JP6463807B2 - TGFβに対する抗体 - Google Patents
TGFβに対する抗体 Download PDFInfo
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- JP6463807B2 JP6463807B2 JP2017148818A JP2017148818A JP6463807B2 JP 6463807 B2 JP6463807 B2 JP 6463807B2 JP 2017148818 A JP2017148818 A JP 2017148818A JP 2017148818 A JP2017148818 A JP 2017148818A JP 6463807 B2 JP6463807 B2 JP 6463807B2
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Description
本発明は、抗体分子、特に、トランスフォーミング増殖因子β(TGFβ)に結合する抗体分子、およびその使用に関する。より具体的には、本発明は、TGFβ1、TGFβ2、およびTGFβ3に結合し、かつ好ましくは中和する抗体分子、いわゆる「汎特異的(pan-specific)」抗体分子、ならびにそのような抗体分子の使用に関する。
TGFβは、1981年に最初に同定された(Roberts et al., 1981)。ヒトでは、3種のアイソフォーム、すなわちTGFβ1、TGFβ2、およびTGFβ3(それぞれ、Swiss Protアクセッション番号P01137、P08112、およびP10600)があり、これらは、生物学的に活性な状態において、鎖間のジスルフィド架橋によって結合された2つの112アミノ酸単量体を含む、25kDaのホモ二量体である。TGFβ1は、TGFβ2と27個のアミノ酸が異なり、かつTGFβ3と22個のアミノ酸が異なり、主に保存的アミノ酸変化である。これらの差異は、X線結晶構造解析によって決定されたTGFβの3次元構造上にマッピングされ(Schlunegger et al.,1992;Peer et al.,1996)、かつ受容体結合領域が定められた(Griffith et al., 1996;Qian et al., 1996)。
本発明の様々な局面において、以下を含む態様の主題が提供される。本発明のさらなる局面および態様は、本明細書における説明において開示される。
HCDR1 SEQ ID NO:3、HCDR2 SEQ ID NO:4、HCDR3 SEQ ID NO:5(本明細書において、「HCDRのPET1073G12セット」と呼ばれる);
HCDR1 SEQ ID NO:13、HCDR2 SEQ ID NO:14、HCDR3 SEQ ID NO:15(本明細書において、「HCDRのPET1074B9セット」と呼ばれる);
HCDR1 SEQ ID NO:23、HCDR2 SEQ ID NO:24、HCDR3 SEQ ID NO:25(本明細書において、「HCDRのPET1287A10セット」と呼ばれる)。
LCDR1 SEQ ID NO:8、LCDR2 SEQ ID NO:9、LCDR3 SEQ ID NO:10(本明細書において、「LCDRのPET1073G12セット」と呼ばれる);
LCDR1 SEQ ID NO:18、LCDR2 SEQ ID NO:19、LCDR3 SEQ ID NO:20(本明細書において、「LCDRのPET1074B9セット」と呼ばれる);
LCDR1 SEQ ID NO:28、LCDR2 SEQ ID NO:29、LCDR3 SEQ ID NO:30(本明細書において、「LCDRのPET1287A10セット」と呼ばれる)。
用語
特異的結合メンバー
この用語は、互いに対する結合特異性を有する一対の分子のメンバーを示す。特異的結合対のメンバーは、天然に由来しても、または、全体的もしくは部分的に合成によって作製されてもよい。分子対の一方のメンバーは、分子対のもう一方のメンバーの表面上の領域またはくぼみに特異的に結合する、表面上の領域またはくぼみを有する。したがって、対のメンバーは、互いに特異的に結合する特性を有している。本発明は、標的抗原に結合する特異的結合メンバーに関係している。
この用語は、ある特異的結合メンバーが、所与の動物に由来するその特異的結合相手以外の分子に対していかなる有意な結合も示さないと考えられる状況を意味するために使用され得る。例えば、ヒトTGFβに特異的な特異的結合メンバーは、他のTGFβ以外のヒト分子には有意な結合を示さないと考えられるが、他の種に由来するTGFβとは交差反応し得る。
この用語は、天然であろうと、部分的または全体的に合成によって作製されようと、免疫グロブリンを示す。この用語はまた、抗体の抗原結合ドメインを含む任意のポリペプチドまたはタンパク質も包含する。抗原結合ドメインを含む抗体断片は、Fab、scFv、Fv、dAb、Fd、およびジアボディ(diabody)などの分子である。
しかしながら、ファージディスプレイによって単離された抗体集団は、単一の抗原に対して単離された場合でさえ、典型的には、広範な生殖系列遺伝子を使用する(Edwards B. et al J. Mol Biol, 334, 103-118, 2003)。
この用語は、結合対、すなわち抗原中の他のメンバーの一部分または全体に接触し、かつそれらに相補的である、抗体分子のような特異的結合メンバーの一部分を示す。抗体分子において、抗原結合部位は、抗体の抗原結合部位と呼ぶことができ、かつ標的抗原の全体または一部分に特異的に結合し、かつそれらに相補的である、抗体の一部分を含む。抗原が大型である場合、抗体は、エピトープと呼ばれる、抗原の特定の部分にしか結合しないことがある。
抗原結合ドメインは、抗原結合部位を含み、かつ標的抗原に結合する、特異的結合メンバーの一部分である。いくつかの態様において、抗原結合ドメインは、1つもしくは複数の抗体可変ドメイン(例えば、VHドメインからなるいわゆるFd抗体断片)またはその抗原結合部分によって提供され得る。いくつかの態様において、抗原結合ドメインは、抗体の軽鎖可変領域(VL)および抗体の重鎖可変領域(VH)を含む。
(a)置換される予定のCDR3を含むか、またはCDR3コード領域を欠くVHドメインをコードしている核酸の出発レパートリーを提供する段階;
(b)HCDR3に関して実質的に本明細書において説明されるアミノ酸配列をコードしているドナー核酸がレパートリー中のCDR3領域中に挿入されて、VHドメインをコードする核酸の生成物レパートリーを提供するように、前記レパートリーを該ドナー核酸と組み合わせる段階;
(c)前記生成物レパートリーの核酸を発現させる段階;
(d)TGFβの少なくとも1種のアイソフォームに特異的な特異的結合メンバーを選択する段階;および
(e)前記特異的結合メンバーまたはそれをコードする核酸を回収する段階。
抗TGFβ ScFvの作製
ScFvのナイーブ抗体ライブラリー
ドナー20名の脾臓リンパ球から誘導され、かつファージミドベクター中にクローニングされた、大型の単鎖Fv(scFv)ヒト抗体ライブラリー(Hutchings et al., 2001)を選択のために使用した。
1D11.16VH-ヒトVLライブラリーを構築し、かつ所望の結合特性を有するマウス-ヒトキメラ抗体を選択するのに使用した。次いで、これらのキメラ抗体に由来するヒト軽鎖を、ヒトVH-VLライブラリーおよびヒトVH(1D11CDR3)-VLアクセプターライブラリー中にクローニングした。これらのライブラリーを、所望の結合特性を有するヒト抗体についてスクリーニングした。
組換えヒトTGFβ1およびTGFβ2は、Genzyme Corp.(Framingham, MA)によって供給され、かつTGFβ3は、R&D Systemsから購入した。
抗TGFβ scFvの最適化
実施例1で説明したようにして、TGFβに結合し、かつ中和するScFvを作製した。TGFβ1および/またはTGFβ2および/またはTGFβ3に対するこれらの抗体の中和力価を、DNA変異誘発および/または組み合わせ技術によって増大させた。本質的に実施例1で説明されているようにして、ファージ抗体ライブラリーを選択およびスクリーニングすることによって、TGFβ1および/またはTGFβ2および/またはTGFβ3に対する力価が有意に改善された抗体を作製した。作製したscFvを、MLEC増殖アッセイ法において1D11.16と比較した。
IgG4の作製
生殖系列化されたPET1073G12、PET1074B9、およびPET1287A10のscFvを、全抗体の重鎖および軽鎖をそれぞれ発現するベクター中にそれらのVHドメインおよびVLドメインをサブクローニングすることによって、scFv型からIgG4型に変換した。VH遺伝子セグメントをscFv発現ベクターpCantab6から増幅させ、かつヒトγ4重鎖の定常ドメイン、および哺乳動物細胞において完全な重鎖を発現させるための調節エレメントを含むpEU8.1(+)ベクター中にクローニングした。同様に、VL遺伝子セグメントをscFv発現ベクターpCantab6から増幅させ、かつヒトκ軽鎖の定常ドメイン、および哺乳動物細胞において完全な軽鎖を発現させるための調節エレメントを含むpEU3.1(-)ベクター中にクローニングした。pEU3.1(-)ベクターおよびpEU8.1(+)ベクターは、Persicら(1987)によって説明されたベクターに基づき、かつ産生される抗体の収量を増加させるためのoriP配列を導入するように改変された(Shen. et al., 1995;Langle-Rouault et al., 1998)。クローニング後、3種すべての抗体のVHドメインおよびVLドメインを配列決定して、クローニング手順の進行中に変異が導入されなかったことを確認した。
TGFβ依存性のMLEC増殖アッセイ法における抗TGFβ抗体の中和力価
ミンク肺上皮細胞(MLEC)増殖アッセイ法を用いて、ヒトTGFβの生物活性に対する、精製した抗体調製物の中和力価を評価した。
MLECの平板培養
MLEC系統をAmerican Type Culture Collectionから得た(カタログ番号CCL-64)。10%FBS(Gibco)、1%ペニシリン/ストレプトマイシン(Gibco)、および1%MEM非必須アミノ酸溶液(Gibco)を含む最小必須培地(MEM、Gibco)中で細胞を増殖させた。T-175フラスコ中のコンフルエントな細胞をフラスコから分離し、遠心沈殿させ、洗浄し、かつ1%FBS、1%ペニシリン/ストレプトマイシン、および1%MEM非必須アミノ酸溶液を含むMEMで作られたMLECアッセイ用培地中に再懸濁した。次いで、細胞のアリコートをトリパンブルーで標識し、血球計算器で計数し、かつアッセイ用培地を用いて、1ml当たり1.75×105細胞の濃度に細胞ストック溶液を希釈した。この懸濁液100μlを平底の96ウェル組織培養プレートの各ウェルに添加し、かつ3〜5時間インキュベートした。
6ng/ml(最終アッセイ濃度の6倍)のTGFβ1、TGFβ2、またはTGFβ3の希釈標準溶液、および最高の最終アッセイ濃度の3倍の(1D11.16のような対照を含む)抗体の希釈標準溶液を、MLECアッセイ用培地中で調製した。アッセイ法におけるTGFβの最終濃度(1ng/mlまたは40pM)は、TGFβを含まない対照と比べて約80%の細胞増殖阻害を誘導する濃度(すなわちEC80値)に相当した。
試験抗体および対照抗体の試料を、MLECアッセイ用培地中で3倍希釈ステップで滴定し、かつTGFβ1、TGFβ2、またはTGFβ3の存在下および不在下でインキュベートした。1D11.16および/または必要に応じて参照抗体を試験し、かつTGFβ1、TGFβ2、もしくはTGFβ3の滴定を実施するすべての実験において、関連するすべての対照が含まれた。完了したプレートは、組織培養用の加湿インキュベーター中に1時間±15分入れておいた。
適切なインキュベーション時間の後、希釈プレートの各ウェルから100μlを平板培養したMLECに移し、かつそれらのプレートをインキュベーターに戻して44±2時間インキュベートした。
10μCi/ml[3H]-チミジン25μl(PBS中で希釈)を各ウェルに添加した(0.25μCi/ウェル)。次いで、プレートをインキュベーターに戻して4時間±30分間インキュベートした。
トリプシン-EDTA(0.25%、Gibco)100μLを各ウェルに添加し、プレートをインキュベーター中で10分間インキュベートし、かつTomtecまたはPackardの96ウェル用細胞回収装置を用いて細胞を回収した。
βプレートリーダー(TopCount、Packard)を用いて、回収した細胞からのデータを読み取った。データを解析して、IC50値および標準偏差値を得た。IC50値は、Prism 2.0(GraphPad)ソフトウェアを用いることによって得た。
精製した、PET1073G12、PET1074B9、およびFET1287A10の生殖系列化されたIgG4を、1D11.16と一緒にMLEC増殖アッセイ法において試験した。IgG4は、実施例3で説明したようにして作製した。IC50の算術平均±標準偏差(IC50は、40pMのTGFβ1、TGFβ2、またはTGFβ3を50%中和するのに必要とされる抗体の濃度である)を表1に示す。
TGFβ3依存性のNHLF細胞アッセイ法における抗TGFβ抗体の力価の中和
正常ヒト肺線維芽細胞(NHLF)フィブロネクチン産生アッセイ法を用いて、ヒトTGFβの生物活性に対する、精製した抗体調製物の中和力価を評価した。このアッセイ法では、抗体が細胞外基質(ECM)の糖タンパク質であるフィブロネクチンの産生を中和する能力を測定する。TGFβは、培養された線維芽細胞におけるフィブロネクチン産生の強力な刺激因子であり(IgnotzおよびMassaoue, 1986)、c-JunのN末端キナーゼ経路の活性化を介してそれらの効果を及ぼす(Hocevar et al., 1999)。
NHLF細胞をClonetics(商標)から入手し、かつ5%CO2を含む37℃の加湿インキュベーター中で、完全な線維芽細胞増殖培地2(FGM-2)中で維持した。90〜100%コンフルエントになった段階で、FGM-2培地1.5ml中に線維芽細胞を播種し(1.5×105個/ウェル、24ウェル型)、かつ37℃で24時間、付着させた。無血清線維芽細胞基本培地(FBM)で細胞を洗浄し、かつヒトインスリン(100μg/ml)、ゲンタマイシン/フンギソン(50μg/ml)、およびアスコルビン酸(50μg/ml)を添加したFBM1.5ml中で一晩、血清飢餓状態にし、かつ37℃で24時間インキュベートした。実験はすべて、3〜6継代の間の細胞に対して実施した。
25ng/ml(1nM)のTGFβ1、TGFβ2、またはTGFβ3の希釈標準溶液、および(1D11.16のような対照を含む)抗体の希釈標準溶液を、アッセイ用培地中で調製した。アッセイ法におけるTGFβの最終濃度(250pg/mlまたは10pM)は、TGFβを含まない対照と比べて約80%のフィブロネクチン産生の刺激を誘導する濃度(すなわちEC80値)に相当した。
試験抗体および対照抗体の試料を、アッセイ用培地中で10倍希釈ステップで順次希釈し、かつTGFβ1、TGFβ2、またはTGFβ3 32の存在下および不在下で30分間プレインキュベートした。NHLF細胞を2ml/ウェルのアッセイ用培地中で、37℃で48時間インキュベートした。48時間後、培地上清の0.5mlのアリコートを、ELISAによるフィブロネクチン解析のために採取した。
ヒト抗フィブロネクチン捕捉モノクローナル抗体(クローン6FN)およびHRP結合型抗フィブロネクチンモノクローナル二次抗体を含むTechnoclone(商標)ヒトフィブロネクチン抗原ELISAキットを用いて、新鮮なNHLF上清試料または凍結した(-20℃)NHLF上清試料を解析した。この方法論は以下のとおりであった。
データは、TGFβアイソフォームに対する供試の対照の応答(100%)に対する百分率として示される。4パラメーターのロジスティック曲線の当てはめを用いて(Prism 2,GraphPad Software, San Diego, USA)、pIC50の幾何平均値および95%信頼限界を推定した。4パラメーターの当てはめが失敗した場合は、曲線の最高値および/または最低値を一定に保つことによって、3パラメーターまたは2パラメーターの当てはめを実施した。
精製した、PET1073G12、PET1074B9、およびPET1287A10の生殖系列化されたIgG4を、1D11.16と一緒にNHLFフィブロネクチン産生アッセイ法において試験した。IgG4は、実施例3で説明したようにして作製した。IC50の算術平均±標準偏差(IC50は、10pMのTGFβ1、TGFβ2、またはTGFβ3を50%中和するのに必要とされる抗体の濃度である)を表2に示す。
IL-11誘導アッセイ法における力価
本発明者らは、A549細胞(ヒト肺上皮癌細胞)IL-11誘導アッセイ法を用いて、ヒトTGFβの生物活性に対する、精製した抗体調製物の中和力価を評価した。
本発明者らは、TGFβ1(1.8ng/ml)、TGFβ2(4.2ng/ml)、またはTGFβ3(4.2ng/ml)、および(対照を含む)抗体の増殖/アッセイ用培地中の希釈標準溶液を調製した。
本発明者らは、試験抗体および対照抗体の試料を、増殖/アッセイ用培地中で、5倍(TGFβ2もしくはTGFβ3)または10倍(TGFβ1)の希釈ステップで順次希釈し、かつTGFβ1、TGFβ2、またはTGFβ3の存在下および不在下、37℃で75分間プレインキュベートした。本発明者らは、37℃で18〜24時間、200μl/ウェルのアッセイ用培地中でA549細胞をインキュベートした。18〜24時間後、培地上清の100μlのアリコートを、ELISAによるIL-11解析のために採取した。
慢性腎疾患、および病原性の線維化を特徴とする他の臨床的適応症を治療するための、TGFβを汎的に中和するヒトモノクローナル抗体の生物学的有効性を判定するために、本発明者らは、一側尿管閉塞(UUO)ラットモデルにおける抗体の効果を研究した。
Claims (12)
- ヒトTGFβ1、TGFβ2、およびTGFβ3に結合する単離された特異的結合メンバーを含む、乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療剤:
ここで、該単離された特異的結合メンバーは、PET1073G12 VHドメイン(SEQ ID NO:2)およびPET1073G12 VLドメイン(SEQ ID NO:7)を含む、抗体の抗原結合部分を含む。 - 該単離された特異的結合メンバーが、さらにヒトIgG4定常領域を含む、請求項1記載の治療剤。
- 該単離された特異的結合メンバーが、さらにヒトIgG1定常領域を含む、請求項1記載の治療剤。
- 該単離された特異的結合メンバーが、さらにヒトκ軽鎖定常領域を含む、請求項1乃至3のいずれか一項記載の治療剤。
- ヒトTGFβ1、TGFβ2、およびTGFβ3に結合する単離された特異的結合メンバーを含む、乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療剤:
ここで、該単離された特異的結合メンバーは、PET1073G12 VHドメイン(SEQ ID NO:2)およびPET1073G12 VLドメイン(SEQ ID NO:7)を含む単離された単鎖Fv分子を含む。 - PET1073G12 VHドメイン(SEQ ID NO:2)およびヒトIgG4定常領域を含む重鎖、ならびにPET1073G12 VLドメイン(SEQ ID NO:7) およびヒトκ軽鎖定常領域を含む軽鎖を含む抗体を含む、乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療剤。
- 乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療のための医薬の製造における、ヒトTGFβ1、TGFβ2、およびTGFβ3に結合する単離された特異的結合メンバーの使用:
ここで、該単離された特異的結合メンバーは、PET1073G12 VHドメイン(SEQ ID NO:2)およびPET1073G12 VLドメイン(SEQ ID NO:7)を含む、抗体の抗原結合部分を含む。 - 該単離された特異的結合メンバーが、さらにヒトIgG4定常領域を含む、請求項7記載の使用。
- 該単離された特異的結合メンバーが、さらにヒトIgG1定常領域を含む、請求項7記載の使用。
- 該単離された特異的結合メンバーが、さらにヒトκ軽鎖定常領域を含む、請求項7乃至9のいずれか一項記載の使用。
- 乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療のための医薬の製造における、ヒトTGFβ1、TGFβ2、およびTGFβ3に結合する単離された特異的結合メンバーの使用:
ここで、該単離された特異的結合メンバーは、PET1073G12 VHドメイン(SEQ ID NO:2)およびPET1073G12 VLドメイン(SEQ ID NO:7)を含む単離された単鎖Fv分子を含む。 - 乳癌、前立腺癌、卵巣癌、胃癌、腎臓癌、膵臓癌、結腸直腸癌、皮膚癌、肺癌、子宮頚癌、膀胱癌、神経膠腫、中皮腫、白血病または肉腫の治療のための医薬の製造における、PET1073G12 VHドメイン(SEQ ID NO:2)およびヒトIgG4定常領域を含む重鎖、ならびにPET1073G12 VLドメイン(SEQ ID NO:7) およびヒトκ軽鎖定常領域を含む軽鎖を含む抗体の使用。
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