JP6797767B2 - バイオ医薬品の投与に関連した免疫応答を調節可能にする方法および製剤 - Google Patents
バイオ医薬品の投与に関連した免疫応答を調節可能にする方法および製剤 Download PDFInfo
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Description
(i)・ヘキサン二酸もしくはその少なくとも1種の塩、および/または
・クエン酸もしくはその少なくとも1種の塩
を含む緩衝液を提供する工程、
(ii)前記緩衝液をバイオ医薬品と接触させる工程、
(iii)前記製剤を必要に応じて凍結乾燥させる工程、および
(iv)(ii)の製剤もしくは懸濁液および/または(iii)の凍結乾燥された製剤を得る工程、を含む。
・ヘキサン二酸もしくはその少なくとも1種の塩、および/または
・クエン酸もしくはその少なくとも1種の塩、
または前述の方法によって得ることができる製剤、を含む。
・ヘキサン二酸もしくはその少なくとも1種の塩、および/または
・クエン酸もしくはその少なくとも1種の塩
の濃度を適合させる工程を含む。
・酢酸または酢酸塩、
・グルタミン酸またはグルタミン酸塩、
・リンゴ酸またはリンゴ酸塩、
・クエン酸および/またはクエン酸塩、
・リン酸および/またはリン酸塩、
・酒石酸または酒石酸塩、および/または
・コハク酸またはコハク酸塩、
からなる群から選択されるうちの少なくとも1つである。
a)水性形態、
b)凍結乾燥形態、および/または
c)懸濁液、
からなる群から選択される形態である。
・酢酸または酢酸塩、
・グルタミン酸またはグルタミン酸塩、
・リンゴ酸またはリンゴ酸塩、
・リン酸および/またはリン酸、
・酒石酸または酒石酸塩、および/または
・コハク酸またはコハク酸塩、
からなる群から選択される少なくとも1つのさらなる緩衝化合物、または対象へ注入すると免疫原性を誘発するまたは免疫原性を増強することが知られているその他の物質(expedient)を実質的に含まなくてもよい。
・界面活性剤、
・等張化剤、および/または
・金属イオンキレート剤
からなる群から選択される少なくとも1種の薬剤をさらに含む。
(i)ハイブリドーマ由来抗体、
(ii)キメラ化抗体、
(iii)ヒト化抗体、および/または
(iv)ヒト抗体
からなる群から選択される少なくとも1種の抗体またはその断片もしくは誘導体であることが特に好ましい。
・相補性決定領域(CDR)
・高頻度可変領域、
・可変ドメイン(Fv)、
・IgG重鎖(VH、CH1、ヒンジ、CH2およびCH3領域からなる)
・IgG軽鎖(VLおよびCL領域からなる)、および/または
・Fabおよび/またはF(ab)2
などの標的結合能力を保持している、そのような抗体の断片を指すものとする。
・配列番号1および2がコードするものと同じタンパク質またはタンパク鎖をコードするが、遺伝子コードの縮重として許容可能なヌクレオチドの置換を有する核酸配列、
・配列番号1および2によってコードされるタンパク質またはタンパク鎖の一部、変異体、ホモログもしくは誘導体をコードする配列、
・所与の発現宿主に対して最適化されたコードである核酸配列、および/または
・配列番号1または2のいずれかと少なくとも70%、好ましくは95%の配列同一性を有する核酸分子、
によって相同的に置き換えられることを理解されたい。
・自己免疫疾患、
・感染症、
・腫瘍性および/または悪性の疾患(癌)、および
・神経系疾患
からなる群から選択される少なくとも1つの病理学的状態の治療に使用される。
実施例1:実験1
動物
純血種のメスのニュージーランドホワイト(NZW)ウサギ45匹を民間の育種業者から購入した。体重は約3kgで、すべての動物は疾病の外的徴候がないか調べ、健康な個体のみになるようにした。各個体に番号を入れ墨して印を付けた。
実験第1日目に一人の動物技師がすべての動物の背部皮下にボーラス投与した。注入速度は約15秒/投与で投与量は体重1キログラム当たり0.2mLとした。
3つの処置群を決定し、そのうちの2群(第1および第3群)を譲受人の型のアダリムマブを含む製剤で処置し、残りの1群(第2群)はヒュミラ(登録商標)を含む製剤で処置した。
動物には、認可された市販の餌(ssniff(登録商標)K−H(ssniff Spezialdiaten有限責任会社、59494 ゾースト、ドイツ)と飲料水道水を自由摂取で与えた。動物を個別に標準的なケージに入れ、室温を約20℃±3℃、相対湿度を55%±15%にした。清掃中は短時間その条件からずれが生じた。飼育室は12時間明期/12時間暗期のサイクルで照らした(約1.50m天井高から約150ルクス)。
血液試料を、投与前、2、8(実験1日目)、24、40(実験2日目)、48、60時間経過後および実験4、5、8、15、22、29日目の時点で採取した。試料を処理して血清を分離し、出荷してこの用途に適した慣習的なサンドイッチELISA法でアダリムマブ濃度を解析するまで、−20℃以下で凍結保存した。
動物
純血種のオスのニュージーランドホワイト(NZW)ウサギ100匹を、実験1と同じ民間の育種業者から購入した。得られるデータの信頼性をあげるため群の大きさをわずかに増やし、実験1のn=15/群に対しn=20/群とした。実験1の結果が性別に影響されないかどうかを評価するためにオスを選んだ。動物の特徴ならびに実験計画のその他の側面、つまり実験群への無作為な割り振り、投与量、処置量、食餌、飼育条件、飲料水および照明条件、血液試料の処理および試料の保存は実験1と同様とした。
5つの処置群を決定し、そのうちの4群(第2〜5群)を譲受人のアダリムマブ型を含む製剤で処置し、残りの1群(第1群)を、ヒュミラ(登録商標)を含む製剤で処置した。
確実にクリアランスを最大にし、ADA検出による薬剤干渉を最小化するため、アダリムマブの血清濃度および免疫原性の解析のための採血をする時点を、にわずかに遅らせた。試料は以下の時点で収集した:投与前、2、8(実験1日目)、24、40(実験2日目)、56時間経過後および実験4、5日目、およびその後週間隔、つまり実験8、15、22、29、36、43、50、57、64、71、78日目。試料を処理して血清を分離し、出荷されこの用途に適した慣習的なELISA法によってアダリムマブ濃度およびADAを解析するまで、−20℃以下で凍結保存した。
図1−aは、実験1で皮下に1回注入した後のアダリムマブ濃度の経時変化を示している。投与して約一週間後から、約40%の個体において血清レベルの顕著な低下が見られた。アダリムマブはヒトおよび霊長類のTNFに対する特異性が高いので、この種では標的介在性の薬物動態は起こらない。そのため、クリアランスの増加は免疫原性、つまり抗薬物抗体によって、ともすると中和/阻害特性によって引き起こされた可能性が高い。そのようなクリアランスの増加は、抗体が結合していない薬剤と比べて、抗体−薬剤抱合体の主要な特徴である。また、一例目が発生した時点、つまり一週間後というのはこの解釈とよく一致しており、動物種へ投与されたヒトタンパク質について、特に皮下投与のような免疫原性を刺激するリスクがある経路で投与されたヒトタンパク質について予想される効果であると解釈される。
Claims (7)
- 免疫グロブリンを含む医薬組成物の免疫原性を低減するために、ヘキサン二酸もしくはその少なくとも1種の塩、および、クエン酸もしくはその少なくとも1種の塩を使用する方法であって、
前記方法は、以下のステップを含む:
(1)ヘキサン二酸もしくはその少なくとも1種の塩、および、クエン酸もしくはその少なくとも1種の塩を含む、緩衝液を提供すること、
ここで、クエン酸もしくはその少なくとも1種の塩は、上記医薬組成物における最終濃度が1.3mM以下になるように含まれ、および、
(2)前記緩衝液を、少なくとも1つの免疫グロブリンと接触させること。 - 組成物がさらに、アミノ酸、糖ポリオール、二糖類および/または多糖類からなる群から選択される少なくとも1種の安定剤を含む、請求項1に記載の方法。
- 前記二糖類が、ショ糖、トレハロース、麦芽糖および/または乳糖からなる群から選択される少なくとも1種の薬剤である、請求項2に記載の方法。
- 前記糖ポリオールが、マンニトールおよび/またはソルビトールからなる群から選択される少なくとも1種の薬剤である、請求項2に記載の方法。
- 前記免疫グロブリンが抗TNFα抗体である、請求項1〜4のいずれか1項に記載の方法。
- 組成物が、筋肉内にまたは皮下に投与されるように設計された、請求項1〜5のいずれか1項に記載の方法。
- 組成物が、非経口で投与されるように設計された、請求項1〜5のいずれか1項に記載の方法。
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EP2702077A2 (en) | 2011-04-27 | 2014-03-05 | AbbVie Inc. | Methods for controlling the galactosylation profile of recombinantly-expressed proteins |
US9067990B2 (en) | 2013-03-14 | 2015-06-30 | Abbvie, Inc. | Protein purification using displacement chromatography |
WO2013158279A1 (en) | 2012-04-20 | 2013-10-24 | Abbvie Inc. | Protein purification methods to reduce acidic species |
WO2013158273A1 (en) | 2012-04-20 | 2013-10-24 | Abbvie Inc. | Methods to modulate c-terminal lysine variant distribution |
WO2013176754A1 (en) | 2012-05-24 | 2013-11-28 | Abbvie Inc. | Novel purification of antibodies using hydrophobic interaction chromatography |
US9512214B2 (en) | 2012-09-02 | 2016-12-06 | Abbvie, Inc. | Methods to control protein heterogeneity |
AU2013381687A1 (en) | 2013-03-12 | 2015-09-24 | Abbvie Inc. | Human antibodies that bind human TNF-alpha and methods of preparing the same |
US9499614B2 (en) | 2013-03-14 | 2016-11-22 | Abbvie Inc. | Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides |
US9017687B1 (en) | 2013-10-18 | 2015-04-28 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same using displacement chromatography |
US9598667B2 (en) | 2013-10-04 | 2017-03-21 | Abbvie Inc. | Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins |
US9181337B2 (en) | 2013-10-18 | 2015-11-10 | Abbvie, Inc. | Modulated lysine variant species compositions and methods for producing and using the same |
US9085618B2 (en) | 2013-10-18 | 2015-07-21 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same |
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SG175188A1 (en) * | 2009-05-04 | 2011-11-28 | Abbott Biotech Ltd | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
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US20160151484A1 (en) | 2016-06-02 |
JP2016525110A (ja) | 2016-08-22 |
MX2020005247A (es) | 2020-08-24 |
SI3021833T1 (sl) | 2018-10-30 |
EP3021833A1 (en) | 2016-05-25 |
CN105377237A (zh) | 2016-03-02 |
WO2015007912A1 (en) | 2015-01-22 |
SI3021833T2 (sl) | 2022-08-31 |
ES2688726T3 (es) | 2018-11-06 |
RU2662558C2 (ru) | 2018-07-26 |
BR112016000563A2 (pt) | 2017-09-05 |
AU2014291970B2 (en) | 2017-09-28 |
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MX2016000405A (es) | 2016-09-09 |
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