JP2022521840A - タンパク質含有製剤を安定化するための組成物および方法 - Google Patents
タンパク質含有製剤を安定化するための組成物および方法 Download PDFInfo
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Abstract
Description
タンパク質の凝集は、主に疎水性相互作用によって引き起こされ、最終的に変性をもたらす。部分的または完全に折り畳まれていないタンパク質の疎水性領域が水にさらされると、通常は埋め込まれている疎水性内部が親水性の水性環境にさらされるため、熱力学的に好ましくない状況が生じる。その結果、疎水性領域の周りの構造化水分子からのエントロピーの減少は、主に露出した疎水性領域を介して、変性タンパク質を凝集させる。したがって、タンパク質の溶解性も損なわれ得る。場合によっては、天然またはミスフォールドしたタンパク質サブユニットの自己会合が、ある特定の条件下で起こり得、これは沈殿および活性の喪失をもたらし得る。
本開示は、ある特定のコール酸塩界面活性剤が治療上有用な製剤中の抗体または他のタンパク質の安定化または凝集を低減するのに有用であるという新規な知見に基づいている。例示的なコール酸塩には、双性イオン性コール酸塩、例えば25℃の水中で約8~10mMまたは0.5~0.6%の臨界ミセル濃度(CMC)を有するCHAPS(3-[(3-コラミドプロピル)ジメチルアンモニオ]-1-プロパンスルホネート)(CAS75621-03-3)、アニオン性コール酸塩、例えばSGH(グリココール酸ナトリウム水和物)(CAS338950-81-5)(25℃の水中でCMC約13mMまたは約0.6%(w/v))、タウロコール酸ナトリウム水和物(STH)(CAS345909-26-4)(25℃の水中でCMC約3~11mMまたは約0.2%~0.6%)およびコール酸ナトリウム水和物(SCH)(25℃の水中でCMC約9~15mMまたは約0.4%~0.7%)、ならびに非イオン性コール酸塩、例えば「BigCHAP」(N,N’-ビス-(3-D-グルコンアミドプロピル)コールアミド)(CAS86303-22-2)(25℃の水中でCMC約2.9~3.4mMまたは約0.26%)が含まれるが、これらに限定されない。いくつかの実施形態では、コール酸塩は、25℃の水中で少なくとも1mM、または少なくとも2mM、または少なくとも0.1%(w/v)、または少なくとも0.2%(w/v)のCMCを有し得る。
本発明の製剤は、多種多様なタンパク質またはポリペプチドと適合性である。
抗体は、典型的には、目的の「抗原」に対して指向する。所与の抗原に「対して指向する」または「特異的に結合する」または「特異的な」抗体は、任意の他のポリペプチドまたはポリペプチドエピトープに実質的に結合することなく、その特定の抗原に結合する抗体である。特定のポリペプチドまたは特定のポリペプチド抗原上のエピトープに「対して指向する」または「特異的に結合する」または「特異的な」抗体は、任意の他のポリペプチドまたはポリペプチドエピトープに実質的に結合することなく、その特定のポリペプチドまたは特定のポリペプチド抗原上のエピトープに結合する抗体である。
Leukocyte Typing III(McMichael編、440頁、Oxford University Press(1987));1H4(Haismaら、Blood 92:184(1998));抗CD20アウリスタチンEコンジュゲート(Seattle Genetics);抗CD20-IL2(EMD/Biovation/City of Hope);抗CD20MAb療法(EpiCyte);抗CD20抗体TRU015(Trubion)。
基本的な4本鎖の抗体ユニットは、2つの同一な軽(L)鎖と2つの同一な重(H)鎖とから構成されるヘテロ四量体糖タンパク質である。IgM抗体は、5つの基本的なヘテロ四量体ユニットと併せて、J鎖と呼ばれる追加のポリペプチドからなり、10個の抗原結合部位を含むが、一方でIgA抗体は、2~5個の基本的な4本鎖ユニットから構成されており、このユニットは、重合してJ鎖と組み合わさった多価集合体を形成することができる。IgGの場合、4本鎖ユニットは、一般に、約150,000ダルトンである。各L鎖は、1つのジスルフィド共有結合によってH鎖に連結されているが、一方で2つのH鎖は、H鎖アイソタイプに応じて1つ以上のジスルフィド結合によって互いに連結されている。H鎖およびL鎖はそれぞれ、規則的に離間した鎖内ジスルフィド架橋も有する。各H鎖は、N末端に可変ドメイン(VH)を有し、続いてαおよびγ鎖のそれぞれについては3つの定常ドメイン(CH)、ならびにμおよびεアイソタイプについては4つのCHドメインを有する。各L鎖は、N末端に可変ドメイン(VL)を有し、続いてその反対側の末端に定常ドメインを有する。VLは、VHと整列しており、CLは、重鎖の第1の定常ドメイン(CH1)と整列している。特定のアミノ酸残基は、軽鎖可変ドメインと重鎖可変ドメインとの間に界面を形成すると考えられている。VHとVLとが一緒に対合することにより、単一の抗原結合部位を形成する。様々なクラスの抗体の構造および特性については、例えば、Basic and Clinical Immunology、第8版、Daniel P.Sties,Abba I.TerrおよびTristram G.Parsolw(編)、Appleton&Lange、Norwalk、Conn.、1994、71頁および第6章を参照されたい。
本明細書の開示は、例えば治療的使用のための特定のタンパク質製剤に関する。本明細書の製剤は、少なくとも1種のタンパク質種および少なくとも1種のコール酸塩界面活性剤を含むが、以下に記載のように、他の賦形剤または成分を含んでもよい。例えば、本明細書の製剤は、薬学的に許容され得る酸または塩基、バッファー、塩、凍結乾燥保護剤(製剤が凍結乾燥される場合)、糖、糖アルコール、アミノ酸、追加のタンパク質種、希釈剤、保存剤、多価金属塩、および場合によっては別の界面活性剤のうちの1つ以上を含み得る。
コール酸塩界面活性剤を含む本明細書のある特定の製剤は、貯蔵またはストレスに供されていない対照溶液と比較して、貯蔵後またはストレス(撹拌または高温貯蔵などの)後に、目に見える凝集体または高分子量種(HMWS)の存在のいずれかで、タンパク質の凝集体の程度の低下を示し得る。
「処置」とは、治療的処置および予防的または防止措置の両方を指す。処置を必要とする者には、障害を既に有する者、および障害を予防するべき者が含まれる。処置には、障害の症状の軽減、対象の生活の質の改善、ならびに障害の安定化、本開示の悪化の予防、治癒、再発のリスクの低減などの対象の任意の緩和または改善が含まれる。
一般的な方法
振盪または撹拌誘発性凝集
この一連の研究では、モノクローナル抗体の緩衝溶液(20mMヒスチジンアセテートまたは200mMアルギニンスクシネートまたは20mM酢酸ナトリウム、pH5.5~5.8)を室温で100rpmのアームシェーカーでの振盪に供した。これらの研究は、15ccガラスバイアルに充填した5mLの抗体溶液を使用して実施した。試料を一定の時間間隔で取り出し、サイズ排除クロマトグラフィー(SEC)を使用してサイズバリアント分布について分析した。コール酸塩のクラスの様々な界面活性剤を、振盪中のタンパク質の凝集を防止するためのそれらの有効性について評価した。界面活性剤は、それぞれの臨界ミセル濃度(CMC)未満またはそれを超える濃度で使用した。
本発明者らはまず、0.05%(w/v)のコール酸塩が、低イオン強度または高イオン強度の製剤条件で、激しい撹拌条件からモノクローナル抗体を保護するのに十分であるかどうかを調べた。本発明者らは、0.05%(w/v)のコール酸塩界面活性剤(CHAPS、SGHまたはSTH)または対照界面活性剤(PS20またはPX188)を、pH5.5の20mMヒスチジンアセテートおよび240mMスクロースの低イオン強度溶液中で1mg/mLの例示的モノクローナル抗体(抗PDL1)またはpH5.8の200mMアルギニンスクシネートの高イオン強度溶液中で1mg/mLの別の例示的モノクローナル抗体(抗トリプターゼ)と混合した。両溶液を15ccガラスバイアル中に、充填体積5mLで充填した。上記成分を含むが界面活性剤は含まない対照溶液も調製し、充填した。溶液を、100rpmのアームシェーカー(Glas-Colベンチトップアームシェーカー)にて、周囲温度で24時間撹拌した。図1および図2に示すように、界面活性剤を含まない対照溶液の撹拌は、目に見える濁った溶液をもたらしたが、他のすべての溶液は視覚的に透明のままであった。
表1-撹拌試験-低イオン強度バッファーに製剤化した抗PDL1抗体-HMWS(%)
表3:撹拌試験-高および低イオン強度バッファーに製剤化された抗トリプターゼ抗体(HMWS(%))(表2も参照)
表4:撹拌試験-高および低イオン強度バッファーに製剤化された抗PDL1抗体-HMWS(%)(表1も参照)
撹拌後の目に見える微粒子を、以下の界面活性剤の濃縮ストック溶液から0.01%、0.025%、または0.05%(w/v)のスパイクインで様々なコール酸塩界面活性剤を含む、低イオン強度製剤(20mMヒスチジンアセテート、240mMスクロース、pH5.5)および高イオン強度製剤(20mMヒスチジンアセテート、272mM NaCl、pH5.5)で1mg/mLの抗タウモノクローナル抗体を含む溶液中で評価した:グリココール酸ナトリウム水和物(SGH)、タウロコール酸ナトリウム水和物(STH)、コール酸ナトリウム水和物(SCH)、デオキシタウロコール酸ナトリウム水和物(SDTH)、デオキシコール酸ナトリウム水和物(SDCH)、ケノデオキシコール酸ナトリウム水和物(SCDCH)、CHAPS、およびBigCHAP。すべての製剤をヒスチジンアセテートバッファーを使用して調製し、高イオン強度製剤をアルギニンスクシネートの代わりに塩化ナトリウムを使用して調製した。これは、バッファー種を同じに保つためである。目的は、イオン強度が実際にHMWS形成を防止する役割を果たすが、製剤に使用されるバッファー種(例えば、アルギニン)は防止しないかどうかを理解することである。
表5:撹拌試験-低イオン強度バッファーに製剤化された抗タウ-目に見える微粒子の分析
表6:撹拌試験-高イオン強度バッファーに製剤化された抗タウ-目に見える微粒子の分析
表7:撹拌試験-低イオン強度バッファーに製剤化された抗タウ
-HMWS(%)
表8:撹拌試験-高イオン強度バッファーに製剤化された抗タウ
-HMWS(%)
抗体電荷バリアント分布を、画像化キャピラリー等電点電気泳動(iCIEF)を使用して実施例2に記載の撹拌実験に従って評価し、コール酸塩が試験された抗体の相対電荷バリアント分布に影響を及ぼすかどうかを判定した。以下の表9および表10に示す結果は、撹拌後に電荷バリアント分布が維持されたこと、およびコール酸塩は、それらが荷電種であるにもかかわらず、抗体の電荷不均一性を変化させなかったことを示す。抗PDL1(1mg/mL)を、20mMヒスチジンアセテートpH5.5の低イオン強度バッファー(表9)中で0.05%の界面活性剤と共にインキュベートした。抗トリプターゼ(1mg/mL)を、200mMアルギニンスクシネートpH5.8の高イオン強度バッファー(表10)中で0.05%の界面活性剤と共にインキュベートした。
表9:撹拌試験-低イオン強度バッファーに製剤化された抗PDL1-電荷バリアントアッセイ結果(icIEF)
表10:撹拌試験-低イオン強度バッファーに製剤化された抗トリプターゼ-電荷バリアントアッセイ結果(icIEF)
*これは予想外の変化または値であり、アッセイのアーチファクトである可能性がある
コール酸塩がPS20含有タンパク質溶液を安定化できるかどうかをさらに試験するために、本発明者らは、PS20を含有するタンパク質溶液にCHAPSまたはSGHのいずれかを添加し、溶液を40℃で2週間の熱ストレスに供した。試料を0日目(D0)、D7およびD14に取り出し、インタクトなPS20 HPLC-ELSD定量法を使用して試験した。以下の2つのモノクローナル抗体をそれらのベース製剤で試験した:20mM酢酸ナトリウムpH5.5中の30mg/mL抗PDL1および200mMアルギニンスクシネートpH5.8中の抗トリプターゼ。界面活性剤スパイクイン設定および抗PDL1および抗トリプターゼ抗体を使用した試験の結果を表11に示す。
表11:抗体溶液に共製剤化された界面活性剤-40℃で2週間の熱ストレス
Claims (41)
- タンパク質、および25℃の水中で2.0mM以上または0.2%(w/v)以上の臨界ミセル濃度(CMC)値を有する少なくとも1種のコール酸塩界面活性剤を含む、タンパク質製剤。
- 前記タンパク質が抗体である、請求項1に記載の製剤。
- 前記抗体がモノクローナル抗体である、請求項2に記載の製剤。
- 前記コール酸塩界面活性剤が、双性イオン性、非イオン性、アニオン性であるか、またはCHAPS(3-[(3-コラミドプロピル)ジメチルアンモニオ]-1-プロパンスルホネート)、SGH(グリココール酸ナトリウム水和物)、タウロコール酸ナトリウム水和物(STH)、コール酸ナトリウム水和物(SCH)、SdTH、SdCH、ScdCHおよびBigCHAP(N,N’-ビス-(3-D-グルコンアミドプロピル)コールアミド)から選択される、請求項1から3のいずれか一項に記載の製剤。
- 0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)でCHAPSを含む、請求項4に記載の製剤。
- 0.025%~0.05%(w/v)の濃度でCHAPSを含む、請求項5に記載の製剤。
- 0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)でBigCHAPを含む、請求項4に記載の製剤。
- 0.025%~0.05%(w/v)の濃度でBigCHAPを含む、請求項7に記載の製剤。
- 0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)でSGH、STH、またはSCHを含む、請求項4に記載の製剤。
- 0.025%~0.05%の濃度でSGH、STHまたはSCHを含む、請求項9に記載の製剤。
- 前記少なくとも1種のコール酸塩界面活性剤が、25℃の水中でそのCMC値より低い濃度で存在する、請求項1から10のいずれか一項に記載の製剤。
- 双性イオン性または非イオン性コール酸塩界面活性剤を含み、低イオン強度製剤である、請求項1から8、または11のいずれか一項に記載の製剤。
- 50mM未満の塩、40mM未満の塩、30mM未満の塩、または25mM未満の塩、例えばナトリウム、アルギニン、またはヒスチジン塩を含む、請求項12に記載の製剤。
- アニオン性コール酸塩界面活性剤を含み、高イオン強度製剤である、請求項1から4、9、または10のいずれか一項に記載の製剤。
- 少なくとも175mMの塩、少なくとも200mMの塩、少なくとも225mMの塩、または少なくとも250mMの塩、例えばナトリウム、アルギニン、またはヒスチジン塩を含む、請求項14に記載の製剤。
- 治療的使用に適している、請求項1から15のいずれか一項に記載の製剤。
- 凍結乾燥に供されていない、請求項1から16のいずれか一項に記載の製剤。
- すぐに使用できる液体製剤である、請求項17に記載の製剤。
- 再構成凍結乾燥製剤である、請求項1から16のいずれか一項に記載の製剤。
- ポリソルベート、ポロキサマー、プルロニック、Brij、またはアルキルグリコシド界面活性剤のいずれも含まない、請求項1から19のいずれか一項に記載の製剤。
- 非コール酸塩界面活性剤をいずれも含まない、請求項1から20のいずれか一項に記載の製剤。
- 少なくとも一種のコール酸塩界面活性剤、少なくとも一種のタンパク質種、少なくとも一種のバッファー種、および少なくとも一種の非界面活性剤の安定剤(例えば、糖、糖アルコール、アミノ酸、ペプチド、塩、または他のタンパク質)から本質的になる、請求項20または21に記載の製剤。
- 少なくとも1種のポリソルベートまたはポロキサマーをさらに含む、請求項1から19のいずれか一項に記載の製剤。
- ポリソルベート20またはポリソルベート80をさらに含む、請求項23に記載の製剤。
- 0.05%以下または0.01%以下のポリソルベート20または80を含む、請求項24に記載の製剤。
- 前記コール酸塩界面活性剤および前記ポリソルベート20または80以外のいずれの界面活性剤も含まない、請求項25に記載の製剤。
- 少なくとも1種の治療用タンパク質種、および0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)のCHAPSから本質的になる界面活性剤を含む治療用タンパク質製剤であって、任意に、バッファー、塩、凍結乾燥保護剤、または糖、糖アルコール、アミノ酸、もしくは他のタンパク質種のうちの1つ以上を含む安定剤のうちの1つ以上をさらに含み、任意に、
a.前記製剤が低イオン強度であり;
b.前記少なくとも1種の治療用タンパク質が抗体であり;および/または
c.前記製剤が、使用前に凍結乾燥されていない液体製剤である、治療用タンパク質製剤。 - 前記界面活性剤が、0.01%~0.05%または0.025%~0.05%(w/v)のCHAPSから本質的になる、請求項27に記載の製剤。
- 少なくとも1種の治療用タンパク質種、および0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)のBigCHAPから本質的になる界面活性剤を含む治療用タンパク質製剤であって、任意に、バッファー、塩、凍結乾燥保護剤、または糖、糖アルコール、アミノ酸、もしくは他のタンパク質種のうちの1つ以上を含む安定剤のうちの1つ以上をさらに含み、任意に、
a.前記製剤が低イオン強度であり;
b.前記少なくとも1種の治療用タンパク質が抗体であり;および/または
c.前記製剤が、使用前に凍結乾燥されていない液体製剤である、治療用タンパク質製剤。 - 前記界面活性剤が、0.01~0.05%または0.025%~0.05%(w/v)のBigCHAPから本質的になる、請求項29に記載の製剤。
- 少なくとも1種の治療用タンパク質種、および0.5%以下、0.4%以下、0.3%以下、0.1%以下、0.05%以下、0.04%以下、0.025%以下、0.02%以下、0.01~0.5%、0.01~0.1%、0.01~0.05%、または0.025%~0.05%の濃度(w/v)のSTH、SGH、またはSCHから本質的になる界面活性剤を含む治療用タンパク質製剤であって、前記製剤が高イオン強度製剤であり、任意に、バッファー、塩、凍結乾燥保護剤、または糖、糖アルコール、アミノ酸、もしくは他のタンパク質種のうちの1つ以上を含む安定剤のうちの1つ以上をさらに含み、任意に
a.前記少なくとも1種の治療用タンパク質が抗体であり;および/または
b.前記製剤が、使用前に凍結乾燥されていない液体製剤である、治療用タンパク質製剤。 - 前記界面活性剤が、0.01~0.05%、または0.025%~0.05%(w/v)のSTH、SGH、またはSCHから本質的になる、請求項27に記載の製剤。
- 以下の特性:
a.前記製剤が、室温で100rpmで24時間撹拌した後、目に見える凝集体を示さない;
b.前記製剤が、室温で100rpmで24時間撹拌した後、2%以下の高分子量タンパク質の凝集体を示す;
c.前記製剤が、室温で100rpmで24時間撹拌した後、1%以下の高分子量タンパク質の凝集体を示す;
d.前記製剤中の高分子量タンパク質の凝集体が、撹拌していない対照と比較して、室温で100rpmで24時間撹拌した後、0.2%を超えて増加しない;
e.前記製剤がポリソルベート20またはポリソルベート80を含む場合、前記製剤中の前記ポリソルベート20またはポリソルベート80は、同じ成分および濃度を有するがコール酸塩を含まない製剤よりも、40℃で2週間貯蔵した後、またはCALBリパーゼで処理した後に、大部分がインタクトなままである、のうちの1つ以上を有する、請求項1から32のいずれか一項に記載の製剤。 - 請求項1から33のいずれか一項に記載の製剤を含む容器。
- 請求項34に記載の容器を含む製品。
- 請求項1から33のいずれか一項に記載のタンパク質製剤を製造する方法であって、前記タンパク質を前記少なくとも1種のコール酸塩界面活性剤と混合して、コール酸塩含有水溶液を形成することを含む、方法。
- 水溶液中に存在するタンパク質の凝集を阻害する方法であって、25℃の水中で約2mM以上または0.2%(w/v)の臨界ミセル濃度(CMC)値を有する少なくとも1種のコール酸塩界面活性剤を、25℃の水中でそのCMC値より低い濃度で前記水溶液に添加して、コール酸塩含有水溶液を形成することを含む、方法。
- 前記タンパク質が抗体である、請求項37に記載の方法。
- 前記抗体がモノクローナル抗体である、請求項38に記載の方法。
- 前記コール酸塩含有水溶液を凍結乾燥することをさらに含む、請求項36から39のいずれか一項に記載の方法。
- 前記コール酸塩含有水溶液を凍結乾燥することを含まない、請求項36から39のいずれか一項に記載の方法。
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