JP2022521200A - タンパク質の安定性を決定する方法 - Google Patents
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Abstract
Description
本出願は、本開示の別個の一部として、コンピュータ可読形式の配列表(ファイル名:53583A_SeqListing.txt;270,082バイト-2020年2月19日に作成されたASCIIテキストファイル)を含み、この配列表は、その全体が参照により本明細書に組み込まれる。
本開示の方法は、任意選択的に製剤中での治療用タンパク質に対して熱安定性(Tm)分析を実行する工程を使用する。「熱安定性分析」は、いくつかの物理的パラメータが温度の関数として決定される及び/又は記録される技術を指す。熱安定性は、温度変化に応じたタンパク質の天然構造における立体構造変化(例えば、分解、変性、凝集、又は他の非天然の立体構造)に抵抗する、このタンパク質の属性を指す。
示差走査熱量測定(DSC)は、調節された温度の上昇又は低下内でサンプル中に起こる熱エネルギーの取り込みの直接評価のための熱力学的ツールである。熱力測定は、相転移をモニタリングするために適用される。DSCでは、物質の転移と関連する温度及び熱流量を時間及び温度の関数として決定する熱分析装置を使用して、温度の関数として熱容量が測定される。用語「熱容量」は、単位物質が保持し得るエネルギーの量を指す。熱容量は、温度と共に増加する。
示差走査蛍光量測定(DSF)は、固有の蛍光強度比(350:330nm)の変化を温度の関数として測定する。芳香族アミノ酸残基(トリプトファン、チロシン、及びフェニルアラニン)を含むタンパク質は、固有の蛍光を示す。分子が展開する場合には、この芳香族アミノ酸残基の位置が変化し、その結果、蛍光スペクトルが変化する。DSF分析又はナノDSF分析の最中に、この固有の蛍光強度比(350:330nm)が、連続的に測定されて記録される。この固有の蛍光強度比(又はこの比の一次導関数)の温度の関数としてのプロットにより、DSFサーモグラムが作成される。実行後のデータ解析により、熱変性温度の中間点(Tm)が得られる。DSFから得られた熱変性温度を使用して、タンパク質の熱安定性を評価し得る。
統計的アプローチを使用して、タンパク質の安定性を予測するための熱安定性属性の使用の可能性を評価する。統計学的な仮説検証では、ある試験で定義される有意水準αとは、帰無仮説が真実であると仮定すると、この試験の、この帰無仮説を拒絶する確率のことである。試験の有意水準は、典型的には5%(0.05)に設定される。p値は、帰無仮説の検証の文脈では、統計的有意性の考えを定量するために使用される。p値とは、所与の統計モデルに関する算出された確率のことである。所与の統計モデルの結果(即ち予測)は、p<α(即ちp<0.05)の場合に統計的に有意と見なされる。
「治療用タンパク質」は、治療用の生物活性を示す任意のタンパク質分子を指す。本開示の一実施形態では、この治療用タンパク質分子は、完全長タンパク質である。他の実施形態では、この治療用タンパク質は、完全長タンパク質の活性フラグメントである。本開示の様々な実施形態では、この治療用タンパク質は、その天然の供給源から生成されて精製され得る。或いは、本開示によれば、用語「治療用組換えタンパク質」は、組換えDNA技術により得られた任意の治療用タンパク質を含む。
ムテインは、核酸配列の変異(例えば、置換、欠失、又は挿入)に起因するアミノ酸変化を少なくとも有するタンパク質である。例示的なムテインは、野生型アミノ酸配列に対して少なくとも約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85%、少なくとも約90%、又は約90%超(例えば、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、若しくは約99%)の配列同一性を有するアミノ酸配列を含む。加えて、ムテインは、上記で説明されている融合タンパク質であり得る。
I.小さい脂肪族の非極性か又はわずかに極性の残基:Ala、Ser、Thr、Pro、Gly;
II.極性の負に帯電した残基、並びにそのアミド及びエステル:Asp、Asn、Glu、Gln、システイン酸、及びホモシステイン酸;
III.極性の正に耐電した残基:His、Arg、Lys;オルニチン(Orn)
IV.大きい脂肪族の非極性残基:Met、Leu、Ile、Val、Cys、ノルロイシン(Nle)、ホモシステイン
V.大きい芳香族残基:Phe、Tyr、Trp、アセチルフェニルアラニン。
二重特異性T細胞エンゲージャー(BiTE)分子は、互いに連結された2つの抗体結合ドメイン(又はターゲティング領域)を含む二重特異性抗体コンストラクト又は二重特異性融合タンパク質である。この分子の一方のアームは、細胞傷害性T細胞の表面上で見出されるタンパク質と結合するように操作されており、他方のアームは、主に腫瘍細胞上で見出される特定のタンパク質に結合するように設計されている。両方の標的が関与している場合には、BiTE分子は、細胞傷害性T細胞と腫瘍細胞との間に架橋を形成し、この架橋により、T細胞は、腫瘍細胞を認識して毒性分子の注入により腫瘍細胞と戦い得る。例えば、この分子の腫瘍結合アームを、異なるタイプの癌を標的とする異なるBiTE抗体コンストラクトが作られるように変更し得る。
方法
サイズ排除クロマトグラフィー
サイズ排除クロマトグラフィー(SEC)実験を、Agilent 1100 HPLCシステム、TSK-GEL G3000SWxl、5μm粒径、7.8mm ID×300mm 長さのカラム(Tosoh Biosep)、波長が280nmに設定されたAgilent UV検出器(Agilent;Santa Clara,CA)を使用して実施した。SEC-LSの行程を、移動相として使用される100mMのリン酸カリウム、250mMの塩化カリウム、pH6.8±0.1の緩衝液により室温で実施し、流速は0.5mL/分であった。
示差走査熱量測定(DSC)実験を、MicroCal VP-Capillary DSCシステム(Malvern Panalytical Inc.;Westborough,MA)で実施した。このDSC実験で使用するサンプル濃度は、対応する製剤緩衝液を使用して元のサンプルを希釈することにより、約1mg/mLであった。このサンプルを、60℃/時間の速度で10℃から100℃へと加熱した。プレスキャンは15分であり、フィルタリング期間は10秒であり、フィードバックモードはなしとした。サンプルセル中における吸熱性の熱転移により、シグナルの正の偏向が生じる。データ解析を、MicroCal Origin 7ソフトウェア(OriginLab;Northampton,MA)を使用して実施した。
ナノ示差走査蛍光量測定(nanoDSF)実験を、nanoTemper nanoDSFシステム(Nanotemper;South San Francisco,CA)で実施した。このDSC実験で使用するサンプル濃度は、対応する製剤緩衝液を使用して元のサンプルを希釈することにより、約1mg/mLであった。このサンプルを、60℃/時間の速度で20℃から95℃へと加熱した。データ解析を、PR.ThermControlソフトウェア(Nanotemper)を使用して実施した。
統計解析を、統計ソフトウェアJMP(登録商標)(Cary,North Carolina)を使用して行なった。p値及びレバレッジプロットを、JMPデータ解析から得た。様々な統計結果のレバレッジプロットの典型的な結果を、図1に示す。
熱安定性データから、モノクローナル抗体の安定性が予測される
モノクローナル抗体(mAb-1)を含む製剤を、実施例1で説明されているSEC及びDSC法を使用して分析した。サンプルの情報、並びにSEC及びDSCのデータを、表1に示す。主要ピークは、天然形態のmAb-1からなった。
熱安定性データから、二重特異性T細胞エンゲージャー分子の安定性が予測される
二重特異性T細胞エンゲージャー(BiTE-1)分子の様々な構築物を含む製剤を、実施例1で説明されているSEC及びDSC法を使用して分析した。サンプルの情報を表2に示し、SEC及びDSCのデータを表3に示す。
熱安定性データから、Fc融合タンパク質の安定性が予測される
ムテインFc融合タンパク質(ムテイン-1)を含む製剤を、実施例1で説明されているSEC及びDSC法を使用して分析した。サンプルの情報を表4に示し、SEC及びDSCのデータを表5に示す。
統計的アプローチを使用することにより、SEC法により測定されたタンパク質の安定性を、熱安定性属性(Tm)を使用して統計的に有意に予測し得ることが実証された。SECにより測定されたタンパク質の安定性を予測するために熱安定性属性(Tm)を測定する方法により、医薬品開発での分析中に時間及び資源が大幅に節約される。
Claims (18)
- 治療用タンパク質の安定性を評価する方法であって、前記治療用タンパク質の熱安定性を測定する工程、及び前記治療用タンパク質の熱変性温度Tmと、コントロールタンパク質のTmとを比較する工程を含み、前記コントロールタンパク質のTmと比較した前記治療用タンパク質のTmの上昇は、前記治療用タンパク質の安定性の増加を示し、前記治療用タンパク質のTmは、サイズ排除クロマトグラフィー(SEC)により決定された主要ピーク増減率と統計的有意性で相関する、方法。
- サイズ排除クロマトグラフィー(SEC)により測定した場合に治療用タンパク質の安定性を予測する方法であって、前記治療用タンパク質の熱安定性を測定する工程、及び前記治療用タンパク質の熱変性温度Tmと、コントロールタンパク質のTmとを比較する工程を含み、前記治療用タンパク質のTmは、サイズ排除クロマトグラフィー(SEC)により決定された主要ピーク増減率と統計的有意性で相関する、方法。
- 前記治療用タンパク質のTmは、0.05未満のp値で、SECにより決定された主要ピーク増減率と相関する、請求項1又は2に記載の方法。
- 前記治療用タンパク質のTmは、0.01未満のp値で、SECにより決定された主要ピーク増減率と相関する、請求項1又は2に記載の方法。
- 前記治療用タンパク質のTmは、0.005未満のp値で、SECにより決定された主要ピーク増減率と相関する、請求項1又は2に記載の方法。
- 熱安定性を、示差走査熱量測定(DSC)又は示差走査蛍光量測定(DSF)により測定する、請求項1~5のいずれか一項に記載の方法。
- 前記治療用タンパク質のTm値と、SECにより決定された前記主要ピーク増減率との間の相関関係の統計的有意性を決定する工程をさらに含む、請求項1~6のいずれか一項に記載の方法。
- 統計的有意性を、線形回帰分析又は多項式回帰により決定する、請求項7に記載の方法。
- 前記治療用タンパク質のTm値から、少なくとも6ヶ月の期間にわたる前記治療用タンパク質の安定性が予測される、請求項1~8のいずれか一項に記載の方法。
- 前記治療用タンパク質のTm値から、サイズ排除クロマトグラフィーで測定した場合の治療用タンパク質の前記主要ピーク増減率が予測される、請求項1~9のいずれか一項に記載の方法。
- 前記治療用タンパク質は、モノクローナル抗体又はその断片若しくは誘導体、多重特異性抗体、二重特異性T細胞エンゲージャー(BiTE(登録商標))分子、Fc融合分子、又はムテインである、請求項1~10のいずれか一項に記載の方法。
- 前記モノクローナル抗体は、表Aで表されているものからなる群から選択される、請求項11に記載の方法。
- 前記BiTE分子は、CD33、BCMA、FLT3、CD-19、EGFRvIII、DLL3、及びCD-3の内の1つ又は複数に特異的に結合する、請求項11に記載の方法。
- 前記Fc融合分子又は前記ムテインは、IL-2、IL-7、IL-10、IL-12、IL-15、IL-21、CTLA-4、PD-1、PD-L1、PD-L2、B7-H3、B7-H4、CEACAM-1、TIGIT、LAG3、CD112、CD112R、CD96、TIM3、BTLA、ICOS、OX40、41BB、CD27、GITRに特異的に結合する、請求項11に記載の方法。
- 前記治療用タンパク質は、製剤化されている、請求項1~14のいずれか一項に記載の方法。
- 前記治療用タンパク質は、70mg/mL超の濃度で製剤化されている、請求項15に記載の方法。
- 前記治療用タンパク質は、70mg/ml未満の濃度で製剤化されている、請求項15に記載の方法。
- 前記治療用タンパク質は、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、及び220、並びにこれらの間の全ての増分からなる群から選択されるmg/mLの濃度で存在する、請求項15に記載の方法。
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