TWI641384B - 抗-催乳素受體抗體調配物 - Google Patents
抗-催乳素受體抗體調配物 Download PDFInfo
- Publication number
- TWI641384B TWI641384B TW102131178A TW102131178A TWI641384B TW I641384 B TWI641384 B TW I641384B TW 102131178 A TW102131178 A TW 102131178A TW 102131178 A TW102131178 A TW 102131178A TW I641384 B TWI641384 B TW I641384B
- Authority
- TW
- Taiwan
- Prior art keywords
- prlr antibody
- prlr
- sucrose
- item
- histidine
- Prior art date
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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Abstract
係提供一廣泛濃度範圍,特別是高濃度、實質上無鹽的抗催乳素受體抗體調配物,其實質上為等滲壓和低黏度的。
Description
本揭示文一般係關於一廣泛濃度範圍之實質上等滲壓和低黏度的抗-催乳素受體抗體調配物,包括可用於皮下和一般注射給藥之調配物。
催乳素(PRL)為一199個胺基酸所組成之多肽激素。PRL係屬於多肽激素之生長激素(GH),胎盤生乳素(PL)家族且係在腦下垂體的激乳細胞中及數個垂體外組織,例如淋巴細胞、乳線上皮細胞、子宮肌層和前列腺中合成。二種不同的促進劑調節腦下垂體和垂體外PRL合成(BioEssays 28:1051-1055(2006))。
PRL係與PRL受體(PRLR),一種單一跨膜受體屬於第1類細胞激素受體超家族,相結合(Endocrine Reviews 19:225-268(1998))。PRLR係以三種不同的同型物存在,短、長和中間型,其可藉由其胞質尾之長度來區分。因與配體結合,一連續的過程導致PRLR活化。PRL係經由其結合區1與一PRLR分子相互作用及然後經由其結合區2吸引第二受體分子,產生活化的PRLR二聚物。
PRLR二聚化作用使得JAK/STAT(Janus激媒/轉錄之訊號轉導子活化子)路徑優先活化。因受體二聚化,JAK(主要JAK2)與此受體結合,轉磷酸化並相互活化。此外,PRLR亦被磷酸化並可與含有SH2-區之蛋白例如STAT結合。受體結合STAT隨後被磷酸化,與受體解離並轉移到核上,於該處
其刺激目標基因轉錄。此外,PRLR之Ras-Raf-MAPK路徑的活化和細胞質src激酶之活化已有描述(參見Endocrine Reviews 19:225-268(1998))。
PRLR-媒介的訊號傳遞之角色已於良性疾病子宮內膜異位的情況中有研究。在一研究中,係於月經周期的中-晚期增生期期間分析PRLR在子宮內膜異位病患之子宮內膜異位樣本中和在位內膜的表現模式(Acta Obstet Gynecol Scand 81:5-10,2002)。其驗證,於79%分析的子宮內膜異位病患之在位內膜中存有PRLR mRNA,而在86%子宮內膜異位病患的子宮內膜異位病灶則無。這些數據顯示正常和子宮內膜異位組織間可能的PRLR表現之差別調節。然而,從這些表現數據,其不能結論出抑制PRLR可能代表一適合的子宮內膜異位治療-特別是因為在子宮內膜異位病灶中並未發現PRLR表現(Acta Obstet Gynecol Scand 81:5-10(2002))。
為了阻斷PRLR功能正致力開發抗催乳素受體(PRLR)之抗體,包括抗-PRLR單株抗體(aPRLR mAbs)。一此種aPRLR mAb為IgG2抗-PRLR mAb,其係經開發供子宮內膜異位病患之非-激素性治療。
抗體可經由靜脈內、肌肉內及/或皮下注射投予病患。為了確保病患的服從性,最好肌肉內注射和皮下注射劑型為等張的並包括小注射量(每個注射位置<2ml)。為了降低注射量及提供有效劑量,抗體通常係以從1mg/ml至150mg/mL,包括範圍在20mg/ml至150mg/ml內的高濃度之廣泛的濃度範圍來給藥。
當液體和凍乾劑型二者為目前市面上抗體藥物產品所使用時,凍乾形式更常用於具有高蛋白濃度之抗體藥物產品。高濃度抗體調配物在調配物開發上可能存有許多的挑戰,特別是就液體調配物而言。對於其中抗體濃度接近其表觀溶解度限制之調配物,可能經由沉澱、成膠及/或結晶發生相分離。在高蛋白濃度時,由於形成可溶和不可溶的蛋白-蛋白聚合物,抗體的穩定性可能變成問題。高濃縮抗體調配物通常為高黏度,其處理上存有難度,例如超過濾和無菌過濾及用於注射劑量溶液時。且高抗體濃度,其
對於希望用於肌肉內或皮下給藥之調配為需要的,則需要按比例的高濃度安定劑,例如蔗糖和氯化鈉,以達到長期蛋白安定性。所生成的高張溶液常常因組織傷害而造成注射疼痛。因此,經常需要就高蛋白濃度調配物之安定性和滲透壓,平衡安定劑的量。
本揭示文係提供具有廣泛範圍之抗-PRLR抗體濃度之液體和凍乾的抗-PRLR抗體調配物,其為實質上等張及低黏度且其實質上不含有用於緩衝此調配物之有機鹽或無機鹽以外的鹽。
文中所示的抗-PRLR抗體調配物係含有從約0mM至約70mM組胺酸;從約50ppm至約300ppm的非離子界面活性劑,例如聚山梨醇酯(Tween®)80及/或聚山梨醇酯(Tween®)20;從約34mM至約292mM的糖或糖醇,例如甘露醇、右旋糖、葡萄糖、海藻糖及/或蔗糖;從約0mM至約50mM精胺酸;從約0mM至約50mM離胺酸;從約0mM至約270mM甘胺酸或丙胺酸;從約0mM至約10mM甲硫胺酸;及從約1mg/ml至約150mg/ml的抗-PRL抗體,包括aPRLR-專一性IgG2單株抗體(mAb),pH係從約pH 5.0至約pH 6.5。
各本文所揭示的抗體調配物實質上不含有用於緩衝此調配物之有機鹽或無機鹽以外的鹽。使其得以添加另外的安定劑而維持調配物的等滲壓性(亦即滲透壓範圍從約240mmol/kg至約380mmol/kg),藉此提升較高的病患服從性。
各目前所揭示的抗體調配物在22℃-23℃具有範圍從約1至約8mPa-S之低黏度,其提高處理的容易性,例如促進超過濾及無菌過濾以及給藥期間經由注射針注射抗體調配物。
文中所揭示的調配物使液體形式或凍乾形式中高蛋白濃度之抗體安定,特別是抗-PRLR抗體,包括抗-PRLR IgG2抗體。
如上所述,本揭示文係提供在希望的儲存條件下安定液體形式或凍乾形式中廣泛濃度範圍的抗-PRLR抗體之抗-PRLR抗體調配物。文中所述的調配物係包括一或多種醫藥上可接受的賦形劑或安定劑,且係包含於適當pH的緩衝媒劑中,及實質上與生理體液等滲壓。就全身性給藥,注射為一可能的給藥路徑,包括肌肉內、靜脈內、腹膜內及皮下注射。
因為其低黏度,本文所揭示的抗-PRLR抗體調配物可方便地處理,例如超過濾和無菌過濾且可經由注射投予病患,包括靜脈內和皮下注射二者。再者,因為其實質上為等滲壓的,本文所揭示的抗-PRLR抗體調配物降低了組織傷害或其他不良的生理效應而因此達到有利的病患耐受性並增加病患的服從性。
文中所述的調配物其特徵在於實質上無用於緩衝此調配物之有機鹽或無機鹽以外的添加鹽,其提供增加其他安定劑,例如蔗糖之濃度的彈性,而同時維持調配物的滲透壓,供改善活體內的耐受性,且因此增加病患的服從性。再者,本文所述的調配物之低黏度使其得以方便處理,包括超過濾和無菌過濾,及經由針注射藥物產品溶液。
就闡釋本說明書之目的,係應用下列定義。就下列所述的任何定義與任何其他文件(包括以引用的方式併入本文中之任何文件)的字詞用法有衝突之情況下,除非另有清楚地指出相反的意義(例如最初使用此術語的文件中),否則就闡述本說明書及其所連結的申請專利範圍之目的,應以下述的定義為主。
若適當時,使用單數之術語亦包括多數而反之亦然。除非另有說明,或其中明顯地「一或多個」之用法為不適當的,否則文中「一」之用法係指「一或多個」。除非另有說明,否則「或」係指「及/或」。「包括」、「包含」、「含有」之用法可相互交換且不希望受限。術語「例如」亦不
希望受限。例如,術語「包括」應係指「包括,但不限於」。再者,當一或多個實施例之說明使用「包含」時,熟習本項技術者應了解,在某些特定的情況下,該一或多個實施例可使用「基本上組成」及或「組成」之語言替代描述。
如文中所用,術語「黏度」係指液體調配物對流動之阻抗性,例如當於投藥給病患期間經由注射針注射時。黏度測量可藉由錐板技術以珀耳帖元件(Peltier element)設定於一定義的溫度,例如文中所述22℃-23℃來進行。典型地,係將一定義明確的剪應力梯度施予該液體調配物並測量所生成的剪切速率。黏度為剪應力與剪切速率的比例。如文所用,黏度係以22℃-23℃時mPa-S之單位來表示,其中1mPa-S=1cP。文中所述之高濃度、低黏度、實質上等滲壓的調配物典型地其特徵為在22℃-23℃時具有範圍從1至8mPa-S之黏度。
如文中所用,術語「滲透壓」係指溶質濃度之測量,係定義為每公斤(kg)溶液之溶質的毫莫耳數(mmole)。所欲的滲透壓之程度可藉由添加一或多種安定劑,例如糖或糖醇,包括甘露醇、右旋糖、葡萄糖、海藻糖及/或蔗糖來達成。適合提供滲透壓之另外的安定劑係描述於參考文獻中,例如Pharmaceutical Excipients手冊(第四版,Royal Pharmaceutical Society of Great Britain,Science & Practice Publishers)或Remingtons:The Science and Practice of Pharmacy(第九版,Mack Publishing Company)。
如文中所用,術語「大約」係指所提供的單位值之+/- 10%。如文中所用,術語「實質上」係指展現所指特性或性質之整體或大約程度的質性狀況。因為許多影響生物和化學組成物及物質之試驗、生產及儲存的變數,及因為用於生物和化學組成物及物質之試驗、生產及儲存的儀器和設備之固有錯誤,生物技術之一般技術者應了解生物和化學現象很少,若有,達到或避免絕對結果。術語實質上因此用於文中係擷取許多生物和化學現象中固有之可能缺乏的完整性。
如文中所用,術語「等滲壓」和「等張」係與「實質上等滲壓」和「實質上等張」交換使用,且係指調配物的特徵為具有與另外溶液之滲透壓相同或至少實質上相等之滲透壓,其係藉由其中溶質的總濃度(包括滲透性和非滲透性溶質)在調配物中係與另外溶液之總溶質數相同或至少實質上相等之調配物來達成。因此,當熟習本項技術者應了解「等滲壓」和「等張」調配物係用於活體內給藥時一般具有範圍從約270mmol/kg至約310mmol/kg之滲透壓,在本揭示文之高濃度、低黏度調配物的情況下,術語「等滲」、「等張」、「實質上等滲壓」和「實質上等張」可相互交換使用並係指調配物具有範圍從約240mmol/kg至約380mmol/kg,或從約270mmol/kg至約370mmol/kg,或從約300mmol/kg至約330mmol/kg之滲透壓。
本文所揭示的高濃度、低黏度、實質上等滲壓的抗-PRLR抗體調配物係含有從約0mM至約70mM組胺酸;從約50ppm至約300ppm的非離子界面活性劑,例如聚山梨醇酯(Tween®)80及/或聚山梨醇酯(Tween®)20;從約34mM至約292mM的糖或糖醇,例如甘露醇、右旋糖、葡萄糖、海藻糖及/或蔗糖;從約0mM至約50mM精胺酸;從約0mM至約50mM離胺酸;從約0mM至約270mM甘胺酸或丙胺酸;從約0mM至約10mM甲硫胺酸;及從約1mg/ml至約150mg/ml的抗-PRLR抗體,pH從約pH 5.0至約pH 6.5。文中所揭示的調配物在22℃-23℃具有範圍從約1至約8mPa-S之黏度及從約240至約380mmol/kg之滲透壓。
在這些調配物中,組胺酸為一緩衝劑,可用於使調配物pH維持在從約pH 5.0至約pH 6.5,或從約pH 5.5至約pH 6.0,例如約pH 5.0,約pH 5.5,約pH 6.0或約pH 6.5。
糖或糖醇,例如甘露醇、右旋糖、葡萄糖、海藻糖及/或蔗糖可分開或組合使用作為液體調配物中以及冷凍乾燥期間抗-PRLR抗體之低溫保存劑和安定劑。
非離子界面活性劑,例如聚山梨醇酯,包括聚山梨醇酯20及/或聚山梨醇酯80;泊洛沙姆(poloxamer),包括泊洛沙姆184和188;pluronic®多醇;及其他乙烯/聚丙烯嵌段聚合物,在處理和儲存期間藉由降低界面作用安定抗-PRLR抗體並防止抗體被吸收。
精胺酸為一蛋白增溶劑以及安定劑,其降低抗體和其他蛋白聚集作用,例如抗-PRLR抗體聚集作用及其他可能的降解。甲硫胺酸為一抗氧化劑,其係於處理和儲存期間防止抗體氧化。
糖類和無機鹽類通常係用作蛋白質安定劑;然而,糖類和無機鹽類二者亦為有效的張度劑。若調配物需要高濃度的一或多種糖類來安定抗-PRLR抗體,則無機鹽濃度應為零或保持在非常低以便於維持調配物的滲透壓,而得以降低給藥之注射疼痛。
如文中所用,術語「鹽」係指無機鹽類,其包括氯化鈉(NaCl)、硫酸鈉(Na2SO4)、硫氰酸鈉(NaSCN)、氯化鎂(MgCl)、硫酸鎂(MgSO4)、硫氰酸銨(NH4SCN)、硫酸銨((NH4)2SO4)、氯化銨(NH4Cl)、氯化鈣(CaCl2)、硫酸鈣(CaSO4)、氯化鋅(ZnCl2)及其類似物,或其組合物。文中所揭示之抗-PRLR抗體調配物其特徵為實質上無添加鹽且,因此文中係指無鹽的抗體調配物。熟習本項技術者應了解,存在於文中所揭示的調配物中之無機鹽,係藉由pH調整所導入,而不應視為添加的鹽類。此等無機鹽類當藉由pH調整導入時,若存在於本揭示文之調配物中,應不超過約2mM的濃度。
如文中所用,術語「界面活性劑」包括非離子界面活性劑,其包括(不限於)聚山梨醇酯,例如聚山梨醇酯20或80,及泊洛沙姆,例如泊洛沙姆184和188,pluronic®多醇及其他乙烯/聚丙烯嵌段聚合物。有效提供安定的高濃度抗-PRLR抗體調配物之界面活性劑的量通常係在50ppm至300ppm的範圍內。使用非離子界面活性劑使調配物能暴露在剪應力和表面壓力下而不會造成抗-PRLR抗體變性,且亦降低處理和儲存期間表面的吸收。文中所揭示的調配物包括(不限於)具有一或多種非離子界面活性劑之調配物,
其包括例如一或多種聚山梨醇酯,例如聚山梨醇酯20或80;一或多種泊洛沙姆,例如泊洛沙姆184和188;pluronic®多醇類;及/或一或多種乙烯/聚丙烯嵌段聚合物。文中作為示例的為具有聚山梨醇酯,例如聚山梨醇酯20(Tween®20)及/或聚山梨醇酯80(Tween®80)之調配物。
如文中所用,術語「抗體」係指一種一般稱為免疫球蛋白之蛋白質。抗體包括全長單株抗體(mAb),例如IgG2單株抗體,其係包括免疫球蛋白Fc區。術語抗體亦包括雙專一性抗體、二抗體、單鏈分子和抗體片段,例如Fab、F(ab')2和Fv。
如文中所用,術語「抗-PRLR抗體」係指具有結合專一性抗人類PRLR蛋白以及人類PRLR蛋白之片段和變體之抗體。文中所示的抗-PRLR抗體可為IgG2抗體並包括抗-PRLR IgG2單株抗體,例如嵌合人源化及全人類抗-PRLR IgG2單株抗體。適合用於文中所揭示的調配物之抗-PRLR單株抗體,包括全長抗體及其抗原結合片段和變體,係如PCT專利申請案號WO/2011/069799、WO/2011/069798、WO/2011/069797、WO/2011/069796、WO/2011/069795及WO/2011/069794中所示,其各自係以全文引用的方式併入本文中。
「單株抗體」其特徵為對單一抗原決定位具有專一性。單株抗體可藉由例如Kohler和Milstein,Nature 256:495(1975)所述的雜交瘤方法,或藉由例如該等美國專利第4,816,567號中所述的重組DNA法來製造。單株抗體亦可使用例如該等Clackson等人,Nature 352:624-628(1991)和Marks等人,J.Mol.Biol.222:581-597(1991)中所述的技術自噬菌體表現庫分離。
單株抗體包括「嵌合的單株抗體」,其中一部分的重鏈及/或輕鏈包含來自衍生自一物種之抗體的序列,而抗體的剩餘部份(包括Fc區)係包含來自衍生自第二物種之抗體的序列,且該第二物種可為人類。參見,例如美國專利第4,816,567號及Morrison等人,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984)。
單株抗體亦包括「人源化單株抗體」,其中一或多個來自衍生自一物種之抗體的重鏈及/或輕鏈序列之互補決定區(CDR)係被一或多個來自衍生自第二物種之抗體的重鏈及/或輕鏈序列之CDR所取代,且該第二物種可為人類。「人源化」之方法通常係應用於開發投予人類之單株抗體。參見,例如Riechmann等人,Nature 332(6162):323-27(1988)及Queen等人,Proc.Natl.Acad.Sci.USA 86(24):10029-33(1989)。
單株抗體亦包括「全人類單株抗體」,其中整個重鏈及輕鏈序列係衍生自人類抗體序列。全人類單株抗體可藉由噬菌體表現技術來產生並可從經基因工程化表現人類抗體譜之小鼠中分離。參見,例如McCafferty等人,Nature 348(6301):552-554(1990),Marks等人,J.Mol.Biol.222(3):581-597(1991)及Carmen and Jermutus,Brief Funct.Genomic Proteomic 1(2):189-203(2002)。
如文中所用,術語抗-PRLR抗體調配物之「醫藥上有效量」係指於一給藥療法中調配物的量提供了治療效用。文中所揭示的高濃度抗-PRLR抗體調配物典型地係包括濃度範圍從約1mg/ml至約150mg/ml,或從約2mg/ml至約120mg/ml,或從約5mg/ml至約100mg/ml,或從約7.5mg/ml至約60mg/ml之抗-PRLR抗體。在某些方面,這些調配物內的抗-PRLR抗體之濃度為約2mg/ml,或約7.5mg/ml,或約20mg/ml,或約50mg/ml,或約60mg/ml。此等調配物典型地係以每個注射處低於約2ml,或約1.5ml,或約1ml,或約0.5ml之量供皮下注射給藥。
在特定的態樣,抗-PRLR抗體調配物含有約30mM組胺酸,約100ppm聚山梨醇酯80,約292mM蔗糖,約20mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約10mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約234mM蔗糖,約60mg/ml抗-PRLR抗體,pH範圍從
約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約30mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯80,約234蔗糖,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約30mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯80,約88mM蔗糖,約133mM甘胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約10mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯20,約88mM蔗糖,約133nM甘胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約10mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約200ppm聚山梨醇酯20,約88mM蔗糖,約133mM甘胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約10mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約70mM組胺酸,約80ppm聚山梨醇酯80,約200mM蔗糖,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約10mM至約50mM精胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約292mM蔗糖,約10mM精胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至約10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約70mM組胺酸,約80ppm聚山梨醇酯80,約176mM蔗糖,約133mM甘胺酸,約30mM離胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯80,約234mM蔗糖,約30mM精胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約234mM蔗糖,約20mM精胺酸,約150mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約205mM蔗糖,約20mM精胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約205mM蔗糖,約20mM精胺酸,約2mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約80ppm聚山梨醇酯80,約205mM蔗糖,約20mM精胺酸,約1mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯80,約205海藻糖,約20mM精胺酸,約2mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5.在相關的態樣,抗-PRLR抗體調配物
亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約75ppm聚山梨醇酯80,約205mM海藻糖,約20mM精胺酸,約60mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在相關的態樣,抗-PRLR抗體調配物亦含有從約0mM至10mM甲硫胺酸。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約234mM蔗糖,約80ppm聚山梨醇酯80,約30mM精胺酸,約5mM甲硫胺酸,約7.5mg/ml抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5,例如pH 5.5。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約234mM蔗糖,約80ppm聚山梨醇酯80,約30mM精胺酸,約5mM甲硫胺酸,約60mg/mL抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5,例如pH 5.5。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約234mM蔗糖,約75ppm Tween 80,約30mM精胺酸,約10mM甲硫胺酸,約60mg/mL抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5,例如pH 5.5。
在其他態樣,抗-PRLR抗體調配物含有約10mM組胺酸,約263mM蔗糖,約80ppm聚山梨醇酯80,約60mg/mL抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5例如pH 6.0。
因此,本揭示文係提供抗-PRLR mAb調配物,包括抗-PRLR IgG2 mAb調配物,其中該抗-PRLR mAb在高蛋白濃度時為可溶的。相較於目前可取得的抗體調配物,文中所揭示的調配物中之抗-PRLR mAb在介於約1mg/ml至約150mg/ml的濃度下仍溶為可溶的,且在等滲壓儲存條件下仍為穩定的並具有降低的黏度。
抗-PRLR抗體具有包括SEQ ID NO:1胺基酸序列之輕鏈和包括SEQ ID NO:7胺基酸序列之重鏈,為一阻斷催乳素受體(PRLR)之IgG2抗體。抗-PRLR抗體可藉由阻斷PRLR藉此克服子宮內膜路徑之缺陷來防止子宮內膜異位之發生或惡化。文中所示的高濃度、無鹽之抗-PRLR抗體調配物可
經由靜脈注射或皮下注射或其他注射路徑投予病患。
作為本揭示文的部分,抗-PRLR抗體的安定性係受賦形劑所影響。在定義的pH範圍內,抗-PRLR抗體的安定性係隨NaCl濃度減少而增加。此外,帶正電的胺基酸,例如精胺酸和離胺酸可增進抗-PRILR抗體安定性且pH大大地影響抗-PRLR抗體聚集作用。抗體溶液的聚集作用係隨pH增加而增加。穩定文中所示的抗-PRLR抗體之最適pH範圍係從約pH 5.0至約pH 6.5或從約pH 5.5至約pH 6.0,例如約pH 5.0,約pH 5.5,約pH 6.0或約pH 6.5。
文中所提供的為抗-PRLR抗體調配物,其中該抗-PRLR抗體包括IgG2抗體,包括人類IgG2單株抗-PRLR抗體,其係具有一或多個PCT專利公開案第WO/2011/069799號、第WO/2011/069798號、第WO/2011/069797號、第WO/2011/069796號、第WO/2011/069795號及第WO/2011/069794號中所示之輕鏈和重鏈序列。
可適當用於文中所述的抗-PRLR抗體調配物中之抗體係以表1中所示的Mat3-hIgG2抗體作為示例,其係得自BioInvne噬菌體表現庫(Lund,Sweden)及後續就親和力、活性、物種交叉反應性和可製造性進行種系化及序列最適化。
Fab部分包括λ輕鏈(VL:DPL3生殖系列;CL:Mcg-/Kern-/Oz-同型)及輕鏈VH DP47-生殖系列架構區。抗體經再格式化成為缺乏C-端離胺酸之IgG2m(n-)重鏈異的人類IgG2。可能的去醯胺化位置係存在於輕鏈之98胺基酸位置的CDR3中且在此抗體中被留下未改變。此標準的IgG2之N-糖基化位置係存在重鏈的N294。
表1作為示例的人類抗-PRLR IgG2單株抗體Mat3-hIgG2之重鏈和輕鏈序列
因此,本揭示文係提供抗-PRLR mAb調配物,包括抗-PRLR IgG2 mAb調配物,其中抗-PRLR mAb於高蛋白濃度時為可溶的。典型地,相較於目前可取得的抗體調配物,文中所揭示的調配物中之抗-PRLR mAb在介於約1mg/ml至約150mg/ml的濃度下仍溶為可溶的,且在等滲壓儲存條件下仍為穩定的並具有降低的黏度。
抗-PRLR抗體具有一或多個PCT專利公開案第WO/2011/069799號、第WO/2011/069798號、第WO/2011/069797號、第WO/2011/069796號、第WO/2011/069795號及第WO/2011/069794號中所示之輕鏈序列和重鏈序列,可為一阻斷催乳素受體活性之IgG2抗體。抗-PRLR抗體可藉由阻斷PRLR藉此克服子宮內膜路徑之缺陷來防止子宮內膜異位之發生或惡化。廣泛的蛋白濃度範圍,包括文中所示的高濃度抗-PRLR抗體調配物可經由靜脈注射、肌肉內注射或皮下注射路徑投予病患。
本揭示文亦提供一病患子宮內膜異位之非激素治療的方法,其包括投
予該病患一治療上有效量之一或多種文中所述的調配物。例如,係於一病患中提供子宮內膜異位之非激素治療的方法,其包括投予該病患一治療上有效量之抗-催乳素受體抗體(aPRLR Ab)調配物,包括aPRLR-專一性IgG2單株抗體(mAb)調配物,其含有從約0mM至約70mM組胺酸;從約50ppm至約300ppm聚山梨醇酯(Tween®)80及/或聚山梨醇酯(Tween®)20;從約34mM至約292mM蔗糖;從約0mM至約50mM精胺酸。從約0mM至約50mM離胺酸。從約0mM至約270mM甘胺酸或丙胺酸。從約0mM至約10mM甲硫胺酸及從約1mg/ml至約150mg/ml的抗-PRLR抗體,pH範圍從約pH 5.0至約pH 6.5。在這些方法的至少一態樣中,抗-PRLR抗體調配物可以靜脈給藥。在這些方法的其他態樣中,抗-PRLR抗體調配物可以皮下給藥。在這些方法的其他態樣中,抗-PRLR抗體調配物可以肌肉內給藥。
根據這些用於一病患中子宮內膜異位之非激素治療的方法之特定態樣,此抗-PRLR抗體為一人類抗-PRLR IgG2單株抗體,例如人類抗-PRLR IgG2單株抗體,其含有一或多個PCT專利公開案第WO/2011/069799號、第WO/2011/069798號、第WO/2011/069797號、第WO/2011/069796號、第WO/2011/069795號及第WO/2011/069794號中所示之輕鏈序列和重鏈序列。
本揭示文之態樣可根據下列實例進一步了解,其不應理解為在任何方面限制本教導文之範圍。
此實例係揭示鹽(NaCl)濃度和pH對含有抗-PRLR人類單株抗體之溶液聚集作用的效應,其中該抗體係含有一或多個PCT專利公開案第WO/2011/069799號、第WO/2011/069798號、第WO/2011/069797號、第WO/2011/069796號、第WO/2011/069795號及第WO/2011/069794號中所示之輕鏈序列和重鏈序列。溶液的濁度係藉由肉眼觀察評估,用以快速地評估鹽濃度和pH對aPRLR mAb溶液之效應。調配物在缺乏鹽下以pH 5.5-6.5於5℃和25℃放置2個月後,並無觀察到沉澱。
推薦無氯化鈉、pH 5.0至6.5之溶液作為本文所揭示的抗-PRLR抗體調配物。
不受限於理論,就帶有高NaCl濃度之抗-PRLR mAb調配物的濁度或聚集作用而言,咸信安定性降低係因中和了抗-PRLR mAb精胺酸側鏈的正電荷所致。在不同pH時,aPRLR mAb之相行為,對單價鹽(NaCl)之影響解釋了為何可達到穩定、無鹽及實質上等滲透壓aPRLR mAb調配物。
在pH低於PI時,例如pH 5-6.5,抗-PRLR抗體具有淨正電荷。在此一抗-PRLR抗體表面上的正電斥力可能防止個別分子間的蛋白-蛋白結合,且由此顯著地增加溶解度。假設鹽的陰離子(Cl-)與抗-PRLR抗體表面上精胺酸的胍鎓基團結合,中和了此正電荷,其增進了蛋白-蛋白相互作用而因此造成較低溶解度和溶液濁度。藉由將pH轉移至5.0-6.5,產生文中所述的無鹽調配物以達到增加抗體溶解度和安定性。在無鹽的存在下,其他安定劑,例如蔗糖的濃度,可在無損及滲透壓下增加至>150mM及<300mM。
實質上等滲壓的高濃度抗-PRLR Ab調配物係在無NaCl下製備。這些調配物係使用高蔗糖濃度來幫助穩定抗-PRLR Ab。
將冷凍的抗-PRLR抗體抗體融解並根據表1中所示的配方調配。製備
調配物並以過濾器無菌過濾,及無菌填入玻璃管型瓶中並以塞子塞住。
在無NaCl及在蔗糖或海藻糖34mM至292mM及聚山梨醇酯80(50-300ppm)之存在下,且於pH 5.0-6.5時,正電荷胺基酸,例如精胺酸(10-50mM)可有效地抑制aPRLR Ab聚合作用。
代表的抗-PRLR mAb調配物係以HPLC-SEC分析蛋白聚集作用和降解作用分析,LC-MS分析aPRLR結構變化(糖化和氧化),黏度計進行黏度測
量,及滲透壓儀器進行滲透壓測量。HPLC-SEC之蛋白聚集作用分析結果係如表3所示,濁度之比濁法分析結果係如表4所示,aPRLR結構變化之LC-MS分析結果係如表5所示,而黏度和滲透壓之分析結果係如表6所示。
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Claims (16)
- 一種抗-PRLR抗體調配物,係包括:a. 10mM至70mM組胺酸;b. 75ppm至100ppm的非離子界面活性劑;c. 88mM至292mM選自甘露醇、右旋糖、葡萄糖、海藻糖及蔗糖之糖;d. 10mM至30mM精胺酸;e. 5mM至10mM甲硫胺酸;及h. 7.5mg/ml至150mg/ml的抗-PRLR抗體;該中該抗-PRLR抗體調配物具有範圍從pH 5.0至pH 6.5之pH,其中該抗-PRLR抗體調配物實質上不含有緩衝該調配物之有機鹽或無機鹽以外的無機鹽,且其中該抗-PRLR抗體係包含重鏈及輕鏈之人類IgG2單株抗體,其中該重鏈之胺基酸序列係根據SEQ ID NO:7且該輕鏈之胺基酸序列係根據SEQ ID NO:1。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,其中該抗-PRLR調配物實質上不含有由下列組成之群選出之無機鹽:氯化鈉(NaCl)、硫酸鈉(Na2SO4)、硫氰酸鈉(NaSCN)、氯化鎂(MgCl)、硫酸鎂(MgSO4)、硫氰酸銨(NH4SCN)、硫酸銨((NH4)2SO4)、氯化銨(NH4Cl)、氯化鈣(CaCl2)、硫酸鈣(CaSO4)及氯化鋅(ZnCl2)。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,其中該調配物在22℃-23℃時具有範圍從1至8mPa-S之黏度。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,其中該調配物具有範圍從240mmol/kg至380mmol/kg之滲透壓。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,其中該非離子界面活性劑為選自聚山梨醇酯20和聚山梨醇酯80之聚山梨醇酯。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,其中該糖為蔗糖。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 30mM組胺酸,b. 100ppm聚山梨醇酯80,c. 292mM蔗糖,d. 30mM精胺酸,e. 10mM甲硫胺酸,及f. 20mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 70mM組胺酸,b. 80ppm聚山梨醇酯80,c. 200mM蔗糖,d. 30mM精胺酸,e. 10mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 75ppm聚山梨醇酯80,c. 292mM蔗糖,d. 10mM精胺酸,e. 10mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 75ppm聚山梨醇酯80,c. 234mM蔗糖,d. 30mM精胺酸,e. 10mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 75ppm聚山梨醇酯80,c. 234mM蔗糖,d. 30mM精胺酸,e. 10mM甲硫胺酸,及f. 7.5mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 80ppm聚山梨醇酯80,c. 205mM蔗糖,d. 20mM精胺酸,e. 10mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 234mM蔗糖,c. 80ppm聚山梨醇酯80,d. 30mM精胺酸,e. 5mM甲硫胺酸,及f. 7.5mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 234mM蔗糖,c. 80ppm聚山梨醇酯80,d. 30mM精胺酸,e. 5mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 如申請專利範圍第1項之抗-PRLR抗體調配物,係包括:a. 10mM組胺酸,b. 234mM蔗糖,c. 75ppm聚山梨醇酯80,d. 30mM精胺酸,e. 10mM甲硫胺酸,及f. 60mg/ml抗-PRLR抗體。
- 一種如申請專利範圍第1項之抗-PRLR抗體調配物用於製造非激素治療子宮內膜異位之藥物的用途,其中該抗-PRLR抗體調配物實質上不含有無機鹽,藉此該藥物係以靜脈內、皮下或肌肉內給藥。
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