CN101679507A - 结晶抗人类il-12抗体 - Google Patents
结晶抗人类il-12抗体 Download PDFInfo
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- CN101679507A CN101679507A CN200880010488A CN200880010488A CN101679507A CN 101679507 A CN101679507 A CN 101679507A CN 200880010488 A CN200880010488 A CN 200880010488A CN 200880010488 A CN200880010488 A CN 200880010488A CN 101679507 A CN101679507 A CN 101679507A
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Abstract
本发明涉及将hIL-12抗体结晶的分批结晶方法,其允许以工业规模产生所述抗体;根据所述方法获得的抗体晶体;含有所述晶体的组合物;以及使用所述晶体和组合物的方法。
Description
相关申请的交叉参考
本申请要求2007年3月29日申请的美国临时申请第60/920,608号的优先权。
发明领域
本发明涉及一种将抗体结晶的分批结晶方法,其允许以工业规模产生所述抗体;抗体的晶体,尤其根据所公开的方法获得的抗体的晶体;和含有所述晶体的组合物以及使用所述晶体和组合物的方法。
发明背景
a)抗体晶体
就目前正处于2或3期临床研究中进行评估的100种以上单克隆抗体(mAb)而言,mAb销售被视为最有前途的生物药物销售之一。因为这些药物是以经常超过100mg的单一剂量递送,所以急需找到满足稳定性、安全性和患者顺应性的合适配制策略。然而,高度浓缩的液体mAb制剂显示粘度增加,从而阻碍经由患者友好性细针的可注射性。此外,mAb分子于所述高浓度下聚集的趋势与适度浓缩的溶液相比按指数规律增加。此为安全性和稳定性要求所不可接受的。
因此,高mAb剂量的递送是专供大体积的用,其通常必须通过输注递送。此给药方式成本高且显著降低患者的顺应性。
因此,药物学上适用的皮下注射用低体积mAb晶体悬浮液将非常合乎需要。理论上,影响mAb完整性的降解路径应由于晶格的刚度而显著减速,其中蛋白质结构的移动受阻。此外,当将高度浓缩的晶体悬浮液与液体制剂比较时,粘度的增加将显著减少。对于持续释放而言,可能产生或改变蛋白质晶体以使其进入患者体内时缓慢溶解。此将为递送持续释放制剂的极好方式,这是因为将避免广泛使用会损害mAb结构的赋形剂和方法。
尽管使用蛋白质晶体作为药物物质有极大潜在性,但对系统性评估此策略的尝试尚且很少。
熟知的例外(exemption)为胰岛素,其已在几十年前得以成功地结晶。现今,已充分描述对胰岛素的晶体悬浮液的使用,从而提供正在市场上明确销售的稳定和长效制剂。开发胰岛素晶体与所有其它蛋白质的结晶体之间的差别可能与有序胰岛素聚集物天然地形成于胰腺中的事实有关。为此,当使胰岛素与过量锌离子接触时,容易获得胰岛素晶体。大多数其它蛋白质倾向于形成无序沉淀物而非晶体,且因此,找到蛋白质的结晶条件是一个耗时、不平凡的任务。
尽管对收获蛋白质晶体以作X射线绕射分析很感兴趣,但找到合适的结晶条件仍为经验科学,这是因为原则上任何蛋白质表现有所不同。迄今为止,尚未发现能可靠地预测所选蛋白质的成功结晶条件的通用规律。因此,获得特定蛋白质的晶体始终被称为关于后来计划任何所要应用的“瓶颈”。
抗体由于分子的柔性而特别难以结晶。不过,免疫球蛋白晶体的实例已经知道很长时间。免疫球蛋白晶体的第一个实例已在150年前由英国医师Henry Bence Jones作了描述;其从骨髓瘤患者的尿液分离出异常Ig轻链二聚物的晶体(Jones H.B.(1848)PhilosophicalTransactions of the Royal Society,London 138:55-62)。所述异常Ig从此之后被称为本斯琼司蛋白(Bence Jones protein)。在1938年,描述了从骨髓瘤患者的血清自发结晶出独特的异常Ig(von Bonsdorf,B.等人(1938)Folia Haematologia 59:184-208),显然其为Ig重链寡聚物(MW200kDa)。
在随后的三十年里已描述了正常结构的结晶人类免疫球蛋白(两个重链连接于两个轻链),其也主要是从骨髓瘤患者分离得的(Putnam,F.W.(1955)Science 122:275-7)。Davies和同事最先使用X-射线晶体术来表征名为“Dob”的完整人类骨髓瘤抗体的结构(Terry,W.D.等人(1968)Nature 220(164):239-41),且其在1971年测定了其三维结构(Sarma,V.R.等人(1971)J.Biol.Chem.246(11):3753-9)。继其开拓性研究之后,紧随其它人的研究,从而获得IgG“Kol”(Huber,R.等人(1976)Nature 264(5585):415-20)、IgG“Mcg”(Rajan,S.S.等人(1983)Mol.Immunol.20(7):787-99)和犬淋巴瘤IgG2a(Harris,L.J.等人(1992)Nature 360(6402):369-72)的晶体结构。
免疫球蛋白的晶体在再溶解后保留其特殊免疫活性。Nisonoff等人于1968年报导了兔抗对偶氮苯甲酸酯抗体,“X4”,其易于结晶(Nisonoff,A.等人(1968)Cold Spring Harbor Symposia on QuantitativeBiology 32:89-93)。抗体X4在结晶之前以及在晶体再溶解之后已被广泛表征。发现[125I]-对碘苯甲酸酯特异性且有效地与再溶解X4结合;再溶解晶体亦展现未经纯化的兔血清特有的多特异性Ouchterlony免疫扩散反应(Nisonoff等人,1968)。Connell和同事描述了人类骨髓瘤γ-免疫球蛋白-1κ(IgG-κ),称为“Tem”,其于低温下从血清自发结晶(Connell,G.E.等人(1973)Canad.J.Biochem.51(8):1137-41)。发现Tem晶体结构良好且具有菱面体对称性。含有Tem的血清是广泛地通过琼脂糖免疫扩散技术表征。Tem晶体的再溶解溶液的电泳和免疫扩散显示其与通过冷沉淀法从血清获得的物质相同,且与分离的骨髓瘤蛋白相同(Connell等人,1973)。
Mills和同事于1983年报导了由白蛋白的人类单克隆抗体引起的罕见结晶冷球蛋白血症(crystallocryoglobulinemia)(Mills,L.E.等人(1983)Annals of Internal Med 99(5):601-4)。在此,从两位患者分离出极其类似的立方形晶体。使晶体再溶解,接着电泳和免疫电泳,结果指示,晶体由两个蛋白质组份组成,即1∶2比率的单克隆IgG-λ与人类血清白蛋白(Jentoft,J.E.等人(1982)Biochem.21(2):289-294)。通过溶解原始晶体,接着柱色谱以制备规模分离所述组份。尽管任一分离的组份自身皆不结晶,但一旦再组合后原始两组份复合物重新形成且接着结晶。对再溶解、分离的IgG及其具有人类血清白蛋白的Fab片段的特殊沉降特征和免疫反应性的进一步研究指示,两个再溶解、分离的组份的重新缔合在性质上具免疫性,即结晶性抗体一旦再溶解后仍然具有其天然、高度特异性(针对人类血清白蛋白)结合特征(Mills等人1983)。
最近,Margolin和同事报导了结晶性抗体的潜在性治疗用途(Yang,M.X.等人(2003)Proc.Natl.Acad.Sci.100(12):6934-6939)。其发现治疗性单克隆抗体曲妥珠单抗(trastuzumab)可得以结晶(Shenoy,B.等人(2002)PCT国际申请WO/2002/072636,(Altus BiologiesInc.,USA).第173页)。结晶性曲妥珠单抗悬浮液于小鼠肿瘤模型中在治疗上是有效的,由此证明结晶性曲妥珠单抗保留生物活性(Yang等人,2003)。
b)结晶技术
各种蛋白质的结晶无法使用明确的方法或规则程序(algorithm)成功地进行。当然,在最近20-30年内有巨大技术进步,此如蛋白质结晶方面的世界闻名的专家A.McPherson所提。McPherson提供了关于大分子结晶的方式、策略、试剂和装置的广泛细节(McPherson,A.(1999)Crystallization of Biological Macromolecules.Cold Spring Harbor,NewYork,Cold Spring Harbor Laboratory Press,第159页)。然而,其未提供确保实际上可由本领域技术人员以合理的成功期望结晶出任何特定大分子的方法。例如,McPherson陈述:“无论何种程序,在改进和最优化系统的参数、溶剂和溶质方面必须不遗余力,以促进和增进分子之间的特异性结合相互作用且在其形成后使其稳定。此后面的问题方面通常视正结晶的特殊蛋白质或核酸的特定化学和物理特性而定”。
蛋白质结晶领域技术人员已普遍认可,尚无任何规则程序可用于获取所关注的新蛋白质、实施明确的方法步骤且由此获得所要晶体。
几种筛选系统为市售的(例如Hampton 1和2、Wizzard I和II),其允许以微升规模筛选特定蛋白质的潜在合适的结晶条件。然而,在此类筛选系统中获得的阳性结果未必允许工业上适用的较大分批规模的成功结晶。据描述,微升型结晶试验至工业尺寸的转化是一个具挑战性的任务(参见Jen,A.,Merkle,H.P.(2001)Pharm.Res.18,11,1483)。
Baldock等人报导对于结晶条件的初始筛选而言微批与蒸气扩散(vapor diffusion)的比较(Baldock,P.等人(1996)J.Crystal Growth168(1-4):170-174)。使用一组结晶溶液筛选六种市售蛋白质。所述筛选是使用最常见的蒸气扩散方法和微批结晶方法的三种变体(包括新蒸发技术)来进行。在所鉴别的58种结晶条件中,43种(74%)是以微批鉴定,而41种(71%)是以蒸气扩散鉴定。通过两种方法找到二十六种条件,且若根本未使用微批,则将错过17种(29%)。由此可见,在初始结晶筛选中最常用的蒸气扩散技术并不保证阳性结果。
c)抗人类IL-12抗体晶体
人类IL-12在与几种涉及免疫反应和炎性反应的疾病相关的病变中起关键作用,所述疾病例如多发性硬化症、克罗恩氏病(Crohn′sdisease)和牛皮癣。因此,对治疗所述人类IL-12相关病症的合适方法存在很大需求。一种有前景的治疗方法包括施用药物学上有效的剂量的抗人类IL-12抗体。
由于人类IL-12在多种人类病症中的作用,已针对抑制或抵抗IL-12活性设计治疗策略。特别是,已寻找与IL-12结合且中和IL-12的抗体作为抑制IL-12活性的工具。一些最早抗体为鼠类单克隆抗体(mAb),其由从用IL-12免疫的小鼠的淋巴细胞制备的杂交瘤分泌(参见例如WO 97/15327)。然而,这些鼠类IL-12抗体在体内的使用由于与向人类施用小鼠抗体相关的问题而受到限制,所述问题诸如血清半衰期短暂、不能触发某些人类效应功能和在人类体内引起不希望有的抵抗小鼠抗体的免疫反应(“人类抗小鼠抗体”(HAMA)反应)。
一般而言,对克服与在人类中使用完全鼠类抗体相关的问题的尝试涉及将所述抗体遗传工程化成更“像人类”。例如,已制备嵌合抗体,其中抗体链的可变区源自鼠类且抗体链的恒定区源自人类。然而,因为这些嵌合且人源化的抗体仍然保留一些鼠类序列,所以其仍然可能会引起不希望有的免疫反应,即人类抗嵌合抗体(HACA)反应,此在长期给药时尤然。
美国专利第6,914,128号公开与人类白介素-12(hIL-12)特异性结合的人类抗体,优选重组人类抗体。其中所公开的优选抗体对于hIL-12具有高亲和力且在体外和体内中和hIL-12活性。抗体或抗体部分适用于检测hIL-12和抑制hIL-12活性,例如在患有hIL-12活性为有害源的病症的人类个体中。还包括用于表达本发明的重组人类抗体的核酸、载体和宿主细胞以及合成所述重组人类抗体的方法。抗hIL-12抗体的结晶形式或制备所述结晶形式的方法在所述′128专利中并未有具体描述。
因此,根据本发明待解决的问题在于开发适合于抗-IL-12抗体的结晶条件(尤其分批结晶条件)和建立适用于工业抗体晶体产生相关的体积的结晶过程条件。同时,建立不使用毒性剂的结晶方法,其中所述毒性剂可能会负面地影响所述抗体的药物适用性。
发明概述
令人惊奇地,通过有可能经由应用生理学上可接受的聚亚烷基多元醇作为结晶诱导剂以超过微升规模的分批结晶体积获得完整抗人类IL-12抗体的晶体的发现,上文所提及的问题得以解决。
在第一个方面中,本发明提供了一种将抗人类IL-12抗体结晶的分批结晶方法,所述方法包括下列步骤:
(a)提供IL-12抗体与至少一种聚亚烷基多元醇型结晶试剂(如下文更详细地定义,例如聚亚烷基二醇)的混合物的水溶液;例如通过将抗体(其中抗体优选是以溶解形式存在)的水溶液与包含至少一种聚亚烷基二醇作为溶解形式的结晶试剂的结晶水溶液混合,或者通过添加固体形式的结晶试剂来进行;
(b)和培养所述含水结晶混合物直至形成抗体的晶体。
根据另一实施方案,也可进行本发明的方法以便可用合适量的预先存在的抗人类IL-12抗体晶体作为晶种补充步骤a)中获得的结晶混合物以引发或促进结晶。
本发明的结晶方法通常是于在约pH 4至约6.5特别是其约4.5至约6.0、约5.0至约5.8或约5.3至约5.7(诸如5.4、5.5或5.6)的范围内的含水结晶混合物的pH值下进行。
此外,含水结晶混合物可含有至少一种缓冲剂。所述缓冲剂可包含作为主要组份的乙酸盐组份,尤其是碱金属盐,例如钠盐或钾盐,诸如乙酸钠。所述盐是通过添加酸,尤其乙酸来调节至所需pH值。在结晶方法的优选实施方案中,含水结晶混合物中的缓冲剂浓度(总乙酸盐)为约0M至约0.5M,或约0.02M至约0.5M,例如约0.05M至约0.3M,或约0.07M至约0.2M,或约0.09M至约0.12M。
在下文中对“聚亚烷基多元醇型结晶试剂”作更详细的定义:
本领域技术人员将认识到,所述术语必须被广义理解且包含聚亚烷基多元醇以及其衍生物。
如根据本发明所使用,“聚亚烷基多元醇”是直链或支链,尤其是直链聚-C2-C6亚烷基多元醇。聚醚是由至少一种类型的多官能脂族醇形成,所述脂族醇带有2至6个、2至4个且尤其是2或3个、优选连位的羟基且具有2至6个,尤其是2、3或4个碳原子,优选形成直链碳主链。非限制性实例为乙-1,2-二醇(乙二醇)、丙-1,2-二醇、丙-1,3-二醇以及亚正丁基-1,3-二醇和亚正丁基-1,4-二醇。尤其是优选的二醇为乙二醇。
本发明的聚亚烷基多元醇可由一种单一类型的多元醇或至少两种不同多元醇的混合物构成,其可为无规聚合的或可以嵌段共聚物形式存在。
此外,所述术语“聚亚烷基多元醇”也包括其衍生物。非限制性实例为烷基酯和醚,尤其是单烷基醚和二烷基醚。“烷基”特别是被定义为直链或支链C1-C6烷基残基,尤其是为甲基、乙基、正丙基或异丙基、正丁基、异丁基、仲丁基和叔丁基、正戊基或异戊基和正己基。
如根据本发明所使用,聚亚烷基多元醇,尤其是聚亚烷基二醇进一步是通过各种分子量来表征。陈述为数均分子量或重均分子量的分子量范围通常在400至10,000的范围内,例如1,000至8,000,或2,000至6,000,3,000至6,000,或3,200至6,000,例如3,350至6,000,3,350至5000,或3,800至4,200,尤其是约4,000。
特定聚亚烷基多元醇为聚乙二醇(PEG)和聚丙二醇(PPG)以及相应无规或嵌段共聚物。合适多元醇的特定实例为PEG 2,000、PEG 3,000、PEG 3,350、PEG 4,000、PEG 5,000和PEG 6,000。
特别是,结晶混合物中的聚亚烷基多元醇浓度,尤其是聚乙二醇浓度在约5%至约30%(w/v)的范围内,例如约7%至约15%(w/v)或约9%至约16%(w/v)或约10%至约14%(w/v)或约11%至约13%(w/v)。优选地,平均分子量为约4,000的聚乙二醇是以在结晶混合物中约11%至约13%(w/v)的浓度使用。
在本发明的一优选实施方案中,抗体蛋白溶液和结晶溶液是以约1∶1的比率组合。因此,原始结晶溶液中缓冲剂/结晶试剂的摩尔浓度高达结晶混合物中的约两倍。
通常,结晶方法是以在下列范围内的批量体积进行:约1ml至约20,000升,或1ml至约15,000升,或1ml至约12,000升,或约1ml至约10,000升,或1ml至约6,000升,或1ml至约3,000升,或1ml至约1,000升,或1ml至约100升,例如约50ml至约8,000ml,或约100ml至约5,000ml,或约1,000ml至约3,000ml;或约1升至约1,000升;或约10升至约500升。
另外,可进行本发明的结晶方法以便达到下列其它结晶条件中的至少一个:
a)进行培养历时约1小时至约250天,或1天至250天或13天至250天,例如约1天至约30天或约2天至10天;
b)于约0℃至约50℃、例如约4℃至约37℃或约15℃至约25℃之间的温度下进行培养;
c)结晶混合物中的抗体浓度(即蛋白质浓度)在约0.5mg/ml至280mg/ml、或约1mg/ml至200mg/ml、或1mg/ml至100mg/ml(例如1.5mg/ml至20mg/ml)的范围内,尤其是在约2mg/ml至15mg/ml或5mg/ml至10mg/ml的范围内。所述蛋白质浓度可根据蛋白质测定的标准方法来测定。
在一优选实施方案中,例如以聚乙二醇作为结晶试剂,进行结晶方法,以便于约20℃的温度下且于约5mg/ml至10mg/ml的抗体浓度下进行培养历时约13至60天。
根据特别优选的方法,于结晶混合物的下列条件下进行结晶:
聚亚烷基二醇:PEG 4000 10至15%(w/v)
缓冲剂: 乙酸钠, 0M至0.3M(总乙酸盐)
pH值: 5.3至5.8
抗hIL-12浓度:3至10mg/ml
温度: 18至24℃
批量体积: 1至100l
搅拌: 无
持续时间: 约1天至60天
如上文概述的结晶混合物通常是通过将结晶试剂溶液或固体添加至蛋白质溶液中来获得。两种溶液可以是被缓冲的,但并非必须被缓冲的。原始结晶溶液中的结晶试剂浓度和缓冲剂摩尔浓度通常高于结晶混合物中的浓度,这是因为所述结晶混合物被蛋白质溶液“稀释”。
在另一实施方案中,本发明的结晶方法可进一步包含干燥所获得的晶体的步骤。合适的干燥方法包含蒸发干燥、喷雾干燥、冷冻干燥、真空干燥、流化床干燥、喷雾冷冻干燥、近临界干燥、超临界干燥和氮气干燥。
在另一实施方案中,本发明的结晶方法可进一步包含例如通过离心、透滤、超滤或其它常用缓冲剂交换技术将结晶母液与不同液体或缓冲剂交换的步骤,所述不同液体或缓冲缓冲剂是例如含有不同于用于结晶的聚亚烷基多元醇且摩尔质量在约300道尔顿至8,000道尔顿范围内的聚亚烷基多元醇或所述多元醇的混合物的液体或缓冲剂。所述不同液体或缓冲剂也可称为“人造母液”,其不同于晶体的“天然”结晶母液,并且防止所形成的晶体溶解。
本发明还涉及一种可通过如上文所定义的结晶方法获得的抗hIL-12抗体的晶体,且一般涉及抗hIL-12抗体的晶体。
本发明的晶体可具有不同形状。所述形状通常被指为“剑状”。特别是,所述术语也包括“片状”、“针状”或“针簇状”(海胆状)。例如,本发明晶体的特征可在于,最大长度(l)为约2-500μm或约100-300μm且长度/直径(l/d)比率为约1至100的针状形态。所述针状晶体的高度一般在直径的尺寸内。
本发明的片状物可具有下列尺寸:最大长度(1)为约2-500μm或约100-300μm且长度/直径(l/d)比率为约1至100。所述片状物的高度显著小于直径。
本发明的针簇物可具有下列尺寸:最大长度l为约2-200μm或约10-100μm且长度/直径(l/d)比率为约1至3。
晶体可从多克隆抗体或优选从单克隆抗体获得。
特别是,抗体选自非嵌合或嵌合抗体、人源化抗体、非糖基化抗体、人类抗体和小鼠抗体。尤其是,待结晶的抗体为任选进一步经处理以改良抗原结合和/或功效的非嵌合、人类抗体。
优选地,晶体是从IgG抗体(诸如IgG1、IgG2、IgG3或IgG4抗体)获得。尤其是,抗体为IgG1组的完整抗人类IL-12抗体。
在一优选实施方案中,晶体是由从hIL-12解离的分离人类抗体制备的,其中皆通过表面等离子体共振所测定,Kd为1×10-10M或更小,并且koff速率常数为1×10-3s-1或更小。
尤其是,晶体可从具有包含SEQ ID NO:2的氨基酸序列的轻链可变区(LCVR)和包含SEQ ID NO:1的氨基酸序列的重链可变区(HCVR)的分离的人类抗体制备。
优选的人类抗体例如描述于美国专利第6,914,128号中。
最优选为从抗体ABT-874制备的晶体。
在另一实施方案中,本发明涉及固体、液体或半固体药物组合物,所述组合物包含:(a)如上文所定义的抗hIL-12抗体的晶体和(b)至少一种稳定维持所述抗体晶体的药物学上可接受的赋形剂。
本发明的另一方面涉及固体、液体或半固体药物组合物,所述组合物包含:(a)如本文所定义的抗hIL-12抗体的晶体和(b)至少一种囊封或包埋所述抗体晶体的药物学上可接受的赋形剂。所述组合物可进一步包含(c)至少一种稳定维持所述抗体晶体的药物学上可接受的赋形剂。此外,囊封和包埋可一起实施。
特别是,本发明的组合物可具有高于约1mg/ml,尤其是约200mg/ml或更大(例如约200mg/ml至约600mg/ml或约300mg/ml至约500mg/ml)的抗体晶体浓度。
所述赋形剂可包含至少一种聚合、任选生物可降解的载体或至少一种油类或脂质载体。
所述聚合载体可为一或多种选自下列的聚合物:聚(丙烯酸)、聚(氰基丙烯酸酯)、聚(氨基酸)、聚(酸酐)、聚(缩肽)、聚(酯)、聚(乳酸)、聚(乳酸-共-乙醇酸)或PLGA、聚(β-羟基丁酸酯)、聚(己内酯)、聚(二氧杂环己酮);聚(乙二醇)、聚(羟基丙基)甲基丙烯酰胺、聚(有机)磷腈、聚(原酸酯)、聚(乙烯醇)、聚(乙烯吡咯烷酮)、马来酸酐烷基乙烯基醚共聚物、pluronic polyol、白蛋白、藻酸盐、纤维素和纤维素衍生物、胶原、血纤蛋白、明胶、透明质酸、寡糖、葡糖胺基葡聚糖、硫酸化多糖、其掺合物和共聚物。
所述油类(或油性液体)可为一或多种选自下列的油类(或油性液体):油质杏仁油、玉米油、棉籽油、油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油、轻质矿物油、辛基十二烷醇、橄榄油、花生油、桃仁油、芝麻油、豆油、角鲨烷、液体甘油三酯、液体蜡和高级醇。
所述脂质载体可为一或多种选自下列的脂质:脂肪酸和脂肪酸盐、脂肪醇、脂肪胺、脂肪酸的甘油单酯、甘油二酯和甘油三酯、磷脂、糖脂、类固醇和蜡以及相关类似物质。蜡进一步是以天然和合成产物分类。天然物质包括从植物、动物或矿物来源获得的蜡,诸如蜂蜡、巴西棕榈蜡或褐煤蜡。氯化萘和烯系聚合物为合成蜡产物的实例。
在一优选实施方案中,组合物为包含如上文所定义的抗hIL-12抗体晶体且具有在约10mg/ml至约400mg/ml或约50mg/ml至约300mg/ml的范围内的抗体晶体浓度的可注射组合物。
在另一方面中,本发明涉及晶体浆料,其包含如上文所定义的具有高于约100mg/ml(例如约150mg/ml至约600mg/ml或约200至约400mg/ml)的抗体晶体浓度的抗hIL-12抗体晶体。
本发明还涉及用于治疗哺乳动物的方法,所述方法包括向所述哺乳动物施用有效量的如上文所定义的完整抗hIL-12抗体晶体或有效量的如上文所定义的组合物的步骤。优选地,所述组合物是通过胃肠外途径、口服途径或通过注射来施用。
此外,本发明涉及治疗个体的hIL-12相关病症的方法,所述方法包括施用治疗有效量的如上文所定义的抗体晶体。
特别是,hIL-12相关病症选自:
类风湿性关节炎、骨关节炎、青少年慢性关节炎、莱姆关节炎(Lymearthritis)、牛皮癣性关节炎、反应性关节炎、脊柱关节病、全身性红斑狼疮、克罗恩氏病(Crohn′s diseas)、溃疡性结肠炎、炎性肠病、胰岛素依赖性糖尿病、甲状腺炎、哮喘、过敏性疾病、牛皮癣、皮炎硬皮病、特应性皮炎、移植物抗宿主疾病、器官移植排斥反应、与器官移植相关的急性或慢性免疫疾病、类肉瘤病、动脉粥样硬化、弥漫性血管内凝血、川崎氏病(Kawasaki′s disease)、格雷氏病(Grave′s disease)、肾病综合征、慢性疲劳综合征、韦格纳肉芽肿病(Wegener′s granulomatosis)、亨偌-丝奇恩赖紫癜(Henoch-Schoenlein purpurea)、显微肾血管炎、慢性活动性肝炎、葡萄膜炎、脓毒性休克、中毒性休克综合征、脓毒综合征、恶病质、传染性疾病、寄生虫疾病、获得性免疫缺陷综合征、急性横贯性脊髓炎、亨廷顿舞蹈病(Huntington′s chorea)、帕金森病(Parkinson′s disease)、阿尔茨海默病(Alzheimer′s disease)、中风、原发性胆汁性肝硬化症、溶血性贫血、恶性肿瘤、心力衰竭、心肌梗塞、阿迪森氏病(Addison′s disease)、散发病(sporadic)、I型多腺缺乏症和II型多腺缺乏症、施密特氏综合征(Schmidt′s syndrome)、成人(急性)呼吸窘迫综合征、秃发症、斑秃、血清阴性关节病、关节病、莱特尔氏病(Reiter′s disease)、牛皮癣性关节病、溃疡性结肠炎性关节病、肠病性滑膜炎、衣原体疾病、耶氏菌(yersinia)和沙门氏菌(salmonella)相关关节病、脊柱关节病、动脉粥样化病/动脉硬化症、特应性过敏、自身免疫性大疱病、寻常天疱疮、落叶状天疱疮、类天疱疮、线性IgA疾病、自身免疫性溶血性贫血、库姆阳性溶血性贫血(Coombs positivehaemolytic anaemia)、后天性恶性贫血、青少年恶性贫血、肌痛性脑炎/贵族自由疾病(Royal Free Disease)、慢性皮肤粘膜念珠菌病、巨细胞性动脉炎、原发性硬化性肝炎、隐原性自身免疫性肝炎、获得性免疫缺陷疾病综合征(Acquired Immunodeficiency Disease Syndrome)、获得性免疫缺陷相关疾病(Acquired Immunodeficiency Related Diseases)、丙型肝炎、普通可变性免疫缺陷(普通可变性低γ-球蛋白血症)、扩张型心肌病、女性不孕症、卵巢衰竭、卵巢早衰、纤维化肺病、隐原性纤维化肺泡炎、炎症后间质性肺病、间质性肺炎、结缔组织疾病相关间质性肺病、混合型结缔组织疾病相关肺病、全身性硬化症相关间质性肺病、类风湿性关节炎相关间质性肺病、全身性红斑狼疮相关肺病、皮肌炎/多肌炎相关肺病、休格连氏病(Sjodgren′s disease)相关肺病、强直性脊椎炎相关肺病、血管炎弥漫性肺病、血铁质沉着症相关肺病、药物诱导间质性肺病、放射性纤维化、阻塞性细支气管炎、慢性嗜酸性肺炎、淋巴球性浸润性肺病、感染后间质性肺病、痛风性关节炎、自身免疫性肝炎、1型自身免疫性肝炎(典型自身免疫性或狼疮样肝炎)、2型自身免疫性肝炎(抗LKM抗体肝炎)、自身免疫介导性低血糖症、B型抗胰岛素症伴有黑棘皮病、甲状旁腺机能减退、与器官移植相关的急性免疫疾病、与器官移植相关的慢性免疫疾病、骨关节病、原发性硬化性胆管炎、特发性白血球减少症、自身免疫性嗜中性白血球减少症、肾病NOS、肾小球肾炎、显微肾血管炎、莱姆病(lyme disease)、盘状红斑狼疮、特发性男性不育症或NOS、精子自身免疫疾病、多发性硬化症(所有亚型)、胰岛素依赖性糖尿病、交感性眼炎、结缔组织疾病继发性肺动脉高血压、古德帕斯彻氏综合征(Goodpasture′s syndrome)、结节性多动脉炎的肺部表现、急性风湿热、类风湿性脊椎炎、史提尔氏病(Still′s disease)、全身性硬化症、高安氏病(Takayasu′s disease)/动脉炎、自身免疫性血小板减少症、特发性血小板减少症、自身免疫性甲状腺病、甲状腺机能亢进、甲状腺肿性自身免疫性甲状腺功能低下(桥本氏病(Hashimoto′s disease))、萎缩性自身免疫性甲状腺功能低下、原发性粘液水肿、晶体原性葡萄膜炎、原发性血管炎和白癜风。本发明的人类抗体和抗体部分可用于治疗自身免疫性疾病,尤其是与炎症相关的那些,包括类风湿性脊椎炎、过敏、自身免疫性糖尿病、自身免疫性葡萄膜炎。
此外,本发明涉及如上文所定义的完整抗hIL-12抗体晶体在制备用于治疗如上文所定义的hIL-12相关疾病的药物组合物中的用途。
最后,本发明提供了用于药物的如上文所定义的抗hIL-12抗体晶体。
附图简述
在与附图一起阅读时,从以下优选实施方案的描述,将对本发明之前提及的和其它目标、特征和优点以及本发明本身有更充分的理解。
图1显示了ABT-874晶体结晶时的光学显微镜照片。
图2至图5显示了ABT-874晶体在不同放大倍数下的SEM;图2:1,250×;图3:10,000×;图4:3,227×;图5:15,000×。
图6显示了关于ABT-874毛细管等电点聚焦(cIEF)实验的结果;A)ABT-874晶体缓冲剂和pI 8.4、8.5、10.1和10.4的pI标记;B)ABT-874晶体;相同pI标记和pI=9.29处的特征ABT-874信号;C)参考标准;相同pI标记和pI=9.29处的特征ABT-874信号。
图7显示了根据实施例28(伴以搅拌的结晶)获得的晶体(针簇状)的光学显微镜照片。
图8显示了根据实施例32(无搅拌的结晶)获得的晶体(针状)的光学显微镜照片。
图9显示了根据实施例33(无搅拌的结晶)获得的晶体(针状)的光学显微镜照片。
图10显示了根据实施例34b(无搅拌的结晶)获得的晶体(针状)的光学显微镜照片。
图11显示了ABT-874样品的二阶导数IR光谱。图11A显示了用BioATR单元记录的晶体悬浮液的光谱。图11B显示了用AquaSpec单元记录的再溶解晶体的光谱。实线表示结晶性ABT-874的样品,虚线表示液体标准物。为了更好的说明,插入样品与标准物之间的偏移。
图12显示了于25℃下储存3个月的ABT-874样品(50mg/mL于22%PEG 4,000缓冲剂、0.1M乙酸钠缓冲剂(pH 5.5)中的结晶蛋白质)的二阶导数IR光谱。图11A显示了以BioATR单元记录的晶体悬浮液的光谱。图11B显示了用AquaSpec单元记录的再溶解晶体的光谱。为了更好的说明,插入样品与标准物之间的偏移。
图13:ABT-874在有和无接种(例如,相对于来自批料的ABT-874质量而言使用3.25%结晶蛋白质作为接种物质)的情况下的40mL分批结晶。R2对于未接种而言为0.9711,且对于接种批料而言为0.9763。
发明详述
A.定义
“分批结晶方法”包括将包含结晶试剂(优选为溶解形式)的结晶溶液添加至待结晶的抗体溶液中的步骤。
“微量规模结晶方法”可例如为基于蒸气扩散且包括下列步骤:将微升范围内的少量抗体溶液与含有结晶试剂的蓄池缓冲剂(reservoirbuffer)混合;将混合物液滴置于一邻近于蓄池缓冲剂的等份试样的密封容器中;允许通过蒸气扩散使所述液滴与所述蓄池溶液之间交换溶剂,在此期间液滴的溶剂含量发生变化,并且如果达到合适的结晶条件,则可观察到结晶。
“结晶试剂”(例如聚乙二醇)有利于待结晶的抗体的晶体形成。
“结晶溶液”含有溶解形式的结晶试剂。优选地,所述溶液为水性系统,即其液体组分主要由水组成。例如,80wt.-%至100wt.-%或95wt.-%至100wt.-%或98wt.-%至100wt.-%可为水。
抗体“晶体”为蛋白质物质的固态的一种形式,其不同于第二固体形式,即非晶形状态,所述非晶形状态基本上以无组织的异质固体形式存在。晶体具有规则三维结构,通常称为晶格。抗体晶体包含抗体分子的规则三维阵列(参见Giege,R.和Ducruix,A.Barrett,Crystallization of Nucleic Acids and Proteins,a Practical Approach,第2版,第1-16页,Oxford University Press,New York(1999))。
如根据本发明结晶的“完整”抗hIL-12抗体是能够在体外和/或体内识别其抗原人类IL-12且与后者结合的功能抗体。所述抗体可引发与抗体与其抗原结合相关的患者的后续免疫系统反应,尤其是直接细胞毒性、补体依赖性细胞毒性(CDC)和抗体依赖性细胞毒性(ADCC)。抗体分子具有由两条互相共价结合的相同重链(MW各约50kDa)和两条分别与重链中的一条共价结合的相同轻链(MW各约25kDa)构成的结构。四条链排列成典型“Y”基元。各重链由重链可变区(本文中缩写为HCVR或VH)和重链恒定区构成。所述重链恒定区由三个域(CH1、CH2和CH3)构成。各轻链由轻链可变区(本文中缩写为LCVR或VL)和轻链恒定区构成。所述轻链恒定区由一个域CL构成。VH和VL区可进一步再分成称为互补决定区(CDR)的高变区,其间散布有较为保守、称为构架区(FR)的区域。各VH和VL由按以下顺序自氨基末端至羧基末端排列的三个CDR和四个FR构成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。完整抗体分子具有两个抗原结合位点,即为“二价”。所述两个抗原结合位点对于一个hIL-12抗原具特异性,即抗体具“单特异性”。
“单克隆抗体”为源自B淋巴细胞(B细胞)的单一克隆且识别相同抗原决定簇的抗体。完整单克隆抗体为具有上文所提及的包括两条完整重链和两条完整轻链的典型分子结构的那些。单克隆抗体常规是通过将产生抗体的B细胞与永生骨髓瘤细胞融合以产生B细胞杂交瘤而产生,其中所述B细胞杂交瘤在细胞培养物中不断地产生单克隆抗体。可利用其它产生方法,例如使用噬菌体显示技术使单克隆抗体表达于细菌、酵母、昆虫或哺乳动物细胞培养物中;在诸如牛、山羊、猪、兔、小鸡的遗传改良动物中或在已经改良而含有且表达整个人类B细胞基因组的转基因基因小鼠中体内产生;或在诸如烟草和玉米的遗传改良植物中产生。所有所述来源的抗hIL-12抗体可根据本发明结晶。
根据本发明待结晶的单克隆抗体包括“嵌合”抗hIL-12抗体,其中重链和/或轻链的一部分与源自特定物种或属于特定抗体种类或亚类的抗体中的相应序列相同或同源,而所述链的其余部分与源自另一物种或属于另一抗体种类或亚类的抗体中的相应序列相同或同源。例如,小鼠/人类嵌合体含有鼠类抗体的可变抗原结合部分和源自人类抗体的恒定部分。
非人类(例如鼠类)抗hIL-12抗体的“人源化形式”亦由本发明涵盖。人源化抗体为含有源自非人类免疫球蛋白的最小序列的嵌合抗体。多半而言,人源化抗体为来从人类免疫球蛋白的一或多个互补决定区(CDR)或高变环(HVL)的残基由来自非人类物种(诸如小鼠、大鼠、兔或非人类灵长类)的CDR或HVL且具有所需功能性的残基置换的人类免疫球蛋白。人类免疫球蛋白的构架区(FR)残基可由相应非人类残基置换以改良抗原结合亲和力。此外,人源化抗体可包含不存在于相应人类或非人类抗体部分中的残基。这些改良可为进一步改良抗体功效所必需的。
“人类抗体”或“完全人类抗体”是具有对应于由人类产生或重组产生的抗体的氨基酸序列的氨基酸序列的抗体。如本文所使用,术语“人类抗体”意欲包括具有源自人类种系免疫球蛋白序列的可变区和恒定区的抗体。本发明的人类抗体可包括不由人类种系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或位点特异性突变诱导或通过体内体细胞突变引入的突变体),例如在CDR且尤其是CDR3中。然而,如本文所使用,术语“人类抗体”不欲包括源自另一哺乳动物物种(诸如小鼠)的种系的CDR序列已嫁接于人类构架序列上的抗体。
如本文所使用,术语“重组人类抗体”意欲包括通过重组方式制备、表达、形成或分离的所有人类抗体,诸如使用转染至宿主细胞中的重组表达载体表达的抗体、从重组性组合人类抗体库分离的抗体、从人类免疫球蛋白基因转基因动物(例如小鼠)分离的抗体(参见例如,Taylor,L.D.等人(1992)Nucl.Acids Res.20:6287-6295)或通过包含将人类免疫球蛋白基因序列与其它DNA序列剪接的任何其它方式制备、表达、形成或分离的抗体。所述重组人类抗体具有源自人类种系免疫球蛋白序列的可变区和恒定区。然而,在特定实施方案中,使所述重组人类抗体经受体外突变诱导(或,当使用人类Ig序列转基因动物时,经受体内体细胞突变诱导)且因此,重组抗体的VH和VL区的氨基酸序列为虽然源自人类种系VH和VL序列且与其有关但可能在体内不天然存在于人类抗体种系谱中的序列。
如本文所使用,“中和抗体”(或“中和hIL-12活性的抗体”)意欲指与hIL-12结合导致抑制hIL-12的生物活性的抗体。对hIL-12的生物活性的此抑制作用可在体外或体内通过测量hIL-12生物活性的一或多个指标来评估,诸如hIL-12诱导的细胞增殖和hIL-12与hIL-12受体的结合或hIL-12诱导的体内白血球减少。
hIL-12生物活性的这些指标可通过本领域中已知的几种标准体外或体内检定中的一种或多种来评估。优选地,抗体中和hIL-12活性的能力是通过植物性血球凝集素胚细胞和鼠类2D6细胞中hIL-12诱导的细胞增殖的抑制来评估。
“亲和力成熟”抗hIL-12抗体为在一或多个高变区中具有一个或多个变化的抗体,此导致所述抗体与亲本抗体相比对于抗原的亲和力得到改良。亲和力成熟抗体对于靶抗原将具有纳摩尔或甚至皮摩尔的亲和力值。亲和力成熟抗体是通过本领域中已知的方法产生。Marks等人(1992)Bio/Technology 10:779-783描述通过VH和VL域改组达到的亲和力成熟。CDR和/或构架残基的随机突变诱导是由下列文献描述:Barbas等人(1994)Proc.Nat.Acad.Sci.USA 91:3809-3813(1994);Scier等人(1995)Gene 169:147-155;Yelton等人(1995)J.Immunol.155:1994-2004;Jackson等人(1995)J.Immunol.154(7):3310-9;和Hawkins等人(1992)J.Mol Biol.226:889-896。
如本文所使用,“分离的抗体”意欲指基本上不含具有不同抗原特异性的其它抗体的抗体(例如,特异性结合hIL-12的分离的抗体基本上不含特异性结合除hIL-12外的抗原的抗体)。然而,特异性结合hIL-12的分离的抗体可具有与其它抗原的交叉反应性,诸如来自其它物种的hIL-12分子。此外,分离的抗体可基本上不含其它细胞物质和/或化学品。
如本文所使用,短语“人类白介素12”(本文中缩写为hIL-12或IL-12)包括主要由巨噬细胞和树突状细胞分泌的人类细胞因子。所述术语包括异二聚蛋白质,其包含两者以二硫桥连接在一起的35kD亚单位(p35)和40kD亚单位(p40)。所述异二聚蛋白质被称为″p70亚单位″。人类IL-12的结构进一步被描述于(例如)下列文献中:Kobayashi,等人(1989)J.Exp Med.170:827-845;Seder,等人(1993)Proc.Natl.Acad.Sci.90:10188-10192;Ling,等人(1995)J.Exp Med.154:116-127;Podlaski,等人(1992)Arch.Biochem.Biophys.294:230-237。术语人类IL-12意欲包括重组人类IL-12(rh IL-12),其可通过标准重组表达方法制备。
如本文所使用,术语“koff”意欲指抗体从抗体/抗原复合物解离的解离速率常数(off rate constant)。
如本文所使用,术语“Kd”意欲指特定抗体-抗原相互作用的解离常数(dissociation constant)。
如根据本发明结晶的特定“亲本”抗hIL-12抗体的“功能等效物”为显示相同抗原特异性但然而就“亲本”抗体的分子组成而言在氨基酸含量或糖基化程度方面不同的物质。所述差异可能仅使得结晶条件不偏离本文所公开的参数范围。
抗体晶体的“囊封”是指所合并的晶体个别地涂有至少一层涂覆物质的配制。在一优选实施方案中,所述被涂覆的晶体可具有持续溶解速率。
抗体晶体的“包埋”是指可能被囊封或未被囊封的晶体以分散方式掺入固体、液体或半固体载体中的配制。所述经包埋的结晶抗体分子可以受控、持续方式从所述载体释放或溶解。
B.结晶方法
本发明的结晶方法原则上适用于任何抗hIL-12抗体。所述抗体可为多克隆抗体或优选为单克隆抗体。抗体可为嵌合抗体、人源化抗体、人类抗体或非人类(例如小鼠)抗体,各呈糖基化或非糖基化形式。尤其是,所述方法适用于ABT-874及其功能等效物。
优选地,抗hIL-12抗体为IgG抗体,尤其是IgG 1组的抗人类IL-12抗体。
除非另有说明,否则本发明的结晶方法使用本领域中熟知的技术设备、化学品和方法。然而,如上文所阐明,本发明是基于以下令人惊讶的发现:特定结晶条件的选择,尤其是特定结晶试剂的选择任选进一步与特定pH值条件和/或相应试剂(缓冲剂、抗体、结晶试剂)的浓度范围组合,首次允许可再现地且大规模地制备抗hIL-12的抗体(尤其是非嵌合人类抗体)的稳定晶体,其可进一步经处理以形成优良、高度有利的药物组合物的活性成份。
用于进行结晶方法的起始物质通常包含待结晶的抗体的浓缩溶液。蛋白质浓度可(例如)在约5mg/ml至约300mg/ml、优选约5mg/ml至约200mg/ml、优选约5mg/ml至约75mg/ml的范围内。所述溶液可含有使溶解抗体稳定的添加剂,且预先将添加剂移除可为可取的。此可通过进行缓冲剂交换步骤来达到。
优选地,用于进行结晶的起始物质含有于水溶液中具有经调节在约3.2至约8.2、或约4.0至约8.0、尤其是约4.5至约6.5、优选约5.0至约5.5的范围内的pH值的抗体。pH值可经由以约1mM至约500mM、尤其是约1mM至约100mM或1mM至约10mM的最终浓度应用的合适缓冲剂来调节。溶液可含有添加剂,例如比例为以溶液的总重量计约0.01至约15、或约0.1至约5、或约0.1至约2wt.-%,诸如盐、糖、糖醇和表面活性剂,以便进一步使溶液稳定。赋形剂优选选自常规应用于药物制剂中的生理学上可接受的化合物。作为非限制性实例,赋形剂包括盐,诸如NaCl;表面活性剂,诸如聚山梨醇酯80(Tween80)、聚山梨醇酯20(Tween 20);糖,诸如蔗糖、海藻糖;糖醇,诸如甘露糖醇、山梨糖醇;和缓冲剂,诸如基于磷酸盐的缓冲系统、磷酸氢钠和磷酸氢钾缓冲剂(如上文所定义)、乙酸盐缓冲剂、磷酸盐缓冲剂、柠檬酸盐缓冲剂、TRIS缓冲剂、顺丁烯二酸盐缓冲剂或琥珀酸盐缓冲剂、组氨酸缓冲剂;氨基酸,诸如组氨酸、精氨酸和甘氨酸。
缓冲剂交换可经由常规方法进行,例如透析、透滤或超滤。
用作起始物质的水溶液的初始蛋白质浓度应在约0.5mg/ml至约200mg/ml或约1mg/ml至约50mg/ml的范围内。
根据所欲的最终批量大小(其可在1ml至20,000公升的范围内),将初始体积的抗体水溶液置于由惰性材料(例如玻璃、聚合物或金属)制成的适当容器(例如器皿、瓶子或贮槽)中。所述水溶液的初始体积可对应于最终批量大小的约30至80%、通常约50%。
必要时,在溶液已填充至容器中之后,使溶液达到标准化条件。特别是,将温度调节在约4℃与约37℃的范围内。
接着将含有适当浓度结晶剂的结晶溶液,任选以抗体溶液相同的方式预调节,添加至抗体溶液中。
结晶溶液的添加连续或间断地进行,任选于缓和搅拌下以有助于混合两种液体。优选地,所述添加是于搅拌下提供蛋白质溶液和以控制方式添加结晶溶液(或固体形式的试剂)的条件下进行。
抗体晶体的形成是通过应用如上文所定义的聚亚烷基多元醇,尤其是聚亚烷基二醇,且优选聚乙二醇(PEG),或至少两种如上文所定义的不同聚亚烷基二醇的混合物作为结晶剂来引发。结晶溶液含有所述剂的浓度足以提供聚亚烷基多元醇在结晶混合物中的最终浓度在约5%至30%(w/v)的范围内。
优选地,结晶溶液另外含有酸性缓冲剂,例如不同于抗体溶液的缓冲剂,于适合允许调节结晶混合物的pH在约4至6的范围内的浓度。
在完成结晶溶液的添加后,所获得的混合物可进一步培育约1小时至约250天以获得最高产率的抗体晶体。适当时,可以例如搅拌、轻微搅拌、搅动或者移动混合物。
最后,所获得的晶体可通过已知方法分离,例如过滤或离心,例如于约200-20,000rpm、优选500-2,000rpm于室温或4℃离心。剩余母液可丢弃或进一步处理。
必要时,所分离的晶体可以洗涤且随后干燥,或母液可用适合悬浮抗体的储存和/或最终使用的不同溶剂系统交换。
如上文已阐明,根据本发明形成的抗体晶体的形状可不同。对于治疗性给药而言,晶体的尺寸将视给药途径而不同,例如对于皮下给药而言晶体的尺寸可大于静脉内给药。
如先前对于蛋白质晶体和低分子量有机和无机分子的晶体所描述,晶体形状可通过将特定另外的添加剂添加至结晶混合物中来改变。
必要时,可验证晶体事实上为抗体的晶体。可用显微镜分析抗体的晶体的双折射。一般而言,晶体除非具有立方内部对称性,否则将使偏振光的偏振平面旋转。在另一方法中,可将晶体分离、洗涤、再溶解且通过SDS-PAGE分析,并任选用抗Fc受体抗体染色。任选,也可利用标准检定测试再溶解抗体与其hIL-12的结合。
根据本发明获得的晶体也可互相交联。所述交联可增强晶体的稳定性。使晶体交联的方法例如描述于美国专利第5,849,296号中。可使用诸如戊二醛的双官能试剂使晶体交联。交联后,可将晶体冷冻干燥且储存以例如用于诊断性或治疗性应用。
在一些情况下,可能需要使晶体干燥。晶体可经由如氮气的惰性气体、真空烘箱干燥、冷冻干燥、蒸发、盘式干燥、流化床干燥、喷雾干燥、真空干燥或滚筒干燥来干燥。合适的方法为众所周知。
根据本发明形成的晶体可维持于原始结晶溶液中,或其可用如惰性载体或成份的其它物质洗涤并组合以形成包含本发明的晶体的组合物或制剂。所述组合物或制剂可例如用于治疗性和诊断性应用。
一优选实施方案为将合适的载体或成份与本发明的晶体以制剂的晶体为赋形剂所包埋或囊封的方式组合。合适的载体可取自下列各物的非限制性群:聚(丙烯酸)、聚(氰基丙烯酸酯)、聚(氨基酸)、聚(酸酐)、聚(缩肽)、聚(酯)、聚(乳酸)、聚(乳酸-共-乙醇酸)或PLGA、聚(β-羟基丁酸酯)、聚(己内酯)、聚(二氧杂环己酮);聚(乙二醇)、聚(羟基丙基)甲基丙烯酰胺、聚(有机)磷腈、聚(原酸酯)、聚(乙烯醇)、聚(乙烯吡咯烷酮)、马来酸酐烷基乙烯基醚共聚物、泊洛尼克多元醇、白蛋白、藻酸盐、纤维素和纤维素衍生物、胶原、血纤蛋白、明胶、透明质酸、寡糖、葡糖胺基葡聚糖、硫酸化多糖、其掺合物和共聚物、SAIB、脂肪酸和脂肪酸盐、脂肪醇、脂肪胺、脂肪酸的甘油单酯、甘油二酯和甘油三酯、磷脂、糖脂、固醇和蜡以及相关类似物质。蜡进一步是以天然和合成产物分类。天然物质包括自植物、动物或矿物来源获得的蜡,诸如蜂蜡、巴西棕榈蜡或褐煤蜡。氯化萘和烯系聚合物为合成蜡产物的实例。
C.组合物
本发明的另一方面涉及包含抗hIL-12抗体晶体与至少一种载体/赋形剂的组合的组合物/制剂。
所述制剂可为固体、半固体或液体。
本发明的制剂是通过将具有必需纯度的抗体与生理学上可接受的添加剂(如载体、赋形剂和/或稳定剂)以悬浮液的形式混合(参见例如Remington′s Pharmaceutical Sciences,第16版,Osol,A.编(1980))且将的冷冻干燥或以另一方式干燥而以适合于储存和/或使用的形式来制备。任选也可掺入其它活性成份,例如不同抗体、生物分子、化学或酶促合成低分子量分子。
可接受的添加剂在所用的剂量和浓度下对接受者无毒。其非限制性实例包括:
-酸化剂,如乙酸、柠檬酸、富马酸、盐酸、苹果酸、硝酸、磷酸、稀磷酸、硫酸、酒石酸;
-气雾剂推进剂,如丁烷、二氯二氟甲烷、二氯四氟乙烷、异丁烷、丙烷、三氯单氟甲烷;
-排气,如二氧化碳、氮气;
-醇变性剂,如甲基异丁基酮、八乙酸蔗糖酯;
-碱化剂,如氨溶液、碳酸铵、二乙醇胺、二异丙醇胺、氢氧化钾、碳酸氢钠、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺;
-消泡剂,如二甲聚硅氧烷、聚二甲基硅氧烷;
-抗菌防腐剂,如氯化苯甲烃铵、氯化苯甲烃铵溶液、氯苄硫铵、苯甲酸、苄醇、对羟基苯甲酸丁酯、氯化十六烷基吡啶、氯丁醇、氯甲酚、甲酚、脱氢乙酸、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸甲酯钠、苯酚、苯乙醇、乙酸苯汞、硝酸苯汞、苯甲酸钾、山梨酸钾、对羟基苯甲酸丙酯、对羟基苯甲酸丙酯钠、苯甲酸钠、脱氢乙酸钠、丙酸钠、山梨酸、硫柳汞、瑞香草酚;
-抗氧化剂,如抗坏血酸、棕榈酸抗坏血酯、丁基化羟基茴香醚、丁基化羟基甲苯、次磷酸、单硫代甘油(monothioglycerol)、没食子酸丙酯、甲醛合次硫酸氢钠、偏亚硫酸氢钠、硫代硫酸钠、二氧化硫、生育酚、生育酚赋形剂;
-缓冲剂,如乙酸、碳酸铵、磷酸铵、硼酸、柠檬酸、乳酸、磷酸、柠檬酸钾、偏磷酸钾、磷酸二氢钾、乙酸钠、柠檬酸钠、乳酸钠溶液、磷酸氢二钠、磷酸二氢钠、组氨酸;
-螯合剂,如依地酸二钠、乙二胺四乙酸和盐、依地酸;
-涂覆剂,如羧甲基纤维素钠、乙酸纤维素、酞酸乙酸纤维素、乙基纤维素、明胶、药物糖衣、羟丙基纤维素、羟丙基甲基纤维素、酞酸羟丙基甲基纤维素、甲基丙烯酸共聚物、甲基纤维素、聚乙二醇、聚乙酸乙烯酯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米蛋白、聚氨基酸、如PLGA等的其它聚合物和SAIB;
-着色剂,如氧化铁;
-络合剂,如乙二胺四乙酸和盐(EDTA)、依地酸、龙胆酸、乙醇酰胺、硫酸氧基喹啉;
-干燥剂,如氯化钙、硫酸钙、二氧化硅;
-乳化剂和/或增溶剂,如阿拉伯胶、胆固醇、二乙醇胺(佐剂)、单硬脂酸甘油酯、羊毛脂醇、卵磷脂、甘油单酯和甘油二酯、单乙醇胺(佐剂)、油酸(佐剂)、油醇(稳定剂)、泊洛沙姆、聚氧乙烯50硬脂酸酯、聚烃氧35蓖麻油、聚烃氧40氢化蓖麻油、聚烃氧10油醚、聚烃氧20十六基十八基醚、聚烃氧40硬脂酸酯、聚山梨醇酯20、聚山梨酸酯40、聚山梨酸酯60、聚山梨醇酯80、丙二醇二乙酸酯、丙二醇单硬脂酸酯、月桂基硫酸钠、硬脂酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、硬脂酸、三乙醇胺、乳化蜡;
-助滤剂,如粉末状纤维素、纯化硅质土;
-香料和芳香剂,如大茴香脑、苯甲醛、乙基香兰素、薄荷脑、水杨酸甲酯、谷氨酸单钠、橙花油、胡椒薄荷、薄荷、薄荷油、玫瑰油、浓玫瑰水、瑞香草酚、吐鲁香脂酊、香草、香草兰酊、香兰素;
-助流剂和/或防结块剂,如硅酸钙、硅酸镁、胶体二氧化硅、滑石粉;
-保湿剂,如甘油、己二醇、丙二醇、山梨糖醇;
-软膏基质,如羊毛脂、无水羊毛脂、亲水性软膏、白色软膏、黄色软膏、聚乙二醇软膏、石蜡油、亲水性石蜡油、白色石蜡油、玫瑰水软膏、角鲨烷;
-增塑剂,如蓖麻油、羊毛脂、矿物油、石蜡油、甲酸苄酯、氯丁醇、邻苯二甲酸二乙酯、山梨糖醇、二乙酰化甘油单酯、邻苯二甲酸二乙酯、甘油、丙三醇、单乙酰化甘油单酯和二乙酰化甘油单酯、聚乙二醇、丙二醇、三乙酸甘油酯、柠檬酸三乙酯、乙醇;
-多肽,如低分子量(小于约10个残基)的多肽;
-蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;
-聚合物膜,如乙酸纤维膜;
-溶剂,如丙酮、醇、稀醇、水合戊烯、苯甲酸苄酯、丁醇、四氯化碳、氯仿、玉米油、棉籽油、乙酸乙酯、甘油、己二醇、异丙醇、甲醇、二氯甲烷、甲基异丁基酮、矿物油、花生油、聚乙二醇、碳酸丙二酯、丙二醇、芝麻油、注射用水、注射用无菌水、灌洗用无菌水、纯水、液体甘油三酯、液体蜡、高级醇;
-吸附剂,如粉末状纤维素、炭、纯化硅质土、二氧化碳吸附剂、氢氧化钡石灰、碱石灰;
-硬化剂,如氢化蓖麻油、十六醇十八醇混合物、十六烷醇、十六烷基酯蜡、硬脂、石蜡、聚乙烯赋形剂、硬脂醇、乳化蜡、白蜡、黄蜡;
-栓剂基质,如可可脂、硬脂、聚乙二醇;
-悬浮剂和/或粘度增加剂,如阿拉伯胶、琼脂、海藻酸、单硬脂酸铝、膨土、纯化膨土、岩浆膨土、卡波姆(carbomer)934p、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素钠12、角叉菜胶、微晶和羧甲基纤维素钠纤维素、糊精、明胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸镁铝、甲基纤维素、果胶、聚氧化乙烯、聚乙烯醇、聚维酮、丙二醇海藻酸酯、二氧化硅、胶体二氧化硅、海藻酸钠、黄蓍胶、黄原胶;
-甜味剂,如阿斯巴甜糖、葡萄糖结合剂(dextrate)、右旋糖、赋形剂右旋糖、果糖、甘露糖醇、糖精、糖精钙、糖精钠、山梨糖醇、溶液状山梨糖醇、蔗糖、可压缩糖、糖粉、糖浆;
-片剂粘合剂,如阿拉伯胶、海藻酸、羧甲基纤维素钠、微晶纤维素、糊精、乙基纤维素、明胶、液状葡萄糖、瓜尔胶、羟丙基甲基纤维素、甲基纤维素、聚氧化乙烯、聚维酮、预胶凝化淀粉、糖浆;
-片剂和/或胶囊稀释剂,如碳酸钙、磷酸氢二钙、磷酸三钙、硫酸钙、微晶纤维素、粉末状纤维素、葡萄糖结合剂、糊精、右旋糖赋形剂、果糖、高岭土、乳糖、甘露糖醇、山梨糖醇、淀粉、预胶凝化淀粉、蔗糖、可压缩糖、糖粉;
-片剂崩解剂,如海藻酸、微晶纤维素、交联羧甲基纤维素钠、交联聚乙烯吡咯酮、泊拉可林钾(polacrilin potassium)、羟基乙酸淀粉钠、淀粉、预胶凝化淀粉;
-片剂和/或胶囊润滑剂,如硬脂酸钙、山嵛酸甘油酯、硬脂酸镁、轻质矿物油、聚乙二醇、硬脂酰富马酸钠、硬脂酸、纯化硬脂酸、滑石粉、氢化植物油、硬脂酸锌;
-渗透剂,如右旋糖、甘油、甘露糖醇、氯化钾、氯化钠;
-载体:调味和/或甜味芳香酏剂、复方苯甲醛酏剂、等醇酏剂、薄荷水、山梨糖醇溶液、糖浆、吐鲁香脂糖浆;
-载体,如油质杏仁油、玉米油、棉籽油、油酸乙酯、十四烷酸异丙酯、棕榈酸异丙酯、矿物油、轻质矿物油、十四烷醇、辛基十二烷醇、橄榄油、花生油、桃仁油、芝麻油、豆油、角鲨烷;固体载体糖球;注射用无菌抑菌水、抑菌氯化钠注射剂、液体甘油三酯、液体蜡、高级醇;
-拒水剂,如环甲聚硅氧烷、二甲聚硅氧烷、聚二甲硅氧烷;
-湿润剂和/或增溶剂,如氯化苯甲烃铵、苄索氯铵、氯化十六烷基吡啶、多库酯钠(docusate sodium)、壬苯醇醚9(nonoxynol 9)、壬苯醇醚10(nonoxynol 10)、辛苯昔醇9(octoxynol 9)、泊洛沙姆、聚烃氧35(polyoxyl 35)蓖麻油、聚烃氧40(polyoxyl 40)、氢化蓖麻油、聚烃氧50(polyoxyl 50)硬脂酸酯、聚烃氧10(polyoxyl 10)油基醚、聚烃氧20(polyoxyl 20)、十六烷基十八烷基醚、聚烃氧40硬脂酸酯、聚山梨醇酯20、聚山梨酸酯40、聚山梨酸酯60、聚山梨醇酯80、月桂基硫酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯和泰洛沙泊(tyloxapol)。
可将晶体与聚合载体组合以提供稳定性和/或持续释放。所述聚合物包括生物兼容性和生物可降解聚合物。聚合载体可为单一聚合物类型或其可由聚合物类型的混合物构成。聚合载体的非限制性实例已在上文陈述。
优选的成份或赋形剂的实例包括:
-氨基酸的盐,所述氨基酸诸如甘氨酸、精氨酸、天冬氨酸、谷氨酸、赖氨酸、天冬酰胺、谷氨酰胺、脯氨酸、组氨酸;
-单糖,诸如葡萄糖、果糖、半乳糖、甘露糖、阿拉伯糖、木糖、核糖;
-二糖,诸如乳糖、海藻糖、麦芽糖、蔗糖;
-多糖,诸如麦芽糊精、葡聚糖、淀粉、肝糖;
-醛糖醇,诸如甘露糖醇、木糖醇、乳糖醇、山梨糖醇;
-葡糖醛酸、半乳糖醛酸;
-环糊精,诸如甲基环糊精、羟基丙基-(3-环糊精);
-无机盐,诸如氯化钠、氯化钾、氯化镁、钠和钾的磷酸盐、硼酸、碳酸铵和磷酸铵;
-有机盐,诸如乙酸盐、柠檬酸盐、抗坏血酸盐、乳酸盐;
-乳化剂或增溶剂,如阿拉伯胶、二乙醇胺、单硬脂酸甘油酯、卵磷脂、单乙醇胺、油酸、油醇、泊洛沙姆、聚山梨醇酯、月桂基硫酸钠、硬脂酸、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单硬脂酸酯及其它脱水山梨糖醇衍生物、聚烃氧(polyoxyl)衍生物、蜡、聚氧乙烯衍生物、脱水山梨糖醇衍生物;和
-粘度增加剂,如琼脂、海藻酸及其盐、瓜尔胶、果胶、聚乙烯醇、聚氧化乙烯、纤维素及其衍生物、碳酸丙二酯、聚乙二醇、己二醇和泰洛沙泊。
本文所述的制剂也包括有效量的结晶性抗体。特别是,本发明的制剂可包括“治疗有效量”或“预防有效量”的本发明的抗体晶体。“治疗有效量”是指在必需剂量下且在必需时间内有效达到所需治疗效果的量。抗体晶体的“治疗有效量”可随诸如个体的疾病状况、年龄、性别和体重以及抗体引起个体体内所需反应的能力的因素而变化。治疗有效量亦为抗体的治疗性有益效应胜过任何毒性或不利效应的量。“预防有效量”是指在必需剂量下且在必需时间内有效达到所需预防效果的量。通常,因为在疾病早期阶段之前或在疾病早期阶段时对个体使用预防剂量,所以预防有效量将小于治疗有效量。
合适的剂量可容易地使用标准方法来确定。适当地向患者施用抗体一次或历经一系列治疗。视上述因素而定,约1μg/kg至约50mg/kg(例如0.1-20mg/kg)抗体为向患者施用的初始候选剂量,无论(例如)通过一或多次分开给药或通过连续输注皆然。典型每日或每周剂量可在约1μg/kg至约20mg/kg或以上的范围内,此根据病症而定,重复治疗直至出现疾病症状的所需抑制。然而,其它给药方案可为适用的。在一些情况下,制剂包含再溶解时为至少约1g/L或以上的浓度的抗体。在其它实施方案中,再溶解时抗体浓度为至少约1g/L至约100g/L。
抗体的晶体或包含所述晶体的制剂可单独施用或作为药物制剂的部分施用。其可通过胃肠外、口服或局部途径施用。例如,其可通过经口、肺、鼻、耳、肛门、皮肤、眼睛、静脉内、肌肉内、动脉内、腹膜内、粘膜、舌下、皮下、经皮、局部或颅内途径施用或施用至口腔中。给药技术的特定实例包含肺吸入、病灶内施用、用针注射、干粉吸入、皮肤电穿孔、气雾剂递送和无针注射技术,包括无针皮下给药。
现将通过下列非限制性说明性实例来更详细地解释本发明。根据说明书的一般部分且基于一般知识,将使得本领域技术人员能够提供本发明的其它实施方案而无需不当实验。
举例说明
A.材料
a)蛋白质
冷冻单克隆抗体(mAb)ABT-874是得自Abbott实验室。所有实验是根据产物批次进行,其中原始mAb浓度为64mg/mL。
b)精细化学品
乙酸钠是得自Grüssing GmbH,Filsum。不同聚合度的聚乙二醇是得自Clariant GmbH,Sulzbach。此外,将商业结晶筛选系统和试剂(Hampton Research,Nextal Biotechnologies)用于某些微量实验。所有其它化学物是来自Sigma-Aldrich、Steinheim或Merck,Darmstadt。
B.通用方法
a)ABT-874药物的解冻
于25℃下将ABT-874于搅拌水浴中解冻。
b)缓冲剂交换-方法A
将ABT-874溶液的等份试样用移液管移入30KDa MWCOVivaspin 20浓缩器(Vivascience)中。将蛋白质样品用新缓冲剂以1∶10的比率稀释,且通过于4℃下以5,000×g离心(Sigma 4K 15实验室离心机)使样品体积回到原始样品体积。将稀释/离心步骤重复一次,产生原始样品缓冲剂的1∶100稀释物。调节蛋白质浓度后,经由0.2μm针头式过滤器单元无菌过滤溶液。
b)缓冲剂交换-方法B
将ABT-874溶液的等份试样置于SLIDE-A-LYZER透析盒(PierceBiotechnology Inc.)中。将所述透析盒置于含有所选缓冲剂的烧杯中,且于4℃下伴以搅拌进行缓冲剂交换过夜。调节蛋白质浓度后,经由0.2μm针头式过滤器单元无菌过滤溶液。
c)OD280蛋白质浓度测量
使用ThermoSpectronics UV1装置来评估于280nm波长下的蛋白质浓度,其中应用1.42cm2mg-1的消光系数。出于此目的,将结晶浆料的等份试样于14,000rpm下离心,且测定上清液中的残余蛋白质浓度。
d)pH值测量
pH值测量是通过使用Mettler Toledo MP220pH计进行。利用Inlab413电极和Inlab 423微电极。
e)结晶方法
e1)微量规模结晶-沉滴蒸气扩散(Sitting Drop Vapor Diffusion)Hydra II
初始结晶筛选是使用Hydra II结晶自动机和Greiner 96孔板(三个滴孔,Hampton Research)进行。安置所述板后,用Clearseal薄膜(Hampton Research)密封所述孔。
e2)微量规模结晶-悬滴蒸气扩散(Hanging Drop Vapor Diffusion)
悬滴蒸气扩散实验是分别使用VDX板(具有密封剂,HamptonResearch)和OptiClear塑料盖玻片(正方形,Hampton Research)或硅化玻璃盖玻片(圆形,Hampton Research)进行。制备蓄池溶液(reservoirsolution)后,将一滴蓄池溶液与一滴蛋白质溶液于盖玻片上混合,且用倒置盖玻片以使液滴悬于蓄池上方的方式密封孔。
e3)分批结晶-方法A(24孔板)
分批结晶是通过将蛋白质溶液与等量结晶缓冲剂(500μl)于孔中混合来进行。随后用胶带密封所述孔以防止水蒸发。
e4)分批结晶-方法B(Eppendorff反应管)
分批结晶是通过将蛋白质溶液与等量结晶缓冲剂于1.5mL或2mLEppendorff反应管中混合来进行。
e5)分批结晶-方法C(Falcon管,无搅拌)
分批结晶是通过将蛋白质溶液与等量结晶缓冲剂于15mL或50mL Falcon管中混合来进行。
e6)分批结晶-方法D(Falcon管,搅拌)
分批结晶是通过将蛋白质溶液与等量结晶缓冲剂于15mL或50mL Falcon管中混合来进行。封闭后立即将所述管置于实验室摇动器(GFL 3013或GFL 3015)上或者通过翻转搅拌。通过应用这些方法,避免将搅拌器引入样品中。
f)SDS-PAGE
样品是通过将蛋白质浓度调节至8μg/20μL来制备。将所述样品用含有溴酚蓝的SDS/Tris/甘油缓冲剂稀释。定性SDS PAGE分析是使用Invitrogen NuPage 10% Bis-Tris凝胶、NuPage MES SDS运行缓冲剂(Running Buffer)和Mark12宽范围蛋白质标准物(Wide Range ProteinStandards)来进行。将20μL样品用移液管移入凝胶袋中。在跑胶且用乙酸/甲醇试剂固定后,使用Novex胶体蓝染色试剂盒(Colloidal BlueStain Kit)进行染色。使用Invitrogen Gel-Dry干燥溶液将凝胶干燥。
g)光学显微镜法
使用Zeiss Axiovert 25或Nikon Labophot显微镜观察到晶体。后者装备有偏振滤光镜设置和JVC TK C1380彩色视频摄影机。
h)SE-HPLC
ABT-874样品的聚集程度是通过SE-HPLC评估。使用Dionex P680泵、ASI-100自动取样器和UVD170U检测器装置。通过AmershamBioscience Superdex 20010/300GL凝胶过滤管柱,应用有效的Abbott标准方案(A-796874.0-ABT 874,J 695)将聚集物质与单体分离开。
C.蒸气扩散结晶实验
下列实施例中给出的浓度值为关于抗体溶液和蓄池溶液在混合两种溶液之前的初始值。
如果未另外描述,则所有pH值是指乙酸盐缓冲剂储备物在其与其它物质(如结晶试剂)组合之前的pH值。
如果未另外描述,则所有缓冲剂摩尔浓度是指在通常使用冰醋酸进行的pH值调节之前储备溶液中的乙酸钠浓度。
实施例1-悬滴蒸气扩散模式的PEG 4,000/乙酸钠栅格筛选
对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水(完全脱盐且任选预蒸馏的)在各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约6%w/v变化至约28%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔未观察到晶体。
实施例2-悬滴蒸气扩散模式、不同蛋白质浓度下的PEG 4,000/乙酸钠栅格筛选
于不同蛋白质浓度下对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至50mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约6%w/v变化至约28%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔,于约16%的PEG 4,000浓度下观察到晶体。所述晶体显示针状或针簇状形态。
实施例3-悬滴蒸气扩散模式的PEG 400/乙酸钠栅格筛选
使用PEG 400对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 400溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 400以2%梯度从约30%w/v变化至约40%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的12个孔未观察到晶体。
实施例4-悬滴蒸气扩散模式、不同蛋白质浓度下的PEG 400/乙酸钠栅格筛选
于不同蛋白质浓度下对AB T-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至50mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 400溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 400以2%梯度从约30%w/v变化至约40%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的12个孔未观察到晶体。
实施例5-悬滴蒸气扩散模式、不同蛋白质浓度和设置下的PEG 400/乙酸钠栅格筛选
使用不同蛋白质浓度和不同设置对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至50mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 400溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 400以2%梯度从约30%w/v变化至约40%w/v。pH值分别为约5.7或6.7。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后二十一天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔未观察到晶体。
实施例6-悬滴蒸气扩散模式的PEG 10,000/乙酸钠栅格筛选
使用PEG 10,000对AB T-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 10,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 10,000以2%梯度从约4%w/v变化至约14%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的12个孔未观察到晶体。
实施例7-悬滴蒸气扩散模式、不同蛋白质浓度下的PEG 10,000/乙酸钠栅格筛选
使用PEG 10,000且于不同蛋白质浓度下对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至50mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 10,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 10,000以2%梯度从约4%w/v变化至约14%w/v。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的12个孔未观察到晶体。
实施例8-悬滴蒸气扩散模式、不同设置下的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000和不同设置对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约22%w/v变化至约28%w/v。pH值分别为约4.2、4.7、5.2、5.7、6.2和6.7。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的48个孔未观察到晶体。
实施例9-悬滴蒸气扩散模式、不同设置下的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000和另一设置对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约8%w/v变化至约14%w/v。pH值分别为约5.7、6.2和6.7。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:在本实施例中从所评估的24个孔,在所包括的所有pH值下于约10%至14%的PEG 4,000浓度下观察到晶体。所述晶体显示针状或针簇状形态。
实施例10-悬滴蒸气扩散模式的PEG 400结合4,000/乙酸钠栅格筛选
使用PEG 400和4,000/乙酸钠对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约8%w/v变化至约12%w/v。同时,将PEG 400分别以约26%w/v、28%w/v、30%w/v和32%w/v的浓度加入PEG 4,000/乙酸盐溶液中。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔未观察到晶体。
实施例11-悬滴蒸气扩散模式、不同蛋白质浓度下的PEG 400合并4,000/乙酸钠栅格筛选
使用PEG 400和4,000/乙酸钠以不同蛋白质浓度对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.2的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至50mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约4%w/v变化至约8%w/v。同时,将PEG 400分别以约30%w/v、32%w/v、34%w/v和36%w/v的浓度加入PEG 4,000/乙酸盐溶液中。期间pH值为约5.2。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后三十天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔未观察到晶体。
实施例12-以悬滴蒸气扩散模式、不同蛋白质缓冲剂进行的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000和不同蛋白质缓冲剂对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约4%w/v变化至约26%w/v。期间pH值为5.5。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后五天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔,分别于约12%w/v、18%w/v、20%w/v、22%w/v和24%w/v的PEG 4,000浓度下观察到晶体。所述晶体显示针状或针簇状形态。
实施例13-悬滴蒸气扩散模式、不同蛋白质浓度下的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000和不同蛋白质浓度对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至5mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约4%w/v变化至约26%w/v。期间pH值为5.5。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后五天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔,分别于约10%w/v和14%w/v的PEG4,000浓度下观察到晶体。所述晶体显示针状或针簇状形态。
实施例14-以悬滴蒸气扩散模式、不同蛋白质缓冲剂进行的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000/乙酸钠和不同蛋白质缓冲剂对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至20mg/mL。
使用涂脂VDX板和正方形OptiClear塑料盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使PEG 4,000以2%梯度从约4%w/v变化至约26%w/v。期间pH值为5.5。对每一条件作一式两份评估。将约1μL蛋白质溶液与约1μL特定蓄池溶液于正方形OptiClear塑料盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。在随后五天期间对液滴进行多次显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所评估的24个孔,分别于约10%w/v、14%w/v、16%w/v、20%w/v和22%w/v的PEG 4,000浓度下观察到晶体。所述晶体显示针状或针簇状形态。
实施例15-以蒸气扩散模式对条件的广泛筛选
对ABT-874进行广泛筛选悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH 7.4的20mM HEPES/150mM氯化钠缓冲剂中。将蛋白质浓度调节至10mg/mL。在另一情况下,将蛋白质浓度调节至5mg/mL。在另一情况下,将蛋白质浓度调节至20mg/mL。
使用Hydra II结晶自动机且利用几种市售结晶筛选系统,将96孔Greiner板设置于室温下。将蛋白质溶液和结晶试剂以约1∶1、优选1∶1的比率混合。
使用下列筛选系统。Hampton Crystal Screen 1和2、Hampton IndexScreen、Hampton SaltRX Screen(均来自Hampton Research)、Nextal TheClassics、The Classics Lite、The PEGs、The Anions、The pH clear和TheAmmonium sulphate(均来自Nextal Biotechnologies)。
在将蛋白质添加至结晶试剂中(每一条件三滴,含有如上文所述的三种不同蛋白质浓度)后,用Clearseal薄膜密封板。将任何板设置四份且分别储存于室温、4℃、27℃和37℃下。六天后对液滴进行显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所测试的10,368种条件中,4种呈现晶体。所述条件包含由制造商所公开的下列蛋白质浓度和结晶试剂:
-室温,约20mg/mL的ABT-874
0.2M硫酸铵,30%w/v PEG 8,000
(Hampton Crystal Screen,C6)
-4℃,约5mg/mL的ABT-874
0.1M HEPES pH 7.5,5% w/v PEG 8,000
(Nextal The Classics Lite,F4)
-4℃,约10mg/mL的ABT-874
0.1M HEPES pH 7.5,5% w/v PEG 6,000,2.5% v/v MPD
(Nextal The Classics Lite,H9)
-4℃,约20mg/mL的ABT-874
0.1M HEPES,5%w/v PEG 6,000,pH 7.00
(Nextal pH clear,C4)
所述晶体显示针状或针簇状形态。
实施例16-悬滴蒸气扩散模式、不同设置下的PEG 4,000/乙酸钠栅格筛选
使用PEG 400和4,000/乙酸钠以不同设置对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH 7.4的20mM HEPES/150mM氯化钠缓冲剂中。将蛋白质浓度调节至10mg/mL。在另一情况下,将蛋白质浓度调节至5mg/mL。
使用涂脂VDX板和圆形硅化玻璃盖玻片。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且分别使用约12%w/v、18%w/v、24%w/v和30%w/v的PEG4,000浓度。使pH值以0.2梯度从约3.6变化至约5.6,从而形成48种不同条件。如上文所述,对任何条件设置两种蛋白质浓度。将约1μL蛋白质溶液与约1μL特定蓄池溶液于圆形硅化玻璃盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。六天后对液滴进行显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所测试的96种条件中,于pH值约5.6下对5mg/mLABT-874和约24%PEG 4,000观察到呈针簇形状的晶体。
实施例17-悬滴蒸气扩散模式、不同设置下的PEG 4,000/柠檬酸钠栅格筛选
使用PEG 4,000/柠檬酸钠和不同设置对ABT-874进行悬滴蒸气扩散结晶方法。将ABT-874缓冲加入到pH 7.4的20mM HEPES/150mM氯化钠缓冲剂中。将蛋白质浓度调节至10mg/mL。在另一情况下,将蛋白质浓度调节至5mg/mL。
使用涂脂VDX板和圆形硅化玻璃盖玻片。500μL特定蓄池溶液是通过将柠檬酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将柠檬酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且使用约12%w/v、18%w/v、24%w/v或30%w/v的PEG4,000浓度。使pH值以0.2梯度从约4.2变化至约6.4,从而形成48种不同条件。如上文所述,对任何条件设置两种蛋白质浓度。将约1μL蛋白质溶液与约1μL特定蓄池溶液于圆形硅化玻璃盖玻片上混合,且用倒置玻片将孔密封,从而形成悬滴实验。将所述板储存于室温下。六天后对液滴进行显微镜检查。将条件分为澄清液滴、含有无规沉淀物的液滴、含有晶体的液滴和含有沉淀物质和晶体的混合物的液滴。
结果:从所测试的96种条件,未观察到晶体。
D.分批结晶实验
对ABT-874进行分批结晶方法。下列实施例中所示的浓度值为抗体溶液和结晶溶液两种溶液混合之前的初始值。
如果未另外描述,则所有pH值是指乙酸盐缓冲剂储备物在与其它物质(如结晶剂)组合之前的pH值。
如果未另外描述,则所有缓冲剂摩尔浓度是指在通常使用冰醋酸进行pH值调节之前储备溶液中的乙酸钠浓度。
实施例18-1 Ml批量体积的PEG 4,000/乙酸钠条件
使用PEG 4,000/乙酸钠以1Ml批量体积对ABT-874进行结晶方法。将ABT-874在pH约5.2的含有约0.1M乙酸钠的缓冲剂中缓冲。将蛋白质浓度调节至10mg/mL。
分批结晶是通过约500μL蛋白质溶液与等体积结晶缓冲剂于1.5mL Eppendorff反应管中混合来进行。500μL特定蓄池溶液是通过乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为0.1M,乙酸盐缓冲剂pH为约6.7。使用浓度为约14%w/v的PEG 4,000。将所述反应管储存于室温下。16天后对1μL等份试样进行显微镜检。
结果:16天后未观察到晶体。
实施例19-300μL体积分批模式的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000/乙酸钠以300μL体积分批模式对ABT-874进行结晶方法。ABT-874于pH约5.5的含有约0.1M乙酸钠的缓冲剂中缓冲。将蛋白质浓度调节至10mg/mL。
分批结晶是通过约150μL蛋白质溶液与等体积结晶缓冲剂于孔中混合来进行。随后用胶带密封所述孔板以防止水蒸发。150μL特定蓄池溶液是通过乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且期间乙酸盐缓冲剂pH为约5.5。使PEG 4,000以2%梯度从约12%w/v变化至约34%w/v。对任何条件作三次评估。将所述板储存于室温下。在随后两天期间对液滴进行显微镜检查。
结果:从所检查的36个孔中,于设置在22%w/v与26%w/v PEG4,000之间的实验中观察到晶体。
实施例20-1 Ml批量体积、不同PEG 4,000浓度下的PEG 4,000/乙酸钠条件
使用PEG 4,000/乙酸钠以1Ml批量体积使用不同PEG 4,000浓度对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约500μL蛋白质溶液与等体积结晶缓冲剂于1.5mL Eppendorff反应管中混合来进行。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v的PEG 4,000。将实验设置四份。将所述反应管储存于室温下。在随后78天期间对1μL等份试样进行多次显微镜检查。此外,通过OD 280测定晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:七天后出现剑状晶体。在随后储存数月期间未观察到沉淀物质。六十天后通过OD280根据上清液中的残余蛋白质浓度测定的晶体产率介于50%与70%之间。
实施例21-1 Ml批量体积、不同PEG 4,000浓度下的PEG 4,000/乙酸钠条件
使用PEG 4,000/乙酸钠以1 Ml批量体积使用不同PEG 4,000浓度对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约500μL蛋白质溶液与等体积结晶缓冲剂于1.5mL Eppendorff反应管中混合来进行。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约26%w/v的PEG 4,000。将所述反应管储存于室温下。在随后数月期间对1μL等份试样进行多次显微镜检查。
结果:在一天后,观察到沉淀物质。五天后除了沉淀物外还观察到剑状晶体。
实施例22-1 Ml批量体积、不同PEG 4,000浓度下的PEG 4,000/乙酸钠条件
使用PEG 4,000/乙酸钠以1 Ml批量体积使用不同PEG 4,000浓度对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约500μL蛋白质溶液与等体积结晶缓冲剂于1.5mL Eppendorff反应管中混合来进行。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约24%w/v的PEG 4,000。将所述反应管储存于室温下。在随后数月期间对1μL等份试样进行多次显微镜检查。此外,通过OD 280测定晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:一天后出现针簇状晶体。五天后,除了针簇状晶体外还观察到针状晶体和片状物。十三天后通过OD280根据上清液中的残余蛋白质浓度测定的晶体产率介于60%与70%之间。
实施例23-1 Ml体积分批模式、不同蛋白质浓度下的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000/乙酸钠以1 Ml批量体积使用不同蛋白质浓度对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至5mg/mL。
分批结晶是通过将约500μL蛋白质溶液与等体积结晶缓冲剂于孔中混合来进行。随后用胶带密封所述孔板以防止水蒸发。
500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且期间乙酸盐缓冲剂pH值为约5.5。使PEG 4,000以2%梯度从约12%w/v变化至约34%w/v。对任何条件作两次评估。将所述板储存于室温下。在下一月期间对液滴进行显微镜检查。
结果:从所检查的24个孔中,于设置在24%w/v与26%w/v PEG4,000之间的实验中观察到剑状晶体。
实施例24-1 Ml体积分批模式、不同设置下的PEG 4,000/乙酸钠栅格筛选
使用PEG 4,000/乙酸钠以1 Ml批量体积使用不同设置对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约500μL蛋白质溶液与等体积结晶缓冲剂于孔中混合来进行。随后用胶带密封所述孔板以防止水蒸发。500μL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于各孔中混合来制备。在本实施例中,将乙酸盐缓冲剂摩尔浓度在约0.1M保持恒定,且乙酸盐缓冲剂pH值分别为约4.1、4.6和5.1。使PEG 4,000以2%梯度从约20%w/v变化至约28%w/v。将板储存于室温下。在随后四天期间对液滴进行显微镜检查。
结果:从所检查的18个孔中,于设置有pH 5.1的28%w/v PEG4,000和乙酸钠缓冲剂的实验中观察到剑状晶体。
实施例25-2 Ml批量体积、不同温度下的PEG 4,000/乙酸钠条件
使用PEG 4,000/乙酸钠以2Ml批量体积使用不同温度对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约1mL蛋白质溶液与等体积结晶缓冲剂于2mL Eppendorff反应管中混合来进行。1mL特定蓄池溶液是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v的PEG 4,000。将所述反应管储存于4-8℃下。在下一月期间对1μL等份试样进行多次显微镜检查。
结果:在储存过夜后观察到沉淀物质。
实施例26-10 Ml批量体积、搅拌下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以10Ml批量体积使用搅拌对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于50mL Falcon管中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于管中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约24%w/v的PEG 4,000。将管储存于室温下,用实验室摇动器搅拌批料。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。
结果:六天后出现剑状晶体,但几乎完全吸附于容器表面。无法自显微镜检查推断批料不含沉淀物质。结晶溶液几乎为澄清的。
实施例27-10 Ml批量体积、无搅拌的PEG 4,000/乙酸钠结晶条件
用PEG 4,000/乙酸钠以10 Ml批量体积在无搅拌的情况下对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于50mL Falcon管中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于管中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约24%w/v的PEG 4,000。将所述管储存于室温下。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD280测定晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:一天后出现针簇状晶体。四天后,除了针簇状晶体外还观察到针状晶体。七天后通过OD280根据上清液中的残余蛋白质浓度测定的晶体产率介于30%与40%之间。
实施例28-10 Ml批量体积、搅拌、不同容器材料下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以10 Ml批量体积使用搅拌和不同容器材料对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于50mL I型玻璃小瓶中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于小瓶中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约24%w/v的PEG 4,000。将小瓶储存于室温下,用实验室摇动器搅拌批料。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD 280测定晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:十八天后观察到剑状晶体。十八天后通过OD 280根据上清液中的残余蛋白质浓度测定的晶体产率介于40%与50%之间。针簇的光学显微镜照片(图的宽度对应于450μm的长度)显示于图7中。
实施例29-10 Ml批量体积、搅拌、不同容器材料和聚山梨醇酯80的影响下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以10 Ml批量体积使用搅拌、不同容器材料和聚山梨醇酯80的影响对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于50mL I型玻璃小瓶中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于小瓶中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约24%w/v的PEG 4,000。此外,将浓度为0.1%的聚山梨醇酯80添加至缓冲剂中。将小瓶储存于室温下,用实验室摇动器搅拌批料。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD 280测定晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:十八天后观察到剑状晶体。在本实施例和实施例28(未添加聚山梨醇酯80)的晶体形状之间未观察到差异。十八天后通过OD 280根据上清液中的残余蛋白质浓度测定的晶体产率介于25%与35%之间。实施例30-10 Ml批量体积下的不同PEG 4,000/乙酸钠结晶条件和搅拌与未搅拌批料的比较
使用PEG 4,000/乙酸钠以10 Ml批量体积使用搅拌与未搅拌批料的比较对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于50mL I型玻璃小瓶中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于小瓶中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v和24%w/v的PEG 4,000。将所述小瓶储存于室温下,不伴以搅拌或通过翻转搅拌。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD 280测定一个批料的晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:在两个搅拌批料中,26天后观察到沉淀物质。具有约22%w/vPEG 4,000的缓冲剂的未搅拌批料在26天后含有剑状晶体,但由于据目测悬浮液几乎澄清,所以认为晶体产率较低。具有约24%w/v PEG4,000的缓冲剂的未搅拌批料在26天后含有剑状晶体。70天后根据上清液测定的产率介于65%与75%之间。
实施例31-接种的影响
检验接种对ABT-874晶体产率的影响。来自实施例30的具有含有约22%w/v PEG 4,000的结晶缓冲剂的未搅拌批料在26天后显示极低晶体产率。因此,将批料与约100μL来自同一实施例的具有含有约24%w/v PEG 4,000的结晶缓冲剂的未搅拌批料一起培养。
结果:与晶种一起培养未引起明显的产率增加。
实施例32-10 Ml批量体积、不同蛋白质浓度、搅拌与未搅拌批料的比较下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以10 Ml批量体积使用不同蛋白质浓度和搅拌与未搅拌批料的比较对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至5mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于15mL I型玻璃小瓶中混合来进行。5mL结晶缓冲剂通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于小瓶中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v、24%w/v和26%w/v的PEG 4,000。将所述小瓶储存于室温下,不伴以搅拌或用实验室摇动器搅拌批料。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD 280测定一批的晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:含有具有约22%w/v和约24%w/v PEG 4,000的缓冲剂的批料在65天后为澄清的。当含有具有约26%w/v PEG 4,000的结晶缓冲剂的搅拌批料在4天后含有沉淀物质时,相同结晶缓冲剂的未搅拌批料在4天后含有剑状晶体。26天后根据上清液测定的此特定批料的晶体产率介于40%与50%之间。未经搅拌获得的晶体的光学显微镜照片(图的宽度对应于225μm的长度)显示于图8中。
实施例33-10 Ml批量体积、不同设置下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以10 Ml批量体积使用不同设置对ABT-874进行结晶方法。将AB T-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约5mL蛋白质溶液与等体积结晶缓冲剂于15mL Falcon管中混合来进行。5mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于管中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v的PEG 4,000。将所述管储存于室温下。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD280测定批料的晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:11天后观察到剑状晶体。26天后根据上清液测定的此批料的晶体产率介于40%与50%之间。26天后未经搅拌获得的晶体的光学显微镜照片(图的宽度对应于450μm的长度)显示于图9中。
实施例34a-50mL批量体积下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以50mL批量体积对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约25mL蛋白质溶液与等体积结晶缓冲剂于50mL Falcon管中混合来进行。25mL结晶缓冲剂是通过将乙酸盐缓冲剂、50%w/v PEG 4,000溶液和Milli Q水于管中混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v的PEG 4,000。将所述管储存于室温下。在随后数周期间对溶液的1μL等份试样进行多次显微镜检查。此外,通过OD280测定批料的晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:3天后观察到剑状晶体。16天后根据上清液测定的此批料的晶体产率介于50%与60%之间。
实施例34b-700Ml批量体积下的PEG 4,000/乙酸钠结晶条件
使用PEG 4,000/乙酸钠以700mL批量体积对ABT-874进行结晶方法。将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约350mL蛋白质溶液与等体积结晶缓冲剂于1L聚丙烯瓶子中混合来进行。350mL结晶缓冲剂是通过将乙酸盐缓冲剂、PEG 4,000和Milli Q水混合来制备。在本实施例中,乙酸盐缓冲剂摩尔浓度为约0.1M,且乙酸盐缓冲剂pH值为约5.5。使用浓度为约22%w/v的PEG 4,000。将所述瓶子储存于室温下。40天后对溶液的1μL等份试样进行显微镜检查。此外,通过OD 280测定批料的晶体产率。于14,000rpm下离心悬浮液的等份试样,且评估上清液中的蛋白质浓度。
结果:40天后观察到剑状晶体。40天后根据上清液测定的此批料的晶体产率介于50%与60%之间。40天后未经搅拌获得的晶体的光学显微镜照片(图的宽度对应于450μm的长度)显示于图10中。
上述分批实验的实验条件总结于以下表1中:
表1-分批实验
1%(w/v)
E.用于晶体加工和分析的方法
实施例35-晶体的洗涤
形成晶体后,无需再溶解晶体的洗涤步骤可为有利的。在完成结晶过程后,将晶体浆料转移至离心管中且以500至1000×g离心二十分钟。于4℃或室温下进行所述离心。在离心后,倒出上清液,且使晶体离心块容易地再悬浮于含有于约0.1M乙酸钠中的约24%w/v PEG4,000的缓冲剂(pH值约5.5)中。如通过OD280所分析,所述种洗涤缓冲剂中不存在可测量的ABT-874晶体溶解度。随后将离心/再悬浮步骤重复一至三次,且在此洗涤程序后,将离心块再悬浮且储存于所述种缓冲剂中。
实施例36-通过SDS PAGE分析晶体
为证实晶体的蛋白质特征,如实施例32中所述用洗涤缓冲剂洗涤晶体。在通过OD280确信蛋白质不再溶解于溶液中后,将晶体离心,倒出上清液,且随后将晶体溶解于蒸馏水中。此溶液的OD280测量显示现在存在蛋白质,这是因为现在样品的吸收率显著高于残余洗涤缓冲剂中的吸收率。此再溶解晶体溶液的SDS PAGE分析与原始AB T-874样品相比时显示相同图案。
实施例37-通过SE-HPLC分析晶体
为评估ABT-874晶体的聚集物质的含量,将经洗涤晶体的等份试样离心且再溶解于SE-HPLC运行缓冲液(92mM磷酸氢二钠/211mM硫酸钠pH 7.0)中。恰在结晶过程结束后,在本实施例中于室温下16天,聚集含量通常略微从约0.9%增加至约1.6-1.7%。目前尚不清楚是否所述聚集物含于晶体中或其表面处且未通过洗涤过程完全移除。
F.其它实施例
下列实施例中给出的浓度值为关于抗体溶液和结晶溶液在混合两种溶液之前的初始值。
如果未另外描述,则所有pH值是指乙酸盐缓冲剂储备物在其与其它物质(如结晶试剂)组合之前的pH值。
如果未另外描述,则所有缓冲剂摩尔浓度是指在通常使用冰醋酸进行的pH值调节之前储备溶液中的乙酸钠浓度。
实施例38-固体结晶试剂
将ABT-874缓冲加入到pH值约5.5的含有约0.1M乙酸钠的缓冲剂中。将蛋白质浓度调节至10mg/mL。
分批结晶是通过将约500μL蛋白质溶液与约380μL乙酸盐缓冲剂(0.1M,pH 5.5)于2mL Eppendorf反应管中混合来进行。随后,添加固体聚乙二醇至12%m/v(120mg/mL)的最终浓度。随后将所述管封闭且搅拌直至结晶试剂完全溶解。在无搅拌的情况下将管储存于室温下。在随后数周期间对结晶混合物的等份试样进行多次显微镜检查。
结果:七天后观察到剑状晶体。
实施例39-不同缓冲剂制备方案和晶体的制备
在本实施例中,乙酸盐缓冲剂是如以下所述制备:用约840mL纯水稀释60g冰醋酸。用氢氧化钠溶液调节pH值且将体积调节至1,000mL。在所述种状况下,将总乙酸盐量固定为1M(100mM于蛋白质溶液、结晶缓冲剂和结晶混合物中)。
根据实施例34a进行结晶;三天后观察到剑状晶体。
实施例40-囊封晶体的制备
如经由ζ电位测量使用Malvern Instruments Zetasizer nano所测定,实施例34中所获得的晶体带正电。将晶体洗涤且悬浮于含有保持结晶性的赋形剂且具有保持晶体带电的pH值的缓冲剂中。随后,将适当囊封剂添加至晶体悬浮液中。就此而言,适当囊封剂为具有低毒性、生物可降解性和抗衡离子特征的(聚合)物质。由于此抗衡离子特征,所述物质吸附于晶体上且允许涂覆。通过此技术,优选维持晶体溶解于不含有任何其它维持结晶性的赋形剂的介质中。
实施例41-囊封/包埋晶体的制备
如实施例34中所述获得晶体。将晶体洗涤且悬浮于含有保持结晶性的赋形剂的缓冲剂中。
接着可通过干燥晶体且将这些经干燥晶体与载体组合(例如通过压缩、熔融分散等)来包埋晶体。
-通过将晶体悬浮液与不可与水混溶的载体溶液组合来囊封/包埋。所述载体在移除载体的溶剂后沉淀。随后,将物质干燥。
-通过将晶体悬浮液与水可混溶性载体溶液组合来囊封/包埋。当超过载体在混合物中的溶解度极限时所述载体沉淀。
-通过将经干燥晶体或晶体悬浮液与水可混溶性载体溶液组合来包埋。
-通过将经干燥晶体与水不可混溶性载体溶液组合来包埋。
实施例42-沉淀ABT-874的研究
a)沉淀
乙酸盐缓冲剂是通过将1摩尔乙酸钠溶解于水中且用乙酸(100%)将pH值调节至5.5来制备。将储备溶液用水以1∶10稀释以供缓冲剂交换。PEG 4000溶液是通过将20g PEG 4000溶解于5mL 1M乙酸钠缓冲剂pH 5.5和水中来制备。在溶解后,用水将体积调节至50mL。将5mL 10mg/mL ABT874(于0.1M乙酸钠缓冲剂pH 5.5中)(通过透滤交换的原始缓冲剂)与5mL于0.1M乙酸钠缓冲剂pH 5.5中的40%PEG4000混合。
在无搅拌的情况下将沉淀物批料保持于室温下过夜。形成大小为约1-10μm的非双折射粒子。
b)沉淀物的洗涤
将2mL沉淀物浆料置放入离心机中且以500×g离心20min。丢弃上清液,且将离心块再悬浮于2mL于0.1M乙酸钠缓冲剂pH 5.5中的40%PEG 4000(根据上述方法制备)中。最终悬浮液的蛋白质浓度通过OD280测定为3.9mg/mL。
G.晶体表征
在以下章节中,概述为测定是否结晶性单克隆抗体ABT-874在使所述结晶性物质再溶解后保留未曾结晶的ABT-874的生物活性特征而进行的实验。
G1.通过测定NK-92细胞的IFN-γ产生的生物活性测试
a)通用方法
再溶解ABT-874晶体的生物活性是通过监测NK-92细胞响应于IL-12刺激的IFN-γ产生的基于细胞的检定来测量。在分析之前,首先将样品于细胞培养介质(具有20% FCS和200mM L-麸胺酰胺的α-MEM介质)中稀释至30μg/mL。随后,以11个步骤将样品进一步自3μg/mL稀释至0.1ng/mL。将IL-12溶液于细胞培养介质中稀释至10ng/mL且添加至ABT-874样品中。接着将混合物于37℃和5%CO2下培养1小时。
将NK-92细胞的悬浮液(2.0×106个细胞/毫升)用移液管移至96孔微量培养板中,将ABT-874/IL-12混合物添加至细胞中且接着将微量培养板于37℃和5%CO2下培养约20小时。培养后,将微量培养板于1,000rpm和5℃下离心10min且使用各孔的50μl上清液通过ELISA(ELISA试剂盒人类干扰素-γ,Pierce,目录号EHIFNG)测量由细胞产生的IFN-γ的量。
将生物素标记抗IFN-γ抗体溶液用移液管移至96孔预涂微量培养板中且添加细胞培养物上清液(两种样品各4列)。于室温下将微量培养板培养2小时后,将其洗涤。此后,添加链霉抗生物素蛋白-HRP溶液且将微量培养板再培养30min,且接着加以洗涤。在添加TMB底物后,将微量培养板于室温下在黑暗中培养约20min且接着通过添加停止溶液停止反应。
最后,在随后5min内用微量培养板读数器于450nm下(校正波长为550nm)测量吸收且将结果相对于ABT-874浓度作图。接着使用4参数非线性曲线拟合估算IC50值且通过以样品的IC50值除参考标准的IC50值且乘以100%来计算样品的相对生物活性。
b)ABT-874晶体的相对活性
将样品的生物活性与参考标准的生物活性比较来进行测试。由细胞产生的IFN-γ的量是通过市售ELISA试剂盒测量且以于450nm的波长下的吸收单位报导。将这些值相对于ABT-874的浓度作图且通过4参数非线性回归评估,结果公开ABT-874抑制IL-12效应的IC50值。因为将两种样品于一个微量培养板上重复四次,因此此导致ABT-874参考标准和样品分别有四个IC50值。随后,计算参考标准的IC50值的平均值且通过以样品的相关IC50值除参考标准的平均IC50值且乘以100%来评估每次重复的样品的相对活性。
对样品(晶体悬浮液2.9mg/mL)的测试公开98%的相对生物活性。因此,样品可视作具有完全生物学活性。
G2.显微镜表征
以下将呈现关于ABT-874晶体的显微镜表征的资料。
a)对mAb晶体分批样品的光学分析
在匀化后,将1至10μL样品体积的等份试样用移液管移至物体固持器板上且用玻璃盖玻片覆盖。使用分别装备有E-PI 10×目镜和10×、20×和40×物镜的Zeiss Axiovert 25倒置光学显微镜评估晶体制剂。使用数字摄影机(Sony Cybershot DSC S75)获取图像。
b)对ABT-874晶体的扫描电子显微镜(SEM)表征
为用电子显微镜使蛋白质晶体成像,所述晶体必须足够的干燥、具足够的导电性和稳定性以耐受高真空和电子束的能量。此方案通过过滤使晶体与其缓冲液分离,通过用基于戊二醛的固定剂将晶体化学固定而使晶体稳定,经由梯度系列乙醇使晶体脱水,通过临界点方法将晶体干燥且用金等离子体涂覆晶体以使其导电。
b1)材料
-0.2M索伦森氏磷酸盐缓冲剂(Sorensen′s Phosphate Buffer,SPB)-0.15M磷酸氢二钠、0.05M磷酸二氢钾,pH 7.3
-卡洛夫斯基氏固定剂(Karnovsky′s fixative)-2.5%戊二醛、1.5%三聚甲醛、0.1M SPB
-50%、75%、95%和100%乙醇
-于结晶缓冲剂中的ABT-874晶体样品(来自实施例34,储存于来自实施例35的洗涤缓冲剂中)
-ABT-874结晶缓冲剂(来自实施例35的洗涤缓冲剂)
-用于将13mm过滤膜附接于注射器的微孔不锈钢过滤器装配物
-0.4μm聚碳酸酯过滤膜(Nucleopore,Cat# 110407)
b2)设备
-临界点干燥器(CPD)-Baltec型号CPD030,Asset LC978501
-扫描电子显微镜(SEM)-Philips XL30场致发射扫描电子显微镜
-溅射涂覆机-Denton Desk II溅射涂覆机,Asset LC827847
b3)程序
通过使溶液冲过过滤器装配物且将所述注射器固持于过滤器装配物上历时指定固持时间来进行步骤3-12。
1.将聚碳酸酯过滤器装至注射器过滤器固持器上;
2.将0.1ml晶体样品与0.4ml晶体缓冲剂混合于1.0ml注射器中;
3.经由过滤器装配物分配经稀释晶体溶液;
4.分配1ml晶体缓冲剂且保持2min;
5.分配1ml 50%固定剂、50%晶体缓冲剂且保持2min;
6.分配1ml 100%固定剂且保持2min;
7.分配1ml SPB且保持2min;
8.再次分配1ml SPB且保持2min;
9.分配1ml 50%乙醇且保持2min;
10.分配1ml 75%乙醇且保持2min;
11.分配1ml 95%乙醇且保持2min;
12.分配1ml 100%乙醇且保持2min,重复步骤3次;
13.将具有附着晶体的过滤膜转移至填充有100%乙醇的CPD;
14.如下处理过滤器至CPD:
a.于10℃下五次交换液体CO2,每次交换混合5分钟;
b.加热至40℃、80巴压力;且
c.经20分钟缓慢回渗至大气压;
15.将过滤膜安装于SEM支撑物上
16.溅射涂覆以金历时60秒;
17.用SEM检查。
c)结果
在附图1至5中,呈现ABT-874晶体的代表性图。
图1显示根据实施例34获得的于结晶缓冲剂中的ABT-874晶体(来自实施例34,储存于来自实施例35的洗涤缓冲剂中)的光学显微镜照片。晶体惯态类似于图2至5中显示的经固定干燥的晶体的惯态。所述晶体展现双折射。
图2至图5显示根据实施例34获得的ABT-874晶体在不同放大倍数下的SEM。
G3.双折射
从所有分批实验产生的晶体展现双折射。
G4.可注射性
150mg/mL蛋白质掺入晶体中且配制于来自实施例35的洗涤缓冲剂中的ABT-874晶体悬浮液可经由27G针注射。
H.对ABT-874的毛细管等电点聚焦(cIEF)实验
a)设备
使用iCE280分析器(Convergent Bioscience)进行分析。系统ID1054(IS #2785)。
b)材料
所使用的毛细管为经涂覆的50mm长度、100μm ID管柱(Convergent,目录号101700)。所使用的电解液为阳极电解液(80mMH3PO4)和阴极电解液(100mM NaOH)。(Convergent,目录号101800)。载体两性电解质为4% Pharmalyte(8-10.5)(GE Healthcare,目录号17-0455-01)。添加剂为甲基纤维素(0.35%)(Convergent,目录号101876)。内部pI标记是来自BioRad(8.4、8.5、10.1和10.4-BioRad,目录号148-2100,货号482-511)pI标记混合物。
体积(μL) | |
PI标记8.4 | 2.5 |
PI标记8.5 | 2.5 |
PI标记10.1 | 2.5 |
PI标记10.4 | 2.5 |
水 | 40 |
总计 | 50 |
c)方法
聚焦时间于1500V下为2分钟且于3000V下为20分钟。样品制备程序-将Mab晶体、Mab沉淀物和参考标准均于Milli-Q水中稀释至约1mg/ml。样品制备程序(用尿素)。
体积(μL) | |
Milli-Q水 | 92 |
1%甲基纤维素 | 70 |
载体-Pharmalyte | 8 |
样品(1mg/mL) | 30 |
PI标记混合物(表1) | 16 |
总计 | 216 |
如上表中所示,将样品混合于1.5mL微量离心管中。接着添加尿素(20mg)以产生约1.6M的最终浓度。接着将离心管涡旋,离心10分钟且接着小心地转移至小瓶中以供分析。
d)结果
分析下列样品:
ABT-874晶体缓冲剂(来自实施例35的洗涤缓冲剂)
ABT-874晶体(根据实施例33获得,于来自实施例35的洗涤缓冲剂中)
参考标准(ABT-874液体样品)。
结果显示于附图6A至C中。
实施例43:晶体结晶/再溶解后的天然二级结构的保持
根据制造商说明书用Confocheck系统于Bruker Optics Tensor 27上记录IR光谱。使用MicroBiolytics AquaSpec单元分析液体样品。用Harrick BioATRII单元TM进行蛋白质悬浮液的测量。各样品是通过于25℃下进行120至500次扫描的至少两次测量来评估。分别自蛋白质光谱减去空白缓冲剂光谱。通过傅里叶变换(Fourier transformation)产生蛋白质二阶导数光谱且将向量自1580-1720cm-1标准化以供相对比较。
如下进行晶体的再溶解。将晶体悬浮液离心,丢弃上清液,且将晶体离心块溶解于0.1M乙酸钠缓冲剂pH 5.5中达10mg/mL蛋白质浓度。
图11图标按照实施例34b中所述的处理结晶、按照实施例35中所介绍的程序洗涤且经再溶解的结晶性ABT-874悬浮液的FT-IR二阶导数光谱。所述光谱显示在结晶性固体状态下或再溶解后,观察到二级结构无显著变化。
实施例44:稳定性数据(SE HPLC、FT-IR、形态)
使用实施例34b中所述的结晶程序使ABT-874结晶。如实施例35中所述,用含有22%PEG 4,000和0.1M乙酸钠的分散缓冲剂洗涤晶体,且用冰醋酸将pH值调节至5.5。随后,通过离心分别将晶体浓缩至5mg/mL和50mg/mL蛋白质,且储存于2-8℃下。
经3个月储存于2-8℃下,5mg/mL和50mg/mL结晶性ABT-874的稳定性数据指示超过90%单体的保持率。
(a)SE-HPLC
表2-5mg/mL结晶性ABT-874在再溶解后的稳定性数据
时间点 | 聚集物(%) | 单体(%) | 片段(%) |
T0 | 3.9 | 95.8 | 0.3 |
1个月 | 5.7 | 94.0 | 0.3 |
3个月 | 8.7 | 91.0 | 0.3 |
表3-50mg/mL结晶性ABT-874在再溶解后的稳定性数据
时间点 | 聚集物(%) | 单体(%) | 片段(%) |
T0 | 3.8 | 96.0 | 0.2 |
1个月 | 4.6 | 95.0 | 0.4 |
3个月 | 6.3 | 93.4 | 0.3 |
使用Dionex HPLC系统(P680泵、ASI 100自动取样器、UVD 170U)测量ABT-874抗体的稳定性。将ABT-874样品于GE200管柱上,应用0.75mL/min的流速分离。于214nm的波长下进行检测。运行缓冲液由于0.09M磷酸钠缓冲剂(pH 7.0)中的0.2M硫酸钠组成。
(b)FT-IR
用Confocheck系统于Bruker Optics Tensor 27上记录IR光谱。使用MicroBiolytics AquaSpec单元分析液体样品。用Harrick BioATRII单元TM进行蛋白质悬浮液的测量。各样品是通过于25℃下进行120至500次扫描的至少两次测量来评估。分别自蛋白质光谱减去空白缓冲剂光谱。通过傅里叶变换产生蛋白质二阶导数光谱且将向量自1580-1720cm-1标准化以供相对比较。
如下进行晶体的再溶解。将晶体悬浮液离心,丢弃上清液,且将晶体离心块溶解于0.1M乙酸钠缓冲剂pH 5.5中达10mg/mL蛋白质浓度。
图2图示结晶性ABT-874悬浮液(50mg/mL存放稳定性样品,如上文所述制备且储存于25℃下历时3个月)和所述经预处理晶体在再溶解后的FT-IR二阶导数光谱。所述光谱显示在结晶性固体状态下或再溶解后,于25℃下储存三个月后观察到二级结构无显著变化。
(c)形态
于2-8℃下储存3个月后,在晶体的光学显微镜法分析中观察到无显著形态变化。将1μL至10μL样品体积的等份试样用移液管移至物体固持器板上,用配制缓冲剂(22%PEG)稀释且用玻璃盖玻片覆盖。使用分别装备有E-PI 10×目镜和10×、20×和40×物镜的Zeiss Axiovert 25倒置光学显微镜评估制剂。
实施例45-结晶过程的产率增加
结晶过程的终点可定义为在结晶浆料的上清液的等份试样的OD280测量不变(例如在随后三天里)时的时间点。产率增加通过将一定量另外的PEG 4,000(于约0.1M乙酸钠缓冲剂中的50%w/v溶液,pH值为约5.5)添加至结晶浆料的上清液中而成为可能。类似于第一次收获结果的晶体在随后数天期间形成。应用此程序,容易使总产率超过90%,而不引入沉淀。
例如,在实施例34b的上清液的等份试样中,将PEG 4,000浓度从约11%w/v升至约22%w/v、约20%w/v、约18%w/v、约16%w/v或约14%w/v。于室温(例如介于约20℃与约25℃之间)下储存几种天后,于某些PEG 4,000浓度(例如约22%w/v、约20%w/v或约18%w/v PEG4,000)下观察到沉淀物质。于较低PEG 4,000浓度(例如于约16%w/v和约14%w/v PEG 4,000)下发现晶体但不伴有沉淀。通过将PEG 4,000添加至结晶浆料的残余上清液中达例如约14%w/v的总体浓度,使总体晶体产率在数天内从约60%提升至约70%直至超过90%。
实施例46:应用连续方法增加产率
在本实施例中,将其它沉淀物和/或蛋白质以预定速率″滴定″至结晶批料(任选含有一定量的结晶试剂)中。随时间促使连续结晶,最后产生超过90%的晶体产率。
实施例47-ABT-874结晶批料的接种
自发成核在性质上具统计性。可能由相同蛋白质(均质接种)或除结晶者外的另一物质(异质接种)组成的晶种提供可组装其它分子的模板。因此,接种可由此加速结晶。
如实施例34b中所述制备ABT-874结晶批料。在将蛋白质溶液与结晶缓冲剂混合后,通过用ABT-874晶体均质接种来接种混合物。例如,将如实施例34b中所述制备的展现约50%至60%晶体产率的晶体悬浮液的等份试样例如以1/20比率(v/v)添加至结晶批料中。应用此策略,进一步将总晶体产率和处理持续时间向较短处理时间内的较高产率最优化。
简言之,制备ABT-874结晶混合物(于0.1M乙酸盐缓冲剂pH 5.5中的5mg/mL蛋白质和11% PEG 4,000)且分成两个40mL等份试样。将第一批料储存于RT下而无其它程序且通过添加已展现65%晶体产率的2mL相同组成的结晶混合物(6.5mg晶种,基于结晶蛋白质计算,与批料中的200mg ABT-874相比)来接种第二批料。图13中所绘的图说明通过应用此接种方法,在80天内总产率增加约15%,而平行曲线行进表明达到最大产率的处理时间并不显著减少。图13表明尽管未接种批料在约80天后达到产率的平台,但理论上可能的产率可能高达接种批料的产率,此意谓接种减少结晶过程的持续时间而不增加产率。
以引用的方式引入
本申请可能通篇引用的所有引用参考数据(包括文献参考、专利、专利申请和网站)的内容明确地以全文引用的方式引入本文中,其中所引用的参考文献亦然。除非另有指示,否则本发明的实践将利用本领域中熟知的结晶和配制的常规技术。
等效性
在不脱离本发明的精神或基本特征的情况下可以其它特定形式体现本发明。因此,就各方面而言上述实施例视为说明性的而非限制本文所述的本发明。因此,本发明的范畴是由随附申请专利范围而非由上述描述所指示,且因此在申请专利范围的等效性的意义和范围内的所有变化意欲包含在本发明中。
序列表
<110>Abbott GmbH Co.KG
<120>结晶抗人类IL-12抗体
<130>8215.US.01
<160>2
<170>PatentIn version 3.3
<210>1
<211>444
<212>PRT
<213>人类
<400>1
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Claims (44)
1.一种将抗人类IL-12抗体结晶的分批结晶方法,所述方法包括下列步骤:
(a)提供所述抗体与作为结晶试剂的至少一种聚亚烷基二醇的混合物的水溶液;和
(b)培育所述含水结晶混合物直至形成所述抗体的晶体。
2.根据权利要求1的结晶方法,其中所述含水结晶混合物的pH在约pH 4至约6.5的范围内。
3.根据前述权利要求任一项的结晶方法,其中所述含水结晶混合物包含缓冲剂。
4.根据权利要求3的结晶方法,其中所述缓冲剂包含乙酸盐缓冲剂。
5.根据权利要求4的结晶方法,其中所述缓冲剂包含乙酸钠。
6.根据权利要求3至5中任一项的结晶方法,其中所述含水结晶混合物中缓冲剂浓度最高达约0.5M。
7.根据前述权利要求任一项的结晶方法,其中所述聚亚烷基二醇具有在约400至约10,000的范围内的平均分子量。
8.根据权利要求7的结晶方法,其中所述聚亚烷基二醇为聚乙二醇。
9.根据前述权利要求任一项的结晶方法,其中所述结晶混合物中所述聚亚烷基二醇浓度在约5%至30%(w/v)的范围内。
10.根据权利要求9的结晶方法,其中所述聚亚烷基二醇为聚乙二醇。
11.根据前述权利要求任一项的结晶方法,其中符合下列另外结晶条件中的至少一个:
a)进行培育约1小时至约250天;
b)于约4℃至约37℃之间的温度进行培育;
c)所述抗体浓度在约0.5mg/mL至约280mg/mL的范围内。
12.根据前述权利要求任一项的结晶方法,所述方法进一步包括干燥所述晶体的步骤。
13.根据前述权利要求任一项的结晶方法,所述方法进一步包括用人造母液交换结晶母液的步骤。
14.根据前述权利要求任一项的结晶方法,其中批量体积在约1ml至约20,000升的范围内。
15.一种抗人类IL-12抗体的晶体。
16.一种抗人类IL-12抗体的晶体,其可通过根据权利要求1至14中任一项的结晶方法获得。
17.根据权利要求15或16的晶体,其中所述晶体具有剑状形态。
18.根据权利要求15至17中任一项的晶体,其中所述抗体为多克隆抗体或单克隆抗体。
19.根据权利要求18的晶体,其中所述抗体选自嵌合抗体、人源化抗体、非糖基化抗体、人类抗体和小鼠抗体。
20.根据权利要求15至19中任一项的晶体,其中所述抗体为IgG抗体。
21.根据权利要求20的晶体,其中所述抗体选自IgG1、IgG2、IgG3和IgG4抗体。
22.根据权利要求21的晶体,其中所述抗体为IgG1组的抗人类IL-12抗体。
23.根据权利要求22的晶体,其中所述晶体是由从人类IL-12解离的分离人类抗体制备的,其中通过表面等离子体共振测定,Kd为1×10-10M或更小,koff速率常数为1×10-3s-1或更小。
24.根据权利要求22或23的晶体,其中所述晶体是从具有包含SEQ ID NO:2的氨基酸序列的轻链可变区(LCVR)和包含SEQ ID NO:1的氨基酸序列的重链可变区(HCVR)的分离的人类抗体制备的。
25.根据权利要求23的晶体,其中所述晶体是从抗体ABT-874制备的。
26.一种药物组合物,其包含:(a)根据权利要求15至25中任一项的抗人类IL-12抗体的晶体和(b)至少一种药物赋形剂;其中所述组合物是以固体、半固体或液体制剂提供,各制剂含有呈结晶形式的所述抗体。
27.一种药物组合物,其包含:(a)根据权利要求15至25中任一项的抗人类IL-12抗体的晶体和(b)至少一种包埋或囊封所述晶体的药物赋形剂。
28.根据权利要求26或27的组合物,其中所述组合物具有大于约1mg/ml的抗体浓度。
29.根据权利要求28的组合物,其中所述组合物具有大于约200mg/ml的抗体浓度。
30.根据权利要求26和27的组合物,其中所述组合物包含至少一种选自聚合的生物可降解载体、聚合的非生物可降解载体、油类载体和脂质载体的载体。
31.根据权利要求30的组合物,其中所述聚合载体是选自一或多种下列的聚合物:聚(丙烯酸)、聚(氰基丙烯酸酯)、聚(氨基酸)、聚(酸酐)、聚(缩肽)、聚(酯)、聚(乳酸)、聚(乳酸-共-乙醇酸)或PLGA、聚(β-羟基丁酸酯)、聚(己内酯)、聚(二氧杂环己酮);聚(乙二醇)、聚(羟基丙基)甲基丙烯酰胺、聚(有机)磷腈、聚(原酸酯)、聚(乙烯醇)、聚(乙烯吡咯烷酮)、马来酸酐烷基乙烯基醚共聚物、pluronic polyols、白蛋白、藻酸盐、纤维素和纤维素衍生物、胶原、血纤蛋白、明胶、透明质酸、寡糖、葡糖胺基葡聚糖、硫酸化多糖、其掺合物和共聚物。
32.一种可注射液体组合物,所述组合物包含根据权利要求15至25中任一项的抗人类IL-12抗体晶体,并且具有在约10mg/ml至约400mg/ml范围内的抗体浓度。
33.一种晶体浆料组合物,所述组合物包含根据权利要求15至25中任一项的抗人类IL-12抗体晶体,具有大于约100mg/ml的抗体浓度。
34.一种治疗哺乳动物的方法,所述方法包括向所述哺乳动物施用有效量的根据权利要求15至25中任一项的抗人类IL-12抗体晶体的步骤。
35.一种治疗哺乳动物的方法,所述方法包括向所述哺乳动物施用有效量的根据权利要求26至33中任一项的组合物的步骤。
36.根据权利要求34或35的方法,其中所述组合物是通过胃肠外途径、口服途径或通过注射施用。
37.一种治疗个体中IL-12相关病症的方法,所述方法包括施用治疗有效量的根据权利要求15至25中任一项的抗体晶体。
38.根据权利要求37的方法,其中所述IL-12相关病症选自:类风湿性关节炎、骨关节炎、青少年慢性关节炎、莱姆关节炎、牛皮癣性关节炎、反应性关节炎、脊柱关节病、全身性红斑狼疮、克罗恩氏病、溃疡性结肠炎、炎性肠病、胰岛素依赖性糖尿病、甲状腺炎、哮喘、过敏性疾病、牛皮癣、皮炎硬皮病、特应性皮炎、移植物抗宿主疾病、器官移植排斥反应、与器官移植相关的急性或慢性免疫疾病、类肉瘤病、动脉粥样硬化、弥漫性血管内凝血、川崎氏病、格雷氏病、肾病综合征、慢性疲劳综合征、韦格纳肉芽肿病、亨偌-丝奇恩赖紫癜、显微肾血管炎、慢性活动性肝炎、葡萄膜炎、脓毒性休克、中毒性休克综合征、脓毒综合征、恶病质、传染性疾病、寄生虫疾病、获得性免疫缺陷综合征、急性横贯性脊髓炎、亨廷顿舞蹈病、帕金森病、阿尔茨海默病、中风、原发性胆汁性肝硬化症、溶血性贫血、恶性肿瘤、心力衰竭、心肌梗塞、阿迪森氏病、散发病、I型多腺缺乏症和II型多腺缺乏症、施密特氏综合征、成人(急性)呼吸窘迫综合征、秃发症、斑秃、血清阴性关节病、关节病、莱特尔氏病、牛皮癣性关节病、溃疡性结肠炎性关节病、肠病性滑膜炎、衣原体疾病、耶氏菌和沙门氏菌相关关节病、脊柱关节病、动脉粥样化病/动脉硬化症、特应性过敏、自身免疫性大疱病、寻常天疱疮、落叶状天疱疮、类天疱疮、线性IgA疾病、自身免疫性溶血性贫血、库姆阳性溶血性贫血、获得性恶性贫血、青少年恶性贫血、肌痛性脑炎/贵族自由疾病、慢性皮肤粘膜念珠菌病、巨细胞性动脉炎、原发性硬化性肝炎、隐原性自身免疫性肝炎、获得性免疫缺陷疾病综合征、获得性免疫缺陷相关疾病、丙型肝炎、普通可变性免疫缺陷(普通可变性低γ-球蛋白血症)、扩张型心肌病、女性不孕症、卵巢衰竭、卵巢早衰、纤维化肺病、隐原性纤维化肺泡炎、炎性后间质性肺病、间质性肺炎、结缔组织疾病相关间质性肺病、混合型结缔组织疾病相关肺病、全身性硬化症相关间质性肺病、类风湿性关节炎相关间质性肺病、全身性红斑狼疮相关肺病、皮肌炎/多肌炎相关肺病、休格连氏病相关肺病、强直性脊椎炎相关肺病、血管炎弥漫性肺病、血铁质沉着症相关肺病、药物诱导的间质性肺病、放射性纤维化、阻塞性细支气管炎、慢性嗜酸性肺炎、淋巴球性浸润性肺病、感染后间质性肺病、痛风性关节炎、自身免疫性肝炎、1型自身免疫性肝炎(典型自身免疫性或狼疮样肝炎)、2型自身免疫性肝炎(抗LKM抗体肝炎)、自身免疫介导性低血糖症、B型抗胰岛素症伴有黑棘皮病、甲状旁腺机能减退、与器官移植相关的急性免疫疾病、与器官移植相关的慢性免疫疾病、骨关节病、原发性硬化性胆管炎、特发性白血球减少症、自身免疫性嗜中性白血球减少症、肾病NOS、肾小球肾炎、显微肾血管炎、莱姆病、盘状红斑狼疮、特发性男性不育症或NOS、精子自身免疫疾病、多发性硬化症(所有亚型)、胰岛素依赖性糖尿病、交感性眼炎、结缔组织疾病继发性肺动脉高血压、古德帕斯彻氏综合征、结节性多动脉炎的肺部表现、急性风湿热、类风湿性脊椎炎、史提尔氏病、全身性硬化症、高安氏病/动脉炎、自身免疫性血小板减少症、特发性血小板减少症、自身免疫性甲状腺病、甲状腺机能亢进、甲状腺肿性自身免疫性甲状腺功能低下(桥本氏病)、萎缩性自身免疫性甲状腺功能低下、原发性粘液水肿、晶状体原性葡萄膜炎、原发性血管炎和白癜风。本发明的人类抗体和抗体部分可用于治疗自身免疫性疾病,尤其是与炎症相关的那些,包括类风湿性脊椎炎、过敏、自身免疫性糖尿病、自身免疫性葡萄膜炎。
39.一种根据权利要求15至25中任一项的抗人类IL-12抗体晶体在制备用于治疗如权利要求37中所定义的IL-12相关疾病的药物组合物中的应用。
40.用于药物的根据权利要求15至25中任一项的抗人类IL-12抗体晶体。
41.根据前述权利要求任一项的结晶方法,所述方法进一步包括通过添加另外的聚亚烷基二醇来增加所述晶体产率的步骤。
42.根据权利要求41的方法,其中所述聚亚烷基二醇为聚乙二醇。
43.根据权利要求41的方法,其中连续添加所述聚亚烷基二醇。
44.根据前述权利要求任一项的结晶方法,所述方法进一步包括用ABT-874接种反应的步骤。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115397394A (zh) * | 2020-01-31 | 2022-11-25 | 赛诺菲 | 抗体的肺部递送 |
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TW201350504A (zh) | 2013-12-16 |
RU2476442C2 (ru) | 2013-02-27 |
US20120177704A1 (en) | 2012-07-12 |
US8404819B2 (en) | 2013-03-26 |
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RU2009139922A (ru) | 2011-05-10 |
EP2142565A4 (en) | 2010-03-31 |
BRPI0809209A2 (pt) | 2014-09-02 |
US20080292642A1 (en) | 2008-11-27 |
NZ580379A (en) | 2012-10-26 |
EP2527364A1 (en) | 2012-11-28 |
KR20100014674A (ko) | 2010-02-10 |
NZ598881A (en) | 2013-11-29 |
RU2012150809A (ru) | 2014-06-10 |
MX2009010361A (es) | 2009-10-16 |
AU2008233173A1 (en) | 2008-10-09 |
JP2014012674A (ja) | 2014-01-23 |
AU2008233173B2 (en) | 2013-09-19 |
US20140017256A1 (en) | 2014-01-16 |
ZA201203820B (en) | 2013-04-24 |
CA2681752A1 (en) | 2008-10-09 |
IL201184A0 (en) | 2010-05-17 |
ZA200906432B (en) | 2015-08-26 |
EP2142565A1 (en) | 2010-01-13 |
US8940873B2 (en) | 2015-01-27 |
TWI429657B (zh) | 2014-03-11 |
JP2010522752A (ja) | 2010-07-08 |
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