JP2017163998A - 新規な多価免疫グロブリン - Google Patents
新規な多価免疫グロブリン Download PDFInfo
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- JP2017163998A JP2017163998A JP2017120279A JP2017120279A JP2017163998A JP 2017163998 A JP2017163998 A JP 2017163998A JP 2017120279 A JP2017120279 A JP 2017120279A JP 2017120279 A JP2017120279 A JP 2017120279A JP 2017163998 A JP2017163998 A JP 2017163998A
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Abstract
【解決手段】細胞表面分子に対する更なる結合を提供するために修飾された構造ループを介して細胞表面タンパク質と結合する、免疫グロブリンドメインの提供に関する。それにより、細胞表面受容体の架橋が可能となる。また、多価免疫グロブリン又はその結合部分の提供に関する。それらは詳細には、前記免疫グロブリンの少なくとも1つの構造ループ領域中に少なくとも1つの修飾を有し、単一の細胞中の少なくとも2つの細胞表面分子と特異的に結合し、単一の細胞上に位置するか又は同種の細胞集団内に存在する、前記細胞表面分子のエピトープ(抗原性特性に関与する構造を含む)に対する結合性を決定し、未修飾の免疫グロブリンは前記エピトープと顕著に結合しない。
【選択図】なし
Description
− 少なくとも1つの構造ループ領域を含んでなる免疫グロブリンをコードする核酸を準備するステップと、
− 前記構造ループ領域内の少なくとも1つのヌクレオチド残基を修飾するステップと、
− 発現システム中に上記の修飾された核酸を移すステップと、
− 前記多価免疫グロブリンを発現させるステップと、
− 上記で発現された、多価免疫グロブリンをエピトープと接触させ、前記多価免疫グロブリンが前記エピトープと結合するかどうかを測定するステップ。
− 少なくとも1つの第1のエピトープに特異的に結合し、少なくとも1つの構造ループ領域を有する免疫グロブリンをコードする核酸を準備するステップと、
− 前記核酸によってコードされる少なくとも1つの前記ループ領域の少なくとも1つのヌクレオチド残基を修飾するステップと、
− 前記修飾された核酸を発現システム中に移すステップと、
− 前記修飾免疫グロブリンを発現させるステップと、
− 前記少なくとも1つの第2のエピトープと、発現された前記修飾免疫グロブリンとを接触させるステップと、
− 前記修飾免疫グロブリンが第2のエピトープと特異的に結合するか否かを測定するステップ。
Virnekasら、ucleic Acids Res.(1994)22:5600−5607)。
− 少なくとも1つのループ領域を有する免疫グロブリンをコードする核酸を準備するステップと、
− 少なくとも1つの前記ループ領域の少なくとも1つのヌクレオチド残基を修飾するステップと、
− 発現システム中に前記修飾された核酸を存在させるステップと、
− 前記修飾免疫グロブリンを発現させるステップと、
− 発現された修飾免疫グロブリンとエピトープとを接触させるステップと、
− 前記修飾免疫グロブリンが前記エピトープと結合するか否かを測定するステップと、
− 前記エピトープに結合する修飾免疫グロブリンを準備し、任意にそれを医薬品として調製するステップ。
− 少なくとも1つの構造ループ領域を有し、少なくとも1つの第1の分子に特異的に結合する免疫グロブリンをコードする核酸を準備するステップと、
− 前記核酸によってコードされる少なくとも1つの前記ループ領域中の少なくとも1つのヌクレオチド残基を修飾するステップと、
− 発現システム中に前記修飾された核酸を存在させるステップと、
− 前記修飾免疫グロブリンを発現させるステップと、
− 発現された修飾免疫グロブリンと前記少なくとも1つの第2の分子とを接触させるステップと、
− 前記修飾免疫グロブリンが第2の分子と特異的に結合するか否かを測定するステップと、
− 前記少なくとも1つの第2の分子に特異的に結合する修飾免疫グロブリンを準備し、任意に医薬品として調製するステップ。
(a)前記分子を含むと考えられる試験サンプルと、本発明に係る修飾免疫グロブリン又は本発明に係る方法により得られる修飾免疫グロブリンとを接触させるステップと、
(b)特異的な免疫グロブリン/分子複合体の形成を検出するステップ。
(a)前記分子を含有するサンプルと、本発明に係る修飾免疫グロブリン又は本発明に係る方法により得られる修飾免疫グロブリンとを接触させるステップと、
(b)形成された特異的な免疫グロブリン/分子複合体を分離するステップと、
(c)任意に前記分子を前記複合体から分離するステップ。
(a)前記化合物と特異的に結合できる、本発明に係る修飾免疫グロブリンを又は本発明に係る方法により得られる修飾免疫グロブリン接触させるステップと、
(b)標的に免疫グロブリン/化合物複合体を輸送するステップ。
overlap span=1、
overlap fraction=0.125、
word threshold(T)=11、
及びscoring matrix=BLOSUM62。
WU−BLAST−2を使用するとき、アミノ酸配列同一性%は、以下の(a)/(b)により算出される:
(a)天然の免疫グロブリンドメインに由来する、目的の配列を有する免疫グロブリンドメインのアミノ酸配列と、目的の比較用アミノ酸配列(すなわち、目的の免疫グロブリンドメインと比較するための配列。未修飾の免疫グロブリンドメインであってもよい)との間で一致する同一アミノ酸残基の数(WU−BLAST−2として定義される);
(b)目的の免疫グロブリンドメイン中の非ランダム化部分のアミノ酸残基の総数。例えば「アミノ酸配列Aを含んでなり、アミノ酸配列Bと少なくとも80%のアミノ酸配列同一性を有するポリペプチド」というときは、アミノ酸配列Aが、目的の比較用アミノ酸配列であり、アミノ酸配列Bが、目的の免疫グロブリンドメインのアミノ酸配列である。
結晶構造のIgG1 Fc断片(Brookhaven Databaseにおいてエントリー1OQO.pdbとして公知)を、変異CH3ドメインのデザインの補助に用いた。CH3ライブラリの構築の根拠として用いた配列を、配列番号1に示す。この配列において、第1のアミノ酸は、Brookhavenデータベースエントリーloqo.pdb.の鎖Aのプロリン343に対応する。loqo.pdbに含まれる最後の残基は、配列番号1のセリン102である。loqo.pdbの構造の詳細なアッセイ、及び、β鎖を連結するループを形成している残基の視覚による確認の後残基17、18及び19をランダム化するを決定し、それはβ鎖ABを連結しているループの一部であり、71、72、73、76及び77も同様であり、それは配列番号1のβ鎖EFを連結しているループの一部である。デザインされた遺伝子は、一連のPCR反応に、更に得られるPCR産物のライゲーションによって得た。ライゲーションを容易にするために、配列番号1のためのヌクレオチド配列コードのコドンの幾つかを、アミノ酸配列(サイレント突然変異)を変えることのない制限部位を生じさせるために修飾した。pHEN1(Nucleic Acids Res.1991 Aug 11;19(15):4133−7.Multi−subunit proteins on the surface of filamentous phage:methodologies for displaying antibody(Fab) heavy and light chains.Hoogenboom HR,Griffiths AD,Johnson KS,Chiswell DJ,Hudson P,Winter G.)への、pelB分泌シグナルとのインフレームでのクローニングベクターへの挿入のために、Met−Alaをコードする余分のヌクレオチド残基を、配列の5’末端に連結し、Ncol制限部位を設けた。ランダム化された残基の場合、全ての20の天然アミノ酸をコードするが、3つの停止コドン中2つを回避するコドンNNS(IUPACコード、SがC又はGを意味する)を選択した。デザインされた配列を、配列番号2のヌクレオチド配列として及び配列番号3のアミノ酸配列として示す。配列番号3の文字Xは、ランダム化されたアミノ酸残基を意味する。変異CH3ドメインの組立のために使用するPCRプライマの配列を、配列番号4から9に示す。
CH3ライブラリと同様に、このライブラリを構築し、クローニングした。構築物のアミノ酸配列を配列番号10に示し、対応するヌクレオチド配列を配列番号11に示し、構築のために使用するプライマを配列番号4から7、配列番号9及び配列番号12に示す。
CH3ライブラリと同様に、このライブラリを構築し、クローニングした。構築物のアミノ酸配列を配列番号13に示し、対応するヌクレオチド配列を配列番号14に示し、構築のために使用するプライマを配列番号4から7、配列番号9及び配列番号15に示す。
ヒトのIgG1 CH1ライブラリにおいて、Ser93、Ser94、Ser95、Gly98、Thr99及びGln100をランダム化し、更に3つのランダムな残基を、部位特異的ランダムな突然変異導入した。Leu96は変異しなかった。他のヒトのIgG1 CH1ライブラリにおいて、Pro92、Ser93、Ser94、Ser95、Leu96、Thr101、Gly98、Thr99及びGln100をランダム化し、更に3つのランダムな残基を、部位特異的ランダムな突然変異導入した。ファージミドベクターpHENlのNcol及びNotl制限酵素部位を用いて、ライブラリをコードする遺伝子を、N末端でpelBリーダーとインフレームで、C末端でfdファージ由来のタンパク質IIIとインフレームでクローニングした。特異的結合クローンのファージ粒子の調製、パニング及び選抜は、標準的方法を使用して実施した。
ヒトのIgG1 CLライブラリにおいて、Ser92、Lys93、Ala94、Asp95、Glu97、Lys98及びHis99をランダム化し、Ser16とGly17の間に、更に3つのランダムな残基を、部位特異的ランダムな突然変異導入した。ファージミドベクターpHENlのNcol及びNotl制限酵素部位を用いて、ライブラリをコードする遺伝子を、N末端でpelBリーダーとインフレームで、C末端でfdファージ由来のタンパク質IIIとインフレームでクローニングした。特異的結合クローンのファージ粒子の調製、パニング及び選抜は、標準的方法を使用して実施した。
3つのパニングラウンドを実施した。マレイミド活性化プレート(Pierce社製)は合成ペプチドRp10−Lでコーティングされ、B細胞分子標識CD20(Perosaら、Ann N Y Acad Sci.(2005)51:672−83)のミモトープ(mimotope)を発現する。その推定アミノ酸配列は以下の通りである:ITPWPHWLERSS。以下の溶液の200μlをウェルに添加した:PBS(pH=7.2)以下の濃度のペプチドを溶解させる:−1回目のパニングラウンド:100μg/ml−2回目のパニングラウンド:100μg/ml−3回目のパニングラウンド:50μg/ml。
形質転換したCH3ドメイン−コード配列(抽出したファージ粒子内に含まれる)をPCRによりバッチ増幅した。Ncol及びNotlによる制限酵素処理の後、それらをpNOTBAD(Invitrogen社製ベクターpBAD、後にNot1部位を挿入)に挿入した。E.coll E104への形質変換の後、細胞を、1%のブドウ糖及び100μg/mlアンピシリンを有するTYE培地で30℃で選抜した。
3つのパニングラウンドを実施した。マレイミド活性化プレート(Pierce社製)は合成ペプチドでコーティングされ、B細胞分子標識CD20のミモトープ(mimotope)を発現する。以下の溶液の200μlをウェルに添加した:
PBS(pH=7.2)以下の濃度のペプチドを溶解させる:
−1回目のパニングラウンド:100μg/ml
−2回目のパニングラウンド:100μg/ml
−3回目のパニングラウンド:50μg/ml。
−1パニングラウンドの後:10×200μl T−PBS、5×200μl T−PBS;
−1パニングラウンドの後:15×200μl T−PBS、10×200μl T−PBS;
−1パニングラウンドの後:20×200μl T−PBS、20×200μl T−PBS。
3つのパニングラウンドを実施した。マレイミド活性化プレート(Pierce社製)は合成ペプチドでコーティングされ、B細胞分子標識CD20のミモトープ(mimotope)を発現する。以下の溶液の200μlをウェルに添加した:PBS(pH=7.2)以下の濃度のペプチドを溶解させる:−1回目のパニングラウンド:100μg/ml−2回目のパニングラウンド:100μg/ml−3回目のパニングラウンド:50μg/ml。
−1パニングラウンドの後:10×200μl T−PBS、5×200μl T−PBS;
−1パニングラウンドの後:15×200μl T−PBS、10×200μl T−PBS;
−1パニングラウンドの後:20×200μl T−PBS、20×200μl T−PBS。
元来環状ペプチドであるCRGDCLは、最初、Koivunenその他によって1993年、繊維状ファージにおいて発現する6−アミノ酸ペプチドライブラリから単離され(J.Biol.Chem.1993 Sep 25、268(27):20205−10)、RGDを発現するファージのαvβ1インテグリンへの結合、又はフィブロネクチンへのαvβ1発現細胞の結合を阻害することが示されている。上記ペプチドはまた、αvβ1、αvβ3及びαvβ5インテグリンにより媒介される細胞接着を阻害することが知られている。
Claims (19)
- 多価の免疫グロブリン又はその部分であって、単一の細胞上の少なくとも2つの細胞表面分子と特異的に結合し、前記免疫グロブリンの少なくとも1つの構造ループ領域の中に少なくとも1つの修飾を有し、前記細胞表面分子のエピトープに対する結合を決定し、未修飾の免疫グロブリンが前記エピトープと顕著に結合しない、前記多価の免疫グロブリン又はその部分。
- 修飾された前記構造ループ領域が、前記免疫グロブリンの定常ドメイン中に、好ましくはCH1、CH2、CH3、CH4、Igk−C、Igl−C又はその部分中に存在する、請求項1記載の免疫グロブリン。
- 修飾された前記構造ループ領域が、少なくとも6つのアミノ酸修飾を有する、請求項2記載の免疫グロブリン。
- ヒト若しくはマウス由来のCH1、CH2、CH3又はCH4の修飾されたループ領域が、アミノ酸7〜21、アミノ酸25〜39、アミノ酸41〜81、アミノ酸83〜85、アミノ酸89〜103又はアミノ酸106〜117の範囲内に少なくとも1つの修飾を有する、請求項1から3のいずれか1項記載の免疫グロブリン。
- ヒト由来のIgk−C又はIgI−Cのループ領域が、アミノ酸8〜18、アミノ酸27〜35、アミノ酸42〜78、アミノ酸83〜85、アミノ酸92〜100、アミノ酸108〜117又はアミノ酸123〜126の範囲内に少なくとも1つの修飾を有する、請求項1から3のいずれか1項記載の免疫グロブリン。
- マウス由来のIgk−C又はIgl−Cのループ領域が、アミノ酸8〜20、アミノ酸26〜36、アミノ酸43〜79、アミノ酸83〜85、アミノ酸90〜101、アミノ酸108〜116又はアミノ酸122〜125の範囲内に少なくとも1つの修飾を有する、請求項1から3のいずれか1項記載の免疫グロブリン。
- 免疫グロブリン定常ドメインがラクダ科の動物由来である、請求項1から3のいずれか1項記載の免疫グロブリン。
- 免疫グロブリンが、CH1、CH2及びCH3からなる群から選択される、少なくとも1つの修飾された定常ドメインを有する、請求項7記載の免疫グロブリン。
- CH1、CH2及び/又はCH3の修飾されたループ領域が、アミノ酸8〜20、アミノ酸24〜39、アミノ酸42〜78、アミノ酸82〜85、アミノ酸91〜103又はアミノ酸108〜117の範囲内に少なくとも1つの修飾を有する、請求項8記載の免疫グロブリン。
- 可変ドメインがVH、Vκ、Vλ、VHH及びそれらの組み合わせからなる群から選択される、請求項1記載の免疫グロブリン。
- VH、Vκ、Vλ又はVHHの修飾されたループ領域が、アミノ酸7〜21、アミノ酸25〜39、アミノ酸41〜81、アミノ酸83〜85、アミノ酸89〜103又はアミノ酸106〜117の範囲内に少なくとも1つの修飾を有し、ドメインのアミノ酸位の付番がIMGTに従う、請求項1から10のいずれか1項記載の免疫グロブリン。
- ヒト由来のVH又はVκ又はVλのループ領域が、アミノ酸8〜20、アミノ酸44〜50、アミノ酸67〜76及びアミノ酸89〜101、最も好ましくはアミノ酸位12〜17、アミノ酸位45〜50、アミノ酸位69〜75及びアミノ酸位93〜98の範囲内に少なくとも1つの修飾を有し、ドメインのアミノ酸位の付番がIMGTに従う、請求項1から10のいずれか1項記載の免疫グロブリン。
- マウス由来のVHのループ領域が、アミノ酸6〜20、アミノ酸44〜52、アミノ酸67〜76及びアミノ酸92〜101の範囲内に少なくとも1つの修飾を有し、ドメインのアミノ酸位の付番がIMGTに従う、請求項1から10のいずれか1項記載の免疫グロブリン。
- ラクダ科の動物由来のVHHの修飾されたループ領域が、アミノ酸7〜18、アミノ酸43〜55、アミノ酸68〜75及びアミノ酸91〜101の範囲内に少なくとも1つの修飾を有し、ドメインのアミノ酸位の付番がIMGTに従う、請求項1から10のいずれか1項記載の免疫グロブリン。
- 修飾された前記免疫グロブリンが更に、1つ以上の修飾された免疫グロブリン若しくは未修飾の免疫グロブリン、又はその部分と組み合わされることにより、組み合わせ免疫グロブリンが得られる、請求項1から10のいずれか1項記載の免疫グロブリン。
- 前記修飾が、削除、置換、挿入又はそれらの組み合わせである、請求項1から15のいずれか1項記載の免疫グロブリン。
- 請求項1から14のいずれか1つに記載の免疫グロブリン又はその部分をコードする核酸。
- 請求項1から16のいずれか1項記載の多価免疫グロブリンを設計するための方法であって、
− 少なくとも1つの構造ループ領域からなる免疫グロブリンをコードする核酸を準備するステップと、
− 前記構造ループ領域の中の少なくとも1つのヌクレオチド残基を修飾するステップと、
− 発現システム中に前記修飾された核酸を存在させるステップと、
− 前記多価免疫グロブリンを発現させるステップと、
− 発現された多価免疫グロブリンとエピトープとを接触させ、前記多価免疫グロブリンが前記エピトープと結合するか否かを測定するステップを有してなる方法。 - 薬剤の調製への、請求項1から16のいずれか1項記載の多価免疫グロブリンの使用。
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EP2463302B1 (en) | 2015-04-01 |
ES2539593T3 (es) | 2015-07-02 |
US20180051095A1 (en) | 2018-02-22 |
SI2463302T1 (sl) | 2015-08-31 |
DK2046831T3 (da) | 2012-05-29 |
JP6681855B2 (ja) | 2020-04-15 |
CN101522712A (zh) | 2009-09-02 |
JP2013240338A (ja) | 2013-12-05 |
PT2463302E (pt) | 2015-07-21 |
EP2046831A2 (en) | 2009-04-15 |
CN110078828A (zh) | 2019-08-02 |
EP2463302A1 (en) | 2012-06-13 |
WO2008003103A2 (en) | 2008-01-10 |
AT503889A1 (de) | 2008-01-15 |
WO2008003103A3 (en) | 2008-04-17 |
PT2046831E (pt) | 2012-04-24 |
SI2046831T1 (sl) | 2012-03-30 |
US11827720B2 (en) | 2023-11-28 |
JP2009540837A (ja) | 2009-11-26 |
EP2046831B1 (en) | 2012-01-04 |
AT503889B1 (de) | 2011-12-15 |
PL2463302T3 (pl) | 2015-08-31 |
DK2463302T3 (en) | 2015-06-15 |
JP5924751B2 (ja) | 2016-05-25 |
JP6215603B2 (ja) | 2017-10-18 |
US20240150495A1 (en) | 2024-05-09 |
PL2046831T3 (pl) | 2012-06-29 |
ES2380127T3 (es) | 2012-05-08 |
US20100048877A1 (en) | 2010-02-25 |
ATE540056T1 (de) | 2012-01-15 |
HUE025035T2 (en) | 2016-01-28 |
CN110041430A (zh) | 2019-07-23 |
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