JP6495884B2 - 改変抗tgfベータ抗体および抗原結合フラグメント - Google Patents
改変抗tgfベータ抗体および抗原結合フラグメント Download PDFInfo
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Description
本出願は、ASCIIフォーマットで電子的に提出されており、その全体が参照によって組み入れられる配列表を含む。2014年3月7日に作成した前記ASCIIコピーを209262−0001−00−WO−(509735)_SL.txtと命名し、そのサイズは10,335バイトである。
VHドメインは、パラトープ残基の20個以下の置換および非パラトープ残基の20個以下の置換を含み、
VLドメインは、パラトープ残基の20個以下の置換および非パラトープ残基の20個以下の置換を含み、
前記抗体またはその抗原結合フラグメントは、ヒトTGFβ(TGFβ1、TGFβ2およびTGFβ3)に結合することができる。
GC1008抗体の改変VHドメインを含む抗体またはその抗原結合フラグメントとして、全抗体、例えばIgG1、IgG2もしくはIgG4等のIgGまたはその抗原結合フラグメント、例えばF(ab’)2ポリペプチド、scFvポリペプチド、FabポリペプチドもしくはdAbポリペプチドが挙げられるがこれらに限定されない。一価の抗原結合フラグメントとして、Fab、Fv、scFvおよびジ−scFvを挙げることができ、ジ−scFvは、ペプチドリンカーで連結されている2個のscFv分子である。抗原結合フラグメントは、例えばTGFβと別の抗原とを対象とする多価であってもよい。多価フラグメントとしてF(ab’)2およびジ−scFvが挙げられ、ジ−scFvでは、2個のscFv成分が、別々の抗原を対象とする異なる可変ドメインから構成されている。本抗体またはその抗原結合フラグメントは、例えば改変GC1008(全ヒトIgG4抗体)であってもよく、改変GC1008(Fab)(GC1008のFabフラグメント)であってもよく、または改変GC1009(scFv)(GC1008のscFvバージョン)であってもよい。GC1009(scFv)は、ペプチドリンカーで連結されているヒト重鎖PET1073G12 VHドメイン(配列番号1)およびヒト軽鎖PET1073G12 VLドメイン(配列番号2)を含む、組み換えにより産生された抗原結合フラグメントであり、このペプチドリンカーにより、2個のドメインが会合して抗原結合部位になることができる。GC1008およびGC1009は、米国特許第7,723,486号明細書およびGrutter(2008)に更に詳細に開示されている。GC1009(scFv)のアミノ酸配列を下記に記載し、この配列において、(Gly4/Ser)nモチーフのペプチドリンカー(配列番号10)を太字で表すとともにイタリック体で表し、シグナルペプチドを灰色で強調表示する。
本抗体またはその抗原結合の重鎖および/または軽鎖の可変ドメインを組み換えにより改変して、生殖細胞系列配列由来のアミノ酸配列を変更することができる。例えば、重鎖CDRセットにおけるCDRの内の1個もしくはそれ以上を改変してもよいし、軽鎖CDRセットの内の1個もしくはそれ以上のCDRを改変してもよいし、ならびに/またはVHドメインおよび/もしくはVLドメインにおけるフレームワーク領域の内の1個を改変してもよい。パラトープアミノ酸に対して、例えばTGFβアイソフォームに対する結合親和性を強化もしくは弱化する置換を行うことができる、または置換されても結合親和性は比較的未変化のままであってもよい。非パラトープアミノ酸残基に対してその他の置換を行い、抗体またはその抗原結合フラグメントに様々な特性、例えば安定性の向上または共有結合により改変することができるドメイン表面の反応基の導入を付与することができる。従って、本明細書において、本抗体またはその抗原結合フラグメントのVHドメインおよび/またはVLドメインに対するアミノ酸置換の下記の4つのカテゴリー:(1)ヒトTGFβアイソフォームへの選択的結合を付与する置換;(2)3種全てのヒトTGFβアイソフォームへの汎特異的な結合を維持する置換;(3)非パラトープアミノ酸に対する置換;および(4)多重アミノ酸置換が意図される。これらのカテゴリーのアミノ酸置換は互いに排他的ではない。
TGFβアイソフォーム選択的抗体またはその抗原結合フラグメントは、VHドメイン(配列番号1)内にアミノ酸置換を含むことができる。例えば、抗体またはその抗原結合フラグメントは、ヒトTGFβ2およびヒトTGFβ3と比較してヒトTGFβ1に選択的に結合することができる、またはヒトTGFβ1およびヒトTGFβ2と比較してヒトTGFβ3に選択的に結合することができる。1個またはそれ以上のパラトープアミノ酸を置換することにより、選択的結合を実現することができる。
TGFβアイソフォームに対する結合親和性を大きく変更しない置換を行うことができる。TGFβアイソフォームに対する結合親和性を「大きく変更」しない置換により、野生型の解離速度(off−rate)(kd 野生型)に対するバリアントの解離速度(kd バリアント)の比は2.4を超えて増加しない(即ち、kd バリアント/kd 野生型は2.4以下である)。この目的のために「汎特異的な結合」を示す抗体またはその抗原結合フラグメントは、TGFβ(TGFβ1、TGFβ2およびTGFβ3)に対して少なくとも10nM、30nMまたは100nMの見かけ上の結合定数を有することができる。当業界におけるあらゆる適切な技法、例えばGrutter(2008)に開示されているMLEC増殖アッセイまたはBiacore(登録商標)3000(GE Healthcare)結合アッセイを使用して、TGFβアイソフォームに対する親和性を測定することができる。この目的のために「汎特異的な結合」を示す抗体またはその抗原結合
フラグメントは、TGFβ(TGFβ1、TGFβ2およびTGFβ3)に対して、野生型と比較して2.4倍以下の、3倍以下の、5倍以下のまたは10倍以下の見かけ上の結合親和性(kd バリアント:kd 野生型)を有することができ、好ましくは野生型と比較して2.4倍以下の見かけ上の結合親和性(kd バリアント:kd 野生型)を有することができる。この置換を、GC1008/GC1009と3種のTGFβアイソフォームとの間の3種の共結晶構造から導くことができる。Oberlinら(2012)J.Chem.Inf.Model.52:2204〜2214頁を参照されたい。
非パラトープのアミノ酸を組み換えにより置換して、生殖細胞系の可変ドメインと比較して同様のまたは変更された特性を有する可変軽ドメインまたは可変重ドメインを作ることができる。「改変された」可変ドメインはアミノ酸欠失も含み、更に置換も含む。例えば、改変された可変ドメインにおいて、N末端のまたはC末端のアミノ酸置換を欠失させることができる。
抗体またはその抗原結合フラグメントに対して多重アミノ酸置換を行うことができる。一般に、少なくともいくつかの無作為に選択されたアミノ酸置換後に、抗体またはその抗原結合フラグメントは安定性および機能性を維持すると予想される。例えばWells、Biochemistry 29:8509〜17頁(1990)を参照されたい。しかしながら、更なる置換が可変ドメイン中に無作為に導入されることから、例えば、ドメイン全体の安定性が低下する可能性があり、該可変ドメインの凝集する傾向が高まる可能性があり、該可変ドメインのTGFβに対する親和性が増加する可能性があり、および該可変ドメインの考えられる免疫原性が高まる可能性がある。そのため、多重アミノ酸置換を行う場合の好ましい置換は上述した置換から選択され、この置換により、安定性および機能性が維持されると予想される。当業界公知の慣例的な方法を使用して、改変した可変ドメインの機能性を試験することができ、この方法として、Grutter(2008)に開示されているMLEC増殖アッセイが挙げられるがこれに限定されない。
本発明の更なる態様は、本明細書に開示している抗体またはその抗原結合フラグメントをコードする核酸を提供する。単離核酸は、例えば合成DNA、天然には存在しないmRNAまたはcDNAであってもよい。核酸を、プラスミド、ベクターまたは転写カセットもしくは発現カセットに挿入することができる。組み換え宿主細胞は、上記の1種またはそれ以上の構築物を含むことができる。「単離」核酸(または抗体もしくはこの抗原結合フラグメント)をその天然の環境から取り出し、更に実質的に純粋、例えば90%以上の純度にしてもよいし、または均一の形態にしてもよい。
患者に有効量を投与することを含む、ヒト患者の疾患または障害の処置(予防的処置を含むことができる)の方法等のヒトまたは動物の身体の処置または診断の方法で、本抗体またはその抗原結合フラグメントを使用することができる。処置可能な状態として、TGFβが役割を果たすあらゆるもの、例えば線維性疾患、癌、免疫介在性疾患および創傷治癒が挙げられる。
米国特許第7,723,486号の実施例1に開示されている下記の非限定的な実施例に従って、抗TGFβ単鎖Fv(scFv)を調製することができた。変異誘発技法および/またはコンビナトリアル技法を使用して、TGFβ1、TGFβ2および/またはTGFβ3に対する中和力価を高めることができた。米国特許第7,723,486号の実施例1に記載されているファージ抗体ライブラリの選択およびスクリーニングにより、TGFβ1、TGFβ2および/またはTGFβ3に対する力価が改善されたscFvを生成することができた。この実施例で生成されたscFvをMLEC増殖アッセイにおいて1D11.16と比較しており、この1D11.16は米国特許第7,723,486号に開示されている。
米国特許第7,723,486号の実施例4に開示されているTGFβ依存性MLEC増殖アッセイを使用して、抗TGFβ抗体またはその抗原結合フラグメントの中和力価をアッセイすることができた。MLEC増殖アッセイは、Danielpourら、J.Cell.Physiol.、138:79〜86頁(1989)により説明されているアッセイに基づいていた。このアッセイは、ミンク肺上皮細胞に添加したTGFβ1、TGFβ2またはTGFβ3が血清誘導性細胞増殖を阻害するという原理で機能する。細胞増殖の修復を引き起こすTGFβ1、TGFβ2またはTGFβ3の中和に関して抗体を試験した。[3H]−チミジンの取り込みにより増殖を測定した。抗体の力価を、単一の濃度のTGFβ1、TGFβ2またはTGFβ3を50%のレベルで中和する抗体の濃度(IC50、nM)と定義した。
加えて、Biacore(登録商標)3000(GE Healthcare)機器を使用して、GC1008抗体のTGFβアイソフォーム結合親和性を測定した。内製したTGFβ1およびTGFβ2を10mMの酢酸塩(pH4.5)で〜1μg/mLに希釈し、TGFβ3(R&D Systems)を10mMの酢酸塩(pH4.0)で〜2μg/mLに希釈した。GE Healthcareの標準アミンカップリングキットを使用して、CM5センサーチップのフローセル2、3および4に50〜100RUのTGFβ1、TGFβ2およびTGFβ3それぞれを共有結合で固定した。フローセル1を対照表面として使用した。動力学的結合(kinetic binding)を分析するために、GC1008をHBS−EP緩衝液で33.3nM〜1.2nMの1:3に順次希釈し、4個全てのフローセルに5分にわたり3連で注入し、続いて30μL/分の流量の緩衝液で5分解離させた。75μL/分での40mMのHClの2回にわたる30秒の注入により、表面を再生した。BIA Evaluation Software Kit(GE Healthcare)による緩衝液および対照のフローセル屈折率変化の減算後の1:1結合モデルを使用して、各センサーグラムを合わせた。表6に示すKDは、25を超える独立したアッセイの平均である。
米国特許第7,723,486号の実施例7に記載のラット一側尿管閉塞(UUO)モデルを使用して、慢性腎疾患およびその他の臨床的適応症を処置するための抗体またはその抗原結合フラグメントの生物学的効力を測定することができた。体重250〜280g(約6週齢)の成体のスプラーグドーリーラット(Taconic Farms、Germantown、N.Y.)を、空気、温度および光を制御した環境中で飼育した。UUOを実施するラットの腹側正中線に小さい正中切開を施して、左側の腎臓および尿管上部を露出させた。絹の縫合糸を用いて腎臓の下極のレベルで尿管を結紮し、最初の結紮の約0.2cm下で2回目の結紮を行った。偽手術ラットに同じ外科的プロトコルを施したが、尿管を結紮しなかった。
GC1008(Fab)−TGFβ2複合体の構造を下記のようにして決定した。C末端がHis6タグである(配列番号11)組み換えGC1008(Fab)をHEK293FS細胞中で過度的に発現させ、Nickel−NTA親和性樹脂で精製し、続いてサイズ排除クロマトグラフィーで精製した。精製したGC1008(Fab)をTGFβ2ホモ二量体と混合し、この複合体を、サイズ排除クロマトグラフを使用して単離した。GC1008(Fab)−TGFβ2複合体を35% PEG400、100mM 2−(N−モルホリノ)エタンスルホン酸(pH6.0)中において20℃で結晶化させ、播種およびpH最適化により更に最適化した。空間群P21212において2.83Åに最終データセットを収集し、Grutter(2008)に開示されているGC1008(Fab)−TGFβ3構造に置き換えた分子を使用して構造を解いた。GC1008(Fab)−TGFβ2複合体の構造を図1に示す。
GC1009(scFv)−TGFβ1複合体の構造を下記のようにして決定した。C末端がHis6タグである(配列番号11)組み換えGC1009(scFv)を大腸菌(E.coli)中で過剰発現させ、Nickel−NTA親和性樹脂で精製し、続いてサイズ排除クロマトグラフィーで精製した。精製したGC1009(scFv)をTGFβ1ホモ二量体と混合し、この複合体を、サイズ排除クロマトグラフを使用して単離した。GC1009(scFv)−TGFβ1複合体を16% PEG4K、0.1M クエン酸塩(pH5.0)、4% 2−プロパノール中において21℃で結晶化させた。空間群C2において3.00Åに構造を決定し、この構造を、実施例4で決定したGC1008(Fab)−TGFβ2構造に置き換えた分子を使用して解いた。GC1009(scFv)−TGFβ1複合体の構造を図2に示す。
GC1008の重鎖または軽鎖のどちらかをコードするプラスミドを、PCRベース変異誘発反応でのテンプレートとして使用した。コードするDNAの変異を行って、コードされた重鎖アミノ酸配列の155個の単一アミノ酸置換およびコードされた軽鎖アミノ酸配列の1個の単一アミノ酸置換を引き起こした。QuikChange(登録商標)Lightning Site−Directed Mutagenesisキット(Agilent Technologies、Santa Clara CA)を製造業者の説明書に従って使用して、縮重コドン(NNK)により特定のアミノ酸または20種全てのアミノ酸のどちらかに対して設計した1組のフォワードプリマ−およびリバースプライマーを使用してDNA変異を引き起こした。配列決定による確認後、Expi293F(商標)宿主細胞懸濁液(Life Techonologies Corp.、Grand Island、NY)中にトランスフェクトするために、同定した変異体DNAを野生型の軽鎖DANまたは重鎖DNAと対にした。トランスフェクション後4日目に馴化培地(1mL)を回収し、1mLのプロテインA PhyTip(登録商標)カラム(PhyNexus,Inc.、San Jose、CA)およびPureSpeed(商標)12チャンネルピペット(Rainin Instrument LLC、Oakland、CA)を使用して精製した。精製したバリアント抗体サンプルを、100RUレベルのTGFβ1を固定した表面、TGFβ2を固定した表面およびTGFβ3を固定した表面を使用して50nMの濃度でBiacore(登録商標)3000(GE Healthcare)上において2連で分析した。バリアントの解離速度(kd)を野生型対照のkdで割ることにより、kdの倍率変化を得た。(kd バリアント/kd 野生型)が1未満である場合には親和性の増加が示され、この値が1を超える場合には減少が示された。ヒートマップを作成して結果を視覚化した。TGFβに対する親和性を完全に失っているバリアントを、番号なしの黒色で示した。結果を表7A、表7Bおよび表7Cに示す。
Claims (23)
- ヒトTGFβ1、TGFβ2およびTGFβ3に結合し中和することができる単離抗体またはその抗原結合フラグメントであって、前記単離抗体またはその抗原結合フラグメントは、
S30A、S30H、S30W、E74A、E74C、E74D、E74F、E74G、E74H、E74L、E74P、E74Q、E74R、E74S、E74T、E74WおよびE74Yからなる群から選択される置換を有する、配列番号1の配列を含む可変重鎖(VH)ドメイン;および
配列番号2の配列を含む可変軽鎖(VL)ドメイン
を含む、上記単離抗体またはその抗原結合フラグメント。 - 抗体はさらにヒトIgG定常領域を含む、請求項1に記載の単離抗体またはその抗原結合フラグメント。
- IgG定常領域はヒトIgG4定常領域である、請求項2に記載の単離抗体またはその抗原結合フラグメント。
- 抗体はさらにヒトκ定常領域を含む、請求項3に記載の単離抗体またはその抗原結合フラグメント。
- ヒトIgG4定常領域は配列番号3の配列を含み、ヒトκ定常領域は配列番号4の配列を含む、請求項4に記載の単離抗体またはその抗原結合フラグメント。
- 抗原結合フラグメントは、Fab、Fab’、F(ab’)2、scFvまたはジ−s
cFvである、請求項1に記載の単離抗体またはその抗原結合フラグメント。 - 請求項1〜6のいずれか1項に記載の単離抗体またはその抗原結合フラグメントを含む医薬組成物。
- ヒトTGFβ1、TGFβ2およびTGFβ3に結合し中和することができる単離抗体
またはその抗原結合フラグメントの重鎖および軽鎖の両方をコードする単離核酸であって、前記単離抗体またはその抗原結合フラグメントは、
S30A、S30H、S30W、E74A、E74C、E74D、E74F、E74G、E74H、E74L、E74P、E74Q、E74R、E74S、E74T、E74WおよびE74Yからなる群から選択される置換を有する、配列番号1の配列を含む可変重鎖(VH)ドメイン;および
配列番号2の配列を含む可変軽鎖(VL)ドメイン
を含む、上記単離核酸。 - 請求項8に記載の単離核酸を含むベクター。
- 請求項9に記載のベクターを含む宿主細胞。
- 請求項1〜6のいずれか1項に記載の単離抗体またはその抗原結合フラグメントを製造するための方法であって、前記方法は、
抗体またはその抗原結合フラグメントのそれぞれの重鎖および軽鎖をコードする核酸配列を含む宿主細胞を提供すること;および
前記核酸配列の発現を可能にする条件下で宿主細胞を培養すること
を含む、上記方法。 - TGFβ1、β2およびβ3の1つまたはそれ以上を阻害することが必要な患者の治療のための医薬の製造における、請求項1〜6のいずれか1項に記載の単離抗体またはその抗原結合フラグメントの使用。
- 患者は、線維性疾患、癌、または免疫介在性疾患を有している、請求項12に記載の使用。
- 患者は、腎不全を有している、請求項12に記載の使用。
- 患者は、巣状分節性糸球体硬化症を有している、請求項12に記載の使用。
- 患者は、特発性肺線維症を有している、請求項12に記載の使用。
- 患者は、全身性硬化症を有している、請求項12に記載の使用。
- TGFβ1、β2およびβ3の1つまたはそれ以上を阻害することが必要な患者の治療のための、請求項1〜6のいずれか1項に記載の単離抗体またはその抗原結合フラグメントを含む、医薬組成物。
- 患者は、線維性疾患、癌、または免疫介在性疾患を有している、請求項18に記載の医薬組成物。
- 患者は、腎不全を有している、請求項18に記載の医薬組成物。
- 患者は、巣状分節性糸球体硬化症を有している、請求項18に記載の医薬組成物。
- 患者は、特発性肺線維症を有している、請求項18に記載の医薬組成物。
- 患者は、全身性硬化症を有している、請求項18に記載の医薬組成物。
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