JP2018504383A - システイン結合ナノボディダイマー - Google Patents
システイン結合ナノボディダイマー Download PDFInfo
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- JP2018504383A JP2018504383A JP2017532920A JP2017532920A JP2018504383A JP 2018504383 A JP2018504383 A JP 2018504383A JP 2017532920 A JP2017532920 A JP 2017532920A JP 2017532920 A JP2017532920 A JP 2017532920A JP 2018504383 A JP2018504383 A JP 2018504383A
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Abstract
Description
本発明は、第1のポリペプチド及び第2のポリペプチドを含むダイマーであって、前記第1の及び第2のポリペプチドがそれぞれ、少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、(好ましくはC末端において)システイン部分を含むC末端伸長部とを含み、前記第1のポリペプチド及び前記第2のポリペプチドが、前記第1のポリペプチドのシステイン部分と、前記第2のポリペプチドのシステイン部分との間のジスルフィド結合を介して共有結合されているダイマーに関し、該ダイマーは、様々なアッセイにおいて、ベンチマーク構築物(例えば、同種の多価及び多重特異性構築物)よりもパフォーマンスが優れていた。本発明は、本発明のダイマーを作製するための方法を提供する。本発明はさらに、(本明細書で定義される)可変ドメイン、及び本発明の方法によって取得可能な1つ以上の可変ドメインを含むポリペプチド(「本発明のポリペプチド」とも称される)、並びに1つ以上の基、残基又は部分にカップリングされたこのような可変ドメイン及び/又はポリペプチドを含む化合物(「本発明の化合物」とも称される)を提供する。
20個超のモノクローナル抗体(mAb)が治療に承認され、より多くが臨床開発中であり、このクラスの分子は、様々な疾患の確立された処置モダリティになっている(Reichert (2011) MAbs 3:76-99; Nelson et al. (2010) Nat Rev Drug Discov 9:767-74)。しかしながら、ガン又は炎症性障害などの複雑な疾患は、通常、本質的に多因子性であり、疾患を媒介する多数のリガンド及びレセプター、並びにシグナルカスケード間のクロストークが関与する。複数のターゲット又は1つのターゲット上の複数の部位の遮断は、治療効果の改善をもたらすはずである。従来のモノクローナル抗体治療が有意な抗腫瘍活性を誘導する能力は限定的であったので、二重特異性物質(2つの異なる抗原に同時に結合し得る抗体)が開発された(Kontermann (2012) mAbs 4:182-197)。過去10年間に、併用療法又は混合物の使用の代替策として、二重特異性抗体による二重ターゲティングが登場した。二重特異性抗体による二重ターゲティングの概念は、1つの薬物による複数の疾患改変分子のターゲティングに基づくものである。製造、前臨床及び臨床試験は、単一二重特異性分子に縮小されるので、技術及び規制の観点から、これは開発をより容易にする(Kontermann (2012)前掲)。組み合わせではなく単一二重ターゲティング薬物による治療はまた、患者にとっても負担が少ないはずである。
(i)第1のポリペプチドを提供する工程であって、前記第1のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含む工程;
(ii)第2のポリペプチドを提供する工程であって、前記第2のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含む工程;並びに
(iii)好ましくはpH6.5〜pH7.5において、場合により酸化銅イオン(Cu2+)を追加することによって、前記第1のポリペプチドのC末端伸長部の前記システイン部分のチオール部分と、前記第2のポリペプチドのC末端伸長部の前記システイン部分のチオール部分とをジスルフィド誘導体シスチンに酸化し、前記シスチンが、該ダイマー中に存在する唯一の分子間ジスルフィド結合であり、それによって、前記ダイマーを作製する工程を含む方法に関する。
好ましくは、前記ダイマーの前記[C末端]シスチンを還元する工程は、前記第1のポリペプチド及び/又は前記第2のポリペプチドの分子内ジスルフィド結合の酸化状態が維持される条件下で実施される。換言すれば、ISVDの完全性は維持される。該方法は、前記ダイマーの前記(C末端に位置する)シスチンを還元する工程を場合によりさらに含む。
(i)シスチン結合を介して二量体化されたポリペプチドを提供する工程;
(ii)前記シスチン結合を還元する工程を含む方法に関し、
それにより、反応性システイン部分を含むポリペプチドを作製する。
好ましくは、前記シスチン結合は、前記ポリペプチドのC末端部に位置する。好ましくは、前記工程(ii)の還元条件は、内部シスチン結合が還元されないように選択される。
本明細書を通して先行技術に関するいかなる議論も、このような先行技術が広く公知であること、及び当技術分野における共通の一般知識の一部を形成することを決して自認するものではない。
−競合FACSによって決定した場合に、多くとも100nM、例えば50nM、20nM、10nM、9nM、8nM、7nM、6nM、5nM、4nM、3nM、好ましくはさらに多くとも2nM、例えば1nMのIC50で;
−10−5〜10−12モル/リットル以下、好ましくは10−7〜10−12モル/リットル以下、より好ましくは10−8〜10−12モル/リットルの解離定数(KD)で;
−102M−1s−1〜約107M−1s−1、好ましくは103M−1s−1〜107M−1s−1、より好ましくは104M−1s−1〜107M−1s−1、例えば105M−1s−1〜107M−1s−1の会合速度(kon速度)で;及び/又は
−1s−1〜10−6s−1、好ましくは10−2s−1〜10−6s−1、より好ましくは10−3s−1〜10−6s−1、例えば10−4s−1〜10−6s−1の解離速度(koff速度)で、
前記第1のポリペプチドが第1のターゲットに結合するダイマーに関する。
−競合FACSによって決定した場合に、多くとも100nM、例えば50nM、20nM、10nM、9nM、8nM、7nM、6nM、5nM、4nM、3nM、好ましくはさらに多くとも2nM、例えば1nMのIC50で;
−10−5〜10−12モル/リットル以下、好ましくは10−7〜10−12モル/リットル以下、より好ましくは10−8〜10−12モル/リットルの解離定数(KD)で;
−102M−1s−1〜約107M−1s−1、好ましくは103M−1s−1〜107M−1s−1、より好ましくは104M−1s−1〜107M−1s−1、例えば105M−1s−1〜107M−1s−1の会合速度(kon速度)で;及び/又は
−1s−1〜10−6s−1、好ましくは10−2s−1〜10−6s−1、より好ましくは10−3s−1〜10−6s−1、例えば10−4s−1〜10−6s−1の解離速度(koff速度)で、
前記第2のポリペプチドが第2のターゲットに結合するダイマーに関する。
は、ジスルフィド誘導体シスチンを示し;
−[Cys−S]及び−[AAx]−[Cys−S]−[AAy]は、前記ポリペプチドのシステインを含むC末端伸長部を示し;
「AA」は、本明細書で定義される任意のアミノ酸を表し;
先頭の「N」は、ポリペプチドのN末端を表し;
末尾の「C」は、ポリペプチドのC末端を表し;
下付き文字「x」、「y」、「p」及び「q」は、0〜50の範囲、例えば1〜40の範囲又は2〜30の範囲の整数、例えば0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19又は20などから独立して選択される数字を表す。例えば、「x」、「y」、「p」及び「q」の全てが0である場合、C末端伸長部はシステインのみであり;「y」及び「q」の両方が0であるが、「x」及び「p」が0ではない場合、C末端伸長部のC末端はシステインである)中に存在する唯一の鎖間ジスルフィド結合である。
(i)第1のポリペプチドを提供する工程であって、前記第1のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含む工程;
(ii)第2のポリペプチドを提供する工程であって、前記第2のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含み、
前記第1のポリペプチドが、前記第2のポリペプチドと異なるものである工程;並びに
(iii)好ましくはpH6.5〜pH7.5において、酸化銅イオン(Cu2+)を場合により追加することによって、前記第1のポリペプチドのC末端の前記システイン部分のチオール部分と、前記第2のポリペプチドのC末端の前記システイン部分のチオール部分とをジスルフィド誘導体シスチンに酸化し、それにより、前記ダイマーを作製する工程
を含む方法に関する。
−細菌株、限定されないが、グラム陰性株、例えばEscherichia coli;Proteus、例えばProteus mirabilis;Pseudomonas、例えばPseudomonas fluorescensの株;及びグラム陽性株、例えばBacillus、例えばBacillus subtilis又はBacillus brevis;Streptomyces、例えばStreptomyces lividans;Staphylococcus、例えばStaphylococcus carnosus;及びLactococcus、例えばLactococcus lactisの株が挙げられる;
−真菌細胞、限定されないが、Trichodermaの種、例えばTrichoderma reesei;Neurospora、例えばNeurospora crassa;Sordaria、例えばSordaria macrospora;Aspergillus、例えばAspergillus niger又はAspergillus sojae;又は他の糸状菌の細胞が挙げられる;
−酵母細胞、限定されないが、Saccharomycesの種、例えばSaccharomyces cerevisiae;Schizosaccharomyces、例えばSchizosaccharomyces pombe;Pichia、例えばPichia pastoris又はPichia methanolica;Hansenula、例えばHansenula polymorpha;Kluyveromyces、例えば Kluyveromyces lactis;Arxula、例えばArxula adeninivorans;Yarrowia、例えばYarrowia lipolyticの細胞が挙げられる;
−両生類細胞又は細胞株、例えばXenopus卵母細胞;
−昆虫由来細胞又は細胞株、例えば鱗翅目由来細胞/細胞株、限定されないが、Spodoptera SF9及びSf21細胞又はDrosophila由来細胞/細胞株、例えばSchneider及びKc細胞が挙げられる;
−植物又は植物細胞、例えばタバコ植物;並びに/又は
−哺乳類細胞/細胞株、例えばヒト由来細胞又は細胞株、哺乳動物由来細胞又は細胞株、限定されないが、CHO細胞(例えば、CHO−K1細胞)、BHK細胞及びヒト細胞又は細胞株、例えばHeLa、COS、Caki及びHEK293H細胞が挙げられる;
並びに、抗体及び抗体フラグメント(限定されないが、(単一)ドメイン抗体及びScFvフラグメントが挙げられる)の発現及び生産のためのそれ自体が公知の全ての他の宿主細胞又は(非ヒト)宿主(これは、当業者には明らかであろう)。本明細書の上記で引用される一般的な背景技術、並びに例えば国際公開公報第94/29457号;国際公開公報第96/34103号;国際公開公報第99/42077号;Frenken et al. (Res Immunol. 149: 589-99, 1998); Riechmann and Muyldermans (1999)、前掲; van der Linden (J. Biotechnol. 80: 261-70, 2000); Joosten et al. (Microb. Cell Fact. 2: 1, 2003); Joosten et al. (Appl. Microbiol. Biotechnol. 66: 384-92, 2005)及び本明細書で引用されるさらなる参考文献も参照のこと。
1.第1のポリペプチドを提供する工程であって、前記第1のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含む工程;
2.前記第1のポリペプチドを還元する工程;
3.工程2の還元型の第1のポリペプチドを、還元条件下で担体に結合させる工程;
4.第2のポリペプチドを提供する工程であって、前記第2のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端においてシステイン部分を含むC末端伸長部とを含む工程;
5.前記第2のポリペプチドを還元する工程;
6.場合により全ての第1のポリペプチドがジスルフィド結合を介して第2のポリペプチドに完全にコンジュゲートするまで、工程5の還元型の第2のポリペプチドを、工程3の担体に結合させた還元型の第1のポリペプチドに、場合により軽度の酸化条件下で適用して、前記第1のポリペプチドの好ましくはC末端の前記システイン部分のチオール部分と、前記第2のポリペプチドの好ましくはC末端の前記システイン部分のチオール部分とをジスルフィド誘導体シスチンに酸化し、それにより、前記二重特異性ダイマーを作製する工程;
7.場合により、コンジュゲートしていない第2のポリペプチドを回収し、工程5及び6にしたがって再び還元及び適用する工程;
8.担体から二重特異性ダイマーを溶出させる工程
を含む方法に関する。
(i)シスチン(ジスルフィド結合;2つのシステイン間のSS結合又はジスルフィド架橋)を介して二量体化された本発明のポリペプチドを提供する工程;
(ii)前記シスチンを還元し、それにより、反応性システイン部分を含むポリペプチドを作製する工程
を含む方法に関する;好ましくは、前記シスチン結合は、前記ポリペプチドのC末端に位置する。好ましくは、前記工程(ii)の還元条件は、内部シスチン結合が還元されないように選択される。
表4に示されているように、EGFR結合ナノボディ7D12及び9G08、並びにアルブミン結合ナノボディALB11から出発して、様々な構築物をP. pastorisにおいて作製した。
例えば、Garaicoechea et al. (Garaicoechea et al. (2008) J Virol. 82: 9753-9764)に記載されている標準的なプロトコールにしたがって遺伝子融合によって、ビルディングブロック7D12及びAlb11及びリンカーのカップリングを、T023800001、T023800003、T023800005及びT023800006において様々に置き換えて(順序)実施した。様々なリンカー長及び組成物を含むポリペプチドを作製した(ISVD及び個々のISVDの順序)。遺伝子融合によって、GGCを含むC末端伸長部も構築した。T023800001(配列番号:27)、T023800003(配列番号:28)、T023800005(配列番号:29)及びT023800006(配列番号:30)及びT023800008(配列番号:31)の配列を表6に提供する。
十分に確立されたプロトコール(以下を参照のこと)にしたがって、アラニン部分(N−マレオイル−β−アラニン;Sigma-Aldrich)を、ほぼ中性の条件(pH6.5〜7.5)において、マレイミド化学反応を介して、C末端に位置するシステインのスルフヒドリル基(−SH)にコンジュゲートして、安定なチオエーテル結合を形成した。簡潔に言えば、最初に、問題のポリペプチドの濃度を決定した。2〜5モル過剰のN−マレオイル−β−アラニンをポリペプチドに追加して、利用可能な全てのシステインを遮断した。混合物を室温で1時間インキュベーションし、続いて4℃で一晩インキュベーションした。翌日、LCMSを介して、コンジュゲーション効率を確認した。SECクロマトグラフィーを介して、Ala伸長部を含むポリペプチドを均一に精製して、過剰なN−マレオイル−β−アラニンを除去した。
Pichia使用済み培地中で、前記2つの各ポリペプチドのC末端伸長部のC末端システインを、ほぼ中性のpHにおいて、それらのチオール部分を介して、ジスルフィド誘導体シスチンに酸化した化学的コンジュゲーションによってダイマーへのポリペプチドのカップリングを実施した。酸化プロセスを最適化するために、基本的には国際公開公報第2010/125187号に示されているように、酸化銅イオン(CuSO4の形態のCu2+)を追加した。ダイマーを均一に精製し、続いて、サイズ排除クロマトグラフィーを介して分析した。LC−MSによっても、サンプルを検証した。得られたデータにより、チオール部分のほぼ100%が、1mM CuSO4によって室温で2時間処理した後に酸化されたことが実証された。いずれのクロマトグラムにおいても、有意な(望ましくない)プレピークの形成は観察されなかった。また、いずれのクロマトグラムにおいても、有意なプレピークの形成に関する証拠は見られなかったが、これは、銅処理がタンパク質中のメチオニンを酸化しないようであり、全質量分析が+16Daのいかなる質量増加も検出しないことを示しており、例えば、メチオニンの単独酸化と一致している。
ストリンジェントなストレス条件下で、異なる本発明の構築物、例えばダイマー、ポリペプチド及びベンチマークを、保存後の安定性について試験した。これらの条件は、基本的には国際公開公報第2014/184352号に示されているように、本発明のポリペプチドを異なる温度(25℃及び40℃)で長期間(3週間及び6週間)インキュベーションすることから構成されていた。
EGFR結合親和性を評価するために、結合競合アッセイにおいて、ポリペプチドを特性評価した。
を使用して、絶対阻害定数Kiを計算した。
競合FACS(上記実施例2を参照のこと)において観察された効力の増加が、EGFR媒介性シグナル伝達のモデュレーションにもつながるかを検証するために、本発明者らは、NH3T3/HER14細胞において、ナノボディによるEGF媒介性EGFRリン酸化の遮断実験を設定した。使用した構築物は、T023800001−A及びT023800006−A並びにT023800001−ダイマーであった。EGFRのみを発現するHER14細胞において、EGFRリン酸化の用量依存的阻害を評価した。
4.1 背景情報
少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、C末端においてシステイン部分を含むC末端伸長部とを含む本発明のポリペプチドは、マレイミド化学反応ベースのカップリング反応に適切であることが分かった(上記実施例1.2を参照のこと)。
還元プロトコールは、D−PBS中、10mM DTTによって4℃で一晩(又は室温で最低2時間)処理することであった。ISVD濃度は、2〜10mg/mlであった。これらの条件は、内部標準ジスルフィド結合に対して影響を与えないことが実証された(以下の図4を参照のこと)。TCEPを使用して同様の結果が得られた(ここでは、本発明者らは、製造業者のプロトコールにしたがって固定化TCEP(Pierce, Immobilized TCEP Disulfide Reducing Gel, #77712)を使用した)。あるいは、4℃における10mM TCEPへの30分間の短時間曝露を使用した。
精製では、最大3つのISVDを含むポリペプチドのために、好ましくはSuperdex 75 column (GE Healthcare)(分離範囲5〜100kDa)を使用して、還元型モノマー生成物を作製した。分析目的のために、Agilent SEC-3などのHPLCカラムを使用した。平衡化バッファー及びランニングバッファーは、D−PBSであった。
疎水性抗有糸分裂剤モノメチルアウリスタチンE(MMAE)は、天然物ドラスタチン10の合成類似体である。MMAEは、分裂細胞におけるチューブリン重合の強力な阻害剤である。
T023800001=>T023800001−mc−val−cit−PAB−MMAE(ABL100−NC003−1)
T023800003=>T023800003−mc−val−cit−PAB−MMAE(ABL100−NC003−3)
T023800005=>T023800005−mc−val−cit−PAB−MMAE(ABL100−NC003−5)
T023800006=>T023800006−mc−val−cit−PAB−MMAE(ABL100−NC003−6)
T023800008=>T023800008−mc−val−cit−PAB−MMAE(ABL100−BF012−1)
XCELLIGENCE(登録商標)instrument (Analyser Model W380; SN: 281081212038, Roche)を使用して、細胞成長及び/又は細胞毒性に対するMMAEコンジュゲートポリペプチドの効果を試験した。この機器は、培養皿において細胞が付着及び拡散する際の電気インピーダンスの変化を定量し、無次元パラメータと称される細胞指数(これは、細胞によって覆われている組織培養ウェルの総面積に正比例する)としてそれらを表示する(Duchateau et al. 2013. Phys. Status Solidi 10: 882-888及びGiaever and Keese 1991. Proc. Natl. Acad. Sci. USA 88: 7896-7900)。XCELLIGENCE(登録商標)instrument (Analyser Model W380; SN: 281081212038)は、細胞を播種するための組織培養ウェルプレートとしてE-plates 96 (ACEA Biosciences; cat#05 232 368 001; lot#20140138; plate 1: ID#079605; plate 2: ID#079606)を利用する。使用した構築物は、T023800001−A及びT023800001−MMAE、T023800003−A及びT023800003−MMAE、T023800005−A及びT023800005−MMAE並びにT023800006−A及びT023800006−MMAEであった。非コンジュゲートナノボディ及びMMAEコンジュゲートナノボディのMDA−MB−468(乳腺/乳房;転移部位由来:胸水;ABL216)細胞増殖に対する用量依存的阻害効果を、以下のプロトコールを使用してXCELLIGENCE(登録商標)instrumentを用いて評価した。
抗EGFRポリペプチド薬物コンジュゲートのin vivo有効性研究を、皮下異種移植マウスモデルにおいて評価した。
にしたがって、腫瘍の体積を推定した:
この実施例では、二重特異性ダイマー(すなわち、ポリペプチド1がポリペプチド2と異なるものであるダイマー)の作製を可能するプロトコールを提供する。
最初に、1つのPichia株が両方の異なるポリペプチドを産生する以外は、上記実施例1.3のプロトコールに従う。また、Pichia使用済み培地中で、前記2つの各ポリペプチドのC末端伸長部のC末端システインを、ほぼ中性のpHにおいて、それらのチオール部分を介して、ジスルフィド誘導体シスチンに酸化する化学的コンジュゲーションによって、ダイマーへのポリペプチドのカップリングを実施する。酸化プロセスを最適化するために、基本的には国際公開公報第2010/125187号に示されているように、酸化銅イオン(CuSO4の形態のCu2+)を追加する。ダイマーを均一に精製し(イオン交換クロマトグラフィー)、続いて、サイズ排除クロマトグラフィーを介して分析する。LC−MSによっても、サンプルを検証する。標準的なプロトコールは、目的の二重特異性NB1−NB2ダイマーを作製するであろう。しかしながら、画分は、単一特異性ダイマー(例えば、NB1−NB1及びNB2−NB2)も含有すると予想される。
架橋リンカーを使用せずに、2つの異なるC末端システイン伸長Nbを使用して、ナノボディヘテロダイマー(二重特異性ダイマー)を作製することができる。
上記のように、既にサイズの差異に起因して、本発明のポリペプチドの二量体化及びそれに対する薬物のコンジュゲーションは、従来の抗体よりもはるかに大きな影響を有する。したがって、本発明者らは、DAR=1でナノボディにコンジュゲートされたペイロードがPK特性に対して及ぼす効果を評価することを試みた。
放射性標識ポリペプチドを介して、PK特性を試験した。簡潔に言えば、遊離−NH2に対するランダムなコンジュゲーションを介して、ポリペプチドを89Zr、NCS−Bz−Dfで放射性標識した(図12を参照のこと)。最終体積が500μL(最終濃度2mg/mL)になるまで、ポリペプチド22nmol(1.0mg)を0.9%NaClと混合した。次に、0.1M Na2CO3を追加することによって、pHを8.9〜9.1に設定した。最後に、NCS−Bz−Df 66nmolのDMSO溶液(3当量、10μL)を追加し、37℃で30分間反応させた。30分後、50mM NaOAc/200mMスクロースでプレウォッシュ加工したPD10カラムを使用することによって、反応混合物を精製した。生成物を1.0mLの画分で回収した。次に、Df−PK−ポリペプチドを、89ZrによってpH約7、室温で60分間放射性標識した(反応混合物は、89Zrを含有する1Mシュウ酸100μL、2M Na2CO345μL、0.5M Hepesバッファー(pH7.2)500μL及びNCS−Df−ポリペプチド355μL(約0.4mg)を含有していた)。次に、反応混合物を、50mM NaOAc/200mMスクロースを含むプレウォッシュ加工したPD10カラムで精製し、生成物を1.5mLで回収した。
放射性標識(89Zr)ポリペプチドを3匹のマウスに注射し、9つの時点(5分、1時間、3時間、24時間、48時間、72時間、140時間、168時間及び192時間)で、cpm(カウント毎分)値を検出した。次いで、これらの値を使用して、マウス1g当たりのポリペプチドの%注射線量(%ID/g)を計算した。各ポリペプチドについて、3匹のマウスの結果を平均した。
この実験の目的は、Cys連結ダイマーDIM T023800001(すなわち、機能的な観点から二価)が、そのモノマーカウンターパート(T023800001−A)及び伝統的な連結−遺伝子融合−二価フォーマット(T023800006−A)と比較して増加したインターナリゼーションを示すかを評価することであった。この目的のために、EGFレセプターを適度に発現するNCI−H292細胞において、インターナリゼーション実験を実施した。インターナリゼーションしたナノボディの生細胞内の蓄積を、検出ツールとしてpHrodo(商標)標識アルブミン(50μg/ml)を使用して、フローサイトメトリー(FCM)を介して測定した。pHrodo(登録商標)色素はpH感受性の分子プローブであり、中性pHではほぼ非蛍光性である。エンドソーム及びリソソームなどの酸性環境では、それは、明るく蛍光を発する。細胞(細胞30,000個/ウェル)を平底96ウェルプレートに移し、pHrodo(商標)標識アルブミン(50μg/ml)と一緒に異なる濃度の特定のポリペプチド及び構築物と共に、37℃で5時間インキュベーションした。次いで、細胞を洗浄し、回収し、FCMによって測定し、分析した。
Claims (16)
- 少なくとも:
(i)第1のポリペプチドを提供する工程であって、前記第1のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端において、システイン部分を含むC末端伸長部とを含む、工程;
(ii)第2のポリペプチドを提供する工程であって、前記第2のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−好ましくはC末端において、システイン部分を含むC末端伸長部とを含む、工程;並びに
(iii)好ましくはpH6.5〜pH7.5において、場合により酸化銅イオン(Cu2+)を追加することによって、前記第1のポリペプチドのC末端の前記システイン部分のチオール部分と、前記第2のポリペプチドのC末端の前記システイン部分のチオール部分とをジスルフィド誘導体シスチンに酸化する工程
を含む、ダイマーを作製するための方法であって、
該ISVDの完全性が維持されており、前記シスチンが、該ダイマー中に存在する唯一の分子間ジスルフィド結合であり、それによって、前記ダイマーを作製することを特徴とする方法。 - 例えば質量分析によって決定した場合に、前記第1の及び前記第2のポリペプチドの少なくとも80%、例えば85%、90%、95%、99%又はさらにそれ以上、例えば100%が二量体化されている、請求項1に記載の方法。
- 好ましくはサイズ排除クロマトグラフィーを介して、前記ダイマーを精製する工程をさらに含む、請求項1又は2に記載の方法。
- 前記第1のポリペプチド及び前記第2のポリペプチドが同一のものである、請求項1〜3のいずれか一項に記載の方法。
- 前記第1のポリペプチド及び前記第2のポリペプチドが異なるものである、請求項1〜3のいずれか一項に記載の方法。
- 前記第1のポリペプチド及び/又は前記第2のポリペプチドが、好ましくはC末端において、システイン部分を含む50個、40個、30個、20個、10個、9個、8個、7個、6個、5個、4個、3個、2個又は1個のアミノ酸残基のC末端伸長部を含む、請求項1〜5のいずれか一項に記載の方法。
- 前記C末端伸長部が、前記ポリペプチドの最もC末端に位置するISVDのC末端部に遺伝子融合されている、請求項1〜6のいずれか一項に記載の方法。
- 第1のポリペプチド及び第2のポリペプチドを含むダイマーであって、
前記第1のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−(好ましくはC末端において)システイン部分を含むC末端伸長部とを含み;
前記第2のポリペプチドが、
−少なくとも1つの免疫グロブリン単一可変ドメイン(ISVD)と、
−(好ましくはC末端において)システイン部分を含むC末端伸長部とを含み;
前記第1のポリペプチド及び前記第2のポリペプチドが、前記第1のポリペプチドのC末端伸長部のシステイン部分と、前記第2のポリペプチドのC末端伸長部のシステイン部分との間のジスルフィド結合を介して共有結合されており;前記第1のポリペプチドのC末端伸長部のシステイン部分と、前記第2のポリペプチドのC末端伸長部のシステイン部分との間の前記ジスルフィド結合が、該ダイマー中に存在する唯一の分子間ジスルフィド結合である、ダイマー。 - 前記第1のポリペプチド及び/又は前記第2のポリペプチドが、好ましくはC末端において、システイン部分を含む50個、40個、30個、20個、10個、9個、8個、7個、6個、5個、4個、3個、2個又は1個のアミノ酸残基のC末端伸長部を含む、請求項8に記載のダイマー。
- 前記第1のポリペプチド及び前記第2のポリペプチドが同一のものである、請求項8又は9に記載のダイマー。
- 前記第1のポリペプチド及び前記第2のポリペプチドが異なるものである、請求項8又は9に記載のダイマー。
- 薬物をさらに含む、請求項8〜11のいずれか一項に記載のダイマー。
- 前記薬物が、細胞増殖抑制剤、細胞傷害剤、化学療法剤、成長阻害剤、毒素(例えば、細菌起源、真菌起源、植物起源若しくは動物起源の酵素的に活性な毒素又はそのフラグメント)、毒素部分及び放射性同位体からなる群より選択される、請求項12に記載のダイマー。
- 薬物対ダイマー比(DAR)が1である、請求項12又は13に記載のダイマー。
- ガンの処置に使用するための、請求項8〜14のいずれか一項に記載のダイマーであって、インターナリゼーションする、ダイマー。
- ガンの処置のための医薬を製造するための、請求項8〜14のいずれか一項に記載のダイマーの使用であって、前記ダイマーがインターナリゼーションする、使用。
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CN107406497A (zh) | 2017-11-28 |
US20230211006A1 (en) | 2023-07-06 |
ES2772348T3 (es) | 2020-07-07 |
WO2016097313A1 (en) | 2016-06-23 |
PL3233910T3 (pl) | 2020-06-01 |
JP6862343B2 (ja) | 2021-04-21 |
CA2971278A1 (en) | 2016-06-23 |
EP3233910B1 (en) | 2019-12-11 |
EP3233910A1 (en) | 2017-10-25 |
AU2015366284A1 (en) | 2017-06-29 |
US20170360955A1 (en) | 2017-12-21 |
PT3233910T (pt) | 2020-03-17 |
US11426468B2 (en) | 2022-08-30 |
AU2015366284B2 (en) | 2021-07-22 |
HK1246329A1 (zh) | 2018-09-07 |
CA2971278C (en) | 2023-09-19 |
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