JP2022501357A - ヘテロ二量体多重特異性抗体を精製するための方法 - Google Patents
ヘテロ二量体多重特異性抗体を精製するための方法 Download PDFInfo
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Abstract
Description
本出願は、2018年9月21日出願の米国仮特許出願第62/734,566号、ならびに2018年10月8日出願の米国仮特許出願第62/742,821号の出願日の優先権の利益を主張し、これらの出願の開示内容は、それらの全体が参照によって本明細書に組み込まれる。
「含む」は、記載の要素が組成物/方法/キットにおいて必要であるが、特許請求の範囲に含まれる組成物/方法/キットを形成させるためには他にも要素が含められ得ることを意図する。
多重特異性抗体の精製方法
ヘテロ二量体多重特異性抗体(例えば、二重特異性抗体(BsAb)を含む)の精製では、捕捉のためにプロテインAクロマトグラフィーを使用することが問題になることが多く、この原因は、未精製のBsAb混合物中に望ましくないFc含有産物バリアント(例えば、望ましくないホモ二量体種)が存在することにある。さらに、多量体タンパク質(抗体など)は凝集する傾向がより強く、このことが不純物レベルを顕著に高める一因となっている。したがって、BsAbのための製造プロセスの設計では、代替の親和性捕捉方法が必要である。本明細書では、プロテインAクロマトグラフィー単位工程の特性及び能力特徴、ならびに代替の捕捉方法について論じられている。
本発明の態様は、多重特異性抗体及び1つ以上の混入物を含む混合物から、親和性クロマトグラフィー手順を使用して多重特異性抗体を精製するための方法を含む。混合物は、一般に、多重特異性抗体の組換え産生から得られるものであり、例えば、培養組換えポリペプチド発現細胞株または培養宿主細胞から得られるものである。試料または混合物は、例えば、限定されないが、収集細胞培養液(HCCF)から得られるものであるか、精製プロセスにおけるある特定のステップの時点のプロセス中プールから得られるものであるか、または最終精製産物から得られるものであり得る。試料は、希釈剤、緩衝剤、界面活性剤、ならびに所望の分子(多重特異性抗体(例えば、二重特異性抗体)など)と混ざって見られる混入種、デブリ、及び同様のものも含み得る。
本明細書に記載の精製プロセスの設計において、いくつかのBsAbは低pHに曝露されると凝集する傾向を有することが発見された。それ故に、そのような場合、プロテインAクロマトグラフィーを使用するにあたって低pHでの溶出を行うことが特に問題となり、このことが、プロテインAの適切な代替物として働き得る親和性樹脂を検討するきっかけとなった。本明細書に記載のようにプロテインA溶出緩衝液に添加剤を含めることで観察凝集レベルは低下したものの、望ましくないホモ二量体種(例えば、TAAホモ二量体種)が一緒に精製されてしまうことが依然として観察された。さらに、酸に対してBsAbが不安定であることから、低pHでのウイルス不活化単位工程を使用することが不可能である。それ故に、本発明の実施形態による方法は、さまざまな型の親和性樹脂(限定されないが、プロテインA親和性樹脂を含む)を用いるクロマトグラフィー単位工程を含む。ある特定の実施形態では、プロテインA溶出緩衝液に対して本明細書に記載の抗凝集組成物が添加されることで、溶出液中の望ましくないホモ二量体凝集体が低減される。
本明細書で使用される溶出は、クロマトグラフィー材料からの産物(例えば、多重特異性抗体)の脱離または解離を指す。溶出緩衝液は、クロマトグラフィー材料からの多重特異性抗体の溶出に使用される緩衝液である。いくつかの実施形態では、溶出緩衝液は、クエン酸、アセテート、酢酸、4−モルホリンエタンスルホン酸(MES)、クエン酸−リン酸、コハク酸、及び同様のものを含み得る。ある特定の実施形態では、プロテインAを含む親和性クロマトグラフィーカラムからの多重特異性抗体の溶出に使用される溶出緩衝液は、約5mM〜約50mMの範囲の濃度(約10mM、約15mM、約20mM、約25mM、約30mM、約35mM、約40mM、または約45mMなど)のクエン酸を含む。いくつかの実施形態では、溶出緩衝液中のクエン酸の濃度の範囲は、約20mM〜約30mMである。いくつかの実施形態では、溶出緩衝液は、約25mMの濃度のクエン酸を含む。ある特定の実施形態では、IgG抗体のCH1ドメインに結合するドメイン特異的クロマトグラフィー樹脂を含む親和性クロマトグラフィーカラムからの多重特異性抗体の溶出に使用される溶出緩衝液は、約5mM〜約60mMの範囲の濃度(約10mM、約15mM、約20mM、約25mM、約30mM、約35mM、約40mM、約45mM、約50mM、または約55mMなど)の酢酸を含む。いくつかの実施形態では、溶出緩衝液中の酢酸の濃度の範囲は、約45mM〜約55mMである。いくつかの実施形態では、溶出緩衝液は、約50mMの濃度の酢酸を含む。
プロテインA樹脂を用いてBsAbを精製する場合、プロテインA樹脂からの溶出を低pHで行うと高分子量凝集体が生じることが、最初の試験から明らかとなった。溶出緩衝液に添加剤を添加することによって、BsAb凝集体の量が低減されることが発見された。したがって、ある特定の好ましい実施形態では、抗凝集組成物を溶出緩衝液に添加してから、多重特異性抗体の溶出が行われる。いくつかの実施形態では、抗凝集組成物は、1つ以上のポリオールを含む。ポリオールの例としては、限定されないが、マンニトール、グリセロール、スクロース、トレハロース、及びソルビトールが挙げられる。いくつかの実施形態では、溶出緩衝液は、1つ以上のポリオールを含む抗凝集組成物を含む。ある特定の実施形態では、1つ以上のポリオールは、マンニトール、グリセロール、スクロース、トレハロース、及びそれらの組み合わせ、からなる群から選択される。いくつかの実施形態では、1つ以上のポリオールは、約5%〜約25%w/vの範囲の濃度(5%w/v、10%w/v、15%w/v、または20%w/vなど)を有する。他の実施形態では、1つ以上のポリオールは、約5%〜約15%w/vの範囲の濃度を有するグリセロールを含む。一実施形態では、溶出緩衝液は、約10%w/vの濃度のグリセロールを含む。他の実施形態では、1つ以上のポリオールは、約5%〜約15%w/vの範囲の濃度を有するスクロースを含む。いくつかの実施形態では、溶出緩衝液は、約10%w/vの濃度のスクロースを含む。ある特定の実施形態では、溶出緩衝液は、約10%w/vのグリセロール及び約10%w/vのスクロースを含む。本発明の実施形態による方法は、本明細書に記載の添加剤を任意の組み合わせで含む溶出緩衝液を本明細書に記載の任意のpHで使用するプロテインAクロマトグラフィーを含む。本発明の実施形態による別の方法は、本明細書に記載の添加剤を任意の組み合わせで含む溶出緩衝液を本明細書に記載の任意のpHで使用して、IgG抗体のCH1ドメインに結合するドメイン特異的クロマトグラフィー樹脂を利用する親和性クロマトグラフィーを含む。ある特定の実施形態では、IgG抗体のCH1ドメインに結合するドメイン特異的クロマトグラフィー樹脂を利用する親和性クロマトグラフィーは、CaptureSelect(商標)樹脂を利用するものである。いくつかの実施形態では、CaptureSelect(商標)樹脂は、CaptureSelect(商標)CH1−XLである。
ある特定の実施形態では、親和性クロマトグラフィーから得られる溶出液は、1つ以上の追加の精製ステップに供される。例えば、ある特定の実施形態では、親和性クロマトグラフィーステップから得られる溶出液は、その後に例えば、陰イオン交換クロマトグラフィー手順及び/または陽イオン交換クロマトグラフィー手順に供される。
本発明の別の態様は医薬組成物を提供し、この医薬組成物は、本発明の方法によって精製された1つ以上の多重特異性抗体が適切な医薬的に許容可能な担体と混合されたものを含む。本明細書で使用される医薬的に許容可能な担体の例としては、限定されないが、補助剤、固体担体、水、緩衝液、もしくは治療成分を保持するために当該技術分野で使用される他の担体、またはそれらの組み合わせが挙げられる。
本明細書に記載の方法によって精製された多重特異性抗体、及び/または本明細書に記載の方法によって精製されたポリペプチドを含む製剤は、製造物品中に含められ得る。本発明の方法に従って精製された1つ以上の多重特異性抗体を含む製造物品または「キット」は、本明細書に記載の疾患及び障害の治療に有用である。一実施形態では、キットは、本明細書に記載のように精製された多重特異性抗体(例えば、二重特異性抗CD3抗体)を含む容器を含む。キットは、容器上または容器付属のラベルまたは添付文書をさらに含み得る。「添付文書」という用語は、治療医薬品の商用パッケージに慣習的に含められ、そのような治療医薬品の使用に関する適応症、用法、用量、投与、禁忌、及び/または警告についての情報を含む説明物を指すために使用される。適切な容器には、例えば、ボトル、バイアル、シリンジ、ブリスターパックなどが含まれる。容器は、さまざまな材料(ガラスまたはプラスチックなど)から形成され得る。容器は、本明細書に記載の多重特異性抗体の1つ以上または状態の治療に有効なその製剤(例えば、2つ以上の多重特異性抗体の合剤)を含み得、滅菌アクセスポートを有し得る(例えば、容器は、静脈内輸液バッグであるか、または皮下注射針によって貫通可能なストッパーを有するバイアルであり得る)。ラベルまたは添付文書は、選択される状態(がんまたは免疫障害など)の治療に組成物が使用されることを示す。あるいは、またはさらに、製造物品は、医薬的に許容可能な緩衝液(注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンゲル液、及びデキストロース溶液など)を含む第2の容器をさらに含み得る。製造物品は、他の緩衝液、希釈剤、フィルター、針、及びシリンジを含めて、商用及びユーザーの観点から望ましい他の材料をさらに含み得る。
ある特定の態様では、本発明は、親和性クロマトグラフィー手順を使用して混合物から多重特異性抗体を精製するための方法を提供し、この方法は、第1の親和性クロマトグラフィーカラムを混合物と接触させること、第1の親和性クロマトグラフィーカラム上で多重特異性抗体を固定化すること、第1の親和性クロマトグラフィーカラムを、抗凝集組成物を含む溶出緩衝液と接触させること、及び第1の親和性クロマトグラフィーカラムから多重特異性抗体を溶出させて混合物から多重特異性抗体を精製すること、を含む。
BsAb CD3−BCMAは、図2に示されており、下記のように精製した。BsAb CD3−BCMAは二重特異性抗体であり、構造的には三量体である。この三量体では、一方のアーム(例えば、CD3結合アーム)は、完全ヒト重鎖及び完全ヒトκ軽鎖の両方を含み、もう一方のアーム(例えば、BCMAアーム)(UniRat(商標)技術から得られたもの)は、ヒト重鎖(CHドメイン(例えば、ヒンジ−CH2−CH3を含み、CH1ドメインを含まないもの)に直接的に融合した1つ以上のVHドメインを有するもの)からなる。BsAb CD3−BCMAを構成する可変ドメイン配列は、以下の表1に示される。具体的には、BsAb CD3−BCMAは、2つの重鎖(HC−1及びHC−2)ならびに1つのカッパ軽鎖(κLC)を有する完全ヒトIgG4二重特異性モノクローナル抗体であり、酸に対して不安定である。重鎖の正しい対形成は、ノブ・イントゥ・ホール(knob−into−hole)技術を介して達成される。CD3アームは、HC−1及びκLCを含み、T細胞受容体CD3と結合する。TAAアーム、すなわちBCMAアームは、HC−2のみを含み、BCMAを認識する2つの同一のVHドメインからなる。TAAアームは、結合親和性を向上させるために二価であり(1nM未満)、UniRat(商標)技術から得られたものである。このBsAbは特有の構造を有するため、ヘテロ二量体産物のみが、ヒト重鎖のCH1ドメイン(CD3結合アームの一部)を含む。
重鎖のみの抗体の重鎖可変領域をそれぞれが含む第1の結合単位及び第2の結合単位を含む二重特異性抗体が、本明細書に記載の方法に従って、当該抗体を含む混合物から精製される。当該二重特異性抗体を含む混合物は、第1の親和性クロマトグラフィー材料と接触され、それによって当該抗体が固定化される。当該抗体は、本明細書に記載のポリオールを含む抗凝集組成物を含む溶出緩衝液を用いて溶出され、それによって溶出プールにおける当該二重特異性抗体の凝集が低減される。
抗体の重鎖可変領域及び抗体の軽鎖可変領域をそれぞれが含む第1の結合単位及び第2の結合単位を含む二重特異性抗体が、第1の親和性クロマトグラフィーカラムと接触され、それによって当該抗体が固定化される。当該抗体は、本明細書に記載のポリオールを含む抗凝集組成物を含む溶出緩衝液を用いて溶出され、それによって溶出プールにおける当該二重特異性抗体の凝集が低減される。
Claims (35)
- 親和性クロマトグラフィーによって混合物から多重特異性IgG抗体を精製するための方法であって、前記方法が、
前記混合物から前記多重特異性IgG抗体を、前記IgG抗体の重鎖定常ドメインに結合特異性を有する第1の親和性クロマトグラフィーカラム上に固定化すること、及び
1つ以上のポリオールを含む抗凝集組成物を含む溶出緩衝液を用いて前記第1の親和性クロマトグラフィーカラムから前記多重特異性抗体を溶出させて前記混合物から前記多重特異性抗体を精製すること、
を含む、前記方法。 - 前記1つ以上のポリオールが、マンニトール、グリセロール、スクロース、トレハロース、及びそれらの組み合わせ、からなる群から選択される、請求項1に記載の方法。
- 前記1つ以上のポリオールが、約5%〜約25%w/vの範囲の濃度を有する、請求項2に記載の方法。
- 前記1つ以上のポリオールが、約5%〜約15%w/vの範囲の濃度を有するグリセロールを含む、請求項3に記載の方法。
- 前記グリセロールが、約10%w/vの濃度を有する、請求項4に記載の方法。
- 前記1つ以上のポリオールが、約5%〜約15%w/vの範囲の濃度を有するスクロースを含む、請求項3に記載の方法。
- 前記スクロースが、約10%w/vの濃度を有する、請求項6に記載の方法。
- 前記溶出緩衝液が、約10%w/vのグリセロール及び約10%w/vのスクロースを含む、請求項3に記載の方法。
- 前記親和性クロマトグラフィーカラムが、プロテインAクロマトグラフィー樹脂を含む、請求項1に記載の方法。
- 前記溶出緩衝液が、クエン酸、アセテート、酢酸、4−モルホリンエタンスルホン酸(MES)、クエン酸−リン酸、コハク酸、及びそれらの組み合わせ、からなる群から選択される、請求項9に記載の方法。
- 前記溶出緩衝液が、約20mM〜約30mMの範囲の濃度のクエン酸を含む、請求項10に記載の方法。
- 前記溶出緩衝液が、約25mMの濃度のクエン酸を含む、請求項11に記載の方法。
- 前記溶出緩衝液が、約3.2〜約4.2の範囲のpHを有する、請求項9に記載の方法。
- 前記溶出緩衝液が、約3.4〜約3.8の範囲のpHを有する、請求項13に記載の方法。
- 前記溶出緩衝液が、約3.6のpHを有する、請求項14に記載の方法。
- 前記溶出緩衝液が、約25mMのクエン酸、約10%のグリセロール、及び約10%のスクロースを含み、前記溶出緩衝液が、約3.6のpHを有する、請求項9に記載の方法。
- 前記親和性クロマトグラフィーカラムが、前記IgG抗体のCH1ドメインに結合するドメイン特異的クロマトグラフィー樹脂を含む、請求項1に記載の方法。
- 前記溶出緩衝液が、クエン酸、アセテート、酢酸、4−モルホリンエタンスルホン酸(MES)、クエン酸−リン酸、コハク酸、及びそれらの組み合わせ、からなる群から選択される緩衝液を含む、請求項17に記載の方法。
- 前記溶出緩衝液が、約45mM〜約55mMの範囲の濃度の酢酸を含む、請求項18に記載の方法。
- 前記溶出緩衝液が、約50mMの濃度の酢酸を含む、請求項19に記載の方法。
- 前記溶出緩衝液が、約3.4〜約4.4の範囲のpHを有する、請求項17に記載の方法。
- 前記溶出緩衝液が、約3.8〜約4.2の範囲のpHを有する、請求項21に記載の方法。
- 前記溶出緩衝液が、約4.0のpHを有する、請求項22に記載の方法。
- 前記溶出緩衝液が、約50mMの酢酸、約10%のグリセロール、及び約10%のスクロースを含み、前記溶出緩衝液が、約4.0のpHを有する、請求項17に記載の方法。
- 親和性クロマトグラフィー手順から得られる溶出プールにおける多重特異性IgG抗体の凝集を低減する方法であって、前記方法が、
プロテインA親和性クロマトグラフィーカラム上、前記多重特異性IgG抗体を固定化すること、及び
25mMのクエン酸、10%w/vのグリセロール、及び10%w/vのスクロースを含むpH3.6の溶出緩衝液を用いて前記プロテインA親和性クロマトグラフィーカラムから前記多重特異性IgG抗体を溶出させること、
を含む、前記方法。 - 親和性クロマトグラフィー手順から得られる溶出プールにおける多重特異性IgG抗体の凝集を低減する方法であって、前記方法が、
前記多重特異性IgG抗体を、前記多重特異性IgG抗体のCH1ドメインに結合親和性を有するドメイン特異的クロマトグラフィー樹脂を含む親和性クロマトグラフィーカラム上に固定化すること、及び
50mMの酢酸、10%のグリセロール、及び10%のスクロースを含むpH4.0の溶出緩衝液を用いて前記親和性クロマトグラフィーカラムから前記多重特異性IgG抗体を溶出させること、
を含む、前記方法。 - 前記多重特異性IgG抗体が、第1の結合単位及び第2の結合単位を含む、請求項1、請求項25、及び請求項26のいずれか1項に記載の方法。
- 前記第1の結合単位が、重鎖のみの抗体の重鎖可変領域を含む、請求項27に記載の方法。
- 前記第2の結合単位が、抗体の重鎖可変領域及び抗体の軽鎖可変領域を含む、請求項27に記載の方法。
- 前記第1の結合単位が、重鎖のみの抗体の重鎖可変領域を含み、前記第2の結合単位が、抗体の重鎖可変領域及び抗体の軽鎖可変領域を含む、請求項27に記載の方法。
- 前記第1の結合単位が、腫瘍関連抗原に対する結合親和性を有する、請求項27に記載の方法。
- 前記第2の結合単位が、エフェクター細胞に結合親和性を有する、請求項27に記載の方法。
- 前記エフェクター細胞が、T細胞である、請求項32に記載の方法。
- 前記第2の結合単位が、前記T細胞上のCD3タンパク質に結合親和性を有する、請求項33に記載の方法。
- 前記多重特異性IgG抗体が、二重特異性IgG抗体である、請求項1、請求項25、及び請求項26のいずれか1項に記載の方法。
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JP7432363B2 (ja) | 2016-06-21 | 2024-02-16 | テネオバイオ, インコーポレイテッド | Cd3結合抗体 |
FI4050034T3 (fi) | 2016-09-14 | 2024-06-10 | Teneoone Inc | Cd3:een sitoutuvia vasta-aineita |
JP7240335B2 (ja) | 2017-06-20 | 2023-03-15 | テネオワン, インコーポレイテッド | 抗bcma重鎖のみ抗体 |
JOP20200157A1 (ar) | 2017-12-22 | 2022-10-30 | Teneobio Inc | أجسام مضادة ذات سلسلة ثقيلة ترتبط بـ cd22 |
CA3140816A1 (en) | 2019-06-14 | 2020-12-17 | Nathan Trinklein | Multispecific heavy chain antibodies binding to cd22 and cd3 |
CA3214992A1 (en) * | 2020-04-29 | 2021-11-04 | Teneobio, Inc. | Multispecific heavy chain antibodies with modified heavy chain constant regions |
CA3176792C (en) * | 2020-04-29 | 2024-06-18 | Katherine HARRIS | Anti-cd3 and anti-bcma bispecific antibodies wth modified heavy chain constant regions |
CN114539417A (zh) * | 2020-11-26 | 2022-05-27 | 盛禾(中国)生物制药有限公司 | 一种有效去除双特异性抗体同源二聚体的层析纯化工艺 |
TW202241924A (zh) * | 2021-04-23 | 2022-11-01 | 大陸商和鉑醫藥(上海)有限責任公司 | 一種雙特異性抗體的純化方法 |
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- 2019-09-20 KR KR1020217010141A patent/KR20210063354A/ko unknown
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MX2021003169A (es) | 2021-08-11 |
AU2019343053A1 (en) | 2021-04-15 |
CA3113057A1 (en) | 2020-03-26 |
WO2020061478A3 (en) | 2020-04-30 |
IL281570A (en) | 2021-05-31 |
SG11202102713TA (en) | 2021-04-29 |
WO2020061478A2 (en) | 2020-03-26 |
KR20210063354A (ko) | 2021-06-01 |
BR112021004680A2 (pt) | 2021-08-31 |
US20210355215A1 (en) | 2021-11-18 |
EP3853253A2 (en) | 2021-07-28 |
CN112839959A (zh) | 2021-05-25 |
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