CN112057419B - 单克隆抗体的配制品 - Google Patents
单克隆抗体的配制品 Download PDFInfo
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- CN112057419B CN112057419B CN202010229368.0A CN202010229368A CN112057419B CN 112057419 B CN112057419 B CN 112057419B CN 202010229368 A CN202010229368 A CN 202010229368A CN 112057419 B CN112057419 B CN 112057419B
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Abstract
本发明提供了一种配制品,该配制品包含:(i)单克隆抗体;和(ii)离子型赋形剂;其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至6.5的pH。
Description
本申请为中国发明专利申请(申请日为2018年2月28日、申请号为201880014493.0(PCT申请号为:PCT/EP2018/054960)、发明名称为“单克隆抗体的配制品”)的分案申请。
技术领域
本发明涉及一种抗体配制品(特别是单克隆抗体配制品)及其用途。本发明特别涉及在抗体配制品中提供改进的胶体稳定性。
背景技术
由于许多单克隆抗体的等电点(pI)处于蛋白质的优选药物pH配制品范围内(pH5.5至pH 7.5),所以这些分子存在独特的配制挑战。
分子pI的胶体不稳定性是由于分子上缺乏静电荷,这允许更密切的蛋白质- 蛋白质相互作用(所谓的“自缔合”),其导致物理不稳定性。出于这一原因,典型地,将蛋白质配制品的pH选择为偏离蛋白质pI至少1个pH单位。这旨在提供胶体稳定性并因此预防物理不稳定性,例如聚集、沉淀、乳光、相分离和/或颗粒形成。
根据“偏离1个pH单位”规则,具有低或中性pI(例如pH 5.5至pH 7.5的 pI)的抗体因此应被配制成具有在5.5至7.5范围之外的pH的配制品。然而,在此范围之外,可以观察到另外的不稳定性。在更高酸性的pH下,可以观察到片段化速率的增加降低了构象稳定性并且增加了聚集。在更高碱性的pH下,存在增加氧化、脱酰胺和片段化以及与玻璃容器不相容的可能性。
上述不稳定性在抗体配制品(其中抗体以商业上所希望的浓度(例如50mg/ml 及以上)存在)中尤其成问题。
因此,对提供具有低或中性pI的抗体的改进的配制品存在需求。具体地,对提供具有低或中性pI的抗体的稳定配制品,并且特别是具有商业上所希望的抗体浓度的配制品存在需求。
发明内容
本发明提供了新的抗体配制品,特别是新的单克隆抗体配制品。具体地,本发明的配制品提供了用于改进具有低或中性pI的抗体的胶体稳定性的手段。因此,本发明提供了用于提供胶体稳定性的“偏离1个pH”规则的替代方案。因此,本发明允许在抗体pI的1个pH单位内配制具有低或中性pI的抗体。因此,本发明使得能够在5.5至7.5的pH范围内并且以商业上有用的浓度配制此类抗体,同时基本上避免了与更高酸性或更高碱性pH相关的不稳定性。
本发明提供了一种配制品,该配制品包含:
i.单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
本发明的配制品特别适用于具有低或中性pI的抗体,例如在pH 5.5至pH 7.5 的范围内。本发明提供了一种配制品,该配制品包含:
i.具有低或中性pI(例如5.5至7.5)的单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.具有低或中性pI(例如5.5至7.5)的单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中配制的相同抗体的聚集速率相比降低。
在一个实施例中,该单克隆抗体具有在5.5至7.5范围内的pI。在一个实施例中,该单克隆抗体具有在6.0至7.5范围内的pI。在一个实施例中,该单克隆抗体具有在6.3至7.5范围内的pI。在一个实施例中,该单克隆抗体具有在6.4至7.5 范围内的pI。不希望受到理论的束缚,对于其中在蛋白质上存在带有相反电荷(阳性的胺基和阴性的羧基)的氨基酸侧链的净平衡或者不同域具有总体相反电荷在 5.5至7.5的pH范围内的情况下,蛋白质可以具有低至中性的pI。同样,不希望受到理论的束缚,本发明的配制品中的离子型赋形剂可能屏蔽这些相反且相互吸引的电荷,从而使具有在该范围内的pI的蛋白质胶体稳定。因此,本发明提供了离子型赋形剂在抗体配制品中用于改变该配制品中的抗体的电荷状态或分布的用途。本发明进一步提供了离子型赋形剂在抗体配制品中用于胶体稳定该配制品中的抗体的用途。
在一个实施例中,该单克隆抗体以约75mg/ml或更高(例如约75mg/ml至约200mg/ml)的浓度存在于本文所述的配制品中。在一个实施例中,该单克隆抗体以约100mg/ml或更高(例如约100mg/ml至约200mg/ml)的浓度存在于本文所述的配制品中。在一个实施例中,该单克隆抗体以约100mg/ml至约165mg/ml 的浓度存在于本文所述的配制品中。在一个实施例中,该单克隆抗体以约100 mg/ml的浓度存在。
在一个实施例中,该离子型赋形剂以约75mM至约100mM的浓度存在。在一个实施例中,该离子型赋形剂以约75mM的浓度存在。在一个实施例中,该离子型赋形剂以约80mM的浓度存在。
在一个实施例中,该单克隆抗体是IgG1或IgG4单克隆抗体。最优选地,该单克隆抗体是IgG4单克隆抗体。IgG4抗体典型地具有低或中性pI。因此,本发明提供了一种配制品,该配制品包含:
i.IgG4单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.IgG4单克隆抗体;和
ii.离子型赋形剂;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
在一个实施例中,本文所述的配制品具有在约pH 5.5至约pH 6.5范围内的 pH。在一个实施例中,本文所述的配制品具有在约pH 5.7至约pH 6.3范围内的 pH。在一个实施例中,本文所述的配制品具有在约pH 5.7至约pH 6.1范围内的 pH。优选的配制品具有约5.8的pH。其他优选的配制品具有约6.0的pH。
在一个实施例中,该离子型赋形剂是带电荷的氨基酸。在一个实施例中,该离子型赋形剂是赖氨酸。在另一个实施例中,该离子型赋形剂是精氨酸。
在一个实施例中,该离子型赋形剂是盐。因此,本发明提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;和
ii.盐;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该盐以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5 的pH。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;和
ii.盐;
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该盐以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5 的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含盐中的相同抗体的聚集速率相比降低。
在一个实施例中,该盐以约75mM至约100mM的浓度存在。在一个实施例中,该盐以约75mM或约80mM的浓度存在。
在一个实施例中,该盐是NaCl,例如为约75mM至约100mM的浓度,合适地为约75mM的浓度。
在一个实施例中,该盐是精氨酸盐酸盐,例如为约75mM至约100mM的浓度,合适地为约80mM的浓度。
在一个实施例中,该配制品进一步包含糖。在其他已知的益处中,糖的存在可以改进配制品的张力。这是所希望的,因为优选的配制品是等渗的或接近等渗的(例如,具有240至500mOsm/kg之间的重量摩尔渗透压浓度。在一个实施例中,该离子型赋形剂是盐,并且该配制品进一步包含糖。
在一个实施例中,该配制品进一步包含糖,并且该离子型赋形剂以在约75mM 至约150mM范围内的浓度存在。在一个实施例中,该配制品进一步包含糖,并且该离子型赋形剂以在约75mM至约100mM范围内的浓度存在。在一个实施例中,该配制品进一步包含以在约100mM至140mM范围内的浓度存在的糖,并且该离子型赋形剂以约75mM至100mM范围内的浓度存在。
因此,本发明提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;
ii.如本文任何地方所定义的离子型赋形剂(例如盐);
iii.如本文任何地方所定义的糖;并且
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。该离子型赋形剂优选地以在约75mM至约150mM,更优选地约75mM至约100mM范围内的浓度存在。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;和
ii.如本文任何地方所定义的离子型赋形剂(例如盐);
iii.如本文任何地方所定义的糖;并且
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。该离子型赋形剂优选地以在约75mM至约150mM,更优选地约75mM至约100mM范围内的浓度存在。
在一个实施例中,该糖是海藻糖。在另一个实施例中,该糖是蔗糖。例如,该糖被发现在约100mM至约140mM的浓度,合适地在约120mM的浓度。
在一个实施例中,该配制品进一步包含一种或多种缓冲剂。在一个实施例中,该一种或多种缓冲剂是包含组氨酸的缓冲剂。在一个实施例中,该一种或多种缓冲剂选自包含组氨酸琥珀酸盐、组氨酸乙酸盐、组氨酸柠檬酸盐、组氨酸氯化物或组氨酸硫酸盐的缓冲剂。在一个实施例中,该一种或多种缓冲剂是组氨酸、组氨酸盐酸盐或其组合(组氨酸/组氨酸盐酸盐)。在一个实施例中,该一种或多种缓冲剂是L-组氨酸/L-组氨酸盐酸盐一水合物。例如,该缓冲剂可以为约10mM至约50mM的浓度,合适地为约30mM的浓度。应理解,缓冲剂本身可以是离子型赋形剂。因此,在一个实施例中,该缓冲剂是离子型赋形剂。在这个实施例中,缓冲剂的浓度应当高于50mM,即与本文披露的离子型赋形剂的浓度一致。换句话说,在一个实施例中,该离子型赋形剂也用作配制品中的缓冲剂。在这个实施例中,另外的缓冲剂可以存在也可以不存在。
在一个实施例中,该配制品进一步包含表面活性剂。在一个实施例中,该表面活性剂是聚山梨醇酯,包括例如聚山梨醇酯-80。
在一个实施例中,该配制品进一步包含糖和一种或多种缓冲剂。在一个实施例中,该离子型赋形剂是盐,并且该配制品进一步包含糖和一种或多种缓冲剂。
在一个实施例中,该配制品进一步包含表面活性剂、糖和一种或多种缓冲剂。在一个实施例中,该离子型赋形剂是盐,并且该配制品进一步包含表面活性剂、糖和一种或多种缓冲剂。
因此,本发明提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;
ii.如本文任何地方所定义的离子型赋形剂(例如盐);
iii.如本文任何地方所定义的糖;
iv.一种或多种如本文任何地方所定义的缓冲剂;和
v.任选地如本文任何地方所定义的表面活性剂
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。
因此,本发明进一步提供了一种配制品,该配制品包含:
i.如本文任何地方所定义的单克隆抗体;和
ii.如本文任何地方所定义的离子型赋形剂(例如盐);
iii.如本文任何地方所定义的糖;
iv.一种或多种如本文任何地方所定义的缓冲剂;和
v.任选地如本文任何地方所定义的表面活性剂
其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml) 的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
本文所述的配制品还可以包括一种或多种另外的赋形剂,包括例如一种或多种糖、盐、氨基酸、多元醇、螯合剂、乳化剂和/或防腐剂。
本发明提供的一种优选的配制品包含150mg/ml抗体、50mM乙酸钠/乙酸、 106mM海藻糖脱水物、70mM氯化钠、0.05%(w/v)聚山梨醇酯80,其中该配制品具有pH 5.8的pH。此配制品中的抗体优选地为抗GM-CSF-RαIgG4抗体,更优选地为具有本文所述CAM-3001抗体的VH和VL序列的抗GM-CSF-RαIgG4 抗体。此配制品中的抗体优选地为抗GM-CSF-RαIgG4抗体,该抗体具有与本文所述的CAM-3001抗体相同的6个CDR。
本发明提供的一种优选的配制品包含150mg/ml抗体、50mM乙酸钠、85mM 氯化钠和0.01%聚山梨醇酯80,其中该配制品具有pH 5.5的pH。此配制品中的抗体优选地为抗IL-13IgG4抗体,更优选地为具有本文所述CAT-354抗体的VH和 VL序列的抗IL-13IgG4抗体。此配制品中的抗体优选地为抗IL-13IgG4抗体,该抗体具有与本文所述的CAT-354抗体相同的6个CDR。
本发明的配制品优选地是药物配制品。
本发明提供了如本文任何地方所述的药物配制品,用于作为药物使用。
本发明提供了如本文任何地方所述的药物配制品,用于在疾病的治疗中使用。
本发明提供了在受试者中治疗疾病的方法,该方法包括向该受试者给予如本文任何地方所述的药物配制品。本文还提供了通过向受试者给予治疗有效量的如本文任何地方所述的药物配制品来治疗该受试者的方法。
在一个实施例中,该受试者是人类。
待治疗的疾病将取决于配制品中含有的特定抗体。在一个实施例中,该疾病是癌症。该疾病可选自下组,该组由以下组成:糖尿病、心血管疾病、传染病、类风湿性关节炎、血管炎、巨细胞动脉炎、肾小球疾病、狼疮性肾炎、葡萄膜炎、特应性皮炎、肝硬化、银屑病关节炎、慢性阻塞性肺病、重症哮喘、中性粒细胞性哮喘、和髓细胞性白血病。
本发明提供了一种冻干饼,其能够仅使用无菌水重构成如本文所定义的配制品或如本文所定义的药物配制品。本文还提供了能够被冻干以形成冻干饼的配制品,其中该冻干饼能够仅使用无菌水重构成如本文定义的配制品或如本文所定义的药物配制品。
附图说明
图1示出了IgG4单克隆抗体向半分子的转化。
图1-1和图1-2示出了与CAT-354抗体有关的序列。标记了VH和VL序列,并且6个CDR加下划线。
图2示出了盐对IgG4分子聚集速率的影响。
图3A示出了改变pH对kD的结果。
图3B示出了在100mM盐存在下改变pH对Kd的结果。
图4示出了盐对kD的影响。通常注意到在pH 5下胶体稳定性降低,但在pH 6和pH 7下胶体稳定性增加。
图5示出了具有或不具有100mM盐的配制品在40℃下的聚集速率数据。
图6示出了配制品pH对MEDI7814的聚集速率的变化。
图7示出了离子型赋形剂对pH 6下抗体(MEDI7814)聚集速率的影响。
图8示出了MEDI8897重链核苷酸序列和翻译。CDR加下划线,形成等位基因恒定区的氨基酸差异被圈出,并且在可变区和恒定区之间由‘|’标记划分。
图9示出了MEDI8897轻链核苷酸序列和翻译。CDR加下划线并且在可变区和恒定区之间由‘|’标记划分。
图10示出了在5℃、25℃和40℃下,经3个月时期,MEDI8897配制品的稳定性。
图11示出了离子型赋形剂对pH 6下抗体(MEDI578)聚集速率的影响。
图12示出了通过尺寸排阻色谱法的纯度。
图13示出了在热应激条件下含有离子型赋形剂的配制品中亚可见颗粒的减少。胶体稳定性得到改进。
图14示出了向基于组氨酸的缓冲剂中添加盐对IgG4稳定性的影响。LLPS 代表液-液相分离。
具体实施方式
由于许多单克隆抗体(并且特别是IgG4抗体)具有接近生理pH(即通常用于人类给予的所希望的pH)的pI的事实,因此配制这些单克隆抗体时遇到困难。这些困难可能特别地与胶体稳定性有关。
IgG4单克隆抗体的特征在于防止补体活化的结构,并且还允许两个IgG4分子之间的体内半分子交换(一条重链和一条轻链),产生具有二价反应性的新IgG4。参见图1。IgG4铰链比IgG1的铰链短三个氨基酸,并且IgG4具有可用于H链之间的共价相互作用的两个半胱氨酸。[Aalberse和Schuurman,“IgG4 breaking the rules[IgG4打破规则],”Immunology[免疫学]2002 105:9-19]。
本发明提供了新的单克隆抗体配制品,特别是新的IgG4单克隆抗体配制品和新的IgG1单克隆抗体配制品。
本发明提供了一种配制品,该配制品包含:(i)单克隆抗体;和(ii)离子型赋形剂(例如盐);其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml 至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。
本发明进一步提供了一种配制品,该配制品包含:(i)单克隆抗体;和(ii)离子型赋形剂(例如盐);其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml 至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
聚集速率可以根据如本文所述的标准技术来测量。令人惊讶的是,已经示出了根据本发明的配制品具有良好的稳定性并具有降低的自聚集,例如当在室温下储存3个月时展示≤2.0%的聚集。因此,本发明提供了离子型赋形剂在抗体配制品中用于提高该配制品中抗体的稳定性的用途。本发明进一步提供了离子型赋形剂在抗体配制品中用于减少该配制品中抗体的自聚集的用途。
本发明的配制品特别适用于具有低或中性pI的抗体,例如具有在pH 5.5至 pH7.5、pH 6.0至pH 7.5、pH 6.3至pH 7.5、pH 6.4至pH 7.5或pH 6.5至pH 7.5 范围内的pI的抗体。可以根据标准技术例如通过毛细管等电聚焦(cIEF)来测量抗体的pI。因此,本发明提供了一种配制品,该配制品包含:(i)具有低或中性pI (例如5.5至7.5)的单克隆抗体;和(ii)离子型赋形剂;其中该单克隆抗体以约 50mg/ml或更高(例如约50mg/ml至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH。因此,本发明进一步提供了一种配制品,该配制品包含:(i)具有低或中性pI(例如5.5 至7.5)的单克隆抗体;和(ii)离子型赋形剂;其中该单克隆抗体以约50mg/ml 或更高(例如约50mg/ml至约200mg/ml)的浓度存在且该离子型赋形剂以约50 至约150mM的浓度存在,并且该配制品具有5.5至7.5的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
在一个实施例中,该单克隆抗体具有在pH 6.4至pH 7.5范围内的pI。在另一个实施例中,本文所述的单克隆抗体具有在约pH 5.5至约pH 6.0的范围内、约pH 5.7至约pH6.0的范围内、或约pH 5.5、约pH 5.6、约pH 5.7、约pH 5.8、约pH 5.9、约pH 6.0、约pH 6.1、约pH 6.2、约pH 6.3、约pH 6.4或约pH 6.5的pI。在实施例中,本文提供的单克隆抗体的pI为5.7至6.0,更合适地,约5.8或6.0的pI。
在一个实施例中,该单克隆抗体是IgG1或IgG4单克隆抗体。最优选地,该单克隆抗体是IgG4单克隆抗体。因此,本发明提供了一种配制品,该配制品包含: (i)具有低或中性pI(例如5.5至7.5)的IgG4单克隆抗体;和(ii)离子型赋形剂;其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5 至7.5的pH。因此,本发明进一步提供了一种配制品,该配制品包含:(i)具有低或中性pI(例如5.5至7.5)的IgG4单克隆抗体;和(ii)离子型赋形剂;其中该单克隆抗体以约50mg/ml或更高(例如约50mg/ml至约200mg/ml)的浓度存在且该离子型赋形剂以约50至约150mM的浓度存在,并且该配制品具有5.5至7.5 的pH;并且其中该配制品中的单克隆抗体的聚集速率与相同配制品但不含离子型赋形剂中的相同抗体的聚集速率相比降低。
在一个实施例中,该单克隆抗体是抗GM-CSF-Rα单克隆抗体、抗IL-13单克隆抗体、抗RSV单克隆抗体或抗C5/C5a单克隆抗体。在示例性实施例中,该单克隆抗体是IgG4单克隆抗体,例如抗GM-CSF-Rα单克隆抗体。在一个实施例中,该单克隆抗体是CAM-3001。在一个实施例中,该单克隆抗体是MEDI8897。
单克隆抗体包括抗体功能部分,例如抗体或其抗原结合片段、变体或衍生物。单克隆抗体进一步包括但不限于人类抗体、人源化抗体、或嵌合抗体、单链抗体、双特异性抗体、表位结合片段,例如Fab、Fab'和F(ab')2、Fd、Fv、单链Fv(scFv)、单链抗体、二硫化物连接的Fv(sdFv)、包含VL或VH结构域的片段、由Fab 表达文库产生的片段。ScFv分子在本领域中是已知的并且描述于例如美国专利5,892,019中。本披露涵盖的免疫球蛋白或抗体分子可以是免疫球蛋白分子的任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如IgG1、IgG2、IgG3、 IgG4、IgA1和IgA2)或子类。在优选的实施例中,该单克隆抗体是IgG1或IgG4 单克隆抗体。
抗体浓度
合适地,单克隆抗体以例如约50mg/ml至约300mg/ml、约50mg/ml至约200 mg/ml、约100mg/ml至约200mg/ml、约100mg/ml至约165mg/ml、约100mg/ml 至约150mg/ml、或约50mg/ml、约75mg/ml、约100mg/ml、约105mg/ml、约 110mg/ml、约115mg/ml、约120mg/ml、约125mg/ml、约130mg/ml、约135mg/ml、约140mg/ml、约145mg/ml、约150mg/ml、约155mg/ml、约160mg/ml、约165 mg/ml、约170mg/ml、约175mg/ml、约180mg/ml、约185mg/ml、约190mg/ml、约195mg/ml、或约200mg/ml(包括这些范围内的值和范围)的商业上所希望的浓度存在于本文所述的配制品中。
合适地,单克隆抗体以约100mg/ml至约165mg/ml的浓度存在于本文所述的配制品中。合适地,单克隆抗体以约100mg/ml的浓度存在于本文所述的配制品中。
pH
合适地,为了提供接近最佳或最佳的化学稳定性(水解、脱酰胺、异构化),本文所述的配制品具有在约pH 5.5至约pH 7.5范围内的pH。在一个实施例中,本文所述的配制品具有在约pH 5.7至约pH 6.3范围内的pH。在一个实施例中,本文所述的配制品具有在约5.5至约6.5范围内的pH。在一个实施例中,本文所述的配制品具有在约pH 5.7至约pH 6.1范围内的pH。优选的配制品具有约5.8 的pH。其他优选的配制品具有约6.0的pH。
合适地,本文所述的配制品具有在约pH 5.5至约pH 6.0的范围内、在约pH 5.7 至约pH 6.0的范围内、或约pH 5.5、约pH 5.6、约pH 5.7、约pH 5.8、约pH 5.9、约pH 6.0、约pH6.1、约pH 6.2、约pH 6.3、约pH 6.4或约pH 6.5的pH。在实施例中,本文提供的配制品的pH为5.7至6.0,更合适地,该配制品具有约5.8 或6.0的pH。
接近约pH 7.4的配制品pH对于注射部位耐受性也是希望的。
离子型赋形剂
用于配制品中的示例性离子型赋形剂包括盐和带电荷的氨基酸。离子型赋形剂可以包含盐和带电荷的氨基酸的组合。
示例性的带电荷的氨基酸包括精氨酸和赖氨酸。
示例性的盐包括带电荷的氨基酸的盐,例如精氨酸和赖氨酸的琥珀酸盐、乙酸盐和硫酸盐。
此外,示例性的盐是本文所述的那些,包括但不限于:氯化钠以及与钠、钾、钙、镁等的其他盐,例如氯化物、碳酸盐、硫酸盐、乙酸盐、葡糖酸盐、乳酸盐、苹果酸盐以及肠胃外给予领域惯用的其他助剂等。
合适地,盐选自氯化钠(NaCl)、赖氨酸盐酸盐和精氨酸盐酸盐。在一个实施例中,该盐是NaCl。在另一个实施例中,该盐是精氨酸盐酸盐。在另一个实施例中,该盐是赖氨酸盐酸盐。
在本文所述的药物配制品中的离子型赋形剂(合适的盐)的浓度通常为在约 50mM至约150mM的范围内、更合适地约50mM至约100mM、约60mM至约 80mM、或约50mM、约55mM、约60mM、约65mM、约70mM、约75mM、约80mM、约85mM、约90mM、约95mM或约100mM,包括在这些范围内的任何范围或值。
在一个实施例中,该离子型赋形剂以约50mM至约125mM的浓度存在。
在一个实施例中,该离子型赋形剂以约50mM至约100mM的浓度存在。
在一个实施例中,该离子型赋形剂以约75mM至约100mM的浓度存在。
在合适的实施例中,该盐是NaCl,浓度为例如约50mM至约100mM,合适地为约70mM。
在合适的实施例中,该盐是精氨酸盐酸盐,浓度为例如约50mM至约100 mM,合适地为约80mM。
缓冲剂
本文所述的配制品合适地包含一种或多种缓冲剂。如本文所使用的,“缓冲剂”是指用于维持配制品的pH的赋形剂。用于本文提供的配制品中的示例性缓冲剂包括但不限于:组氨酸、组氨酸盐酸盐(组氨酸HCl)、琥珀酸钠、乙酸钠、乙酸钠/乙酸、磷酸钠、柠檬酸盐、磷酸盐、琥珀酸盐、甘氨酸和乙酸盐。在一个实施例中,用于本文所述的配制品中的缓冲剂是乙酸钠/乙酸。在一个实施例中,该一种或多种缓冲剂是包含组氨酸的缓冲剂。在一个实施例中,该一种或多种缓冲剂选自包含组氨酸琥珀酸盐、组氨酸乙酸盐、组氨酸柠檬酸盐、组氨酸氯化物或组氨酸硫酸盐的缓冲剂。在一个实施例中,该一种或多种缓冲剂是组氨酸、组氨酸盐酸盐或其组合(组氨酸/组氨酸盐酸盐)。在一个实施例中,该一种或多种缓冲剂是L-组氨酸/L-组氨酸盐酸盐一水合物。
在本文所述的药物配制品中的缓冲剂(合适地为乙酸钠/乙酸)的浓度范围通常为约10mM至约100mM,更合适地约15mM至约80mM、约25mM至约75 mM、约30mM至约60mM、约40mM至约60mM、约40mM至约50mM、或约15mM,约20mM、约25mM、约30mM、约35mM、约40mM,约45mM、约50mM,约55mM、约60mM、约65mM、约70mM或约75mM,包括在这些范围内的任何范围或值。
在一个实施例中,这种或这些缓冲剂是L-组氨酸/L-组氨酸盐酸盐一水合物,浓度为例如约10mM至约50mM、合适地为约30mM。
缓冲剂的pH优选地在pH 5.5至pH 6.0的范围内。
应理解,缓冲剂本身可以是离子型赋形剂。因此,在一个实施例中,该缓冲剂是离子型赋形剂。在这个实施例中,缓冲剂的浓度应当高于50mM,即与本文披露的离子型赋形剂的浓度一致。这个实施例中缓冲剂的优选浓度是如本文任何地方关于离子型赋形剂所讨论的。
换句话说,在一个实施例中,该离子型赋形剂也用作配制品中的缓冲剂。在这个实施例中,另外的缓冲剂可以存在也可以不存在。
糖和表面活性剂
合适地,本文所述的配制品包含糖,例如但不限于:海藻糖、乳糖、甘露糖醇、蜜二糖、松三糖、棉子糖、甘露三糖、水苏糖和蔗糖。在其他实施例中,可以使用多元醇,例如三元或更高分子量的糖醇,例如甘油(glycerin)、葡聚糖、赤藓糖醇、甘油(glycerol)、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇。还原糖的实例包括但不限于:葡萄糖、麦芽糖、麦芽酮糖、异麦芽酮糖和乳果糖。非还原糖的实例包括但不限于:海藻糖、选自糖醇和其他直链多元醇的多羟基化合物的非还原糖苷。糖醇的实例包括但不限于:单糖苷、通过二糖(例如乳糖、麦芽糖、乳果糖和麦芽酮糖)的还原而获得的化合物。糖苷侧基可以是糖苷的或半乳糖苷的。糖醇的另外的实例包括但不限于:葡萄糖醇、麦芽糖醇、乳糖醇和异麦芽酮糖。在一个实施例中,该糖选自下组,该组由以下组成:海藻糖、乳糖、甘露糖醇、棉子糖和蔗糖。在具体的实施例中,海藻糖在本文所述的配制品中用作糖。在具体的实施例中,蔗糖在本文所述的配制品中用作糖。
合适地,本文所述配制品中的糖(例如海藻糖)的量为约1%(w/v)至约10% (w/v)。除非另有说明,否则组分的百分比(%)在本文中用于表示重量/体积(w/v) %。在示例性实施例中,在本文所述的药物配制品中的糖的量为约1%(w/v)至约8%(w/v)、或约2%(w/v)至约6%(w/v)、约2%(w/v)至约5%(w/v)、约3%(w/v)至约5%(w/v)、或约1%(W/V)、约2%(W/V)、约3%(W/V)、约4%(W/V)、约5%(W/V)、约6%(W/V)、约7%(W/V)、约8%(w/v)、约9%(w/v)或约10%(w/v),包括在这些范围内的任何值和范围。
本文所述的配制品合适地包含表面活性剂。
本文使用的术语“表面活性剂”是指具有两亲结构的有机物质;即它们由具有相反溶解度倾向的基团构成,典型地是油溶性烃链和水溶性离子基团。表面活性剂可以取决于表面活性部分的电荷分为阴离子型、阳离子型和非离子型表面活性剂。表面活性剂通常用作生物材料的不同药物配制品和制剂的润湿剂、乳化剂、增溶剂和分散剂。药学上可接受的表面活性剂像聚山梨醇酯(例如聚山梨醇酯20、 40、60或80);泊洛沙姆(例如泊洛沙姆188);曲通;辛基糖苷钠;月桂基-、肉豆蔻基-、亚油基-、或十八烷基-磺基甜菜碱;月桂基-、肉豆蔻基-、亚油基-、或十八烷基-肌氨酸;亚油基-、肉豆蔻基或鲸蜡基-甜菜碱;月桂酰胺丙基-、椰油酰胺丙基-、亚油酰胺丙基、肉豆蔻酰胺丙基-、棕榈酰胺丙基-、或异硬脂酰胺丙基-甜菜碱(例如月桂酰氨丙基);肉豆蔻酰氨丙基-、棕榈酰氨丙基-、或异硬脂酰氨丙基-二甲基胺;甲基椰油酰基牛磺酸钠或甲基油烯基牛磺酸二钠;以及 MONAQUATM系列(孟那工业公司(Mona Industries,Inc.)帕特森市,新泽西州)、聚乙二醇、聚丙二醇以及乙二醇和丙二醇的共聚物(例如普朗尼克(Pluronic), PF68等))可以用于本文所述的药物配制品中。合适地,表面活性剂是聚山梨醇酯,包括例如聚山梨醇酯-20、聚山梨醇酯-40、聚山梨醇酯-60和聚山梨醇酯-80。在一个实施例中,表面活性剂是聚山梨醇酯-80。
合适地,本文所述的配制品包含约0.001%至约0.5%(w/v)的、更合适地约0.002%至约0.1%的表面活性剂(合适地为聚山梨醇酯-80),例如约0.01%至约 0.2%、约0.02%至约0.01%、约0.02%至约0.07%、约0.03%至约0.06%、约0.04%至约0.06%、或约0.02%、约0.025%、约0.03%、约0.035%、约0.04%、约0.045%、约0.05%、约0.055%、约0.060%、约0.065%、约0.07%、约0.075%、约0.08%、约0.085%、约0.09%、约0.095%或约0.1%的表面活性剂,包括在这些范围内的任何范围或值。
本文所述的配制品合适地包含表面活性剂和糖。本文所述的配制品合适地包含表面活性剂和一种或多种缓冲剂。本文所述的配制品合适地包含糖和一种或多种缓冲剂。本文所述的配制品合适地包含表面活性剂、糖和一种或多种缓冲剂。
本文所述的配制品还可以包括一种或多种另外的赋形剂,包括例如一种或多种糖、盐、氨基酸、多元醇、螯合剂、乳化剂和/或防腐剂。
药物用途
本发明的配制品优选地是药物配制品。合适地,本文所述的药物配制品是“药学上可接受的”,并且因此将满足联邦或州政府的管理机构所要求的或在美国药典、欧洲药典或其他公认的药典中列出的必要批准要求,以便用于动物,更具体地用于人类。
本发明提供了如本文任何地方所述的药物配制品,用于作为药物使用。本发明提供了如本文任何地方所述的药物配制品,用于在疾病的治疗中使用。本发明提供了在受试者中治疗疾病的方法,该方法包括向该受试者给予如本文任何地方所述的药物配制品。本文还提供了通过向受试者给予治疗有效量的如本文任何地方所述的药物配制品来治疗该受试者的方法。
如本文所使用的,术语“受试者”包括任何人类或非人类动物。术语“非人类动物”包括所有脊椎动物,例如但不限于:哺乳动物和非哺乳动物,例如非人类灵长动物、绵羊、狗、猫、马、牛、鸡、两栖动物、爬行动物等。在一个实施例中,该受试者是人类。
该疾病可选自下组,该组由以下组成:糖尿病、心血管疾病、传染病、类风湿性关节炎、血管炎、巨细胞动脉炎、肾小球疾病、狼疮性肾炎、葡萄膜炎、特应性皮炎、肝硬化、银屑病关节炎、慢性阻塞性肺病、重症哮喘、中性粒细胞性哮喘、和髓细胞性白血病。
在实施例中,将配制品皮下或通过注射给予至受试者。
合适地,配制品是液体配制品或冷冻配制品。
本文还提供了制备药物配制品的方法,该方法包括制备如本文所述的药物配制品,并且将该药物配制品合适地装载到注射器中以形成预填充的注射器。
合适地,本文所述的药物配制品在无菌水中制备,或以所希望的体积重悬浮在注射用无菌水中。
在示例性实施例中,药物配制品具有约0.1mL至约20.0mL、更合适地约0.5 mL至约15.0mL、约0.5mL至约12.0mL、约1.0mL至约10.0mL、约1.0mL 至约5.0mL、约1.0mL至约2.0mL、或约0.5mL、约0.6mL、约0.7mL、约0.8 mL、约0.9mL、约1.0mL、约1.1mL、约1.2mL、约1.3mL、约1.4mL、约1.5 mL、约1.6mL、约1.7mL、约1.8mL、约1.9mL、约2.0mL、约2.1mL、约2.2mL、约2.3mL、约2.4mL、约2.5mL、约2.6mL、约2.7mL、约2.8mL、约2.9 mL或约3.0mL的体积,包括在这些范围内的任何范围或值。
尽管在合适的实施例中,本文所述的药物配制品是液体配制品,即在无菌水或注射用水(WFI)中制备的药物配制品,但该药物配制品也可以是冷冻配制品或先前的冷冻干燥的配制品。
本发明还提供了冻干饼,该冻干饼能够仅用无菌水重构成如本文所述的根据本发明的配制品。应理解,冻干饼中的抗体:离子型赋形剂的比率与冻干后的配制品中的相同。在一个实施例中,离子型赋形剂:抗体的摩尔比率在450:1至40:1 的范围内。当配制品已被冻干时,本文提供的用于配制品的浓度是重构后浓度,因此是所谓的“药物产品”中的浓度。举例来说,如果使用半重构策略(其中冻干期间去除的水的体积的一半在重建期间中恢复),则在重构之后,抗体的浓度将是冻干前的两倍,即是所谓的冻干前“药物物质”组合物中的浓度的两倍。因此,应理解,本发明进一步提供了能够被冻干以形成冻干饼的组合物,其中该冻干饼能够仅使用无菌水重构成如本文所述的根据本发明的配制品。合适的重构策略对于本领域技术人员是已知的。
在实施例中,令人希望的是通过提供如本文所述的液体药物配制品并在适当的条件下将配制品冷冻来制备冷冻配制品。例如,可通过将液体配制品冷冻至小于0℃、更合适地至约-20℃、约-40℃、约-60℃或合适地至约-80℃来提供冷冻配制品。药物配制品也被合适地制备成液体配制品并储存在约2℃至约8℃、或约2℃、约3℃、约4℃、约5℃、约6℃、约7℃或约8℃下。
用于从液体和/或冷冻配制品来制备冷冻干燥的药物配制品的合适方案和方法是本领域已知的。
配制品的稳定性
在示例性实施例中,本文所述的配制品在室温下或在约2℃至约8℃的温度范围、合适地在约5℃的温度下长期储存是稳定的。如本文所使用的,室温通常在约22℃至约25℃的范围内。合适地,药物配制品在约2℃至约8℃(例如5℃) 储存至少六(6)个月后是稳定的。如本文所使用的,对于储存(或“稳定性”),术语“稳定的”用于表示单克隆抗体,合适地IgG4单克隆抗体、药物配制品抵抗聚集、降解、半抗体形成和/或片段化。与参考相比,如通过高效尺寸排阻色谱法 (HPSEC)、静态光散射(SLS)、傅立叶变换红外光谱法(FTIR)、圆二色性 (CD)、尿素展开技术(urea unfolding technique)、内源色氨酸荧光、差示扫描量热法和/或ANS结合技术所测量的,单克隆抗体的稳定性可以通过聚集、降解、半抗体形成或片段化的程度来评估。
包含单克隆抗体的药物配制品的整体稳定性可以通过不同免疫学测定来评估,包括例如使用分离的抗原分子的ELISA和放射免疫测定。
如本文所使用的,短语“低至不可检测的聚集水平”是指如通过高效尺寸排阻色谱法(HPSEC)或静态光散射(SLS)技术测量的,按蛋白质的重量计药物配制品含有不多于约5%、不多于约4%、不多于约3%、不多于约2%、不多于约 1%或不多于约0.5%的聚集。合适地,药物配制品展现出≤5.0%聚集,更合适地≤4.0%聚集、≤3.0%聚集、≤2.0%聚集、≤1.0%聚集或0.5%聚集。合适地,液体药物配制品和/或冷冻药物配制品展现出≤5.0%聚集,更合适地≤4.0%聚集、≤3.0%聚集、≤2.0%聚集、≤1.0%聚集或0.5%聚集。
如本文所使用的,术语“低至不可检测的片段化水平”是指药物配制品例如在通过HPSEC或还原型毛细管凝胶电泳(rCGE)所确定的单峰内,含有等于或大于约80%、约85%、约90%、约95%、约98%或约99%的总单克隆抗体,代表未降解的单克隆抗体或其非降解片段,并且不包含单克隆抗体总量超过约5%、超过约4%、超过约3%、超过约2%、超过约1%或超过约0.5%的其他单峰。可以在 IgG4单克隆抗体中合适地测量片段化。不希望受到理论的束缚,认为减少的自聚集是由于如通过kD值增加所证明的改进的胶体稳定性引起的。在示例性实施例中,依照视觉观察、光散射、比浊法或浊度测定法,本文所述的配制品具有减少的乳光和降低的相分离。
参照附图,下文详细地描述了这些实施例的另外的实施例、特征、和优点,连同不同实施例的结构和操作。
实例
实例1–IgG4配制品
具有低或中性pI值的抗体的配制品挑战是当这些抗体在5.5至7.5范围之外的pH下配制时(通常需要增加蛋白质电荷和胶体稳定性),观察到另外的不稳定性。在酸性的pH下观察到片段化速率的增加降低了构象稳定性并且增加了聚集。在碱性的pH下,存在增加氧化、脱酰胺和片段化以及与玻璃容器不相容的可能性。 IgG4抗体特别适用于研究这种不稳定性,因为IgG4抗体典型地具有低或中性pI 值。
以下详述了用于开发本文所述配制品的方法,该配制品已经优化了具有中性 pI的单克隆抗体的储存稳定性,并且还克服了上述中性pH物理不稳定性。
如本文所述,该配制品具有中性pH和离子型赋形剂(例如盐)的组合。任选地,糖也可以用于配制品中,并且已经示出这在某些情况下提供了进一步的改进。
糖(例如蔗糖和海藻糖)可以(与离子型赋形剂组合)进一步增加构象稳定性;并且该离子型赋形剂(例如氯化钠、赖氨酸盐酸盐和精氨酸盐酸盐)增加了单克隆抗体分子的胶体稳定性。此外,配制品的中性pH(约pH 6)也使上述酸性和碱性降解途径最小化。这些配制品为这些单克隆抗体提供了优异的总体储存稳定性。配制品的其他合适组分是具有中性pKa的缓冲剂(例如,NaAC、组氨酸 HCl、磷酸钠)。
如本文所述,并且在表1中列出,CAM-3001(抗GM-CSFRα单克隆抗体),两种抗IL-13单克隆抗体和抗C5/C5a单克隆抗体被选择用于此研究,因为它们是具有中性pI值的IgG4。
表1:研究的IgG4分子
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CAT-354是IgG4亚类的人类抗体,其特异性结合人类白细胞介素13(IL-13),阻断与IL-13受体的相互作用。用于CAT-354的轻链和重链的DNA和衍生的氨基酸序列分别在附图的第2-3页和第4-7页提供。在附图的第2-3页和第4-7页中, VH和VL序列被标记,并且6个CDR加下划线。CAT-354分子是人类单克隆IgG4 (λ轻链)抗体,分子量大约为147,000道尔顿(Da)(包括寡糖)。抗体由两条相同的重链组成,每条重链大约49,500Da,并且两条相同的轻链各大约22,500Da。 CAT-354含有岩藻糖基化的双触角复合物和高甘露糖N-连接的碳水化合物,该碳水化合物在Asn-299附接至每条重链。寡糖部分的平均大小为每重链大约1,650Da。
CAM-3001是与粒细胞巨噬细胞集落刺激因子受体α(GM-CSFRα)结合的抗体。CAM-3001披露于国际专利申请公开WO 2007/110631中,其披露内容通过援引并入本文。CAM-3001的重链CDR(HCDR)在WO 2007/110631中披露为SEQ ID NO:53-55。CAM-3001的轻链CDR(LCDR)在WO 2007/110631中披露为SEQ ID NO:58-60。CAM-3001的重链可变区(VH)在WO2007/110631中披露为SEQ ID NO:52。CAM-3001的轻链可变区(VL)在WO 2007/110631中披露为SEQ ID NO:218。
如图2示出的,在浓度为100mM的盐存在下,当分子在pH 5时聚集速率增加,但当分子处于pH 6和pH 7时聚集速率降低。
通过测试构象稳定性和胶体稳定性的组合来检查单克隆抗体的溶液性质与扩散相互作用参数(kD)之间的相关性,以获得最稳定的配制品。测量kD作为胶体稳定性的指示,同时检查差示扫描量热法(DSC)作为构象稳定性的測量。图3 示出了所研究的单克隆抗体在不同pH下的kD。图3B示出了在添加浓度为100mM 的盐后研究的单克隆抗体在不同pH下的kD。在低离子强度下,随着pH的增加, kD通常变得更负。添加盐使得所研究的所有分子的kD负得更少。
在图4中描绘的结果中,以100mM的浓度向配制品中添加盐并检查胶体稳定性。通常注意到在pH 5下胶体稳定性降低,但在pH 6和pH 7下胶体稳定性增加。
在图5中描绘的结果中,对于含有或不含有100mM盐的配制品,在40℃下获得了的聚集速率数据。与没有盐远离pI的配制品相比,具有接近pI(pH 6或7) 的盐的配制品显示出减少的聚集。
根据图6和7中描绘的聚集速率结果,可以看出带电荷的氨基酸也可以作为接近分子pI的离子型稳定剂,并且在某些情况下比NaCl更具稳定化作用。
检查向基于组氨酸的缓冲剂中添加盐以确定对IgG4稳定性的影响。检查以下缓冲系统:对照缓冲剂(25mM组氨酸、7%蔗糖,pH 6);测试缓冲剂(25mM 组氨酸,7%蔗糖;100mMNaCl,pH 6)和盐对外观的影响总结在图14中。
如上所述,盐的添加降低了聚集速率和单体损失速率,并改进了配制品的外观。
总之,包含盐和含或不含糖的配制品在一些情况下具有更低的乳光、减轻的相分离,并且与仅包含蔗糖的配制品相比提供了良好或更好的稳定性。
冻融研究显示,在三次冻融循环后,没有看到产品质量,例如亚可见颗粒的显著变化。总之,即使当在接近其pI的pH下配制时,添加盐和糖两者也改进了 IgG4分子的稳定性。
实例2–IgG1配制品
MEDI8897是针对RSV-F蛋白的人类IgG1κ-YTE单克隆抗体。引入Fc结构域的CH2区中的三个氨基酸取代(M252Y/S254T/T256E;称为YTE)以增加 MEDI8897的血清半衰期。图8和图9中提供了MEDI8897的序列信息。通过cIEF 测量MEDI8897 pI为6.4-6.7,主峰为6.4。pI与配制品缓冲剂范围(5.5-6.5)重叠,表明制造、配制和储存稳定性具有潜在问题。
通过差示扫描量热法测量MEDI8897的热稳定性。发现Tm1为61℃,而Tm2 为82℃。Tm1大于50℃表明该分子具有可接受的胶体稳定性。
稳定性总结
在标准缓冲剂(25mM组氨酸、7%蔗糖、pH 6.0)中接受MEDI8897后,在 2℃至8℃下观察到相分离。上清液层具有75mg/ml的蛋白质浓度,而底层为125 mg/ml。在25℃下平衡时,两个不同的相消失,并且仅观察到一个单相。在2℃-8℃下的相分离被认为是由于MEDI8897的pI接近6.0的配制品pH引起的。开始侦查研究以找到用于MEDI8897稳定性评估的更适当的配制品缓冲剂,靶向 MEDI8897(在100mg/ml处)保持溶解度并防止相分离的条件。
在pH低于5.9或高于6.7,在标准缓冲剂(25mM组氨酸,7%蔗糖)中配制减轻了相分离。在pH 5.0和6.7之间向标准缓冲剂中添加75mM NaCl也减轻了相分离。最后,pH值偏离pI的乙酸盐和磷酸盐缓冲剂也减轻了相分离。基于这些筛选研究以及在配制空间内具有pI的mAb的先前知识,选择替代的缓冲剂(25mM His/HisHCl、75mM NaCl、4%蔗糖、0.02%PS80、pH 6.0)用于评估。
kD研究
对于第一kD筛选,在25℃下在从2-10mg/ml的25mM组氨酸pH 5.5缓冲碱(basebuffer)中评估所有样品。选择该缓冲剂代替pH 6.0,因为MEDI8897在pH 5.5下更易溶,有利于对不溶性颗粒敏感的DLS测量。在10、25、50、75和 100mM浓度下评估包括精氨酸-HCl、赖氨酸-HCl和NaCl的离子型赋形剂。另外,仅在100mM浓度下评估脯氨酸、丙氨酸、Na2SO4和组氨酸。最后,评估2%、4%和6%蔗糖以确定蔗糖是否影响蛋白质-蛋白质相互作用。将所有条件与缓冲剂对照(25mM组氨酸,pH 5.5)进行比较。
对照样品显示出不同的蛋白质-蛋白质相互作用,从2-10mg/ml,流体动力学半径从6.2增加到7.8nm。如通过在2-10mg/ml浓度范围内不增加流体动力学尺寸所证明的,精氨酸-HCl、赖氨酸-HCl和NaCl显示从25mM浓度开始的蛋白质- 蛋白质相互作用(PPI)的降低。在25和100mM之间没有看到另外的效果。在 100mM浓度下,脯氨酸和丙氨酸显示与对照相似的PPI,而Na2SO4和组氨酸减轻PPI。最后,蔗糖浓度显示对PPI没有影响。该数据说明带电荷的赋形剂 (Arg-HCl、Lys-HCl、组氨酸和Na2SO4)减轻蛋白质-蛋白质相互作用,而中性赋形剂(蔗糖、脯氨酸、丙氨酸)不减轻PPI。因此,在pH 5.5下添加离子型赋形剂降低了在100mg/ml下的相分离。
40℃稳定性评估
基于kD筛选,选择用于40℃稳定性评估的若干个条件。表3总结了在40℃下观察到的配制品条件和1个月的降解速率。
表3-40℃稳定性速率,配制品筛选1-赋形剂筛选
编号 | 赋形剂 | 浓度(mM) | %Mon/mo | %Agg/mo | %Frag/mo |
1 | NaCl | 25 | -5.9 | 4.2 | 1.8 |
2 | NaCl | 75 | -6.1 | 4.1 | 1.9 |
3 | NaCl | 95 | -5.4 | 3.5 | 1.9 |
4 | NaCl | 120 | -5.4 | 3.5 | 1.9 |
5 | Arg-HCl | 25 | -5.4 | 3.5 | 1.8 |
6 | Arg-HCl | 75 | -4.8 | 2.8 | 2.0 |
7 | Arg-HCl | 95 | -4.5 | 2.6 | 1.9 |
8 | Arg-HCl | 120 | -4.8 | 2.8 | 2.0 |
9 | Lys-HCl | 25 | -5.7 | 3.9 | 1.9 |
10 | Lys-HCl | 75 | -5.0 | 2.7 | 2.3 |
11 | Lys-HCl | 95 | -5.1 | 3.1 | 2.0 |
12 | Lys-HCl | 120 | -4.9 | 2.9 | 2.0 |
用于该研究的缓冲碱是25mM组氨酸(pH 6.0)
该研究说明精氨酸和赖氨酸比NaCl更具稳定化作用。此外,75mM及以上似乎稳定(针对聚集)。在该研究的基础上,精氨酸被选为最具稳定化作用的lyo 友好赋形剂,并用于下一组研究。
最后的Lyo循环/代表性材料上的药物产品稳定性
评估药物产品的稳定性。在30mM L-组氨酸/L-组氨酸盐酸盐一水合物、80 mM L-精氨酸盐酸盐、120mM蔗糖、0.04%(w/v)聚山梨醇酯80(pH 6.0)中,针对100mg/ml的重构后配制品收集三个月的数据。结果示出于图10中。2℃-8℃储存在3个月期间几乎没有变化,证实了配制品和Lyo循环在临床应用上的适用性。因此,这些数据证明该配制品提供了适当的稳定性和溶解性,并且适合于初次人类临床使用。
表4-药物产品稳定性3个月数据总结
实例3-IgG4配制品
在pH 6下测试抗体MEDI578的配制品。MEDI578是具有6.3至6.8的pI的 IgG4单克隆抗体。
结果示出于图11中。
实例4-IgG4配制品
所有测试的配制品含有100mg/ml MEDI578、20mM组氨酸,pH 6.5而不含聚山梨醇酯。MEDI578是具有6.3至6.8的pI的IgG4单克隆抗体。
表5-配制品信息
图12示出了通过尺寸排阻色谱法的纯度。
图13示出了在热应激条件下含有离子型赋形剂的配制品中亚可见颗粒的减少。胶体稳定性得到改进。
本申请中所引述的所有文件、专利、期刊论文和其他材料通过援引并入本文。
尽管已经结合本发明的若干实施例,参照附图完整地描述本发明,但应理解,不同变化和修改对于本领域的技术人员可以是显而易见的。应理解,此类变化和修改都包括在如所附权利要求书所界定的本发明的范围内,除非它们背离该范围。
序列表
<110> 免疫医疗有限公司(MedImmune Limited)
<120> 单克隆抗体的配制品
<130> FSISO-100-WO-PCT
<150> US 62/465,269
<151> 2017-03-01
<160> 10
<170> PatentIn版本3.5
<210> 1
<211> 1074
<212> DNA
<213> 人工序列
<220>
<223> CAT-354轻链DNA序列的编码链
<400> 1
tcagatcgcc tggagacgcc atccacgctg ttttgacctc catagaagac accgggaccg 60
atccagcctc cgcggccggg aacggtgcat tggaacgcgg attccccgtg ccaagagtga 120
ctcaccgtcc ttgacacgaa gctattcgaa ctacagttac tgagcacaca ggacctcacc 180
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactcctcc 240
tatgtgctga ctcagccacc ctcggtgtca gtggccccag gaaagacggc caggattacc 300
tgtgggggaa acatcattgg aagtaaactt gtacactggt accagcagaa gccaggccag 360
gcccctgtgc tggtcatcta tgatgatggc gaccggccct cagggatccc tgagcgattc 420
tctggctcca actctgggaa cacggccacc ctgaccatca gcagggtcga ggccggggat 480
gaggccgact attattgtca ggtgtgggat actggtagtg atcccgtggt attcggcgga 540
gggaccaagc tgaccgtcct aggtcagccc aaggctgccc cctcggtcac tctgttcccg 600
ccctcctctg aggagcttca agccaacaag gccacactgg tgtgtctcat aagtgacttc 660
tacccgggag ccgtgacagt ggcctggaag gcagatagca gccccgtcaa ggcgggagtg 720
gagaccacca caccctccaa acaaagcaac aacaagtacg cggccagcag ctatctgagc 780
ctgacgcctg agcagtggaa gtcccacaga agctacagct gccaggtcac gcatgaaggg 840
agcaccgtgg agaagacagt ggcccctaca gaatgttcat aggaattcat tgatcataat 900
cagccatacc acatttgtag aggttttact tgctttaaaa aacctcccac acctccccct 960
gaacctgaaa cataaaatga atgcaattgt tgttgttaac ttgtttattg cagcttataa 1020
tggttacaaa taaagcaata gcatcacaaa tttcacaaat aaagcatttt tttc 1074
<210> 2
<211> 1074
<212> DNA
<213> 人工序列
<220>
<223> CAT-354轻链DNA序列的互补链
<400> 2
agtctagcgg acctctgcgg taggtgcgac aaaactggag gtatcttctg tggccctggc 60
taggtcggag gcgccggccc ttgccacgta accttgcgcc taaggggcac ggttctcact 120
gagtggcagg aactgtgctt cgataagctt gatgtcaatg actcgtgtgt cctggagtgg 180
taccctacct cgacatagta ggagaagaac catcgttgtc gatgtccaca ggtgaggagg 240
atacacgact gagtcggtgg gagccacagt caccggggtc ctttctgccg gtcctaatgg 300
acaccccctt tgtagtaacc ttcatttgaa catgtgacca tggtcgtctt cggtccggtc 360
cggggacacg accagtagat actactaccg ctggccggga gtccctaggg actcgctaag 420
agaccgaggt tgagaccctt gtgccggtgg gactggtagt cgtcccagct ccggccccta 480
ctccggctga taataacagt ccacacccta tgaccatcac tagggcacca taagccgcct 540
ccctggttcg actggcagga tccagtcggg ttccgacggg ggagccagtg agacaagggc 600
gggaggagac tcctcgaagt tcggttgttc cggtgtgacc acacagagta ttcactgaag 660
atgggccctc ggcactgtca ccggaccttc cgtctatcgt cggggcagtt ccgccctcac 720
ctctggtggt gtgggaggtt tgtttcgttg ttgttcatgc gccggtcgtc gatagactcg 780
gactgcggac tcgtcacctt cagggtgtct tcgatgtcga cggtccagtg cgtacttccc 840
tcgtggcacc tcttctgtca ccggggatgt cttacaagta tccttaagta actagtatta 900
gtcggtatgg tgtaaacatc tccaaaatga acgaaatttt ttggagggtg tggaggggga 960
cttggacttt gtattttact tacgttaaca acaacaattg aacaaataac gtcgaatatt 1020
accaatgttt atttcgttat cgtagtgttt aaagtgttta tttcgtaaaa aaag 1074
<210> 3
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> CAT-354轻链
<400> 3
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala
20 25 30
Pro Gly Lys Thr Ala Arg Ile Thr Cys Gly Gly Asn Ile Ile Gly Ser
35 40 45
Lys Leu Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
50 55 60
Val Ile Tyr Asp Asp Gly Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val
85 90 95
Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Thr Gly
100 105 110
Ser Asp Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
115 120 125
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210> 4
<211> 1937
<212> DNA
<213> 人工序列
<220>
<223> CAT-354重链DNA序列的编码序列
<400> 4
tcagatcgcc tggagacgcc atccacgctg ttttgacctc catagaagac accgggaccg 60
atccagcctc cgcggccggg aacggtgcat tggaacgcgg attccccgtg ccaagagtga 120
ctcaccgtcc ttgacacgaa gcttactgag cacacaggac ctcaccatgg gatggagctg 180
tatcatcctc ttcttggtag caacagctac aggtgtccac tcccaagtgc agctggtgca 240
gtctggggct gaggtgaaga agcctggggc ctcagtgaag gtctcctgca aggcttctgg 300
ttacaccttt acaaattatg gtctcagctg ggtgcgacag gcccctggac aagggcttga 360
gtggatggga tggatcagcg ctaataatgg cgacacaaat tatggacagg aattccaggg 420
cagagtcacc atgaccacag atacatccac gagcacagcc tacatggagt tgaggagcct 480
gagatctgac gacacggccg tttattactg tgcgagagac tccagcagca gctgggctcg 540
ctggtttttc gatctctggg gccgggggac actggtcacc gtctcgagtg cttccaccaa 600
gggcccatcc gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagccgc 660
cctgggctgc ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg 720
cgccctgacc agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc 780
cctcagcagc gtggtgaccg tgccctccag cagcttgggc acgaagacct acacctgcaa 840
cgtagatcac aagcccagca acaccaaggt cgacaagaga gttgagtcca aatatggtcc 900
cccatgccca tcatgcccag cacctgagtt cctgggggga ccatcagtct tcctgttccc 960
cccaaaaccc aaggacactc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt 1020
ggacgtgagc caggaagacc ccgaggtcca gttcaactgg tacgtggatg gcgtggaggt 1080
gcataatgcc aagacaaagc cgcgggagga gcagttcaac agcacgtacc gtgtggtcag 1140
cgtcctcacc gtcctgcacc aggactggct gaacggcaag gagtacaagt gcaaggtctc 1200
caacaaaggc ctcccgtcct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg 1260
agagccacag gtgtacaccc tgcccccatc ccaggaggag atgaccaaga accaggtcag 1320
cctgacctgc ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa 1380
tgggcagccg gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt 1440
cttcctctac agcaggctaa ccgtggacaa gagcaggtgg caggagggga atgtcttctc 1500
atgctccgtg atgcatgagg ctctgcacaa ccactacaca cagaagagcc tctccctgtc 1560
tctgggtaaa tgagtgccag ggccggcaag cccccgctcc ccgggctctc ggggtcgcgc 1620
gaggatgctt ggcacgtacc ccgtctacat acttcccagg cacccagcat ggaaataaag 1680
cacccaccac tgccctggct cgaattcatt gatcataatc agccatacca catttgtaga 1740
ggttttactt gctttaaaaa acctcccaca cctccccctg aacctgaaac ataaaatgaa 1800
tgcaattgtt gttgttaact tgtttattgc agcttataat ggttacaaat aaagcaatag 1860
catcacaaat ttcacaaata aagcattttt ttcactgcat tctagttgtg gtttgtccaa 1920
actcatcaat gtatctt 1937
<210> 5
<211> 1937
<212> DNA
<213> 人工序列
<220>
<223> CAT-354重链DNA序列的互补链
<400> 5
agtctagcgg acctctgcgg taggtgcgac aaaactggag gtatcttctg tggccctggc 60
taggtcggag gcgccggccc ttgccacgta accttgcgcc taaggggcac ggttctcact 120
gagtggcagg aactgtgctt cgaatgactc gtgtgtcctg gagtggtacc ctacctcgac 180
atagtaggag aagaaccatc gttgtcgatg tccacaggtg agggttcacg tcgaccacgt 240
cagaccccga ctccacttct tcggaccccg gagtcacttc cagaggacgt tccgaagacc 300
aatgtggaaa tgtttaatac cagagtcgac ccacgctgtc cggggacctg ttcccgaact 360
cacctaccct acctagtcgc gattattacc gctgtgttta atacctgtcc ttaaggtccc 420
gtctcagtgg tactggtgtc tatgtaggtg ctcgtgtcgg atgtacctca actcctcgga 480
ctctagactg ctgtgccggc aaataatgac acgctctctg aggtcgtcgt cgacccgagc 540
gaccaaaaag ctagagaccc cggccccctg tgaccagtgg cagagctcac gaaggtggtt 600
cccgggtagg cagaaggggg accgcgggac gaggtcctcg tggaggctct cgtgtcggcg 660
ggacccgacg gaccagttcc tgatgaaggg gcttggccac tgccacagca ccttgagtcc 720
gcgggactgg tcgccgcacg tgtggaaggg ccgacaggat gtcaggagtc ctgagatgag 780
ggagtcgtcg caccactggc acgggaggtc gtcgaacccg tgcttctgga tgtggacgtt 840
gcatctagtg ttcgggtcgt tgtggttcca gctgttctct caactcaggt ttataccagg 900
gggtacgggt agtacgggtc gtggactcaa ggacccccct ggtagtcaga aggacaaggg 960
gggttttggg ttcctgtgag agtactagag ggcctgggga ctccagtgca cgcaccacca 1020
cctgcactcg gtccttctgg ggctccaggt caagttgacc atgcacctac cgcacctcca 1080
cgtattacgg ttctgtttcg gcgccctcct cgtcaagttg tcgtgcatgg cacaccagtc 1140
gcaggagtgg caggacgtgg tcctgaccga cttgccgttc ctcatgttca cgttccagag 1200
gttgtttccg gagggcagga ggtagctctt ttggtagagg tttcggtttc ccgtcggggc 1260
tctcggtgtc cacatgtggg acgggggtag ggtcctcctc tactggttct tggtccagtc 1320
ggactggacg gaccagtttc cgaagatggg gtcgctgtag cggcacctca ccctctcgtt 1380
acccgtcggc ctcttgttga tgttctggtg cggagggcac gacctgaggc tgccgaggaa 1440
gaaggagatg tcgtccgatt ggcacctgtt ctcgtccacc gtcctcccct tacagaagag 1500
tacgaggcac tacgtactcc gagacgtgtt ggtgatgtgt gtcttctcgg agagggacag 1560
agacccattt actcacggtc ccggccgttc gggggcgagg ggcccgagag ccccagcgcg 1620
ctcctacgaa ccgtgcatgg ggcagatgta tgaagggtcc gtgggtcgta cctttatttc 1680
gtgggtggtg acgggaccga gcttaagtaa ctagtattag tcggtatggt gtaaacatct 1740
ccaaaatgaa cgaaattttt tggagggtgt ggagggggac ttggactttg tattttactt 1800
acgttaacaa caacaattga acaaataacg tcgaatatta ccaatgttta tttcgttatc 1860
gtagtgttta aagtgtttat ttcgtaaaaa aagtgacgta agatcaacac caaacaggtt 1920
tgagtagtta catagaa 1937
<210> 6
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> CAT-354重链
<400> 6
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ser Ala Asn Asn Gly Asp Thr Asn Tyr Gly
65 70 75 80
Gln Glu Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Ser Ser Ser Ser Trp Ala Arg Trp Phe Phe
115 120 125
Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Leu Gly Lys
465
<210> 7
<211> 456
<212> PRT
<213> 人工序列
<220>
<223> MEDI8897重链
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Met Val Ser Cys Gln Ala Ser Gly Gly Leu Leu Glu Asp Tyr
20 25 30
Ile Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Val Leu Gly Thr Val His Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Thr Glu Thr Ala Leu Val Val Ser Glu Thr Tyr Leu Pro His Tyr
100 105 110
Phe Asp Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 8
<211> 1368
<212> DNA
<213> 人工序列
<220>
<223> MEDI8897重链
<400> 8
caagtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ccggctcctc cgtgatggtg 60
tcctgccagg cttctggcgg cctgctggaa gattacatca tcaactgggt gcgacaggcc 120
ccaggccagg gacctgaatg gatgggcgga atcatccccg tgctgggcac cgtgcactac 180
ggccctaagt tccagggcag agtgaccatc accgccgacg agtctaccga caccgcctac 240
atggaactgt cctccctgcg gagcgaggac accgccatgt actactgcgc caccgagaca 300
gccctggtgg tgtccgagac atacctgccc cactacttcg acaactgggg ccagggaacc 360
ctcgtgaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 420
tccaagtcca cctccggcgg caccgccgct ctgggctgcc tggtgaagga ctacttccct 480
gagcctgtga ccgtgtcctg gaactctggc gccctgacct ctggcgtgca caccttccct 540
gccgtgctgc agtcctccgg cctgtactcc ctgtcctccg tggtgacagt gccttcctcc 600
tccctgggca cccagaccta catctgcaac gtgaaccaca agcccagcaa caccaaggtg 660
gacaagagag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 720
cctgaactcc tggggggacc gtcagtcttt ctgttccctc ctaagcctaa ggacaccctg 780
tacatcaccc gggagcctga agtgacctgc gtggtggtgg atgtgtccca cgaggaccct 840
gaggtgaagt tcaattggta cgtggacggc gtggaggtgc acaacgccaa gaccaagcct 900
cgggaggagc agtacaactc cacctaccgg gtggtgtctg tgctgaccgt gctgcaccag 960
gactggctga acggcaaaga atacaagtgc aaagtctcca acaaggccct gcctgccccc 1020
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080
cctccctccc gcgaggagat gaccaagaac caggtgtccc tgacctgtct ggtgaagggc 1140
ttctaccctt ccgatatcgc cgtggagtgg gagtccaacg gccagcctga gaacaactac 1200
aagaccaccc ctcctgtgct ggactccgac ggctccttct tcctgtactc caagctgacc 1260
gtggacaagt cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggct 1320
ctgcacaacc actacaccca gaaaagcctc tccctgtctc cgggtaaa 1368
<210> 9
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> MEDI8897轻链
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ala Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Val Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Val Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 10
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> MEDI8897轻链
<400> 10
gacatccaga tgacccagtc cccctcctct ctgtctgctg ccgtgggcga cagagtgacc 60
atcacctgtc aggcctccca ggacatcgtg aactacctga actggtatca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacgtg gcctccaacc tggaaaccgg cgtgccctcc 180
agattctccg gctctggctc tggcaccgac ttcagcctga ccatctccag cctgcagcct 240
gaggacgtgg ccacctacta ctgccagcag tacgacaacc tgcccctgac ctttggcgga 300
ggcaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttccccccc 360
agcgacgagc agctgaagag cggcaccgcc tccgtggtgt gcctgctgaa caacttctac 420
ccccgcgagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caacagccag 480
gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540
ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600
ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642
Claims (14)
1.一种稳定的配制品,该配制品包含:
i.抗GM-CSFRα抗体;和
ii.离子型赋形剂;
其中该抗GM-CSFRα抗体具有在pH 6.7的pI和CAM-3001的VH和VL序列;以及
其中该抗GM-CSFRα抗体以50mg/ml至200mg/ml之间的浓度存在,并且该离子型赋形剂为NaCl,其以50至100mM的浓度存在;
其中该配制品具有5.7至6.3的pH;以及
其中该抗GM-CSFRα抗体是IgG4单克隆抗体。
2.根据权利要求1所述的稳定的配制品,其中该配制品中的单克隆抗体的聚集速率与相同但不含离子型赋形剂的配制品中的相同抗体的聚集速率相比降低。
3.根据权利要求1所述的稳定的配制品,其中该抗GM-CSFRα抗体以100mg/ml至200mg/ml的浓度存在于该配制品中。
4.根据权利要求3所述的稳定的配制品,其中该单克隆抗体以100mg/ml或150mg/ml的浓度存在于该配制品中。
5.根据权利要求1所述的稳定的配制品,其中该配制品具有pH 5.8的pH。
6.根据权利要求1所述的稳定的配制品,其中该离子型赋形剂以70mM的浓度存在。
7.根据权利要求1所述的稳定的配制品,其中该配制品进一步包含糖。
8.根据权利要求1所述的稳定的配制品,其中该配制品进一步包含一种或多种缓冲剂。
9.根据权利要求1所述的稳定的配制品,其中该配制品进一步包含表面活性剂。
10.根据权利要求1所述的稳定的配制品,该配制品包含150mg/ml抗GM-CSFRα抗体、50mM乙酸钠/乙酸、106mM海藻糖脱水物、70mM氯化钠和0.05%(w/v)聚山梨醇酯80,其中该配制品具有pH 5.8的pH。
11.根据权利要求1所述的稳定的配制品,其用作药物或用于治疗疾病。
12.根据权利要求7所述的稳定的配制品,其中该糖是海藻糖或蔗糖,且其中该糖以100mM至140mM的浓度存在。
13.根据权利要求8所述的稳定的配制品,其中该一种或多种缓冲剂选自组氨酸、组氨酸盐酸盐、组氨酸/组氨酸盐酸盐和乙酸钠。
14.根据权利要求9所述的稳定的配制品,其中该表面活性剂是聚山梨醇酯或聚山梨醇酯-80,且其中该表面活性剂以从0.02%(w/v)至0.07%(w/v)的浓度存在于该配制品中。
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CN202010229368.0A CN112057419B (zh) | 2017-03-01 | 2018-02-28 | 单克隆抗体的配制品 |
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CN201880014493.0A CN110366429A (zh) | 2017-03-01 | 2018-02-28 | 单克隆抗体的配制品 |
CN202010229368.0A CN112057419B (zh) | 2017-03-01 | 2018-02-28 | 单克隆抗体的配制品 |
PCT/EP2018/054960 WO2018158332A1 (en) | 2017-03-01 | 2018-02-28 | Formulations of monoclonal antibodies |
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CN (2) | CN110366429A (zh) |
AU (2) | AU2018227036B2 (zh) |
BR (1) | BR112019018022A2 (zh) |
CA (2) | CA3235178A1 (zh) |
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WO2015099175A1 (ja) | 2013-12-26 | 2015-07-02 | 田辺三菱製薬株式会社 | ヒト抗il-33中和モノクローナル抗体 |
WO2015108967A2 (en) | 2014-01-15 | 2015-07-23 | Medimmune, Llc | Rsv-specific antibodies and functional parts thereof |
US9982061B2 (en) | 2014-10-01 | 2018-05-29 | Medimmune Limited | Antibodies to ticagrelor and methods of use |
TW202228779A (zh) | 2017-03-01 | 2022-08-01 | 英商梅迪繆思有限公司 | 抗rsv單株抗體配製物 |
MX2019012255A (es) | 2017-04-11 | 2019-12-05 | Kiniksa Pharmaceuticals Ltd | Formulacion estable de anticuerpo contra el receptor de oncostatina m (osmr). |
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US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
MX2020002086A (es) | 2017-08-31 | 2020-10-28 | Mitsubishi Tanabe Pharma Corp | Agente terapeutico que contiene antagonista de il-33 para endometriosis. |
JP7407723B2 (ja) * | 2018-09-14 | 2024-01-04 | 田辺三菱製薬株式会社 | ヒト抗il-33モノクローナル抗体含有医薬用組成物 |
US20210347915A1 (en) * | 2018-09-20 | 2021-11-11 | Phasebio Pharmaceuticals, Inc. | Methods of reversing ticagrelor activity |
MX2021009851A (es) | 2019-02-18 | 2021-09-10 | Lilly Co Eli | Formulacion de anticuerpos terapeuticos. |
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JP7441389B2 (ja) * | 2020-03-17 | 2024-03-01 | エックスブレイン バイオファーマ エービー | 組換えタンパク質を発現させるためのtis配列およびシグナルペプチド配列の新規の組み合わせ |
JP2023534576A (ja) | 2020-03-23 | 2023-08-10 | メドイミューン・リミテッド | アトピー性皮膚炎及び関連する障害の治療方法 |
GB202108379D0 (en) | 2021-06-11 | 2021-07-28 | Medlmmune Ltd | Methods for treating a topic dermatitis and related disorders |
WO2023023497A1 (en) | 2021-08-16 | 2023-02-23 | Medimmune Llc | Anti-il-13 antibody formulation |
TW202330025A (zh) | 2021-09-28 | 2023-08-01 | 英商梅迪繆思有限公司 | 用於治療異位性皮膚炎及相關病症之方法 |
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- 2018-02-28 EP EP20190885.2A patent/EP3797792A1/en active Pending
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- 2018-02-28 US US16/488,302 patent/US20200283516A1/en not_active Abandoned
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- 2018-02-28 JP JP2019547137A patent/JP2020509025A/ja active Pending
- 2018-02-28 CA CA3235178A patent/CA3235178A1/en active Pending
- 2018-02-28 CN CN201880014493.0A patent/CN110366429A/zh active Pending
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- 2018-02-28 CN CN202010229368.0A patent/CN112057419B/zh active Active
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JP2020138981A (ja) | 2020-09-03 |
US20220089713A1 (en) | 2022-03-24 |
JP2023060016A (ja) | 2023-04-27 |
CA3054386A1 (en) | 2018-09-07 |
JP2023071916A (ja) | 2023-05-23 |
EP3589318A1 (en) | 2020-01-08 |
AU2018227036A1 (en) | 2019-10-10 |
BR112019018022A2 (pt) | 2020-06-02 |
US20220204597A1 (en) | 2022-06-30 |
CA3235178A1 (en) | 2018-09-07 |
WO2018158332A1 (en) | 2018-09-07 |
KR20190121831A (ko) | 2019-10-28 |
EP3797792A1 (en) | 2021-03-31 |
KR102589598B1 (ko) | 2023-10-13 |
AU2018227036B2 (en) | 2021-07-08 |
MX2019010282A (es) | 2020-01-09 |
CN110366429A (zh) | 2019-10-22 |
AU2021240216A1 (en) | 2021-10-28 |
CN112057419A (zh) | 2020-12-11 |
US20200283516A1 (en) | 2020-09-10 |
JP2020509025A (ja) | 2020-03-26 |
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