデキストロースをベースとしたような)などを含む。防腐剤および他の添加物も存在し得、たとえば、抗菌物質、酸化防止剤、キレート試薬および不活性ガスなどである。
vivoクリアランス速度および機構を有する小さく安定したヒト起源タンパク質ドメインが工学技術によって得られる並はずれた親和性および特異性は、初期に、より信頼性の高い結果、より低い毒性/副作用、さらに低い生産コストと貯蔵コスト、および標識調製のさらなる利便性をあわせて提供する。実際に、工学的に作製されたタンパク質造影剤を用いてリアルタイムの画像化の目的を達成できる。プラスミン結合タンパク質、たとえばSPI11は、内出血の部位を特定するために役立つ。
Clinics of America:(1987)16(1):183参照のこと。放射標識されるその他の方法は、たとえばIODOBEADS(商標)などを使用することができる。
開示された組成物ならびに本明細書において開示された方法内で使用される組成物自身を調製するために使用される成分を、開示する。これらおよびその他の物質を本明細書において開示し、およびこれらの物質の組み合わせ、サブセット、相互作用、グループなどを開示する時、各さまざまな個々および集団の組合せおよびこのような化合物の順序の特定の言及が明確に記載されていない場合でも、各々は、具体的に、本明細書において意図および記載されていると理解される。たとえば、特定のアミノ酸配列が開示され、考察され、そしてその配列内の複数の位置でなされ得る複数の改変がなされ得、考察されるならば、具体的に意図しているのは、そのアミノ酸の各々のかつあらゆる組み合わせおよび順序、ならびに特に反することが示されるのでない限りは可能な改変である。従って、分子A、BおよびCの種類が開示され、ならびに、分子D、EおよびFの種類ならびに組合せ分子の例A−Dが開示されるならば、次には、各々が独立に列挙されなくとも、各々は個々にかつ総合的に意図され、組み合わせA−E、A−F、B−D、B−E、B−F、C−D、C−EおよびC−Fが開示されているとみなされること意味する。同様に、いずれものサブセットまたはこれらの組み合わせを、また開示する。従って、たとえば、A−E、B−FおよびC−Eのサブグループが開示されるとみなす。この概念は、限定されるものではないが、開示された組成物の産生および使用の方法のステップを含む出願のすべての側面に適用する。従って、さまざまな追加的ステップがあるならば、このようなそれぞれの追加的ステップは、開示された方法の特定の実施形態または実施形態の組み合わせで行え得ると理解する。
また、本明細書において記載のポリペプチドに対応する組成物および核酸を、開示する。核酸、組成物および投与方法について以下に考察する。また、本明細書において開示されたポリペプチドをコードする核酸も開示する。ポリペプチドおよびそれに対応する核酸を、本明細書において開示する。いずれもの公知の変異体および誘導体または本明細書において開示された核酸およびタンパク質に起因するものを定義する一つの方法は、特定の既知の配列に対する相同性の観点から変異体および誘導体の定義付けを介することであると理解される。たとえば配列番号1は、KD1の特定の配列を示しおよび配列番号2は、変異を含むKD1の特定の配列を示す。本発明時に、当業者は、その他の変異が野生型の核酸およびタンパク質の両方で生じ得ることを理解している。その他が積極的に官能性に影響を及ぼすことができる中、その官能性に影響を及ぼさないそのいくつかの変異は、それ故選ばれる。規定の配列に対して、少なくとも、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99パーセント相同性を有する本明細書に開示されるこれらおよびその他の遺伝子およびタンパク質の変異体は、明確に開示されている。2つのタンパク質または核酸(遺伝子など)の相同性を判定する方法を当業者は容易に理解する。たとえば、相同性は、相同性がその最高レベルにあるように、2つの配列を整列させた後に計算できる。
機能または免疫学的同一性の実質的な変化は、表2に記載した置換よりも保存性の低い置換を選択することによって、すなわち、(a)たとえばシートまたは螺旋構造としての、置換領域におけるポリペプチド主鎖の構造(b)標的部位の分子の電荷または疎水性、もしくは、(c)側鎖の嵩高さ、の維持に対する効果がより大きく異なる残基を選択することによって行われる。一般に、タンパク質特性で最も大きな変化をもたらすと予想される置換は、(a)たとえば、セリルまたはスレオニルなどの親水性残基が、たとえば、ロイシル、イソロイシル、フェニルアラニル、バリルまたはアラニルなどの疎水性残基に代えて(で)置換されるもの;(b)その他いずれもの残基に代えて(または、よって)システインまたはプロリンが置換されるもの;(c)たとえば、リジル、アルギニルまたはヒスチジルなどの電気陽性側鎖を有する残基が、たとえば、グルタミルまたはアスパルチルなどの負電荷を有する残基に代えて(で)置換されるもの、または;(d)たとえば、フェニルアラニンなどの嵩高い側鎖を有する残基が、たとえば、この場合、グリシンなどのそのような側鎖を有さない残基に代えて(で)置換されるもの、(e)硫酸化および/またはグリコシル化の部位の数を増やすことによるものであろう。たとえば、生物学的および/または化学的に類似している別のものによる1つのアミノ酸残基の置換は、保存的置換として当業者に公知である。たとえば、保存的置換は、ある疎水性残基を別の残基に代えて、またはある極性残基を別の残基に代えて置き換えることである。この置換は、たとえば、GIy、Ala;Val、ILe、Leu;Asp、Glu;Asn、Gln;Ser、Thr;Lys、Arg;およびPhe、Tyrのような組み合わせを含む。各々明確に開示された配列の保存的に置換された変種は、本明細書において提供されるモザイクポリペプチドに含まれる。
1.実施例1
材料および方法:発色性基質H−D−Val−Leu−Lys−p−ニトロアニリド(S−2251)は、DiaPharma Group Inc.(ウェストチェスター、OH)社より購入した。ヒトプラスミンは、Enzyme research laboratories社より購入した。ウシアプロチニン(BPTI)は、Zymogenetics社製を利用した。大腸菌株BL21(DE3)pLysおよびpET28a発現ベクターは、Novagen Inc.(マディソン、WI)社の製品であった。QuikChange(登録商標)部位特異的変異誘発キットは、Stratagene(ラホヤ、CA)社より入手した。
命名法情報
R24(R15としても公知)は、P1である
A25(A16としても公知)は、P1’である
L26(L17としても公知)は、P2’である
TFPI−2は、おそらくXIa因子の阻害を経由して内因系凝固を阻害する(Petersenら、Biochemistry、1996 Jan 9;35(1):266−272)。全てのセリンプロテアーゼ同様に、XIa因子は、P1−P1’残基TRAEまたはTRVV(P2−P1−P1’−P2’)の間で切断する。従って、P2’位置でLeu(Valのような疎水性残基)を有するKD1WTは、XIa因子を阻害するはずである。従って、P2’位置でのLeuからArgへの変化は、この阻害を軽減/無効にするはずである。
KD1よりもさらに強力な阻害剤である。
WT KD1およびL26Rはどちらも、効果的にマウスプラスミンを阻害した。これは、図6に示されている。明らかにWT KD1およびL26R変異体は、約80nMというみかけのKd値でマウスプラスミンを阻害するのにかなり効果的である。WTおよびL26R KD1のどちらにも、1μMで完全な阻害を得た(Masciら、Blood Coagulation and Fibrinolysis 2000、Vol11、No4、pages 385−393、in vivoプラスミン阻害に関してその全体およびその内容を参照することにより本明細書に援用される)。野生型および変異体のどちらもマウスプラスミンを阻害するので、当業者は、動物の出血モデルにおいてin vivoでの効果を示すために変異体を使用することができる。
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- 本明細書中に記載される発明。
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EP (3) | EP1976985B1 (ja) |
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CA (2) | CA2635726C (ja) |
DK (1) | DK1976985T3 (ja) |
ES (3) | ES2661002T3 (ja) |
HK (1) | HK1190753A1 (ja) |
PL (1) | PL1976985T3 (ja) |
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WO (1) | WO2007076537A2 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DK1976985T3 (da) | 2005-12-29 | 2013-10-21 | Univ California | Fremgangsmåder og præparater relateret til mutant Kunitz-domæne I af TFPI-2 |
US8088599B2 (en) * | 2009-02-06 | 2012-01-03 | Fudan University | Nucleic acids encoding genetically modified tissue factor pathway inhibitor (TFPI) and method of making the same |
GB0916578D0 (en) * | 2009-09-22 | 2009-10-28 | Malmsten Nils M | Polypeptides and uses thereof |
EP2970434B1 (en) * | 2013-03-15 | 2018-12-05 | The Regents of The University of California | Dual reactivity potent kunitz inhibitor of fibrinolysis |
US20140288000A1 (en) * | 2013-03-15 | 2014-09-25 | The Regents Of The University Of California | Dual reactivity potent kunitz inhibitor of fibrinolysis |
WO2016084912A1 (ja) * | 2014-11-27 | 2016-06-02 | 公立大学法人横浜市立大学 | 卵巣明細胞腺癌の検査方法及び検査薬 |
WO2022055882A1 (en) * | 2020-09-10 | 2022-03-17 | The Regents Of The University Of California | Improved highly potent specific human kunitz inhibitor of fibrinolytic enzyme plasmin |
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AU560584B2 (en) | 1983-07-28 | 1987-04-09 | Bayer Aktiengesellschaft | Homologues of aprotinin |
US4609725A (en) | 1984-10-09 | 1986-09-02 | Merck & Co., Inc. | Cardiac atrial peptides |
GB2188322A (en) | 1986-03-26 | 1987-09-30 | Bayer Ag | Aprotinin and analogues thereof produced by a recombinant host |
US5032573A (en) | 1987-03-23 | 1991-07-16 | Bayer Aktiengesellschaft | Homologs of aprotinin produced from a recombinant host, process, expression vector and recombinant host therefor and pharmaceutical use thereof |
US5663143A (en) | 1988-09-02 | 1997-09-02 | Dyax Corp. | Engineered human-derived kunitz domains that inhibit human neutrophil elastase |
US7078383B2 (en) | 1988-09-02 | 2006-07-18 | Dyax Corp. | ITI-D1 Kunitz domain mutants as HNE inhibitors |
IL104326A0 (en) | 1992-01-07 | 1993-05-13 | Novo Nordisk As | Variant of human kunitz-type protease inhibitor |
US5455338A (en) | 1993-11-05 | 1995-10-03 | Zymogenetics, Inc. | DNA encoding novel human kunitz-type inhibitors and methods relating thereto |
JP4137997B2 (ja) | 1994-01-11 | 2008-08-20 | ダイアックス コープ. | クニッツドメインから誘導されたヒトプラスミンの阻害剤 |
JP3805785B2 (ja) | 1994-01-11 | 2006-08-09 | ダイアックス コープ. | カリクレイン阻害クニッツドメイン蛋白質およびその相同体 |
US6057287A (en) | 1994-01-11 | 2000-05-02 | Dyax Corp. | Kallikrein-binding "Kunitz domain" proteins and analogues thereof |
US5981471A (en) | 1997-02-06 | 1999-11-09 | Entremed, Inc. | Compositions and methods for inhibiting cellular proliferation |
AUPP345098A0 (en) | 1998-05-11 | 1998-06-04 | National Institute Of Biological Standards And Control, United Kingdom | Novel anti-fibrinolytic agents |
US20050222023A1 (en) * | 2002-02-07 | 2005-10-06 | Hans-Peter Hauser | Albumin-fused kunitz domain peptides |
WO2003070770A2 (en) * | 2002-02-21 | 2003-08-28 | Geneprot, Inc. | Engineered human kunitz-type protease inhibitor |
US7585842B2 (en) * | 2004-04-16 | 2009-09-08 | The Reagents Of The University Of California | Human kunitz-type inhibitor with enhanced antifibrinolytic activity |
US7432238B2 (en) * | 2004-04-16 | 2008-10-07 | Stc.Unm | Human Kunitz-type inhibitor with enhanced antifibrinolytic activity |
CN1634986A (zh) * | 2004-11-18 | 2005-07-06 | 复旦大学 | 一种新型Kunin型多肽及其制备方法 |
DK1976985T3 (da) | 2005-12-29 | 2013-10-21 | Univ California | Fremgangsmåder og præparater relateret til mutant Kunitz-domæne I af TFPI-2 |
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Also Published As
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EP1976985A2 (en) | 2008-10-08 |
EP1976985B1 (en) | 2013-07-17 |
JP2013063086A (ja) | 2013-04-11 |
EP1976985A4 (en) | 2009-04-29 |
EP3088522B1 (en) | 2017-11-29 |
EP2653542B1 (en) | 2016-06-29 |
AU2006330424A1 (en) | 2007-07-05 |
CA2635726A1 (en) | 2007-07-05 |
CA2635726C (en) | 2016-10-11 |
AU2006330424B2 (en) | 2013-11-14 |
JP2009521935A (ja) | 2009-06-11 |
US20090018069A1 (en) | 2009-01-15 |
PL1976985T3 (pl) | 2014-03-31 |
ES2594607T3 (es) | 2016-12-21 |
JP5770966B2 (ja) | 2015-08-26 |
PT1976985E (pt) | 2013-10-24 |
ES2661002T3 (es) | 2018-03-27 |
WO2007076537A2 (en) | 2007-07-05 |
ES2431526T3 (es) | 2013-11-26 |
JP2018093882A (ja) | 2018-06-21 |
EP3088522A1 (en) | 2016-11-02 |
EP2653542A1 (en) | 2013-10-23 |
US20150191528A1 (en) | 2015-07-09 |
CA2924836A1 (en) | 2007-07-05 |
HK1190753A1 (zh) | 2014-07-11 |
US8993719B2 (en) | 2015-03-31 |
DK1976985T3 (da) | 2013-10-21 |
WO2007076537A3 (en) | 2008-02-14 |
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