JP2016538832A - 抗rspo2及び/又はrspo3抗体及びそれらの使用 - Google Patents
抗rspo2及び/又はrspo3抗体及びそれらの使用 Download PDFInfo
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Abstract
Description
この出願は、2013年10月18日に出願された米国仮出願番号61/893,141、及び2014年9月26日に出願された米国仮出願番号62/056324に対して、米国特許法第119条の下で優先権を主張し、その内容は参照することにより本明細書中にその全体が援用される。
本出願は、EFS−Web経由で提出された配列表を含み、その全体が本明細書中で参照することにより援用される。2014年10月14日に作成された前記ASCIIコピーは、P5719R1−WO_SequenceListing.txtと命名され、大きさは124950バイトである。
(b)(i)配列番号83のアミノ酸配列を含むHVR−L1、(ii)配列番号84のアミノ酸配列を含むHVR−L2、及び(iii)配列番号85のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号86のアミノ酸配列を含むHVR−H1、(ii)配列番号87のアミノ酸配列を含むHVR−H2、及び(iii)配列番号88のアミノ酸配列を含むHVR−H3を含むVHを含む。また本明細書に提供されるのは、RSPO3に結合する単離された抗体であり、ここで、抗体は、(a)(i)配列番号77のアミノ酸配列を含むHVR−L1、(ii)配列番号78のアミノ酸配列を含むHVR−L2、及び(iii)配列番号79のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号80のアミノ酸配列を含むHVR−H1、(ii)配列番号81のアミノ酸配列を含むHVR−H2、及び(iii)配列番号216のアミノ酸配列を含むHVR−H3を含むVHを含む。
用語「Rスポンジン」及び「RSPO」とは本明細書では、別段の指示がない限り、霊長類(例えば、ヒト)及び齧歯類(例えば、マウス及びラット)などの哺乳類を含む任意の脊椎動物供給源由来の任意の天然RSPO(例えば、RSPO1、RSPO2、RSPO3、及び/又はRSPO4)のことである。前記用語は、「完全長」非プロセス型RSPO並びに細胞におけるプロセシングから生じる任意の形態のRSPOを包含する。前記用語は、RSPOの天然に存在する変異体、例えば、スプライス変異体又は対立遺伝子変異体も包含する。幾つかの実施態様において、例示的なヒトRSPOのアミノ酸配列は、例えば、配列番号3に示されるように、RSPO1である。幾つかの実施態様において、例示的なヒトRSPOのアミノ酸配列は、例えば、配列番号1に示されるように、RSPO2である。幾つかの実施態様において、例示的なヒトRSPOのアミノ酸配列は、例えば、配列番号2に示されるように、RSPO3である。幾つかの実施態様において、例示的なヒトRSPOのアミノ酸配列は、例えば、配列番号4に示されるように、RSPO4である。
(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 and Lesk, J. Mol. Biol. 196:901-917 (1987));
(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 et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));
(b)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(MacCallum et al. J. Mol. Biol. 262: 732-745 (1996));及び
(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)の組合せ
を含む。
分率X/Yの100倍
ここで、Xは、A及びBのプログラムアラインメントにおいて、配列アラインメントプログラムALIGN−2によって同一であると一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基の全数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと一致しない場合、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一致しないと評価されるであろう。特に断らない限りは、ここで使用される全ての%アミノ酸配列同一性値は、直前のパラグラフに記載したように、ALIGN−2コンピュータプログラムを用いて得られる。
本明細書中で提供されるのは、抗RSPO抗体及びその使用である。ある実施態様において、RSPO2及び/又はRSPO3に結合する抗体が提供される。提供される抗体は、例えば、結腸直腸がんなどのがんの診断又は治療のために、有用である。
一態様において、本発明は、(a)配列番号8のアミノ酸配列を含むHVR−H1;(b)配列番号9のアミノ酸配列を含むHVR−H2;(c)配列番号10のアミノ酸配列を含むHVR−H3;(d)配列番号5のアミノ酸配列を含むHVR−L1;(e)配列番号6のアミノ酸配列を含むHVR−L2;及び(f)配列番号7のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号14のアミノ酸配列を含むHVR−H1;(b)配列番号15のアミノ酸配列を含むHVR−H2;(c)配列番号16のアミノ酸配列を含むHVR−H3;(d)配列番号11のアミノ酸配列を含むHVR−L1;(e)配列番号12のアミノ酸配列を含むHVR−L2;及び(f)配列番号13のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号20のアミノ酸配列を含むHVR−H1;(b)配列番号21のアミノ酸配列を含むHVR−H2;(c)配列番号22のアミノ酸配列を含むHVR−H3;(d)配列番号17のアミノ酸配列を含むHVR−L1;(e)配列番号18のアミノ酸配列を含むHVR−L2;及び(f)配列番号19のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号26のアミノ酸配列を含むHVR−H1;(b)配列番号27のアミノ酸配列を含むHVR−H2;(c)配列番号28のアミノ酸配列を含むHVR−H3;(d)配列番号23のアミノ酸配列を含むHVR−L1;(e)配列番号24のアミノ酸配列を含むHVR−L2;及び(f)配列番号25のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号32のアミノ酸配列を含むHVR−H1;(b)配列番号33のアミノ酸配列を含むHVR−H2;(c)配列番号34のアミノ酸配列を含むHVR−H3;(d)配列番号29のアミノ酸配列を含むHVR−L1;(e)配列番号30のアミノ酸配列を含むHVR−L2;及び(f)配列番号31のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号38のアミノ酸配列を含むHVR−H1;(b)配列番号39のアミノ酸配列を含むHVR−H2;(c)配列番号40のアミノ酸配列を含むHVR−H3;(d)配列番号35のアミノ酸配列を含むHVR−L1;(e)配列番号36のアミノ酸配列を含むHVR−L2;及び(f)配列番号37のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号44のアミノ酸配列を含むHVR−H1;(b)配列番号45のアミノ酸配列を含むHVR−H2;(c)配列番号46のアミノ酸配列を含むHVR−H3;(d)配列番号41のアミノ酸配列を含むHVR−L1;(e)配列番号42のアミノ酸配列を含むHVR−L2;及び(f)配列番号43のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号50のアミノ酸配列を含むHVR−H1;(b)配列番号51のアミノ酸配列を含むHVR−H2;(c)配列番号52のアミノ酸配列を含むHVR−H3;(d)配列番号47のアミノ酸配列を含むHVR−L1;(e)配列番号48のアミノ酸配列を含むHVR−L2;及び(f)配列番号49のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO2/3抗体を提供する。
一態様において、本発明は、(a)配列番号80のアミノ酸配列を含むHVR−H1;(b)配列番号81のアミノ酸配列を含むHVR−H2;(c)配列番号82のアミノ酸配列を含むHVR−H3;(d)配列番号77のアミノ酸配列を含むHVR−L1;(e)配列番号78のアミノ酸配列を含むHVR−L2;及び(f)配列番号79のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO3抗体を提供する。
一態様において、本発明は、(a)配列番号56のアミノ酸配列を含むHVR−H1;(b)配列番号57のアミノ酸配列を含むHVR−H2;(c)配列番号58のアミノ酸配列を含むHVR−H3;(d)配列番号53のアミノ酸配列を含むHVR−L1;(e)配列番号54のアミノ酸配列を含むHVR−L2;及び(f)配列番号55のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO2抗体を提供する。
一態様において、本発明は、(a)配列番号68のアミノ酸配列を含むHVR−H1;(b)配列番号69のアミノ酸配列を含むHVR−H2;(c)配列番号70のアミノ酸配列を含むHVR−H3;(d)配列番号65のアミノ酸配列を含むHVR−L1;(e)配列番号66のアミノ酸配列を含むHVR−L2;及び(f)配列番号67のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO2抗体を提供する。
一態様において、本発明は、(a)配列番号74のアミノ酸配列を含むHVR−H1;(b)配列番号75のアミノ酸配列を含むHVR−H2;(c)配列番号76のアミノ酸配列を含むHVR−H3;(d)配列番号71のアミノ酸配列を含むHVR−L1;(e)配列番号72のアミノ酸配列を含むHVR−L2;及び(f)配列番号73のアミノ酸配列を含むHVR−L3から選択される、少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む抗RSPO2抗体を提供する。
ある実施態様において、本明細書において与えられる抗体は、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、又は≦0.001nM(例えば、10−8M未満、例えば、10−8Mから10−13M、例えば、10−9Mから10−13M)の解離定数(Kd)を有する。
ある実施態様において、本明細書で提供される抗体は抗体断片である。抗体断片には、Fab、Fab’、Fab’−SH、F(ab’)2、Fv及びscFv断片ならびに下に記載される他の断片が含まれるが、これらに限定されない。ある種の抗体断片の概説については、Hudsonら、Nat.Med.9:129〜134(2003)を参照されたい。scFv断片の概説については、例えば、Pluckthun、The Pharmacology of Monoclonal Antibodies、第113巻、Rosenburg及びMoore編、(Springer−Verlag、New York)、269〜315ページ(1994)を参照されたい。国際公開第93/16185号;ならびに米国特許第5571894号及び米国特許第5587458号も参照されたい。サルベージ受容体結合エピトープ残基を含みインビボ半減期が増大しているFab及びF(ab’)2断片の考察については、米国特許第5869046号を参照されたい。
ある特定の実施態様では、本明細書に提供される抗体はキメラ抗体である。ある種のキメラ抗体は、例えば、米国特許第4816567号及びMorrisonら、Proc.Natl.Acad.Sci.USA、81:6851〜6855(1984)に記載されている。一例では、キメラ抗体は非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、又はサルなどの非ヒト霊長類由来の可変領域)及びヒト定常領域を含む。更なる例では、キメラ抗体は、クラス又はサブクラスが親抗体のクラス又はサブクラスから変えられている「クラス転換された」抗体である。キメラ抗体にはその抗原結合断片が含まれる。
ある特定の実施態様では、本明細書に提供される抗体はヒト抗体である。ヒト抗体は当技術分野で公知の種々の技術を使用して産生することができる。ヒト抗体は一般的には、van Dijk及びvan de Winkel、Curr.Opin.Pharmacol.5:368〜74(2001)ならびにLonberg、Curr.Opin.Immunol.20:450〜459(2008)に記載されている。
本発明の抗体は、1種又は複数の所望の活性を有する抗体を求めてコンビナトリアルライブラリーをスクリーニングすることにより単離しうる。例えば、ファージディスプレイライブラリーを作製し所望の結合特徴を有する抗体を求めてそのようなライブラリーをスクリーニングするための種々の方法は当技術分野では公知である。そのような方法は、Hoogenboomら、Methods in Molecular Biology 178:1〜37(O’Brienら編、Human Press、Totowa、NJ、2001)で概説されており、例えば、McCaffertyら、Nature 348:552〜554;Clacksonら、Nature 352:624〜628(1991);Marksら、J.Mol.Biol.222:581〜597(1992);Marks及びBradbury、Methods in Molecular Biology 248:161〜175(Lo編 Human Press、Totowa、NJ、2003);Sidhuら、J.Mol.Biol.338(2):299〜310(2004);Leeら、J.Mol.Biol.340(5):1073〜1093(2004);Fellouse、Proc.Natl.Acad.Sci.USA 101(34):12467〜12472(2004);ならびにLeeら、J.Immunol.Methods 284(1−2):119〜132(2004)に更に記載されている。
ある特定の実施態様では、本明細書に提供される抗体は多特異的抗体、例えば、二重特異的抗体である。多特異的抗体は、少なくとも2つの異なる部位に対する結合特異性を有するモノクローナル抗体である。ある種の実施態様では、結合特異性の1つは、RSPO(例えば、RSPO2及び/又はRSPO3)であり、他は、他の任意の抗原に対してである。ある特定の実施態様では、二重特異的抗体はRSPOの2つの異なるエピトープに結合しうる。二重特異的抗体はまた、RSPO(例えば、RSPO2及び/又はRSPO3)を発現する細胞に細胞傷害剤を局在化させるために使用することもできる。幾つかの実施態様において、多重特異性抗体(例えば、二重特異性抗体)は、RSPO2及びRSPO3に結合する。幾つかの実施態様において、多重特異性抗体(例えば、二重特異性抗体)は、5E11のHVRを含む第一可変ドメイン及び36D2のHVRを含む第二可変ドメインを含む。幾つかの実施態様において、多重特異性抗体(例えば、二重特異性抗体)は、5D6のHVRを含む第一可変ドメイン及び36D2のHVRを含む第二可変ドメインを含む。幾つかの実施態様において、多重特異性抗体(例えば、二重特異性抗体)は、5E11のHVRを含む第一可変ドメイン及び1A1のHVRを含む第二可変ドメインを含む。幾つかの実施態様において、多重特異性抗体(例えば、二重特異性抗体)は、5D6のHVRを含む第一可変ドメイン及び1A1のHVRを含む第二可変ドメインを含む。二重特異的抗体は、完全長抗体又は抗体断片として調製することができる。
ある実施態様において、本明細書に提供される抗体のアミノ酸配列変異体が意図される。例えば、抗体の結合親和性及び/又は他の生物学的特性を改善することが望まれ得る。抗体のアミノ酸配列変異体は、抗体をコードするヌクレオチド配列に適切な改変を導入することにより、又はペプチド合成によって調製することができる。このような改変は、例えば、抗体のアミノ酸配列内における、残基の欠失、及び/又は挿入及び/又は置換を含む。最終コンストラクトが所望の特性、例えば、抗原結合を有していることを条件として、欠失、挿入、及び置換の任意の組み合わせが、最終コンストラクトに到達させるために作成され得る。
ある実施態様において、一つ以上のアミノ酸置換を有する抗体変異体が提供される。置換型変異誘発の対象となる部位は、HVRとFRを含む。保存的置換は、表1の「好ましい置換」の見出しの下に示されている。より実質的な変更が、表1の「例示的置換」の見出しの下に与えられ、アミノ酸側鎖のクラスを参照して以下に更に説明される。アミノ酸置換は対象の抗体に導入され、生成物は、所望の活性、例えば、保持された/改善された抗原結合性、減少した免疫原性、又は改善されたADCCもしくはCDCについてスクリーニングされうる。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性の親水性: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
ある実施態様において、本明細書で提供される抗体は、抗体がグリコシル化される程度を増加又は減少させるように改変される。抗体へのグリコシル化部位の付加又は削除は、1つ又は複数のグリコシル化部位が作り出される又は取り除かれるようにアミノ酸配列を変化させることにより都合よく実現しうる。
ある特定の実施態様では、1つ又は複数のアミノ酸改変を本明細書に提供される抗体のFc領域に導入し、それによりFc領域変異体を産生しうる。前記Fc領域変異体は、1つ又は複数のアミノ酸位にアミノ酸改変(例えば、置換)を含むヒトFc領域配列(例えば、ヒトIgG1、IgG2、IgG3又はIgG4Fc領域)を含みうる。
ある特定の実施態様では、抗体の1つ又は複数の残基がシステイン残基で置換されているシステイン操作抗体、例えば、「チオMAb」を作り出すのが望ましいことがある。特定の実施態様では、置換される残基は抗体の接触可能部位に存在する。更に本明細書で説明されるように、それらの残基をシステインで置換することにより、反応性チオール基はそれにより抗体の接触可能部位に置かれ、この基を使用して抗体を、薬物部分又はリンカー薬物部分などの他の部分にコンジュゲートさせて、免疫コンジュゲートを作り出しうる。ある特定の実施態様では、以下の残基:軽鎖のV205(Kabat番号付け);重鎖のA118(EU番号付け);及び重鎖Fc領域のS400(EU番号付け)のうちの任意の1つ又は複数をシステインで置換しうる。システイン操作抗体は、例えば、米国特許第7521541号に記載される通りに産生しうる。
ある実施態様において、本明細書で提供される抗体は、当技術分野で知られ、容易に入手される追加の非タンパク質部分を含むように更に改変することができる。抗体の誘導体化に適した部分としては、限定されないが、水溶性ポリマーを含む。水溶性ポリマーの非限定的な例は、限定されないが、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールの共重合体、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/無水マレイン酸共重合体、ポリアミノ酸(単独重合体又はランダム共重合体の何れか)及びデキストラン又はポリ(n−ビニルピロリドン)ポリエチレングリコール、プロピレングリコール単独重合体、プロピレンオキシド/エチレンオキシド共重合体、ポリオキシエチル化ポリオール(例えばグリセロール)、ポリビニルアルコール及びこれらの混合物を包含する。ポリエチレングリコールプロピオンアルデヒドはその水中での安定性に起因して製造における利点を有し得る。ポリマーは何れかの分子量のものであってよく、そして分枝鎖又は未分枝鎖であってよい。抗体に結合するポリマーの数は変動してよく、そして、一以上の重合体が結合する場合は、それらは同じか又は異なる分子であることができる。一般的に、誘導体化に使用するポリマーの数及び/又は種類は、限定されないが、向上させるべき抗体の特定の特性又は機能、抗体誘導体が限定された条件下で治療に使用されるのか等を含む考慮に基づいて決定することができる。
抗体は、例えば、米国特許第4816567号に記載されている組換え法及び組成物を使用して産生しうる。一実施態様では、本明細書に記載される抗RSPO抗体をコードする単離された核酸が提供される。このような核酸は、抗体のVLを含むアミノ酸配列、及び/又は抗体のVHを含むアミノ酸配列(例えば、抗体の軽鎖及び/又は重鎖)をコードし得る。更なる実施態様において、そのような核酸を含む一以上のベクター(例えば、発現ベクター)が提供される。更なる実施態様において、そのような核酸を含む宿主細胞が提供される。一つのそのような実施態様では、宿主細胞は、(1)抗体のVLを含むアミノ酸配列、及び抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、又は(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第一ベクター、及び抗体のVHを含むアミノ酸配列をコードする核酸を含む第二ベクターを含む(例えば、これらのベクターで形質転換されている)。一実施態様において、宿主細胞は、真核生物、例えばチャイニーズハムスター卵巣(CHO)細胞、又はリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施態様において、抗RSPO抗体を作製する方法であって、抗体の発現に適した条件下で、上に提供される抗体をコードする核酸を含む宿主細胞を培養し、場合により、宿主細胞(又は宿主細胞培養培地)から抗体及び/又はポリペプチドを回収することを含む方法が提供される。
本明細書で提供される抗RSPO抗体は、当技術分野で公知の様々なアッセイによってその物理的/化学的性質及び/又は生物学的活性について同定され、スクリーニングされ、又は特徴づけることができる。
一態様において、本発明の抗体は、例えばELISA、ウエスタンブロット法など公知の方法により、その抗原結合活性について試験される。
一態様において、アッセイは、生物学的活性を有するそれらの抗RSPO抗体を同定するために与えられる。生物学的活性は、例えば、wntシグナル伝達を阻害する、血管新生を阻害する、細胞増殖を阻害する、がん幹細胞の増殖を阻害する、及び/又はがん幹細胞を枯渇させることを含み得る。インビボ及び/又はインビトロでこのような生物学的活性を有する抗体もまた提供される。
本発明はまた、化学療法剤又は薬物、成長抑制剤、毒素(例えば、タンパク質毒素、細菌、真菌、植物、又は動物起源の酵素活性毒素、又はそれらの断片)、又は放射性同位元素など、1つ以上の細胞傷害性薬物にコンジュゲートした本明細書中の抗RSPO抗体を含むイムノコンジュゲートを提供する。
ある実施態様において、本明細書で提供される抗RSPO抗体の何れかは、試料中のRSPOの存在を検出するために有用である。本明細書で使用する「検出」という用語は、定量的又は定性的検出を包含する。ある実施態様において、試料は、消化管、胃、食道、大腸、直腸、及び/又は結腸直腸組織などの細胞又は組織を含む。幾つかの実施態様において、試料は、腎臓、膀胱、脳、乳房、子宮頸部、結腸、頭部及び頸部、腎臓、白血病、肝臓、肺、リンパ節、卵巣、膵臓、前立腺、直腸、皮膚、胃、甲状腺、及び/又は子宮組織などの細胞又は組織を含む。幾つかの実施態様において、試料は、肺、卵巣、乳房、肝臓、又は多発性骨髄腫の組織などの細胞又は組織を含む。
本明細書に記載の抗RSPO抗体の薬学的製剤は、所望の程度の純度を有するその抗体と任意の薬学的に許容される一以上の担体(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.: Williams and Wilkins PA, USA (1980))とを、凍結乾燥製剤又は水性溶液の形態で混合することによって調製される。薬学的に許容される担体は、使用される投薬量及び濃度でレシピエントに毒性でなく、そしてこれには、限定しないが、リン酸塩、クエン酸塩及び他の有機酸のような緩衝液;アスコルビン酸及びメチオニンを含む抗酸化剤;防腐剤(例えば、オクタデシルジメチオルベンジルアンモニウムクロライド;ヘキサメトニウムクロライド;塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、ブチル又はベンジルアルコール;アルキルパラベン、例えば、メチル又はプロピルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;及びm−クレゾール);低分子量(約10残基未満)ポリペプチド;タンパク質、例えば、血清アルブミン、ゼラチン、又は免疫グロブリン;親水性ポリマー、例えば、ポリビニルピロリドン;アミノ酸、例えば、グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン又はリジン;マンノサッカライド、ジサッカライド、及びグルコース、マンノース又はデキストリンを含む他の炭水化物;キレート剤、例えば、EDTA;糖、例えば、スクロース、マンニトール、トレハロース又はソルビトール;塩形成対イオン、例えば、ナトリウム、金属錯体(例えば、Zn−タンパク質錯体);及び/又はポリエチレングリコール(PEG)等の非イオン性界面活性剤が挙げられる。本明細書における典型的な薬学的に許容される担体は、水溶性の中性アクティブヒアルロニダーゼ糖タンパク質(sHASEGP)などの介在性薬物分散剤、例えば、rHuPH20(HYLENEX(登録商標)、Baxter International, Inc.)などのヒト可溶性PH−20ヒアルロニダーゼ糖タンパク質を更に含む。特定の例示的sHASEGP及び使用方法は、rHuPH20を含めて、米国特許公開第2005/0260186号及び第2006/0104968号に記載されている。一態様において、sHASEGPは、コンドロイチナーゼなどの一以上の付加的なグルコサミノグリカナーゼと組み合わされる。
本明細書で提供される抗RSPO抗体の何れかを、治療方法で使用することができる。
本発明の別の態様において、上述した障害の治療、予防、及び/又は診断に有用な物質を含む製造品が提供される。製造品は、容器とラベル又は容器上にある又は容器に付属する添付文書を含む。好適な容器は、例としてボトル、バイアル、シリンジ、IV輸液バッグ等を含む。容器はガラス又はプラスチックなどの様々な物質から形成されうる。容器は、疾患の治療、予防、及び/又は診断に有効である、それ自体か、又はその他の組成物と併用される化合物を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針による穴あきストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも一の活性剤は本発明の抗体である。ラベル又は添付文書は、組成物が選択した症状の治療のために使用されることを示している。更に、製造品は、(a)組成物が本発明の抗体を包含する組成物を含む第一の容器;及び(b)組成物が更なる細胞障害性又はその他の治療的薬剤を包含する組成物を含む第2の容器を含み得る。本発明の本実施態様における製造品は、組成物が特定の疾患を治療することに用いることができることを示す添付文書を更に含んでいてもよい。別法として、又は加えて、製造品は、薬学的に許容される緩衝液、例えば注射用静菌水(BWFI)、リン酸緩衝化塩水、リンガー溶液及びデキストロース溶液を含む第二(又は第三)の容器を更に含んでもよい。これは、他の緩衝液、希釈剤、フィルター、針、及びシリンジを含む、商業的及びユーザーの立場から望まれる他の物質を更に含んでもよい。
以下は本発明の方法及び組成物の例である。上記提供される一般的な説明を前提として、他の様々な実施態様が実施され得ることが理解される。
クローニング及び精製:FLAGタグ付きRNF43は、抗FLAG親和性クロマトグラフィー(Genentech)、続いてサイズ排除クロマトグラフィー(Superdex 75, GE Healthcare)により精製された。FLAGタグ付きR−スポンジン(hRSPO2、hRSPO2 L186、cynoRSPO2、hRSPO3、及びcynoRSPO3FLAG)は、抗FLAG親和性クロマトグラフィー、続いて陽イオン交換クロマトグラフィー(Mono S, GE Healthcare)により精製された。ヒトIgG1のFcタグ付きLGR細胞外ドメインは、親和性クロマトグラフィー(MabSelect SuRe, GE Healthcare)、続いてサイズ排除クロマトグラフィー(Superdex 200、GE Healthcare)により精製された。
機能遮断及びIHC反応性抗RSPO抗体の産生
抗RSPO抗体を産生する試みにおいて、マウス及びハムスターは、組換えヒトRSPO2及び/又はヒトRSPO3で免疫され、ハイブリドーマ細胞株が作製された。これらの細胞から上澄液は、最初に、ELISAによってhRSPO1、hRSPO2、hRSPO3及びhRSPO4への結合についてスクリーニングされた。hRSPO2及び/又はhRSPO3結合を示す上清は、その後、WNTレポーター活性のhRSPO2及びhRSPO3刺激を遮断する能力について試験された。候補は、その後、クローニングされ、発現され、精製された。図1に示すように、精製されたクローンのサブセットは、rhRSPO2刺激WNTレポーター活性(図1A)及び/又はrh RSPO3刺激WNTレポーター活性(図1B)を強力に阻害した。
抗RSPO抗体を更に特徴づけるために、抗体が分類される固有のエピトープビンの数が、OCTET REDアッセイを用いて決定された。抗体は、最初に親和性がランク付けされた。最も高い親和性を有する抗体は、hRSPO2又はhRSPO3結合バイオセンサーへ飽和に至るまで結合させた。二次抗体による結合が、その後評価された。試験された抗RSPO2抗体は、1A1又は11F11の何れかと競合する能力によって定義される2つの固有のエピトープビンに分類された。第一の固有のエピトープビンは1A1、49G5、及び36D2を含み、第二の固有のエピトープビンは11F11を含んでいた。試験された抗RSPO3抗体は、26E11、4H1、又は21C2と競合する能力によって定義される3つの固有のエピトープビンに分類された。第一の固有のエピトープビンは、26E11、5D6、5E11、及び6E9を含み、第二の固有のエピトープビンは4H1を含み、第三の固有のエピトープビンは5C2及び21C2を含んでいた。
抗RSPO抗体を更に特徴づけるために、それらの機能遮断活性がマウスRSPO2(R&D Systems)及びカニクイザルRSPO2(Genentech)に対して試験された。抗体クローンのサブセットは、WNTレポーター細胞のhRSPO2、cynoRSPO2、及びmRSPO2刺激を遮断できた(図3A−C)RSPO2中の位置186での多型は、ヒト集団において同定された。この多型に対する抗RSPO抗体の機能遮断活性及びこの患者集団における潜在的有用性を評価するために、hRSPO2 L186Pタンパク質が最初に精製され、次いでWNTレポーター細胞を刺激するために使用された。抗RSPO抗体のサブセットは、hRSPO2 L186Pの機能を遮断できた(図3D)。
以前に、RSPOタンパク質は、膜貫通タンパク質の2つの異なるクラス:E3−リガーゼ(RNF43及びZNRF3)及びLGR(LGR4及びLGR5)(Hao et al., Nature 485(7397):195-200 (2012))に結合することが示されている。抗RSPO抗体がこの2つのクラスのタンパク質のとの結合を阻害することができるかどうかを試験するために、競合結合ELISAアッセイが開発された。LGR4又はLGR5のhRSPO2及びhRSPO3への結合を阻害する能力について試験するとき、抗RSPO抗体は、次の3つのカテゴリに分類された:LGR4及びLGR5の相互作用を阻害できたもの、阻害しなかったもの、及び促進したもの(図6A−B、データは示さず)。同様に、抗RSPO抗体のパネルのサブセットは、RNF43のhRSPO2又はRSPO3への結合を阻害した(図7A−B)。抗RSPO結果の概要は以下の通りである(表5)。
ヒト化5D6v1(hu5D6v1と称される)抗体の結合親和性が、キメラ5D6と比較された。hu5D6v1のマウスバーニア位置は、hRSPO3に結合するマウスバーニア位置の寄与を評価するために、ヒト残基に変換された。4つの付加的軽鎖(L1:v1 + Y36(v2.1と称される)、v1+L46(v2.2と称される)、v1+T69(v2.3と称される)、v1+F71(v2.4と称される))及び4つの付加的重鎖(v1+V71(v2.8と称される)、v1+R94(v2.10と称される)、v1+W47+I48+F78(v3.2と称される)、v1+W47+I48+v67+F78(v3.3と称される))。上述の変異体抗体の結合親和性評価に基づいて(データは示さず)、軽鎖上のF36及びT46は、鍵となるマウスのバーニア残基であり、重鎖上のV71及びR94は、鍵となるマウスのバーニア残基であると決定された。キメラ5D6は、3.3E−11MのKDで結合したが、一方、v1+T69(LC)+(W47+I48+V67+F78(HC)(hu5D6v4.1と称される)、v1+T69(LC)+(W47+I48+F78(HC)(hu5D6v4.3と称される)は、それぞれ、6.3E−11M、及び7.0E−11MのKDで結合した。
抗RSPO抗体を更に特徴付けるために、RSPO3/Fab複合体(5D6及び26E11)の結晶が上記のように調製され、結晶構造が決定された。図8を参照。表6は、5D6の重鎖(HC)及び軽鎖(LC)とRSPO3(F鎖)との間の接触のリストを含む。表6におけるカットオフは4オングストロームである。表7は、26E11の重鎖(HC)及び軽鎖(LC)とRSPO3(F鎖)との間の接触のリストを含む。表7におけるカットオフは4オングストロームである。5D6及び26E11の両方における接触の大部分はRSPO3のフリン1ドメインとである。
抗RSPO3抗体の有効性は、結腸直腸がんPTPRD−RSPO融合患者由来の腫瘍モデルにおいて試験された。PTPRD−RSPO融合患者由来の腫瘍モデル及び/又はNSCLC組織において、抗RSPO3抗体(5D6)は、腸管幹細胞マーカー:Myc、Axin2、LGR5、TERT、BIRC5、及び/又はAscl2のマーカーの遺伝子発現を有意に減少させたが、一方、分化のマーカー、例えば、 CEACAM7、SLC26A3、CA1、SYTl5、CA4、TFF1、及びKRT20は、抗RSPO3抗体による処置の前の発現レベルに比較して増加した(データは示さず)。いかなる特定の理論に縛られることを望まないが、これらの結果は、抗RSPO3抗体(5D6)は、遺伝子発現マーカーによって決定されるように、幹細胞様マーカープロファイルから分化マーカープロファイルへの遷移を促進することが可能であることを示唆している。
配列番号1 >sp|Q6UXX9|RSPO2_HUMAN R−スポンジン−2 OS=ホモサピエンス GN=RSPO2
MQFRLFSFALIILNCMDYSHCQGNRWRRSKRASYVSNPICKGCLSCSKDNGCSRCQQKLFFFLRREGMRQYGECLHSCPSGYYGHRAPDMNRCARCRIENCDSCFSKDFCTKCKVGFYLHRGRCFDECPDGFAPLEETMECVEGCEVGHWSEWGTCSRNNRTCGFKWGLETRTRQIVKKPVKDTILCPTIAESRRCKMTMRHCPGGKRTPKAKEKRNKKKKRKLIERAQEQHSVFLATDRANQ
配列番号2 >sp|Q9BXY4|RSPO3_HUMAN R−スポンジン−3 OS=ホモサピエンス GN=RSPO3
MHLRLISWLFIILNFMEYIGSQNASRGRRQRRMHPNVSQGCQGGCATCSDYNGCLSCKPRLFFALERIGMKQIGVCLSSCPSGYYGTRYPDINKCTKCKADCDTCFNKNFCTKCKSGFYLHLGKCLDNCPEGLEANNHTMECVSIVHCEVSEWNPWSPCTKKGKTCGFKRGTETRVREIIQHPSAKGNLCPPTNETRKCTVQRKKCQKGERGKKGRERKRKKPNKGESKEAIPDSKSLESSKEIPEQRENKQQQKKRKVQDKQKSVSVSTVH
配列番号3 >sp|Q2MKA7|RSPO1_HUMAN R−スポンジン−1 OS=ホモサピエンス GN=RSPO1
MRLGLCVVALVLSWTHLTISSRGIKGKRQRRISAEGSQACAKGCELCSEVNGCLKCSPKLFILLERNDIRQVGVCLPSCPPGYFDARNPDMNKCIKCKIEHCEACFSHNFCTKCKEGLYLHKGRCYPACPEGSSAANGTMECSSPAQCEMSEWSPWGPCSKKQQLCGFRRGSEERTRRVLHAPVGDHAACSDTKETRRCTVRRVPCPEGQKRRKGGQGRRENANRNLARKESKEAGAGSRRRKGQQQQQQQGTVGPLTSAGPA
配列番号4 >sp|Q2I0M5|RSPO4_HUMAN R−スポンジン−4 OS=ホモサピエンス GN=RSPO4
MRAPLCLLLLVAHAVDMLALNRRKKQVGTGLGGNCTGCIICSEENGCSTCQQRLFLFIRREGIRQYGKCLHDCPPGYFGIRGQEVNRCKKCGATCESCFSQDFCIRCKRQFYLYKGKCLPTCPPGTLAHQNTRECQGECELGPWGGWSPCTHNGKTCGSAWGLESRVREAGRAGHEEAATCQVLSESRKCPIQRPCPGERSPGQKKGRKDRRPRKDRKLDRRLDVRPRQPGLQP
EIF3E(e1)−RSPO2(e2)転座融合ポリヌクレオチド(配列番号173)
GAGCACAGACTCCCTTTTCTTTGGCAAGATGGCGGAGTACGACTTGACTACTCGCATCGCGCACTTTTTGGATCGGCATCTAGTCTTTCCGCTTCTTGAATTTCTCTCTGTAAAGGAGGTTCGTGGCGGAGAGATGCTGATCGCGCTGAACTGACCGGTGCGGCCCGGGGGTGAGTGGCGAGTCTCCCTCTGAGTCCTCCCCAGCAGCGCGGCCGGCGCCGGCTCTTTGGGCGAACCCTCCAGTTCCTAGACTTTGAGAGGCGTCTCTCCCCCGCCCGACCGCCCAGATGCAGTTTCGCCTTTTCTCCTTTGCCCTCATCATTCTGAACTGCATGGATTACAGCCACTGCCAAGGCAACCGATGGAGACGCAGTAAGCGAGCTAGTTATGTATCAAATCCCATTTGCAAGGGTTGTTTGTCTTGTTCAAAGGACAATGGGTGTAGCCGATGTCAACAGAAGTTGTTCTTCTTCCTTCGAAGAGAAGGGATGCGCCAGTATGGAGAGTGCCTGCATTCCTGCCCATCCGGGTACTATGGACACCGAGCCCCAGATATGAACAGATGTGCAAGATGCAGAATAGAAAACTGTGATTCTTGCTTTAGCAAAGACTTTTGTACCAAGTGCAAAGTAGGCTTTTATTTGCATAGAGGCCGTTGCTTTGATGAATGTCCAGATGGTTTTGCACCATTAGAAGAAACCATGGAATGTGTGGAAGGATGTGAAGTTGGTCATTGGAGCGAATGGGGAACTTGTAGCAGAAATAATCGCACATGTGGATTTAAATGGGGTCTGGAAACCAGAACACGGCAAATTGTTAAAAAGCCAGTGAAAGACACAATACTGTGTCCAACCATTGCTGAATCCAGGAGATGCAAGATGACAATGAGGCATTGTCCAGGAGGGAAGAGAACACCAAAGGCGAAGGAGAAGAGGAACAAGAAAAAGAAAAGGAAGCTGATAGAAAGGGCCCAGGAGCAACACAGCGTCTTCCTAGCTACAGACAGAGCTAACCAATAA
EIF3E(e1)−RSPO2(e2)転座融合ポリペプチド配列(配列番号174)
MAEYDLTTRIAHFLDRHLVFPLLEFLSVKEVRGGEMLIALNMQFRLFSFALIILNCMDYSHCQGNRWRRSKRASYVSNPICKGCLSCSKDNGCSRCQQKLFFFLRREGMRQYGECLHSCPSGYYGHRAPDMNRCARCRIENCDSCFSKDFCTKCKVGFYLHRGRCFDECPDGFAPLEETMECVEGCEVGHWSEWGTCSRNNRTCGFKWGLETRTRQIVKKPVKDTILCPTIAESRRCKMTMRHCPGGKRTPKAKEKRNKKKKRKLIERAQEQHSVFLATDRANQ
PTPRK(e1)−RSPO3(e2)転座融合ポリヌクレオチド配列(配列番号175)
ATGGATACGACTGCGGCGGCGGCGCTGCCTGCTTTTGTGGCGCTCTTGCTCCTCTCTCCTTGGCCTCTCCTGGGATCGGCCCAAGGCCAGTTCTCCGCAGTGCATCCTAACGTTAGTCAAGGCTGCCAAGGAGGCTGTGCAACATGCTCAGATTACAATGGATGTTTGTCATGTAAGCCCAGACTATTTTTTGCTCTGGAAAGAATTGGCATGAAGCAGATTGGAGTATGTCTCTCTTCATGTCCAAGTGGATATTATGGAACTCGATATCCAGATATAAATAAGTGTACAAAATGCAAAGCTGACTGTGATACCTGTTTCAACAAAAATTTCTGCACAAAATGTAAAAGTGGATTTTACTTACACCTTGGAAAGTGCCTTGACAATTGCCCAGAAGGGTTGGAAGCCAACAACCATACTATGGAGTGTGTCAGTATTGTGCACTGTGAGGTCAGTGAATGGAATCCTTGGAGTCCATGCACGAAGAAGGGAAAAACATGTGGCTTCAAAAGAGGGACTGAAACACGGGTCCGAGAAATAATACAGCATCCTTCAGCAAAGGGTAACCTGTGTCCCCCAACAAATGAGACAAGAAAGTGTACAGTGCAAAGGAAGAAGTGTCAGAAGGGAGAACGAGGAAAAAAAGGAAGGGAGAGGAAAAGAAAAAAACCTAATAAAGGAGAAAGTAAAGAAGCAATACCTGACAGCAAAAGTCTGGAATCCAGCAAAGAAATCCCAGAGCAACGAGAAAACAAACAGCAGCAGAAGAAGCGAAAAGTCCAAGATAAACAGAAATCGGTATCAGTCAGCACTGTACACTAG
PTPRK(e1)−RSPO3(e2)転座融合ポリペプチド配列(配列番号176)
MDTTAAAALPAFVALLLLSPWPLLGSAQGQFSAVHPNVSQGCQGGCATCSDYNGCLSCKPRLFFALERIGMKQIGVCLSSCPSGYYGTRYPDINKCTKCKADCDTCFNKNFCTKCKSGFYLHLGKCLDNCPEGLEANNHTMECVSIVHCEVSEWNPWSPCTKKGKTCGFKRGTETRVREIIQHPSAKGNLCPPTNETRKCTVQRKKCQKGERGKKGR
PTPRK(e7)−RSPO3(e2)転座融合ポリヌクレオチド配列(配列番号177)
ATGGATACGACTGCGGCGGCGGCGCTGCCTGCTTTTGTGGCGCTCTTGCTCCTCTCTCCTTGGCCTCTCCTGGGATCGGCCCAAGGCCAGTTCTCCGCAGGTGGCTGTACTTTTGATGATGGTCCAGGGGCCTGTGATTACCACCAGGATCTGTATGATGACTTTGAATGGGTGCATGTTAGTGCTCAAGAGCCTCATTATCTACCACCCGAGATGCCCCAAGGTTCCTATATGATAGTGGACTCTTCAGATCACGACCCTGGAGAAAAAGCCAGACTTCAGCTGCCTACAATGAAGGAGAACGACACTCACTGCATTGATTTCAGTTACCTATTATATAGCCAGAAAGGACTGAATCCTGGCACTTTGAACATATTAGTTAGGGTGAATAAAGGACCTCTTGCCAATCCAATTTGGAATGTGACTGGATTCACGGGTAGAGATTGGCTTCGGGCTGAGCTAGCAGTGAGCACCTTTTGGCCCAATGAATATCAGGTAATATTTGAAGCTGAAGTCTCAGGAGGGAGAAGTGGTTATATTGCCATTGATGACATCCAAGTACTGAGTTATCCTTGTGATAAATCTCCTCATTTCCTCCGTCTAGGGGATGTAGAGGTGAATGCAGGGCAAAACGCTACATTTCAGTGCATTGCCACAGGGAGAGATGCTGTGCATAACAAGTTATGGCTCCAGAGACGAAATGGAGAAGATATACCAGTAGCCCAGACTAAGAACATCAATCATAGAAGGTTTGCCGCTTCCTTCAGATTGCAAGAAGTGACAAAAACTGACCAGGATTTGTATCGCTGTGTAACTCAGTCAGAACGAGGTTCCGGTGTGTCCAATTTTGCTCAACTTATTGTGAGAGAACCGCCAAGACCCATTGCTCCTCCTCAGCTTCTTGGTGTTGGGCCTACATATTTGCTGATCCAACTAAATGCCAACTCGATCATTGGCGATGGTCCTATCATCCTGAAAGAAGTAGAGTACCGAATGACATCAGGATCCTGGACAGAAACCCATGCAGTCAATGCTCCAACTTACAAATTATGGCATTTAGATCCAGATACCGAATATGAGATCCGAGTTCTACTTACAAGACCTGGTGAAGGTGGAACGGGGCTCCCAGGACCTCCACTAATCACCAGAACAAAATGTGCAGTGCATCCTAACGTTAGTCAAGGCTGCCAAGGAGGCTGTGCAACATGCTCAGATTACAATGGATGTTTGTCATGTAAGCCCAGACTATTTTTTGCTCTGGAAAGAATTGGCATGAAGCAGATTGGAGTATGTCTCTCTTCATGTCCAAGTGGATATTATGGAACTCGATATCCAGATATAAATAAGTGTACAAAATGCAAAGCTGACTGTGATACCTGTTTCAACAAAAATTTCTGCACAAAATGTAAAAGTGGATTTTACTTACACCTTGGAAAGTGCCTTGACAATTGCCCAGAAGGGTTGGAAGCCAACAACCATACTATGGAGTGTGTCAGTATTGTGCACTGTGAGGTCAGTGAATGGAATCCTTGGAGTCCATGCACGAAGAAGGGAAAAACATGTGGCTTCAAAAGAGGGACTGAAACACGGGTCCGAGAAATAATACAGCATCCTTCAGCAAAGGGTAACCTGTGTCCCCCAACAAATGAGACAAGAAAGTGTACAGTGCAAAGGAAGAAGTGTCAGAAGGGAGAACGAGGAAAAAAAGGAAGGGAGAGGAAAAGAAAAAAACCTAATAAAGGAGAAAGTAAAGAAGCAATACCTGACAGCAAAAGTCTGGAATCCAGCAAAGAAATCCCAGAGCAACGAGAAAACAAACAGCAGCAGAAGAAGCGAAAAGTCCAAGATAAACAGAAATCGGTATCAGTCAGCACTGTACACTAG
PTPRK(e7)−RSPO3(e2)転座融合ポリペプチド配列(配列番号178)
MDTTAAAALPAFVALLLLSPWPLLGSAQGQFSAGGCTFDDGPGACDYHQDLYDDFEWVHVSAQEPHYLPPEMPQGSYMIVDSSDHDPGEKARLQLPTMKENDTHCIDFSYLLYSQKGLNPGTLNILVRVNKGPLANPIWNVTGFTGRDWLRAELAVSTFWPNEYQVIFEAEVSGGRSGYIAIDDIQVLSYPCDKSPHFLRLGDVEVNAGQNATFQCIATGRDAVHNKLWLQRRNGEDIPVAQTKNINHRRFAASFRLQEVTKTDQDLYRCVTQSERGSGVSNFAQLIVREPPRPIAPPQLLGVGPTYLLIQLNANSIIGDGPIILKEVEYRMTSGSWTETHAVNAPTYKLWHLDPDTEYEIRVLLTRPGEGGTGLPGPPLITRTKCAVHPNVSQGCQGGCATCSDYNGCLSCKPRLFFALERIGMKQIGVCLSSCPSGYYGTRYPDINKCTKCKADCDTCFNKNFCTKCKSGFYLHLGKCLDNCPEGLEANNHTMECVSIVHCEVSEWNPWSPCTKKGKTCGFKRGTETRVREIIQHPSAKGNLCPPTNETRKCTVQRKKCQKGERGKKGRERKRKKPNKGESKEAIPDSKSLESSKEIPEQRENKQQQKKRKVQDKQKSVSVSTVH
Claims (56)
- 膜貫通E3ユビキチナーゼとのRSPO2の相互作用を阻害する、RSPO2に結合する単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO2の相互作用を阻害しない(例えば、LGR4、LGR5、及び/又はLGR6の一以上とのRSPO2の相互作用を増強する)、請求項1に記載の単離された抗体。
- (a)(i)配列番号53のアミノ酸配列を含む超可変領域−L1(HVR−L1);(ii)配列番号54のアミノ酸配列を含むHVR−L2;及び(iii)配列番号55のアミノ酸配列を含むHVR−L3を含む軽鎖可変ドメイン(VL)、及び(b)(i)配列番号56のアミノ酸配列を含むHVR−H1;(ii)配列番号57のアミノ酸配列を含むHVR−H2;及び(iii)配列番号58のアミノ酸配列を含むHVR−H3を含む重鎖可変ドメイン(VH)を含む、RSPO2に結合する単離された抗体。
- (a)配列番号105のVL配列、及び配列番号106のVH配列を含む、請求項3に記載の単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO2の相互作用を阻害する、請求項1に記載の単離された抗体。
- (a)(i)配列番号59のアミノ酸配列を含むHVR−L1、(ii)配列番号60のアミノ酸配列を含むHVR−L2、及び(iii)配列番号61のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号62のアミノ酸配列を含むHVR−H1、(ii)配列番号63のアミノ酸配列を含むHVR−H2、及び(iii)配列番号64のアミノ酸配列を含むHVR−H3を含むVH;
(b)(i)配列番号65のアミノ酸配列を含むHVR−L1、(ii)配列番号66のアミノ酸配列を含むHVR−L2、及び(iii)配列番号67のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号68のアミノ酸配列を含むHVR−H1、(ii)配列番号69のアミノ酸配列を含むHVR−H2、及び(iii)配列番号70のアミノ酸配列を含むHVR−H3を含むVH;又は
(c)(i)配列番号71のアミノ酸配列を含むHVR−L1、(ii)配列番号72のアミノ酸配列を含むHVR−L2、及び(iii)配列番号73のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号74のアミノ酸配列を含むHVR−H1、(ii)配列番号75のアミノ酸配列を含むHVR−H2、及び(iii)配列番号76のアミノ酸配列を含むHVR−H3を含むVH
を含む、RSPO2に結合する単離された抗体。 - (a)配列番号107のVL配列及び配列番号108のVH配列;
(b)配列番号109のVL配列及び配列番号110のVH配列;又は
(c)配列番号111のVL配列及び配列番号112のVH配列
を含む、請求項6に記載の単離された抗体。 - 膜貫通E3ユビキチナーゼとのRSPO3の相互作用を阻害する、RSPO3に結合する単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO3の相互作用を阻害する、請求項8に記載の単離された抗体。
- (a)(i)配列番号5のアミノ酸配列を含むHVR−L1、(ii)配列番号6のアミノ酸配列を含むHVR−L2、及び(iii)配列番号7のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号8のアミノ酸配列を含むHVR−H1、(ii)配列番号9のアミノ酸配列を含むHVR−H2、及び(iii)配列番号10のアミノ酸配列を含むHVR−H3を含むVH;
(b)(i)配列番号11のアミノ酸配列を含むHVR−L1、(ii)配列番号12のアミノ酸配列を含むHVR−L2、及び(iii)配列番号13のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号14のアミノ酸配列を含むHVR−H1、(ii)配列番号15のアミノ酸配列を含むHVR−H2、及び(iii)配列番号16のアミノ酸配列を含むHVR−H3を含むVH;
(c)(i)配列番号17のアミノ酸配列を含むHVR−L1、(ii)配列番号18のアミノ酸配列を含むHVR−L2、及び(iii)配列番号19のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号20のアミノ酸配列を含むHVR−H1、(ii)配列番号21のアミノ酸配列を含むHVR−H2、及び(iii)配列番号22のアミノ酸配列を含むHVR−H3を含むVH;
(d)(i)配列番号23のアミノ酸配列を含むHVR−L1、(ii)配列番号24のアミノ酸配列を含むHVR−L2、及び(iii)配列番号25のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号26のアミノ酸配列を含むHVR−H1、(ii)配列番号27のアミノ酸配列を含むHVR−H2、及び(iii)配列番号28のアミノ酸配列を含むHVR−H3を含むVH;
(e)(i)配列番号29のアミノ酸配列を含むHVR−L1、(ii)配列番号30のアミノ酸配列を含むHVR−L2、及び(iii)配列番号31のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号32のアミノ酸配列を含むHVR−H1、(ii)配列番号33のアミノ酸配列を含むHVR−H2、及び(iii)配列番号34のアミノ酸配列を含むHVR−H3を含むVH;
(f)(i)配列番号35のアミノ酸配列を含むHVR−L1、(ii)配列番号36のアミノ酸配列を含むHVR−L2、及び(iii)配列番号37のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号38のアミノ酸配列を含むHVR−H1、(ii)配列番号39のアミノ酸配列を含むHVR−H2、及び(iii)配列番号40のアミノ酸配列を含むHVR−H3を含むVH;
(g)(i)配列番号41のアミノ酸配列を含むHVR−L1、(ii)配列番号42のアミノ酸配列を含むHVR−L2、及び(iii)配列番号43のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号44のアミノ酸配列を含むHVR−H1、(ii)配列番号45のアミノ酸配列を含むHVR−H2、及び(iii)配列番号46のアミノ酸配列を含むHVR−H3を含むVH;
(h)(i)配列番号23のアミノ酸配列を含むHVR−L1、(ii)配列番号24のアミノ酸配列を含むHVR−L2、及び(iii)配列番号25のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号26のアミノ酸配列を含むHVR−H1、(ii)配列番号27のアミノ酸配列を含むHVR−H2、及び(iii)配列番号188のアミノ酸配列を含むHVR−H3を含むVH;又は
(i)(i)配列番号23のアミノ酸配列を含むHVR−L1、(ii)配列番号24のアミノ酸配列を含むHVR−L2、及び(iii)配列番号25のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号26のアミノ酸配列を含むHVR−H1、(ii)配列番号27のアミノ酸配列を含むHVR−H2、及び(iii)配列番号189のアミノ酸配列を含むHVR−H3を含むVH
を含む、RSPO3に結合する単離された抗体。 - (a)配列番号89のVL配列及び配列番号90のVH配列;
(b)配列番号91のVL配列及び配列番号92のVH配列;
(c)配列番号93のVL配列及び配列番号94のVH配列;
(d)配列番号95のVL配列及び配列番号96のVH配列;
(e)配列番号97のVL配列及び配列番号98のVH配列;
(f)配列番号99のVL配列及び配列番号100のVH配列;
(g)配列番号101のVL配列及び配列番号102のVH配列;
(h)配列番号190のVL配列及び配列番号191のVH配列;
(i)配列番号192のVL配列及び配列番号193のVH配列;
(j)配列番号194のVL配列及び配列番号195のVH配列;
(k)配列番号196のVL配列及び配列番号197のVH配列;
(l)配列番号198のVL配列及び配列番号199のVH配列;
(m)配列番号200のVL配列及び配列番号201のVH配列;
(n)配列番号202のVL配列及び配列番号203のVH配列;
(o)配列番号204のVL配列及び配列番号205のVH配列;
(p)配列番号206のVL配列及び配列番号207のVH配列;
(q)配列番号208のVL配列及び配列番号209のVH配列;
(r)配列番号210のVL配列及び配列番号211のVH配列;
(w)配列番号212のVL配列及び配列番号213のVH配列;又は
(x)配列番号214のVL配列及び配列番号215のVH配列
を含む、請求項10に記載の単離された抗体。 - RSPO2及びRSPO3に結合する単離された抗体。
- 膜貫通E3ユビキチナーゼとのRSPO2及びRSPO3の相互作用を阻害する、請求項12に記載の単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO3の相互作用を阻害する、請求項12又は13に記載の単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO2の相互作用を阻害する、請求項12−14の何れか一項に記載の単離された抗体。
- LGR4、LGR5、及び/又はLGR6の一以上とのRSPO2の相互作用を阻害しない(例えば、LGR4、LGR5、及び/又はLGR6の一以上へのRSPO2の結合を増強する)、請求項12−14の何れか一項に記載の単離された抗体。
- 第一の可変ドメイン及び第二の可変ドメインを含み、ここで、第一の可変ドメインは六つのHVRの第一の組を含み、第二の可変ドメインは六つのHVRの第二の組を含み、ここで、六つのHVRの第一及び第二の組は同一である、請求項12−16の何れか一項に記載の単離された抗体。
- (a)(i)配列番号47のアミノ酸配列を含むHVR−L1、(ii)配列番号48のアミノ酸配列を含むHVR−L2、及び(iii)配列番号49のアミノ酸配列を含むHVR−L3を含むVL;及び(b)(i)配列番号50のアミノ酸配列を含むHVR−H1、(ii)配列番号51のアミノ酸配列を含むHVR−H2、及び(iii)配列番号52のアミノ酸配列を含むHVR−H3を含むVHを含む、RSPO2及びRSPO3に結合する単離された抗体。
- (a)配列番号103のVL配列、及び配列番号104のVH配列を含む、請求項18に記載の単離された抗体。
- 第一の可変ドメイン及び第二の可変ドメインを含み、ここで、第一の可変ドメインは六つのHVRの第一の組を含み、第二の可変ドメインは六つのHVRの第二の組を含み、ここで、六つのHVRの第一及び第二の組は異なる、請求項12−19の何れか一項に記載の単離された抗体。
- 六つのHVRの第一の組は、4H1、4D4、5C2、5D6、5E11、6E9、及び21C2の何れか一の六つのHVRであり、六つのHVRの第二の組は、1A1、11F11、36D2、及び49G5の何れか一の六つのHVRである、請求項12−16及び20の何れか一項に記載の単離された抗体。
- 六つのHVRの第一の組は、4H1、4D4、5C2、5D6、5E11、6E9、及び21C2の何れか一の六つのHVRであり、六つのHVRの第二の組は、1A1の六つのHVRである、請求項21に記載の単離された抗体。
- 膜貫通E3ユビキチナーゼが、ZNRF3及び/又はRNF43である、請求項1、2、5、8、9、13−17、及び20−22の何れか一項に記載の単離された抗体。
- (a)(i)配列番号77のアミノ酸配列を含むHVR−L1、(ii)配列番号78のアミノ酸配列を含むHVR−L2、及び(iii)配列番号79のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号80のアミノ酸配列を含むHVR−H1、(ii)配列番号81のアミノ酸配列を含むHVR−H2、及び(iii)配列番号82のアミノ酸配列を含むHVR−H3を含むVH;
(b)(i)配列番号83のアミノ酸配列を含むHVR−L1、(ii)配列番号84のアミノ酸配列を含むHVR−L2、及び(iii)配列番号85のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号86のアミノ酸配列を含むHVR−H1、(ii)配列番号87のアミノ酸配列を含むHVR−H2、及び(iii)配列番号88のアミノ酸配列を含むHVR−H3を含むVH;又は
(c)(i)配列番号77のアミノ酸配列を含むHVR−L1、(ii)配列番号78のアミノ酸配列を含むHVR−L2、及び(iii)配列番号79のアミノ酸配列を含むHVR−L3を含むVL;及び(i)配列番号80のアミノ酸配列を含むHVR−H1、(ii)配列番号81のアミノ酸配列を含むHVR−H2、及び(iii)配列番号216のアミノ酸配列を含むHVR−H3を含むVH
を含む、RSPO3に結合する単離された抗体。 - RSPO3のアミノ酸47−108内の領域(例えば、49−108)に結合する、RSPO3に結合する単離された抗体。
- RSPO3のアミノ酸残基:Gln72、Pro90、Asp91、及びLys94を含むRSPO3のエピトープに結合する単離された抗体。
- RSPO3のエピトープが、RSPO3のアミノ酸:Asn52、Leu55、Phe63、Gln72、Tyr89、Pro90、Asp91、Lys94、及びLys97を含む、請求項26に記載の単離された抗体。
- RSPO3のエピトープが、RSPO3のアミノ酸残基:Ser49、Asn52、Cys54、Leu55、Ser56、Phe63、Leu65、Gln72、Ile73、Gly74、Tyr84、Tyr89、Pro90、Asp91、Ile92、Lys94、Lys97、及びLys108を含む、請求項27に記載の単離された抗体。
- RSPO3のエピトープが、RSPO3のアミノ酸:Thr47、Leu55、Gln72、Pro90、Asp91、及びLys94を含む、RSPO3のエピトープに結合する単離された抗体。
- RSPO3のエピトープが、RSPO3のアミノ酸:Thr47、Asn52、Leu55、Phe63、Gln72、Tyr89、Pro90、Asp91、Ile92、Lys94、及びLys97を含む、請求項29に記載の抗体。
- RSPO3のエピトープが、RSPO3のアミノ酸残基:Thr47、Asn52、Cys54、Leu55、Ser56、Phe63、Leu65、Gln72、Tyr84、Tyr89、Pro90、Asp91、Ile92、Asn93、Lys94、Lys97、及びLys108を含む、請求項30に記載の単離された抗体。
- RSPO2及び/又はRSPO3媒介性wntシグナル伝達を阻害する、請求項1−31の何れか一項に記載の単離された抗体。
- RSPO2及び/又はRSPO3に結合する抗体断片である、請求項32に記載の単離された抗体。
- モノクローナル抗体である、請求項1−33の何れか一項に記載の抗体。
- ヒト、ヒト化、又はキメラ抗体である、請求項1−34の何れか一項に記載の抗体。
- 完全長IgG1又はIgG2a抗体である、請求項1−35の何れか一項に記載の抗体。
- 請求項1−36の何れか一項に記載の抗体をコードする単離された核酸。
- 請求項37に記載の核酸を含む宿主細胞。
- 抗体が産生されるように、請求項38に記載の宿主細胞を培養することを含む、抗体を産生する方法。
- 宿主細胞から抗体を回収することを更に含む、請求項39に記載の方法。
- 請求項1−36の何れか一項に記載の抗体及び細胞傷害剤を含むイムノコンジュゲート。
- 請求項1−36の何れか一項に記載の抗体及び薬学的に許容可能な担体を含む薬学的製剤。
- 付加的治療剤を更に含む、請求項42に記載の薬学的製剤。
- 医薬として使用のための、請求項1−36の何れか一項に記載の抗体。
- がんの治療において使用のための、請求項1−36の何れか一項に記載の抗体。
- がんが、消化管がん、胃がん、結腸がん、結腸直腸がん、肺がん、又は直腸がんである、請求項45に記載の抗体。
- wntシグナル伝達を阻害すること、血管新生及び/又は脈管形成を阻害すること、及び/又は細胞増殖を阻害することに使用のための、請求項1−36の何れか一項に記載の抗体。
- がんの治療のための医薬の製造における、請求項1−36の何れか一項に記載の抗体の使用。
- がんが、消化管がん、胃がん、結腸がん、結腸直腸がん、肺がん、又は直腸がんである、請求項1−36の何れか一項に記載の抗体の使用。
- wntシグナル伝達を阻害するため、血管新生及び/又は脈管形成を阻害するため、及び/又は細胞増殖を阻害するための医薬の製造における、請求項1−36の何れか一項に記載の抗体の使用。
- 請求項1−36の何れか一項に記載の抗体の有効量を個体に投与することを含む、がんを有する個体を治療する方法。
- がんが、消化管がん、胃がん、結腸がん、結腸直腸がん、肺がん、又は直腸がんである、請求項51に記載の方法。
- 個体に付加的治療剤を投与することを更に含む、請求項51又は52に記載の方法。
- wntシグナル伝達を阻害するため、血管新生及び/又は脈管形成を阻害するため、及び/又は細胞増殖を阻害するために、請求項1−36の何れか一項に記載の抗体の有効量を個体に投与することを含む、個体において、wntシグナル伝達を阻害する、血管新生及び/又は脈管形成を阻害する、及び/又は細胞増殖阻害する方法。
- がんが、基準と比較して、一以上のRSPO(例えば、RSPO2及び/又はRSPO3)の増加した発現によって特徴付けられる、請求項45、46、48、49、及び51−53の何れか一項に記載の抗体、使用又は方法。
- がんが、RSPO転座(例えば、RSPO2転座及び/又はRSPO3転座)によって特徴付けられる、請求項45、46、48、49、及び51−53の何れか一項に記載の抗体、使用又は方法。
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- 2014-10-17 KR KR1020167012644A patent/KR20160070136A/ko unknown
- 2014-10-17 WO PCT/US2014/061215 patent/WO2015058132A2/en active Application Filing
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TWI658052B (zh) | 2019-05-01 |
CN105744954A (zh) | 2016-07-06 |
TW201605899A (zh) | 2016-02-16 |
JP2020096603A (ja) | 2020-06-25 |
CA2925598A1 (en) | 2015-04-23 |
MX2016004802A (es) | 2016-07-18 |
EP3057615A2 (en) | 2016-08-24 |
US20180312579A1 (en) | 2018-11-01 |
WO2015058132A3 (en) | 2015-06-11 |
RU2016114074A3 (ja) | 2018-06-14 |
JP6677638B2 (ja) | 2020-04-08 |
EP3057615B1 (en) | 2021-02-24 |
BR112016008477A2 (pt) | 2017-10-03 |
CN105744954B (zh) | 2021-03-05 |
KR20160070136A (ko) | 2016-06-17 |
US20150147333A1 (en) | 2015-05-28 |
RU2016114074A (ru) | 2017-11-23 |
WO2015058132A2 (en) | 2015-04-23 |
TW201940514A (zh) | 2019-10-16 |
US20200199208A1 (en) | 2020-06-25 |
WO2015058132A9 (en) | 2016-04-28 |
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