JP5438886B2 - IgA1沈着症の治療 - Google Patents
IgA1沈着症の治療 Download PDFInfo
- Publication number
- JP5438886B2 JP5438886B2 JP2006509132A JP2006509132A JP5438886B2 JP 5438886 B2 JP5438886 B2 JP 5438886B2 JP 2006509132 A JP2006509132 A JP 2006509132A JP 2006509132 A JP2006509132 A JP 2006509132A JP 5438886 B2 JP5438886 B2 JP 5438886B2
- Authority
- JP
- Japan
- Prior art keywords
- iga1
- protease
- tag
- molecule
- iga1 protease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Description
本発明は、全部または一部、NIH, NIDCRからの助成NIH R01 DE 09677によって支援された。合衆国政府は本発明に一定の権利を有する。
本発明は、組織および器官におけるIgA1沈着を治療するための細菌のIgA1プロテアーゼの使用を開示する。細菌のIgA1プロテアーゼはIgA1分子を特異的に切断するため、IgA1沈着を特異的に切断し、除去する手段を提供する。従って、IgA1沈着を特徴とする疾患の治療のための治療薬を提供する。特に、IgA腎症、疱疹状皮膚炎(DH)、およびヘノッホ・シェーンライン紫斑病(HS)を治療するための治療薬を開示する。
本発明は、IgA1沈着を特徴とする疾患を治療するための細菌の免疫グロブリンA1プロテアーゼ(IgA1プロテアーゼ)の使用に関する。
本明細書において用いられる場合、「IgA1プロテアーゼ」はヒトIgA1分子を特異的に切断する細菌酵素を指す。「特異的に切断する」とは、プロテアーゼがヒトIgA1分子のヒンジ領域で切断し、ヒトIgA2分子を切断しないことを意味する。IgA1プロテアーゼは、細菌膜を貫通する単鎖前駆体としてグラム陰性菌およびグラム陽性菌で発現される。グラム陰性菌のIgA1プロテアーゼは自己触媒性切断を受け、N末端の可溶性IgA1成熟型プロテアーゼを放出する。
本明細書において、IgA1プロテアーゼはIgA1沈着を特徴とする疾患の治療のために使用される。IgA1プロテアーゼは、ヒトIgA1分子を特異的に切断する細菌酵素である。IgA2分子はすべてのIgA1分子に存在するヒンジ領域を欠如しているので、ヒトIgA2はほとんどすべての既知のIgA1プロテアーゼに耐性がある。IgA1分子のヒンジ領域は、図1に示されるように、様々なIgA1プロテアーゼのための切断部位を含む一連のアミノ酸から成る。IgA1プロテアーゼは、細菌の内膜を貫通する単鎖前駆体としてグラム陰性菌で発現される。前駆体タンパク質はその後、それ自身を細菌外膜に挿入し、自己触媒性切断を受けて、可溶性の成熟型IgA1プロテアーゼを放出する(図2a)。グラム陽性菌のIgAプロテアーゼは、自己触媒性分泌機構を持たないが、それらもまた本発明において有用である。このようなプロテアーゼに対して、エピトープタグが酵素タンパク質に付加される。
-003098); ならびにStreptococcus Sanguis (Genebank 受入番号, NC-003098)および細菌株SK85 (Genebank 受入番号, Y13461), SK49 (Genebank 受入番号, Y13460), SK4 (Genebank 受入番号, Y13459), SK162 (Genebank 受入番号, Y13458), SK161 (Genebank 受入番号, Y13457), SK115 (Genebank 受入番号, Y13456), およびSk112 (Genebank 受入番号, Y13455)である。
本発明において、可溶性IgA1プロテアーゼを産生、単離できるように、IgA1プロテアーゼをコードする配列は、タンパク質の発現に適したベクターにクローニングされる。ベクターは標準的な方法を用いて構築することができ(Sambrookら、Molecular Biology: A laboratory Approach, Cold Spring Harbor, N. Y. 1989 ; Ausubel,ら、Current protocols in Molecular Biology, Greene Publishing, 1995)、下記において議論される原理によって誘導される。簡潔には、従来のライゲーション技術を使用して、IgA1プロテアーゼをコードするDNA配列を細菌のクローニングベクターおよび/または発現ベクターに挿入する。
任意のベクターが本発明において使用され得る。本明細書において用いられる場合、ベクターは、その発現および/または複製のために、異種DNAを細菌細胞に導入するために用いられる個別のエレメントを指す。本発明に適した多数のベクターは公的に入手可能であり、細菌プラスミドおよびバクテリオファージを含む。それぞれのベクターは様々な機能要素を含み、それは通常、クローニング(すなわち「ポリリンカー」)部位、複製起点および少なくとも1つの選択マーカー遺伝子を含む。与えられたベクターが発現ベクターである場合、それは更に以下の1つ以上、すなわち、エンハンサーエレメント、プロモーター、転写終止配列およびシグナル配列を有し、各々は、それらが本発明のIgA1プロテアーゼをコードする遺伝子に機能しうる形で連結されるように、クローニング部位の近傍に配置される。
ベクターは、当業者に知られている任意の多数の適切な方法によって選択された宿主細胞に導入され得る。例えば、ベクター構築物は、ラムダもしくはM13などのバクテリオファージベクター粒子を用いた感染によって、またはプラスミドベクターもしくはバクテリオファージDNAのための任意の多数の形質転換法によって、適切な細菌細胞に導入されうる。例えば、標準的な塩化カルシウムを介した細菌の形質転換は、未だに、裸のDNAを細菌に導入するために一般に使用されるが(Sambrookら、1989, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY)、エレクトロポレーションもまた使用されうる(Ausubelら、Current Protocols in Molecular Biology,(1988), (John Wiley & Sons, Inc., NY, NY))。
適切な細菌宿主細胞へのIgA1プロテアーゼをコードする発現ベクターの導入後、可溶性IgA1プロテアーゼの過剰産生のために、標準的な方法によって、その細菌を増殖させる(Sambrookら、Molecular Biology: A laboratory Approach, Cold Spring Harbor, N. Y. (1989) およびAusubel, ら、Current protocols in Molecular Biology, Greene Publishing, (1995)、参照により本明細書に組み入れられる)。簡潔には、IgA1プロテアーゼをコードする発現ベクターを有するE. Coliのような細菌、または細菌ゲノム内に組み込まれたIgA1プロテアーゼをコードするDNAを有する細菌は、細菌増殖培地において37℃で培養される。細菌培養物が対数増殖期に達する時、可溶性IgA1プロテアーゼは増殖培地から当技術分野においてよく知られている方法によって精製される。
IgA1プロテアーゼは、Plaut, AGおよびBachovchin WW, IgA-specific prolyl endopeptidases: serine type. Methods Enzymol. 1994 ; 244:137-51(参照により本明細書に組み入れられる)に記載される標準的な方法によって酵素活性を検査される。アッセイは、精製されたプロテアーゼまたは細菌増殖培地に存在するIgA1プロテアーゼを用いて行われ得る。37℃で1分間当たり1μgのヒトIgA1の切断に相当するユニットによって、1ユニットの活性を有する場合、IgA1プロテアーゼは本発明に有用な十分な活性を有する。
1つの実施形態では、IgA1プロテアーゼはタグに融合される。本発明のIgA1プロテアーゼへのタグの融合は、IgA1プロテアーゼが治療目的で抗タグ抗体のようなリガンドと複合体を形成できる手段を提供するだけでなく、プロテアーゼの精製および検出を支援する。
本明細書において、IgA1プロテアーゼはIgA1沈着症を治療するための治療薬として使用される。IgA1分子の異常な沈着は、腎不全、皮膚の水疱形成、発疹、関節炎、消化管出血および腹痛の原因となることが知られている。
1つの実施形態では、本発明は、このような治療を必要とする患者にIgA1プロテアーゼを投与することによって、IgA腎症を治療する方法を提供する。IgA腎症は腎臓の疾患である。その疾患は、糸球体メサンギウム領域へのIgA1の顆粒状沈着を特徴とする、免疫複合体介在型糸球体腎炎であると考えられている。腎症は糸球体メサンギウム細胞における増殖性変化を生じ、それによって定義される。
本発明は更に、このような治療を必要とする患者にIgA1プロテアーゼを投与することによって、疱疹状皮膚炎(DH)を治療する方法を提供する。疱疹状皮膚炎は、真皮・表皮接合部でのIgA1の沈着を伴う慢性水疱形成性皮膚疾患である(Hall, RPおよびT. J. Lawley, J. Immunol. (1985) 135 (3): 1760-5)。DH患者は顆粒状のIgA1沈着を有し、関連したグルテン過敏性腸症(GSE)を有する。
別の実施形態では、本発明は、このような治療を必要とする患者にIgA1プロテアーゼを投与することによって、ヘノッホ・シェーンライン紫斑病(HS)を治療する方法を提供する。ヘノッホ・シェーンライン紫斑病は皮膚および腎臓の疾患である。HSPは、IgA1を含む免疫複合体の組織への沈着を特徴とする。その疾患は、免疫蛍光顕微鏡検査法によって、皮膚組織または腎臓へのIgA1沈着の証拠を観察することによって診断される。臨床症状は一般的に、発疹、関節痛、腹痛、および腎疾患を含む。
本発明のIgAプロテアーゼの治療効果は、当業者に知られている任意の適切な動物モデルにおいて検査され得る。いくつかの典型的な動物モデルが以下に記載される。
多数のIgA腎症のラットおよびマウス動物モデルが利用可能であり、本発明に有用である。これらのモデルはEmancipator, S. N. ら、(1987) Animal models of IgA Nephropathy In IgA Nephropathy. A. R. Clarkson,編. Martinus Nijhoff publishing, Boston. 188-203に記載され、参照により本明細書に完全に組み入れられる。典型的なモデルは、Gesualdo L. ら、(1990) J. Clin. Invest. 86 : 715-722に記載され、同様に本明細書に完全に組み入れられる。簡潔には、IgA抗体/硫酸デキストラン複合体をマウスに注射する。免疫複合体は腎臓にとどまり、マウスはヒトIgA腎症の典型例に類似した糸球体腎炎を示す。どのようにモデルが作製され、治療薬の検査に使用されるかは、以下に更に詳細に記載される。
本明細書において、細菌のIgAプロテアーゼは、IgA沈着症の治療のために使用される。本発明のIgA1プロテアーゼは、製薬上許容されうる担体と組み合わされた組成物に使用され得る。このような組成物はまた、希釈剤、充填剤、塩、バッファー、安定剤、可溶化剤、および当技術分野においてよく知られている他の物質を含みうる。1つの態様では、IgA1プロテアーゼは抗体と複合体を形成し、治療用免疫複合体を形成する。大きな免疫複合体は投与により腎糸球体にとどまると考えられているので、このような治療用免疫複合体は腎臓へのIgA1沈着を特徴とする疾患の治療に特に有用である。
タグ付きIgA1プロテアーゼの構築
PCRに基づく部位指定突然変異導入によって、Haemophilus influenzae IgA1プロテアーゼをコードするDNA配列を含むプラスミドpFG26を用いて、Haemophilus influenzae IgA1プロテアーゼの読み枠にHisタグを融合させた。図4に図示されるように、2つのPCR断片がpFG26から生成した。第一断片、新たに挿入されるHISタグおよびPml I部位を含むXba IおよびPml I断片は、下記に示されるオリゴヌクレオチドプライマー「HFD6His1」(プライマー1)ならびに「HFD6His2」(プライマー2)を用いて生成された。第二断片、Pml IおよびAcc I断片は、また下記に示されるプライマー3ならびにプライマー4を用いて生成された。
タグ付きIgA1プロテアーゼを発現する細菌株の作製
酵素活性のあるタグ付きIgA1プロテアーゼのみを発現するHaemophilus influenzae細菌株を、標準的な組み換え技術によって作製した。簡潔には、実施例1において作製したプラスミドpJQ/Rd6Hisを、制限酵素Cla IおよびNde Iによって切断した。その遺伝子を単離し、組み換えによって細菌ゲノム内へのHisタグ付きIgA1プロテアーゼの挿入を可能にするように、酵素活性を持たないIgA1プロテアーゼを産生するHaemophilus influenzae Rd細菌株(Rd 3-13)(Plaut AG, Qiu, J, Grundy, F.およびWright, A. J Infect Dis. (1992) Jul; 1 66(1):43-52)に形質転換した。その後、活性のあるプロテアーゼの存在について、基質としてヒトIgA1を用いて、選択されたコロニーの細菌増殖培地を検査することによって、細菌の酵素活性の回復についてスクリーニングした。
IgA腎症の治療のためのIgA1プロテアーゼの治療効果は、IgA腎症についてのマウスモデルにおいて検査され得る。
疱疹状皮膚炎の治療のためのIgA1プロテアーゼの治療効果は、疱疹状皮膚炎についてのマウスモデルにおいて検査され得る。
ヘノッホ・シェーンライン紫斑病の治療のためのIgA1プロテアーゼの治療効果は、ヘノッホ・シェーンライン紫斑病についてのマウスモデルにおいて検査され得る。
Claims (5)
- ヒトIgA1分子を切断する活性を有するIgA1プロテアーゼをコードする第一DNA配列およびタグをコードする第二DNA配列を含む核酸分子であって、該第一DNA配列が、シグナル配列と活性部位を含む酵素ドメインとをコードするDNA配列を含み、該核酸分子がタグ付きIgA1プロテアーゼをコードするように、該第二DNA配列が、プロテアーゼ自己触媒性切断部位を含むα−ドメインをコードするDNA配列の上流に位置し、該核酸分子は、該α−ドメインをコードするDNA配列の下流に、β−ドメインをコードする配列をさらに含むことを特徴とする核酸分子。
- ヒトIgA1分子を切断する活性を有するIgA1プロテアーゼを含む第一アミノ酸配列およびタグを含む第二アミノ酸配列を含む単離ポリペプチド分子であって、該第一アミノ酸配列が、シグナル配列と活性部位を含む酵素ドメインとを含み、該単離ポリペプチド分子がタグ付きIgA1プロテアーゼを含むように、該第二アミノ酸配列が、プロテアーゼ自己触媒性切断部位を含むα−ドメインの上流に位置し、該単離されたポリペプチド分子が、該α−ドメインの下流に、β−ドメインをさらに含むことを特徴とする単離ポリペプチド分子。
- 前記タグがタンパク質リガンドに特異的に結合する、請求項1または2に記載の分子。
- 前記タンパク質リガンドが抗体である、請求項3に記載の分子。
- 前記タグがc-Myc、HA、VSV-G、HSV、FLAG、V5、およびHISからなる群より選択される、請求項1または2に記載の分子。
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- 2004-03-05 WO PCT/US2004/006615 patent/WO2004096157A2/en active Application Filing
- 2004-03-05 EP EP04749338A patent/EP1603511B1/en not_active Expired - Lifetime
- 2004-08-19 US US10/921,676 patent/US7407653B2/en not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
---|---|
EP1603511B1 (en) | 2011-01-26 |
ATE496992T1 (de) | 2011-02-15 |
CA2558873A1 (en) | 2004-11-11 |
JP2015096079A (ja) | 2015-05-21 |
WO2004096157A2 (en) | 2004-11-11 |
KR20060015468A (ko) | 2006-02-17 |
CN1777673A (zh) | 2006-05-24 |
US20050136062A1 (en) | 2005-06-23 |
US20090130084A1 (en) | 2009-05-21 |
CA2558873C (en) | 2015-10-20 |
EP1603511A2 (en) | 2005-12-14 |
HK1090950A1 (en) | 2007-01-05 |
KR20130026513A (ko) | 2013-03-13 |
JP2013230157A (ja) | 2013-11-14 |
US20090041746A1 (en) | 2009-02-12 |
DE602004031199D1 (de) | 2011-03-10 |
EP1603511A4 (en) | 2007-06-06 |
US7407653B2 (en) | 2008-08-05 |
CN1777673B (zh) | 2010-04-28 |
US8216568B2 (en) | 2012-07-10 |
JP2006519619A (ja) | 2006-08-31 |
ES2360291T3 (es) | 2011-06-02 |
WO2004096157A3 (en) | 2005-10-20 |
JP2011101645A (ja) | 2011-05-26 |
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