CN112243379A - 稳定的抗体制剂 - Google Patents
稳定的抗体制剂 Download PDFInfo
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- CN112243379A CN112243379A CN201980038032.1A CN201980038032A CN112243379A CN 112243379 A CN112243379 A CN 112243379A CN 201980038032 A CN201980038032 A CN 201980038032A CN 112243379 A CN112243379 A CN 112243379A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Microbiology (AREA)
- Mycology (AREA)
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- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了抗体的稳定的药物制剂,其中所述制剂含有缓冲剂、表面活性剂和盐,并且其中所述制剂不含游离氨基酸。公开的抗体制剂是也适合冻干的液体制剂。
Description
技术领域
本发明涉及抗体分子的稳定的制剂,其中用最小量的赋形剂稳定抗体。公开的制剂与冻干形式和液体形式相容,并且还适合静脉内和/或皮下途径的施用。
背景技术
在过去的二十年中,重组DNA技术已导致许多蛋白质(特别是抗体治疗剂)的商业化。这些治疗性抗体的有效性主要取决于稳定性、施用途径以及它们的剂型和浓度。继而,需要适当地配制治疗性抗体以保持治疗性抗体的稳定性和活性。
用于每种施用途径和剂型的制剂可以是独特的,并且因此具有特定要求。固体剂型(例如冻干粉剂)通常比液体(水性)制剂更稳定。然而,相对于液体制剂,冻干制剂的重构需要显著的小瓶过量填充、在处理时当心、并且而涉及高的生产成本。虽然液体制剂在这些方面是有利的,并且通常对于可注射蛋白质治疗剂而言是优选的(就最终用户的便利性和制造商的制备容易性而言),但鉴于蛋白质在诸如温度、pH值变化、搅拌等胁迫下易于变性、聚集、降解和氧化,此种形式可能并不总是可行的。这些应激因素均可能导致治疗性蛋白质/抗体的生物学活性的丧失。特别地,高浓度液体制剂易于降解和/或聚集。然而,由于降低了施用的频率和注射体积,可能期望高浓度制剂用于皮下或静脉内施用途径。另一方面,特定的治疗方案和剂量可能需要低浓度制剂,并且优选静脉内施用途径,以用于实现治疗药物的更可预测的递送以及完全生物利用度。
因此,设计在高或低浓度的治疗性蛋白质/抗体下稳定,有助于不同的施用途径(静脉内或皮下)并且适合冻干或液体形式的制剂造成了重大的开发挑战。此外,每种具有其独特的特征和降解特性的蛋白质或抗体增加了开发稳定的制剂的复杂性,并且可能需要特定的制剂。
治疗性蛋白质或抗体的稳定的制剂涉及多种稳定剂/赋形剂(包括氨基酸、糖、多元醇、表面活性剂、盐、聚合物、胺、抗氧化剂、螯合剂等)的添加。许多FDA批准的治疗性蛋白质/抗体含有一种以上稳定剂。
具有增加的蛋白质和/或稳定剂浓度的制剂组合可增加制剂的粘度,继而增加注射部位的疼痛和注射时间,并且在药物原料的加工过程中也造成困难。因此,有必要开发处于冻干形式以及液体形式的改进的制剂,其含有最小量或浓度的赋形剂,并且在宽范围的浓度下稳定药物。
发明简述
本发明公开了抗体的稳定的药物制剂,所述制剂包含缓冲剂、盐和表面活性剂,其中所述制剂不含游离氨基酸。公开的制剂任选地含有糖。
特别地,本发明公开了α4β7抗体的稳定的药物制剂,所述制剂包含缓冲剂、糖、盐和表面活性剂,其中所述制剂不含游离氨基酸。所述制剂中的抗体在40℃下稳定4周,并且在制剂中维持抗体的至少95%的单体含量。抗体还可在50℃下稳定2周,并且在制剂中维持抗体的至少97%的单体含量。
公开的α4β7抗体制剂中存在的盐控制抗体分子的片段化速率以及主峰含量向碱性变体的转化速率,并且稳定制剂。
附图简述
图1说明了盐对根据实施例1制备并使用SEC色谱分析的维多珠单抗(60mg/ml)制剂的LMW和单体含量的影响。在40℃的储存条件下4周期间,图1(a)表示LMW含量,图1(b)表示单体含量。
发明详述
定义
术语“抗体”是指包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链的糖蛋白或其抗原结合部分。本文所使用的“抗体”涵盖完整抗体或其任何抗原结合片段(即“抗原结合部分”)或其融合蛋白。
术语“稳定的”制剂是指其中的抗体在储存时保持其物理稳定性和/或化学稳定性和/或生物学活性的制剂。
稳定性研究提供了一段时间内多种环境因素的影响下抗体质量的证据。ICH的“Q1A:新药原料和产品的稳定性测试”指出了加速的稳定性研究中的数据可用于评价抗体运输过程中可能发生的高于或低于标记储存条件的短期偏移的影响。
多种分析方法可用于测量药物制剂中抗体的物理和化学降解。如果在肉眼检查颜色和/或透明度、或通过UV光散射、或通过体积排阻色谱测量时基本上未显示出聚集、沉淀和/或变性迹象,则抗体在药物制剂中“保持了其物理稳定性”。当抗体显示无产物变体形成或最小量的产物变体形成时,则称抗体在药物制剂中“保持了其化学稳定性”,所述产物变体可包括由于对感兴趣的抗体的化学修饰(如脱氨、氧化等)而导致的产物变体。诸如离子交换色谱和疏水离子色谱等的分析方法可用于研究化学产物变体。
本文使用的术语“单体”描述了由两条轻链和两条重链组成的抗体。通常通过尺寸排阻色谱(SEC)分析抗体组合物的单体含量。根据SEC的分离原理,大分子或具有高分子量(HMW)的分子首先被洗脱,然后较小或较低分子量的分子被洗脱。在抗体组合物的典型SEC谱中,聚集体(可包括二聚体、多聚体等)首先被洗脱,然后单体被洗脱,且被剪切的抗体变体或降解物可最后被洗脱。在一些情况下,聚集体峰或降解物峰可不以基线分离峰洗脱,而是以肩峰或异常宽的峰洗脱。为维持抗体(特别是治疗性抗体)的适当活性,期望减少产物的片段化或聚集体的形成,并由此将单体含量控制在目标值。在稳定性研究期间的多个时间点测量的抑制聚集体和降解物含量形成的能力可表明候选制剂对感兴趣的抗体的适合性。TOSCH的TSK-GEL G3000SWXL(7.8mm×30cm)色谱柱可用于水HPLC以进行SEC。
本文使用的术语“主峰”是指在阳离子交换色谱过程中大量洗脱的峰(主峰)。在阳离子交换色谱过程中比主峰更早洗脱,具有相对于主峰为酸性的电荷的峰被称为酸性变体峰。在阳离子交换色谱过程中比主峰更晚洗脱,具有相对于主峰为碱性的电荷的峰被称为碱性变体峰。主峰含量可通过离子交换色谱(IEC)确定。存在两种可用的IEC模式,即阳离子交换色谱和阴离子交换色谱。带正电的分子结合至阴离子交换树脂,而带负电的分子结合至阳离子交换树脂。在抗体组合物的阳离子交换色谱的典型分布中,酸性变体首先洗脱,然后是主峰,然后是碱性变体。酸性变体是抗体修饰(例如天冬酰胺残基脱酰胺)的结果。碱性变体是C末端赖氨酸残基不完全去除的结果。通常,在抗体中,赖氨酸残基在重链和轻链的C末端均存在。重链和轻链均含有赖氨酸的抗体分子称为K2变体,重链和轻链中的任何一个含有赖氨酸残基的抗体分子称为K1变体,并且不具有赖氨酸残基的抗体分子为K0分子。羧肽酶B(CP-B酶)酶作用于K2和K1变体上存在的C末端赖氨酸残基,从而将其转化为K0分子。根据情况,可对用羧肽酶B(CP-B)酶消化的样品进行IEC分析。在典型的稳定性研究中,预期在研究过程中稳定的配制剂导致电荷变体(酸性和碱性变体)的形成减少,从而将主峰含量的任何减少最小化。
药学上可接受的赋形剂是指可有助于抗体在制剂中的稳定性的添加剂或载体。赋形剂可涵盖稳定剂和张力调节剂。稳定剂和张力调节剂的实例包括但不限于糖、多元醇、盐、表面活性剂以及它们的衍生物和组合。
本文的糖包括糖和糖醇(例如多元醇)。糖可指单糖、二糖和多糖。糖的实例包括但不限于蔗糖、海藻糖、葡萄糖、右旋糖、棉子糖等。多元醇的实例包括但不限于甘露醇,山梨糖醇和其它。
表面活性剂是指用于保护蛋白质制剂免受多种压力条件(例如搅动、剪切、暴露于高温等)的药学上可接受的赋形剂。合适的表面活性剂包括但不限于聚氧乙烯失水山梨醇脂肪酸酯,例如Tween 20TM或Tween 80TM、聚氧乙烯-聚氧丙烯共聚物(例如泊洛沙姆、普朗尼克)、十二烷基硫酸钠(SDS)等或它们的组合。
本文使用的术语“游离氨基酸”是指包含在制剂中并且不是缓冲剂组分的一部分的氨基酸。氨基酸可以以其D-和/或L-形式存在。氨基酸可以以任何合适的盐(例如盐酸盐,例如精氨酸盐酸盐)的形式存在。
盐的实例包括但不限于氯化钠、氯化钾、氯化镁、硫氰酸钠、硫氰酸铵、硫酸铵、氯化铵、氯化钙、氯化锌和/或醋酸钠。
通过参考以下实例更全面地描述了本发明的某些特定方面和实施方式。然而,这些实例不应以任何方式解释为限制本发明的范围。
实施方式的详细描述
本发明公开了抗体的稳定的药物制剂,所述制剂包含缓冲剂、盐和表面活性剂。
在一个实施方式中,本发明公开了抗体的稳定的药物制剂,所述制剂包含缓冲剂、盐和表面活性剂,其中所述制剂不含游离氨基酸。
在本发明的上述实施方式中,抗体制剂中存在的盐为氯化钠,并且其在10mM至小于约100mM的浓度下控制制剂中抗体分子的片段化速率。优选地,盐浓度为20mM-90mM。
在上述实施方式中,在储存期间,制剂中存在的盐控制主峰含量向碱性变体的转化速率,此外减少了抗体分子的片段化。
在以上实施方式中,抗体为治疗性单克隆抗体,并且选自由嵌合抗体、人源化抗体和人抗体所组成的组。
在上述实施方式中,治疗性抗体为人源化抗体并且结合α4β7。
在实施方式中,本发明公开了包含缓冲剂、盐和表面活性剂的稳定的α4β7抗体制剂,其中所述制剂不含游离氨基酸。
在上述实施方式中,当在40℃下贮存4周时,所述α4β7抗体制剂是稳定的,并且维持了抗体的至少95%的单体含量。
在上述实施方式中,当在40℃下储存4周时,所述α4β7抗体制剂是稳定的,并且在制剂中含有小于1%的低分子量(LMW)物质或片段。
在本发明的上述任一实施方式中,所述α4β7抗体制剂任选地含有糖。优选地,糖为蔗糖或海藻糖。
在上述任一实施方式中,制剂中提及的缓冲剂包括有机缓冲剂、无机缓冲剂和/或它们的组合。
在本发明的上述实施方式中,所述有机缓冲剂包括组氨酸缓冲剂、琥珀酸盐缓冲剂或醋酸盐缓冲剂。
在本发明的另一个实施方式中,制剂中提及的无机缓冲剂包括磷酸盐缓冲剂。
在本发明的所有上述实施方式中,制剂中抗体的浓度为约50mg/ml至约200mg/ml。
在本发明的上述任何实施方式中,α4β7抗体制剂的pH为6.0-7.0。
在一个实施方式中,本发明公开了α4β7抗体的稳定的药物制剂,所述制剂包含缓冲剂、氯化钠、表面活性剂和糖,其中制剂不包含游离氨基酸。
在上述实施方式中,当在50℃下储存2周时,α4β7抗体制剂是稳定的,并且维持了制剂中的抗体的至少97%的单体含量并将制剂中的低分子量物质控制为小于1.5%。
在实施方式中,当在50℃下储存2周时,包含缓冲剂、氯化钠、表面活性剂和糖的α4β7抗体制剂含有小于15%的碱性变体和小于约1.5%的低分子量物质。
在本发明的上述任一实施方式中,α4β7抗体制剂中存在的盐的浓度选自10mM至小于约100mM,优选20mM至90mM。
在本发明的上述任一实施方式中,盐可为氯化钠、氯化钾、氯化铵或硫酸铵。
在上述任一实施方式中,在储存期间,制剂中存在的盐有助于维持主峰含量,并且还控制主峰含量向碱性变体的转化速率,此外减少了抗体分子的片段化。本文的储存条件包括加速稳定性和货架稳定性条件。
在上述任一实施方式中,α4β7抗体的制剂是稳定的液体(水)制剂,其可以用于肠胃外施用。肠胃外施用包括静脉内、皮下、腹膜内、肌内施用或任何其它通常认为属于肠胃外施用范围并且本领域技术人员熟知的递送途径。
在本发明的上述任一实施方式中,稳定的液体/水性制剂是合适的并且可冻干为冻干粉。此外,可用适当的稀释剂对α4β7抗体的冻干制剂进行重构,以获得适合施用的液体制剂。
本发明公开的制剂使用较少量的赋形剂来稳定治疗性抗体。
实施例
通过本领域已知的标准方法生产本药物组合物中的适合储存的α4β7抗体维多珠单抗(vedolizumab)。例如,通过在哺乳动物宿主细胞(例如中国仓鼠卵巢细胞)中重组表达免疫球蛋白轻链和重链基因来制备维多珠单抗。此外,获得表达的维多珠单抗,并且对粗获取物进行标准下游工艺步骤,包括纯化、过滤以及任选的稀释或浓缩步骤。例如,可使用标准色谱技术(例如亲和色谱、离子交换色谱以及它们的组合)来纯化维多珠单抗的粗获取物。纯化的维多珠单抗溶液可额外进行一个或多个过滤步骤,并且将获得的溶液进行进一步的制剂研究。
实施例1:不含糖和游离氨基酸的维多珠单抗制剂
为获得不含游离氨基酸和糖的维多珠单抗的稳定制剂,作为实验设计的一部分,制备了不同浓度的氯化钠溶液。将从下游色谱过程中获得的醋酸Tris缓冲剂中的维多珠单抗(浓度为7mg/ml)进行缓冲剂交换,并在50mM组氨酸缓冲剂中浓缩至抗体浓度为65mg/ml。将浓缩的抗体分为3个样品。将50mM和100mM氯化钠添加至维多珠单抗的2个样品中。将0.6mg/ml聚山梨醇酯80添加至所有3个维多珠单抗样品中。在该实验中使用不含氯化钠的样品作为对照。表1中提及了所有3个维多珠单抗制剂的详细信息。所有维多珠单抗制剂均在40℃下进行4周加速稳定性研究。之后使用尺寸排阻色谱(SEC)分析样品的低分子量(LMW)种类和单体含量[图1(a)和图1(b)中示出了结果],并且还进行了肉眼观察检查[表2]。
表1:不含糖和游离氨基酸的多种维多珠单抗制剂的组成
表2:根据实施例1制备的维多珠单抗(60mg/ml)制剂的肉眼观察数据
W表示星期
实施例2:不含游离氨基酸的维多珠单抗的制剂
为获得含糖且不含游离氨基酸的维多珠单抗的稳定制剂,作为实验设计的一部分,将维多珠单抗60mg/ml配制成以下缓冲剂组合物,其含有20mM磷酸盐缓冲剂、50mM氯化钠、60mg/ml蔗糖和0.6mg/ml聚山梨醇酯80。氯化钠的浓度选自上述实验,其给予抗体更高的稳定性。在该实验中使用不含氯化钠的维多珠单抗制剂作为对照。表3给出了该实验使用的制剂的详细信息。将样品在50℃下进行2周加速稳定性研究。之后使用尺寸排阻色谱(SEC)分析样品的低分子量(LMW)种类和单体含量[表4中示出了结果],并且使用离子交换色谱法分析主峰含量、酸性变体、碱性变体[表5]并进行肉眼观察检查[表7]。
表3:不含游离氨基酸的多种维多珠单抗制剂的组成
表4:根据实施例2制备的维多珠单抗(60mg/ml)制剂的SEC数据
W-表示星期
表5:根据实施例2制备的维多珠单抗(60mg/ml)制剂的IEX数据
W-表示星期
表6:根据实施例2制备的维多珠单抗制剂的主峰含量的百分比
W-表示星期
表7:根据实施例2制备的维多珠单抗(60mg/ml)制剂的肉眼观察数据
W-表示星期
由实施例1和实施例2制备的液体维多珠单抗制剂适合冻干,并使用本领域已知的技术进行冻干过程并检查稳定性。
Claims (9)
1.抗体的稳定的药物制剂,所述制剂包含缓冲剂、盐和表面活性剂,其中所述制剂不含游离氨基酸。
2.如权利要求1所述的抗体制剂,其中所述抗体制剂中存在的盐在10mM至小于约100mM的浓度下控制所述制剂中所述抗体分子的片段化速率,并且还控制主峰含量向碱性变体的转化速率。
3.如权利要求1所述的抗体制剂,其中所述抗体为结合α4β7的治疗性抗体。
4.稳定的α4β7抗体制剂,所述制剂包含缓冲剂、盐、表面活性剂和糖,并且其中所述制剂不含游离氨基酸。
5.如权利要求4所述的α4β7抗体制剂,当在50℃下储存2周时,所述制剂是稳定的,并且维持制剂中抗体的至少97%单体含量并控制低分子量物质少于1.5%。
6.如权利要求4所述的α4β7抗体制剂,当在50℃下储存2周时,所述制剂含有少于15%的碱性变体。
7.如权利要求1或4所述的抗体制剂,所述制剂中所述抗体的浓度为约50mg/ml至约200mg/ml。
8.如权利要求1或权利要求4所述的制剂,所述制剂的pH为约6.0-7.0。
9.如权利要求1或4所述的制剂,所述制剂为液体或冻干制剂。
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IN201841013645 | 2018-04-10 | ||
IN201841013645 | 2018-04-10 | ||
PCT/IN2019/050291 WO2019198099A1 (en) | 2018-04-10 | 2019-04-10 | Stable antibody formulation |
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WO2010102241A1 (en) * | 2009-03-06 | 2010-09-10 | Genentech, Inc. | Antibody formulation |
CN103533959A (zh) * | 2011-05-02 | 2014-01-22 | 米伦纽姆医药公司 | 抗α4β7抗体的制剂 |
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JP4728948B2 (ja) * | 2003-02-10 | 2011-07-20 | エラン ファーマシューティカルズ,インコーポレイテッド | 免疫グロブリン製剤およびその調製の方法 |
US20090208492A1 (en) * | 2007-06-14 | 2009-08-20 | Elan Pharmaceuticals, Inc. | Lyophilized Immunoglobulin Formulations and Methods of Preparation |
UA116189C2 (uk) * | 2011-05-02 | 2018-02-26 | Мілленніум Фармасьютікалз, Інк. | КОМПОЗИЦІЯ АНТИ-α4β7 АНТИТІЛА |
BR112020020703A2 (pt) * | 2018-04-10 | 2021-01-12 | Dr. Reddy's Laboratories Limited | Formulações farmacêuticas estáveis de um anticorpo e do anticorpo ¿lfa4¿eta7 . |
CN112218654A (zh) * | 2018-04-10 | 2021-01-12 | 雷迪博士实验室有限公司 | 抗体制剂 |
WO2020252072A1 (en) * | 2019-06-10 | 2020-12-17 | Millennium Pharmaceuticals, Inc. | Antibody purification methods and compositions thereof |
MA56129A (fr) * | 2019-06-10 | 2022-04-13 | Takeda Pharmaceuticals Co | Procédés de production d'un anticorps anti-alpha4béta7 |
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US20100098712A1 (en) * | 2008-05-20 | 2010-04-22 | Michael Adler | Pharmaceutical formulation of an antibody against OX40L |
WO2010102241A1 (en) * | 2009-03-06 | 2010-09-10 | Genentech, Inc. | Antibody formulation |
CN102414221A (zh) * | 2009-03-06 | 2012-04-11 | 健泰科生物技术公司 | 抗体配制剂 |
CN103533959A (zh) * | 2011-05-02 | 2014-01-22 | 米伦纽姆医药公司 | 抗α4β7抗体的制剂 |
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ZA202006262B (en) | 2023-01-25 |
US20210253714A1 (en) | 2021-08-19 |
AU2019251452A2 (en) | 2020-12-03 |
SG11202009872YA (en) | 2020-11-27 |
BR112020020741A2 (pt) | 2021-01-19 |
EP3773695A1 (en) | 2021-02-17 |
US12024561B2 (en) | 2024-07-02 |
AU2019251452A1 (en) | 2020-11-26 |
JP2021521168A (ja) | 2021-08-26 |
CO2020013545A2 (es) | 2021-01-18 |
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