JP2022522816A - 高分子量種のインビボでの可逆性 - Google Patents
高分子量種のインビボでの可逆性 Download PDFInfo
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Abstract
Description
2019年3月4日に出願された米国仮出願第62/813,529号及び2019年12月6日に出願された米国仮出願第62/944,758号の35 U.S.C.§119(e)の下での利益が本明細書により主張されており、これらの内容全体が、参照により本明細書に組み込まれる。
本明細書と同時に提出されたコンピュータ可読のヌクレオチド/アミノ酸の配列表は、その全体が参照により組み込まれ、下記のように識別される:「53990_Seqlisting.txt」という名称の270,234バイトASCII(テキスト)ファイル、2020年3月4日作成。
例示的な態様では、治療用タンパク質は、抗体である。本明細書で使用される場合、用語「抗体」は、重鎖及び軽鎖を含み、且つ可変領域及び定常領域を含む、従来の免疫グロブリン構成を有するタンパク質を指す。例えば、抗体は、2個の同一ペアのポリペプチド鎖の「Y字形」構造であるIgGであり得、各ペアは、1本の「軽」(典型的には、分子量が約25kDa)及び1本の「重」鎖(典型的には、分子量が約50~70kDa)を有する。抗体は、可変領域及び定常領域を有する。IgG型では、可変領域は、一般に、約100~110個又はより多くのアミノ酸であり、3個の相補性決定領域(CDR)を含み、主に抗原認識に関与し、異なる抗原に結合する抗体間で実質的に異なる。定常領域は、抗体が免疫系の細胞及び分子を動員することを可能にする。可変領域は、各軽鎖及び重鎖のN末端領域からできているが、定常領域は、重鎖及び軽鎖のそれぞれのC末端部分からできている。(Janeway et al.,“Structure of the Antibody Molecule and the Immunoglobulin Genes”,Immunobiology:The Immune System in Health and Disease,4thed.Elsevier Science Ltd./Garland Publishing,(1999))。
この実施例は、大きなタンパク質が枯渇したヒト血清(Large Protein Depleted Human Serum)(LPDS)法と呼ばれる本開示の第1の例示的な方法を示す。
この実施例は、BiTE(登録商標)分子タンパク質のHMW種の可逆性の%を決定する例示的な方法を示す。
この実施例は、IgGが枯渇したヒト血清(IgG Depleted Human Serum)(IgGDS)法と呼ばれる本開示の第2の例示的な方法を示す。
この実施例は、蛍光標識を伴う全血清(whole serum with fluorescence labeling)(WSFL)法と呼ばれる本開示の第3の例示的な方法を示す。
この実施例は、抗体捕捉を伴う全血清(Whole Serum with Antibody Capture)(WSAC)法と呼ばれる本開示の第4の例示的な方法を示す。
この実施例は、実施例2で説明されている方法を実施する代替方法を示す。
この実施例は、実施例4で説明されている免疫分離工程中の混合時間を変更したWSAC法を示す。
この実施例は、実施例2及び実施例4の両方で説明されている免疫分離工程中での適切な溶出条件を特定するために実行した一連の実験を示す。
Claims (48)
- 治療用タンパク質の高分子量(HMW)種のインビボでのレベルをアッセイするインビトロ方法であって、
a.(i)前記治療用タンパク質を含むサンプルと、(ii)血清又はその枯渇画分とを含む混合物をインキュベートすること、
及び
b.工程(a)後の1つ又は複数の時点で、前記混合物中に存在する前記治療用タンパク質のHMW種のレベルをアッセイすること
を含み、
任意選択的に、(i)アッセイされる前記HMW種のサイズは、約0.1ミクロン未満のサイズであるか、(ii)前記混合物中の前記治療用タンパク質のHMW種のレベルを、サイズ排除クロマトグラフィー(SEC)によりアッセイするか、又は(iii)(i)及び(ii)の両方である、
インビトロ方法。 - アッセイされる前記HMW種のサイズは、99nm未満のサイズであり、任意選択的に、約10nm~約99nmのサイズである、請求項1に記載のインビトロ方法。
- 前記HMW種は、前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体の内の1つ又は複数を含む、請求項1又は2に記載のインビトロ方法。
- (i)前記方法は、工程(a)前に前記サンプル中に存在するHMW種のレベルをアッセイすることをさらに含むか、又は(ii)工程(a)前に前記サンプル中に存在するHMW種のレベルは既知である、請求項1~3のいずれか一項に記載のインビトロ方法。
- (i)前記方法は、工程(a)前に前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体の内の1つ又は複数のレベルをアッセイすることをさらに含むか、又は(ii)工程(a)前に前記サンプル中に存在する前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体の内の1つ又は複数のレベルは既知である、請求項1~4のいずれか一項に記載のインビトロ方法。
- 工程(b)は、前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体のそれぞれのレベルをアッセイすることを含む、請求項1~5のいずれか一項に記載のインビトロ方法。
- 工程(b)でアッセイされる際に前記混合物中に存在するHMW種のレベルと、工程(a)前に前記サンプル中に存在するHMW種のレベルとを比較することをさらに含み、任意選択的に、工程(b)でアッセイされる際に前記混合物中に存在する前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体の内の1つ又は複数のレベルと、工程(a)前の前記サンプル中の前記治療用タンパク質の二量体、三量体、四量体、五量体、六量体、七量体、及び八量体のレベルとを比較する、請求項1~6のいずれか一項に記載のインビトロ方法。
- 工程(a)は、少なくとも約1時間、少なくとも約2時間、少なくとも約3時間、又は少なくとも約4時間にわたり前記混合物をインキュベートすることを含み、任意選択的に、少なくとも約6時間、少なくとも約12時間、少なくとも約18時間、又は少なくとも約24時間にわたり前記混合物をインキュベートすることを含む、請求項1~8のいずれか一項に記載のインビトロ方法。
- 工程(a)は、少なくとも約30時間、少なくとも約36時間、少なくとも約42時間、及び/又は少なくとも約48時間にわたり前記混合物をインキュベートすることを含み、任意選択的に、少なくとも約3日、少なくとも約4日、少なくとも約5日、又は少なくとも約1週間にわたり前記混合物をインキュベートすることを含む、請求項1~9のいずれか一項に記載のインビトロ方法。
- 前記治療用タンパク質は、組換えタンパク質である、請求項1~10のいずれか一項に記載のインビトロ方法。
- 前記組換えタンパク質は、ホルモン、サイトカイン、リンホカイン、融合タンパク質、抗体、その抗原結合断片、又は抗体タンパク質製品である、請求項11に記載のインビトロ方法。
- 前記治療用タンパク質は、約10μg/mL~約300μg/mLの最終濃度で前記混合物中に存在し、任意選択的に、約100μg/mLを超える又は約200μg/mLを超える最終濃度で前記混合物中に存在する、請求項1~12のいずれか一項に記載のインビトロ方法。
- 前記混合物は、工程(a)の開始時に、約87%(v/v)を超える血清又は枯渇血清を含み、任意選択的に、約90%(v/v)を超える血清又は枯渇血清を含み、例えば、約92%~約98%(v)の血清又は枯渇血清を含む、請求項1~13のいずれか一項に記載のインビトロ方法。
- 前記血清の枯渇画分は、IgG枯渇血清画分であり、任意選択的に、プロテインA親和性クロマトグラフィーにより血清からIgGを除去することにより得られたIgG枯渇血清画分である、請求項1~14のいずれか一項に記載のインビトロ方法。
- 前記血清の枯渇画分は、予め選択された分子量範囲を有する分子が枯渇した画分であり、任意選択的に、前記予め選択された分子量範囲は、約30kDa~約300kDaであるか、又はより高く、任意選択的に、前記枯渇画分は、サイズに基づくろ過により得た画分である、請求項1~15のいずれか一項に記載のインビトロ方法。
- 前記枯渇画分は、2回枯渇画分であり、任意選択的に、IgGが2回枯渇した画分、又は予め選択された分子量を有する分子が2回枯渇した画分である、請求項1~16のいずれか一項に記載のインビトロ方法。
- 前記混合物は、全血清を含む、請求項1~14のいずれか一項に記載のインビトロ方法。
- 前記全血清は、ヒト血清、ウシ血清、ウサギ血清、マウス血清、ラット血清、カニクイザル血清、ウマ血清、又はブタ血清である、請求項18に記載のインビトロ方法。
- 前記全血清は、ヒト血清である、請求項19に記載のインビトロ方法。
- (i)前記サンプルは、蛍光標識を含む治療用タンパク質を含むか、又は(ii)前記方法は、工程(a)前に、前記治療用タンパク質を蛍光標識で標識することをさらに含む、請求項18~20のいずれか一項に記載のインビトロ方法。
- 前記蛍光標識は、フルオレセイン、ローダミン、緑色蛍光タンパク質(及びこれらのバリアント)等からなる群から選択される、請求項21に記載のインビトロ方法。
- 工程(a)後に且つ工程(b)前に、希釈工程をさらに含み、任意選択的に、前記混合物を、工程(b)前に水又は緩衝液で希釈する、請求項20~22のいずれか一項に記載のインビトロ方法。
- 工程(b)は、SECにより、血清又はその枯渇画分を含む前記混合物中のHMW種のレベルをアッセイすることを含む、請求項1~23のいずれか一項に記載のインビトロ方法。
- 前記SECは、SEC-高速液体クロマトグラフィー(SEC-HPLC)、又はSEC蛍光(SEC-Fluor)、又はSEC-UVである、請求項1~24のいずれか一項に記載のインビトロ方法。
- 工程(a)後に且つ工程(b)前に、前記混合物の成分を分離することをさらに含む請求項1~25のいずれか一項に記載のインビトロ方法。
- 前記成分を、クロマトグラフィーにより分離し、任意選択的に、親和性クロマトグラフィーにより分離する、請求項26に記載のインビトロ方法。
- 前記親和性クロマトグラフィーは、プロテインA、プロテインL、又は前記治療用タンパク質に特異的な抗体による親和性クロマトグラフィーである、請求項27に記載のインビトロ方法。
- 前記親和性クロマトグラフィーは、酸性溶出緩衝液により溶出させることを含む溶出工程を含む、請求項28に記載のインビトロ方法。
- 前記酸性溶出緩衝液は、グリシン、酢酸、又はクエン酸塩を含む、請求項29に記載のインビトロ方法。
- 前記酸性溶出緩衝液は、pHが約2.5~約4.5であり、任意選択的に、約2.75~約4.0である、請求項31に記載のインビトロ方法。
- 前記pHは、約3.0~約4.0である、請求項31に記載のインビトロ方法。
- 前記溶出工程により、前記治療用タンパク質を含む溶出液が得られ、前記方法は、前記溶出液中に存在する前記治療用タンパク質のHMW種のレベルをアッセイすることを含む、請求項29~32のいずれか一項に記載のインビトロ方法。
- プロテインA、プロテインL、又は前記治療用タンパク質に特異的な抗体が結合した樹脂を、前記混合物と共に、1時間未満にわたりインキュベートする、請求項28~33のいずれか一項に記載にインビトロ方法。
- プロテインA、プロテインL、又は前記治療用タンパク質に特異的な抗体が結合した樹脂を、前記混合物と共に、30分未満にわたりインキュベートする、請求項34に記載にインビトロ方法。
- プロテインA、プロテインL、又は前記治療用タンパク質に特異的な抗体が結合した樹脂を、前記混合物と共に、20分未満にわたりインキュベートする、請求項35に記載にインビトロ方法。
- プロテインA、プロテインL、又は前記治療用タンパク質に特異的な抗体が結合した樹脂を、前記混合物と共に、約15分未満にわたりインキュベートし、任意選択的に、約5分~約10分にわたりインキュベートする、請求項36に記載のインビトロ方法。
- 治療用タンパク質のHMW種のインビボでの可逆性を決定する方法であって、(A)請求項1~37のいずれか一項に記載のインビトロ方法により治療用タンパク質の高分子量(HMW)種のインビボでのレベルをアッセイすることを含み、(i)該方法は、前記インキュベートする工程前に前記サンプル中に存在するHMW種のレベルをアッセイすることをさらに含むか、又は(ii)前記インキュベートする工程前に前記サンプル中に存在するHMW種のレベルは既知であり、及び(B)前記混合物中に存在するHMW種のレベルと、前記インキュベートする工程前に前記サンプル中に存在するHMW種のレベルとを比較することを含む方法。
- 治療用タンパク質のHMW種のインビボでの可逆性を決定する方法であって、
a.前記治療用タンパク質を含むサンプルと、枯渇血清とを含む混合物をインキュベートする工程であって、前記枯渇血清は、予め選択された分子量範囲を有する分子が枯渇した画分であり、任意選択的に、前記予め選択された分子量範囲は、約30kDa~約300kDaであるか、又はより高く、任意選択的に、前記枯渇画分は、サイズに基づくろ過により得られた画分である、工程、
b.SECにより、工程(a)後の1つ又は複数の時点で、前記混合物中に存在する前記治療用タンパク質のHMW種のレベルをアッセイする工程、
c.工程(b)でアッセイされる際に前記混合物中に存在する前記HMW種のレベルと、工程(a)前に前記サンプル中に存在する前記HMW種のレベルとを比較する工程、
及び
d.前記治療用タンパク質の前記HMW種のインビボでの可逆性の割合を算出する工程
を含む方法。 - 前記治療用タンパク質は、分子量が約15kDaであるか、又はより高い、請求項39に記載の方法。
- 治療用タンパク質のHMW種のインビボでの可逆性を決定する方法であって、
a.前記治療用タンパク質を含むサンプルと、枯渇血清とを含む混合物をインキュベートする工程であって、前記枯渇血清は、IgG枯渇血清画分であり、任意選択的に、プロテインL親和性クロマトグラフィー又はプロテインA親和性クロマトグラフィーにより血清からIgGを除去することにより得られたIgG枯渇血清画分である、工程、
b.捕捉分子による親和性クロマトグラフィーにより前記混合物の成分を分離して、前記治療用タンパク質及びそのHMW種を含む画分を得る工程、
c.SECにより、前記画分中に存在する前記治療用タンパク質のHMW種のレベルをアッセイする工程、
d.工程(c)でアッセイされる際に前記画分中に存在する前記HMW種のレベルと、工程(a)前に前記サンプル中に存在する前記HMW種のレベルとを比較する工程、
並びに
e.前記治療用タンパク質の前記HMW種のインビボでの可逆性の割合を算出する工程
を含む方法。 - 前記捕捉分子は、プロテインAであり、前記治療用タンパク質は、プロテインAに結合し、任意選択的に、前記治療用タンパク質は、プロテインA結合部位を含む、抗体、Fc融合タンパク質、又は抗体タンパク質製品である、請求項41に記載の方法。
- 工程(b)は、(i)前記混合物を親和性クロマトグラフィーカラムにロードして、前記治療用タンパク質を含む結合画分を得ること、及び(ii)前記結合画分を前記カラムから溶出させることを含む、請求項41又は42に記載の方法。
- 治療用タンパク質のHMW種のインビボでの可逆性を決定する方法であって、
a.前記治療用タンパク質を含むサンプルと、全血清とを含む混合物をインキュベートする工程であって、前記治療用タンパク質は、蛍光標識を含む、工程、
b.前記混合物を希釈する工程、
c.SECにより、工程(a)後の1つ又は複数の時点で、前記混合物中に存在する前記治療用タンパク質のHMW種のレベルをアッセイする工程、
d.工程(c)でアッセイされる際に前記混合物中に存在する前記HMW種のレベルと、工程(a)前に前記サンプル中に存在する前記HMW種のレベルとを比較する工程、
及び
e.前記治療用タンパク質の前記HMW種のインビボでの可逆性の割合を算出する工程
を含む方法。 - 治療用タンパク質のHMW種のインビボでの可逆性を決定する方法であって、
a.前記治療用タンパク質を含むサンプルと、全血清とを含む混合物をインキュベートする工程、
b.捕捉分子による親和性クロマトグラフィーにより、前記混合物の成分を分離して、前記治療用タンパク質及びそのHMW種を含む画分を得る工程、
c.SECにより、前記画分中に存在する前記治療用タンパク質のHMW種のレベルをアッセイする工程、
d.工程(c)でアッセイされる際に前記画分中に存在する前記HMW種のレベルと、工程(a)前に前記サンプル中に存在する前記HMW種のレベルとを比較する工程、
並びに
e.前記治療用タンパク質の前記HMW種のインビボでの可逆性の割合を算出する工程
を含む方法。 - 前記捕捉分子は、前記治療用タンパク質に結合する抗体又は抗体以外の分子である、請求項45に記載の方法。
- 工程(b)は、(i)前記混合物を親和性クロマトグラフィーカラムにロードして、前記治療用タンパク質を含む結合画分を得ること、及び(ii)前記結合画分を前記カラムから溶出させることを含む、請求項45又は46に記載の方法。
- 前記治療用タンパク質の前記HMW種のインビボでの可逆性の割合を、方程式1に従って算出する、請求項39~47のいずれか一項に記載の方法。
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