JP5826180B2 - 分離マトリックス - Google Patents
分離マトリックス Download PDFInfo
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- JP5826180B2 JP5826180B2 JP2012533117A JP2012533117A JP5826180B2 JP 5826180 B2 JP5826180 B2 JP 5826180B2 JP 2012533117 A JP2012533117 A JP 2012533117A JP 2012533117 A JP2012533117 A JP 2012533117A JP 5826180 B2 JP5826180 B2 JP 5826180B2
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- 230000035945 sensitivity Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- PUVAFTRIIUSGLK-UHFFFAOYSA-M trimethyl(oxiran-2-ylmethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1CO1 PUVAFTRIIUSGLK-UHFFFAOYSA-M 0.000 description 1
- 238000002460 vibrational spectroscopy Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000006886 vinylation reaction Methods 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/36—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving ionic interaction
- B01D15/361—Ion-exchange
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
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- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/36—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving ionic interaction
- B01D15/361—Ion-exchange
- B01D15/362—Cation-exchange
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- B01D—SEPARATION
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- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/36—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving ionic interaction
- B01D15/361—Ion-exchange
- B01D15/363—Anion-exchange
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3847—Multimodal interactions
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
- B01J20/287—Non-polar phases; Reversed phases
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3285—Coating or impregnation layers comprising different type of functional groups or interactions, e.g. different ligands in various parts of the sorbent, mixed mode, dual zone, bimodal, multimodal, ionic or hydrophobic, cationic or anionic, hydrophilic or hydrophobic
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/08—Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/16—Organic material
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- B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/08—Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/16—Organic material
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- B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
- B01J39/26—Cation exchangers for chromatographic processes
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- B01J41/00—Anion exchange; Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
- B01J41/08—Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
- B01J41/12—Macromolecular compounds
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- B01J41/00—Anion exchange; Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
- B01J41/20—Anion exchangers for chromatographic processes
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Description
本明細書では、用語「標的化合物」は水溶液から単離したい化合物、分子又は他の要素を意味する。標的化合物は、所望の生成物でも、液状生成物の不要な不純物でもよい。標的化合物が生体分子である場合、それを標的生体分子と呼ぶことができる。
本発明の一態様は、ベースマトリックスを含有し、上記ベースマトリックスに疎水性官能基を有する第1リガンドが共有結合し、かつ上記ベースマトリックスにエクステンダーが共有結合し、上記エクステンダーが第2イオン交換リガンドを有する、分離マトリックスを提供する。本発明の1つの利点は、ベースマトリックス上のエクステンダー及び疎水性リガンドの組み合わせが、モノクローナル抗体などのタンパク質に対して驚くほど高い選択性を示し、高い動的タンパク質結合能も兼ね備えることである。疎水性官能基を有するリガンドの量及び/又は種類を変化させることにより、選択性を微調整することも可能である。
図1はベースマトリックスに付加したn−ブチル量の関数としてモノクローナル抗体の動的結合能及びカチオン交換プールのHCPレベルを示す。
フィードは、CHO細胞で発現させた、等電点pH9.2のIgGモノクローナル抗体のタンパク質Aカラム溶出液であった。抗体濃度は約5g/Lであり、宿主細胞タンパク質の濃度は16,000ppmであり、ゲンタマイシン(細胞培養の添加剤)の濃度は約175ng/mlであった。フィード導電率は、約4mS/cmに調整した。
Bergの米国特許第6,602,990号に記載されている通りに製造したアガロースゲルビーズ、即ちフロー/圧力特性を向上したアガロースを以下の合成例1a)に記載する条件を用いてn−ブチルグリシジルエーテルと反応させて、制御された疎水性をマトリックスに導入した。その後、以下の合成例1b)に記載する条件を用いてアガロースビーズのエポキシ活性化及び所定レベルのデキストランカップリングによりエクステンダーを導入した。最後に、合成例1c)にしたがってゲルをビニルスルホン酸ナトリウムと反応させてカチオン交換リガンドを所望レベルに導入した。
125gのゲル(沈降物)を37.5mLの水に懸濁させ、20.6gの硫酸ナトリウムを添加し、その後、室温で30分間攪拌した。攪拌したスラリーに37.5gの50重量%水酸化ナトリウム溶液及び0.52gの水素化ホウ素ナトリウムを添加した。混合物を1時間室温で攪拌し、その後、31.25mLのブチルグリシジルエーテルを添加し、続いて50℃でさらに20時間攪拌した。反応が完了した後、100mLの水を添加し、反応懸濁液を酢酸で中性pHに中和した。
疎水性リガンドを導入したゲル(沈降物)120gに32.8mLの水及び36mLの50重量%水酸化ナトリウム水溶液を添加し、続いて、スラリーを室温で20分間攪拌した。その後、ドシメーターポンプ(dosimeter pump)を用いて、総量40mLのエピクロロヒドリンを0.33mL/分で添加し、その後、室温でさらに2時間攪拌した。最後に、水を用いてゲルをガラスフィルター上で洗浄した。これらの反応条件により、沈降ゲル1mL当たり11μmolのエポキシ活性化レベルが得られた。
60gの上記のように製造したゲル(沈降物)をガラスフィルター上で120mLの30%ビニルスルホン酸ナトリウム塩(VSA)で4回洗浄し、最後の洗浄によりゲルとVSAの合計重量が120gになった。75mLの50重量%水酸化ナトリウム溶液を添加し、続いて、52℃で3.75時間攪拌した。その後、ゲルをガラスフィルター上で水で洗浄した。これらの条件により、沈降ゲル1mL当たり99μmolのイオンリガンド密度をもつゲルが得られた。
20cmベット高のカラム及び20分間のサンプル滞留時間を用いて、IgGモノクローナル抗体に対する10%破過(QB10%)での動的結合能を測定した。カラムを25mMの酢酸ナトリウム(pH5.0)で平衡化した後にサンプルを添加した。添加が完了したら、カラムを平衡緩衝液で洗浄し、移動相で溶出した。条件はpH5及び4mS/cmであった。
モノクローナル抗体の添加量を1mlのゲルに対して130mgに低減した、即ちプロセス条件下での現実的な観点の不純物排除を示すために動的破過容量よりかなり少なくした以外は、動的結合能の測定で記載したのと同様な方法で不純物の除去を試験した。結合したモノクローナル抗体は、酢酸ナトリウムを500mMまで増加させて導電率勾配よって溶出させた。溶出相を280nmでのUV吸光度でモニターし、光学濃度(OD)0.5のピークフロントとOD0.5のピークテール間で溶出プールを回収し、残留HCP及びゲンタマイシンの分析をした。
Claims (10)
- ベースマトリックスを含む分離マトリックスであって、疎水性官能基を有する第1リガンドが前記ベースマトリックスに共有結合しているとともに、第2イオン交換リガンドを有するエクステンダーが前記ベースマトリックスに共有結合しており、前記エクステンダーが平均分子量1000Da以上のポリヒドロキシポリマーを含んでいる、分離マトリックス。
- 疎水性官能基を有するリガンドが1以上のC2〜C18炭化水素鎖又は1以上の炭化水素環を有する、請求項1記載の分離マトリックス。
- エクステンダーがデキストランを含む、請求項1又は請求項2記載の分離マトリックス。
- ベースマトリックスが、架橋ポリヒドロキシポリマーを含む、請求項1乃至請求項3のいずれか1項記載の分離マトリックス。
- エクステンダーが疎水性リガンドを5マイクロモル/g未満含む、請求項1乃至請求項4のいずれか1項記載の分離マトリックス。
- 疎水性官能基を有するリガンドの量が分離マトリックス1ml当たり10〜100マイクロモルである、請求項1乃至請求項5のいずれか1項記載の分離マトリックス。
- 請求項1乃至請求項6のいずれか1項記載の分離マトリックスの製造方法であって、
a)疎水性官能基を有する第1リガンドをベースマトリックスにカップリングする工程と、
b)エクステンダーを前記ベースマトリックスにカップリングする工程と、
c)第2イオン交換リガンドを前記エクステンダーにカップリングする工程と
を任意の順序で含む、方法。 - 疎水性官能基を有するリガンドをベースマトリックスにカップリングした後にエクステンダーをカップリングする、請求項7記載の方法。
- 液体製剤から1種以上の標的生体分子を分離する方法であって、
請求項1乃至請求項6のいずれか1項記載の分離マトリックスに液体製剤を接触させる工程を含む方法。 - 標的生体分子がタンパク質である、請求項9記載の方法。
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US9994609B2 (en) | 2013-03-15 | 2018-06-12 | Biogen Ma Inc. | Hydrophobic interaction protein chromatography under no-salt conditions |
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