JP2018531000A - Cd3結合ポリペプチド - Google Patents
Cd3結合ポリペプチド Download PDFInfo
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Abstract
Description
本出願で電子提出されたテキストファイルの内容は、その全体が参照として本明細書に組み込まれる:配列表のコンピュータ可読フォーマットのコピー(ファイル名:APVO_052_01WO_SeqList_ST25.txt、記録日:2016年9月21日、ファイルサイズ544キロバイト)。
CD3結合分子DRA222の熱安定性を改良するため、ヒト化Cris7抗体の改変変異体であるCris7可変ドメインを、代替的ヒト生殖系列フレームワーク配列を用いてし再ヒト化した。DRA222可変H鎖ドメインは、配列番号87であり、DRA222可変L鎖ドメインは、配列番号90である。Fc DRA222は、時にTSC311またはTSC312(アミノ酸配列は配列番号2;核酸配列は配列番号1)と呼ばれる。親Cris7の抗体の説明として、Reinherz,E.L.et al.(eds.),Leukocyte typing II.,Springer Verlag,New York,(1986)を参照のこと。さらなる変更もまた、親和性及び熱安定性を改良するためになされた。
以下の方法を使用し、この実施例に示される結果を得た。
標準的な精製技術により精製された組換えタンパク質のサーモグラムを、オートサンプラーを備えたGE VPキャピラリーDSC機器で得た。PBS中のそれぞれのサンプル(通常0.5mg/mL)の約550μLを、第2のキャピラリーにおける対照としてPBSを用いて、サンプルキャピラリーに注入した。1℃/分の加熱率で25℃〜130℃の温度で、分析を行った。フィードバックを低く設定し、サンプリング時間は8msを使用した。原物を用いてデータ分析を行った。サンプルサーモグラムを、製剤媒体を用いた以前の緩衝液/緩衝液スキャンを引いて緩衝液の熱容量について修正し、サンプル濃度及びベースライン補正に基づいて正規化した。
ハイスループット形態においては、標準の精製技術により精製された組換えタンパク質のサーモグラムを、リアルタイムPCR機器(Bio−Rad iCycler iQ5)で実行するDSFアッセイにより得た。約40μLの、PBS中濃度0.8mg/mLのそれぞれのサンプルを、5μLの予備希釈したSYPROオレンジダイ(カタログ#S‐6650,Life Technologies)と混合した。融解曲線プロトコールは、温度を25℃から90℃まで、1ステップ当たり0.2℃上昇させるように設定した。575/30X励起フィルター及び620/30M発光フィルターであるテキサスレッド蛍光染料フィルターセットを介して、蛍光信号を収集した。収集した蛍光強度データを、データ分析ソフトウェアPrism6(GraphPad Software,Inc.)へエクスポートした。タンパク質熱Tm値は、温度−d(RUF)/dT2=0に対する蛍光強度の二次微分値が0のときの温度として算出した。
CD3+ジャーカットT細胞株を用いる標準的なフローサイトメトリーに基づく染色法により結合試験を行った。全ての標識及び洗浄は、3%BSA及び2mM EDTAを含む生理食塩水緩衝液中のU底96ウェルプレートで行った。ジャーカット細胞を、200,000細胞/ウェルで播種し、氷上で30分間、50μL容量/ウェルの試験分子濃度の0.1nM〜200nMの範囲でインキュベートした。細胞を3回洗浄し、次いで、蛍光標識された最小交差反応性二次ポリクローナル抗体、F(ab’)2ヤギ抗ヒトIgG(Jackson ImmunoResearch Laboratories)及び生存性色素7‐ADDと共に氷上でさらに30分間インキュベートした。次いで細胞を2回洗浄し、BD LSRIIフローサイトメトリーにおいてサンプルを得た。FlowJoソフトウェアを使用してサンプルファイルを分析した。各ウェルにおけるジャーカット細胞の生きた集団の平均蛍光強度(MFI)を、生細胞(前方対側方散乱、次いで7‐ADD−細胞)上でゲーティングした後に計算した。
アノテート抗体シーケンス、同定フレームワークテンプレート、モデル抗体フレームワーク、及びモデル抗体ループプロトコールを使用して、可変ドメインについてAccelrys Discovery Studio 4.0内で相同性モデルを構築した。また、計算凝集スコアプロトコールを用いて、Accelrys Discovery Studio 4.0内で空間的凝集傾向分析を行った。
標的陽性腫瘍細胞株(MDA−MB−231、Kasumi−2、C4−2B及びラモス細胞株)を全て、与えられたプロトコールに従い培養した。末梢血単核細胞(PBMC)を、標準的なフィコール密度勾配を用いてヒト血液から単離した。単離した細胞を生理食塩水緩衝液内で洗浄した。T細胞を、Pan T細胞アイソレーションキット(catalogue#130−096−535,Miltenyi Biotec,Bergisch Gladbach,Germany)を用いて、製造業者の手順でさらに単離した。単離したT細胞を等分し、液体窒素内で長時間保管した。予備調製したT細胞を、アッセイの1日前に10%ヒト血清を含む暖かいRPMI培地に解凍した。アッセイの間、最終濃度が200pM〜0.01pMである二重特異性分子の濃度を予備調製したT細胞に添加した(約100,000/ウェル)。処置として0.04%のNP‐40を含めることにより、総溶解対照を生成した。
ヘパリンチューブに収集したカニクイザルマカク末梢血を供給業者(Charles River laboratories)から一晩かけて輸送した。受領時、末梢血細胞(PBMC)を、密度分離チューブ(CPTチューブ、Beckton Dickinson)を用いて単離した。血液をCPTチューブに移す前に、生理食塩水緩衝液において1〜1.5に希釈した。CPTチューブを遠心分離し、分離したPBMC個体群を収集し、0.2%BSA及び5nMのEDTAを含む生理食塩水緩衝液で洗浄した。調製物中の残りの赤血球を、アンモニウム‐クロライド‐カリウム赤血球溶解緩衝液を用いて溶解させた。細胞をさらに洗浄して残りの血小板を除去した。
C4‐2B及びラモス細胞株を与えられた手順に従い、両方培養した。末梢血単核細胞(PBMC)を、ヘパリンナトリウム(Cat#362753))を含むBD VACUTAINER(登録商標)CPT(商標)細胞調製チューブを用いて、カニクイザルマカク末梢血から単離した。単離した細胞を生理食塩水緩衝液内で洗浄した。最終濃度が10000pM〜0.0128pMである二重特異性分子の濃度を単離したPBMCに添加した(約100,000)。処置として0.04%のNP‐40を含めることにより、総溶解対照を生成した。
ステップ1:初期ヒト化CD3結合コンストラクトの生成
原則として、改良された熱力学的安定性を有するタンパク質もまた、貯蔵時での凝集に対してより耐性であり、安定性のより低いタンパク質と比較して保存性が上昇するはずである。改良された保存性に相関するTmにおける増加が確認されるかどうかを特定するため、表10に列挙したタンパク質を、25℃で2週間を超えてPBSにおける保存性について評価した。
(無処置の分子のピーク面積)/(総ピーク面積)×100=純度%
保存性と類似して、より高い熱力学的安定性を有する分子もまた、ヒト血清における安定性を改良し得るタンパク質分解に、より耐性であることが多い。これにより、今度は、全体の血清薬物動態及び治療薬の全体の曝露が改良される。
実施例4 タンパク質発現及び品質に対する改良された熱力学的安定性の影響
二重特異性結合分子の安定性及び薬物動態に対する安定化された抗CD3 scFvの効果を試験するため、TSC266(抗PSMA×DRA222 CD3結合ドメインを含む抗CD3二重特異性分子)のPSMA結合ドメインをTSC456抗CD3 scFvを利用する二重特異性分子に導入した。この新規の二重特異性分子をTSC471と呼ぶ。BALB/cマウスに約10mg/kgでTSC266及びTSC471を静脈内投与した。TSC266をPBSに希釈し、一方TSC471を製剤緩衝液に希釈し、これを全ての希釈液(5mMのコハク酸塩、6.5%のスクロース、0.02%のTween80、pH4.8)に使用した。血清を3の動物から10時点で収集した(n=合計30)。時点は、二重特異性分子の投与の15分後、ならびに2、6、24、48、72、96、168,336、及び504時間後であった。大容量を収集するため、末端ブリードを使用した。抗PSMA結合ドメインを捕え、抗CD3結合ドメインを検出するELISA法を用いて血清濃度を決定した。経時的な血清濃度を用いて、非コンパートメント分析(NCA)及びコンパートメント分析により薬物動態(PK)パラメータ推定値を決定した。後期時点からの血清サンプルもまた、それぞれの二重特異性分子+/−ビオチンを用いた標準的な架橋ELISAを用いて抗薬物抗体について試験した。
より安定でないDRA222 CD3結合ドメインまたはより安定なTSC456 CD3結合ドメインのいずれかを含む抗ROR1×抗CD3二重特異性分子の薬物動態を比較した。以下のコンストラクトを評価した。コンストラクトの配列を、表14に示す。
MDA‐MB‐231細胞をドナーT細胞及びマトリゲルと共混合し、試験の0日目にNOD/SCIDマウスの側腹部に移植した。それぞれの群は1のドナーからのT細胞を有するN=5動物を含んだ。図18は、ドナーT細胞による腫瘍増殖に対するT細胞の最小の影響を示す例示的なグラフを示す。動物をPBSまたは30μgもしくは3μgのROR208(DRA222抗CD3結合ドメイン)またはROR209(TSC456抗CD3結合ドメイン)で処置した。0日目、4日目、及び8日目に投与量を投与した。腫瘍増殖は、試験時間の経過とともにキャリパーで測定した。
Kasumi‐2細胞をドナーT細胞及びマトリゲルと共混合し、試験の0日目にNOD/SCIDマウスの側腹部に移植した。それぞれの群は1のドナーからのT細胞を有するN=10動物を含んだ。図19に示すように、動物をPBSまたは30μg、3μgもしくは0.3μgのROR243(TSC456抗CD3結合ドメイン)で処置した。0日目、4日目、及び8日目に投与量を投与した。投与経路は、皮下(SC)投与を行った1群を除いて静脈内(IV)経路であった。図19はアッセイの結果を示す。腫瘍増殖は、試験時間の経過とともにキャリパーで測定した。
Claims (70)
- ヒトCD3に特異的に結合し、かつ免疫グロブリンL鎖可変領域及び免疫グロブリンH鎖可変領域を含むCD3結合ドメインであって;
前記免疫グロブリンL鎖可変領域は、
(a)配列番号88におけるアミノ酸配列と少なくとも約93%同一、少なくとも約95%同一、少なくとも約97%同一、少なくとも約98%同一もしくは少なくとも約99%同一である;または
(b)配列番号89におけるアミノ酸配列と少なくとも約94%同一、少なくとも約95%同一、少なくとも約97%同一、少なくとも約98%同一もしくは少なくとも約99%同一であるアミノ酸配列を含み、;かつ
前記免疫グロブリンH鎖可変領域は、配列番号86におけるアミノ酸配列と少なくとも約82%同一、少なくとも約85%同一、少なくとも約約87%同一、少なくとも約90%同一、少なくとも約92%同一、少なくとも約95%同一、少なくとも約97%同一、少なくとも約98%同一もしくは少なくとも約99%同一であるアミノ酸配列を含む、前記CD3結合ドメイン。 - 配列番号83または配列番号84におけるアミノ酸配列と少なくとも約87%同一、 少なくとも約90%同一、少なくとも約92%同一、少なくとも約95%同一、少なくとも約97%同一、 少なくとも約98%同一もしくは少なくとも約99%同一であるアミノ酸配列を含む、請求項1に記載のCD3結合ドメイン。
- 前記免疫グロブリンL鎖可変領域が、(a)配列番号94のLCDR1アミノ酸配列、配列番号95のLCDR2アミノ酸配列、及び配列番号96のLCDR3アミノ酸配列を含み、前記免疫グロブリンH鎖可変領域が配列番号91のHCDR1アミノ酸配列、配列番号92のHCDR2アミノ酸配列、及び配列番号93のHCDR3アミノ酸配列を含む;または
(b)配列番号202のLCDR1アミノ酸配列、配列番号203のLCDR2アミノ酸配列、及び配列番号204のLCDR3アミノ酸配列を含み、前記免疫グロブリンH鎖可変領域が配列番号199のHCDR1アミノ酸配列、配列番号200のHCDR2アミノ酸配列、及び配列番号201のHCDR3アミノ酸配列を含む、請求項1に記載のCD3結合ドメイン。 - ヒトCD3に特異的に結合し、かつ免疫グロブリンL鎖可変領域及び免疫グロブリンH鎖可変領域を含むCD3結合ドメインであって;
(a)前記免疫グロブリンL鎖可変領域が配列番号94のLCDR1アミノ酸配列、配列番号95のLCDR2アミノ酸配列、及び配列番号96のLCDR3アミノ酸配列を含み、前記免疫グロブリンH鎖可変領域が配列番号91のHCDR1アミノ酸配列、配列番号92のHCDR2アミノ酸配列、及び配列番号93のHCDR3アミノ酸配列を含む;または
(b)前記免疫グロブリンL鎖可変領域が配列番号202のLCDR1アミノ酸配列、配列番号203のLCDR2アミノ酸配列、及び配列番号204のLCDR3アミノ酸配列を含み、前記免疫グロブリンH鎖可変領域が配列番号199のHCDR1アミノ酸配列、配列番号200のHCDR2アミノ酸配列、及び配列番号201のHCDR3アミノ酸配列を含み:かつ
任意の以下の性質:
(i)CD3結合ドメインの熱転移中間点は、少なくとも約54℃、少なくとも約55℃、少なくとも約56℃、または少なくとも約57℃であり得、及び約72℃以下である;
(ii)CD3結合ドメインは約25℃のPBSでの保管において、少なくとも約6日、少なくとも約10日、または少なくとも約13日及び約90日以下にわたり安定的である;
(iii)CD3結合ドメインは、約10nM以下のEC50を有するヒトCD3に結合する;及び
(iv)CD3結合ドメインは、約30nM以下のEC50を有するカニクイザルCD3に結合するの、1以上を有する、前記CD3結合ドメイン。 - 前記免疫グロブリンL鎖可変領域及び前記免疫グロブリンH鎖可変領域は、フレームワーク領域を含み、前記免疫グロブリンL鎖可変領域及び前記免疫グロブリンH鎖可変領域の少なくとも一方はヒト化されている、先行請求項いずれか一項に記載のCD3結合ドメイン。
- 前記免疫グロブリンL鎖可変領域は、ヒトIGKV3D‐20*1生殖系列アミノ酸配列に基づくフレームワーク領域を含む、請求項3〜5のいずれか一項に記載のCD3結合ドメイン。
- 前記免疫グロブリンH鎖可変領域は、ヒトIGHV1‐69*02生殖系列アミノ酸配列に基づくフレームワーク領域を含む、請求項3〜6のいずれか一項に記載のCD3結合ドメイン。
- 前記免疫グロブリンL鎖可変領域の、IMGTナンバリングシステムに従い位置52におけるアミノ酸残基はアルギニンであり、かつ/または前記免疫グロブリンL鎖可変領域の、IMGTナンバリングシステムによる位置53におけるアミノ酸残基はトリプトファンである、先行請求項いずれか一項に記載のCD3結合ドメイン。
- CD3結合ドメインにおける前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムに従い位置27におけるアミノ酸残基はチロシンである、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、以下:
(a)前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置9におけるアミノ酸残基はプロリンである;
(b)前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置53におけるアミノ酸残基はイソロイシンである;及び
(b)前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置21におけるアミノ酸残基はメチオニンであるの1以上を含む、請求項1に記載のCD3結合ドメイン。 - 前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置87におけるアミノ酸残基はチロシンである、請求項1に記載のCD3結合ドメイン。
- 前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置86におけるアミノ酸残基はアスパラギン酸である、請求項1に記載のCD3結合ドメイン。
- 前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置86におけるアミノ酸残基はアスパラギン酸であり、かつ前記免疫グロブリンH鎖可変領域の、IMGTナンバリングシステムによる位置87におけるアミノ酸残基はチロシンである、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、配列番号83または配列番号84を含む、先行請求項のいずれか一項に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、単鎖可変フラグメント(scFv)を含む、先行請求項のいずれか一項に記載のCD3結合ドメイン。
- 前記scFvは、前記scFvのH鎖可変領域とL鎖可変領域との間にリンカーを含み、前記リンカーはアミノ酸配列QRHNNSSLNTGTQMAGHSPNS(配列番号148)を含む、請求項15に記載のCD3結合ドメイン。
- 前記scFvのH鎖可変領域は前記scFvのL鎖可変領域にアミノ末端である、請求項15に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、配列番号90を含むL鎖可変領域及び配列番号87を含むH鎖可変領域を含むCD3結合ドメインの熱安定性と比較する場合、少なくとも約10%増加する熱安定性を有する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインの熱転移中間点(Tm)は、配列番号90を含むL鎖可変領域及び配列番号87を含むH鎖可変領域を含むCD3結合ドメインのTmと比較した場合、少なくとも約3℃、少なくとも約4℃、少なくとも約5℃、または少なくとも約6℃上昇し、約20℃以下上昇する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインの熱転移中間点は、少なくとも約54℃、少なくとも約55℃、少なくとも約56℃、または少なくとも約57℃であり、及び約72℃以下である、請求項1に記載のCD3結合ドメイン。
- 前記熱安定性または熱転移中間点は、示差走査熱量測定もしくは示差走査蛍光定量法により計測される、請求項18〜20のいずれか一項に記載のCD3結合ドメイン。
- 前記CD3結合ドメインが、配列番号90を含むL鎖可変領域及び配列番号87を含むH鎖可変領域を含むCD3結合ドメインの保存性と比較した場合、少なくとも約5%、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、及び約100%以下増加する保存性を有する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインが、PBS中において約25℃で保管される、請求項22に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、PBS中で約25℃での保管において、少なくとも約6日、少なくとも約10日、または少なくとも約13日及び90日以下にわたり安定的である、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは、配列番号90を含むL鎖可変領域及び配列番号87を含むH鎖可変領域を含むCD3結合ドメインの、組換え発現の間に生成される高分子量凝集体のレベルと比較して、少なくとも約5%、少なくとも約10%、少なくとも約20%減少、少なくとも約30%減少、ならびに約50%以下減少した組換え発現の間に生成される高分子量凝集体のレベルを有する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは約10nM以下のEC50を有するヒトCD3に結合する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインが、カニクイザルCD3に特異的に結合する、請求項1に記載のCD3結合ドメイン。
- 前記CD3結合ドメインは約30nM以下のEC50を有するカニクイザルCD3に結合する、請求項27に記載のCD3結合ドメイン。
- 先行請求項のいずれか一項に記載のCD3結合ドメインを含むCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドが免疫グロブリン定常領域を含む、請求項29に記載のCD3結合ポリペプチド。
- T細胞上のCD3タンパク質に結合する場合、前記CD3結合ポリペプチドは、前記T細胞からサイトカイン放出を誘導しないか、またはごくわずかに検出可能なサイトカイン放出を誘導する、請求項29または30に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドがT細胞活性化またはT細胞増殖を誘導する、請求項29〜31のいずれか一項に記載のCD3結合ポリペプチド。
- 第2の結合ドメインをさらに含む、請求項29〜32のいずれか一項に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドは、アミノ末端からカルボキシル末端の順で、(i)前記第2の結合ドメイン、(ii)ヒンジ領域、(iii)免疫グロブリン定常領域、(iv)カルボキシル末端リンカー、及び(v)CD3結合ドメインを含む、請求項33に記載のCD3結合ポリペプチド。
- (i)前記CD3結合ドメインは、(a)LCDR1、LCDR2、及びLCDR3を含む免疫グロブリンL鎖可変領域、ならびに(b)HCDR1、HCDR2、及びHCDR3を含む免疫グロブリンH鎖可変領域を含み;かつ
(ii)前記第2の結合ドメインは、(a)LCDR1、LCDR2、及びLCDR3を含む免疫グロブリンL鎖可変領域、ならびに(b)HCDR1、HCDR2、及びHCDR3を含む免疫グロブリンH鎖可変領域を含む、請求項33または34に記載のCD3結合ポリペプチド。 - 前記ヒンジ領域は、免疫グロブリンヒンジ領域由来である、請求項34または35に記載のCD3結合ポリペプチド。
- 前記カルボキシル末端リンカーは、配列番号196を含むか、またはそれからなる、請求項34〜36のいずれか一項に記載のCD3結合ポリペプチド。
- 前記免疫グロブリン定常領域は、IgG1、IgG2、IgG3、IgG4、IgA1、IgA2またはIgDの免疫グロブリンCH2及びCH3ドメインを含む、請求項27〜37のいずれか一項に記載のCD3結合ポリペプチド。
- 前記免疫グロブリン定常領域は、EUナンバリングシステムに従い、置換L234A、L235A、G237A、及びK322Aを含むヒトIgG1 CH2ドメインを含む、請求項38に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドがリダイレクトT細胞細胞障害性(RTCC)を誘導する、請求項33〜39のいずれか一項に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドは約30nM以下のEC50を有するRTCCを誘導する、請求項40に記載のCD3結合ポリペプチド。
- 前記第2の結合ドメインは、単鎖可変フラグメント(scFv)である、請求項33〜41のいずれか一項に記載のCD3結合ポリペプチド。
- 前記第2の結合ドメインが腫瘍関連抗原に結合するか、または相互作用する、請求項33〜42のいずれか一項に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドは、前記腫瘍関連抗原を発現する細胞のT細胞依存性溶解を誘導する、請求項43に記載のCD3結合ポリペプチド。
- 前記腫瘍関連抗原は、PSMA、CD19、CD20、CD37、CD38、CD123、Her2、ROR1、RON、糖タンパク質A33抗原(gpA33)、及びCEAからなる群から選択される、請求項43に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドが免疫グロブリンヘテロ二量体化ドメインをさらに含む、請求項29〜45のいずれか一項に記載のCD3結合ポリペプチド。
- 前記免疫グロブリンヘテロ二量体化ドメインが、免疫グロブリンCH1ドメインまたは免疫グロブリンCLドメインを含む、請求項46に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドが、(i)アミノ末端からカルボキシル末端またはカルボキシル末端からアミノ末端の順で、(a)特異的にヒトCD3に結合するCD3結合ドメイン、(b)第1のヒンジ領域、(c)第1の免疫グロブリン定常領域、及び(d)第1の免疫グロブリンヘテロ二量体化ドメインを含む第1のポリペプチド鎖;ならびに(ii)アミノ末端からカルボキシル末端またはカルボキシル末端からアミノ末端の順で、(a’)第2のヒンジ領域、(b’)第2の免疫グロブリン定常領域、及び(c’)前記第1の単鎖ポリペプチドの第1の免疫グロブリンヘテロ二量体化ドメインと異なる第2の免疫グロブリンヘテロ二量体化ドメインを含む第2のポリペプチド鎖を含むヘテロ二量体CD3結合タンパク質であり、前記第1及び第2の免疫グロブリンヘテロ二量体化ドメインは互いに関連し、ヘテロ二量体を形成する、請求項29〜47のいずれか一項に記載のCD3結合ポリペプチド。
- 前記第1の免疫グロブリンヘテロ二量体化ドメインは免疫グロブリンCH1ドメインを含み、前記第2の免疫グロブリンヘテロ二量体化ドメインは免疫グロブリンCLドメインを含むか、または前記第1の免疫グロブリンヘテロ二量体化ドメインは免疫グロブリンCLドメインを含み、前記第2の免疫グロブリンヘテロ二量体化ドメインは免疫グロブリンCH1ドメインを含む、請求項48に記載のCD3結合ポリペプチド。
- 前記第1及び第2の免疫グロブリン定常領域の少なくとも一方は、IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgDもしくは任意のそれらの組み合わせの免疫グロブリンCH2及びCH3ドメイン;IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgD、IgE、IgMもしくは任意のそれらの組み合わせの免疫グロブリンCH3ドメイン;またはIgE、IgMもしくは任意のそれらの組み合わせの免疫グロブリンCH3及びCH4ドメインを含む、請求項49に記載のCD3結合ポリペプチド。
- 前記第2のポリペプチド鎖は、第2の結合ドメインをさらに含む、請求項48に記載のCD3結合ポリペプチド。
- 前記第2の結合ドメインは、前記第2のヒンジ領域にアミノ末端である、請求項51に記載のCD3結合ポリペプチド。
- 前記CD3結合ポリペプチドが、CD3結合ドメイン及び第2の結合ドメインを含む二重特異性単鎖抗体分子であり、前記結合ドメインは、VH CD3‐VL CD3‐VH 第2の結合ドメイン‐VL 第2の結合ドメインもしくはVL CD3‐VH CD3‐VH 第2の結合ドメイン‐VL 第2の結合ドメインまたはVH 第2の結合ドメイン‐VL 第2の結合ドメイン‐VH CD3‐VL CD3もしくはVH 第2の結合ドメイン‐VL 第2の結合ドメイン‐VL CD3‐VH CD3の順で配置されている、請求項29〜45のいずれか一項に記載のCD3結合ポリペプチド。
- 請求項1〜28のいずれか一項に記載のCD3結合ドメインもしくは請求項29〜53のいずれか一項に記載のCD3結合ポリペプチドまたは前記CD3結合ドメインもしくはポリペプチドの一部をコードする単離核酸分子。
- 請求項1〜28のいずれか一項に記載のCD3結合ドメインまたは請求項29〜47のいずれか一項に記載のCD3結合ポリペプチドをコードする核酸セグメントを含む発現ベクターであって、前記核酸セグメントは、宿主細胞において前記核酸セグメントの発現に好適な制御配列に作動可能に結合している、前記発現ベクター。
- 請求項55に記載の発現ベクターを含む、組換え宿主細胞。
- 第1及び第2の発現ユニットを含む発現ベクターであって、
前記第1及び第2の発現ユニットは、それぞれ請求項48〜52のいずれか一項に記載のヘテロ二量体CD3結合ポリペプチドの前記1及び第2のポリペプチド鎖をコードする1及び第2の核酸セグメントを含み、
前記1及び第2の核酸セグメントは宿主細胞において前記核酸セグメントの発現に好適な制御配列に作動可能に結合している、前記発現ベクター。 - 請求項57に記載の発現ベクターを含む、組換え宿主細胞。
- CD3結合ポリペプチドの生成方法であって、請求項56に記載の発現ベクターを含む組換え宿主細胞を、核酸セグメントが発現する条件下で培養し、それによりCD3結合ポリペプチドを生成する、前記方法。
- CD3結合ポリペプチドを回収することをさらに含む、請求項59に記載の方法。
- ヘテロ二量体CD3結合タンパク質の生成方法であって、
第1及び第2の発現ユニットを含む発現ベクターを含む組換え宿主細胞を培養することを含み、前記第1及び第2の発現ユニットはそれぞれ、請求項48〜52のいずれか一項に記載のヘテロ二量体CD3結合タンパク質の前記第1及び第2のポリペプチド鎖をコードする第1及び第2の核酸セグメントを含み、前記第1及び第2の核酸セグメントは、宿主細胞中の核酸セグメントの発現に好適な制御配列に、動作可能に結合し、
前記培養は、前記第1及び第2の核酸セグメントが発現し、前記コードされたポリペプチド鎖がヘテロ二量体CD3結合タンパク質として生成される条件下で行われる、前記方法。 - 前記ヘテロ二量体CD3結合タンパク質を回収することをさらに含む、請求項61に記載の方法。
- 請求項29〜53のいずれか一項に記載のCD3結合ポリペプチド及び医薬的に許容される担体、希釈剤、または賦形剤を含む医薬品組成物。
- 腫瘍関連抗原を発現する細胞に対するリダイレクトT細胞細胞障害性(RTCC)を誘導する方法であって、前記腫瘍関連抗原発現細胞を、請求項44〜53のいずれか一項に記載のCD3結合ポリペプチドに接触させることを含み、前記接触は、前記腫瘍関連抗原発現細胞に対するRTCCが誘導される条件下で行われる、前記方法。
- 腫瘍増殖の阻害をそれを必要とする対象において行うための方法であって、治療的有効量の請求項29〜53のいずれか一項に記載のCD3結合ポリペプチドまたは請求項63に記載の組成物を前記対象に投与することを含む、前記方法。
- がんまたは自己免疫異常の治療をそれを必要とする対象において行うための方法であって、治療的有効量の請求項29〜53のいずれか一項に記載のCD3結合ポリペプチドまたは請求項63に記載の医薬品組成物を前記対象に投与することを含む、前記方法。
- 前記がんは、前立腺がん、結腸直腸がん、腎細胞がん、膀胱がん、唾液腺がん、膵がん、卵巣がん、非小細胞肺がん、乳がん(例えば、三種陰性乳がん)、メラノーマ、副腎がん、マントル細胞リンパ腫、急性リンパ性白血病、慢性リンパ性白血病、非ホジキンリンパ腫、急性骨髄性白血病(AML)、Bリンパ球白血病、芽球性形質細胞様樹状細胞腫瘍(BPDCN)、またはヘアリーセル白血病である、請求項66に記載の方法。
- 配列番号4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、または60を含むヒトCD3に特異的に結合するCD3結合ドメイン。
- 2つの同一のポリペプチドの二量体であるCD3結合タンパク質であって、それぞれのポリペプチドは、請求項29〜45のいずれか一項に記載のCD3結合ポリペプチドである、前記CD3結合タンパク質。
- 前記CD3結合ポリペプチドは、抗体依存細胞媒介細胞障害性(ADCC)活性及び/または補体依存細胞障害性(CDC)活性を示さないか、またはごくわずかに示す、請求項29〜53のいずれか一項に記載のCD3結合ポリペプチド。
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KR20180053322A (ko) | 2018-05-21 |
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JP7002446B2 (ja) | 2022-03-04 |
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EA201890613A1 (ru) | 2018-10-31 |
IL258202A (en) | 2018-05-31 |
EP3352760A4 (en) | 2019-03-06 |
CN108367004B (zh) | 2022-09-13 |
IL258202B2 (en) | 2023-02-01 |
AU2016326449A1 (en) | 2018-03-22 |
WO2017053469A3 (en) | 2017-05-04 |
BR112018005573A2 (pt) | 2019-01-22 |
UA126278C2 (uk) | 2022-09-14 |
PH12018500520A1 (en) | 2018-08-29 |
US11352426B2 (en) | 2022-06-07 |
ZA201802440B (en) | 2023-05-31 |
CO2018004094A2 (es) | 2018-07-10 |
US20180273622A1 (en) | 2018-09-27 |
WO2017053469A2 (en) | 2017-03-30 |
MX2018003292A (es) | 2018-08-01 |
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