JP2008510007A - 抗体依存性細胞性細胞傷害活性が増強されたEph受容体Fc変異体 - Google Patents
抗体依存性細胞性細胞傷害活性が増強されたEph受容体Fc変異体 Download PDFInfo
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Abstract
Description
本出願は、以下の米国仮出願番号:60/601,634(2004年8月16日出願)および60/608,852(2004年9月13日出願)の35 U.S.C.§119(e)に従う利益を請求する。優先権出願は、すべての目的のために本明細書にその全文を参照として組み込む。
本発明は、少なくとも1つの抗体結合領域と、本発明の少なくとも1つの新規アミノ酸残基をさらに含むFc領域とを含む新規の抗体を提供する。本発明はまた、少なくとも1つのEph受容体に免疫特異的に結合する可変領域、またはそのフラグメントと、少なくとも1つの高エフェクター機能アミノ酸残基をさらに含むFc領域とを含む新規の抗体に関する。本発明はさらに、そのFc領域に1以上の置換を含む、少なくとも1つのEph受容体に免疫特異的に結合する抗体の新規の変異体に関する。本明細書では、これらの新規の抗体を総称的に「本発明のFc変異体」または「Fc変異体」と呼ぶ。一実施形態では、本発明のFc変異体は、増強されたエフェクター機能を有する。別の実施形態では、本発明のFc変異体は、1以上のFcリガンドに対し、改変された結合親和性を有する。別の実施形態では、本発明のFc変異体は、FcγRIIIAとの結合が増強され、かつ、抗体依存性細胞性細胞傷害(ADCC)を仲介する能力が高められている。別の実施形態では、Fc変異体は、FcγRIIIAとの結合が低減され、ADCC(本明細書では「ADCC活性」と呼ぶ)を仲介する能力が低減されている。さらに別の実施形態では、Fc変異体は、C1qとの結合が増強され、補体依存性細胞傷害(CDC)を仲介する能力が高められている。別の実施形態では、C1qとの結合が低減され、CDCを仲介する能力が低減されている。特に、本発明は、1以上のEph受容体に結合することができるFc変異体に関する。加えて、本発明は、特に治療を目的とする、Fc変異体の適用または使用のための方法およびプロトコルを提供する。具体的には、本方法およびプロトコルは、単独で、あるいは、Eph受容体仲介(および/またはエフリン仲介)および/または関連の疾患および障害もしくは1以上のそれらの症状(限定するものではないが、癌、炎症性疾患および自己免疫疾患など)の治療および/または予防に有用な1以上の他の治療法の投与と組み合わせて、予防または治療に有効な量の1以上のFc変異体を投与することを含む。治療目的で用いるFc変異体は、1成分(例えば、治療薬剤または薬剤)と結合または融合させても、させなくてもよい。本発明の方法は、特に、様々な形態の癌の予防、管理、治療に有用である。本発明はまた、少なくとも1つのEph受容体に免疫特異的に結合する抗体をスクリーニングする方法、ならびに、Fc領域を操作し、これにより、該Fc領域がADCCおよび/またはCDC活性を仲介する能力、および/または1以上のFcリガンドに対する結合親和性をモジュレートする方法も提供する。本発明はまた、少なくとも1つのEph受容体に免疫特異的に結合するFc変異体融合物を作製する方法も提供する。さらに、本発明は、Eph受容体仲介(および/またはエフリン仲介)および/または関連の疾患および障害もしくは1以上のそれらの症状(限定するものではないが、癌、炎症性疾患および自己免疫疾患など)の予防、管理、治療もしくは改善に使用するための医薬製剤およびキットを提供する。
3.1 癌
新生物、すなわち、腫瘍は、異常な非制御細胞増殖によって生じる新生物塊であり、良性および悪性の両方がある。良性腫瘍は一般に局在した状態を維持する。悪性腫瘍は総称的に癌と呼ばれる。「悪性」という用語は、一般に、腫瘍が隣接する身体構造に侵入して、これを破壊し、遠位の部位まで広がって死に至らしめることを意味する(詳しくは、RobbinsおよびAngenll, 1976, Basic Pathology, 第2版、W.B. Saunders Co., フィラデルフィア、pp. 68-122参照)。癌は身体の様々な部位に起こる可能性があり、その起源によって異なる挙動を呈する。癌細胞は、それが発生した身体の部分を破壊した後、身体の他の部分に広がり、そこで新たな増殖を開始し、さらなる破壊を引き起こす。
癌の最も生命を脅かす形態は、腫瘍細胞の集団が身体の遠位および異質部位にコロニー化する能力を獲得するときに発生する。これらの転移細胞は、異なる組織への細胞コロニー化を通常抑制している制限をオーバーライドする(overriding)ことにより、生存する。例えば、典型的な乳房上皮細胞は、肺に移植しても一般に増殖または生存しないが、肺転移は、乳癌罹患および致死の主な原因である。近年の証拠から、身体への転移細胞の播種は、原発性腫瘍の臨床上の出現よりはるかに前に起こりうることが示唆されている。これらの微小転移細胞は、原発性腫瘍の検出および除去後何ヶ月または何年もの間潜伏したままの場合もある。従って、異質微小環境における転移細胞の増殖および生存を可能にする作用機構をよりよく理解することが、転移性癌を克服するために設計した治療法、ならびに、転移の早期発見および位置決定のための診断の改善に重要である。
癌は異常シグナル伝達の疾患である。異常シグナル伝達は、細胞増殖および生存に関する足場依存性制約をオーバーライドする(Rhimら、Critical Reviews in Oncogenesis 8:305, 1997;Patarca, Critical Reviews in Oncogenesis 7:343, 1996;Malikら、Biochimica et Biophysica Acta 1287:73, 1996;Canceら、Breast Cancer Res Treat 35:105, 1995)。チロシンキナーゼ活性は、EMC足場により誘導され、実際に、チロシンキナーゼの発現または機能は通常、悪性細胞で増大する(Rhimら、Critical Reviews in Oncogenesis 8:305, 1997;Canceら、Breast Cancer Res Treat 35:105, 1995;Hunter, Cell 88:333, 1997)。チロシンキナーゼ活性が悪性細胞増殖に必要であるという証拠に基づき、新しい治療法では、チロシンキナーゼが標的とされている(Levitzkiら、Science 267:1782, 1995;Kondapakaら、Molecular & Cellular Endocrinology 117:53, 1996;Fryら、Current Opinion in BioTechnology 6: 662, 1995)。残念なことに、腫瘍細胞の特異的ターゲッティングに伴う障害により、これら薬剤の適用は往々にして制限される。特に、チロシンキナーゼ活性は、良性組織の機能および生存に必要であることが多い(Levitzkiら、Science 267:1782, 1995)。側副毒性を最小限にするため、腫瘍細胞に選択的に過剰発現するチロシンキナーゼを同定し、標的とすることが重要である。
受容体のEphファミリーは、受容体チロシンキナーゼ(RTK)の最大のファミリーである。Eph受容体、ならびにそれらの膜結合エフリンリガンドは、細胞接着、形状および移動性を調節する細胞間連絡の重要なメディエーターである。Eph RTKシグナル伝達事象は、特に神経系において胚発生の様々な面を制御する(詳しくは、Kullanderら、2002, Nat, Rev. Mol. Cell Biol. 3:473およびMamlingら、2002, Trends Biochem Sci 27:514-520参照)。EPHサブファミリーにおける受容体は、典型的に、単一キナーゼドメインと、Cysの豊富なドメインおよび2つのフィブロネクチンIII型反復配列を含む細胞外領域とを有する(図18参照)。エフリン受容体は、その細胞外ドメイン配列、およびエフリンAおよびエフリンBリガンドに結合するその親和性の類似性に基づいて、2つの群に分けられる。エフリン受容体の多くのメンバーは、癌の発生および進行の重要なマーカーおよび/または調節因子として同定されている(例えば、Thakerら、2004, Clin. Cancer Res. 10:5145; Fox BPら、2004, Biochem. Biophys. Res. Commun. 318:882;Nakadaら、2004, Cancer Res. 64:3179;Coffmanら、2003, Cancer Res. 63:7907;また、Dodeletら、2000, Oncogene 19:5614の総説も参照)。癌に関与することが知られるEph受容体のうち、EphA2およびEphA4の役割および発現パターンが最もよく特性決定されているものとして挙げられる。
抗転移薬開発の障害の一つは、これらの薬剤を設計および評価するのに用いられるアッセイシステムであった。最も一般的な癌治療法は、急速に増殖する細胞を標的とすることである。しかし、癌細胞は、必ずしもより迅速に増殖するわけではなく、正常細胞に対しては非許容状態で生存し、増殖する(LawrenceおよびSteeg, 1996, World J. Urol. 14:124-130)。正常および悪性細胞の挙動のこのような基本的相違により、治療ターゲッティングの機会がもたらされる。微小転移腫瘍が身体全体にすでに広がっているというパラダイムは、異質および三次元微小環境に関して潜在的化学療法薬を評価する必要性を強調するものである。多くの標準的癌治療薬アッセイでは、典型的な細胞培養条件下(すなわち、単層増殖)で、腫瘍細胞増殖または生存を測定する。しかし、二次元アッセイでの細胞挙動は、in vivoでの腫瘍細胞挙動について信頼性の高い予測を提供しないことが多い。
抗体は、特定の抗原に結合する免疫タンパク質である。ヒトやマウスを含むほとんどの哺乳動物において、抗体は、対合した重および軽ポリペプチド鎖から構築されている。各々の鎖は、2つの異なる領域から構成され、これらは可変(Fv)領域および定常(Fc)領域と呼ばれる。軽および重鎖Fv領域は、分子の抗原結合決定基を含み、標的抗原の結合を担当する。Fc領域は、抗体(例えば、IgG)のクラス(またはイソタイプ)を決定し、多数の天然タンパク質と結合して、重要な生化学事象を誘発する役割を果たす。
本発明は、免疫グロブリン分子の免疫学的に活性のフラグメントと、本発明の少なくとも1つの新規アミノ酸残基(本明細書では「高エフェクター機能アミノ酸残基」とも呼ぶ)をさらに含むFc領域とを含む新規の抗体を提供する。この新規抗体は、本明細書において「本発明のFc変異体」または「Fc変異体」もしくは「改変抗体」と称する。Fc結合相互作用は、多様なエフェクター機能、ならびに、下流のシグナル伝達事象、限定するものではないが、抗体依存性細胞性細胞傷害(ADCC)および補体依存性細胞傷害(CDC)に必須である。従って、本発明は、本発明の分子と同じアミノ酸配列を有するが、本発明の新規アミノ酸残基を含まない抗体(本明細書では「同等分子」と呼ぶ)、例えば、Fcドメインの対応位置に天然に存在するアミノ酸残基を含む非改変Fc領域を含んでなる抗体と比較して、少なくとも1以上のFcリガンド(例えば、FcγR、C1q)に対する改変された結合親和性を呈示するFc変異体を提供する。加えて、本発明は、1以上のEph受容体に免疫特異的に結合する可変領域、またはそのフラグメントと、少なくとも1つの高エフェクター機能アミノ酸残基を含む新規のFc変異体を提供する。
(後述の図面の簡単な説明を参照のこと。)
本発明は、高エフェクター機能と相関するIgG抗体のFc領域における特定のアミノ酸残基を提供する。さらに、本発明は、Fc受容体であるFcγRIIIAに対し高い結合親和性を呈示する抗体のFc領域における高エフェクター機能残基を提供する。さらに別の実施形態では、本発明は、少なくとも1個の本発明の高エフェクター機能アミノ酸残基の導入であって、FcγRIIB受容体との結合の増大を伴わない、上記導入を包含する。別の実施形態では、本発明は、少なくとも1個の本発明の高エフェクター機能アミノ酸残基を導入することにより、FcγRIIB受容体および/またはC1qとの結合を低下させることを包含する。さらに別の実施形態では、少なくとも1個の本発明の高エフェクター機能アミノ酸残基を導入することにより、FcγRIIIA およびFcγRIIB受容体両方との結合を増大させる。好ましくは、FcγRIIIA/FcγRIIB平衡解離定数(KD)の比を低下させる。さらに、少なくとも1個の本発明の高エフェクター機能アミノ酸残基の存在により、抗体依存性細胞性細胞傷害(ADCC)活性が増強した抗体が得られる。従って、本発明は、本発明の分子と同じアミノ酸配列を有するが、本発明の新規アミノ酸残基を含まない抗体(または他のFcドメイン含有ポリペプチド)(本明細書では「同等分子」と呼ぶ)、例えば、Fcドメインの対応位置に天然に存在するアミノ酸残基を含む非改変Fc領域を含んでなる抗体と比較して、改変されたエフェクター機能(例えば、ADCC、CDCなど)、および/または少なくとも1つのFcリガンド(例えば、FcγRIIIA、FcγRIIB、C1qなど)に対し改変された結合親和性を呈示するFc変異体を提供する。特に、本発明は、少なくとも1つのEph受容体に免疫特異的に結合する可変領域、またはそのフラグメントと、少なくとも1つの高エフェクター機能アミノ酸残基をさらに含むFc領域とを含んでなる新規のFc変異体を提供する。
例示される)、EphB2(ephチロシンキナーゼ3、elk関連チロシンキナーゼ、発生調節eph関連チロシンキナーゼとしても知られ、GenBank受託番号:NP 0059145.1およびNP 004432.2イソ型2aおよび2bによりそれぞれ例示される)、EphB3(ヒト胎児キナーゼ2、EPH様チロシンキナーゼ-2としても知られ、GenBank受託番号:NP 004434.2により例示される)、EphB4(ヘパトーマ膜貫通キナーゼとしても知られ、GenBank受託番号:NP 004435.3により例示される)、ならびにB6(GenBank受託番号:NP 004445.1により例示される)。本発明により考慮されるいくつかのEph受容体ポリペプチドのアラインメントを図18に示す。
04/029207(これらは各々、参照としてその全文を本明細書に組み込む)。
前述したように、本発明は、少なくとも1つのEph受容体に免疫特異的に結合する可変領域と、さらに少なくとも1つの高エフェクター機能アミノ酸残基(例えば、239D、330L、332Eが挙げられ、ここで、残基の番号付けはKabatにより記載されたEU指数によるものである)を含むFc領域とを含んでなるFc変異体を包含する。本発明はさらに、少なくとも1つのEph受容体に免疫特異的に結合し、同等分子と比較して、改変されたADCCおよび/またはCDC活性と、1以上のFcリガンド(例えば、FcγR、C1q)に対し変更された結合親和性とを有する。本発明は具体的に、限定するものではないが、以下のものを含む抗Eph受容体抗体またはそのフラグメントから誘導されたFc変異体を包含する:Eph099B-102.147(ATCC受託番号PTA-4572)、Eph099B-208.261(ATCC受託番号PTA-4573)、Eph099B-210.248(ATCC受託番号PTA-4574)、Eph099B-233.152(ATCC受託番号PTA-5194)、(PCT公開番号WO 03/094859:参照としてその全文を本明細書に組み込む);EA2(ATCC受託番号PTA-4380)、EA3、EA4、EA5(ATCC受託番号PTA-4381)、(PCT公開番号WO 04/014292:参照としてその全文を本明細書に組み込む);LX-13およびscFv(ATCC受託番号PTA-6044)、(米国特許出願番号10/863,729:参照としてその全文を本明細書に組み込む)、および12G3H11(後述)ならびにこれらの類似体、誘導体、もしくは断片。具体的には、本発明のFc変異体は、12G3H11(表3参照)および/または表4に記載した抗体のいずれかに由来する可変領域の全部または一部(例えば、1以上のCDR)を含むものが考えられる。
本発明のFc変異体には、限定するものではないが、合成抗体、モノクローナル抗体、オリゴクローナル抗体、組換えにより作製した抗体、イントラボディー(intrabodies)、多重特異性抗体、二重特異性抗体、ヒト抗体、ヒト化抗体、キメラ抗体、合成抗体、一本鎖FvFc(scFvFc)、一本鎖Fv(scFv)、ならびに抗イディオタイプ(抗Id)抗体が含まれる。特に、本発明に用いる抗体は、免疫グロブリン分子、および免疫グロブリン分子の免疫学的に活性の部分を含む。本発明の抗体は、あらゆるタイプ(例えば、IgG、IgE、IgM、IgD、IgAおよびIgY)、クラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1およびIgA2)もしくはサブクラスの免疫グロブリン分子でよい。
本発明のFc変異体は、変更された(すなわち、任意のタイプの分子を抗体に共有結合させることにより)誘導体を含む。例えば、限定するものではないが、抗体誘導体は、例えば、グリコシル化、アセチル化、ペグ化(pegylation)、リン酸化、アミド化、既知の保護/遮断基による誘導体化、タンパク質分解切断、細胞リガンドまたはその他のタンパク質との結合などにより、変更された抗体を含む。多数の化学的変更のいずれかを周知の技術(限定するものではないが、特異的化学的切断、アセチル化、ホルミル化、ツニカマイシンの代謝合成など)により実施することができる。さらに、誘導体は、1以上の非古典的アミノ酸を含んでいてもよい。
本発明のFc変異体は、抗体を合成するための当分野では周知の任意の方法により、特に、化学的合成または組換え発現方法により作製することができる。
本発明は、Eph受容体に免疫特異的に結合するポリペプチドおよび融合タンパク質を包含する。
変異体Fcドメインを含むFc変異体または融合タンパク質(本明細書では「変異体Fcドメイン融合タンパク質」または「変異体Fcドメイン融合物」と呼ぶ)、その誘導体、類似体もしくはフラグメント(例えば、本発明の抗体の重または軽鎖もしくはその部分、または本発明の一本鎖抗体)の組換え発現は、抗体または融合タンパク質をコードするポリヌクレオチドを含む発現ベクターの構築を必要とする。本発明の抗体、または融合タンパク質の抗体分子もしくは重または軽鎖をコードするポリヌクレオチドを取得したら、抗体または融合タンパク質の作製のためのベクターを、当分野では周知の方法を用いた組換えDNA技術により作製する。従って、抗体または融合タンパク質をコードするヌクレオチド配列を含むポリヌクレオチドの発現によりタンパク質を作製する方法を本明細書に記載する。当業者には周知の方法を用いて、抗体または融合タンパク質をコードする配列、ならびに適切な転写および翻訳制御シグナルを含む発現ベクターを構築することができる。これらの方法として、例えば、in vitro組換えDNA技術、合成技術、およびin vivo遺伝子組換えなどが挙げられる。従って、本発明は、プロモーターに機能的に結合した、本発明のFc変異体または変異体Fc融合物をコードするヌクレオチド配列を含む複製可能なベクターを提供する。このようなベクターとして、抗体分子の定常領域および抗体の可変領域をコードするヌクレオチド配列(例えば、国際公開番号WO 86/05807;国際公開番号WO 89/01036;および米国特許第5,122,464号)があり、また、変異体Fc融合物を作製するためのポリペプチドを全長抗体鎖(例えば、重または軽鎖)または完全変異体Fc融合タンパク質の発現のためのベクターにクローン化することもできる。
本発明は、少なくとも1つのEph受容体のアンタゴニストである本発明のFc変異体、または変異体Fc融合物を包含する。本明細書で用いる用語「アンタゴニスト」とは、Eph受容体のような標的分子の機能、活性および/または発現を阻止、阻害、低減もしくは中和する、あらゆるタンパク質、ポリペプチド、ペプチド、ペプチド模倣物、糖タンパク質、抗体、抗体フラグメント、炭水化物、核酸、有機分子、無機分子、高分子、もしくは小分子を意味する。様々な実施形態で、アンタゴニストは、リン酸緩衝食塩水(PBS)のような対照と比較して、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、もしくは少なくとも99%、別の分子の機能、活性および/または発現を低減する。さらに具体的には、少なくとも1つのEph受容体のアンタゴニストは、少なくとも1つのEph受容体の機能、活性および/または発現を阻害、低減もしくは中和するか、あるいは、少なくとも1つのEph受容体仲介の病因を低減する。
本明細書で用いる「アゴニスト」とは、Eph受容体のような標的分子の1以上の生物学的活性を活性化することができる、あらゆるタンパク質、ポリペプチド、ペプチド、ペプチド模倣物、糖タンパク質、抗体、抗体フラグメント、炭水化物、核酸、有機分子、無機分子、高分子、もしくは小分子を意味する。様々な実施形態において、アゴニストは、リン酸緩衝食塩水(PBS)のような対照と比較して、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、もしくは少なくとも99%、別の分子の機能、活性および/または発現を活性化する。さらに別の様々な実施形態では、アゴニストは、リン酸緩衝食塩水(PBS)のような対照と比較して、少なくとも約10%、少なくとも約15%、少なくとも約20%、少なくとも約25%、少なくとも約30%、少なくとも約35%、少なくとも約40%、少なくとも約45%、少なくとも約50%、少なくとも約55%、少なくとも約60%、少なくとも約65%、少なくとも約70%、少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、もしくは少なくとも約99%、別の分子の機能、活性および/または発現を活性化する。さらに具体的には、少なくとも1つのEph受容体のアゴニストは、少なくとも1つのEph受容体の機能、活性および/または発現を活性化する。具体的には、少なくとも1つのEph受容体を作動する作用により、少なくとも1つのEph受容体が仲介する病因の阻害または低減がもたらされることが考えられる。
1以上の本発明のFc変異体、または変異体Fc融合タンパク質のアンタゴニストおよび/またはアゴニスト効果は、当分野で周知のいずれかの方法により決定することができる。このような方法として、限定するものではないが、後述する方法、ならびに以下の文献に記載されているものがある:PCT公開番号WO 04/014292、WO 03/094859、WO 04/069264、WO 04/028551、WO 03/004057、WO 03/040304、米国特許第5,795,734号、ならびに米国特許出願番号10/770,543、および10/863,729(各々、参照として本明細書にその全文を組み込む)。例えば、Eph受容体活性および/またはEph受容体の血漿濃度の阻害は、Eph受容体の活性および/または発現を測定する当分野で周知のいずれかの方法(限定するものではないが、ウエスタンブロット、ノーザンブロット、RNase保護アッセイ、酵素活性アッセイ、in situハイブリダイゼーション、免疫組織化学、ならびに、免疫細胞化学など)によりアッセイすることができる。さらに具体的には、Fc変異体または変異体Fc融合タンパク質の活性は、Eph受容体との結合、他のEph受容体との交差反応性、Eph受容体リン酸化の阻害または刺激、Eph受容体分解、Eph受容体リガンド(例えば、エフリン)結合を測定することにより決定する。
をインキュベートする。
前述のように、Eph受容体に免疫特異的に結合する薬剤を用いて、血管新生の阻害、Eph受容体仲介の、またはその影響を受ける他の機能、限定するものではないが、細胞増殖、細胞接着、細胞遊走、肉芽組織発生、および/または炎症の阻害が含まれる。従って、本発明は、癌またはその1以上の症状の予防、管理、治療もしくは改善および/または血管新生の阻害を目的とする、少なくとも1つのEph受容体に免疫特異的に結合し、かつ、好ましくはその活性をモジュレートする薬剤の使用に関する。
ンスオリゴヌクレオチド、シグナル伝達阻害剤、シグナル伝達モジュレーター、一本鎖抗原結合タンパク質、シゾフィラン、ソブゾキサン、ナトリウムボロカプテート、フェニル酢酸ナトリウム、ソルベロール、ソマトメジン結合タンパク質、ソネルミン、スパルフォシン酸、スピカマイシンD、スピロムスチン、スプレノペンチン、スポンジスタチン1、スクアラミン、幹細胞阻害剤、幹細胞分裂阻害剤、スチピアミド、ストロメリシン阻害剤、スルフィノシン、過度活性血管作用性腸管ペプチドアンタゴニスト、スラジスタ、スラミン、スワインソニン、合成グリコサミノグリカン、タリムスチン、タモキシフェンメチオジド、タウロムスチン、タキソール、タザロテン、テコガランナトリウム、テガフル、テルラピリリウム、テロメラーゼインヒビター、テモポルフィン、テモゾロミド、テニポシド、テトラクロロデカオキシド、テトラゾミン、タリブラスチン、チオコラリン、チオグアニン、トロンボポイエチン、トロンボポイエチン模倣物、チマルファシン、チモポイエチン受容体アゴニスト、チモトリナン、甲状腺刺激ホルモン、錫エチルエピオプルプリン、チラパザミン、チタノセンビクロリド、トプセンチン、トレミフェン、全能性幹細胞因子、翻訳阻害剤、トレチノイン、トリアセチルウリジン、トリシリビン、トリメトレキセート、トリプトレリン、トロピセトロン、ツロステリド、チロシンキナーゼインヒビター、チルホスチン、UBC阻害剤、ウベニメクス、尿生殖洞由来の成長阻害因子、ウロキナーゼ受容体アンタゴニスト、バプレオチド、バリオリンB、ベクター系、赤血球遺伝子療法薬、ベラレソール、ベラミン、ベルジン、ベルテポルフィン、ビノレルビン、ビンキサルチン、ビタキシン、ボロゾール、ザノテロン、ゼニプラチン、ジラスコルブ、ならびにジノスタチンスチマラマー。別の抗癌薬は5-フルオロウラシルおよびロイコボリンである。
前述のように、本発明は、Eph受容体仲介の疾患(例えば、癌)もしくはその1以上の症状の予防、管理、治療もしくは改善および/または血管新生の阻害を目的とする、1以上のEph受容体に免疫特異的に結合し、好ましくはこれを阻害する薬剤の使用に関する。従って、本発明は、1以上のFcリガンド(例えば、FcγR、C1q)に対する結合親和性が変更され、かつADCCおよび/またはCDC活性が改変された、Eph受容体に免疫特異的に結合する1以上のFc変異体および/または変異体Fc融合タンパク質を含む製剤(例えば、医薬組成物)(本明細書では「本発明の製剤」または簡単に「製剤」とも呼ぶ)を提供する。具体的実施形態では、上記Fc変異体および/またはFc変異体融合タンパク質は、1以上のEph受容体のアンタゴニストである。別の具体的実施形態では、上記Fc変異体および/またはFc変異体融合タンパク質は、1以上のEph受容体のアゴニストである。
用量(mL)=[患者の体重(kg)×用量レベル(mg/kg)/薬剤濃度(mg/mL)]
状態に応じて、製剤を患者に経口、非経口、筋内、鼻内、膣内、直腸、舌、舌下、頬側、口腔内、静脈内、皮膚、皮下および/または経皮投与することができる。
以下に示す実施例を参照にしながら、本発明を説明する。これらの実施例は、説明の目的のために記載するにすぎず、本発明がこれら実施例に限定されると解釈すべきではない。むしろ本発明は、本明細書に記載する教示の結果明らかになるすべての変種を包含すると解釈すべきである。
抗体の新規Fc変異体の構築および発現
Fc- FcγRIIIβ複合体について入手可能な構造に関する情報に基づき、考えられるすべての単一突然変異を組み込む変性オリゴヌクレオチドを用いて、IgG1 Fc部分の推定FcγR接触残基の各々をランダムに突然変異させた。接触残基を4つの領域に分けた(RI:Leu234、Leu235、Gly236、Gly237、Pro238、Ser239;RII:Asp265、Ser267、Glu269;RII:Ser268およびRIV:Ala327、Leu328、Pro329、Ala330、およびIle332)。増幅およびライブラリー構築に用いるプライマーを表5に列挙する。scFv-Fcフォーマットに変換した抗体Vitaxin(商標)のIgG1をこの試験のモデルとして用いた。scFv-Fc を作製するために用いたVitaxin(商標)重および軽鎖の可変領域のDNAおよび対応アミノ酸配列を図1(それぞれパネルAおよびB)に示す。次に、scFv-Fcを鋳型として利用し、Fc領域に単一突然変異を含む3つのFc突然変異ライブラリーを構築する。ライブラリーIは、RI領域にすべての単一突然変異を含み;ライブラリーIIはRIIおよびRIII領域を含み;ライブラリーIIIはRIV領域を含む。オーバーラップPCR手法を用いて、突然変異を含む全Fc領域を合成した。
Fcライブラリーの構築:FcライブラリーIを構築するために、プライマーMDAD-16、MDAD-2〜-6の等モル混合物、およびMDAD-20をPCR反応に用いた。PCR産物をゲル精製し、制限酵素Not I/Pciにより消化し、CMVプロモーターの制御下で発現ベクターpMIに結合させた。FcライブラリーIIを構築するために、RIIおよびRIII突然変異を組み込んだ2つのPCR産物を3:1のモル比で混合して、pMIベクターにクローン化した。プライマーMDAD-16、MDAD-17、MDAD-7〜-9の等モル混合物、およびMDAD-20を用いて、Fc領域を増幅することにより、RII突然変異を組み込み、また、プライマーMDAD-16、-18、-10および-20を用いて、Fc領域を増幅することにより、RIII突然変異を組み込んだ。FcライブラリーIIIについては、プライマーMDAD-16、MDAD-19、MDAD-11〜-15の等モル混合物、およびMDAD-20をPCR反応に用いた。
FcγRIIIAおよびFcγRIIBの細胞外ドメインの構築および発現
Fc変異体とFcγRの結合試験を容易にする目的で、大腸菌におけるストレプトアビジン融合タンパク質としての発現と、哺乳動物細胞における発現のためにFcγRIIIAおよびFcγRIIBの細胞外ドメインをサブクローン化した。分析のために作製したFcγRIIIAは低親和性(F158)アロタイプである。FcγRIIIAおよびFcγRIIBの2つの形態:ストレプトアビジン融合物として作製した「四量体」と、フラグ−タグとして作製した「モノマー」を作製した。
FcγRIIIAおよびFcγRIIBストレプトアビジン融合タンパク質(四量体)の細胞外ドメインの構築と細菌発現:プライマー対SA1/SA2、A1/A2、およびB1/B2(プライマーリストを参照、表5)を用いて、ストレプトアビジンと、FcγRIIIAおよびFcγRIIBの細胞外ドメインをそれぞれPCR増幅した。ヒト骨髄(Clontech)のcDNAライブラリーをFcγRIIIAおよびFcγRIIB増幅の鋳型として用い、Streptomyces avidiniiのゲノムDNAをストレプトアビジン増幅の鋳型として用いた。オーバーラップPCRを用いて、FcγRIIIA−ストレプトアビジンおよびFcγRIIB−ストレプトアビジンの融合遺伝子を集合させた。融合遺伝子を制限酵素Nco I/Nhe Iにより消化し、発現ベクターpET-28aにクローン化した。C. Gaoら(1997, PNAS USA 94:11777-82)に記載されているように、融合タンパク質を封入体として発現させ、透析により再生することにより、ゆっくりと尿素を除去した。再生した融合タンパク質を免疫ビオチンカラム(PIERCE)により、製造者の指示に従って精製した。
Fc変異体の特性決定
Fcドメインの突然変異誘発(前記実施例1参照)後、以下に詳述するように、ELISAにより、scFv-FcフォーマットのFc変異体をFcγRIIIA四量体に対する結合増強についてスクリーニングした。数個のクローンについての結果を図5に示す。加えて、これらクローンのADCC活性をM21細胞に対して決定する。数個のクローンの結果を図6に示す。これらの試験に基づき、さらなる試験のために次の3つの置換を選択した:S239D、A330LおよびI332E。これら置換をインタクトなVitaxin(登録商標)IgG1重鎖のFc領域に導入し、Vitaxin(登録商標)軽鎖と共発現させることにより、全長Vitaxin(登録商標)Fc変異体IgG1分子を作製した。I332E置換を有するVitaxin(登録商標)Fc変異体をVitaxin(登録商標)-1Mと称し、3つの置換S239D、A330LおよびI332Eを有するVitaxin(登録商標)Fc変異体をVitaxin(登録商標)-3Mと称する。
ELISA受容体結合アッセイ:マイクロプレートにプロテインA/G(PIERCE)溶液(0.25μg/ml)をコートし、4℃で一晩インキュベートした。残っている結合部位をすべて4%脱脂乳でブロックした。1ウェル当たり約25μlの突然変異抗体溶液を各ウェルに添加し、37℃で1時間インキュベートした。洗浄後、FcγRIIIA−ストレプトアビジンまたはFcγRIIB−ストレプトアビジン融合タンパク質(1%BSA)を37℃で1時間添加した後、洗浄し、ビオチン結合HRPに30分付した。30μlのテトラメチルベンジジン基質(Pierce)を添加した後、30μlの0.2 M H2SO4で中和した。吸光度を450 nmで測定した。
その他のエピトープを認識する抗体のFc変異体
Vitaxin(登録商標)Fc変異体のADCC活性の顕著な改善を仮定して、12G3H11(12G3と略す)および3F2と称する2つの別の抗体に(I332E)置換を実施するが、これらは共にEphA2チロシン受容体キナーゼと結合する。12G3(図2A)および3F2(図3A)重鎖の可変領域を、前述のように作製した(第7.1および7.3節参照)wtおよび変異体Fcドメインに融合した。Vitaxin(登録商標)の軽鎖の可変領域を、対応する軽鎖可変領域(すなわち、12G3または3F2、例えば、ぞれぞれ図2Bおよび3B参照)で置換し、プラスミドによりインタクトな12G3または3F2抗体をコードした(Vitaxin(登録商標)をコードするプラスミドのマップについては図4を参照)。上記単一置換を含む抗体をそれぞれ12G3-1Mおよび3F2-1Mと称する。加えて、3F2にS239D、A330L、I332L三重置換を作製し、これを3F2-3Mと称する。
12G3および3F2 Fc変異体の作製:12G3および3F2 Fc変異体を作製するために、Xba I/Apa I制限部位(図4のプラスミドマップを参照)を用いて、Vitaxin(登録商標)1Mまたは3M重鎖(VH)の可変領域をコードするDNA配列を12G3または3F2重鎖の可変領域で置換することにより、12G3-1M、3F2-1Mおよび3F2-3M Fc変異体を作製した。また、SmaI/BsiWI制限部位(図4のプラスミドマップを参照)を用いて、Vitaxin(登録商標)軽鎖の可変領域をコードするDNA配列を12G3または3F2軽鎖の可変領域で置換した。12G3重および軽鎖可変領域のヌクレオチド配列をそれぞれ配列番号62および63として記載する。12G3重および軽鎖可変領域のアミノ酸配列をそれぞれ配列番号64および65として記載する。3F2重および軽鎖可変領域のヌクレオチド配列をそれぞれ配列番号66および67として記載する。3F2重および軽鎖可変領域のアミノ酸配列をそれぞれ配列番号68および69として記載する。
Claims (24)
- IgG1 Fc領域を含む抗体であって、該Fc領域が、Kabatに記載されたEU指数によって番号付けされた少なくとも高エフェクター機能アミノ酸残基332Eを含み、ここで、少なくとも高エフェクター機能アミノ酸残基332Eを含む該抗体が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同じ抗体と比較して、1以上のFcγRに対し改変された結合親和性を有する、上記抗体。
- 前記Fc領域が、Kabatに記載されたEU指数によって番号付けされた少なくとも高エフェクター機能アミノ酸残基239Dおよび330Lを含む、請求項1に記載の抗体。
- 前記高エフェクター機能アミノ酸残基が、234E、235R、235A、235W、235P、235V、235Y、236E、239D、265L、269S、269G、298I、298T、298F、327N、327G、327W、328S、328V、329H、329Q、330K、330V、330G、330Y、330T、330L、330I、330R、330C、332E、332H、332S、332W、332F、332D、および332Yからなる群より選択され、ここで、番号付けの方式は、Kabatに記載されたEU指数によるものである、請求項1に記載の抗体。
- 前記1以上のFcγRに対し改変された結合親和性が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同じ抗体と比較して、増加している、請求項1に記載の抗体。
- 前記FcγRがFcγRIIIAである、請求項4に記載の抗体。
- 前記FcγRがFcγRIIBである、請求項4に記載の抗体。
- 前記1以上のFcγRに対し改変された結合親和性が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同じ抗体と比較して、低減している、請求項1に記載の抗体。
- FcγRIIIAに対する結合の平衡解離定数(KD)が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同じ抗体と比較して、少なくとも2分の1に低減している、請求項5に記載の抗体。
- FcγRIIIAに対する結合の平衡解離定数(KD)が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同等の分子と比較して、少なくとも70分の1に低減している、請求項8に記載の抗体。
- 前記FcγRIIIAに対し増加した親和性により、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同等の分子と比較して、増強されたADCC活性をもたらす、請求項5に記載の抗体。
- 前記増強されたADCC活性が、少なくとも高エフェクター機能アミノ酸残基332Eを含まない同じ抗体と比較して、少なくとも2倍高い、請求項10に記載の抗体。
- 前記抗体が、ヒト化抗体、完全ヒト抗体、CDR移植抗体、もしくはキメラ抗体である、請求項1に記載の抗体。
- 前記抗体が、EphA1、EphA2、EphA3a、EphA3b、EphA4、EphA5a、EphA5b、EphA6、EphA7、EphA8、EphB1、EphB2a、EphB2b、EphB3、EphB4およびEphB6からなる群より選択される、少なくとも1つのEph受容体に結合する、請求項12に記載の抗体。
- 前記抗体が、Eph受容体EphA2に結合する、請求項12に記載の抗体。
- 前記抗体が、Eph受容体EphA4に結合する、請求項12に記載の抗体。
- 前記抗体可変配列が、配列番号68および69を含む、請求項12に記載の抗体。
- 前記抗体が、検出可能な剤、治療薬もしくは薬剤と結合している、請求項12に記載の抗体。
- (a)抗体コード領域を単離し;(b)この単離した抗体コード領域の前記Fc領域に1以上の所望の置換を行うことを含む、請求項1に記載の抗体の作製方法。
- 1以上の高エフェクター機能アミノ酸残基を含む前記Fc領域をコードするベクターに、可変領域をサブクローニングすることを含む、請求項1に記載の抗体の作製方法。
- 薬学的に許容される賦形剤に、治療に有効な量の請求項1に記載の抗体を含む製剤。
- 必要とする患者に、請求項20に記載の製剤を投与することにより、癌を改善、治療もしくは予防する方法。
- 前記癌が、頭部、頸部、眼、口、咽喉、食道、胸部、骨、肺、結腸、直腸、結腸直腸、胃、脾、腎臓、骨格筋、皮下組織、転移性黒色腫、子宮内膜、前立腺、乳房、卵巣、精巣、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、膵臓、脳もしくは中枢神経系の癌である、請求項21に記載の方法。
- 前記投与が、経口、非経口、筋内、鼻内、膣内、直腸、舌、舌下、頬側、口腔内、静脈内、皮膚、皮下もしくは経皮投与である、請求項21に記載の方法。
- 他の治療法、例えば、化学療法、ホルモン療法、生物学的療法、免疫療法もしくは放射線療法と組み合わせて、前記製剤を投与することをさらに含む、請求項21に記載の方法。
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PCT/US2005/028839 WO2006023403A2 (en) | 2004-08-16 | 2005-08-15 | Eph receptor fc variants with enhanced antibody dependent cell-mediated cytotoxicity activity |
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JP2007527897A Pending JP2008510007A (ja) | 2004-08-16 | 2005-08-15 | 抗体依存性細胞性細胞傷害活性が増強されたEph受容体Fc変異体 |
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US7659374B2 (en) | 2010-02-09 |
WO2006023420A2 (en) | 2006-03-02 |
AU2005277567A1 (en) | 2006-03-02 |
CA2577370A1 (en) | 2006-03-02 |
CA2577329A1 (en) | 2006-03-02 |
WO2006023403A3 (en) | 2006-08-31 |
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EP1778726A2 (en) | 2007-05-02 |
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EP1784424A2 (en) | 2007-05-16 |
JP2008510008A (ja) | 2008-04-03 |
US20100203045A1 (en) | 2010-08-12 |
WO2006023403A2 (en) | 2006-03-02 |
WO2006023420A3 (en) | 2006-06-29 |
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