JP2017511301A - 二重特異性抗ハプテン/抗血液脳関門受容体抗体、それらの複合体、及び血液脳関門シャトルとしてのそれらの使用 - Google Patents
二重特異性抗ハプテン/抗血液脳関門受容体抗体、それらの複合体、及び血液脳関門シャトルとしてのそれらの使用 Download PDFInfo
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Abstract
Description
ポリペプチドの治療的適用についての主要なボトルネックは、それらの限定された溶解度、インビボでの安定性、短い血清半減期、及び血流からの速いクリアランスである。
i)ハプテン化ペイロードに特異的に結合する第1の結合特異性及び血液脳関門受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、並びに
ii)ハプテン化ペイロード、
それにおいて、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
それにおいて、共有結合コンジュゲートは、ハプテン化ペイロードと、ハプテン化ペイロードに特異的に結合する第1の結合特異性の間に共有結合を有し、並びに
それにおいて、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化(theophyllinylated)ペイロード、ジゴキシゲニン化ペイロード、カルボラン化(carboranylated)ペイロード、フルオレセイン化(fluoresceinylated)ペイロード、ヘリカー化(helicarylated)ペイロード、及びブロモデオキシウリジン化(bromodeoxyuridinylated)ペイロードからなる群より選択される。
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。
i)ハプテン化ペイロードに特異的に結合する第1の結合特異性及びトランスフェリン受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、並びに
ii)ハプテン化ペイロード、
それにおいて、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
それにおいて、共有結合コンジュゲートは、ハプテン化ペイロードと、第1の結合特異性の重鎖CDR2中の位置52b又は53のシステイン残基の間にジスルフィド結合を有し、それにより、ナンバリングは、Kabatに従い、
それにおいて、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化(theophyllinylated)ペイロード、ジゴキシゲニン化ペイロード、カルボラン化(carboranylated)ペイロード、フルオレセイン化(fluoresceinylated)ペイロード、ヘリカー化(helicarylated)ペイロード、及びブロモデオキシウリジン化(bromodeoxyuridinylated)ペイロードよるなる群より選択され、並びに
それにおいて、二重特異性抗体は、以下を含む:
a)ハプテン化ペイロードのための1つの結合部位及びトランスフェリン受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及びトランスフェリン受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及びトランスフェリン受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及びトランスフェリン受容体のための2つの結合部位。
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。
i)ハプテン化ペイロードに特異的に結合する第1の結合特異性及び血液脳関門受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、及び
ii)ハプテン化ペイロード、
ここで、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
ここで、共有結合コンジュゲートは、ハプテン化ペイロードと、ハプテン化ペイロードに特異的に結合する第1の結合特異性の間に共有結合を有し、並びに
ここで、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化(theophyllinylated)ペイロード、ジゴキシゲニン化ペイロード、カルボラン化(carboranylated)ペイロード、フルオレセイン化(fluoresceinylated)ペイロード、ヘリカー化(helicarylated)ペイロード、及びブロモデオキシウリジン化(bromodeoxyuridinylated)ペイロードからなる群より選択される。
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。
a)重鎖可変ドメインにおいて、配列番号230、239、及び232のHVR、又は
b)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR。
a)軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR、又は
b)軽鎖可変ドメインにおいて、配列番号233、229、及び236のHVR。
a)重鎖可変ドメインにおいて、配列番号230、239、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR、又は
b)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号233、229、及び236のHVR、又は
c)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR。
a)配列番号241の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン、又は
b)配列番号240の重鎖可変ドメイン及び配列番号237の軽鎖可変ドメイン、又は
c)配列番号240の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン、又は
d)配列番号242の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン。
a)配列番号287の重鎖可変ドメイン及び配列番号290の軽鎖可変ドメイン、又は
b)配列番号288の重鎖可変ドメイン及び配列番号291の軽鎖可変ドメイン、又は
c)配列番号289の重鎖可変ドメイン及び配列番号292の軽鎖可変ドメイン。
I.定義
本明細書において使用する通り、重鎖及び軽鎖の全ての定常領域及びドメインのアミノ酸位置が、Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)において記載されるKabatナンバリングシステムに従って番号付けされており、本明細書において「Kabatに従ったナンバリング」として言及される。具体的には、Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)のKabatナンバリングシステム(ページ647−660を参照のこと)は、カッパ及びラムダアイソタイプの軽鎖定常ドメインCLのために使用され、Kabat EUインデックスナンバリングシステム(ページ661−723を参照のこと)は、定常重鎖ドメイン(CH1、ヒンジ、CH2、及びCH3)のために使用される。
(a)アミノ酸残基26−32(L1)、50−52(L2)、91−96(L3)、26−32(H1)、53−55(H2)、及び96−101(H3)で生じる超可変ループ(Chothia, C. and Lesk, A.M., J. Mol. Biol. 196 (1987) 901-917);
(b)アミノ酸残基24−34(L1)、50−56(L2)、89−97(L3)、31−35b(H1)、50−65(H2)、及び95−102(H3)で生じるCDR(Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242);
(c)アミノ酸残基27c−36(L1)、46−55(L2)、89−96(L3)、30−35b(H1)、47−58(H2)、及び93−101(H3)で生じる抗原接触部(MacCallum et al. J. Mol. Biol. 262: 732-745 (1996));並びに
(d)HVRアミノ酸残基46−56(L2)、47−56(L2)、48−56(L2)、49−56(L2)、26−35(H1)、26−35b(H1)、49−65(H2)、93−102(H3)、及び94−102(H3)を含む(a)、(b)、及び/又は(c)の組み合わせ。
式中、Xは、A及びBのそのプログラムのアラインメントにおける配列アラインメントプログラムALIGN-2による同一のマッチとしてスコア化されるアミノ酸残基の数であり、式中、Yは、Bにおけるアミノ酸残基の総数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さとは等しくない場合、AのBに対する%アミノ酸配列同一性は、BのAに対する%アミノ酸配列同一性とは等しくないと理解されるであろう。別に特記なき場合、本明細書において使用する全ての%アミノ酸配列同一性の値は、直前のパラグラフにおいて記載される通りに、ALIGN-2コンピュータプログラムを使用して得られる。
II.本明細書において報告するコンジュゲート
非共有結合複合体
i)重鎖可変ドメインの位置44から軽鎖可変ドメインの位置100、
ii)重鎖可変ドメインの位置105から軽鎖可変ドメインの位置43、又は
iii)重鎖可変ドメインの位置101と軽鎖可変ドメインの位置100。
共有結合コンジュゲート
抗体親和性
抗体フラグメント
キメラ抗体及びヒト化抗体
ヒト抗体
ライブラリー由来抗体
抗体フォーマット
多重特異性抗体
−1つの重鎖のCH3ドメイン及び他の重鎖のCH3ドメイン(各々が、抗体CH3ドメイン間に元の界面を含む界面で会合する)、
それにおいて、界面を変化させ、二重特異性抗体の形成を促し、それにおいて、変化は、以下であることを特徴とする:
a)1つの重鎖のCH3ドメインを変化させ、
元の界面内で、1つの重鎖のCH3ドメインが、二重特異性抗体内の他の重鎖のCH3ドメインの元の界面と会合するようにし、
アミノ酸残基は、より大きな側鎖容積を有するアミノ酸残基を用いて置換されており、それにより、他の重鎖のCH3ドメインの界面内の空洞内に配置可能である、1つの重鎖のCH3ドメインの界面内に突起を生成し、
及び
b)他の重鎖のCH3ドメインを変化させ、
元の界面内で、第2のCH3ドメインが、二重特異性抗体内の第1のCH3ドメインの元の界面と会合するようにし、
アミノ酸残基は、より小さな側鎖容積を有するアミノ酸残基を用いて置換されており、それにより、第2のCH3ドメインの界面内の空洞を生成し、その内で、第1のCH3ドメインの界面内の突起を配置可能である。
−完全長抗体の第1の重鎖のCH3ドメイン及び完全長抗体の第2の重鎖のCH3ドメインは、各々、抗体CH3ドメイン間の元の界面において変化を含む界面で会合する。
それにおいて、i)第1の重鎖のCH3ドメインにおいて、
アミノ酸残基は、より大きな側鎖容積を有するアミノ酸残基を用いて置換されており、それにより、他の重鎖のCH3ドメインの界面内の空洞内に配置可能である、1つの重鎖のCH3ドメインの界面内に突起を生成し、
及び、それにおいて、ii)第2の重鎖のCH3ドメインにおいて、
アミノ酸残基は、より小さな側鎖容積を有するアミノ酸残基を用いて置換されており、それにより、第2のCH3ドメインの界面内の空洞を生成し、その内で、第1のCH3ドメインの界面内の突起を配置可能である。
抗体バリアント
a)置換、挿入、及び欠失バリアント
(1) 疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2) 中性親水性:Cys、Ser、Thr、Asn、Gln;
(3) 酸性:Asp、Glu;
(4) 塩基性:His、Lys、Arg;
(5) 鎖配向に影響する残基:Gly、Pro;
(6) 芳香族:Trp、Tyr、Phe。
b)グリコシル化バリアント
特定の実施形態において、1つ又は複数のアミノ酸改変を、本明細書において提供する抗体のFc領域中に導入してもよく、それにより、Fc領域バリアントを生成する。Fc領域バリアントは、1つ又は複数のアミノ酸位置にアミノ酸改変(例、置換)を含むヒトFc領域配列(例、ヒトIgG1、IgG2、IgG3、又はIgG4 Fc領域)を含んでもよい。
d)システイン操作抗体バリアント
e) 抗体誘導体
ハプテン化化合物
a) 治療用部分
b)標識
(i)基質として水素ペルオキシダーゼを伴う西洋ワサビペルオキシダーゼ(HRP)(それにおいて、水素ペルオキシダーゼは、色素前駆体(例、オルトフェニレンジアミン(OPD)又は3,3’,5,5’−テトラメチルベンジジン塩酸塩(TMB))を酸化する;
(ii)発色基質としてパラ−ニトロフェニルホスフェートを伴うアルカリホスファターゼ(AP);及び
(iii)発色基質(例、p−ニトロフェニル(3−D−ガラクトシダーゼ))又は蛍光発生基質4−メチルウンベリフェリル−(3−D−ガラクトシダーゼ)を伴う3−D−ガラクトシダーゼ(3−D−Gal)。
抗体コンジュゲート
イムノコンジュゲート
リンカー
III.核酸
IV.発現及び精製
V.診断及び検出のための方法及び組成物
VI.医薬的製剤
VII.治療的方法及び組成物
VIII.製造品
IX.具体的な実施形態
i) ハプテン化ペイロードに特異的に結合する第1の結合特異性及び血液脳関門受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、並びに
ii)ハプテン化ペイロード、
ここで、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
ここで、共有結合コンジュゲートは、ハプテン化ペイロードと、ハプテン化ペイロードに特異的に結合する第1の結合特異性の間に共有結合を有し、並びに
ここで、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化(theophyllinylated)ペイロード、ジゴキシゲニン化ペイロード、カルボラン化(carboranylated)ペイロード、フルオレセイン化(fluoresceinylated)ペイロード、ヘリカー化(helicarylated)ペイロード、及びブロモデオキシウリジン化(bromodeoxyuridinylated)ペイロードからなる群より選択される。
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。
a)重鎖可変ドメインにおいて、配列番号230、239、及び232のHVR、又は
b)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR。
a)軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR、又は
b)軽鎖可変ドメインにおいて、配列番号233、229、及び236のHVR。
a)重鎖可変ドメインにおいて、配列番号230、239、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR、又は
b)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号233、229、及び236のHVR、又は
c)重鎖可変ドメインにおいて、配列番号230、231、及び232のHVR、並びに軽鎖可変ドメインにおいて、配列番号234、235、及び236のHVR。
a)配列番号241の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン、又は
b)配列番号240の重鎖可変ドメイン及び配列番号237の軽鎖可変ドメイン、又は
c)配列番号240の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン、又は
d)配列番号242の重鎖可変ドメイン及び配列番号238の軽鎖可変ドメイン。
a)配列番号287の重鎖可変ドメイン及び配列番号290の軽鎖可変ドメイン、又は
b)配列番号288の重鎖可変ドメイン及び配列番号291の軽鎖可変ドメイン、又は
c)配列番号289の重鎖可変ドメイン及び配列番号292の軽鎖可変ドメイン。
マウスハイブリドーマからのカッパ軽鎖を伴うIgG1クラスのマウス抗ジゴキシゲニン抗体及びマウス抗ビオチン抗体のVH及びVLドメインをコードするcDNAの単離及び特徴付け
ハイブリドーマ細胞からのRNA調製:
RACE PCRによるVH及びVHをコードするDNAフラグメントの生成、プラスミド中へのこれらのDNAフラグメントのクローニング、並びにそれらのDNA配列及びアミノ酸配列の決定
マウスハイブリドーマからのカッパ軽鎖を伴うIgG1クラスのマウス抗テオフィリン抗体のVH及びVLドメインをコードするcDNAの単離及び特徴付け
マウス抗ジゴキシゲニン抗体及び抗ビオチン抗体のVH及びVLドメインのヒト化
マウス抗テオフィリン抗体のVH及びVLドメインのヒト化
ジゴキシゲニンの存在におけるマウス抗ジゴキシゲニンFv領域の結合領域の、及びビオチンの存在におけるマウス抗ビオチンFv領域の結合領域の結晶化及びX線構造決定。
共有結合的コンジュゲーションのための、導入された機能性を伴う抗ハプテン抗体の定義及び生成
組換え抗ハプテン抗体の組成、発現、及び精製
発現プラスミド
−ヒトサイトメガロウイルス(hCMV)からの最初期エンハンサー及びプロモーター、
−Kozak配列を含む合成5’−UT、
−シグナル配列イントロンを含むマウス免疫グロブリン重鎖シグナル配列、
−5’末端に固有のBsmI制限部位並びに3’末端にスプライスドナー部位及び固有のNotI制限部位を伴い配置された、クローン化された可変軽鎖cDNA、
−イントロン2マウスIg−κエンハンサーを含むゲノムヒトκ遺伝子定常領域(Picard, D., and Schaffner, W. Nature 307 (1984) 80-82)、並びに
−ヒト免疫グロブリンκポリアデニル化(「ポリA」)シグナル配列。
−ヒトサイトメガロウイルス(hCMV)からの最初期エンハンサー及びプロモーター、
−Kozak配列を含む合成5’−UT、
−シグナル配列イントロンを含む改変マウス免疫グロブリン重鎖シグナル配列、
−5’にユニークなBsmI制限部位並びに3’末端にスプライスドナー部位及びユニークなNotI制限部位を配置した、クローン化された単一特異性可変重鎖cDNA又はクローン化された二重特異性融合scFv可変重鎖cDNA、
−マウスIgμエンハンサーを含むゲノムヒトγl重遺伝子定常領域(Neuberger, M.S., EMBO J. 2 (1983) 1373-1378)、及び
−ヒトγL−免疫グロブリンのポリアデニル化(「ポリA」)シグナル配列。
−ハイグロマイシン耐性遺伝子、
−エプスタインバーウイルス(EBV)の複製起点oriP、
−大腸菌においてこのプラスミドの複製を可能にするベクターpUC18からの複製起点、及び
−大腸菌においてアンピシリン耐性を付与するβラクタマーゼ遺伝子。
組換えDNA技術
DNA及びタンパク質配列分析並びに配列データ管理
抗ハプテン抗体及び誘導体の発現
ジゴキシゲニン、フルオレセイン、テオフィリン、又はビオチンに結合する抗ハプテン抗体の精製
ハプテン化化合物の生成
a)ハプテン−ポリペプチドコンジュゲート:
Ahx=アミノヘキサン酸
Btn=ビオチニル
cme=カルボキシメチル
Cy5=インドジカルボシアニン、シアニン−5
Dadoo=1,8−ジアミノ−3,6−ジオキソ−オクタン
DCM=ジクロロメタン
Dig(OSu)=ジゴキシゲニン−3−カルボキシメチル−N−ヒドロキシスクシンイミド
Dy636=フルオロフォア
eda=エチレンジアミン
Fluo=5−カルボキシ−フルオレセイン
HATU=0−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート
HFIP=1,1,1,3,3,3,−ヘキサフルオロ−2−プロパノール
Mmt=4−メトキシトリチル
MR121=オキサジンフルオロフォア
MTBE=tert.ブチル−メチル−エーテル
NMM=N−メチル−モルホリン
NMP=N−メチル−2−ピロリドン
PEG2=8−アミノ−3,6−ジオキサ−オクタン酸
PEG3=12−アミノ−4,7,10−トリオキサドデカン酸
O2Oc=8−アミノ−3,6−ジオキサ−オクタン酸
Pip=ピペリジン
Pqa=4−オキソ−6−ピペラジン−1−イル−4H−キナゾリン−3−イル)−酢酸
TBTU=2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボレート
TCEP=Tris(2−クロロエチル)ホスフェート
TFE=2,2,2,トリフルオロエタノール
TIS=トリイソプロピルシラン
i)PYY(3−36)由来ポリペプチドコンジュゲーション前駆体の生成のための一般的な方法
シンセサイザー:ボルテックス撹拌システムを伴うMultiple Synthesizer SYRO I(MultiSynTech GmbH, Witten)
樹脂:200mg TentaGel S RAM(0.25mmol/g)、RAPP Polymere、Tubingen、反応容器としてテフロンフリットを伴う10mlプラスチックシリンジ
ストック溶液:
Fmocアミノ酸:DMF又はNMP中の0.5M
デブロッキング試薬:DMF中の30%ピペリジン
活性化剤:それぞれ0.5M TBTU及びHATU
基剤:NMP中の50%NMM
カップリング:
Fmocアミノ酸:519μl
基剤:116μl
活性化剤:519μl
反応時間:二重カップリング:2×30分
Fmoc−デブロック:
デブロッキング試薬:1200μl
反応時間:5分 + 12分
洗浄:
溶媒:1200μl
容積:1300μl
反応時間:5×1分
最終切断:
切断試薬:8ml TFA/チオアニソール/チオクレゾール/TIS(95:2,5:2,5:3)
反応時間:4時間
操作:切断溶液を濾過し、1−2mlに濃縮し、ペプチドを、MTBEの添加により沈殿させた。白色固体を遠心分離により回収し、MTBEで2回洗浄し、乾燥させた。
Ac IK Pqa R(Pbf)H(Trt)Y(tBu)LN(Trt)W(Boc)VT(But)R(Pbf)Q(Trt)−MeArg(Mtr)−Y(tBu)−TentaGel S RAM樹脂(配列番号176)
Ac−PYY(PEG3−Dig)/Ac−IK(PEG3−Dig)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(配列番号177)
ii) システイン含有リンカーを伴うジゴキシゲニン化PYY(3−36)由来ポリペプチドの生成
Ac−IK(PEG3−Cys−4Abu−NH2)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(配列番号178)
精製プロトコール
HPLC:UV-Vis検出器SPD-6Aを伴うShimadzu LC-8A
溶媒A:水中の0.05% TFA
溶媒B:80%アセトニトリル/水中の0.05% TFA
カラム:UltraSep ES, RP-18、10μm、250×20mM(SEPSERV, Berlin)
流速:15ml/分
検出:230nm
勾配:20−50%B(30分間)
分析データ:
HPLC:フォトダイオードアレイ検出器SPD-M6Aを伴うShimadzu LC-9A
溶媒A:水中の0.05% TFA
溶媒B:80%アセトニトリル/水中の0.05% TFA
カラム:UltraSep ES、RP-18、7μm,250×3mM(SEPSERV, Berlin)
流速:0.6ml/分
勾配:5−80%B(30分間)
MS:Shimadzu飛行時間形質量分析計AXIMA Linear(MALDI−TOF)(分子量を質量平均として計算する)
m/z:C122H185N37O28Sの計算値=2650.13;検出:2650.3
Ac−IK(PEG3−Cys−4Abu−Dig)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(配列番号179)
分析データ:
条件は、配列番号178について記載されてものと同じであった。
分取HPLC用の勾配:38−58%B(30分間)
収量:5.3mg
m/z:C147H219N37O34Sの計算値=3080.7;検出:3079.8
PEG3−IK(PEG3−Cys−4Abu−Dig)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(配列番号180)
樹脂結合PYY配列の自動化固相合成:
PEG2−IK(ivDde)−Pqa−R(Pbf)H(Trt)Y(tBu)LN(Trt)W(Boc)VT(tBu)R(Pbf)Q(Trt)−MeArg(Mtr)−Y(tBu)−TentaGel−RAM樹脂(配列番号181)
PEG2−IK(PEG3−Cys−Abu−NH2)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(配列番号182)
PEG2−IK(PEG3−Cys−4Abu−Dig)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2(PEG2−PYY(PEG3−Cys−4Abu−Dig)(配列番号183)
iii)ビオチンを伴う、又はビオチン及びシステイン含有リンカーを伴うPYY(3−36)由来ポリペプチドの生成:
Ac−IK(PEG2−ビオチン)−Pqa−RHYLNWVTRQ−MeArg−Y−アミド/Ac−PYY(PEG2−Biot)(配列番号184)
精製プロトコール
HPLC:UV−Vis検出器SPD−6Aを伴うShimadzu LC-8A
溶媒A:水中の0.05% TFA
溶媒B:80%アセトニトリル/水中の0.05% TFA
カラム:UltraSep ES,RP−18,10μm,250×20mm(SEPSERV,Berlin)
流速:15ml/分
検出:230nm
分析データ:
HPLC:フォトダイオードアレイ検出器SPD-M6Aを伴うShimadzu LC-9A
溶媒A:水中の0.05% TFA
溶媒B:80%アセトニトリル/水中の0.05% TFA
カラム:UltraSep ES, RP-18、7μm、250×3mM(SEPSERV, Berlin)
流速:0.6ml/分
勾配:5−80%B(30分間)
MS:Shimadzu飛行時間形質量分析計AXIMA Linear
(MALDI−TOF)、(分子量を質量平均として計算する)
m/z:C122H181N37O27Sの計算値=2630.10;検出:2631.5
Ac−IK(PEG3−Cys−β−Ala−ビオチン)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2/Ac−PYY(PEG3−Cys−β−Ala−Biot)(配列番号185)
分析データ:
分取HPLC用の勾配:28−58%B(30分間)
m/z:C131H197N39O30S2の計算値=2862.4;検出:2862.4
Ac−IK(PEG3−Cys−PEG2−ビオチン)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2/Ac−PYY(PEG3−Cys−PEG2−Biot)(配列番号186)
Fmoc−PEG3−OHを用いた二重カップリング(標準的なプロトコールを用いる)、
Fmoc Cys(Trt)−OHの二重カップリング(標準的なプロトコールを用いる)、
1.2mlのDMF中の57.8mg(3等量)のFmoc−8−アミノ−ジオキサオクタン酸(PEG2スペーサー)、48.2mg(3等量)のTBTU、及び33.3μL(6等量)のNMMを用いたFmoc−PEG2−OHの二重カップリング(2×30分間)、1.2mlのNMP中の48.9mgビオチン(4等量)、64.2mgのTBTU(4等量)、及び44.4μLのNMM(8等量)の溶液を用いたビオチン化(プレ活性化3分間)、単一カップリング(2時間)。
分析データ:
条件は、配列番号184について記載されてものと同じであった。
分取HPLC用の勾配:25−45%B(30分間)。
m/z:C134H203N39O32S2の計算値=2936.5;検出:2937.8
iv)フルオレセインを用いた、又はフルオレセイン及びシステイン含有リンカーを用いたPYY(3−36)由来ポリペプチドの生成。
Ac−IK(PEG3−Cys−4−Abu−5−Fluo)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2/Ac−PYY(PEG3−Cys−4−Abu−5−Fluo)(配列番号187)
分析データ:
分取HPLC用の勾配:29−49%B(30分間)
m/z:C143H195N37O34Sの計算値=3008.44;検出:3007.2
Ac−IK(PEG3−Cys−PEG2−5−Fluo)−Pqa−RHYLNWVTRQ−MeArg−Y−NH2/Ac−PYY(PEG3−Cys−PEG2−5−Fluo)(配列番号188)
Fmoc−PEG3−OHを用いた二重カップリング(標準的なプロトコールを用いる)、
Fmoc Cys(Trt)−OHの二重カップリング(標準的なプロトコールを用いる)、
二重カップリングFmoc−PEG2−OH(配列番号186を参照のこと)
分析データ:
分取HPLC用の勾配:34−64%B(30分間)。
m/z:C145H199N37O36S1の計算値=3068.5;検出:3069.2
b)ハプテン標識蛍光色素:
i)ジゴキシゲニン化Cy5の生成
ii)Dig−Cys−MR121の生成
iii) DIG−Cys−AHX−Cy5の生成
iv)ビオチンeda−Dy636の生成
v)ビオチン−Ser−Dy636の生成
工程1:ビオチン−O2Oc−Ser−O2Oc−DADOO−NH2
工程2:ビオチン−O2Oc−Ser−O2Oc−DADOO−Dy−636(Bi−Ser−Dy−636)
vi)ビオチン−Cys−Dy636の生成
工程1:ビオチン−O2Oc−Cys−O2Oc−DADOO−NH2
工程2:ビオチン−O2Oc−Cys(TNB)−O2Oc−DADOO−NH2
工程3:ビオチン−O2Oc−Cys(TNB)−O2Oc−DADOO−Dy−636
工程4:ビオチン−O2Oc−Cys−O2Oc−DADOO−Dy−636(Bi−Cys−Dy−636)
vii) ビオチン−Cys−Cy5の生成
工程1:ビオチン−O2Oc−Cys−O2Oc−DADOO−NH2
工程2:ビオチン−O2Oc−Cys(TNB)−O2Oc−DADOO−NH2
工程3:ビオチン−O2Oc−Cys(TNB)−O2Oc−DADOO−Cy5
工程4:ビオチン−O2Oc−Cys−O2Oc−DADOO−Cy5(Bi−Cys−Cy5)
viii) ビオチン−Ser−Cy5の生成
工程1:ビオチン−O2Oc−Ser−O2Oc−DADOO−NH2
工程2:ビオチン−O2Oc−Ser−O2Oc−DADOO−Cy5(Bi−Ser−Cy5)
ビオチン標識化合物(ハプテン化化合物)への組換えヒト化抗ビオチン抗体の結合
表面プラズモン共鳴
抗ハプテン抗体を伴うハプテン化化合物の非共有結合複合体の生成
一般的な方法:
ハプテン化蛍光色素及び抗ハプテン抗体の複合体の形成のための例示的な方法−非共有結合ジゴキシゲニンCy5複合体
ハプテン化蛍光色素及び抗ハプテン抗体の複合体の形成のための例示的な方法−ビオチンCy5/キメラ抗ビオチン抗体(ヒトIgGサブクラス)複合体
ビオチン化蛍光色素及び抗ビオチン抗体のコンジュゲートの形成のための例示的な方法−ビオチン−Ser−Cy5/ヒト化抗ビオチン抗体:
ハプテン化ポリペプチド及び抗ハプテン抗体の複合体の形成のための例示的な方法−ジゴキシゲニンPYY(3−36)/抗ジゴキシゲニン抗体複合体
ハプテン化ポリペプチド及び抗ハプテン抗体の複合体の形成のための例示的な方法−Ac−PYY−PEG3−Cys−β−Ala−Biot/キメラ抗ビオチン抗体複合体
ハプテン化ポリペプチド及び抗ハプテン抗体の複合体の形成のための例示的な方法−Ac−PYY−PEG3−Cys−PEG2−Biot/キメラ抗ビオチン抗体複合体
ハプテン化ポリペプチド及び抗ハプテン抗体の複合体の形成のための例示的な方法−Ac−PYY(PEG3−Cys−PEG2−5−Fluo)/キメラ抗フルオレセイン抗体複合体
酸化還元剤の存在における抗ハプテン抗体VH52bC/VH53Cを伴う、ハプテン化色素又はポリペプチドの定義された共有結合コンジュゲートの生成
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Dig−Cys−Ahx−Cy5/抗ジゴキシゲニン抗体VH52bC
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Dig−Cys−Cy5/抗ジゴキシゲニン抗体VH52bC
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−PEG3−PYY(PEG3−Cys−4Abu−Dig)/ヒト化抗ジゴキシゲニン抗体VH52bC
酸化還元剤の非存在における抗ハプテン抗体VH52bC/VH53Cを伴うハプテン色素及びポリペプチドの定義された共有結合コンジュゲートの生成
一般的な方法:
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Dig−Cys−Ahx−Cy5/抗ジゴキシゲニン抗体VH52bC
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Dig−Cys−Cy5/抗ジゴキシゲニン抗体VH52bC
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−ビオチン−Cys−Cy5/キメラ抗ビオチン抗体VH53C
ハプテン化蛍光色素及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−ビオチン−Cys−Cy5/ヒト化抗ビオチン抗体VH53C
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−4Abu−Dig)/ヒト化抗ジゴキシゲニン抗体VH52bC
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−βAla−Biot)/キメラ抗ビオチン抗体VH53C
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−PEG2−Biot)/キメラ抗ビオチン抗体VH53C
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−βAla−Biot)/ヒト化抗ビオチン抗体VH53C
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−PEG2−Biot)/ヒト化抗ビオチン抗体VH53C
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−PEG2−Fluo)/抗フルオレセイン抗体VH52bC
ハプテン化ポリペプチド及び抗ハプテン抗体のコンジュゲートの形成のための例示的な方法−Ac−PYY(PEG3−Cys−PEG2−Fluo)/抗フルオレセイン抗体VH28C
共有結合テオフィリン抗テオフィリン抗体複合体の生成
インビボ様条件下での共有結合ハプテン−抗体複合体の生成、及びインビボでの有向ジスルフィド形成についての証拠
抗ハプテン抗体を伴う、コンジュゲート中、及び複合体中のポリペプチドは、機能性を保持する。
ヒト化抗ビオチン抗体VH53Cを伴うビオチン化Cy5の共有結合コンジュゲートと比較した、ヒト化抗ビオチン抗体を伴うビオチン化Cy5の複合体の血清中安定性。
小さな蛍光基質の抗体複合体化又は抗体コンジュゲーションのPKパラメーターに対する影響を分析するために、13nmolのCy5−ビオチン/ヒト化抗ビオチン抗体VH53Cコンジュゲート、又は対応する抗体非共有結合複合体化化合物、又は蛍光化合物単独(20mMヒスチジン/140mM NaCl(pH 6.0)中)を、各々の物質について6匹の雌マウス(NMRI系統)に投与した。約0.1mlの血液サンプルを以下の時点後に回収した:第1群におけるマウス1、2、及び3について0.08時間、4時間、及び48時間並びに第2群におけるマウス1、2、及び3について0.08時間、24時間、及び48時間。約50μLの血清サンプルを、1時間後、室温で遠心分離(9300 x gで3分間、4℃)により得た。血清サンプルを−80℃で保存した。
ヒト化抗ジコキシゲニン抗体を伴うジゴキシゲニンCys−Cy5の共有結合コンジュゲートと比較した、ヒト化抗ジゴキシゲニン抗体を伴うジゴキシゲニン−Cy5の複合体の血清中安定性。
ヒト化抗ジゴキシゲニン抗体と複合体化したジゴキシゲニン化ポリペプチドの血清中安定性。
共有結合的に連結されたハプテン−抗体コンジュゲート及び非共有結合複合体の血清中半減期及び曝露レベルのインビボでのリアルタイム測定
異なるハプテンに結合する抗体のペプチド複合体化及び共有結合的なコンジュゲーション
ハプテン定方向性結合は、抗ハプテンシステイン化抗体を伴う、ハプテン化色素又はポリペプチドの効率的な共有結的カップリングのための前提条件である。
共有結合的ペイロードカップリングのためのシステイン変異を伴う、適切に折り畳まれた機能的ハプテン結合抗体の生成のために要求されるジスルフィドパターン
共有結合カップリングのためのシステイン変異を有する抗ハプテンジスルフィド安定化一本鎖Fv断片の組成と生成
共有結合的にカップリングされた化合物/ペイロードの標的化送達のための二重特異性抗ハプテン抗体誘導体の組成、発現、及び精製
ビオシチンアミドとの複合体中のマウス抗ビオチン抗体FabフラグメントのX線構造決定
血液脳関門シャトルモジュールの操作
二重特異性抗体(血液脳関門シャトルモジュール)の発現及び精製
二重特異性ハプテン結合血液脳関門シャトルモジュールは、ハプテン化ペイロード及び血液脳関門受容体に同時に結合する。
血液脳関門シャトルモジュールの受容体結合モードは、脳内皮細胞からの放出に影響する。
内皮細胞向を横切るTfRシャトルに対する低下した親和性を伴う血液脳関門シャトルモジュールは、ハプテン化ペイロードのトランスサイトーシス及び放出を支持する。
TfRに対して高親和性を伴う結合部位を伴う血液脳関門シャトルモジュールは、内皮細胞に結合するが、しかし、そこから放出されず、しかし、依然として、ハプテン化ペイロードのトランスサイトーシス及び放出を支持する。
ハプテン化ペイロードは、小胞コンパートメント内の血液脳関門シャトルモジュールから分離する。
ペプチドYYを含むヘリカーモチーフのアミノ酸配列
PYY3−36ペプチドの構造研究(Nygaard, R., et al., Biochem. 45 (2006) 8350-8357;配列番号211)によって、中心アミノ酸についてのヘリカルモチーフ(ヘリカー様モチーフのアミノ酸配列)が明らかになる。N末端イソロイシン及び改変C末端が、ペプチドの機能的活性のために必須であると記載されてきたように、中心ヘリックスを、ヘリカーモチーフのアミノ酸配列中のアミノ酸を反映するために改変した。
抗ヘリカーモチーフのアミノ酸配列抗体とヘリカーモチーフのアミノ酸配列を含む化合物の間での複合体のインビトロ及びインビボでの安定性を増加させるために、結合時でのジスルフィド架橋の形成が使用されてきた。
a)蛍光化合物を含むヘリカーモチーフのアミノ酸配列を伴う複合体。
i)抗体0155を伴う化合物を含むヘリカーモチーフのアミノ酸配列の共有結合コンジュゲート
結果:
ii)抗体0157を伴う化合物を含むヘリカーモチーフのアミノ酸配列の共有結合コンジュゲート
結果:
b)組換えポリペプチドを含むヘリカーモチーフのアミノ酸配列を伴う複合体
BrdU含有ペイロードを伴う複合体からのBrdU結合二重特異性抗体
ビオチン結合二重特異性抗体は、ビオチン含有IgGに結合する
ビオチン標識抗pTau抗体のトランスサイトーシス
ハプテン結合血液脳関門−シャトルによって、短いオリゴヌクレオチドのトランスサイトーシス及び放出が可能になる
血液脳関門を横切ったペイロード送達のためのハプテン及びトランスフェリン受容体結合シャトル媒体のインビボでの機能性の評価
A群:無処置
B群:(ビオチン化)p−Tau結合抗体のみ
C群:二重特異性抗TfR/ビオチン抗体(シャトル媒体)と複合体化されたビオチン化p−Tau結合抗体
D群:抗TfR抗体に共有結合的に連結されたp−Tau結合抗体
(1)右半球:pTau含有凝集体の免疫組織化学
(2)左半球:特異的AlphaLISAによるリン酸化Tauタンパク質及び全Tauタンパク質の測定のための脳ホモジネートの調製。
Claims (20)
- 以下を含む共有結合コンジュゲートの血液脳関門を横切ったハプテン化ペイロードの標的化送達のための使用:
i)ハプテン化ペイロードに特異的に結合する第1の結合特異性及び血液脳関門受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、及び
ii)ハプテン化ペイロード、
ここで、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
ここで、共有結合コンジュゲートは、ハプテン化ペイロードと、ハプテン化ペイロードに特異的に結合する第1の結合特異性の間に共有結合を有し、並びに
ここで、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化ペイロード、ジゴキシゲニン化ペイロード、カルボラン化ペイロード、フルオレセイン化ペイロード、ヘリカー化ペイロード、及びブロモデオキシウリジン化ペイロードからなる群より選択される。 - 使用が、血液脳関門を横切る、遊離の(即ち、単離された)ハプテン化ペイロードの標的化送達用である、請求項1記載の使用。
- 血液脳関門受容体が、トランスフェリン受容体(TfR)、インスリン受容体、インスリン様成長因子受容体(IGF受容体)、低密度リポタンパク質受容体関連タンパク質8(LRP8)、低密度リポタンパク質受容体関連タンパク質1(LRP1)、及びヘパリン結合上皮成長因子様成長因子(HB−EGF)からなる群より選択される、請求項1又は2記載の使用。
- 血液脳関門受容体が、トランスフェリン受容体又は低密度リポタンパク質受容体関連タンパク質8である、請求項1〜3のいずれか一項記載の使用。
- 二重特異性抗体にエフェクター機能がない、請求項1〜4のいずれか一項記載の使用。
- 請求項1〜5のいずれか一項記載の使用であって、ここで、二重特異性抗体は以下を含む:
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。 - 二重特異性抗体が、抗体のCDR2中のアミノ酸残基にシステイン残基を含み、ここで、CDR2は、Kabatに従って決定される、請求項1〜6のいずれか一項記載の使用。
- 共有結合が、抗体のCDR2中のシステイン残基とハプテン化ペイロード中のチオール基の間である、請求項1〜7のいずれか一項記載の使用。
- 以下を含む共有結合コンジュゲート:
i)ハプテン化ペイロードに特異的に結合する第1の結合特異性及び血液脳関門受容体に特異的に結合する第2の結合特異性を有する二重特異性抗体、及び
ii)ハプテン化ペイロード、
ここで、ハプテン化ペイロードは、第1の結合特異性により特異的に結合され、
ここで、共有結合コンジュゲートは、ハプテン化ペイロードと、ハプテン化ペイロードに特異的に結合する第1の結合特異性の間に共有結合を有し、並びに
ここで、ハプテン化ペイロードは、ビオチン化ペイロード、テオフィリン化ペイロード、ジゴキシゲニン化ペイロード、カルボラン化ペイロード、フルオレセイン化ペイロード、ヘリカー化ペイロード、及びブロモデオキシウリジン化ペイロードをからなる群より選択される。 - 請求項9記載のコンジュゲートであって、ここで、血液脳関門受容体は、トランスフェリン受容体(TfR)、インスリン受容体、インスリン様成長因子受容体(IGF受容体)、低密度リポタンパク質受容体関連タンパク質8(LRP8)、低密度リポタンパク質受容体関連タンパク質1(LRP1)、及びヘパリン結合上皮成長因子様成長因子(HB−EGF)からなる群より選択される。
- 血液脳関門受容体が、トランスフェリン受容体又は低密度リポタンパク質受容体関連タンパク質8である、請求項9又は10記載のコンジュゲート。
- 二重特異性抗体にエフェクター機能がない、請求項9〜11のいずれか一項記載のコンジュゲート。
- 請求項9〜12のいずれか一項記載のコンジュゲートであって、ここで、二重特異性抗体は、以下を含む:
a)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
b)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための1つの結合部位、又は
c)ハプテン化ペイロードのための1つの結合部位及び血液脳関門受容体のための2つの結合部位、又は
d)ハプテン化ペイロードのための2つの結合部位及び血液脳関門受容体のための2つの結合部位。 - 二重特異性抗体が、抗体のCDR2中のアミノ酸残基にシステイン残基を含み、ここで、CDR2は、Kabatに従って決定される、請求項9〜13のいずれか一項記載のコンジュゲート。
- 共有結合が、抗体のCDR2中のシステイン残基とハプテン化ペイロード中のチオール基の間である、請求項9〜14のいずれか一項記載のコンジュゲート。
- CDR2が重鎖CDR2であり、システインが、Kabatナンバリングに従った位置52b又は53にある、請求項14又は15記載のコンジュゲート。
- CDR2が軽鎖CDR2であり、システインが、Kabatナンバリングに従った位置55又は51にある、請求項14又は15記載のコンジュゲート。
- 請求項9〜17のいずれか一項記載のコンジュゲート及び医薬的に許容可能な担体を含む医薬的製剤。
- 医薬としての使用のための、請求項9〜17のいずれか一項記載のコンジュゲート。
- 癌又は神経学的障害の処置のための、請求項9〜17のいずれか一項記載のコンジュゲート。
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RU2016129624A3 (ja) | 2018-07-26 |
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JP6476194B2 (ja) | 2019-02-27 |
RU2016129624A (ru) | 2018-02-08 |
KR20160104628A (ko) | 2016-09-05 |
EP3089996B1 (en) | 2021-07-28 |
US20210069338A1 (en) | 2021-03-11 |
US20160324984A1 (en) | 2016-11-10 |
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CN105899540A (zh) | 2016-08-24 |
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CN111228509A (zh) | 2020-06-05 |
US20200000929A1 (en) | 2020-01-02 |
MX2016008187A (es) | 2016-09-29 |
US11273223B2 (en) | 2022-03-15 |
EP3960768A1 (en) | 2022-03-02 |
US10561737B2 (en) | 2020-02-18 |
CN105899540B (zh) | 2020-02-07 |
US10806795B2 (en) | 2020-10-20 |
CA2933384A1 (en) | 2015-07-09 |
BR112016013849A2 (pt) | 2017-10-10 |
RU2693438C2 (ru) | 2019-07-02 |
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