JP6901402B2 - 単量体抗体Fab−dsFv多量体種のパーセンテージを増加させる方法 - Google Patents
単量体抗体Fab−dsFv多量体種のパーセンテージを増加させる方法 Download PDFInfo
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/66—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
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Description
前記方法が、
a)抗体分子を含む組成物を30℃〜60℃の範囲の温度で少なくとも1時間の期間保持する熱変換のステップ
を含み、
b)ステップa)が還元剤の存在下で、又は還元剤による処置後に実施される、上記方法を提供する。
・ VH37+VL95C、例えば、Protein Science 6, 781-788 Zhu et al (1997)を参照;
・ VH44+VL100、例えば、Biochemistry 33 5451-5459 Reiter et al (1994);又はJournal of Biological Chemistry Vol. 269 No. 28 pp.18327-18331 Reiter et al (1994);又はProtein Engineering, vol.10 no.12 pp.1453-1459 Rajagopal et al (1997)を参照;
・ VH44+VL105、例えば、J Biochem. 118, 825-831 Luo et al (1995)を参照;
・ VH45+VL87、例えば、Protein Science 6, 781-788 Zhu et al (1997)を参照;
・ VH55+VL101、例えば、FEBS Letters 377 135-139 Young et al (1995)を参照;
・ VH100+VL50、例えば、Biochemistry 29 1362-1367 Glockshuber et al (1990)を参照;
・ VH100b+VL49;
・ VH98+VL46、例えば、Protein Science 6, 781-788 Zhu et al (1997)を参照;
・ VH101+VL46;
・ VH105+VL43、例えば、Proc. Natl. Acad. Sci. USA Vol. 90 pp.7538-7542 Brinkmann et al (1993);又はProteins 19, 35-47 Jung et al (1994)を参照;
・ VH106+VL57、例えば、FEBS Letters 377 135-139 Young et al (1995)を参照、
及び分子中に位置する可変領域対におけるそれらに対応する位置(単数及び複数)。
a)式(I):VH−CH1−X−V1のポリペプチド鎖;及び、
b)式(II):VL−CL−Y−V2のポリペプチド鎖;
(式中、
VHは、重鎖可変ドメインを表し;
CH1は、重鎖定常領域のドメイン、例えばそのドメイン1を表し;
Xは、結合又はリンカーを表し;
Yは、結合又はリンカーを表し;
V1は、dsFv、sdAb、scFv又はdsscFvを表し;
VLは、軽鎖可変ドメインを表し;
CLは、軽鎖定常領域由来のドメイン、例えばCカッパを表し;
V2は、dsFv、sdAb、scFv又はdsscFvを表し、
ここで、V1及びV2の少なくとも1つはdsscFvである)
を含むか、又はこれらからなる多重特異性抗体分子を開示している。
第1の重鎖可変ドメイン(VH1)、CH1ドメイン及び第2の重鎖可変ドメイン(VH2)をN末端から順に含む重鎖、
第1の軽鎖可変ドメイン(VL1)、CLドメイン及び第2の軽鎖可変ドメイン(VL2)をN末端から順に含む軽鎖
を含む、ヒトOX40及びヒト血清アルブミンに結合する二重特異性抗体融合タンパク質であって、
前記重鎖及び軽鎖は、VH1及びVL1が第1の抗原結合部位を形成し、VH2及びVL2が第2の抗原結合部位を形成するように整列されており、
第1の抗原結合部位によって結合される抗原はヒトOX40であり、第2の抗原結合部位によって結合される抗原はヒト血清アルブミンであり、特に、
重鎖の第1の可変ドメイン(VH1)は、CDR−H1に関する配列番号1に示した配列、CDR−H2に関する配列番号2に示した配列、及びCDR−H3に関する配列番号3に示した配列を含み、軽鎖の第1の可変ドメイン(VL1)は、CDR−L1に関する配列番号4に示した配列、CDR−L2に関する配列番号5に示した配列、及びCDR−L3に関する配列番号6に示した配列を含み、
第2の重鎖可変ドメイン(VH2)は、配列番号11に示した配列を有し、第2の軽鎖可変ドメイン(VL2)は、配列番号12に示した配列を有し、第2の重鎖可変ドメイン(VH2)及び第2の軽鎖可変ドメイン(VL2)は、ジスルフィド結合によって連結されている、上記二重特異性抗体融合タンパク質を提供する。
プロテインA精製Fab−dsFv多量体種の熱変換
A26Fab−dsFvのCHO発現及び清澄化
ヒトOX40と軽鎖配列A26 Fab軽鎖−(3xG4S)−645dsFv(gL4)(配列番号16)及び重鎖配列A26 Fab重鎖−(G4S,G4T,G4S)−645dsFv(gH5)(配列番号15)を有する血清アルブミンを結合する構築物を、安定なジヒドロ葉酸レダクターゼ(DHFR)欠損チャイニーズハムスター卵巣細胞系(CHO DG44)において発現させた。これは、選択可能マーカーとしてのDHFRに関する遺伝子及び生成物をコードする遺伝子の両方を含有するプラスミドベクターを用いて、メーカーの使用説明書に従いNuclefector(Lonza)を使用するトランスフェクションにより生成した。トランスフェクト細胞は、ヒポキサンチン及びチミジン欠失培地で、DHFR阻害剤メトトレキサートの存在下において選択した。
清澄化したCHO上清を、Delbeccosリン酸緩衝生理食塩水(PBS)pH7.4で平衡化した9.4mlのHiScreen(系列中2カラム)MabSelect(GE Healthcare)カラムにアプライした。カラムをPBSで洗浄し、結合物質を0.1Mのクエン酸塩pH3.5で溶出させた。回収した溶出ピークを、2MのTris/HCl、pH8.5を用いて〜pH7に調整した。pH調整した溶出液を、10kDa分子量カットオフ遠心分離機を使用してPBS pH7.4にバッファー交換した。
試料を、50μlの最終容量で必要とされる1.0mg/mlに希釈し、次いで、100mMのNEM 5μlを添加した。次いで、試料をNovexトリス−グリシンSDSサンプルバッファー50μlで希釈し(2×)、ボルテックス処理してから、3分間95℃でインキュベートした。調製した試料を、4〜20%のアクリルアミントリス/グリシンSDSゲル上に1ウェル当たり5μgでロードし、150Vの定電圧で120分間、泳動させた。
試料を、還元剤50μlの最終容量で必要とされる1.0mg/mlに希釈した。次いで、試料をNovexトリス−グリシンSDSサンプルバッファー50μlで希釈し(2×)、ボルテックス処理してから、3分間95℃でインキュベートした。調製した試料を、4〜20%のアクリルアミントリス/グリシンSDSゲル上に1ウェル当たりタンパク質5μgでロードし、150Vの定電圧で120分間、泳動させた。ゲルは、クーマシーブルータンパク質染色液で染色した。図2及び図12を参照されたい。
試料50μgをTSK Gel G3000SWXL、7.8×300mmカラム(Tosoh)上に注入し、1ml/分で200mMリン酸塩pH7.0を均一濃度勾配で展開した。シグナル検出は、280nmの吸光度で行った。図9、図10、図13及び図14を参照されたい。SEC−HPLC解析を使用して、単量体%(A26Fab−645dsFv単量体は約9分の保持時間を有する)、並びに変換プロセスの収率の推定方法の両方を決定した。変換プロセスに関する推定収率は、任意の特定の時点での全ピーク面積をT=0での全ピーク面積のパーセンテージとして表すことにより計算した。
〜5mg/mlのプロテインA精製A26Fab−645dsFvを、PBS/100mM bMEA(β−メルカプトエチルアミン)の変換バッファー中で1:1希釈し、50mMの最終bMEA濃度を得た。希釈後、試料を所定の温度でインキュベートした。時間経過中に得た試料を氷上に置いて温度を下げ、変換プロセスを停止させた後、分析した。分析はSEC−HPLCにより行い、単量体のレベル及び推定収率を決定した。
〜5mg/mlのプロテインA精製A26Fab−645dsFvを、PBS中の所定bMEA濃度(1、5、10、20及び50mM)の2×ストックである変換バッファー中で、1:1希釈した。希釈後、試料を50℃でインキュベートした。時間経過中に得た試料を氷上に置いて温度を下げ、変換プロセスを停止させた後、分析した。分析はSEC−HPLCにより行い、単量体のレベル及び推定収率を決定した。データを図6、図7及び図8、並びに表4、表5及び表6にまとめる。
清澄化した哺乳動物細胞培養上清中のFab−dsFv多量体種の熱変換
哺乳動物細胞培養上清中のA26Fab−645dsFvの熱変換
清澄化した細胞培養上清は、10kDa分子量カットオフ遠心分離機を使用し、原容量の半分まで濃縮した。次いで、濃縮上清を、PBS/100mM bMEAを使用して原容量に希釈し、50mMの最終bMEA濃度を得た。次いで、上清を50℃で一晩(14.5時間)インキュベートした。インキュベーション後、上清を氷上に置き、温度を低下させ、変換プロセスを停止させた。
熱変換したCHO上清を、Delbeccosリン酸緩衝生理食塩水(PBS)pH7.4で平衡化した9.4mlのHiScreen(系列中2カラム)MabSelect(GE Healthcare)カラムにアプライした。カラムをPBSで洗浄し、結合物質を0.1Mのクエン酸塩pH3.5で溶出させた。溶出ピークを回収し、2MのTris/HCl、pH8.5を用いて〜pH7に調整した。精製は、無変換CHOを使用した対照で繰り返した。pHを中和したプロテインA溶出液は、G3000 SEC−HPLC(表7)、並びに非還元条件及び還元条件下のSDS−PAGE(図11及び図12)により解析した。多量体種のカラムへの結合が保持されている間、FabFv単量体を溶出させる溶出pHが確認された。上清の変換プロセスを繰り返し、9.4mlのHiScreenカラムにアプライし、溶出条件(0.1Mクエン酸塩pH3.8)を用いて溶出させた。同一のローティング能力でロードした無変換上清の対照実験も行った。溶出ピークを回収し、2MのTris/HCl、pH8.5を用いて〜pH7にpHを調整した。pHを中和したプロテインA溶出液は、G3000 SEC−HPLC(図13及び図14)解析、並びにA280(表8)により解析した。pH3.5で溶出した場合、有意に高い単量体レベルが、同等の回収率で、変換物質から観察された。SEC−HPLCにより解析した場合、変換の有無にかかわらず両上清からの生成物の品質は、pH3.8溶出液に匹敵したが、変換後にタンパク質量の有意な増加が確認された。
様々なパラメーターの効果についての試験
この実験に使用した供給抗体は、A26Fab−645dsFvであった。すべての実験は、プロテインA精製物質に対して実施した。A26Fab−645dsFv細胞培養液は、プロテインAカラム(MabSelect,GE Heathcare)を使用して精製した。物質をpH7.4でロードしたところ、標的分子は結合されていたが、ほとんどの不純物はカラムを通って流出した。次いで、カラムは、クエン酸ナトリウムバッファーを使用して、pH3.4で溶出させた。これにより、単量体種が多量体種と共に溶出した。溶出プールを13g/Lまで濃縮し、pH7.4のPBSバッファーにダイアフィルトレーションした。供給抗体A26Fab−645dsFvは、変換前に約15%の単量体を含有していた。抗体の濃度(供給濃度g/L)、pH、bMEA還元剤濃度、変換ステップの温度、及び混合速度について、以下の表9に示したようにすべて評価した。単量体、二量体、三量体、四量体及びHMWS%は、BEH200 SEC 1.7μmカラムを使用し、Walters製の装置を使用してSE−UPLCにより0.5、1、1.5、2、3、4、5、6、7及び23時間で測定した。5時間について表10に示す。
リシンと組み合わせたパラメーターの試験
抗体供給濃度g/L、bMEA濃度及び温度パラメーターを、0.7Mリシンの存在下及びリシンの非存在下において試験した。実験は2mLのディープウェルプレートにおいて実施し、二連で行った。2mLのエッペンドルフチューブを使用し、各変換ステップを水浴中で5時間実施した。
0.7Mのリシンが存在する場合、温度は単量体%に対して最も顕著な効果を有し、高い温度ほどより効果が認められた。
異なる還元剤の試験
最初の還元剤スクリーニング実験については、本発明者らは50℃の温度を使用し、分子をオープンアップした。供給は、精製A26Fab−dsFv、濃度1g/L及び15%単量体であった。実験は、Eppendorfsで供給量1mLにて実施した。スクリーニングした還元剤濃度は、10、50及び100mMであった(表15)。試料を加熱し、Thermo Scientific製のVortemp装置を使用して混合した。サンプリングは、加熱前の還元剤を添加した後、及び50℃で2時間加熱した後に実施した。この実験の対照還元剤としてはβ−meaを使用した。
2Lスケールでの変換
2Lスケール実験に対する供給としての清澄化培養液を提供するため、A26Fab−645dsFvのCHO発現及び清澄化を実施例1と同様に実施した。熱変換実験は、2Lの変換量を使用し、2Lの発酵容器中で実施した。実験の供給は清澄化した細胞培養液(CCF)であり、生成物の濃度は2.2g/Lで、その30%が単量体であった。実験条件を表16に示す。変換ステップは、すべての実験において17時間実施した。試料はSE UPLCによって分析した。
Claims (21)
- 組換え発現された抗体分子の組成物中の単量体のパーセンテージを増加させる方法であって、前記抗体分子が、1つのVH及び1つのVLを含む目的の抗原に対する特異性を有する少なくとも1つのFvを含み、前記VH及びVLが1つ又は複数のリンカーを介して直接的又は間接的に結合されており、かつそれらの間のジスルフィド結合によって安定化されており、前記抗体分子が、Fab−dsFv、Fab−dsscFv、及びFab−2xdsscFvからなる群から選択され、
前記方法が、
a)抗体分子を含む組成物を45℃〜55℃の範囲の温度で少なくとも1時間の期間保持する熱変換のステップ
を含み、
b)ステップa)が還元剤の存在下で、又は還元剤による処置後かつ還元剤の存在下で実施され、該還元剤は2−メルカプトエチルアミン(BMEA)である、上記方法。 - 温度が50℃である、請求項1に記載の方法。
- 還元剤の濃度が1mM〜100mMの範囲である、請求項1又は2に記載の方法。
- 期間が1〜70時間の範囲である、請求項1から3までのいずれか一項に記載の方法。
- ステップa)が45〜55℃の温度の範囲で4〜6時間の期間実施され、及びステップb)において、還元剤が60〜90mMの範囲の濃度である、請求項4に記載の方法。
- ステップa)が50℃の温度で5時間の期間実施され、及びステップb)において、還元剤が70〜80mMの範囲の濃度である、請求項5に記載の方法。
- 還元剤がアミノ酸の存在下で使用される、請求項1から6までのいずれか一項に記載の方法。
- アミノ酸がアルギニン、リシン及びプロリンから選択される、請求項7に記載の方法。
- アミノ酸の濃度が0.01〜1.0Mの範囲である、請求項7又は8に記載の方法。
- 抗体分子が組成物中0.5g/L〜5g/Lの範囲の濃度である、請求項1から9までのいずれか一項に記載の方法。
- 熱変換のステップが同時撹拌の存在下で実施される、請求項1から10までのいずれか一項に記載の方法。
- 撹拌が100〜1200rpmの範囲である、請求項11に記載の方法。
- 温度が45〜55℃の範囲に上昇する前に、還元剤が抗体分子を含む組成物に添加される、請求項1から12までのいずれか一項に記載の方法。
- 抗体分子を含む組成物の温度が45〜55℃の範囲まで上昇した後に、還元剤が抗体分子を含む組成物に添加される、請求項1から12までのいずれか一項に記載の方法。
- 下流精製のさらなるステップを含む、請求項1から14までのいずれか一項に記載の方法。
- 下流処理がクロマトグラフィーのステップを含む、請求項15に記載の方法。
- クロマトグラフィーが疎水性相互作用クロマトグラフィーである、請求項16に記載の方法。
- クロマトグラフィーがイオン交換クロマトグラフィーである、請求項16に記載の方法。
- 抗体分子がFab−dsFvである、請求項1〜18までのいずれか一項に記載の方法。
- 抗体分子が、
第1の重鎖可変ドメイン(VH1)、CH1ドメイン及び第2の重鎖可変ドメイン(VH2)をN末端から順に含む重鎖、
第1の軽鎖可変ドメイン(VL1)、CLドメイン及び第2の軽鎖可変ドメイン(VL2)をN末端から順に含む軽鎖
を含む、ヒトOX40及びヒト血清アルブミンに結合する二重特異性抗体融合タンパク質であり、
前記重鎖及び軽鎖は、VH1及びVL1が第1の抗原結合部位を形成し、かつVH2及びVL2が第2の抗原結合部位を形成するように整列されており、
第1の抗原結合部位によって結合される抗原はヒトOX40であり、かつ第2の抗原結合部位によって結合される抗原はヒト血清アルブミンである、請求項19に記載の方法。 - 重鎖の第1の可変ドメイン(VH1)が、CDR−H1に関する配列番号1に示した配列、CDR−H2に関する配列番号2に示した配列、及びCDR−H3に関する配列番号3に示した配列を含み、かつ軽鎖の第1の可変ドメイン(VL1)が、CDR−L1に関する配列番号4に示した配列、CDR−L2に関する配列番号5に示した配列、及びCDR−L3に関する配列番号6に示した配列を含み、
第2の重鎖可変ドメイン(VH2)が配列番号11に示した配列を有し、及び第2の軽鎖可変ドメイン(VL2)が配列番号12に示した配列を有し、並びに
第2の重鎖可変ドメイン(VH2)及び第2の軽鎖可変ドメイン(VL2)がジスルフィド結合によって連結されている、請求項20に記載の方法。
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KR (1) | KR20170138551A (ja) |
CN (1) | CN107683290B (ja) |
AU (1) | AU2016251960A1 (ja) |
BR (1) | BR112017022472A2 (ja) |
CA (1) | CA2983537A1 (ja) |
CL (1) | CL2017002677A1 (ja) |
CO (1) | CO2017010845A2 (ja) |
EA (1) | EA201792325A1 (ja) |
GB (1) | GB201506869D0 (ja) |
IL (1) | IL255094A0 (ja) |
MX (1) | MX2017013419A (ja) |
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GB201223276D0 (en) * | 2012-12-21 | 2013-02-06 | Ucb Pharma Sa | Antibodies and methods of producing same |
GB201411320D0 (en) | 2014-06-25 | 2014-08-06 | Ucb Biopharma Sprl | Antibody construct |
GB201506869D0 (en) * | 2015-04-22 | 2015-06-03 | Ucb Biopharma Sprl | Method |
GB201506870D0 (en) | 2015-04-22 | 2015-06-03 | Ucb Biopharma Sprl | Method |
GB201506868D0 (en) | 2015-04-22 | 2015-06-03 | Ucb Biopharma Sprl | Method for protein purification |
CR20190273A (es) * | 2016-12-09 | 2019-10-17 | Ose Immunotherapeutics | Anticuerpos y polipéptidos dirigidos contra cd127 |
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WO2016170137A1 (en) | 2016-10-27 |
KR20170138551A (ko) | 2017-12-15 |
CN107683290A (zh) | 2018-02-09 |
CN107683290B (zh) | 2022-01-04 |
AU2016251960A1 (en) | 2017-11-02 |
US20210079120A1 (en) | 2021-03-18 |
BR112017022472A2 (pt) | 2018-07-17 |
JP2018515453A (ja) | 2018-06-14 |
IL255094A0 (en) | 2017-12-31 |
CL2017002677A1 (es) | 2018-03-23 |
MX2017013419A (es) | 2018-02-09 |
US11834514B2 (en) | 2023-12-05 |
CA2983537A1 (en) | 2016-10-27 |
EP3286220A1 (en) | 2018-02-28 |
US20180142039A1 (en) | 2018-05-24 |
EA201792325A1 (ru) | 2018-04-30 |
US10829565B2 (en) | 2020-11-10 |
GB201506869D0 (en) | 2015-06-03 |
CO2017010845A2 (es) | 2018-03-20 |
SG11201708430VA (en) | 2017-11-29 |
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