JP5038591B2 - 改変トランスフェリン−抗体の融合タンパク質 - Google Patents
改変トランスフェリン−抗体の融合タンパク質 Download PDFInfo
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Description
[0011] 血液および他の体液中を循環する抗体は体液性抗体と呼ばれ、抗体の親であるリンパ球に結合したままである「膜抗体」とは区別される。免疫グロブリンの用語は、すべての抗体を示すために総称的に使用される。ヒトにおいて、すべての免疫グロブリンは、IgG、IgA、IgM、IgDおよびIgEと名付けられた5つのクラスに分けられる。それぞれの免疫グロブリン分子は、一方が重鎖または軽鎖と名付けられた2対の同一ポリペプチド鎖からなる。「重鎖」は、ガンマ(γ)、アルファ(α)、ミュー(μ)、デルタ(δ)およびイプシロン(ε)と呼ばれる。「軽鎖」はラムダ(λ)またはカッパ(κ)と呼ばれる。
[0018] 一本鎖抗体(SCA)はこれまで、診断および治療への応用においてモノクローナル抗体に取って代わるための手段として基礎研究および応用研究の対象となってきた。SCAは、モノクローナル抗体の結合特異性および結合親和性を有するが、サイズがそれよりも小さい遺伝子操作されたタンパク質であり、より迅速な毛細血管透過性を可能にする。モノクローナル抗体を上回るSCAの利点には、診断的画像化および治療の両方のためのより優れた組織浸透性、免疫原性問題の低下、体内の標的部位へのより特異的な局在化、および、大量に作製することがより容易であり、かつ費用があまりかからないことが挙げられる。
[0020] 抗体がパパインまたはペプシンなどのタンパク質分解酵素にさらされたとき、数個の主要なフラグメントが生じる。抗原結合能を保持しているこれらのフラグメントは抗体のY形態の2つの「アーム」からなり、Fab(フラグメント−抗原結合性)、または、ジスルフィド結合により連結された2つのFabアーム部を表すFab’2と呼ばれている。生じたそれ他の主要なフラグメントはYの1つだけの「テール」または中心軸を構成し、溶液から結晶化するその傾向のためにFc(フラグメント−結晶性)と呼ばれている。IgG、IgA、IgMおよびIgDのFcフラグメントは、それぞれの抗体の2つのカルボキシ末端ドメイン(すなわち、IgG、IgAおよびIgDにおけるCH2およびCH3、IgMにおけるCH3およびCH4)の二量体からなる。これに対して、IgEのFcフラグメントはその3つのカルボキシ末端重鎖ドメイン(Cε2、Cε3およびCε4)の二量体からなる。
[0039] 本発明は、トランスフェリン、改変されたトランスフェリン、または、インビボにおける分子の半減期を延ばすために十分なトランスフェリンもしくは改変されたトランスフェリンの一部にSCAを遺伝子融合することによって、抗体、抗体フラグメント、CDR領域およびSCAが安定化されて、インビボにおけるそれらの血清半減期および/または活性を延ばすことができるという本発明者らによる発見に部分的に基づいている。改変トランスフェリン融合タンパク質は、SCA抗体または抗体フラグメントに共有結合的に連結されたトランスフェリンタンパク質またはトランスフェリンドメインを含み、この場合、トランスフェリン部分は、野生型トランスフェリン配列と比較したとき、1つ以上のアミノ酸置換、アミノ酸挿入またはアミノ酸欠失を含有するために改変されている。一実施形態において、Tf融合タンパク質は、Tf内またはTfドメイン内のグリコシル化を低下させるか、または妨げるために操作される。他の実施形態において、Tfタンパク質またはTfドメインは、鉄イオンもしくは炭酸イオンへの低下した結合を示すか、または鉄イオンもしくは炭酸イオンへの結合を示さないように、あるいはTf受容体(TfR)に対する低下した親和性を有するか、またはTf受容体(TfR)に結合しないように改変される。
[0046] 本明細書中で使用される用語「抗体可変領域」は1つ以上のVH領域、VL領域またはCDR領域を含む。
[0086] 従来の抗体と比較した場合、一本鎖抗体は、サイズがより小さく、著しく低いコストで製造することができる。一本鎖抗体のサイズがより小さいことは、身体の免疫学的反応を低下させることができ、したがって、治療的適用の安全性および効能を増大させることができる。逆に、一本鎖抗体を、非常に抗原性であるように操作することができる。
[0095] 多数の抗体に由来する可変領域を、トランスボディーを製造するためにトランスフェリンに取り込むために適切な形態に変換することができる。これらには、抗erbB2、B3、BR96、OVB3、抗トランスフェリン、Mik−β1およびPR1が含まれる(それぞれ、Batraら、Mol.Cell.Biol.、11:2200〜2205(1991);Batraら、Proc.Natl.Acad.Sci.USA、89:5867〜5871(1992);Brinkmannら、Proc.Natl.Acad.Sci.USA、88:8616〜8620(1991);Brinkmannら、Proc.Natl.Acad.Sci.USA、90:547〜551(1993);Chaudharyら、Proc.Natl.Acad.Sci.USA、87:1066〜1070(1990);Friedmanら、Cancer Res.、53:334〜339(1993);Kreitmanら、J.Immunol.、149:2810〜2815(1992);Nichollsら、J.Biol.Chem.、268:5302〜5308(1993);Wellsら、Cacer Res.、52:6310〜6317(1992)を参照されたい)。
[0098] 本発明ではまた、トランスボディーを作製するためのヒト化可変ドメインの製造および使用が意図される。ヒト抗体は、アミノ酸残基の一部またはすべてが類似のヒト抗体に見出される対応するアミノ酸残基で置換されている非ヒト抗体である。例えば、ヒト抗体から出発する場合、超可変領域における残基、および、可能であれば、FRにおける残基が、齧歯類抗体における類似部位に由来する残基によって置換される。ヒト化は抗体の抗原性潜在的能力を低下させる。
[00102] トランスフェリンに融合または結合され得る抗原性結合フラグメントおよびCDRを、ファージライブラリーからの選択、または、特定の抗体の可変領域を、その抗体のcDNAをクローン化し、可変領域をクローン化するためのプライマーとして隣接の定常領域を使用することによってクローン化すること、または、任意の特定の抗体の可変領域に対応するオリゴヌクレオチドを合成すること(これらに限定されない)を含むいくつかの方法によって製造することができる。cDNAは、トランスフェリンに対するcDNAを含有するベクターにcDNAをクローン化するために、オリゴヌクレオチドリンカーが使用され得るように制限部位を作製するために5’末端および3’末端において調整することができる。これは、スペーサー配列を使用して、またはスペーサー配列を使用することなく、N末端において、またはC末端において、またはN末端およびC末端において行うことができる。融合分子のcDNAはベクターにクローン化することができ、その後、そのベクターから、完全な発現カセットが切り出され、酵母における融合タンパク質の発現を可能にするための発現ベクターに挿入される。その場合、酵母から分泌された融合タンパク質を培地から回収し、精製して、その活性について試験することができる。哺乳動物細胞株における発現の場合、使用された発現カセットにおいて、哺乳動物のプロモーター、リーダー配列およびターミネーターが用いられることを除いて、類似する手順が採用される。この発現カセットは、その後、切り出され、哺乳動物細胞株のトランスフェクションのために適切なプラスミドに挿入される。この様式で製造されるトランスボディーは培地から精製され、標準的な免疫化学的方法を使用してその抗原に対するその結合について試験することができる。
[00110] 本発明ではまた、1つ以上の異なる抗原に対する抗体に由来する抗体可変領域を含むトランスボディーを疾患の治療または予防のために作製および使用することが伴う。好ましくは、抗原の少なくとも1つ(好ましくは、抗原のすべて)が生物学的に重要な分子であり、抗原に対するトランスボディーを、疾患または障害に罹患している哺乳動物に投与することにより、治療的利益がその哺乳動物においてもたらされ得る。本発明の好ましい実施形態において、抗原はタンパク質である。しかしながら、ポリペプチド以外の他の抗原(例えば、腫瘍に関連する糖タンパク質;米国特許第5,091,178号を参照されたい)を使用することができる。
[00112] 本発明は、1つ以上の抗体可変領域と、トランスフェリンまたは改変されたトランスフェリンとを含むトランスボディーを提供する。任意のトランスフェリンを、本発明の改変Tf融合タンパク質を作製するために使用することができる。一例として、野生型ヒトTf(Tf)は、約75kDa(グリコシル化を含まない)である679アミノ酸のタンパク質であり、遺伝子重複に由来すると考えられる2つの主要なドメイン、すなわち、Nドメイン(約330アミノ酸)およびCドメイン(約340アミノ酸)を有する。GenBankアクセション番号NM001063、同XM002793、同M12530、同XM039845、同XM039847および同S95936(www.ncbi.nlm.nih.gov)(これらはすべて、その全体を参照として本明細書中に組み入れる)、ならびに、配列番号1、配列番号2および配列番号3を参照されたい。これらの2つのドメインは、時間の経過とともに異なってきているが、高い程度の同一性/類似性を保持している(図1)。
[00154] 本発明のトランスボディー融合タンパク質は、Tfタンパク質のN末端および/またはC末端に結合した1コピー以上の抗体可変領域を含有することができる。いくつかの実施形態において、抗体可変領域はTfタンパク質のN末端およびC末端の両方に結合させられ、融合タンパク質は抗体可変領域の1つ以上の等価体をTfのいずれかの末端または両末端に含有することができる。他の実施形態において、抗体可変領域は、Tfタンパク質の既知のドメインの中に、例えば、Tfのループの1つ以上の中に挿入される(Aliら(1999)、J.Biol.Chem.274(34):24066〜24073を参照されたい)。他の実施形態において、抗体可変領域はTfのNドメインとCドメインとの間に挿入される。
[00166] 本発明はまた、治療タンパク質(好ましくは、抗体可変領域)に共有結合的に連結または結合されたトランスフェリンタンパク質またはトランスフェリンタンパク質の一部を含むトランスボディーをコードする核酸分子を提供する。先により詳細に論じたように、任意の抗体可変領域を使用することができる。融合タンパク質は、リンカー領域、例えば、約50アミノ酸残基未満、40アミノ酸残基未満、30アミノ酸残基未満、20アミノ酸残基未満または10アミノ酸残基未満のリンカーを更に含むことができる。リンカーは、トランスフェリンタンパク質またはその一部および治療タンパク質(好ましくは抗体可変領域)に対して、また、トランスフェリンタンパク質またはその一部および治療タンパク質(好ましくは、抗体可変領域)の間で共有結合的に連結することができる。本発明の核酸分子は精製されてもよく、または未精製であってもよい。
[00172] 遺伝暗号の縮重性は、トランスフェリンタンパク質および/または目的とする治療タンパク質(好ましくは抗体可変領域)のヌクレオチド配列の様々な変化を可能にし、その一方で、生来的なDNA配列によりコードされるポリペプチドと同一のアミノ酸配列を有するポリペプチドを依然としてもたらす。「コドンの最適化」として知られる手法(これは米国特許第5,547,871号(これはその全体を参照として本明細書中に組み入れる)に記載されている)により、このような変化したDNA配列を設計する手段が提供される。コドンが最適化された遺伝子の設計では、生物におけるコドン使用の頻度、隣接頻度、RNA安定性、二次構造形成に対する可能性、合成経路、およびその遺伝子の意図された将来のDNA操作を含む様々な要因を考慮に入れなければならない。具体的には、利用可能な方法を使用して、酵母発現システムが使用されるときの酵母によって最も容易に認識されるコドンを用いて、所与の融合タンパク質をコードするコドンを変化させることができる。
[00175] 本発明において使用される発現ユニットは、一般に、下記のエレメントを5’から3’の向きで機能的に連結されて含む:転写プロモーター、分泌シグナル配列、目的とする治療タンパク質または治療ペプチド(好ましくは抗体可変領域)をコードするDNA配列に結合された、トランスフェリンタンパク質またはトランスフェリンタンパク質の一部を含む改変Tf融合タンパク質をコードするDNA配列、および転写ターミネーター。先に論じたように、Tfタンパク質またはTfタンパク質内に融合された治療タンパク質または治療ペプチドの任意の配置を本発明のベクターにおいて使用することができる。適切なプロモーター、シグナル配列およびターミネーターの選択は、選択された宿主細胞によって決定され、当業者には明らかであり、そして、より具体的には以下に論じる。
[00181] 菌類を形質転換するための様々な技術が文献では広く知られており、例えば、Beggs(同上)、Hinnenら(Proc.Natl.Acad.Sci.USA、75:1929〜1933、1978)、Yeltonら(Proc.Natl.Acad.Sci.USA、81:1740〜1747、1984)、およびRussell(Nature、301:167〜169、1983)に記載される。クローン化されたDNA配列を菌類細胞に導入するための他の技術、例えば、エレクトポレーション(BeckerおよびGuarente、Methods in Enzymol.、194:182〜187、1991)などを使用することができる。宿主細胞の遺伝子型は、一般には、発現ベクターに存在する選択マーカーによって相補される遺伝的欠陥を含有する。特定の宿主および選択マーカーの選択は十分に当分野における通常の技術レベルの範囲内である。
[00183] 本発明はまた、本発明の改変トランスフェリン融合タンパク質を発現させるために形質転換されている細胞、好ましくは酵母細胞を含む。形質転換された宿主細胞そのものに加えて、本発明はまた、栄養培地におけるこのような細胞の培養物、好ましくは、モノクローナル(クローン的に均一な)培養物、またはモノクローナル培養物に由来する培養物を含む。ポリペプチドが分泌される場合、培地は、ポリペプチドを細胞とともに、または、細胞がろ過もしくは遠心分離によって除かれた場合には細胞を伴うことなく含有する。
[00193] 用語「分泌シグナル配列」または用語「シグナル配列」または用語「分泌リーダー配列」は交換可能に使用され、例えば、米国特許第6,291,212号および米国特許第5,547,871号(これらはともにその全体を参照として本明細書中に組み入れる)に記載されている。分泌シグナル配列またはシグナル配列または分泌リーダー配列により、分泌ペプチドがコードされる。分泌ペプチドは、成熟ポリペプチドまたは成熟タンパク質の細胞からの分泌を行わせるために作用するアミノ酸配列である。分泌ペプチドは、疎水性アミノ酸のコアによって一般には特徴づけられ、典型的には(しかし、絶対的ではないが)、新しく合成されたタンパク質のアミノ末端に見出される。非常に多くの場合、分泌ペプチドは分泌途中で成熟タンパク質から切断される。分泌ペプチドは、分泌経路を通過しているときに成熟タンパク質からのシグナルペプチドの切断を可能にするプロセシング部位を含有する場合がある。プロセシング部位はシグナルペプチド内にコードされ得るか、または、例えば、インビトロ変異誘発法によってシグナルペプチドに付加され得る。
[00195] 本発明の改変トランスフェリン融合タンパク質のTf成分および抗体可変領域は直接的に融合させることができ、または、より大きい物理的分離を融合されたタンパク質の間にもたらし、かつより高い空間移動性を融合されたタンパク質の間で可能にし、したがって、例えば、その同系受容体に対する結合のために抗体可変領域の接近性を最大にするために、様々な長さのリンカーペプチドを使用して融合させることができる。リンカーペプチドは、柔軟であるアミノ酸、または、より剛直であるアミノ酸から構成され得る。例えば、ポリグリシンストレッチ(これに限定されない)などのリンカーである。リンカーは、約50アミノ酸残基未満、40アミノ酸残基未満、30アミノ酸残基未満、20アミノ酸残基未満または10アミノ酸残基未満であり得る。リンカーは、トランスフェリンタンパク質またはその一部および抗体可変領域に対して、また、トランスフェリンタンパク質またはその一部と抗体可変領域との間に共有結合的に連結することができる。
[00197] 生物学的に活性な改変トランスフェリン−トランスボディーを検出するためのアッセイには、ウエスタントランスファーフィルター、タンパク質ブロットフィルターまたはコロニーフィルター、ならびに、トランスフェリンおよび抗体可変領域を含む融合タンパク質を検出する活性に基づくアッセイを挙げることができる。ウエスタントランスファーフィルターは、Towbinら(Proc.Natl.Acad.Sci.USA、76:4350〜4354、1979)によって記載されている方法を使用して調製することができる。簡単に記載すると、サンプルがドデシル硫酸ナトリウムポリアクリルアミドゲルにおいて電気泳動される。ゲル中のタンパク質がニトロセルロースペーパーに電気泳動的に転写される。タンパク質ブロットフィルターは、例えば、マニホールド(Schleicher&Schuell、Keene、N.H.)を使用してニトロセルロースフィルターで上清サンプルまたは濃縮物をろ過することによって調製することができる。コロニーフィルターは、適切な増殖培地を覆って置かれているニトロセルロースフィルターの上でコロニーを増殖させることによって調製することができる。この方法では、固体培地が好ましい。細胞は、少なくとも12時間、フィルター上で増殖させられる。細胞が、フィルターに結合したタンパク質を除かない適切な緩衝液で洗浄することによってフィルターから除かれる。好ましい緩衝液は、25mM Tris塩基、19mMグリシン(pH8.3)、20%メタノールを含む。
[00201] 本発明は更に、本明細書中に記載される核酸分子を使用して本発明の改変融合タンパク質(好ましくは、改変されたTfを含むトランスボディー)を製造するための方法を提供する。一般的に言えば、タンパク質の組換え形態の製造は、典型的には下記の工程を伴う:
[00205] 分泌された生物学的に活性な改変トランスフェリン融合タンパク質(好ましくは、改変されたトランスフェリンを含むトランスボディー)を、生物学的に活性な融合タンパク質の分泌を可能にする条件のもとで増殖させた宿主細胞の培地から単離することができる。細胞物質が培養培地から除かれ、生物学的に活性な融合タンパク質が、当分野では既知の様々な単離技術を使用して単離される。適切な単離技術には、沈殿化、ならびに、ゲルろ過、イオン交換クロマトグラフィーおよびアフェニティークロマトグラフィーを含む様々なクロマトグラフィー的方法による分画化が含まれる。
[00207] 本発明の範囲内において、改変トランスボディーは、トランスフェリンの三価鉄イオンに対して複合体化された分子または小分子治療剤を細胞の内部に送達するためのキャリアとして、または血液脳関門を超えて送達するためのキャリアとして使用することができる。これらの実施形態において、トランスフェリンは、典型的には、トランスボディーおよび/または抗体可変領域の血清半減期を延ばすためにグリコシル化を阻害または防止または除去するために操作または改変される。標的化ペプチドの付加、例えば、一本鎖抗体の付加は、トランスボディーを特定の細胞タイプ(例えば、ガン細胞)に対して更に標的化するために特に意図される。
[00210] 本発明の改変融合タンパク質、好ましくは、改変されたトランスフェリンを含む本発明のトランスボディーは、標準的な投与プロトコルを使用してその必要性のある患者に投与することができる。例えば、本発明の改変Tf融合タンパク質は、単独で、または組合せで、または、特定の病理学的プロセスを調節する他の薬剤との連続した組合せで与えることができる。本明細書中で使用されるように、2種類の薬剤が同時に投与されるとき、または、2種類の薬剤が同時もしくはほぼ同時に作用するような様式で独立して投与されるとき、2種類の薬剤は組合せで投与されると言われる。
[00216] 増大した血清半減期、増大した血清安定性、または増大したバイオアベイラビリティを有する本発明の改変トランスフェリン融合構築物(好ましくはトランスボディー)を含有する遺伝子組換え非ヒト動物の作製が本発明の一実施形態において意図される。いくつかの実施形態において、ラクトフェリンを融合タンパク質のTf部分として使用することができ、その結果、融合タンパク質が乳汁中に産生および分泌される。他の実施形態において、本発明は、Tf融合タンパク質を乳汁に産生させることを含む。
[00224] 改変されたトランスフェリンタンパク質またはトランスフェリンドメインが抗体可変ドメインに連結されている遺伝子治療用の改変トランスフェリン融合構築物の使用が、本発明の一実施形態において意図される。増大した血清半減期または血清安定性を有する本発明の改変トランスフェリン融合構築物は、遺伝子治療による治療に理想的に適している。
[00230] 本発明は、トランスフェリンまたは改変されたトランスフェリンと、毒素に対する抗体可変領域とを含むトランスボディーを提供する。本明細書中で使用される用語「毒素」は、生物学的起源の毒性物質を示す。所望される毒素抗体の1つ以上の抗体可変領域と、トランスフェリンとを含むトランスボディーは、先に論じたようにして得ることができる。毒素に対する抗体可変領域を含むトランスボディーは、毒素に関連する疾患に罹患している患者を治療するために使用することができる。毒素に対する抗体可変領域と、トランスフェリン分子または改変されたトランスフェリン分子とを含むトランスボディーはまた、診断目的のために使用することができる。
[00239] 嫌気性グラム陽性細菌のボツリヌス菌は、ヒト致死量がナノグラム範囲にある既知の最も有毒な生物学的神経毒を産生する。毒素の作用は、大腸の破壊を生じさせ得る下痢性の疾患から、死を生じさせ得る麻痺性の作用にまで及ぶ。ボツリヌス菌の胞子は土壌中に見出されており、また、多くのボツリヌス中毒事例の原因である、自家製缶詰の不適切に滅菌および密封された食品容器において増殖し得る。ボツリヌス中毒の症状は、典型的には、ボツリヌス菌の培養物または胞子が感染した食物を食べた後18時間〜36時間で現れる。ボツリヌス毒素は、明らかに、腸の内張層を弱毒化されずに通過し、末梢運動神経細胞を攻撃し得る。ボツリヌス毒素中毒の症状は、歩行困難、燕下困難および会話困難から、呼吸筋の麻痺および死にまで進行し得る。
[00243] 破傷風は古代から認識されている(例えば、この疾患がヒポクラテスによって記述されている)が、1867年までは、その原因として感染性因子を有することは仮定されていなかった(例えば、Hatheway、上掲、75頁を参照されたい)。破傷風菌により引き起こされるこの厳しい毒素産生性疾患は、重大であるとは考えられない刺創と関連していることが多い。この生物は、土壌および多くの動物種(例えば、ヒト、ウマなど)の腸内容物を含む様々なものから容易に単離される。
[00248] C.perfringensは、最も広く存在する病原性細菌であると報告されている(Hatheway、上掲、77頁を参照されたい)。この生物は、最初はWelchおよびNuttallにより1892年に記載され、Bacillus aerogenes capsulatusと名付けられたが、今では一般にC.welchiiとも言われる。C.perfringensは、一般には、土壌サンプル、ならびにヒトおよび他の動物の腸内容物から単離される。他のクロストリジウム属種(例えば、C.novyi、C.septicum、C.histolyticum、C.tertium、C.bifermentansおよびC.sporogenes)もまたガス壊疽に関連するが、C.perfringensは、最も一般的に関与している種である。これらの生物は、健康な組織に導入されたときには高い病原性を有さず、しかし、組織傷害(例えば、損傷を受けた筋肉)の存在下で導入されたときにはガスの蓄積ならびに筋肉および組織の広範囲にわたる壊死によって特徴づけられる急速に進行する破壊的な感染症に関連する。活発に増殖しているとき、クロストリジウム細菌の侵襲性株が、壊死(すなわち、細胞溶解)性、溶血性および/または致死性の性質を有するエキソトキシンを産生する。また、生物によって産生されるコラゲナーゼ、プロテイナーゼ、デオキシリボヌクレアーゼおよびヒアルロニダーゼなどの酵素は、組織における毒性分解産物の蓄積をもたらす。
[00254] クロストリジウム・ディフィシレは、その単離が困難であるためにその名を得た生物であり、最近では、下痢性疾患の病因因子であることが判明している(Sneathら、1165頁)。クロストリジウム・ディフィシレはヒトおよび動物における偽膜性大腸炎の病因因子である。C.difficileは、患部領域において偽膜を形成する、下痢単独から、炎症性細胞およびフィブリンの蓄積を伴う際だった下痢および胃腸粘膜の壊死にまで及ぶ様々な下痢性の病気に関連する。
[00257] 炭疽毒素は、炭疽菌に由来する生物兵器のよく知られている作用因である。炭疽菌は、適切に組み合わせられたときに2つの強力な毒素(まとめて炭疽毒素と呼ばれる)を形成する3つのタンパク質を産生する。保護抗原(PA、82,684Da(ダルトン))および浮腫因子(EF、89,840Da)が一緒になって浮腫毒素(ET)を形成し、一方で、PAおよび致死因子(LF、90,237Da)が一緒になって致死毒素(LT)を形成する(Leppla,S.H.、Alouf,J.E.およびFreer,J.H.編、Academic Press、London、277〜302、1991)。ETおよびLTはそれぞれがAB毒素モデルと一致しており、この場合、PAが標的細胞結合(B)機能を提供し、EFまたはLFがエフェクター成分または触媒作用成分(A)として作用する。これらの毒素の特異な特徴は、LFおよびEFは、明らかに真核生物細胞の細胞質ゾルに進入することができないので、PAの非存在下では毒性を有しないということである。
[00262] 米国特許第6,440,408号では、その生物に特異的な中和抗体と複合体化されている生きた生物(細菌または原生動物)を含むワクチン製剤が提供される。複合体化されている中和抗体の量は、生物が活性な免疫応答を誘導することができ、一方で同時に、病原体の有害な作用からのある程度の保護を提供することができるような量である。
[00270] 本発明の一実施形態において、トランスボディーは更に、少なくとも1つの抗原性ペプチドまたは免疫調節ペプチドを含むように改変される。これらのペプチドの1つ以上をトランスフェリンまたは改変されたトランスフェリンの中に取り込むことができる。1つ以上の抗原性領域を含有するトランスボディーは、それらの抗原と結合することができるだけでなく、宿主において免疫応答を誘導することもできる。これらのトランスボディーにより誘導される細胞応答および体液性応答は、標準的な抗体よりも強い。これは、ほとんどの宿主は、トランスボディーに取り込まれている抗原性決定基で既に免疫化され、それに対する記憶を有しているからである。
[00299] 免疫グロブリン(Ig)はBリンパ球によって産生され、血漿中に分泌される。単量体形態にあるIg分子は、分子量が約150kDaの糖タンパク質であり、おおよそYのような形状を有する。すでに述べたように、このY形状は、2つの重鎖および2つの軽鎖から構成される。重鎖は、カルボキシル末端(Yの基部)に存在するFc部分と、アミノ末端(Yのアーム部)に存在するFab部分とに分けられる。糖鎖が分子のFc部分に結合している。Ig分子のFc部分は重鎖のみから構成される。IgGおよびIgMのFc部分は、マクロファージなどの免疫調節細胞の表面の受容体に結合し、免疫応答を調節するサイトカインの放出を刺激することができる。Fc部分は、個々のクラスに特有の決定基だけでなく、すべてのIgに共通するタンパク質配列を含有する。これらの領域は、同じクラス内の異なるIg分子の間で大きく変化しないので、定常領域と呼ばれる。Fcフラグメントの定常領域は、分子の様々な生物学的性質、例えば、受容体への結合および補体の活性化をもたらす。
[00326] 一態様において、本発明は、腫瘍壊死因子−α(TNF−α)抗体の1つ以上の抗体可変領域またはCDRと、トランスフェリンまたは改変されたトランスフェリンとを含むトランスボディーを提供する。本発明では、治療目的および診断目的のためのこのようなトランスボディーの使用が意図される。TNF−αの産生に関係づけられる重大な疾患状態の例には、敗血症ショック;エンドトキシンショック;細菌感染(例えば、結核、髄膜炎)、ウイルス感染(例えば、AIDS)、寄生虫感染(例えば、マラリア)および新生物疾患に関連する悪液質症候群;自己免疫疾患、これには関節炎のいくつかの形態(特に、リウマチ様形態および変性形態)が含まれる;移植片拒絶を防止するための治療に関連する有害作用が含まれるが、これらに限定されない。以下に論じるように、TNF−αは様々な疾患状態または状況に関連する。本発明では、様々な疾患を治療および診断するための抗TNFトランスボディーの使用が意図される。
[00327] TNF−αは多面発現性の炎症性サイトカインである。身体のほとんどの器官がTNF−αによって影響を受けるようである。このサイトカインは成長刺激ならびに成長阻害の両方の性質を有する。TNF−αはまた自己調節的性質を有するようである。例えば、TNF−αは、好中球の増殖を炎症時に誘導し、しかし、TNF−R55受容体に結合したときには好中球のアポトーシスをも誘導する(Murrayら、1997、Blood、90(7):2772〜2783)。このサイトカインは、数タイプの細胞によって、しかし、特にはマクロファージによって産生される。病態生理学的状態におけるサイトカインの役割は完全には解明されていないが、TNF−αは、傷害および病的状態のカスケードにおける主要な媒介因子であるようである。
[00338] TNFに結合する抗体に由来する任意のCDR領域、VH領域またはVL領域を使用して、本発明のトランスボディーを作製することができる。TNFに対するポリクローナルマウス抗体がCeramiら(欧州特許庁特許公開0212489、1987年3月4日)によって開示されている。このような抗体は、診断的免疫アッセイにおいて、また、細菌感染におけるショックの治療において有用であると言われていた。Rubinら(欧州特許庁特許公開0218868、1987年4月22日)は、ヒトTNFに対するマウスモノクローナル抗体、このような抗体を分泌するハイブリドーマ、このようなマウス抗体を製造する方法、および、TNFの免疫アッセイにおけるこのようなマウス抗体の使用を開示する。
[00347] 更なる実施形態において、本発明は、例えば、治療用途または非治療用途または診断用途のために使用され得る、トランスフェリン融合タンパク質(好ましくは、免疫調節ペプチドを含むトランスボディーおよび改変されたトランスボディー)を含有するキットを提供する。キットは、ラベル付きの容器を含む。適切な容器には、例えば、ボトル、バイアルおよび試験管が含まれる。容器は、ガラスまたはプラスチックなどの様々な材料から形成され得る。容器は、上述した用途などの治療用途または非治療用途のために有効なトランスフェリン融合タンパク質(好ましくはトランスボディー)を含む組成物を収容する。組成物における活性な薬剤は抗体である。容器上のラベルにより、組成物が特定の治療用途または非治療用途のために使用されることが示され、また、上述した指示などの、インビボまたはインビトのいずれかでの使用についての指示が示されることがある。
[00353] トランスフェリン分子および一本鎖抗体を含むトランスボディーを製造することができる。トランスフェリンに融合され得るSCAの具体的な例には、抗TNF(腫瘍壊死因子)がある。抗TNFは、様々な炎症性疾患および自己免疫疾患(例えば、関節リウマチなど)を治療するために使用されている。TNF−SCAは、TNF−SCAのコードN末端がトランスフェリンのC末端アミノ酸に直接結合されるような様式、または、TNF−SCAのC末端アミノ酸がトランスフェリンのN末端アミノ酸に直接結合されるような様式で、改変トランスフェリンのN末端またはC末端に融合することができる。あるいは、ペプチドリンカーを、トランスフェリンとTNF−SCAとの間のより大きな分離をもたらし、かつ、2種の融合されたタンパク質に対してより大きな空間的可動性を可能にするために挿入することができる。TNF−SCAのいくつかの例が図4A〜図4Bに示される。
[00355] 本プロセスにおける最初の工程では、リンカーが、mTfの5’末端(すなわち、N末端)におけるXbaI部位およびKpnI部位の間でpREX0052に挿入され、続いて、mTfにVHおよびVLをクローン化して、pREX0066を作製することができる。このリンカーは、本実施例ではS(SGGG)3S(配列番号32)リンカーペプチドをコードするDNAリンカーのいずれかの端部にVHおよびVLを挿入するための部位を含有する。
フォワード: AGCCTGCACTTTCCGTCGACCTGAAGTGAAACTGGAAG (5'から3')
リバース: CAGTCATGTCTAAGCTTATTACTTCACTTCCAGGTTGG (5'から3')
配列番号: 25
配列番号: 26
抗TNFαVH
翻訳産物 240アミノ酸
分子量 25964.1
等電点(pI) 5.77
[00361] トランスフェリンおよびCDRを含むトランスボディーを作製することができる。CDRは、通常、ペプチドの比較的短い領域からなる。抗体は、通常、3つのCDRをその重鎖に有し、3つのCDRをその軽鎖に有する。抗原と相互作用することができる抗体の1つ以上のCDRを改変トランスフェリンに融合して、抗原結合活性をトランスフェリン分子に付与することができる。CDRは、N末端、C末端、ならびにN末端およびC末端に融合することができ、または、トランスフェリンの内部足場の中に操作して入れることができる。抗TNF抗体に由来するCDR配列の例がTNF−SCAの図4A〜図4Bに示される。1つ以上のCDRに対応するcDNAを改変トランスフェリンと融合して、TNF結合活性をトランスフェリンに付与することができる。
[00362] ヒトTf(PDB識別子1A8E)のNドメインおよび完全なTfモデルAAAaoTfwo(これは、ウサギモデル1JNFをテンプレートとして用いてExPasy Swiss Model Serverを使用して作製された)を調べることにより、直接的、または多数の残基の置換のいずれかによってペプチドを挿入するための多数の潜在的な部位が明らかにされる。これらの部位は、Cドメインにおけるそれらの等価な部位によって重複する。
aat tat tat ggt tct act tat gat tat (配列番号 80)
N Y Y G S T Y D Y (配列番号 44)
ATAATCATAAGTAGAACCATAATAATTCGTCCCATCCGCACAAGGGGCACAGCTGC
P0110 (配列番号 79)
GAATTATTATGGTTCTACTTATGATTATGACTTCCCCCAGCTGTGTCAACTG
[00368] 実施例1および実施例2におけるトランスボディーは、抗原性ペプチドまたは免疫調節ペプチドを含ませるために更に改変することができる。所望のペプチドをトランスボディーのトランスフェリン部分に挿入することができる。このようにして、改変されたトランスボディーは、その抗原と結合することができるだけでなく、宿主において免疫応答を誘導することもできる。
[00369] 本発明のトランスボディー技術は、従来のモノクローナル抗体法に代わる魅力的な方法を提供する。本実施例では、Tfと、抗TNFαモノクローナル抗体に由来する9アミノ酸のCDRペプチド(配列番号44)とを含むトランスボディーが作製された。このCDRペプチドは、TNFαの細胞障害活性を阻止する能力をTfに与えることができた。
aat tat tat ggt tct act tat gat tat (配列番号 80)
N Y Y G S T Y D Y (配列番号 44)
[00370] 細胞:96ウエル組織培養プレートに、DMEM/10%FBS/10mM HEPES培地において、治療の1日前に、WEHI−164細胞を3x104細胞/ウエルの密度で播種した。翌日、細胞は、70パーセント〜80パーセントのおおよそのコンフルエンシーで一様に分布して現れた。
[00371] Nドメイン(TNF−CDR3):
・pREX0080構築物−TfのNドメインのD166において挿入されたTNF CDR3。
・BXP10株(YO150)で成長させる。
・サンプルをRPMI/10%FBS培地で1/10希釈して、350μg/mlの最終濃度にする。0.22μmでろ過滅菌する。
・pREX0128構築物
・BXP10株(YO051)で成長させる。
・サンプルをRPMI/10%FBS培地で1/10希釈して、350μg/mlの最終濃度にする。0.22μmでろ過滅菌する。
・組換えヒトTNFα(Cell Sciences、カタログ#CRT100、ロット121CY25)。25,000ユニット/ml(dH2O)、0.22μmでろ過滅菌する。
[00379] 図5は、2つの独立した実験から得られた結果を示し、WEHI−164細胞におけるTNF媒介の細胞障害性が25μg/mlの用量のNドメイン(TNF−CDR3)によって防止されたことを示している。同じ用量のTfのNドメインは保護をもたらさなかった。このことは、この活性が抗TNF CDR3により媒介されることを示している。
Claims (5)
- 配列番号3に示されるヒト血清トランスフェリンタンパク質および配列番号44に示されるCDRペプチドを含む融合タンパク質であって、ここで前記CDRペプチドは前記ヒト血清トランスフェリンタンパク質のNドメインのD166において挿入されている、融合タンパク質。
- 請求項1に記載される融合タンパク質をコードする核酸分子。
- 請求項2に記載される核酸分子を含むベクター。
- 請求項3に記載されるベクターまたは請求項2に記載される核酸分子を含む宿主細胞。
- 酵母細胞である、請求項4に記載の宿主細胞。
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WO2004020404A3 (en) | 2004-11-11 |
BR0314093A (pt) | 2005-07-05 |
AU2003272241B2 (en) | 2010-05-27 |
US20080220002A1 (en) | 2008-09-11 |
AU2003272241A1 (en) | 2004-03-19 |
US20030226155A1 (en) | 2003-12-04 |
EP1534730A4 (en) | 2007-10-10 |
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