JP2020172526A - 結晶性抗体製剤 - Google Patents
結晶性抗体製剤 Download PDFInfo
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- JP2020172526A JP2020172526A JP2020115765A JP2020115765A JP2020172526A JP 2020172526 A JP2020172526 A JP 2020172526A JP 2020115765 A JP2020115765 A JP 2020115765A JP 2020115765 A JP2020115765 A JP 2020115765A JP 2020172526 A JP2020172526 A JP 2020172526A
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- antibody
- seq
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- phosphate
- sodium
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- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
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- 229960000281 trometamol Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本出願は、2014年7月14日出願の米国特許仮出願第62/024,393号の利益を主張し、その全体が参照によって本明細書に組み込まれる。
電子的に提出された資料の参照による援用
本出願は、開示の別個の一部として、その全体が参照によって組み込まれるコンピュータ可読形式の配列表(ファイル名称:Seq List10−07−13_ST25.txt、2014年6月26日に作成されたもので、サイズは42KBである)を含有する。
of high concentration formulations,J.Pharm.Sci.93,1390−1402)。今のところ、高濃度製剤の要求は、安定性を増加し、凝集及び粘度を減少させるアミノ酸、糖及び塩のような賦形剤の添加により満たされている(上記Shire及びJenkins,T.W.(1998)Three
solutions of the protein solubility problem,Protein Science 7:376−382)。
crystals from a formulation perspective,Pharm.Res.18,1483−1488.)。
本発明は、例えば、以下の項目を提供する。
(項目1)
配列番号9におけるCDRL1配列の軽鎖相補性領域(CDR)、配列番号9におけるCDRL2配列のCDRL2、及び配列番号9におけるCDRL3配列のCDRL3、ならびに配列番号5におけるCDRH1配列の重鎖相補性決定領域(CDR)、配列番号5におけるCDRH2配列のCDRH2、及び配列番号5におけるCDRH3配列のCDRH3を含む、抗PCSK9 IgG抗体の結晶。
(項目2)
前記抗PCSK9 IgG抗体が、配列番号9または配列番号11の軽鎖可変領域と少なくとも90%同一である軽鎖可変領域及び配列番号5または配列番号7の重鎖可変領域と少なくとも90%同一である重鎖可変領域を含む、項目1に記載の結晶。
(項目3)
前記抗PCSK9 IgG抗体が、配列番号9または配列番号11に示される前記アミノ酸配列を有する軽鎖可変領域及び配列番号5または配列番号7に示される前記アミノ酸配列を含む重鎖可変領域を含む、項目2に記載の結晶。
(項目4)
前記結晶が、約5μM〜約50μMの長さを有する、項目1〜4に記載の結晶。
(項目5)
前記結晶が、棒及び針から成る群から選択される形状を有する、項目1〜4に記載の結晶。
(項目6)
前記結晶が、リン酸二水素ナトリウム、リン酸水素二カリウム、塩化ナトリウム、硫酸アンモニウム、酒石酸ナトリウムカリウム四水和物、クエン酸ナトリウム二水和物、酢酸ナトリウム三水和物、リン酸水素二アンモニウム、酒石酸ナトリウムカリウム、酢酸カルシウム、カコジル酸塩、CHES、CAPS、Tris、硫酸リチウム、リン酸ナトリウム、リン酸カリウム、硫酸ナトリウムから成る群から選択される塩を含む、先行項目のいずれかに記載の結晶。
(項目7)
抗体21B12の結晶の作製方法であって、抗体21B12の溶液と、リン酸二水素ナトリウム、リン酸水素二カリウム、塩化ナトリウム、硫酸アンモニウム、酒石酸ナトリウムカリウム四水和物、クエン酸ナトリウム二水和物、酢酸ナトリウム三水和物、リン酸水素二アンモニウム、酒石酸ナトリウムカリウム、酢酸カルシウム、カコジル酸塩、CHES、CAPS、Tris、硫酸リチウム、リン酸ナトリウム、リン酸カリウム、硫酸ナトリウムから成る群から選択される塩を含む結晶化試薬とを組み合わせることを含む、前記方法。
(項目8)
前記結晶化緩衝液中の塩の濃度が、約0.1M〜約10Mである、項目7に記載の方法。(項目9)
結晶が形成した後に前記結晶化緩衝液の少なくとも一部を除去することをさらに含む、項目7に記載の方法。
(項目10)
結晶化緩衝液の前記部分が、遠心分離により除去される、項目9に記載の方法。
(項目11)
前記結晶が、有機添加剤を含有する溶液中に置かれる、項目10に記載の方法。
(項目12)
前記溶液への賦形剤の添加をさらに含む、項目11に記載の方法。
(項目13)
形成した結晶を乾燥させることをさらに含む、項目7に記載の方法。
(項目14)
前記結晶が、空気への曝露により、または真空への曝露により、または窒素ガスへの曝露により乾燥される、項目13に記載の方法。
(項目15)
項目7に記載の方法により製造される21B12抗体結晶。
(項目16)
抗体21B12の結晶製剤。
(項目17)
哺乳動物対象における血清LDLコレステロールの低下方法または血清LDLコレステロールのレベル増加と関連する障害の処置方法であって、先行項目のいずれかに記載の結晶または結晶製剤を、投薬前の血清LDLコレステロールレベルと比較した場合に、前記対象における血清LDLコレステロールレベルを低下させるのに効果的な量で投与することを含む、前記方法。
いくつかの実施形態では、製剤中の抗PCSK9抗体は、少なくとも約100mg/ml、約101mg/ml、約102mg/ml、約103mg/ml、約104mg/ml、約105mg/ml、約106mg/ml、約107mg/ml、約108mg/ml、約109mg/ml、約110mg/ml、約111mg/ml、約112mg/ml、約113mg/ml、約114mg/ml、約115mg/ml、約116mg/ml、約117mg/ml、約118mg/ml、約119mg/ml、約120mg/ml、約121mg/ml、約122mg/ml、約123mg/ml、約124mg/ml、約125mg/ml、約126mg/ml、約127mg/ml、約128mg/ml、約129mg/ml、約130mg/ml、約131mg/ml、約132mg/ml、約132mg/ml、約133mg/ml、約134mg/ml、約135mg/ml、約136mg/ml、約137mg/ml、約138mg/ml、約139mg/ml、約140mg/ml、約141mg/ml、約142mg/ml、約143mg/ml、約144mg/ml、約145mg/ml、約146mg/ml、約147mg/ml、約148mg/ml、約149mg/ml、約150mg/ml、約151mg/ml、約152mg/ml、約153mg/ml、約154mg/ml、約155mg/ml、約156mg/ml、約157mg/ml、約158mg/ml、約159mg/ml、約160mg/ml、約161mg/ml、約162mg/ml、約163mg/ml、約164mg/ml、約165mg/ml、約166mg/ml、約167mg/ml、約168mg/ml、約169mg/ml、約170mg/ml、約171mg/ml、約172mg/ml、約173mg/ml、約174mg/ml、約175mg/ml、約176mg/ml、約177mg/ml、約178mg/ml、約179mg/ml、約180mg/ml、約181mg/ml、約182mg/ml、約183mg/ml、約184mg/ml、約185mg/ml、約186mg/ml、約187mg/ml、約188mg/ml、約189mg/ml、約190mg/ml、約191mg/ml、約192mg/ml、約193mg/ml、約194mg/ml、約195mg/ml、約196mg/ml、約197mg/ml、約198mg/ml、約199mg/ml、約200mg/ml、約201mg/ml、約202mg/ml、約203mg/ml、約204mg/ml、約205mg/ml、約206mg/ml、約207mg/ml、約208mg/ml、約209mg/ml、約210mg/ml、約211mg/ml、約212mg/ml、約213mg/ml、約214mg/ml、約215mg/ml、約216mg/ml、約217mg/ml、約218mg/ml、約219mg/ml、約220mg/ml、約221mg/ml、約222mg/ml、約223mg/ml、約224mg/ml、約225mg/ml、約226mg/ml、約227mg/ml、約228mg/ml、約229mg/ml、約230mg/ml、約231mg/ml、約232mg/ml、約232mg/ml、約233mg/ml、約234mg/ml、約235mg/ml、約236mg/ml、約237mg/ml、約238mg/ml、約239mg/ml、約240mg/ml、約241mg/ml、約242mg/ml、約243mg/ml、約244mg/ml、約245mg/ml、約246mg/ml、約247mg/ml、約248mg/ml、約249mg/ml、約250mg/mlの濃度(「高タンパク質濃度」)で存在し、最大で、例えば約450mg/ml、約440mg/ml、430mg/ml、420mg/ml、410mg/ml、400mg/ml、約390mg/ml、約380mg/ml、約370mg/ml、約360mg/ml、約350mg/ml、約340mg/ml、約330mg/ml、約320mg/ml、約310mg/ml、約300mg/ml、約290mg/ml、約280mg/ml、約270mg/ml、または約260mg/mlの範囲であってよい。上記端点の組み合わせを特徴とする任意の範囲が企図され、約70mg/ml〜約250mg/ml、約100mg/ml〜約250mg/ml、約150mg/ml〜約250mg/ml、約150mg/ml〜約300mg/ml、約150mg/ml〜約320mg/mlまたは約150mg/ml〜約350mg/mlを含むが、これらに限定されない。
ポリペプチド結晶は、水溶液から、または有機溶媒もしくは添加剤を含有する水溶液からの制御されたポリペプチド結晶化により成長する。制御されてよい溶液条件としては、例えば、溶媒、有機溶媒または添加剤の蒸発速度、適切な共溶質及び緩衝剤の存在、pH、ならびに温度が挙げられる。タンパク質の結晶化に影響する様々な要因の包括的な概説は、McPherson(1985,Methods Enzymol 114:112−120)により公開されている。加えて、McPherson及びGilliland(1988,J Crystal Growth,90:51−59)は、結晶化したポリペプチド、ならびにそれらが結晶化した条件の包括的な一覧表を編集した。結晶及び結晶化手法の概要、ならびに解析済みのタンパク質構造の座標に関するリポジトリは、ブルックヘブン国立研究所のProtein Data Bank(www.rcsb.org/pdb/;Bernstein et al.,1977,J Mol Biol 112:535−542)により維持されている。しかしながら、上に引用した参考文献の多くで報告されている条件は、ほとんどの場合、いくつかの大きな回折品質の結晶を生じるように最適化されていることに留意すべきである。したがって、これらの条件はタンパク質ごとに変動し、任意の所与のポリペプチド結晶を大規模製造するための高収率プロセスを提供する訳ではないことが、当業者には理解されるだろう。
本明細書で使用する場合、「結晶」または「結晶性」は、物質の固体状態の一形態を指し、第2の形態、すなわち非晶質固体状態とは異なる。結晶は、格子構造、特徴的な形状、ならびに光学特性、例えば屈折率及び複屈折などを含む、特徴的な特性を示す。結晶は、3次元で周期的に繰り返すパターンで配置された原子から成る(C.S.Barrett,Structure of Metals,2nd ed.,McGraw−Hill,New York,1952,p.1)。対照的に、非晶質材料は、物質の非結晶性固体形態であって、非晶質沈殿物と称されることもある。このような沈殿物は、結晶性固体状態に特徴的な分子格子構造を全く有さず、物質の結晶形に典型的な複屈折またはその他の分光学的特徴を示さない。
ポリペプチド結晶が形成された後、それらのポリペプチド含有量を確認し、さらにそれらの物理構造を検査するために、その結晶で様々な分析を行うことができる。例えば、必要であれば個々の結晶を結晶化溶液から取り出して、水性もしくは有機溶媒または添加剤で洗浄し、次いで(例えば、空気乾燥により、結晶の上に不活性ガス流を通過させることにより、凍結乾燥により、または真空により)乾燥させることができる。結晶を単離し、結晶成長液滴から取り出して、次いでX線回折のために搭載することができる。
本明細書で使用する場合、「組成物」という用語は、本明細書で使用する場合、少なくとも2種の成分を含む混合物を意味する。特に、結晶性抗PCSK9抗体を含む組成物、または結晶性抗PCSK9抗体を使用して調製される組成物が、本明細書に記載される。いくつかの実施形態では、結晶性抗PCSK9抗体を含む、またはそれを使用して調製される組成物または製剤は、それを必要とする患者への注射及び/または投与に好適であるように調製される。薬学的目的で患者に投与される組成物は、実質的に無菌であり、レシピエントにとって過度に毒性または感染性のある薬剤を一切含有しない。
Publishing Company,Easton,Pa.,1980,ならびにAmerican Pharmaceutical Association及びPharmaceutical Society of Great Britainによって共同出版されたHandbook of Pharmaceutical Excipientsに提示されている。
抗体結晶の固体製剤は、溶液から実質的に単離されていて、または乾燥されていて、例えば粉末形態中の自由結晶として、または粒子として存在する結晶を含む。これに関連して、「粉末」という表現は、本質的に乾燥粒子、すなわち含水率が約10重量%未満、または6重量%未満、または4重量%未満である粒子の群を指す。ポリペプチド結晶または粉末は、場合により担体または界面活性剤と組み合わされ得る。好適な担体剤としては、1)炭水化物、例えば単糖類、例えばフルクトース、ガラクトース、グルコース、ソルボースなど;2)二糖類、例えばラクトース、トレハロースなど;3)多糖類、例えばラフモース(raffmose)、マルトデキストリン、デキストランなど;4)アルジトール、例えばマンニトール、キシリトールなど;5)無機塩、例えば塩化ナトリウムなど;及び6)有機塩、例えばクエン酸ナトリウム、アスコルビン酸ナトリウムなどが挙げられる。ある種の実施形態では、担体は、トレハロース、ラフィノース、マンニトール、ソルビトール、キシリトール、イノシトール、スクロース、塩化ナトリウム、及びクエン酸ナトリウムから成る群から選択される。界面活性剤は、脂肪酸の塩、胆汁塩、リン脂質またはポリソルベートから成る群から選択され得る。脂肪酸塩としては、C10〜14脂肪酸の塩、例えばカプリン酸ナトリウム、ラウリン酸ナトリウム、及びミリスチン酸ナトリウムなどが挙げられる。胆汁塩としては、ウルソデオキシコール酸塩、タウロコール酸塩、グリココール酸塩、及びタウロジヒドロフシド酸塩の塩が挙げられる。ポリソルベートとしては、ポリソルベート20及びポリソルベート80が挙げられる。一実施形態では、界面活性剤は、タウロコール酸塩の塩、例えばタウロコール酸ナトリウムなどである。界面活性剤として使用され得るリン脂質としては、リゾホスファチジルコリンが挙げられる。一実施形態では、界面活性剤はポリソルベート20であり、別の実施形態では、界面活性剤はポリソルベート80である。
ポリペプチド結晶を、懸濁液中での保存に好適とする方法であって、結晶化緩衝液(母液)を非水性溶媒と置き換えることを含む方法もまた、本明細書に記載される。さらに別の実施形態では、結晶スラリーは、第1溶媒を回転除去し、第2有機溶媒または添加剤を使用して残存する結晶性固体を洗浄して水を除去し、続いて非水性溶媒を蒸発させることにより固体にされ得る。結晶性治療用タンパク質の非水性スラリーは、皮下送達に特に有用である。
本明細書で提供される別の実施形態は、医薬組成物の安定した長期保存を可能にする水性製剤であり、結晶性抗PCSK9抗体は、医薬組成物の調製に使用される活性成分である。この製剤が有用である理由の1つは、この製剤が再水和などの任意の追加ステップを必要としないことから、患者への使用により便利であるからである。本明細書で使用する場合、「溶液」または「液体製剤」は、好適な溶媒または相互に混和性の溶媒の混合物に溶解される1種以上の化学物質を含有する液体調製物を意味することを意図する。再構成は、適切な緩衝液または医薬製剤中におけるポリペプチド結晶または結晶製剤または組成物の溶解である。
本医薬組成物は、上記のような結晶性抗PCSK9抗体に加えて、その多くまたは全てが市販業者から入手可能である、以下の段落に列挙された以下の種類の成分または賦形剤のうち1種以上を組み合わせることにより調製される。組成物に含まれる様々な成分の組み合わせは、任意の適切な順序で行われ得、すなわち、緩衝剤が最初に、途中でまたは最後に添加され得、張度調節剤もまた最初に、途中でまたは最後に添加され得ることが、当業者には理解されるだろう。これらの化学物質のいくつかは、ある種の組み合わせにおいて不適合であり得、したがって類似した特性を有するが関連混合物に適合する異なる化学物質と容易に置換されることもまた、当業者には理解されるべきである。例えば、医薬組成物の保存に使用される容器及び/または治療的投与に使用されるデバイス内に存在する賦形剤及びその他の成分または材料の様々な組み合わせの適合性に関する知識が、当該技術分野に存在する(例えば、Akers,2002,J Pharm Sci 91:2283−2300を参照のこと)。
Blue No.1;赤、黄色、黒、青またはブレンド及び酸化第二鉄を含むが、これらに限定されない);錯化剤(エチレンジアミン四酢酸(EDTA)及びその塩、エデト酸、ゲンチシン酸エタノールメイド(ethanolmaide)ならびに硫酸オキシキノリンを含むが、これらに限定されない);乾燥剤(塩化カルシウム、硫酸カルシウム及び二酸化ケイ素を含むが、これらに限定されない);濾過助剤(粉末セルロース及び精製ケイ質土を含むが、これらに限定されない);香味料及び香料(アネトール、アニス油、ベンズアルデヒド、桂皮油、ココア、エチルバニリン、メントール、サリチル酸メチル、グルタミン酸モノナトリウム、オレンジ花油、オレンジ油、ペパーミント、ペパーミント油、ペパーミント精、ローズ油、強ローズ水、チモール、トルーバルサムチンキ、バニラ、バニラチンキ及びバニリンを含むが、これらに限定されない);保湿剤(グリセリン、へキシレングリコール、プロピレングリコール及びソルビトールを含むが、これらに限定されない);軟膏基剤(ラノリン、無水ラノリン、親水軟膏、白色軟膏、黄色軟膏、ポリエチレングリコール軟膏、ワセリン、親水ワセリン、白色ワセリン、ローズ水軟膏及びスクアランを含むが、これらに限定されない);可塑剤(ヒマシ油、ジアセチル化モノグリセリド、フタル酸ジエチル、グリセリン、モノ及びジアセチル化モノグリセリド、ポリエチレングリコール、プロピレングリコール、トリアセチンならびにクエン酸トリエチルを含むが、これらに限定されない);ポリマー膜(酢酸セルロースを含むが、これに限定されない);溶媒(アセトン、アルコール、希アルコール、アミレン水和物、安息香酸ベンジル、ブチルアルコール、四塩化炭素、クロロホルム、コーン油、綿実油、酢酸エチル、グリセリン、へキシレングリコール、イソプロピルアルコール、メチルアルコール、塩化メチレン、メチルイソブチルケトン、鉱油、ピーナッツ油、ポリエチレングリコール、炭酸プロピレン、プロピレングリコール、ゴマ油、注射用水、注射用滅菌水、灌注用滅菌水及び精製水を含むが、これらに限定されない);吸着剤(粉末セルロース、木炭、精製ケイ質土;ならびに二酸化炭素吸着剤:水酸化バリウム石灰及びソーダ石灰を含むが、これらに限定されない);硬化剤(硬化ヒマシ油、セトステアリルアルコール、セチルアルコール、セチルエステルワックス、硬質脂肪、パラフィン、ポリエチレン賦形剤、ステアリルアルコール、乳化ワックス、白色ワックス及び黄色ワックスを含むが、これらに限定されない);坐剤基剤(ココアバター、硬質脂肪及びポリエチレングリコールを含むが、これらに限定されない);懸濁化剤及び/または増粘剤(アカシア、寒天、アルギン酸、モノステアリン酸アルミニウム、ベントナイト、精製ベントナイト、マグマベントナイト、カルボマー934p、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースナトリウム12、カラギーナン、微結晶及びカルボキシメチルセルロースナトリウムセルロース、デキストリン、ゼラチン、グアーガム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ケイ酸アルミニウムマグネシウム、メチルセルロース、ペクチン、ポリエチレンオキシド、ポリビニルアルコール、ポビドン、アルギン酸プロピレングリコール、二酸化ケイ素、コロイド状二酸化ケイ素、アルギン酸ナトリウム、トラガカントならびにキサンタンガムを含むが、これらに限定されない);甘味剤(アスパルテーム、デキストレート、デキストロース、賦形剤デキストロース、フルクトース、マンニトール、サッカリン、サッカリンカルシウム、サッカリンナトリウム、ソルビトール、溶液ソルビトール、スクロース、圧縮糖、粉砂糖及びシロップを含むが、これらに限定されない);錠剤結合剤(アカシア、アルギン酸、カルボキシメチルセルロースナトリウム、微結晶セルロース、デキストリン、エチルセルロース、ゼラチン、液体グルコース、グアーガム、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、ポビドン、アルファ化デンプン及びシロップを含むが、これらに限定されない);錠剤及び/またはカプセル希釈剤(炭酸カルシウム、二塩基性リン酸カルシウム、三塩基性リン酸カルシウム、硫酸カルシウム、微結晶セルロース、粉末セルロース、デキストレート、デキストリン、デキストロース賦形剤、フルクトース、カオリン、ラクトース、マンニトール、ソルビトール、デンプン、アルファ化デンプン、スクロース、圧縮糖及び粉砂糖を含むが、これらに限定されない);錠剤崩壊剤(アルギン酸、微結晶セルロース、クロスカルメロースナトリウム、コースポビドン(corspovidone)、ポラクリリンカリウム、デンプングリコール酸ナトリウム、デンプン及びアルファ化デンプンを含むが、これらに限定されない);錠剤及び/またはカプセル潤滑剤(ステアリン酸カルシウム、ベヘン酸グリセリル、ステアリン酸マグネシウム、軽質鉱油、ポリエチレングリコール、フマル酸ステアリルナトリウム、ステアリン酸、精製ステアリン酸、タルク、硬化植物油及びステアリン酸亜鉛を含むが、これらに限定されない);ビヒクル(香味及び/または甘味付けされたもの(芳香エリキシル剤、複合ベンズアルデヒドエリキシル剤、イソアルコールエリキシル剤、ペパーミント水、ソルビトール溶液、シロップ、トルーバルサムシロップ)を含むが、これらに限定されない);油性(アーモンド油、コーン油、綿実油、オレイン酸エチル、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、鉱油、軽質鉱油、ミリスチルアルコール、オクチルドデカノール、オリーブ油、ピーナッツ油、パーシック油、ゴマ油、大豆油、スクアラン);固体担体、例えば糖球など;ならびに滅菌ビヒクル(注射用静菌水、静菌性塩化ナトリウム注射液);ならびに防水剤(シクロメチコン、ジメチコン及びシメチコンを含むが、これらに限定されない)が挙げられる。
いくつかの実施形態では、結晶性抗PCSK9抗体の徐放性形態(「制御放出」形態とも呼ばれる)が使用され、これは結晶性抗体21B12の徐放性形態;結晶性抗体21B12、及び結晶性抗体21B12の物理的放出または生物学的利用能を、所望の期間にわたって延長するための物質を含む徐放性または制御放出形態を含む。
追加の態様として、本明細書に記載される1種以上の製剤を含むキットであって、対象への投与のためにその使用を容易にする方法でパッケージ化されたキットが、本明細書に記載される。一実施形態では、このようなキットは、本明細書に記載される製剤(例えば、本明細書に記載される抗体のいずれかを含む組成物)を含み、製剤は容器、例えば密閉ボトル、槽、単回使用もしくは複数回使用バイアル、プレフィルドシリンジ、またはプレフィルド注射デバイスなどの中にパッケージ化されて、場合により方法の実施における化合物または組成物の使用について記載し、容器に貼り付けられる、またはパッケージ内に含まれるラベルを有する。一態様では、化合物または組成物は、単位剤形内にパッケージ化される。キットは、特定の投与経路による組成物の投与に好適なデバイスをさらに含んでよい。好ましくはキットは、本明細書に記載される抗体または本明細書に記載される製剤の使用について記載するラベルを含有する。
本明細書に記載される状態を処置する方法に関与する投与レジメンは、薬物の作用を調節する様々な要因、例えば、患者の年齢、状態、体重、性別及び食事、任意の感染の重症度、投与時期ならびにその他の臨床的要因を考慮して、主治医により決定されるだろう。様々な態様では、投与量は、体重1キログラム当たり0.1〜50mgの抗体調製物の範囲内である(化学修飾を含まない、タンパク質単独での質量を計算する)。いくつかの実施形態では、投与量は、約0.5mg/kg〜20mg/kg、または約0.5〜10mg/kgである。いくつかの実施形態では、投与量は、約120mg〜約1200mg、または約280〜約450mgである。
当業者には理解されるように、多様なコレステロール、LDL、LDLR、PCSK9、VLDL−C、アポタンパク質B(「ApoB」)、リポタンパク質A(「Lp(a)」)、トリグリセリド、HDL−C、非HDL−C、及び総コレステロールレベルに関連し、それらに関与し、またはそれらによって影響され得る障害は、本発明の医薬製剤によって対処され得る。一態様では、抗PCS9抗体製剤は、血清コレステロールレベルの上昇に関連する、または血清コレステロールレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、PCSK9値の上昇に関連する、またはPCSK9値の上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、総コレステロールレベルの上昇に関連する、または総コレステロールレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、非HDLコレステロールレベルの上昇に関連する、または非HDLコレステロールレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、ApoBレベルの上昇に関連する、またはApoBレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、Lp(a)レベルの上昇に関連する、またはLp(a)レベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、トリグリセリドレベルの上昇に関連する、またはトリグリセリドレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。一態様では、抗PCS9抗体製剤は、VLDL−Cレベルの上昇に関連する、またはVLDL−Cレベルの上昇が関連する障害を処置及び/もしくは予防する、ならびに/またはその障害のリスクを減少させる方法に使用され得る。
同じ病原体または生化学的経路を標的とする2種以上の薬剤を組み合わせることによる病状の処置は、各薬剤単独の治療に関連する用量の使用と比較して、より高い有効性及び副作用の減少をもたらすことがある。いくつかの場合には、混合薬の有効性は相加的(混合の有効性が各薬剤単独での効果の和にほぼ等しい)であるが、その他の場合には、効果は相乗的(混合の有効性が所与の各薬剤単独での効果の和よりも高い)であり得る。本明細書で使用する場合、「併用療法」という用語は、2種類の化合物が同時に、例えば並行して送達され得る、または化合物のうちの1種が最初に投与されて、続いて第2薬剤が投与されるような、例えば連続して送達され得ることを意味する。望ましい結果は、投与のレシピエントにおける1つ以上の症状の主観的な軽減または客観的に特定可能な改善のいずれかであり得る。
pH5.0の20mMの酢酸ナトリウム、220mMのプロリン、0.010%ポリソルベート80中における抗体21B12(配列番号17及び19、図4A及び図4B)(120mg/ml)を、Bio−Radの脱塩カラムを使用して、pH5.0の20mMの酢酸緩衝液中で脱塩した。抗体21B12を、様々な条件下で結晶化した。
実施例1に記載されるように抗体21B12結晶の生成に成功することを証明した一定の条件を、以下の通りにマイクロバッチ最適化のために選択した。別段の注記がない限り、全ての条件で、Bio−Radの脱塩カラムを使用してpH5.0の20mMの酢酸緩衝液中で脱塩した、pH5.0の10mMの酢酸ナトリウム、220mMのプロリン、0.010%ポリソルベート80中における抗体21B12(120mg/ml)を使用した。2本の成熟重鎖(配列番号19)及び2本の成熟軽鎖(配列番号17)の各々をコードするDNAによって組換え産生された、これらの鎖から成る抗体21B12を、様々な条件下で結晶化した。
抗体21B12を、7〜10mg/mlでWizard II #10(1.0Mの(NH4)2HPO4、pH8.5の0.1MのTris)でスクリーニングし、以下の表2.1に記載されている条件を使用して最適化した。
この条件では、異なる(NH4)2HPO4濃度、異なるNaCl濃度、及び異なる抗体21B12濃度を試験した。最適条件は、0.6Mの(NH4)2HPO4、pH5.5の0.05Mのクエン酸塩、0.1MのNaClであった。結晶のサイズは不均一であって、(NH4)2HPO4塩は、より低いpHにおいてNaClなしで抗体21B12を結晶化した。Wizard II #33の最適化条件は、以下の表2.2及び2.3に記載している。
この条件では、異なる酒石酸Na/K濃度及び異なる抗体21B12濃度を試験した。また、異なる緩衝液をMES緩衝液と置き換えて試験した。最適条件は、0.7Mの酒石酸Na/K、pH6.0の0.05Mの酢酸塩であった。最適化条件は、以下の表2.4に記載している。
この条件では、異なるNaH2PO4/K2HPO4緩衝液濃度(リン酸塩濃度)、異なるpH及び異なる抗体21B12濃度を試験した。脱塩した抗体21B12の最適条件は、pH5.3の1.4Mのリン酸塩、13mg/mlの抗体21B12であって、95%超の結晶化収率をもたらした。pH5.0の10mMの酢酸塩、220mMのプロリン、0.01%ポリソルベート80中における抗体21B12の最適条件は、pH5.3の1.3Mのリン酸塩、64mg/mLの抗体21B12であって、99%の収率であった。最適化条件は、表2.5及び2.6に記載している。
この条件では、異なるPEG及び抗体21B12濃度を、pH8.0のTris緩衝液で試験した。より若干の毛様で細い針をバッチで観察した。最適化条件は、以下の表2.7及び2.8に記載している。
pH5.0の20mMの酢酸塩、220mMのプロリン、0.01%ポリソルベート80中における抗体21B12(配列番号17及び19、図4A及び図4B)を、1.5mlの遠心管内において1.0mlの最終体積でバッチ結晶化した。抗体21B12の結晶化条件は、pH5.3の1.3Mのリン酸塩、64mg/mLの抗体21B12であって、99%の収率であった。pH5.0の20mMの酢酸塩中で脱塩した抗体21B12を、1.5mlの遠心管内において1mlの最終体積で、1.4Mのリン酸塩(pH5.3)の最終濃度で、13mg/mLの抗体21B12を用いて97%の収率でバッチ結晶化した。
結晶形成は、他のpHと比較してpH4.2で急激に速くなった。したがって、このpHを選択し、リン酸塩濃度を試験した。リン酸緩衝液のストック溶液を、3.5Mの濃度で3.7〜4.7のpH範囲において0.2pH単位ずつ増加させて作製した。バッチを、最終抗体21B12濃度が82.8mg/mLで、最終リン酸塩濃度が1.3Mのリン酸塩であるように、異なる試験pHで作製した。リン酸塩を3回に分けて添加し、添加の間に30分間インキュベートした。最初に0.9Mを一度に全て添加し、次いで総リン酸塩濃度を1.3Mにするための残りの量を0.2Mずつ2回に分けて添加した。バッチを2mLの遠心管内において作製し、ボルテックスミキサー上でリン酸塩を添加するごとに3000rpmで約10〜15秒間混合し、室温で静止状態にしてインキュベートした。収率及び結晶サイズを3.0〜3.5時間で測定した。実験の概要を以下の表3.1に示す。
リン酸緩衝液のストック溶液を、3.5Mの濃度においてpH4.2で作製した。0.5M〜1.5Mのリン酸塩濃度を、0.2Mずつ増加させて試験した。バッチを2mLの遠心管内において、最終抗体21B12濃度が75mg/mLで、最終リン酸塩濃度が0.5〜1.5MであるようにpH4.2で作製した。リン酸塩の最終濃度が1.5Mに到達するリン酸塩量の増加に伴い、抗体21B12を75mg/mLまで希釈した。リン酸塩を、0.5M〜1.5Mのバッチで一度に全て抗体21B12に添加し、最高速度設定で約10秒間ボルテックス混合し、室温で静止状態を維持した。収率及び結晶サイズを3.0〜3.5時間で測定した。1.3及び1.5Mの最終リン酸塩濃度について一度での添加に加えて、1.3Mでは2段階添加(0.9M+0.4M)ならびに1.5Mのリン酸塩では2段階添加(0.9M+0.6M)及び3段階添加(0.9+0.3M+0.3M)を、各添加について30分間隔で実施し、各添加におけるリン酸塩の耐性を確認する。実験の概要を表3.2に示す。1.1〜1.5Mには一度でのリン酸塩添加に耐性がなく、ゲル形成をもたらした。したがって、以下の実験では結晶化収率を改善するために、リン酸塩の段階添加を選択した。
結晶化バッチを、60、70及び80mg/mLの最終抗体21B12濃度において1mLスケールで作製した。バッチを、2Mlの遠心管内においてpH4.2で1.3Mのリン酸塩濃度で作製した。リン酸塩を3回に分けて添加し、添加の間に30分間インキュベートした。最初に0.9Mを一度に全て添加し、次いで総リン酸塩濃度を1.3Mにするための残りの量を0.2Mずつ2回に分けて添加した。バッチを、ボルテックスミキサー上でリン酸塩の添加ごとに最高速度設定で10〜15秒間混合し、室温でインキュベートした。収率及び結晶サイズをおよそ3.5時間で試験した。実験の概要を表3.3に示す。60mg/mlのタンパク質バッチに対して、80mg/mlのタンパク質濃度では良好な品質の結晶及び良好な収率が得られたので、およそ80mg/mlのタンパク質をさらなる最適化実験において選択した。
結晶化バッチを、15℃〜25℃の範囲で2℃ずつ増加させた異なる温度において1mLスケールで実施した。バッチを、pH4.2において1.3Mのリン酸塩濃度で作製し、最終抗体21B12濃度が82.8mg/mLであった。バッチを、2mLの遠心管内において試験温度に平衡させた抗体21B12及び試薬を用いて作製した。リン酸塩を3回に分けて添加し、添加の間に30分間インキュベートした。最初に0.9Mを一度に全て添加し、次いで総リン酸塩濃度を1.3Mにするための残りの量を0.2Mずつ2回に分けて添加した。バッチを、ボルテックスミキサー上でリン酸塩の添加ごとに最高速度設定でおよそ10〜15秒間混合し、温度制御水槽内でインキュベートした。収率及び結晶サイズをおよそ3.5時間で試験した。実験の概要を表3.4に示す。より高い19〜25℃での結晶化は、温度の増加に伴い高品質な結晶をもたらした。
バッチを、実施例3におけるような1mLスケールで生成した状態図のさらなる確認のために10mLスケールで作製した。10mLの実験では、データは連続混合を用いて生成したが、その理由とはこのパラメータを1mLスケールで調査できなかったからである。
pH4.1〜4.7のリン酸塩溶液を、0.2pH単位ずつ増加させてスクリーニングした。実験の概要を以下の表4.1に示す。バッチを作製し、室温で最終抗体21B12濃度がおよそ80mg/mLであり1.3Mのリン酸塩であった。結果は表4.1にまとめた。次のパラメータ試験のために、結晶化pH範囲の中間である試薬pH4.4を選択した。
1.0M、1.2M、1.4M及び1.5Mのリン酸塩濃度を、4.4のpHで試験した。実験の概要を以下の表4.2に示す。バッチを作製し、室温で最終抗体21B12濃度がおよそ80mg/mLであり、1.0M、1.2M及び1.3Mのリン酸塩であった。1.4M及び1.5Mのリン酸塩については、所望のリン酸塩濃度を達成するにはより多くのストック溶液が必要であったため、抗体21B12濃度をそれぞれおよそ77mg/mL及びおよそ73mg/mLまで減少させた。結果は表4.2にまとめた。1.5Mのリン酸塩濃度は、より低いリン酸塩濃度と比較して、肉眼での観測で結晶懸濁液の流動が比較的容易であった。したがって、1.5Mのリン酸塩を、次のパラメータを最適化するためにpH4.4と共に選択した。
21、23、25、27、30及び35℃の温度を、4.4のpHで1.5Mのリン酸塩濃度において試験した。結果を含む、実験の概要を以下の表4.3に示す。バッチを作製し、最終抗体21B12濃度がおよそ73mg/mLであった。
抗体21B12(配列番号17及び19、図4A及び図4B)を、pH4.4で1.5Mの最終リン酸塩濃度を有するリン酸緩衝液及び73.8mg/mLの最終21B12抗体濃度を使用して結晶化した。
実施例5に記載されるように抗体21B12結晶の生成に成功することを証明した一定の条件を、以下の通りに最適化のために選択した:
実施例6に記載されるように抗体21B12結晶の生成に成功することを証明した一定の条件を、以下の通りに最適化のために選択した:
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US20170198059A1 (en) | 2017-07-13 |
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AU2015289874A1 (en) | 2017-02-02 |
EP3169710A1 (en) | 2017-05-24 |
MX2017000527A (es) | 2017-08-10 |
AU2021201422A1 (en) | 2021-03-25 |
WO2016010927A1 (en) | 2016-01-21 |
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