CN107184976A - 治疗性蛋白质制剂 - Google Patents
治疗性蛋白质制剂 Download PDFInfo
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- CN107184976A CN107184976A CN201710300195.5A CN201710300195A CN107184976A CN 107184976 A CN107184976 A CN 107184976A CN 201710300195 A CN201710300195 A CN 201710300195A CN 107184976 A CN107184976 A CN 107184976A
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Abstract
本发明一般涉及制剂,该制剂具有抑制在此制剂中包含的治疗蛋白质中的Asp‑Asp基序上的天冬氨酰异构化的pH。
Description
本申请是申请日为2009年11月19日、发明名称为“治疗性蛋白质制剂”的中国专利申请200980154866.5的分案申请。
相关申请的交叉引用
本申请要求2008年11月20日提交的美国临时申请号61/116,541的利益,其公开内容整体合并入本文作为参考。
发明领域
本发明一般涉及制剂,该制剂具有抑制包含在此制剂中的治疗蛋白质的Asp-Asp基序上天冬氨酰异构化的pH。
发明背景
蛋白质制剂
生物技术的进展已使得能够使用重组DNA技术生产各种蛋白质用于药学应用。因为蛋白质比常规有机和无机药物更大且更复杂(即具有多个官能团加上复杂三维结构),所以此类蛋白质的制剂提出了特殊问题。蛋白质对降解敏感,这可以涉及化学不稳定性(例如蛋白质通过键形成或断裂而被修饰,导致新化学实体)或物理不稳定性(例如蛋白质的高级结构的改变)。物理不稳定性可以起因于例如变性、聚集、沉淀或吸附。化学不稳定性可以起因于脱酰胺、外消旋化、异构化、水解、氧化、β消除或二硫键交换。
包括微酸性缓冲液的制剂已用于治疗性蛋白质,包括单克隆抗体,以便使脱酰胺、聚集和断裂降到最低。参见例如,Lam等人的美国专利号6,171,586(描述包括pH 5.0的乙酸盐缓冲液的稳定水性抗体制剂);Johnson等人的WO2004/019861(描述在pH 5.5的乙酸盐缓冲液中配制的聚乙二醇的抗TNFαFab片段);Nesta的WO2004/004639(描述huC242-DM1,一种肿瘤活化的免疫毒素,在pH 6.0的50mM琥珀酸缓冲液中配制);Kaisheva等人的WO03/039485(报道达可珠单抗,一种人源化IL-2受体抗体,在pH 6.0的琥珀酸钠缓冲液中具有最高稳定性);和Oliver等人的WO03/015894(描述在pH 6.0的组氨酸缓冲液中的100mg/mL水性制剂)。
在pH 4-6的条件下,蛋白质中的天冬氨酸(Asp)残基可以通过异构化而降解。Asp异构化通过环状亚胺中间体(琥珀酰亚胺)进行,该中间体经历快速水解断裂,以约3:1的摩尔比形成异天冬氨酸(异Asp)或Asp。参见Wakanar等人Biochemistry 46:1534-1544(2007)。在Asp的C端侧的残基影响Asp对异构化的敏感性,其中在Asp-Gly中出现的Asp对异构化特别敏感。同上引文。在治疗抗体中的Asp异构化可以导致抗原结合活性的大量丧失,特别当Asp出现在抗体的抗原结合区域例如互补决定区(CDR)中时。因此,本领域需要这样的制剂,该制剂可以抑制在制剂中包含的治疗蛋白质在Asp-Asp基序上的天冬氨酰异构化。
抗STEAP-1抗体
STEAP-1是一种细胞表面抗原,特征在于具有6个跨膜结构域和细胞内N和C末端的分子拓扑学,这提示它以“蛇形”方式折叠成3个细胞外和2个细胞内环。STEAP-1在正常人组织中主要在前列腺细胞中表达。它也在多种前列腺癌状态中以及在其它人类癌症,例如肺、结肠、卵巢、膀胱和胰腺癌、和Ewing氏肉瘤,中高水平表达。参见Hubert等人,Proc.Natl.Acad.Sci.USA 96:14523-14528(1999);WO 99/62941;Challita-Eid等人Cancer Res.67:5798-5805;和WO2008/052187。)
已描述过与STEAP-1结合的某些抗体。(参见WO2008/052187,特此并入本文作为参考。)进一步地,衍生自这些抗体的免疫缀合物已显示可以减少前列腺肿瘤异种移植物模型中的肿瘤体积。同上引文。因此,抗STEAP-1抗体或免疫缀合物对于治疗癌症例如前列腺癌有用。因此,用于施用抗STEAP-1抗体或免疫缀合物的合适制剂在癌症治疗中将是有用的。
本发明满足了上述需要且提供了其它的益处。
发明概述
本发明至少部分涉及包括具有Asp-Asp基序的治疗性蛋白质的制剂,其中该制剂通过抑制Asp-Asp基序中Asp残基上的天冬氨酰异构化而改善该蛋白质的稳定性。在一个方面,制剂具有抑制在Asp-Asp基序中的Asp残基的天冬氨酰异构化的pH。
在一个方面,提供了包括具有Asp-Asp基序的治疗蛋白质的制剂,其中制剂的pH为6.0以上且9.0以下。在一个实施方案中,pH是6.25-7.0。在另一个实施方案中,pH是约6.5。在另一个实施方案中,治疗蛋白质是抗体。在一个此类实施方案中,抗体包括包含Asp-Asp基序的高变区(HVR)。在一个此类实施方案中,Asp-Asp基序出现在HVR-H3中。
在一个进一步的实施方案中,抗体是抗STEAP-1抗体,其包括包含SEQ ID NO:16的氨基酸序列的HVR-H3。在一个此类实施方案中,抗STEAP-1抗体还包括选自下述的一个或多个HVRs:(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(d)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(e)包括SEQ ID NO:13的氨基酸序列的HVR-L3。在一个此类实施方案中,抗体包括(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:16的氨基酸序列的HVR-H3;(d)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(e)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(f)包括SEQ IDNO:13的氨基酸序列的HVR-L3。
在一个进一步的实施方案中,抗体是抗STEAP-1抗体,其包括包含SEQ ID NO:16的氨基酸序列的HVR-H3,并且包括包含如下氨基酸序列的重链可变区(VH),所述氨基酸序列与选自SEQ ID NOs:8-10的氨基酸序列至少90%氨基酸序列相同。在一个此类实施方案中,抗体进一步包括轻链可变区(VL),其中该VL包括与选自SEQ ID NOs:5-6的氨基酸序列至少90%氨基酸序列相同的氨基酸序列。
在一个进一步的实施方案中,抗体与细胞毒素剂缀合。在一个此类实施方案中,细胞毒素剂是auristatin。在另一个此类实施方案中,细胞毒素剂是类美登素(maytansinoid)药物部分。
在一个进一步的实施方案中,当在40℃贮存4周时,与在5℃贮存6个月比较,抗体显示<25%的抗原结合丧失。
在一个进一步的实施方案中,制剂包括20mM浓度的组氨酸-乙酸盐缓冲液。在一个进一步的实施方案中,制剂包括20mM浓度的组氨酸-盐酸盐缓冲液。在一个进一步的实施方案中,制剂包括以60mM-250mM量存在的选自海藻糖和蔗糖的糖。在一个进一步的实施方案中,制剂包括0.01%-0.1%量的聚山梨酸酯20。
上述实施方案中的任何实施方案都可以单独或组合存在。
在另一个方面,提供了治疗癌症的方法,该方法包括给哺乳动物施用如上文提供的任何实施方案中的包含抗STEAP-1抗体的制剂。
在一个进一步的方面,提供了抑制包括Asp-Asp基序的治疗性蛋白质中的天冬氨酰异构化的方法,其中该治疗性蛋白质包含在制剂中,该方法包括使制剂的pH升高至足以抑制天冬氨酰异构化的pH。在一个实施方案中,治疗性蛋白质是如上文提供的任何实施方案中的抗体。
附图简述
图1显示来自人、小鼠和食蟹猴的STEAP-1氨基酸序列的比对。
图2A和2B分别显示来自某些抗STEAP-1抗体的VL和VH结构域的氨基酸序列。
图3显示,如实施例A中所述,在40℃贮存不同时间段后,由pH 5.5的抗STEAP-1抗体制剂的离子交换层析得到的洗脱曲线。
图4显示胰蛋白酶消化肽图谱,指出异Asp的存在,如实施例B中所述。
图5显示电子转移解离-质谱(ETD-MS)的结果,这鉴定到经历异构化的特定Asp残基,如实施例B中所述。
图6显示,在40℃贮存4周的抗STEAP-1抗体制剂显示出了抗原结合的丧失。具有增加的pH的制剂在40℃显示出减少的结合丧失。当制剂在5℃贮存6个月时,在测试的任何pHs,未观察到结合丧失。
图7显示在40℃贮存各个时间段后,包含异Asp(iso-Asp)和琥珀酰亚胺的抗体的存在,如通过疏水相互作用层析检测的。
图8显示在各种温度贮存各个时间段后,在抗STEAP-1抗体制剂中的异Asp和琥珀酰亚胺量(以百分比表示),如实施例D中所述。
图9提出关于Asp至异Asp的反应的一级动力学。
图10显示在各种温度测定的Asp至异Asp异构化的速率,如实施例E中所述。
图11显示使用来自图10的速率的阿累尼乌斯(Arrhenius)曲线图。曲线图预测Asp-Asp异构化的活化能是约25-30Kcal/mol。
实施方案详述
I.定义
术语“制剂”指包含活性成分的制品,其不包含对制剂将施用于的受试者具有不能接受的毒性的其它组分。制剂一般是无菌的。
“无菌”制剂是无菌的或不含所有活微生物及其孢子。
此处,“冷冻”制剂是在低于0℃的温度的制剂。一般地,冷冻制剂不是冷冻干燥的,不经历先前或随后的冻干。优选地,冷冻制剂包括用于贮存(例如在不锈钢罐、PETG瓶和Bioprocess ContainerTM贮存系统(Hyclone,Logan,UT)中)的冷冻药物物质,或冷冻药物产品(在最终的小瓶结构中)。
“稳定”制剂指这样的制剂,在贮存后在该制剂中的蛋白质基本上保留物理稳定性和/或化学稳定性和/或生物学活性。优选地,在贮存后蛋白质基本上保留物理和化学稳定性、以及生物学活性。贮存期一般基于制剂的预期保存期限进行选择。用于测量蛋白质稳定性的各种分析技术是本领域可获得的,并且综述在例如Peptide and Protein DrugDelivery,247-301,Vincent Lee编辑,Marcel Dekker,Inc.,New York,New York,Pubs.(1991)和Jones,A.Adv.Drug Delivery Rev.10:29-90(1993)中。稳定性可以在选择的温度经过选择的时间段进行测量。优选地,制剂在约40℃稳定至少约2-4周;和/或在约5℃和/或15℃稳定至少3个月,优选1-2年;和/或在约-20℃稳定至少3个月,优选至少1-2年。此外,制剂优选在制剂的冷冻(至例如-70℃)和融化后是稳定的,例如在1、2或3个冻融循环后。稳定性可以以各种不同方法进行定性和/或定量评估,包括聚集物形成的评估(例如使用尺寸排阻层析、通过测量浊度、和/或通过目视检查);通过使用阳离子交换层析或毛细管区带电泳,评估电荷异质性;氨基末端或羧基末端序列分析;质谱分析;SDS-PAGE分析,以比较还原的和完整的抗体;肽图(例如胰蛋白酶消化肽图或Lys-C肽图)分析;评估抗体的生物活性或抗原结合功能;等。不稳定性可以涉及下述中的任何一种或多种:聚集、脱酰胺(例如Asn脱酰胺)、氧化(例如Met氧化)、异构化(例如Asp异构化)、剪切/水解/断裂(例如铰链区断裂)、琥珀酰亚胺形成、一个或多个不配对半胱氨酸、N末端延长、C末端加工、糖基化差异,等。具有“改善稳定性”的制剂意指,相对于在不同制剂中的蛋白质,在贮存后在该稳定性改善的制剂中包含的蛋白质保留更大的物理稳定性和/或化学稳定性和/或生物学活性。
“天冬氨酰异构化”指在蛋白质中的Asp残基转换为异天冬氨酸。
“Asp-Asp”或“DD”基序指蛋白质中的2个连续天冬氨酸残基。
“抑制天冬氨酰异构化”及其语法变体意指,包含在给定pH(例如6.5)的给定制剂中的蛋白质在Asp-Asp上的天冬氨酰异构化,相对于包含在较低pH(例如5.5)的相同制剂中的该蛋白质在Asp-Asp上的天冬氨酰异构化水平而言,被部分或全部抑制。天冬氨酰异构化的抑制可以直接测定,例如通过使用HIC定量异Asp而直接测定,或可以间接测定,例如通过定量蛋白质的生物活性而间接测定。在一个实施方案中,在Asp-Asp上的天冬氨酰异构化被抑制至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或100%。
“治疗性蛋白质/治疗蛋白”是在具有疾病或病理状态的哺乳动物的治疗中使用的蛋白质。本文公开的治疗抗体包括抗STEAP-1抗体。
除非另有说明,术语“STEAP-1”指来自任何脊椎动物来源,包括哺乳动物例如灵长类(例如人和猴)和啮齿类(例如小鼠和大鼠)来源,的任何天然STEAP-1。该术语包含“全长”、未加工STEAP-1,以及由细胞中的加工而产生的任何形式的STEAP-1。该术语还包含天然存在的STEAP-1变体,例如剪接变体或等位基因变体。来自人、小鼠和食蟹猴的示例性STEAP-1显示于图1中。
抗体的“生物活性”指抗体与抗原结合的能力。
“等渗的”意指目的制剂具有与人血液基本上相同的渗透压。等渗制剂一般将具有约250-350mOsm的渗透压。等渗性可以使用例如蒸气压或冰冻型渗透压计进行测量。
如本文使用的,“缓冲液”指通过其酸-碱共轭成分的作用来抵抗pH的改变的缓冲溶液。此类缓冲液的例子包括乙酸盐、琥珀酸盐、葡糖酸盐、组氨酸、柠檬酸盐、甘氨酰甘氨酸及其他有机酸缓冲液。
“组氨酸缓冲液”是包括组氨酸离子的缓冲液。组氨酸缓冲液的例子包括组氨酸盐酸盐、组氨酸乙酸盐、组氨酸磷酸盐和组氨酸硫酸盐。组氨酸乙酸盐缓冲液可以通过用乙酸(液体)滴定L-组氨酸(游离碱,固体)进行制备。
“糖”(saccharide)在本文中包括一般组成(CH2O)n及其衍生物,包括单糖、二糖、三糖、多糖、糖醇、还原糖、非还原糖,等。糖在本文中的例子包括葡萄糖、蔗糖、海藻糖、乳糖、果糖、麦芽糖、葡聚糖(dextran)、丙三醇、右旋糖酐(dextran)、赤藓醇、甘油、阿拉伯糖醇、sylitol(木糖醇)、山梨糖醇、甘露糖醇、mellibiose(蜜二糖)、松三糖、棉子糖、甘露三糖、水苏糖、麦芽糖、乳果糖、麦芽酮糖、葡萄糖醇、麦芽糖醇、乳糖醇、异麦芽酮糖等。在本文中糖可以是非还原二糖,例如海藻糖或蔗糖。
“表面活性剂”指表面活性物质,优选非离子型表面活性剂。表面活性剂在本文中的例子包括聚山梨酸酯(例如聚山梨酸酯20和聚山梨酸酯80);泊洛沙姆(例如泊洛沙姆188);Triton;十二烷基硫酸钠(SDS);月桂基硫酸钠;辛基糖苷钠;月桂基-、肉豆蔻基-、亚油基-(linoleyl)或硬脂基-磺基甜菜碱;月桂基、肉豆蔻基、亚油基或硬脂基-肌氨酸;亚油基、肉豆蔻基、或鲸蜡基甜菜碱;月桂酰胺基丙基、椰油酰胺基丙基、亚油酰胺基丙基、肉豆蔻酰胺基丙基、palmidopropyl(棕榈酰胺基丙基)或异硬脂酰胺基丙基-甜菜碱(例如月桂酰胺丙基);肉豆蔻酰胺丙基、palmidopropyl(棕榈酰胺丙基)或异硬脂酰胺丙基-二甲胺;甲基椰油酰基牛磺酸钠或甲基油酰基牛磺酸二钠;和MONAQUATTM系列(Mona Industries,Inc.,Paterson,New Jersey);聚乙二醇、聚丙二醇、以及乙二醇和丙二醇的共聚物(例如Pluronics、PF68等);等。
术语“约”就数值而言指该数值加或减5%。
术语“抗体”在本文中以最广泛含义使用,并且尤其地涵盖全长单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们显示所需生物活性。
如本文使用的,术语“单克隆抗体”指得自基本上同质抗体群体的抗体,即,除在单克隆抗体的产生过程中可能出现的可能变异外,群体包括的各个体抗体是相同的和/或结合相同表位,其中所述变异一般以极少量存在。与一般包括针对不同决定簇(表位)的不同抗体的多克隆抗体制品形成对比,每种单克隆抗体针对抗原上的单个决定簇。除其特异性外,单克隆抗体还是有利的,因为它们无其他免疫球蛋白污染。修饰词“单克隆”指抗体得自基本上同质的抗体群的特征,其不应解释为要求通过任何特定方法来产生该抗体。例如,依照本发明使用的单克隆抗体可以通过首先由Kohler等人,Nature,256:495(1975)描述的杂交瘤方法进行制备,或可以通过重组DNA方法进行制备(参见例如,美国专利号4,816,567)。“单克隆抗体”还可以使用例如Clackson等人,Nature,352:624-628(1991)和Marks等人,J.Mol Biol,222:581-597(1991)中描述的技术从噬菌体抗体文库分离。
单克隆抗体在本文中特别包括“嵌合”抗体,其中重和/或轻链的一部分与衍生自特定种类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,而一条或多条链的其余部分与衍生自另一个种类或属于另一个抗体种类或亚类的抗体中的相应序列相同或同源;以及此类嵌合抗体的片段,只要它们显示所需生物活性(美国专利号4,816,567;和Morrison等人,Proc.Natl.Acad.ScL USA,81:6851-6855(1984))。目的嵌合抗体在本文中包括“灵长类化(primatized)”抗体,其包括衍生自非人灵长类(例如旧大陆猴、类人猿等)的可变结构域抗原结合序列和人恒定区序列。
“抗体片段”包括包含抗体的抗原结合区的全长抗体的部分。抗体片段的例子包括Fab、Fab'、F(ab')2和Fv片段;双抗体(diabody);线性抗体;单链抗体分子;和由一或多个抗体片段形成的多特异性抗体。
“全长抗体”是包括抗原结合可变区以及轻链恒定结构域(CL)和重链恒定结构域CH1、CH2和CH3的抗体。恒定结构域可以是天然序列恒定结构域(例如人天然序列恒定结构域)或其氨基酸序列变体。在特定实施方案中,全长抗体具有一种或多种效应子功能。
“氨基酸序列变体”抗体在本文中是具有不同于参考抗体的氨基酸序列的抗体。通常,氨基酸序列变体与参考抗体具有至少约70%同源性,并且优选地,与参考抗体至少约80%、更优选地至少约90%同源。相对于参考抗体,氨基酸序列变体具有在某些位置上的置换、缺失和/或添加。在本文中氨基酸序列变体的例子包括酸性变体(例如脱酰胺的抗体变体)、碱性变体、在其一条或两条轻链上具有氨基末端前导区延长(例如VHS-)的抗体、在其一条或两条重链上具有C末端赖氨酸残基的抗体等,并且包括重和/或轻链的氨基酸序列的变异的组合。在一个实施方案中,相对于参考抗体,抗体变体包括在其一条或两条轻链上的氨基末端的前导区延长,任选地进一步包括其他氨基酸序列和/或糖基化差异。
“糖基化变体”抗体在本文中是指具有附着的一个或多个糖部分的抗体,该附着的糖部分与附着在参考抗体上的一个或多个糖部分是不同的。糖基化变体在本文中的例子包括具有与其Fc区附着的G1或G2寡糖结构而非G0寡糖结构的抗体,具有与其一条或两条轻链附着的一个或两个糖部分的抗体,抗体的一条或两条重链无糖附着的抗体等、和糖基化改变的组合。
“氨基末端前导区延长”在本文中指一个或多个氨基酸残基的氨基末端前导序列,其存在于抗体的任何一条或多条重或轻链的氨基末端上。示例性氨基末端前导区延长包括3个氨基酸残基VHS或由该3个氨基酸残基VHS组成,其存在于抗体变体的一条或两条轻链上。
“同源性”定义为,在比对序列以及在需要时引入空位以达到最大限度同源性百分比后,氨基酸序列变体中的相同残基的百分比。用于比对的方法和计算机程序是本领域众所周知的。一个此类计算机程序是Genentech,Inc.的“Align 2”,这于1991年12月10日连同用户文档提交给United States Copyright Office,Washington,DC 20559。
抗体“效应子功能”指可归于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应子功能的例子包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如B细胞受体;BCR)的下调,等。
根据抗体重链恒定结构域的氨基酸序列,全长抗体可以分为不同“类别”。有5个主要类别的全长抗体:IgA、IgD、IgE、IgG和IgM,并且这些类别中的一些可以进一步分成“亚类”(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA和IgA2。对应于不同类别抗体的重链恒定结构域分别被称为α、δ、ε、γ和μ。不同类别免疫球蛋白的亚基结构和三维构型是众所周知的。
“抗体依赖性细胞介导的细胞毒性”和“ADCC”指细胞介导的反应,其中表达Fc受体(FcRs)的非特异性细胞毒性细胞(例如天然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)识别靶细胞上的结合抗体,并且随后引起该靶细胞的裂解。介导ADCC的主要细胞,NK细胞,仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。造血细胞上的FcR表达总结在Ravetch和Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页的表3中。为了评估目的分子的ADCC活性,可以执行体外ADCC测定试验,例如美国专利号5,500,362或5,821,337中描述的试验。用于此类测定的有用效应细胞包括外周血单核细胞(PBMC)和天然杀伤(NK)细胞。可替代地或另外地,目的分子的ADCC活性可以在体内进行评估,例如在动物模型中,例如Clynes等人PNAS(USA)95:652-656(1998)中公开的动物模型。
“人效应细胞”是表达一种或多种FcRs且执行效应子功能的白细胞。优选地,细胞表达至少FcγRIII,并且执行ADCC效应子功能。介导ADCC的人白细胞的例子包括外周血单核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和嗜中性粒细胞;其中PBMCs和NK细胞是优选的。效应细胞可以从其天然来源中分离,例如如本文描述的从血液或PBMCs中分离。
术语“Fc受体”或“FcR”用于描述与抗体的Fc区结合的受体。在一个实施方案中,FcR是天然序列人FcR。此外,优选结合IgG抗体的FcR(γ受体),包括FcγRI、FcγRII和FcγRIII亚类的受体,包括这些受体的等位变体和可变剪接形式。FcγRII受体包括FcγRIIA(“激活受体”)和FcγRIIB(“抑制受体”),其具有主要在其细胞质结构域中不同的相似氨基酸序列。激活受体FcγRIIA在其细胞质结构域中包含免疫受体酪氨酸基激活基序(ITAM)。抑制受体FcγRIIB在其细胞质结构域中包含免疫受体酪氨酸基抑制基序(ITIM)(参见综述M.in Daeron,Annu.Rev.Immunol.15:203-234(1997))。FcRs在Ravetch和Kinet,Annu.Rev.Immunol 9:457-92(1991);Capel等人,Immunomethods 4:25-34(1994);和deHaas等人,J.Lab.Clin.Med.126:330-41(1995)中综述。其他FcRs,包括将来鉴定的那些,也涵盖在本文的术语“FcR”中。该术语还包括负责将母体IgG转移给胎儿的新生儿受体,FcRn(Guyer等人,J.Immunol.117:587(1976)和Kim等人,J.Immunol.24:249(1994))。
“补体依赖性细胞毒性”或“CDC”指分子在补体的存在下裂解靶的能力。补体激活途径由补体系统的第一组分(C1q)结合到与关联抗原复合的分子(例如抗体)上而起始。为了评估补体激活作用,可以执行例如如Gazzano-Santoro等人,J.Immunol.Methods 202:163(1996)中所述的CDC测定试验。
“天然抗体”通常是由2条相同轻(L)链和2条相同重(H)链组成的约150,000道尔顿的异四聚体糖蛋白。每条轻链通过一个共价二硫键与重链连接,而在不同免疫球蛋白同种型的重链中二硫键的数目是不同的。每条重和轻链还具有规则间隔的链内二硫桥。每条重链在一个末端上具有可变结构域(VH),随后为多个恒定结构域。每条轻链在一个末端上具有可变结构域(VL),并且在其另一个末端上具有恒定结构域。轻链的恒定结构域与重链的第一个恒定结构域对齐,并且轻链可变结构域与重链的可变结构域对齐。特定氨基酸残基被认为形成轻链和重链可变结构域之间的界面。
术语“可变”指下述事实:可变结构域的某些部分在抗体之间序列变化很大,其用于每种具体抗体对其特定抗原的结合和特异性上。然而,变异性在抗体可变结构域上不是均匀分布的。在轻链和重链可变结构域中它集中在称为高变区的3个区段中。可变结构域的较为高度保守的部分称为构架区(FRs)。天然重和轻链的可变结构域各自包括4个FRs,大部分采用β折叠构型,由形成环的3个高变区连接,这些环连接所述β折叠结构,并且在某些情况下构成β折叠结构的一部分。每条链中的高变区通过FRs紧密靠近在一起,并且与来自另一条链的高变区一起促成抗体的抗原结合位点的形成(参见Kabat等人,Sequences ofProteins of Immunological Interest,第5版Public Health Service,NationalInstitutes of Health,Bethesda,MD.(1991))。恒定结构域不直接参与抗体与抗原的结合,但显示各种效应子功能,例如在抗体依赖性细胞毒性(ADCC)中抗体的参与。
如本文使用的,术语“高变区”或“HVR”,也称为“互补决定区”或“CDR”,指主要负责抗原结合的抗体氨基酸残基。其一般是重链中的3个HVRs(HVR-H1、HVR-H2和HVR-H3)和轻链中的3个HVRs(HVR-L1、HVR-L2和HVR-L3)。在某些实施方案中,高变区包括轻链可变结构域中的氨基酸残基24-34(HVR-L1)、50-56(HVR-L2)和89-97(HVR-L3),和重链可变结构域中的氨基酸残基31-35(HVR-H1)、50-65(HVR-H2)和95-102(HVR-H3)(Kabat等人,Sequences ofProteins of Immunological Interest,第5版Public Health Service,NationalInstitutes of Health,Bethesda,MD.(1991))。HVR-H3被认为在对抗体赋予精细特异性方面起独特作用。参见例如,Xu等人(2000)Immunity 13:37-45;Johnson和Wu(2003)inMethods in Molecular Biology 248:1-25(Lo,编辑Human Press,Totowa,NJ)。“构架区”或“FR”残基是除本文定义的高变区残基外的那些可变结构域残基。
抗体的木瓜蛋白酶消化,产生2个相同的抗原结合片段(称为“Fab”片段,各自具有单个抗原结合位点)和一个残留“Fc”片段(其名称反映其容易结晶的能力)。胃蛋白酶消化,产生F(ab')2片段,其具有2个抗原结合位点并且仍能够交联抗原。
“Fv”是包含完整抗原识别和抗原结合位点的最小抗体片段。这个区域由紧密非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。在这种构型中每个可变结构域的3个高变区相互作用,在该VH-VL二聚体表面上限定出抗原结合位点。共同地,6个高变区对抗体赋予抗原结合特异性。然而,即使单个可变结构域(或仅包括对抗原特异的3个高变区的Fv的一半)也具有识别且结合抗原的能力,尽管与完整的结合位点相比具有较低的亲和力。
Fab片段还包含轻链的恒定结构域和重链的第一个恒定结构域(CH1)。Fab'片段与Fab片段的差异在于重链CH1结构域的羧基末端上添加了少数残基,包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH在本文中用于指如下Fab',在该Fab’中恒定结构域的半胱氨酸残基(一个或多个)具有至少一个游离巯基。F(ab')2抗体片段最初作为在之间具有铰链半胱氨酸的Fab'片段对而产生。抗体片段的其他化学偶联也是已知的。
基于恒定结构域的氨基酸序列,来自任何脊椎动物物种的抗体的“轻链”可以被归类至称为kappa(κ)和lambda(λ)的2个明确不同类型之一。
“单链Fv”或“scFv”抗体片段包括抗体的VH和VL结构域,其中这些结构域存在于单条多肽链中。优选地,Fv多肽进一步包括在VH和VL结构域之间的多肽接头,该接头使得scFv能够形成用于抗原结合的所需结构。关于scFv的综述,参见Plückthun in ThePharmacology of Monoclonal Antibodies,第113卷,Rosenburg和Moore编辑,Springer-Verlag,New York,第269-315页(1994)。
术语“双抗体”指具有2个抗原结合位点的小抗体片段,所述片段包括在相同多肽链(VH-VL)中与可变轻结构域(VL)连接的可变重结构域(VH)。通过使用太短而不允许相同链上的这2个结构域之间形成配对的接头,这些结构域被迫与另一条链的互补结构域配对,产生2个抗原结合位点。双抗体在例如EP 404,097;WO 93/11161;和Hollinger等人,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)中更充分地描述。
非人(例如啮齿类)抗体的“人源化”形式是包含衍生自非人免疫球蛋白的最少序列的嵌合抗体。就大部分而言,人源化抗体是人免疫球蛋白(接受者抗体),其中来自接受者高变区的残基被来自具有所需特异性、亲和力和/或能力的非人供体抗体的高变区的残基替换,所述非人供体抗体例如为合成抗体或小鼠、大鼠、兔或非人灵长类抗体。在某些情况下,人免疫球蛋白的构架区(FR)残基由相应非人残基替换。此外,人源化抗体可以包括在接受者抗体和供体抗体中不存在的残基。可以进行这些修饰以进一步精化抗体性能。一般而言,人源化抗体将包括至少一个且一般2个可变结构域的基本上所有,其中所有或基本上所有高变环对应于非人免疫球蛋白的高变环,而所有或基本上所有FRs是人免疫球蛋白序列的。人源化抗体任选地还可以包括至少部分的免疫球蛋白恒定区(Fc),一般是人免疫球蛋白的恒定区。关于进一步细节,参见Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-329(1988);和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
“裸抗体”是不与异源分子,例如细胞毒性部分或放射性标记,缀合的抗体(如本文定义的)。
“亲和力成熟”抗体是在其一个或多个高变区中具有一个或多个改变的抗体,其中所述改变导致,与不具有该改变的亲本抗体比较,抗体对于抗原的亲和力的改善。优选的亲和力成熟抗体对于靶抗原具有纳摩尔或甚至皮摩尔亲和力。亲和力成熟抗体可以通过本领域已知的方法产生。Marks等人Bio/Technology 10:779-783(1992)描述了通过VH和VL结构域改组的亲和力成熟。CDR和/或构架残基的随机诱变由Barbas等人Proc Nat.Acad.Sci,USA 91:3809-3813(1994);Schier等人Gene 169:147-155(1995);Yelton等人J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-9(1995);和Hawkins等人,J.Mol.Biol.226:889-896(1992)描述。
“激动剂抗体”是与受体结合且激活受体的抗体。一般地,激动剂抗体的受体激活能力将至少在性质上类似于(且可能基本上在量上类似于)受体的天然激动剂配体。
“分离的”抗体是已得到鉴定且从其天然环境的组分中分开和/或回收的抗体。其天然环境中的污染组分是将干扰抗体的诊断或治疗用途的物质,并且可以包括酶、激素和其他蛋白质性质或非蛋白质性质的溶质。在特定实施方案中,抗体纯化至(1)如通过Lowry法测定的,95%重量以上的抗体,并且最优选99%重量以上,(2)通过使用转杯式序列分析仪足以获得至少15个残基的N末端或内部氨基酸序列的程度,或(3)使用考马斯蓝或银染色在还原或非还原条件下通过SDS-PAGE,或优选通过CE-SDS和荧光染色,为同质的。分离的抗体包括在重组细胞内的原位抗体,因为不存在抗体的天然环境中的至少一种组分。然而,通常,分离的抗体通过至少一个纯化步骤进行制备。
“生长抑制剂”,当在本文中使用时,指在体外或体内,抑制细胞,例如STEAP-1表达性癌细胞,生长的化合物或组合物。因此,生长抑制剂可以是显著减少在S期中的STEAP-1表达细胞的百分比的物质。生长抑制剂的例子包括阻断细胞周期进展(在除S期外的位置)的物质,例如诱导G1停滞和M期停滞的物质。经典M期阻断剂包括长春花生物碱类(vincas)(长春花新碱和长春花碱)、紫杉烷类和拓扑II抑制剂,例如多柔比星、表柔比星、柔红霉素、依托泊苷和博来霉素。停滞G1的物质也可过溢到S期停滞,例如DNA烷化剂例如他莫西芬、泼尼松、达卡巴嗪、氮芥、顺铂、氨甲蝶呤、5-氟尿嘧啶和阿糖胞苷。进一步信息可以在MolecularBasis of Cancer,Mendelsohn and Israel,编辑,Murakami等人(WB Saunders:Philadelphia,1995)著的名称为"Cell cycle regulation,oncogenes,andantineoplastic drugs"的第1章,特别是第13页中找到。
“诱导细胞凋亡”的抗体是诱导程序性细胞死亡的抗体,程序性细胞死亡可以如通过膜联蛋白V的结合、DNA片段化、细胞收缩、内质网膨胀、细胞碎裂和/或膜囊泡(称为凋亡小体)的形成来确定。所述细胞通常是表达与抗体结合的抗原(例如STEAP-1)的细胞。在一个实施方案中,细胞是肿瘤细胞。例如,磷脂酰丝氨酸(PS)易位可以通过膜联蛋白结合进行测量;DNA片段化可以通过DNA梯(laddering)进行评估;细胞核/染色质浓缩连同DNA片段化可以通过亚二倍体细胞的任何增加进行评估。在特定实施方案中,诱导凋亡的抗体是这样的,在膜联蛋白结合测定试验中,使用表达与抗体结合的抗原的细胞,相对于未处理细胞,该抗体导致约2-50倍、优选约5-50倍、且更优选约10-50倍的膜联蛋白结合诱导。
“治疗”指治疗性处理以及防止性或预防性措施。需要治疗的受试者包括已具有疾病的那些以及待预防疾病的那些。因此,本文中待治疗的患者可以已诊断为具有疾病或可以易患疾病或对疾病易感。
术语“癌”和“癌性”是指或描述的是:典型特征在于不受调节的细胞生长的哺乳动物生理状况。癌症的例子包括但不限于癌、淋巴瘤、胚细胞瘤(包括成神经管细胞瘤和成视网膜细胞瘤)、肉瘤(包括脂肪肉瘤和滑膜细胞肉瘤)、神经内分泌肿瘤(包括类癌瘤、胃泌素瘤和胰岛细胞癌)、间皮瘤、神经鞘瘤(包括听神经瘤)、脑膜瘤、腺癌、黑素瘤和白血病或淋巴性恶性肿瘤。此类癌症的更具体例子包括鳞状细胞癌(例如上皮鳞状细胞癌),肺癌包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状癌,腹膜癌,肝细胞癌,胃癌(gastric cancer或stomach cancer),包括胃肠癌,胰腺癌,成胶质细胞瘤,宫颈癌,卵巢癌,肝癌,膀胱癌,肝瘤,乳腺癌,结肠癌,直肠癌,结肠直肠癌,子宫内膜或子宫癌,唾液腺癌,肾癌(kidneycancer或renal cancer),前列腺癌,外阴癌,甲状腺癌,肝癌,肛门癌,阴茎癌,睾丸癌,食管癌,胆道肿瘤,以及头颈癌。前列腺癌的特定例子包括雄激素不依赖性和雄激素依赖性前列腺癌。
术语“有效量”指有效治疗患者疾病的药物量。当疾病是癌症时,药物的有效量可以减少癌细胞数目;减少肿瘤大小;抑制(即减缓至某种程度且优选停止)癌细胞浸润到外周器官;抑制(即减缓至某种程度且优选停止)肿瘤转移;一定程度地抑制肿瘤生长;和/或一定程度地减轻与癌症相关的一种或多种症状。如果药物可以抑制(部分或全部)生长和/或杀死现有癌细胞,则其可以是细胞抑制性的和/或细胞毒性的。有效量可以延长无进展存活,导致客观应答(包括部分应答PR,或完全应答CR),增加总生存时间,和/或改善一种或多种癌症症状。
“STEAP-1表达性癌”是包括在其细胞表面上呈递STEAP-1蛋白质的细胞的癌症。“超表达”STEAP-1的STEAP-1表达性癌是与相同组织类型的非癌性细胞比较,在其细胞表面上具有显著更高水平的STEAP-1的癌症。此超表达可以因基因扩增或因增加的转录或翻译而引起。STEAP-1表达(或超表达)可以在诊断或预后试验中通过评估细胞表面上存在的STEAP-1水平进行确定(例如经由免疫组织化学试验;IHC)。可替代地或另外地,可以测量细胞中的STEAP-1编码核酸的水平,例如经由荧光原位杂交(FISH;参见1998年10月公开的WO98/45479)、DNA印迹或聚合酶链反应(PCR)技术例如实时定量PCR(RT-PCR)。通过测量生物学液体例如血清中存在的STEAP-1,例如通过检测在循环肿瘤细胞(CTCs)表面上存在的STEAP-1(参见例如,Schaffer等人,Clin.Cancer Res.13:2023-2029(2007),也可以研究STEAP-1表达。除上述测定试验外,多种体内测定试验也可以为本领域技术人员所用。例如,可以使患者体内的细胞暴露于抗体,所述抗体任选用可检测标记例如放射性同位素直接或间接标记;并可以,例如通过外部放射扫描或通过分析得自先前暴露过抗体的患者的活检组织,评估抗体与患者中的细胞的结合。
如本文使用的,术语“细胞毒素剂”指抑制或阻止细胞的功能和/或引起细胞破坏的物质。该术语意欲包括放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32和Lu的放射性同位素),化学治疗剂,以及毒素例如小分子毒素或细菌、真菌、植物或动物起源的酶学活性毒素,包括其片段和/或变体。
“化学治疗剂”是在癌症治疗中有用的化学化合物。化学治疗剂的例子包括烷化剂例如噻替派和环磷酰胺烷基磺酸盐例如白消安、英丙舒凡(Improsulfan)和哌泊舒凡(piposulfan);氮丙啶类,例如benzodopa、卡波醌、meturedopa(美妥替哌)和uredopa(乌瑞替派);乙烯亚胺类和methylamelamines,包括六甲蜜胺、三乙烯三聚氰胺、三乙烯磷酰胺、三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三甲基三聚氰胺(trimethylolomelamine);乙酰配基类(acetogenins)(特别是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));δ-9-四氢大麻酚(屈大麻酚(dronabinol),);β-拉伯醌(beta-lapachone);拉伯醇(lapachol);秋水仙碱(colchicines);白桦脂酸(betulinic acid);喜树碱(包括合成类似物托泊替康((topotecan,),CPT-11(伊立替康,)、乙酰喜树碱、scopolectin和9-氨基喜树碱);薯司他丁(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);pancratistatin;sarcodictyin;海绵抑制素(spongistatin);氮芥例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、cholophosphamide、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、氧化氮芥盐酸盐(mechlorethamineoxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、phenesterine、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲类,例如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、罗莫司汀(lomustine)、尼莫司汀(nimustine)和雷尼司汀(ranimnustine);抗生素,例如烯二炔类(enediyne)抗生素(例如加利车霉素,特别是加利车霉素γ1I和加利车霉素ωI1(参见例如,Agnew,Chem Intl.Ed.Engl,33:183-186(1994));达内霉素(dynemicin),包括达内霉素A;埃斯波霉素(esperamicin);以及新制癌菌素(neocarzinostatin)生色团和相关色蛋白烯二炔类抗生素生色团)、aclacinomysins、放线菌素(actinomycin)、氨茴霉素(authramycin)、重氮丝氨酸(azaserine)、博来霉素、cactinomycin、卡柔比星(carabicin)、洋红霉素(carminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycinis)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯琳多柔比星(2-pyrrolino-doxorubicin)、多柔比星HCl脂质体注射剂脂质体多柔比星TLCD-99聚乙二醇化脂质体多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类,例如丝裂霉素C、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、potfiromycin、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢药,例如氨甲蝶呤、吉西他滨替加氟(tegafur,)、卡培他滨(capecitabine,)、环氧噻唑酮(epothilone)、和5-氟尿嘧啶(5-FU);叶酸类似物,例如二价叶酸(denopterin)、氨甲蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);抗肾上腺药,例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如frolinic acid;乙酰葡醛酯(aceglatone);aldophosphamide glycoside;氨基酮戊酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利乙胺(elliptinium acetate);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲;香菇多糖(lentinan);lonidainine;类美登素,例如美登素(maytansine)和安丝菌素类(ansamitocins);米托胍腙(mitoguazone);米托蒽醌;mopidanmol;nitraerine;喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼;丙卡巴肼;多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);替奴佐酸(tenuazonicacid);三亚胺醌(triaziquone);2,2',2"-三氯乙胺;单端孢菌素类(trichothecenes)(特别是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素A(roridin A)和anguidine);乌拉坦(urethan);达卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside,"Ara-C");噻替派(thiotepa);紫杉类(taxoid),例如紫杉醇(paclitaxel,)、白蛋白改造的紫杉醇纳米颗粒制剂(ABRAXANETM)和多西他赛(docetaxel,);苯丁酸氮芥(chloranbucil);6-硫代鸟嘌呤;巯嘌呤;氨甲蝶呤;铂类药物,例如顺铂、奥沙利铂和卡铂;阻止微管蛋白聚集形成微管的长春花生物碱类,包括长春花碱、长春花新碱长春地辛和长春瑞滨依托泊苷(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);甲酰四氢叶酸(leucovovin);诺消灵(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);伊班膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维甲酸类例如维甲酸,包括贝沙罗汀(bexarotene,);双膦酸盐类,例如氯磷酸(clodronate)(例如或)、依替膦酸(etidronate)NE-58095、唑来膦酸/唑来膦酸盐(zoledronic acid/zoledronate)阿屈膦酸盐(alendronate)、帕玛二磷酸(pamidronate)、替鲁膦酸盐(tiludronate)或利塞膦酸盐(risedronate);曲沙他滨(troxacitabine)(1,3-二氧环戊烷核苷胞嘧啶类似物);反义寡核苷酸,特别是抑制参与异常细胞增殖的信号途径中的基因,例如PKC-α、Raf,H-Ras和表皮生长因子受体(EGF-R),表达的那些;疫苗,例如疫苗和基因治疗疫苗,例如疫苗、疫苗和疫苗;拓扑异构酶1抑制剂(例如);rmRH(例如);BAY439006(索拉非尼(sorafenib);Bayer);SU-11248(Pfizer);哌立福新(perifosine)、COX-2抑制剂(例如塞来昔布(celecoxib)或依托考昔(etoricoxib))、蛋白酶体抑制剂(例如PS341);硼替佐米(bortezomib);CCI-779;替吡法尼(tipifarnib(R11577));orafenib、ABT510;Bcl-2抑制剂,例如奥利默森钠(oblimersen sodium)pixantrone、EGFR抑制剂(参见下文定义);酪氨酸激酶抑制剂(参见下文定义);以及上述任何的药学上可接受盐、酸或衍生物;以及上述中的2种或更多种的组合,例如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙的联合治疗的缩写),和FOLFOX(奥沙利铂(ELOXATINTM)与5-FU和甲酰四氢叶酸组合的治疗方案的缩写)。
此定义中还包括:作用于调节或抑制激素对肿瘤的作用的抗激素剂,例如具有混合激动剂/拮抗剂谱的抗雌激素,包括它莫西芬4-羟基它莫西芬、托瑞米芬(toremifene,)、艾多昔芬(idoxifene)、屈洛昔芬(droloxifene)、雷洛昔芬(raloxifene,)、曲沃昔芬(trioxifene)、keoxifene,和选择性雌激素受体调节剂(SERMs)例如SERM3;不含激动剂性质的纯抗雌激素,例如氟维司群(fulvestrant,)和EM800(此类物质可以阻断雌激素受体(ER)二聚化,抑制DNA结合,增加ER周转,和/或抑制ER水平);芳香酶抑制剂,包括类固醇芳香酶抑制剂,例如福美坦(formestane)和依西美坦(exemestane)和非类固醇芳香酶抑制剂,例如阿那曲唑(anastrazole)来曲唑(letrozole,)和氨鲁米特,及其他芳香酶抑制剂,包括伏氯唑(vorozole,)、乙酸甲地孕酮法倔唑(fadrozole)、咪唑;促黄体激素释放激素激动剂,包括亮丙瑞林(leuprolide,和)、戈舍瑞林(goserelin)、布舍瑞林(buserelin)和曲普瑞林(tripterelin);性类固醇,包括孕酮类,例如乙酸甲地孕酮和乙酸甲羟孕酮,雌激素例如己烯雌酚和倍美力(premarin),和雄激素/维甲酸类例如氟甲睾酮(fluoxymesterone)、全反式维甲酸和芬维A胺(fenretinide);奥那司酮(onapristone);抗孕酮类(anti-progesterones);雌激素受体下调物(ERDs);抗雄激素,例如氟他胺(flutamide)、尼鲁米特(nilutamide)和比卡鲁胺(bicalutamide);睾内酯(testolactone);以及上述任何的药学上可接受的盐、酸或衍生物;以及上述中的2种或更多种的组合。
II.用于制剂的抗体和免疫缀合物
(A)方法和组合物
在一个方面,可以根据本发明配制的治疗蛋白质是包含Asp-Asp基序的蛋白质。在一个实施方案中,治疗蛋白质是抗体或免疫缀合物。此类抗体和免疫缀合物如下例示。
(i)抗原选择和制备
优选地,抗体与之结合的抗原是蛋白质,并且抗体施用于患有疾病或病症的哺乳动物可以在该哺乳动物中导致治疗益处。然而,还考虑针对非多肽抗原(例如肿瘤相关的糖脂抗原;参见美国专利5,091,178)的抗体。
当抗原是多肽时,它可以是跨膜分子(例如受体)或配体例如生长因子。示例性抗原包括分子例如肾素;生长激素包括人生长激素和牛生长激素;生长激素释放因子;甲状旁腺激素;促甲状腺激素;脂蛋白;α-1-抗胰蛋白酶;胰岛素A链;胰岛素B链;胰岛素原;促滤泡激素;降钙素;促黄体激素;胰高血糖素;凝血因子例如因子VIIIC、因子IX、组织因子(TF)和von Willebrands因子;抗凝血因子例如蛋白质C;心钠素;肺表面活性物质;纤溶酶原激活物例如尿激酶或人尿或组织型纤溶酶原激活物(t-PA);铃蟾肽;凝血酶;造血生长因子;肿瘤坏死因子-α和β;脑啡肽酶;RANTES(正常T细胞表达和分泌的活化调节因子);人巨噬细胞炎性蛋白质(MIP-1-α);血清白蛋白例如人血清白蛋白;Mullerian抑制物质;松弛素A链;松弛素B链;松弛素原;小鼠促性腺素相关肽;微生物蛋白质例如β-内酰胺酶;DNA酶;IgE;细胞毒性T淋巴细胞相关抗原(CTLA),例如CTLA-4;抑制素;活化素;血管内皮生长因子(VEGF);激素或生长因子的受体;蛋白质A或D;类风湿因子;神经营养因子例如骨衍生的神经营养因子(BDNF)、神经营养蛋白-3、-4、-5或-6(NT-3、NT-4、NT-5或NT-6),或神经生长因子例如NGF-b;血小板衍生的生长因子(PDGF);成纤维细胞生长因子例如aFGF和bFGF;表皮生长因子(EGF);转化生长因子(TGF)例如TGF-α和TGF-β,包括TGF-b1、TGF-b2、TGF-b3、TGF-b4或TGF-b5;肿瘤坏死因子(TNF)例如TNF-α或TNF-β;胰岛素样生长因子-I和-II(IGF-I和IGF-II);des(1-3)-IGF-I(脑IGF-I),胰岛素样生长因子结合蛋白;CD蛋白例如CD3、CD4、CD8、CD19、CD20、CD22和CD40;促红细胞生成素;骨诱导因子;免疫毒素;骨形态发生蛋白(BMP);干扰素例如干扰素-α、-β和-γ;集落刺激因子(CSFs),例如M-CSF、GM-CSF和G-CSF;白介素(ILs),例如IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9和IL-10;超氧化物歧化酶;T细胞受体;表面膜蛋白质;衰变加速因子;病毒抗原例如AIDS包膜的部分;转运蛋白质;归巢受体;地址素;调节性蛋白质;整联蛋白例如CD11a、CD11b、CD11c、CD18、ICAM、VLA-4和VCAM;肿瘤相关抗原例如HER2、HER3或HER4受体;和上文列出的任何多肽的片段。
本发明抗体的示例性分子靶标包括CD蛋白例如CD3、CD4、CD8、CD19、CD20、CD22、CD34和CD40;ErbB受体家族成员例如EGF受体,HER2、HER3或HER4受体;B细胞表面抗原例如CD20或BR3;肿瘤坏死因子超家族成员,包括DR5;前列腺细胞表面抗原,例如膜联蛋白2、钙粘着蛋白-1、Cav-1、Cd34、CD44、EGFR、EphA2、ERGL、Fas、hepsin、HER2、KAI1、MSR1、PATE、PMEPA-1、Prostasin、Prostein、PSCA、PSGR、PSMA、RTVP-1、ST7、STEAP-1、STEAP-2、TMPRSS2、TRPM2和Trp-p8;细胞粘附分子例如LFA-1、Mac1、p150.95、VLA-4、ICAM-1、VCAM、α4/β7整联蛋白,和αv/β3整联蛋白,包括其α或β亚单位(例如抗CD11a、抗CD18或抗CD11b抗体);生长因子例如VEGF以及其受体;组织因子(TF);肿瘤坏死因子(TNF)例如TNF-α或TNF-β,α干扰素(α-IFN);白介素例如IL-8;IgE;血型抗原;fik2/flt3受体;肥胖(OB)受体;mpl受体;CTLA-4;蛋白质C等。
可溶性抗原或其片段,任选地与其他分子缀合,可以用作免疫原用于生成抗体。对于跨膜分子例如受体,其片段(例如受体的细胞外结构域)可以用作免疫原。可替代地,表达跨膜分子的细胞可以用作免疫原。此类细胞可以源自天然来源(例如癌细胞系),或可以是已通过重组方法转化以表达该跨膜分子的细胞。对于制备抗体有用的其他抗原及其形式对于本领域技术人员是显而易见的。
对于抗STEAP-1抗体的产生,STEAP-1抗原可以是例如STEAP-1的可溶形式、STEAP-1的细胞外环、或包含所需表位的其部分。可替代地,在细胞表面上表达STEAP-1的细胞(例如用编码STEAP-1的载体转化的293T细胞)可以用于生成抗体(参见例如Challita-Eid等人Cancer Res.67:5798-805(2007))。
(ii)单克隆抗体
单克隆抗体得自基本上同质的抗体群体,即群体中各个体抗体是相同的和/或结合相同表位,除了在单克隆抗体的产生过程中可能出现的可能变异外。因此,修饰词“单克隆”是指,该抗体不是不同抗体的混合物的特征。
例如,单克隆抗体可以通过首先由Kohler等人,Nature,256:495(1975)描述的杂交瘤方法进行制备,或可以通过重组DNA方法进行制备(美国专利号4,816,567)。在杂交瘤方法中,小鼠或其他合适的宿主动物例如仓鼠如上所述进行免疫接种,以引发产生或能够产生抗体的淋巴细胞,所述抗体将与用于免疫接种的蛋白质特异性结合。可替代地,可以在体外免疫淋巴细胞。随后使用合适的融合试剂例如聚乙二醇,使淋巴细胞与骨髓瘤细胞融合,以形成杂交瘤细胞(Goding,Monoclonal Antibodies:Principles和Practice,第59-103页(Academic Press,1986))。
在合适培养基中种植且生长由此制备的杂交瘤细胞,所述培养基优选包含抑制未融合的亲本骨髓瘤细胞生长或存活的一种或多种物质。例如,如果亲本骨髓瘤细胞缺乏酶次黄嘌呤鸟嘌呤磷酸核糖基转移酶(HGPRT或HPRT),那么用于杂交瘤的培养基一般将包括次黄嘌呤、氨甲蝶呤和胸苷(HAT培养基),所述物质阻止HGPRT缺陷细胞的生长。
优选骨髓瘤细胞可以有效融合,支持选择的抗体生产细胞稳定高水平地产生抗体,并且对培养基例如HAT培养基敏感。其中,优选的骨髓瘤细胞系是鼠源骨髓瘤系,例如源自可从Salk Institute Cell Distribution Center,San Diego,California USA获得的MOPC-21和MPC-11小鼠肿瘤的那些,以及可从美国典型培养物中心,Rockville,MarylandUSA获得的SP-2或X63-Ag8-653细胞。用于产生人单克隆抗体的人骨髓瘤和小鼠-人杂合骨髓瘤细胞系也已得到描述(Kozbor,J.Immunol,133:3001(1984);和Brodeur等人,Monoclonal Antibody Production Techniques and Applications,第51-63页(MarcelDekker,Inc.,New York,1987))。
在用于生长杂交瘤细胞的培养基上,测定针对抗原的单克隆抗体的产生。优选地,通过免疫沉淀或通过体外结合测定试验,例如放射性免疫测定(RIA)或酶联免疫吸附测定(ELISA),测定杂交瘤细胞产生的单克隆抗体的结合特异性。单克隆抗体的结合亲和性可以例如通过Munson等人,Anal.Biochem.,107:220(1980)的Scatchard分析进行测定。
在鉴定产生所需特异性、亲和力和/或活性的抗体的杂交瘤细胞后,克隆可以通过有限稀释程序进行亚克隆,并且通过标准方法进行生长(Goding,Monoclonal Antibodies:Principles and Practice,第59-103页(Academic Press,1986))。用于这个目的的合适培养基包括例如D-MEM或RPMI-1640培养基。此外,杂交瘤细胞可以作为动物中的腹水肿瘤在体内生长。由亚克隆分泌的单克隆抗体可以通过常规抗体纯化程序从培养基、腹水或血清中适当地分离,所述常规抗体纯化程序例如蛋白质A-Sepharose、羟基磷灰石层析、凝胶电泳、透析或亲和层析。
编码单克隆抗体的DNA可以使用常规程序(例如通过使用能够与编码鼠抗体的重和轻链的基因特异性结合的寡核苷酸探针)容易地分离且测序。杂交瘤细胞可以充当此类DNA的优选来源。一旦分离,DNA可以置于表达载体内,所述表达载体随后转染到原来不产生抗体蛋白质的宿主细胞例如大肠杆菌细胞、猿COS细胞、中国仓鼠卵巢(CHO)细胞或骨髓瘤细胞内,以在重组宿主细胞中获得单克隆抗体的合成。关于编码抗体的DNA在细菌中的重组表达的综述文章包括Skerra等人,Curr.Opinion in Immunol,5:256-262(1993)和Plückthun,Immunol.Revs.,130:151-188(1992)。
在再一实施方案中,单克隆抗体或抗体片段可以从使用如下技术生成的抗体噬菌体文库中分离,所述技术例如在McCafferty等人,Nature,348:552-554(1990)中描述。Clackson等人,Nature,352:624-628(1991)和Marks等人,J.Mol Biol,222:581-597(1991)分别描述了使用噬菌体文库来分离鼠抗体和人抗体。还描述了,通过链改组(Marks等人,Bio/Technology,10:779-783(1992))产生高亲和力(nM级)人抗体、以及组合感染和体内重组用于构建极大型噬菌体文库(Waterhouse等人,Nuc.Acids.Res.,21:2265-2266(1993))。因此,这些技术是可以用于分离单克隆抗体的常规单克隆抗体杂交瘤技术的可行替代方案。
还可以修饰DNA:例如通过用人重链和轻链恒定结构域的编码序列置换同源鼠序列(美国专利号4,816,567;和Morrison,等人,Proc.Natl Acad.Sci.USA,81:6851(1984)),或通过使免疫球蛋白编码序列与非免疫球蛋白多肽的所有或部分编码序列共价连接。一般地,非免疫球蛋白多肽置换抗体的恒定结构域,或它们可以置换抗体的一个抗原组合位点的可变结构域,以生成包括对于抗原具有特异性的一个抗原组合位点和对于不同抗原具有特异性的另一个抗原组合位点的嵌合二价抗体。
单克隆抗体重和轻链的氨基酸序列或其部分可以例如自相应DNA序列获得。例如,可以确定VH、VL和/或一个或多个HVRs的氨基酸序列。
(iii)人源化抗体
用于人源化非人抗体的方法已在本领域中描述。优选地,人源化抗体具有从非人来源引入其内的一个或多个氨基酸残基。这些非人氨基酸残基通常被称为“输入”残基,一般得自“输入”可变结构域。人源化可以基本上根据Winter和同事(Jones等人,Nature,321:522-525(1986);Riechmann等人,Nature,332:323-327(1988);Verhoeyen等人,Science,239:1534-1536(1988))的方法,通过用高变区序列置换人抗体的相应序列,而实施。因此,“人源化”抗体是嵌合抗体(美国专利号4,816,567),其中实质性地少于完整的人可变结构域已由来自非人物种的相应序列置换。在实践中,人源化抗体一般是人抗体,其中某些高变区残基和可能地某些FR残基由来自啮齿类抗体中的类似位点的残基置换。
选择待在制备人源化抗体中使用的人可变结构域(轻和重),对于减少抗原性是非常重要的。根据所谓的“最适配”(best-fit)方法,利用啮齿类抗体的可变结构域的序列,对已知人可变结构域序列的完整文库进行筛选。最接近于啮齿类的人序列随后接受为人源化抗体的人构架区(FR)(Sims等人,J.Immunol.,151:2296(1993);Chothia等人,J.Mol.Biol,196:901(1987))。另一种方法使用衍生自特定亚组的所有人抗体的轻或重链的共有序列的特定构架区。相同构架可以用于几种不同人源化抗体(Carter等人,Proc.Natl.Acad.Sci.USA,89:4285(1992);Presta等人,J.Immunol,151:2623(1993))。
在特定实施方案中,抗体是人源化的,保留对于抗原的高亲和力和其他有利的生物学性质。为了达到这个目的,在一个实施方案中,人源化抗体通过如下方式制备:使用亲本和人源化序列的三维模型,分析亲本序列和各种概念性人源化产物。三维免疫球蛋白模型是通常可获得的,并且是本领域技术人员熟悉的。可获得用于说明且展示所选择候选免疫球蛋白序列的可能三维构象结构的计算机程序。对这些展示的检查,使得可以分析残基在候选免疫球蛋白序列的功能中的可能作用,即分析影响候选免疫球蛋白结合其抗原的能力的残基。以这种方式,可以从接受者和输入序列选择且组合FR残基,从而使得达到所需抗体特征,例如对于一种或多种靶抗原增加的亲和力。一般而言,高变区残基直接且最实质性地涉及影响抗原结合。
在本文中人源化抗体可以例如包括掺入人可变重结构域内的非人高变区残基,并且可以进一步包括在选自69H、71H和73H的位置上的构架区(FR)置换,其中利用Kabat等人,Sequences of Proteins of Immunological Interest,第5版Public Health Service,National Institutes of Health,Bethesda,MD(1991)中所示的可变结构域编号系统。在一个实施方案中,人源化抗体包括在位置69H、71H和73H中的2个或所有上的FR置换。
在本文中特别有利的人源化抗体结合STEAP-1,并且包含Asp-Asp基序。WO 2008/052187描述了在HVR-H3中具有Asp-Asp基序的示例性人源化抗STEAP-1抗体。本文提供了此抗体的VH和VL的氨基酸序列,包括HVRs。如WO 2008/052187中描述的此抗体的所有实施方案特别合并入本文作为参考。
本申请还考虑衍生自本文描述的任何抗体的亲和力成熟抗体,其中此亲和力成熟抗体优选包含Asp-Asp基序。亲本抗体可以是人抗体或人源化抗体,如本文描述的。考虑各种形式的人源化抗体和亲和力成熟的抗体。例如,人源化抗体或亲和力成熟的抗体可以是抗体片段,例如Fab,其任选与恒定区组合和/或与一种或多种细胞毒素剂缀合以生成免疫缀合物。可替代地,人源化抗体或亲和力成熟的抗体可以是全长抗体,例如全长IgG1抗体,其任选与一种或多种细胞毒素剂缀合以生成免疫缀合物。
(iv)人抗体
作为人源化的替代方案,可以生成人抗体。例如,现在可以产生如下转基因动物(例如小鼠),其能够在免疫接种后产生人抗体的完全库而无内源免疫球蛋白产生。例如,已描述了在嵌合和种系突变型小鼠中抗体重链连接区(JH)基因的纯合缺失导致内源抗体生产的完全抑制。人种系免疫球蛋白基因阵列在此种系突变型小鼠中的转移将导致在抗原攻击后人抗体的产生。参见例如,Jakobovits等人,Proc.Natl.Acad.Sci.USA,90:2551(1993);Jakobovits等人,Nature,362:255-258(1993);Bruggermann等人,Year inImmuno.,7:33(1993);和美国专利号5,591,669,5,589,369和5,545,807。
可替代地,噬菌体展示技术(McCafferty等人,Nature 348:552-553(1990))可以用于由来自未免疫接种供体的免疫球蛋白可变(V)结构域基因库,在体外产生人抗体和抗体片段。根据这种技术,抗体V结构域基因在读框内克隆到丝状噬菌体例如M13或fd的主要或次要外壳蛋白质基因中,并且作为功能抗体片段展示在噬菌体颗粒表面上。因为丝状颗粒包含噬菌体基因组的单链DNA拷贝,所以基于抗体功能性质的选择也将导致对编码显示该性质的抗体的基因的选择。因此,噬菌体模拟了B细胞的一些性质。噬菌体展示可以以各种形式执行;关于其综述,参见例如,Johnson,Kevin S.和Chiswell,David J.,CurrentOpinion in Structural Biology 3:564-571(1993)。数种V基因区段来源可以用于噬菌体展示。Clackson等人,Nature,352:624-628(1991)从衍生自免疫接种小鼠的脾的V基因小型随机组合文库中分离了一系列不同的抗恶唑酮抗体。可以基本上根据由Marks等人,J.MolBiol.222:581-597(1991)或Griffith等人,EMBOJ.12:725-734(1993)描述的技术,自未免疫接种的人供体构建V基因库,并且可以分离针对各种不同抗原(包括自身抗原)的抗体。还参见,美国专利号5,565,332和5,573,905。选自人衍生的噬菌体展示文库的Fv可变结构域序列可以如上所述的与已知人恒定结构域序列组合。如上所述,人抗体还可以通过体外激活的B细胞生成(参见美国专利号5,567,610和5,229,275)。
(v)抗体片段
已开发了各种技术用于生成抗体片段。传统地,这些片段经由全长抗体的蛋白酶解消化而产生(参见例如,Morimoto等人,Journal of Biochemical and BiophysicalMethods 24:107-117(1992);和Brennan等人,Science,229:81(1985))。然而,这些片段现在可以通过重组宿主细胞直接产生。例如,抗体片段可以从上文讨论的抗体噬菌体文库中分离。可替代地,Fab'-SH片段可以从大肠杆菌中直接回收,并且化学偶联,以形成F(ab')2片段(Carter等人,Bio/Technology 10:163-167(1992))。根据另一种方法,F(ab')2片段可以从重组宿主细胞培养物中直接分离。用于产生抗体片段的其他技术对于技术人员将是显而易见的。在其他实施方案中,选择的抗体是单链Fv片段(scFv)。参见WO 93/16185;美国专利号5,571,894;和美国专利号5,587,458。抗体片段还可以是“线性抗体”,例如如美国专利5,641,870中所述。此类线性抗体片段可以是单特异性或双特异性的。
(vi)双特异性抗体
双特异性抗体是对于至少2种不同表位具有结合特异性的抗体。示例性双特异性抗体可以与STEAP-1蛋白质的2种不同表位结合。其他此类抗体可以组合STEAP-1结合位点与针对另一种前列腺细胞表面抗原的结合位点(一个或多个),所述另一种抗原例如膜联蛋白2、钙粘着蛋白-1、Cav-1、Cd34、CD44、EGFR、EphA2、ERGL、Fas、hepsin、HER2、KAI1、MSR1、PATE、PMEPA-1、Prostasin、Prostein、PSCA、PSGR、PSMA、RTVP-1、ST7、STEAP-2、TMPRSS2、TRPM2和Trp-p8。(关于前列腺细胞表面抗原的列表,参见例如,Tricoli等人CancerRes.10:3943-3953(2004))。可替代地,STEAP-1臂可以与这样的臂组合,所述臂与白细胞上的触发分子结合,例如T细胞受体分子(例如CD2或CD3),或IgG的Fc受体(FcγR),例如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD 16),以便使细胞防御机制聚焦于STEAP-1表达细胞。双特异性抗体还可以用于使细胞毒素剂局限于至表达STEAP-1的细胞。这些抗体具有STEAP-1结合臂、和结合细胞毒素剂(例如皂草毒蛋白、抗干扰素-α、长春花生物碱、蓖麻蛋白A链、氨甲蝶呤或放射性同位素半抗原)的臂。双特异性抗体可以制备为全长抗体或抗体片段(例如F(ab')2双特异性抗体)。
用于制备双特异性抗体的方法是本领域已知的。全长双特异性抗体的传统生产方法基于2个免疫球蛋白重链-轻链对的共表达,其中2条链具有不同特异性(Millstein等人,Nature,305:537-539(1983))。类似程序公开于WO 93/08829和Traunecker等人,EMBOJ.,10:3655-3659(1991)中。根据不同方法,具有所需结合特异性(抗体-抗原结合位点)的抗体可变结构域与免疫球蛋白恒定结构域序列融合。融合物优选具有免疫球蛋白重链恒定结构域,包括至少部分铰链、CH2和CH3区。优选在至少一个融合物中存在包含轻链结合所需位点的第一重链恒定区(CH1)。编码免疫球蛋白重链融合物和需要时免疫球蛋白轻链的DNAs插入分开的表达载体内,并且共转染到合适的宿主生物内。当在构建中使用不等比率的3条多肽链可以提供最佳得率时,这提供了在实施方案中调整3个多肽片段的相互比例的极大灵活性。然而,当以相同比率表达至少2条多肽链导致高得率时,或当比率不是特别重要时,可以在一个表达载体中插入2条或所有3条多肽链的编码序列。
在这种方法的一个优选实施方案中,双特异性抗体由在一个臂中具有第一种结合特异性的杂合免疫球蛋白重链和在另一个臂中的杂合免疫球蛋白重链-轻链对(提供第二种结合特异性)组成。已经发现,这种不对称结构利于所需双特异性化合物与不希望有的免疫球蛋白链组合的分离,因为免疫球蛋白轻链仅存在于双特异性分子的一半中提供了一种容易的分离方法。这种方法公开于WO 94/04690中。关于生成双特异性抗体的进一步细节,参见例如,Suresh等人,Methods in Enzymology,121:210(1986)。
根据美国专利号5,731,168中所述的另一种方法,可以改造一对抗体分子之间的界面,使从重组细胞培养物中回收的异源二聚体的百分比达到最大。优选的界面包括抗体恒定结构域的CH3结构域的至少一部分。以这种方法,来自第一抗体分子界面的一个或多个小氨基酸侧链由较大侧链(例如酪氨酸或色氨酸)替换。针对该大侧链的相同或相似大小的补偿“腔”,在第二抗体分子的界面上,通过用较小侧链(例如丙氨酸或苏氨酸)替换大氨基酸侧链而产生。这提供了可以用于使异源二聚体得率增加超过其他不需要的终产物例如同源二聚体的一种机制。
双特异性抗体包括交联或“异源缀合物”抗体。例如,异源缀合物中的抗体之一可以与抗生物素蛋白偶联,另一个与生物素偶联。此抗体例如已被提议用于使免疫系统细胞靶向不希望有的细胞(美国专利号4,676,980),以及用于治疗HIV感染(WO 91/00360、WO92/200373和EP 03089)。异源缀合物抗体可以使用任何方便的交联方法进行制备。合适的交联剂是本领域众所周知的,并且连同许多交联技术一起公开于美国专利号4,676,980中。
用于由抗体片段生成双特异性抗体的技术也已在文献中描述。例如,双特异性抗体可以使用化学连接进行制备。Brennan等人,Science,229:81(1985)描述了程序,其中全长抗体进行蛋白酶解切割,以生成F(ab')2片段。这些片段在二硫醇络合剂亚砷酸钠的存在下还原,以稳定邻近的二硫醇以及阻止分子间二硫键形成。生成的Fab'片段随后转换为硫代硝基苯甲酸酯(TNB)衍生物。Fab'-TNB衍生物之一随后通过用巯基乙胺还原而再转换为Fab'-巯基,并且与等摩尔量的另一Fab'-TNB衍生物混合,以形成双特异性抗体。产生的双特异性抗体可以用作试剂用于酶的选择性固定。
近期进展已促进Fab'-SH片段从大肠杆菌中的直接回收,其可以进行化学偶联以形成双特异性抗体。Shalaby等人,J.Exp.Med.,175:217-225(1992)描述了完全人源化双特异性抗体F(ab')2分子的产生。每个Fab'片段由大肠杆菌分开分泌,并且在体外进行直接化学偶联,以形成双特异性抗体。由此形成的双特异性抗体能够结合超表达HER2受体的细胞和正常人T细胞,以及触发人细胞毒性淋巴细胞针对人乳腺肿瘤靶的裂解活性。用于直接自重组细胞培养物制备和分离双特异性抗体片段的各种技术也已描述。例如,双特异性抗体已使用亮氨酸拉链产生。Kostelny等人,J.Immunol.,148(5):1547-1553(1992)。来自Fos和Jun蛋白质的亮氨酸拉链肽通过基因融合与2种不同抗体的Fab'部分连接。抗体同源二聚体在铰链区还原以形成单体,随后再氧化以形成抗体异源二聚体。这种方法还可以用于产生抗体同源二聚体。由Hollinger等人,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)描述的“双抗体”技术已提供了用于制备双特异性抗体片段的替代机制。片段包括通过接头与轻链可变结构域(VL)连接的重链可变结构域(VH),所述接头太短而不允许相同链上的2个结构域之间配对。因此,一个片段的VH和VL结构域被迫与另一个片段的互补VL和VH结构域配对,从而形成2个抗原结合位点。使用单链Fv(scFv)二聚体制备双特异性抗体片段的另一种策略也已报道。参见Gruber等人,J.Immunol,152:5368(1994)。
考虑具有2以上效价的抗体。例如,可以制备三特异性抗体。Tutt等人J.Immunol.147:60(1991)。
(vii)其他氨基酸序列修饰
考虑本文描述的抗体的一种或多种氨基酸序列修饰。例如,可能希望改善抗体的结合亲和力和/或其他生物学性质。通过将合适的核苷酸改变引入编码抗体的核酸内,或通过肽合成,可以制备抗体的氨基酸序列变体。此类修饰包括例如在抗体的氨基酸序列内的残基的缺失和/或插入和/或置换。可以进行缺失、插入和置换的任何组合,以达到最终构建体,条件是最终构建体具有所需特征。氨基酸改变还可以改变抗体的翻译后加工,例如改变糖基化位点的数目或位置。
用于鉴定抗体中作为优选诱变位置的残基或区域的一种有用方法被称为“丙氨酸扫描诱变”,由如Cunningham and Wells Science,244:1081-1085(1989)描述。此处,鉴定靶残基或靶残基组(例如荷电残基,例如arg、asp、his、lys和glu),由中性或带负电荷的氨基酸(最优选丙氨酸或多丙氨酸)替换,以影响氨基酸与抗原例如STEAP-1抗原的相互作用。随后,对于表现出对替换具有功能性敏感性的那些氨基酸位置,通过在或对该置换位置引入进一步或其他变异,而进行精细研究。因此,虽然用于引入氨基酸序列变异的位点是预定的,但突变本身的性质无需是预定的。例如,为了分析在给定位点上的突变的性能,可以在靶密码子或区域上进行ala扫描或随机诱变,并且就所需活性筛选所表达的抗体变体。
氨基酸序列插入包括氨基和/或羧基末端融合(长度范围从一个残基到包含一百或更多个残基的多肽),以及单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N末端甲硫氨酰基残基的抗体或与细胞毒性多肽融合的抗体。抗体分子的其他插入变体包括抗体的N或C末端与酶(例如对于ADEPT)或增加抗体的血清半衰期的多肽的融合物。
另一种类型的变体是氨基酸置换变体。这些变体中,抗体中的至少一个氨基酸残基由不同残基替换。对于置换诱变最有意义的位点包括高变区,但也考虑FR或Fc区改变。保守置换显示于表1中在标题“优选置换”下。可以进行改变一种或多种生物学性质(例如稳定性或功效)但不改变其他性质(例如抗原特异性)的置换。如果优选的置换导致具有所需性质的抗体,那么可以引入在表1中“示例性置换”下的、或如下文述及氨基酸类别时进一步描述的,更实质性改变,并就进一步改善的性质来筛选抗体。
表1
抗体生物学性质的实质性改变可以通过选择置换残基来完成,所述置换残基在其维持下述方面上显著不同:(a)置换区域中多肽主链的结构,例如折叠或螺旋构象,(b)该分子在靶位点上的电荷或疏水性,或(c)侧链的体积。氨基酸可以根据其侧链性质中的相似性进行分组(在A.L.Lehninger,in Biochemistry,第2版,第73-75页,Worth Publishers,NewYork(1975)中):
(1)非极性:Ala(A)、Val(V)、Leu(L)、Ile(I)、Pro(P)、Phe(F)、Trp(W)、Met(M)
(2)不荷电的极性:Gly(G)、Ser(S)、Thr(T)、Cys(C)、Tyr(Y)、Asn(N)、Gln(Q)
(3)酸性:Asp(D)、Glu(E)
(4)碱性:Lys(K)、Arg(R)、His(H)
可替代地,天然存在的残基可以基于共同侧链性质进行分组:
(1)疏水的:正亮氨酸、Met、Ala、Val、Leu、Ile;
(2)中性亲水的:Cys、Ser、Thr、Asn、GIn;
(3)酸性:Asp、Glu;
(4)碱性:His、Lys、Arg;
(5)影响链走向的残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
非保守置换将引起这些类别之一的成员与另一个类别的交换。
不涉及维持抗体的正确构象的任何半胱氨酸残基也可以被置换,一般地以丝氨酸进行置换,以改善分子的氧化稳定性以及阻止异常交联。相反,一个或多个半胱氨酸键可以加入抗体中,以改善其稳定性(特别是当抗体是抗体片段例如Fv片段时)。
在一个实施方案中,置换变体涉及置换亲本抗体的一个或多个高变区残基。一般地,选择用于进一步开发的所得变体将比产生其的亲本抗体具有改善的生物学性质。用于生成此类置换变体的一个方便方法涉及:使用噬菌体展示的亲和力成熟。简言之,使几个高变区位点(例如6-7个位点)突变,以生成在每个位点上的所有可能氨基酸置换。由此生成的抗体变体,作为与每个颗粒内包装的M13的基因III产物的融合物,自丝状噬菌体颗粒以单价方式展示。噬菌体展示的变体随后如本文公开的就其生物活性(例如结合亲和力)进行筛选。为了鉴定用于修饰的候选高变区位点,可以执行丙氨酸扫描诱变,以鉴定显著促成抗原结合的高变区残基。可替代地或另外地,可以有利的是,分析抗原-抗体复合物的晶体结构以鉴定抗体及其抗原之间的接触点。此类接触残基和邻近残基是根据此处详细阐述的该技术进行置换的候选物。一旦生成变体,可以对该组变体实施如本文描述的筛选,并且在一种或多种相关测定试验中具有上佳性质的抗体可以选择用于进一步开发。
抗体的另一类氨基酸变体改变抗体的原始糖基化模式。改变意指缺失存在于该抗体中的一个或多个碳水化合物部分,和/或加入在抗体中不存在的一个或多个糖基化位点。
抗体的糖基化一般是N联或O联的。N联指碳水化合物部分与天冬酰胺残基的侧链的附着。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸是用于碳水化合物部分与天冬酰胺侧链的酶促连接的识别序列,其中X是除脯氨酸外的任何氨基酸。因此,这些三肽序列任一在多肽中的存在将产生潜在糖基化位点。O联糖基化指糖N-乙酰半乳糖胺、半乳糖或木糖之一与羟基氨基酸的附着,所述羟基氨基酸最通常为丝氨酸或苏氨酸,但也可以使用5-羟脯氨酸或5-羟赖氨酸。
向抗体添加糖基化位点可以方便地通过改变氨基酸序列来完成,所述改变使得所述序列包含一个或多个的上述三肽序列(对于N联糖基化位点)。改变还可以通过在原始抗体序列中进行一个或多个丝氨酸或苏氨酸残基的添加或置换来进行(对于O联糖基化位点)。
当抗体包括Fc区时,可以改变与之附着的碳水化合物。例如,在美国专利申请号US2003/0157108 A1,Presta,L中描述了具有成熟碳水化合物结构的抗体,其缺乏与抗体的Fc区附着的岩藻糖。还参见US 2004/0093621 A1(Kyowa Hakko Kogyo Co.,Ltd)。在WO03/011878,Jean-Mairet等人和美国专利号6,602,684,Umana等人中提及在与抗体的Fc区附着的碳水化合物中具有平分型N-乙酰葡糖胺(GlcNAc)的抗体。在WO97/30087,Patel等人中报道了在与抗体的Fc区附着的寡糖中具有至少一个半乳糖残基的抗体。还参见WO98/58964(Raju,S.)和WO99/22764(Raju,S.),其涉及在与Fc区附着的碳水化合物上具有改变的抗体。本文考虑包括具有附着在Fc区的此类碳水化合物结构的主要种类抗体的抗体组合物。
编码抗体的氨基酸序列变体的核酸分子可以通过本领域已知的各种方法进行制备。这些方法包括但不限于,从天然来源中分离(在天然存在的氨基酸序列变体的情况下),或通过对先期制备的变体或非变体形式的抗体进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变以制备。
(viii)半胱氨酸改造的抗体
在一个方面,本发明的抗体包括半胱氨酸改造的抗体(也称为ThioMAbs),其中亲本抗体的一个或多个氨基酸由游离半胱氨酸氨基酸替换,如WO2006/034488中公开的(整体合并入本文作为参考)。半胱氨酸改造的抗体包括具有在0.6-1.0范围中的巯基反应性值的一个或多个游离半胱氨酸氨基酸。游离半胱氨酸氨基酸是这样的半胱氨酸残基,其经改造而进入到亲本抗体内,但不是二硫桥的一部分。半胱氨酸改造的抗体对于,通过例如马来酰亚胺或卤代乙酰基,在改造的半胱氨酸位点上附着细胞毒性和/或成像化合物是有用的。与蛋白质中的任何其他氨基酸官能团,例如赖氨酸残基的氨基基团或N末端氨基基团比较,Cys残基的巯基官能团与马来酰亚胺基团的亲核反应性高约1000倍。碘代乙酰和马来酰亚胺试剂中巯基特异性官能团可以与胺基团反应,但需要更高的pH(>9.0)和更长的反应时间(Garman,1997,Non-Radioactive Labelling:A Practical Approach,Academic Press,London)。
半胱氨酸改造的抗体可以用于癌症治疗,并且包括对于细胞表面和跨膜受体和肿瘤相关抗原(TAA)特异的抗体。此类抗体可以作为裸抗体(未与药物或标记部分缀合)或抗体-药物缀合物(ADC,也称为免疫缀合物)使用。本发明的半胱氨酸改造的抗体可以与巯基反应试剂位点特异性地且有效地偶联。巯基反应试剂可以是多官能连接试剂、捕获标记试剂、荧光团试剂或药物-接头中间体。半胱氨酸改造的抗体可以用可检测标记进行标记,固定在固相载体上和/或与药物部分缀合。巯基反应性可以推广至任何如下抗体,在所述抗体中用反应性半胱氨酸氨基酸进行的氨基酸置换可以发生在选自下述氨基酸范围的轻链范围中:L-10至L-20;L-38至L-48;L-105至L-115;L-139至L-149;L-163至L-173;以及在选自下述氨基酸范围的重链范围内:H-35至H-45;H-83至H-93;H-114至H-127;和H-170至H-184;以及在选自H-268至H-291;H-319至H-344;H-370至H-380;和H-395至H-405的Fc区范围中,其中氨基酸位置编号自Kabat编号系统(Kabat等人(1991)Sequences of Proteins ofImmunological Interest,第5版Public Health Service,National Institutes ofHealth,Bethesda,MD)的位置1开始,并且其后顺次继续,如WO 2006/034488中公开的。在特定实施方案中,用半胱氨酸的氨基酸置换可以在根据EU编号的重链A118(即A118C),和/或根据Kabat编号的轻链V205(即V205C)上进行。巯基反应性还可以推广至抗体的某些结构域,例如轻链恒定结构域(CL)以及重链恒定结构域CH1、CH2和CH3。导致0.6和更高的巯基反应性值的半胱氨酸替换可以在完整抗体IgA、IgD、IgE、IgG和IgM,包括IgG亚类:IgG1、IgG2、IgG3、IgG4、IgA和IgA2的重链恒定结构域(分别为α、δ、ε、γ和μ)中进行。此类抗体及其用途公开于WO 2006/034488中。
本发明的半胱氨酸改造的抗体优选保留亲本抗体的抗原结合能力至至少某种程度。因此,半胱氨酸改造的抗体能够与抗原结合,优选特异性结合。此类抗原包括例如肿瘤相关抗原(TAA)、细胞表面受体蛋白质和其他细胞表面蛋白质和其他细胞表面分子、跨膜蛋白质、信号蛋白质、细胞存活调节因子、细胞增殖调节因子、与组织发育或分化相关(例如已知或疑似在功能上具有促成作用)的分子、淋巴因子、细胞因子、涉及细胞周期调节的分子、涉及血管发生的分子和与血管发生相关(例如已知或疑似在功能上具有促成作用)的分子。
本发明的抗体可以与其他巯基反应试剂缀合,其中反应基团可以是例如马来酰亚胺、碘乙酰胺、吡啶基二硫化物或其他巯基反应性缀合配偶体(Haugland,2003,MolecularProbes Handbook of Fluorescent Probes and Research Chemicals,MolecularProbes,Inc.;Brinkley,1992,Bioconjugate Chem.3:2;Garman,1997,Non-RadioactiveLabelling:A Practical Approach,Academic Press,London;Means(1990)BioconjugateChem.1:2;Hermanson,G.in Bioconjugate Techniques(1996)Academic Press,SanDiego,第40-55,643-671页)。配偶体可以是细胞毒素剂(例如毒素,例如多柔比星(阿霉素)或百日咳毒素)、荧光团例如荧光染料如荧光素或罗丹明、用于成像的螯合剂或放射治疗金属、肽基或非肽基标记物或检测标签(tag)、或改变清除率的物质例如各种聚乙二醇异构体、与第三组分结合的肽、或另一种碳水化合物或亲脂试剂。
(ix)就所需性质筛选抗体
用于生成抗体的技术已在上文描述。需要时,可以进一步选择具有特定生物学特征的抗体。
例如,与细胞表面上的STEAP-1结合的抗体可以使用免疫组织化学、FACs或其他合适技术进行鉴定。使用如Challita-Eid等人Cancer Res.67:5798-5805(2007)中所述的测定试验,可以鉴定与STEAP-1结合且抑制体内肿瘤生长的抗体。简言之,包含患者来源的雄激素依赖性前列腺癌异种移植物LAPC-9AD或膀胱癌UM-UC-3异种移植物的SCID小鼠可以用抗STEAP-1抗体(或包括此抗体的免疫缀合物)进行处理,测量肿瘤体积和/或PSA水平以评估功效。使用如Challita-Eid同上引文中所述的测定试验,可以鉴定与STEAP-1结合且阻断STEAP-1介导的细胞间通讯的抗体。简言之,可以使供体和受体PC3细胞装载上合适的供体和受体染料,混合以允许细胞间通讯发生,通过颜色改变检测该通讯。
(x)免疫缀合物
本发明还涉及包括与细胞毒素剂缀合的抗体的免疫缀合物,所述细胞毒素剂可以例如是化学治疗剂、毒素(例如小分子毒素、或细菌、真菌、植物或动物源的酶学活性毒素,包括其片段和/或变体)、或放射性同位素(即放射性缀合物)。
在此类免疫缀合物的生成中有用的化学治疗剂已在上文描述。本文还考虑抗体和一个或多个小分子毒素的缀合物,所述小分子毒素例如加利车霉素、美登素(美国专利号5,208,020)、单端孢菌素(trichothene)和CC1065。
在本发明的一个实施方案中,抗体与一个或多个美登素分子缀合(例如约1–约10个美登素分子/抗体分子)。美登素可以例如转换为May-SS-Me,其可以还原为May-SH3,并且与修饰抗体反应(Chari等人Cancer Research 52:127-131(1992)),以生成类美登素-抗体免疫缀合物。
另一种免疫缀合物包括与一或多个加利车霉素分子缀合的抗体。加利车霉素抗生素家族能够在亚皮摩尔浓度下产生双链DNA断裂。可以使用的加利车霉素结构类似物包括但不限于γ1 I、α2 I、α3 I、N-乙酰基-γ1 I、PSAG和θI 1(Hinman等人Cancer Research 53:3336-3342(1993)和Lode等人Cancer Research 58:2925-2928(1998))。还参见,特别合并入本文作为参考的美国专利号5,714,586;5,712,374;5,264,586;和5,773,001。
可以使用的酶学活性毒素及其片段包括白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌(Pseudomonas aeruginosa))、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒蛋白A链、α-帚曲霉素、油桐(Aleurites fordii)蛋白质、香石竹毒蛋白、美洲商陆(Phytolaca americana)蛋白质(PAPI、PAPII和PAP-S)、苦瓜(momordicacharantia)抑制剂、麻疯树毒蛋白、巴豆毒蛋白、肥皂草(sapaonaria officinalis)抑制剂、多花白树毒蛋白、mitogellin、局限曲菌素、酚霉素、依诺霉素和单端孢菌毒素类。参见例如,1993年10月28日公开的WO 93/21232。
本发明还考虑在抗体和具有溶核活性的化合物(例如核糖核酸酶或DNA核酸内切酶例如脱氧核糖核酸酶;DNA酶)之间形成的免疫缀合物。本发明进一步考虑在抗体和放射性同位素之间形成的免疫缀合物。各种放射性同位素可用于产生放射缀合的抗体。例子包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32和Lu的放射性同位素。
在另外一个实施方案中,抗体可以与用于肿瘤预靶向的“受体”(例如链霉亲和素)缀合,其中将抗体-受体缀合物施用于患者,随后使用清除试剂从循环中去除未结合的缀合物,并且随后施用与细胞毒素剂缀合的“配体”(例如亲和素)。
抗体和细胞毒素剂的缀合物可以使用各种双官能蛋白质偶联试剂进行制备,例如3-(2-吡啶二巯基)丙酸N-琥珀酰亚胺酯(SPDP)、4-(N-马来酰亚胺基甲基)环己烷-1-羧酸琥珀酰亚胺酯、亚氨基硫烷(IT)、亚氨酸酯的双官能衍生物(例如二甲基己二酸酯HCL)、活性酯(例如辛二酸二琥珀酰亚胺酯)、醛(例如戊二醛)、双-叠氮基化合物(例如双(对叠氮基苯甲酰基)己二胺)、双-重氮衍生物(例如双(对重氮苯甲酰基)-乙二胺)、二异氰酸酯(例如2,6-二异氰酸甲苯酯)、和双-活性氟化合物(例如1,5-二氟-2,4-二硝基苯)。例如,蓖麻毒蛋白免疫毒素可以如Vitetta等人Science 238:1098(1987)中所述进行制备。碳-14标记的1-异硫氰基苯甲基-3-甲基二亚乙基三胺五乙酸(MX-DTPA)是用于放射性核素与抗体缀合的示例性螯合剂。参见WO94/11026。接头可以是促进细胞毒药物在细胞中释放的“可断裂接头”。例如,可以使用对酸敏感的接头、对肽酶敏感的接头、二甲基接头或含二硫键的接头(Chari等人Cancer Research 52:127-131(1992))。
一般地,基于肽的药物部分可以通过在2个或更多个氨基酸和/或肽片段之间形成肽键而制备。此类肽键可以例如根据肽化学领域众所周知的液相合成方法(参见E.和K.Lübke,"The Peptides",第1卷,第76-136页,1965,Academic Press)进行制备。auristatin/多拉司他汀药物部分可以根据下述方法进行制备:US 5635483;US5780588;Pettit等人(1989)J.Am.Chem.Soc.111:5463-5465;Pettit等人(1998)Anti-Cancer Drug Design 13:243-277;Pettit,G.R.,等人Synthesis,1996,719-725;和Pettit等人(1996)J.Chem.Soc.Perkin Trans.1 5:859-863。还参见Doronina(2003)NatBiotechnol 21(7):778-784;"Monomethylvaline Compounds Capable of Conjugationto Ligands",美国专利申请公开号2005-0238649A1,其在此整体合并作为参考(公开了例如接头和制备与接头缀合的单甲基缬氨酸化合物例如MMAE和MMAF的方法)。
美登素和类美登素
在某些实施方案中,免疫缀合物包括与一个或多个类美登素分子缀合的本发明抗体(全长或片段)。
类美登素是通过抑制微管蛋白聚合作用起作用的有丝分裂抑制剂。美登素首先自东非灌木齿叶美登木(Maytenus serrata)中分离(美国专利号3896111)。随后,发现一些微生物也产生类美登素,例如美登木醇和C-3美登木醇酯(美国专利号4,151,042)。合成的美登木醇及其衍生物和类似物公开于例如美国专利号4,137,230;4,248,870;4,256,746;4,260,608;4,265,814;4,294,757;4,307,016;4,308,268;4,308,269;4,309,428;4,313,946;4,315,929;4,317,821;4,322,348;4,331,598;4,361,650;4,364,866;4,424,219;4,450,254;4,362,663;和4,371,533中。
类美登素药物部分是抗体药物缀合物中有吸引力的药物部分,因为它们:(i)相对易于通过发酵或化学修饰、发酵产物的衍生化进行制备,(ii)易于用适于通过非二硫键接头与抗体缀合的官能团衍生化,(iii)在血浆中稳定,和(iv)有效对抗多种肿瘤细胞系。
适于用作类美登素药物部分的美登素化合物是本领域众所周知的,并且可以根据已知方法从天然来源中分离,使用遗传工程化技术产生(参见Yu等人(2002)PNAS 99:7968-7973),或根据已知方法合成制备美登木醇和美登木醇类似物。
示例性类美登素药物部分包括具有修饰的芳族环的那些,例如:C-19-去氯(US4256746)(通过安丝菌素(ansamytocin)P2的氢化铝锂还原制备);C-20-羟基(或C-20-去甲基)+/-C-19-去氯(美国专利号4361650和4307016)(通过使用链霉菌(Streptomyces)或放线菌(Actinomyces)去甲基或使用LAH进行去氯而制备);和C-20-去甲氧基、C-20-酰氧基(-OCOR)、+/-去氯(美国专利号4,294,757)(通过使用酰基氯的酰化制备),以及在其他位置上具有修饰的那些。
示例性类美登素药物部分还包括具有修饰的那些,例如:C-9-SH(US 4424219)(通过美登木醇与H2S或P2S5反应制备);C-14-烷氧基甲基(去甲氧基/CH2OR)(US 4331598);C-14-羟甲基或酰氧基甲基(CH2OH或CH2OAc)(US 4450254)(由诺卡氏菌(Nocardia)制备);C-15-羟基/酰氧基(US 4,364,866)(通过链霉菌转化美登木醇制备);C-15-甲氧基(美国专利号4,313,946和4,315,929)(从滑桃树(Trewia nudlflora)中分离);C-18-N-去甲基(美国专利号4,362,663和4,322,348)(通过链霉菌对美登木醇进行去甲基化而制备);和4,5-脱氧(US 4371533)(通过三氯化钛/LAH还原美登木醇而制备)。
类美登素药物部分的示例性实施方案包括:具有下述结构的DM1;DM3;和DM4:
其中波浪线指示药物的硫原子与抗体药物缀合物的接头(L)的共价连接。已报道通过SMCC将DM1连接至(曲妥珠单抗)(特别整体合并入本文作为参考的WO 2005/037992)。本发明的抗体药物缀合物可以根据本文公开的程序进行制备。
其他示例性类美登素抗体药物缀合物具有下述结构和缩写(其中Ab是抗体,并且p是1–约8):
其中DM1通过BMPEO接头与抗体的巯基基团连接的示例性抗体药物缀合物具有下述结构和缩写:
其中Ab是抗体;n是0、1或2;并且p是1、2、3或4。
包含类美登素的免疫缀合物、制备其的方法及其治疗用途公开于例如美国专利号5,208,020;5,416,064;6,441,163和欧洲专利EP 0 425 235 B1中,其公开内容在此特别合并作为参考。Liu等人,Proc.Natl.Acad.Sci.USA 93:8618-8623(1996)描述了这样的免疫缀合物,其包括与针对人结肠直肠癌的单克隆抗体C242连接的名DM1的类美登素。发现该缀合物对培养的结肠癌细胞是高度细胞毒性的,并且在体内肿瘤生长测定试验中显示抗肿瘤活性。Chari等人,Cancer Research 52:127-131(1992)描述了免疫缀合物,其中类美登素经由二硫化物接头与结合人结肠癌细胞系上抗原的鼠抗体A7缀合,或与结合HER-2/neu癌基因的另一种鼠单克隆抗体TA.1缀合。TA.1-类美登素缀合物的细胞毒性在体外在人乳腺癌细胞系SK-BR-3上进行了测试,该细胞系表达3x105HER-2表面抗原/细胞。该药物缀合物达到类似于游离类美登素药物的细胞毒性程度,该毒性程度可以通过增加类美登素分子数目/抗体分子而得到增加。A7-类美登素缀合物在小鼠中显示出了低全身性细胞毒性。
抗STEAP-1抗体-类美登素缀合物可以通过使抗体与类美登素分子共价连接进行制备,优选不显著减少抗体或类美登素分子的生物活性。参见例如,美国专利号5,208,020(其公开内容在此特别合并作为参考)。每抗体分子缀合的平均3-4个类美登素分子已显示增强对靶细胞的细胞毒性的功效,而不负面影响抗体的功能或可溶性,但甚至一个分子的毒素/抗体也预期增强细胞毒性超过裸抗体的使用。类美登素是本领域众所周知的,并且可以通过已知技术合成或从天然来源中分离。合适的类美登素公开于例如美国专利号5,208,020,以及上文提及的其他专利和非专利出版物中。优选的类美登素是美登木醇和在美登木醇分子的芳族环中或在其他位置上修饰的美登木醇类似物,例如各种美登木醇酯。
本领域已知许多连接基团可以用于制备抗体-类美登素缀合物,包括例如公开于美国专利号5,208,020、6,441,163或EP专利0 425 235 B1,Chari等人,Cancer Research52:127-131(1992)和US 2005/0169933 A1中的那些,其公开内容在此特别合并作为参考。如2005年5月31日提交的美国专利申请号11/141344"Antibody Drug Conjugates andMethods"中公开的,可以制备包括接头组分SMCC的抗体-类美登素缀合物。连接基团包括二硫化物基团、硫醚基团、对酸敏感的基团、对光敏感的基团、对肽酶敏感的基团、或对酯酶敏感的基团,如上文提及的专利中公开的。另外的连接基团在本文中描述且例示。
抗体和类美登素的缀合物可以使用各种双官能蛋白质偶联试剂(接头)进行制备,例如3-(2-吡啶二巯基)丙酸N-琥珀酰亚胺酯(SPDP)、4-(N-马来酰亚胺基甲基)环己烷-1-羧酸琥珀酰亚胺酯(SMCC)、亚氨基硫烷(IT)、亚氨酸酯的双官能衍生物(例如二甲基己二酸酯HCl)、活性酯(例如辛二酸二琥珀酰亚胺酯)、醛(例如戊二醛)、双-叠氮基化合物(例如双(对叠氮基苯甲酰基)己二胺)、双-重氮衍生物(例如双(对重氮苯甲酰基)-乙二胺)、二异氰酸酯(例如2,6-二异氰酸甲苯酯)、和双-活性氟化合物(例如1,5-二氟-2,4-二硝基苯)。优选的偶联试剂包括3-(2-吡啶二巯基)丙酸N-琥珀酰亚胺酯(SPDP)(Carlsson等人,Biochem.J.173:723-737(1978))和4-(2-吡啶巯基)戊酸N-琥珀酰亚胺酯(SPP),以提供二硫化物连接。
接头可以与类美登素分子在多个位置上连接,这取决于连接的类型。例如,酯连接可以通过使用常规偶联技术与羟基反应而形成。该反应可以在具有羟基基团的C-3位置、由羟甲基修饰的C-14位置、由羟基基团修饰的C-15位置、和具有羟基基团的C-20位置上发生。在一个优选实施方案中,连接在美登木醇或美登木醇类似物的C-3位置上形成。
在一个实施方案中,本发明的任何抗体(全长或片段)与一个或多个类美登素分子缀合。在免疫缀合物的一个实施方案中,细胞毒素剂D是类美登素DM1、DM3或DM4。在免疫缀合物的一个此类实施方案中,接头选自SPDP、SMCC、IT、SPDP和SPP。
Auristatin免疫缀合物
在特定优选实施方案中,免疫缀合物包括与多拉司他汀类物质或多拉司他汀肽类似物和衍生物,auristatins(美国专利号5635483;5780588)缀合的抗体。多拉司他汀类物质和auristatins类物质已显示可以干扰微管动力学、GTP水解、以及核和细胞分裂(Woyke等人(2001)Antimicrob.Agents and Chemother.45(12):3580-3584),并且具有抗癌(US5663149)和抗真菌活性(Pettit等人(1998)Antimicrob.Agents Chemother.42:2961-2965)。多拉司他汀或auristatin药物部分可以通过该肽药物部分的N(氨基)末端或C(羧基)末端与抗体附着(WO 02/088172)。
示例性auristatin实施方案包括N末端连接的单甲基auristatin药物部分DE和DF,公开于"Monomethylvaline Compounds Capable of Conjugation to Ligands",美国专利申请号2005-0238649A1中,其公开内容特别整体合并作为参考。在进一步的实施方案中,单甲基auristatin药物部分包括单甲基auristatin E(MMAE)和单甲基auristatin F(MMAF)。
在进一步的实施方案中,提供了具有式Ab-(L-D)p的免疫缀合物,其中:
(a)Ab是抗体,
(b)L是接头;
(c)D是式DE或DF的药物
其中R2和R6各自是甲基,R3和R4各自是异丙基,R7是叔丁基,每个R8独立地选自CH3、O-CH3、OH和H;R9是H;R10是芳基;Z是-O-或-NH-;R11是H、C1-C8烷基或-(CH2)2-O-(CH2)2-O-(CH2)2-O-CH3;R18是-C(R8)2-C(R8)2-芳基;
(d)p为约1-8。
示例性接头组分(L)包括单独或组合的下述:
MC=6-马来酰亚胺己酰基
Val-Cit或"vc"=缬氨酸-瓜氨酸(蛋白酶可切割接头中的示例性二肽)
瓜氨酸=2-氨基-5-脲基戊酸
PAB=对氨基苯甲氧基羰基(“self immolative”接头组分的例子)
Me-Val-Cit=N-甲基-缬氨酸-瓜氨酸(其中接头肽键已进行修饰,以阻止其被组织蛋白酶B切割)
MC(PEG)6-OH=马来酰亚胺己酰基-聚乙二醇(可以与抗体半胱氨酸连接)。
在进一步的实施方案中,接头通过抗体(例如ThioMAb)上的巯基基团与抗体附着。在一个实施方案中,接头可被蛋白酶断裂。在一个实施方案中,接头包括val-cit二肽。在一个实施方案中,接头包括对氨基苯甲基单位。在一个实施方案中,对氨基苯甲基单位置于药物和接头中的蛋白酶切割位点之间。在一个实施方案中,对氨基苯甲基单位是对氨基苯甲氧基羰基(PAB)。在一个实施方案中,接头包括6-马来酰亚胺己酰基。在一个实施方案中,6-马来酰亚胺己酰基置于抗体和接头中的蛋白酶切割位点之间。上述实施方案可以单独或以任何的相互组合方式进行。
在进一步的实施方案中,药物选自下述:
MMAE=单甲基auristatin E(MW 718)
MMAF=auristatin E(MMAE)变体(MW 731.5),在该药物的C末端上具有苯丙氨酸
MMAF-DMAEA=MMAF通过C末端苯丙氨酸与DMAEA(二甲基氨基乙基胺)酰胺连接(MW801.5)
MMAF-TEG=以四甘醇酯化苯丙氨酸的MMAF
MMAF-NtBu=N-叔丁基以酰胺形式与MMAF的C末端连接
在特定实施方案中,药物选自MMAE和MMAF。
在一个实施方案中,免疫缀合物具有下式
其中Ab是抗体,S是硫原子,并且p为2–5。在此实施方案中,免疫缀合物被命名为Ab-MC-val-cit-PAB-MMAE。在另一个实施方案中,免疫缀合物是Ab-MC-MMAE。
在一个实施方案中,免疫缀合物具有下式
其中Ab是抗体,S是硫原子,并且p为2–5。在此实施方案中,免疫缀合物名为Ab-MC-val-cit-PAB-MMAF。在另一个实施方案中,免疫缀合物是Ab-MC-MMAF。
(xi)其他抗体修饰
本文考虑抗体的其他修饰。例如,抗体可以与各种非蛋白质性质聚合物之一连接,例如聚乙二醇、聚丙二醇、聚氧化烯、或聚乙二醇和聚丙二醇的共聚物。抗体还可以截留在例如通过凝聚技术或通过界面聚合制备的微囊中(例如分别地羟甲基纤维素或明胶-微囊和聚-(甲基丙烯酸甲酯)微囊)、在胶体药物递送系统(例如脂质体、白蛋白微球体、微乳液、纳米颗粒和纳米囊)中、或在粗乳液中制备。此类技术公开于Remington's PharmaceuticalSciences,第16版,Oslo,A.,Ed.,(1980)中。
可能希望就效应子功能而言修饰本发明的抗体,例如以便增强抗体依赖性细胞介导的细胞毒性(ADCC)和/或抗体的补体依赖性细胞毒性(CDC)。这可以通过在抗体的Fc区中引入一个或多个氨基酸置换来达到。可替代地或另外地,一个或多个半胱氨酸残基可以引入Fc区中,从而允许在这个区域中链间二硫键形成。因此生成的同源二聚抗体可以具有改善的内在化能力和/或增加的补体介导的细胞杀死和抗体依赖性细胞毒性(ADCC)。参见Caron等人,J.Exp Med.176:1191-1195(1992)和Shopes,B.J.Immunol.148:2918-2922(1992)。具有增强的抗肿瘤活性的同源二聚抗体还可以使用异双官能交联剂进行制备,如Wolff等人Cancer Research 53:2560-2565(1993)中所述。可替代地,可以工程化制备具有双重Fc区的抗体,从而可以具有增强的补体裂解和ADCC能力。参见Stevenson等人Anti-Cancer Drug Design 3:219-230(1989)。
WO00/42072(Presta,L.)描述了在人效应细胞的存在下具有改善的ADCC功能的抗体,其中抗体包括在其Fc区中的氨基酸置换。优选地,具有改善的ADCC的抗体包括在Fc区的位置298、333和/或334上的置换。优选地,改变的Fc区是人IgG1 Fc区,包括在这些位置的一个、两个或三个上的置换,或由在这些位置的一个、两个或三个上的置换组成。
具有改变的C1q结合和/或补体依赖性细胞毒性(CDC)的抗体在WO99/51642、美国专利号6,194,551B1、美国专利号6,242,195B1、美国专利号6,528,624B1和美国专利号6,538,124(Idusogie等人)中描述。这些抗体包括在其Fc区的氨基酸位置270、322、326、327、329、313、333和/或334中的一个或多个上的氨基酸置换。
为了增加抗体的血清半衰期,可以将清道夫受体(salvage receptor)结合表位掺入抗体(特别是抗体片段)内,如例如美国专利5,739,277中所述。如本文使用的,术语“清道夫受体结合表位”指IgG分子(例如IgG1、IgG2、IgG3或IgG4)的Fc区的表位,其负责增加IgG分子的体内血清半衰期。在其Fc区中具有置换和具有增加的血清半衰期的抗体也在WO00/42072(Presta,L.)中描述。
还考虑具有3个或更多个(优选4个)功能性抗原结合位点的工程化抗体(美国申请号US2002/0004587 A1,Miller等人)。
本文公开的抗体还可以配制为免疫脂质体。包含抗体的脂质体可以通过本领域已知的方法进行制备,例如下述中描述的:Epstein等人,Proc.Natl.Acad.Sci.USA,82:3688(1985);Hwang等人,Proc.Natl Acad.Sci.USA,77:4030(1980);美国专利号4,485,045和4,544,545;和1997年10月23日公开的WO97/38731。具有增强的循环时间的脂质体公开于美国专利号5,013,556中。
特别有用的脂质体可以使用包括磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-PE)的脂质组合物,通过反相蒸发法生成。将脂质体通过限定孔径的滤器挤出,以获得具有所需直径的脂质体。本发明的抗体的Fab′片段可以经由二硫化物交换反应,与脂质体缀合,如Martin等人J.Biol.Chem.257:286-288(1982)中所述。化学治疗剂任选包含在脂质体内。参见Gabizon等人J.National Cancer Inst.81(19)1484(1989)。
(B)示例性抗体和免疫缀合物
包含Asp-Asp基序的抗体(例如单克隆抗体)特别考虑用于本文公开的制剂。例如,抗体可以在VH或VL的任何区域中包含Asp-Asp基序。在特定实施方案中,Asp-Asp基序在影响抗原结合的区域中出现,所述区域包括但不限于任何HVR,且在特定实施方案中,HVR-H3。
在一个实施方案中,包含Asp-Asp基序的抗体是抗STEAP-1抗体。WO 2008/052187提供了在HVR-H3中包含Asp-Asp基序的示例性抗STEAP-1抗体。WO 2008/052187中描述的此类抗体的所有实施方案特别合并入本文作为参考。在本文图2A和2B中提供了一些此类抗体的VH和VL的氨基酸序列。一些抗体的HVRs的氨基酸序列提供如下:
HVR-L1:KSSQSLLYRSNQKNYLA(SEQ ID NO:11)
HVR-L2:WASTRES(SEQ ID NO:12)
HVR-L3:QQYYNYPRT(SEQ ID NO:13)
HVR-H1:GYSITSDYAWN(SEQ ID NO:14)
HVR-H2:GYISNSGSTSYNPSLKS(SEQ ID NO:15)
HVR-H3:ERNYDYDDYYYAMDY(SEQ ID NO:16)
本发明明确地考虑包括WO 2008/052187中所述的任何抗体的制剂。
在特定实施方案中,抗STEAP-1抗体包括在影响抗原结合的区域中的Asp-Asp基序,所述区域包括但不限于任何HVR,且在特定实施方案中,HVR-H3。在一个实施方案中,抗STEAP-1抗体包括包含SEQ ID NO:16的氨基酸序列的HVR-H3。在一个此类实施方案中,抗STEAP-1抗体进一步包括选自下述的一个或多个HVRs:(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(d)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(e)包括SEQ ID NO:13的氨基酸序列的HVR-L3。在一个此类实施方案中,抗体包括(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:16的氨基酸序列的HVR-H3;(d)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(e)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(f)包括SEQ ID NO:13的氨基酸序列的HVR-L3。
在特定实施方案中,抗STEAP-1抗体包括重链可变区(VH),其中该VH包括这样的氨基酸序列,其与选自SEQ ID NOs:8-10的氨基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%氨基酸序列相同。在一个实施方案中,抗体进一步包括轻链可变区(VL),其中该VL包括这样的氨基酸序列,其与选自SEQ ID NOs:5-6的氨基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%氨基酸序列相同。在上述任何实施方案中,HVR-H3中的Asp-Asp基序是保守的。在上述任何VH实施方案中,该VH包括包含SEQ ID NO:16的氨基酸序列的HVR-H3和任选地选自下述的至少一个HVR:(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;和(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2。在上述任何VL实施方案中,该VL包括选自下述的至少一个、二个或三个HVRs:(a)包括SEQID NO:11的氨基酸序列的HVR-L1;(b)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(c)包括SEQ ID NO:13的氨基酸序列的HVR-L3。在特定实施方案中,VH和VL根据图2A和2B配对,例如SEQ ID NO:5与SEQ ID NO:8,以及SEQ ID NO:6与SEQ ID NO:9或10。
用于在上文描述的任何免疫缀合物中使用的示例性抗体是如本文描述的抗STEAP-1抗体。优选的抗STEAP-1抗体和免疫缀合物(包括ThioMAb免疫缀合物)也在WO2008/052187中描述,其明确地合并入本文作为参考。本发明明确地考虑包括此免疫缀合物的制剂。在特定实施方案中,上述任何抗STEAP-1抗体与细胞毒素剂缀合。在一个实施方案中,细胞毒素剂是auristatin。在一个此类实施方案中,细胞毒素剂是MMAE或MMAF。
III.示例性制剂
在本文中本发明至少部分地涉及包括具有Asp-Asp基序的治疗蛋白质的制剂,其中该制剂具有抑制Asp-Asp基序中的Asp残基发生天冬氨酰异构化的pH。
在一个方面,提供了包括具有Asp-Asp基序的治疗蛋白质的制剂,其中制剂的pH为6.0以上且9.0以下。在一个实施方案中,其中制剂的pH为6.0以上且8.0以下。在另一个实施方案中,pH是6.25-7.5。在另一个实施方案中,pH是6.25-7.0。在另一个实施方案中,pH是6.5-7.5。在另一个实施方案中,pH是6.5-7.0。在另一个实施方案中,pH是约6.5。在另一个实施方案中,pH在6.0-9.0范围内,并且该范围的起点和终点选自6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9和9.0,其中起点是比终点pH低的pH。
用于特定治疗蛋白质的特别合适的pH或pH范围可以由实验确定,例如通过在各种pHs下配制包含Asp-Asp基序的治疗蛋白质,并且选择最佳化蛋白质的稳定性的pH。例如,显示对Asp-Asp异构化的最大抑制作用的pH(例如碱性pH)可导致不希望水平的脱酰胺、聚集和片段化,而使脱酰胺、聚集和片段化降到最低的pH(例如酸性pH)可导致不希望有水平的Asp-Asp异构化。最佳化蛋白质的稳定性的pH因此可以通过平衡这些降解过程来达到。基于本文教导,此pH预期落入上文提供的范围,这包括微酸性和碱性pHs。
在特定实施方案中,提供了抑制包括Asp-Asp基序的治疗蛋白质中的天冬氨酰异构化的方法,其中治疗蛋白质包含在制剂中,该方法包括使制剂的pH升高至足以抑制蛋白质中的天冬氨酰异构化的pH。此pH可以是上文描述的任何pH。相对于在起始pH下观察到的,天冬氨酰异构化可以被抑制至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或100%。在特定实施方案中,提供了抑制包括Asp-Asp基序的治疗蛋白质中的天冬氨酰异构化的方法,该方法包括使治疗蛋白质维持在如本文上面任何实施方案中提供的制剂中。在上述实施方案的一些中,与制剂的pH是5.5时的异构化水平比较,当制剂的pH是6.5时,治疗蛋白质中的天冬氨酰异构化被抑制。治疗蛋白质可以是抗体,例如本文提供的任何抗STEAP-1抗体或其ADCs。制剂可以是如本文描述的制剂。
Asp-Asp异构化可以使用各种分析方法进行测定,例如质谱法、肽作图、电子转移解离-质谱法和疏水作用层析(HIC),如本文实施例中所述的。制剂中的治疗蛋白质的脱酰胺、聚集和/或断裂可以通过分析方法进行测定,例如Daugherty等人,Advanced DrugDelivery Reviews 58:686-706(2006)中综述的那些。下文进一步提供了评估脱酰胺、聚集和/或断裂的示例性方法。
聚集可以通过在室温在白色荧光下相对于白色和黑色背景观察样品的颜色、外观和澄清度以进行评估。另外,制剂(稀释或未稀释的)的UV吸光度可以用于评估聚集。在一个实施方案中,UV吸光度在HP 8453分光光度计上在278nm和320nm下在具有1cm径长的石英杯中进行测量。来自320nm的吸光度用于校正由较大聚集体、气泡和颗粒所致的本底光散射。相对于配制缓冲液作为空白,确定测量值。蛋白质浓度使用1.65(mg/mL)-1cm-1的吸收率,进行确定。
阳离子交换层析可以用于测量电荷变体中的改变。在一个实施方案中,这种测定利用在HP 1100TMHPLC系统上的DIONEX PROPAC WCX-10TM柱。用包含20mM HEPES pH 7.9的移动相A,将样品稀释至1mg/mL。随后将30-50μL稀释样品装载到维持在40℃的柱上。使用包含20mM HEPES、200mM NaCl,pH 7.9的移动相B,用浅NaCl梯度洗脱峰。洗脱物在280nm下进行监控。使用HP CHEMSTATIONTM软件(Rev B.01.03或更新的)分析数据。
制剂中的Fab和F(ab')2片段的纯度可以通过毛细管区带电泳(CZE)进行测定。这种测定可以在BIORAD BIOFOCUSTM3000TM毛细管电泳系统上运行,所述毛细管电泳系统具有BIOCAP XLTM毛细管,50um I.D.,44.6cm总长度和40cm到检测器。
尺寸排阻层析可以用于定量聚集体和片段。这种测定可以利用在HP 1100TMHPLC系统上的TSK G3000 SWXLTM,7.8x 300mm柱。用移动相将样品稀释至1-2mg/mL,注入体积25-50μL。移动相是pH 6.2的200mM磷酸钾和250mM氯化钾,以0.5mL/分钟等度洗脱蛋白质30分钟。洗脱物吸光度在280nm下进行监控。使用HP CHEMSTATIONTM软件(Rev B.01.03或更新的)进行积分。
制剂中治疗蛋白质的稳定性也可以通过测定蛋白质的活性进行评估。当治疗蛋白质是抗体时,稳定性可以通过测定抗体结合抗原的能力是否得到维持和/或维持至何种程度,进行评估,例如通过ELISA或在细胞表面抗原的情况下通过基于细胞的测定,例如在本文实施例A中所述的基于细胞的测定。在特定实施方案中,制剂中的抗体(例如本文提供的任何抗STEAP-1抗体或免疫缀合物),当在40℃贮存4周时,与在其他方面基本上相同的条件下在5℃贮存6个月的抗体比较,显示≤40%或30%,且优选≤25%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%的抗原结合丧失,其中所述条件包括例如上文描述的pHs和/或在下文示例性制剂中描述的抗体/ADC浓度、缓冲液组分、糖组分和/或表面活性剂组分。
治疗蛋白质(例如如本文描述的抗体或ADC)可以以例如1mg/ml-200mg/ml的浓度存在于制剂中,并且在特定实施方案中,5-50mg/ml,并且在特定实施方案中,以1mg/ml、2mg/ml、3mg/ml、4mg/ml、5mg/ml、10mg/ml、15mg/ml、20mg/ml、25mg/ml、30mg/ml、40mg/ml、50mg/ml、60mg/ml、70mg/ml、80mg/ml、90mg/ml或100mg/ml。在各种实施方案中,治疗蛋白质的浓度适合于施用于受试者,并且在施用于受试者后提供疗效。在特定实施方案中,抗STEAP-1抗体或ADC为1mg/ml、2mg/ml、3mg/ml、4mg/ml、5mg/ml、10mg/ml、15mg/ml、20mg/ml或25mg/ml的浓度。
在另一个方面,制剂包括例如在如上文提供的pH的组氨酸-乙酸盐缓冲液。组氨酸乙酸盐可以为1mm-100mM的浓度,并且在特定实施方案中,5、10、15、20、25、30或40mM。组氨酸乙酸盐缓冲液例如在WO 2006/044908中描述,其特别合并入本文作为参考。在一个示例性实施方案中,组氨酸乙酸盐缓冲液用于“裸”抗体,例如裸抗STEAP-1抗体,或用于ADC,例如抗STEAP-1ADC。在另一个方面,制剂包括组氨酸盐酸盐缓冲液。组氨酸盐酸盐可以为1mm-100mM的浓度,并且在特定实施方案中,5、10、15、20、25、30或40mM。在一个示例性实施方案中,组氨酸盐酸盐缓冲液用于ADC,例如抗STEAP-1ADC,或用于“裸”抗体,例如裸抗STEAP-1抗体。在一个进一步的示例性实施方案中,当制剂待冻干时,使用组氨酸盐酸盐缓冲液。
在另一个方面,制剂包括糖。在一个此类实施方案中,糖选自海藻糖和蔗糖。在一个此类实施方案中,海藻糖或蔗糖以约60mM-约250mM的量存在。在特定实施方案中,海藻糖或蔗糖以100mM、125mM、150mM、175mM、200mM、210mM、220mM、230mM、240mM或250mM存在。
在另一个方面,制剂包括表面活性剂。在一个此类实施方案中,表面活性剂是聚山梨酸酯20(商业上称为TWEEN 20)。在一个此类实施方案中,聚山梨酸酯20以约0.005%-约0.1%的浓度存在。在特定实施方案中,聚山梨酸酯20以0.005%、0.01%、0.0125%、0.015%、0.0175%、0.02%、0.025%、0.03%、0.04%、0.05%、0.06%、0.07%、0.08%、0.09%或0.1%聚山梨酸酯20的浓度存在。
在另一个方面,在上文提供的pH的制剂包括组氨酸-乙酸盐缓冲液、糖和表面活性剂中的一种或多种,如在上文提供的任何实施方案中。在再一方面,在上文提供的pH的制剂包括组氨酸-盐酸盐缓冲液、糖和表面活性剂中的一种或多种,如在上文提供的任何实施方案中。
IV.用制剂进行的治疗
在一个实施方案中,本发明提供了治疗受试者中的疾病或病症的方法,其包括以有效治疗疾病或病症的量给受试者施用本文描述的制剂。
当制剂包括抗STEAP-1抗体(包括“裸”抗STEAP-1抗体以及ADCs)时,制剂可以用于治疗癌症。癌症一般将包括STEAP-1表达细胞,从而使得抗STEAP-1抗体能够与癌细胞结合。因此,本发明在这个实施方案中涉及用于治疗受试者中的STEAP-1表达癌症的方法,该方法包括以有效治疗癌症的量给受试者施用如本文描述的包括抗STEAP-1抗体的制剂。可以用此制剂治疗的各种癌症包括前列腺癌、Ewing氏肉瘤、肺癌、结肠癌、膀胱癌、卵巢癌和胰腺癌。参见Hubert等人,Proc.Natl.Acad.Sci.USA 96:14523-14528(1999);WO 99/62941;Challita-Eid等人Cancer Res.67:5798-5805;和WO2008/052187。
患者可以用抗体制剂和化学治疗剂的组合进行治疗。组合施用包括使用分开制剂或单一制剂的共施用或并行施用,和以任何次序的相继施用。因此,化学治疗剂可以在抗体制剂施用之前或之后施用。在该实施方案中,在化学治疗剂的至少一次施用和抗体制剂的至少一次施用之间的时间优选为约1个月或更少,并且最优选约2周或更少。可替代地,化学治疗剂和抗体制剂在单一制剂或分开制剂中并行地施用于患者。
患者可以用抗STEAP-1抗体制剂和第二抗体的组合进行治疗。第二抗体可以包括结合前列腺细胞表面抗原的抗体,所述抗原例如膜联蛋白2、钙粘着蛋白-1、Cav-1、Cd34、CD44、EGFR、EphA2、ERGL、Fas、hepsin、HER2、KAI1、MSR1、PATE、PMEPA-1、Prostasin、Prostein、PSCA、PSGR、PSMA、RTVP-1、ST7、TMPRSS2、TRPM2和Trp-p8。组合施用包括使用分开制剂或单一制剂的共施用或并行施用,以及以任何次序的相继施用。因此,第二抗体可以在抗STEAP-1抗体制剂施用之前或之后施用。在这个实施方案中,在第二抗体的至少一次施用和抗STEAP-1抗体制剂的至少一次施用之间的时间为优选约1个月或更少,并且最优选约2周或更少。可替代地,抗STEAP-1抗体制剂和第二抗体在单一制剂或分开制剂中并行地施用于患者。
用如本文描述的制剂的治疗将优选导致癌症体征或症状的改善。例如,此疗法可以导致存活(总存活和/或无进展存活)的改善和/或可以导致客观临床应答(部分或完全反应)。此外,用化学治疗剂和抗体制剂的组合治疗可以导致对于患者的协同,或大于加合的,治疗益处。
制剂可以依照已知方法施用于人患者,例如静脉内施用,例如作为推注或通过经过一段时间的连续输注,通过肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内、经口、局部或吸入途径。抗体组合物的静脉内、肌内或皮下施用是优选的,其中静脉内施用是最优选的。
对于皮下递送,制剂可以经由注射器;注射装置(例如INJECT-EASETM和GENJECTTM装置);注射笔GENPENTM);无针装置(例如MEDIJECTORTM和BIOJECTORTM);或皮下贴剂递送系统进行施用。
对于疾病的预防或治疗,抗体的合适剂量将依赖于如上定义的待治疗疾病的类型、疾病的严重性和过程、抗体施用是用于预防还是治疗目的、先前治疗、患者的临床史和对抗体的应答、和主治医师的判断。抗体适宜地一次或经过一系列治疗,施用于患者。依赖于疾病类型和严重性,约1μg/kg-50mg/kg(例如0.1-20mg/kg)抗STEAP-1抗体是用于施用于患者的初始候选剂量,无论是例如通过一次或多次分开施用,或通过连续输注。抗体的剂量一般将在约0.05mg/kg–约10mg/kg的范围中。如果施用化学治疗剂,那么它通常以针对其已知的剂量进行施用,或任选地由于药物的组合作用或可归于化学治疗剂施用的消极副作用而降低。关于化学治疗剂的制剂和给药方案可以根据制造商的说明书或如由技术人员凭经验确定的使用。用于化学疗法的制剂和给药方案也在Chemotherapy Service Ed.,M.C.Perry,Williams&Wilkins,Baltimore,MD(1992)中描述。
其他治疗方案可以与抗体组合,包括但不限于:第二(第三、第四,等)化学治疗剂(即不同化学治疗剂的“混合物(cocktails)”);其他单克隆抗体;生长抑制剂;细胞毒素剂;化学治疗剂;EGFR靶向药物;酪氨酸激酶抑制剂;抗血管发生剂;和/或细胞因子;等。除上述治疗方案外,患者可以接受癌细胞的手术摘除和/或放射疗法。
如本文提供的制剂(例如抗STEAP-1抗体制剂)还可以施用于诊断目的,例如用于体内诊断成像。在此类实施方案中,抗体可以直接或间接标记用于检测。
V.产品
在本发明的另一个实施方案中,提供了包含本发明的制剂且提供关于其使用的说明书的产品。产品包括容器。合适容器包括例如瓶、小瓶(例如双室小瓶)、注射器(例如双室注射器)和试管。容器可以由各种材料例如玻璃或塑料形成。容器容纳制剂并且在容器上或与容器相伴的标签可以指示使用说明。容纳制剂的容器可以是多次使用的(multi-use)小瓶,其允许重构制剂的重复施用(例如2-6次施用)。产品可以进一步包括从商业和用户观点来看所希望的其他材料,包括其他缓冲液、稀释剂、滤器、针头、注射器和关于如先前节段中指出的应用的说明书包装插页。
通过参考下述实施例可以更全面地理解本发明。然而,它们不应解释为限制本发明的范围。所有引用的文献和专利合并入本文作为参考。
实施例
A.通过离子交换层析鉴定琥珀酰亚胺中间体
在具有100mM海藻糖和0.01%Tween 20,pH 5.5的20mM组氨酸乙酸盐缓冲液中,配制具有分别如SEQ ID NO:6和10中的重和轻链可变区的全长抗STEAP-1抗体。使样品维持在40℃(“胁迫条件”),并且在0、1、2或4周后通过离子交换层析进行分析。图3显示在这些时间点上所得到的洗脱图。在胁迫条件下随着时间的增加,“碱性”峰(箭头)从洗脱峰的3.9%增加到20.7%。
样品的“效力”通过在基于细胞的测定试验中评估抗体结合抗原的能力而进行确定。在该测定试验中,稳定转染了STEAP-1的人胚肾(HEK)293细胞,LB50细胞,在生长培养基中生长,所述生长培养基包含HAM's F12/DMEM(1:1比率)、10%FBS以及0.2mg/mL G418和1xGLUTAMAXTM培养基(Invitrogen,Carlsbad,CA)。细胞上的STEAP-1表达水平通过Scatchard分析,确定为~270,000个位点/细胞。LB50细胞以1x105细胞/孔种植在聚-D-赖氨酸包被的96孔微量滴定细胞培养板中,并且在37℃和5%CO2下温育过夜。在温育后,在测定稀释剂(PBS+0.25%BSA)中制备抗STEAP-1抗体和对照样品的稀释物,并且加入板中。板随后温育以允许抗STEAP-1抗体与LB50细胞上表达的STEAP-1结合。随后洗涤板以去除未结合抗体。结合的抗STEAP-1抗体用抗人IgG-辣根过氧化物酶(HRP)和SureBlue ReserveTM四甲基联苯胺过氧化物酶(TMB)底物溶液进行检测,这产生与结合的抗STEAP-1抗体量成比例的比色信号。如图3中的表的最后一列中所示,在胁迫条件下时间的增加导致抗STEAP-1抗体效力的丧失增加。
收集对应于离子交换峰的级分,并且执行质谱。碱性峰(图3中的接头)具有小于主峰的18Da的质量,指示琥珀酰亚胺中间体。琥珀酰亚胺中间体的存在说明,存在天冬酰胺的脱酰胺或天冬氨酸的异构化。
B.通过肽作图和ETD-MS鉴定iso-Asp(异Asp)
对样品执行肽(胰蛋白酶消化)作图。如图4中所示,通过反相层析,2种肽(T11和T11-iso-Asp)差异地运动,说明2种肽呈现不同荷电表面。然而,2种肽具有如通过质谱法测定的相同质量,提示肽之一包含异Asp。电子转移解离用于断裂肽,获得的数据显示HVR-H3(CDR3)的Asp-Asp序列中的第一个Asp是异构化的,如图5中所示。该Asp对应于图5中所示肽(NYDYDD YYYAMD YWGQGTLVTVSSCSTK(SEQ ID NO:17))的位置5,这对应于上文SEQ ID NO:16的位置7。
C.增加pH的作用
实施例A的抗STEAP-1抗体在各种pHs的20mM组氨酸盐酸盐缓冲液、240mM蔗糖和0.02%Tween 20中进行配制,如图6中所示。当在40℃和pH 5.5下贮存4周后,抗体显示丧失对STEAP-1抗原的结合。具有增加的pH的制剂显示在40℃的结合丧失减少。当制剂在5℃贮存6个月时,在测试的任何pHs下均未观察到结合丧失。
D.异Asp和琥珀酰亚胺的HIC检测
疏水作用层析(HIC)用于定量抗STEAP-1抗体中的异Asp和琥珀酰亚胺的量,所述抗STEAP-1抗体如上文实施例C中所述配制在pH 5.5,并且在40℃贮存0、1、2和4周。图7显示包含异Asp和琥珀酰亚胺的洗脱谱,如所示的。图8显示在各种温度贮存各个时间段的抗STEAP-1抗体中的异Asp和琥珀酰亚胺的量(以百分比表示),如所示的。需要HIC以定量异Asp和琥珀酰亚胺的量,因为使用离子交换层析时异Asp峰出现在主峰下。
E.Asp至异Asp的异构化的速率
抗STEAP-1抗体如上文实施例C中所述配制在pH 5.5。假定Asp至异Asp的反应的一级动力学(图9),在各种温度测定了Asp至异Asp异构化的速率(图10)。使用图10中测定的速率,生成Arrhenius曲线图(图11)。曲线图预测Asp-Asp异构化的活化能是约25-30kcal/mol。
尽管为了清楚理解的目的,本发明已通过举例说明和实施例以一定详细程度进行了描述,但说明书和实施例不应解释为限制本发明的范围。本文引用的所有专利和科学文献的公开内容明确地整体并入作为参考。
序列表
<110> 弗·哈夫曼-拉罗切有限公司
<120> 治疗性蛋白质制剂
<130> P4252R1 WO
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Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的多肽
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 11
Lys Ser Ser Gln Ser Leu Leu Tyr Arg Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 12
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 12
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 13
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 13
Gln Gln Tyr Tyr Asn Tyr Pro Arg Thr
1 5
<210> 14
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 14
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala Trp Asn
1 5 10
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 15
Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 16
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 16
Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10 15
<210> 17
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的肽
<400> 17
Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
1 5 10 15
Gly Thr Leu Val Thr Val Ser Ser Cys Ser Thr Lys
20 25
Claims (23)
1.包括具有Asp-Asp基序的治疗蛋白质的制剂,其中所述制剂具有抑制所述Asp-Asp基序中的Asp残基的天冬氨酰异构化的pH。
2.包括具有Asp-Asp基序的治疗蛋白质的制剂,其中所述制剂的pH为6.0以上且9.0以下。
3.权利要求2的制剂,其中pH是6.25-7.0。
4.权利要求3的制剂,其中pH是约6.5。
5.权利要求2的制剂,其中治疗蛋白质是抗体。
6.权利要求5的制剂,其中抗体包括包含Asp-Asp基序的高变区(HVR)。
7.权利要求6的制剂,其中所述Asp-Asp基序出现在HVR-H3中。
8.权利要求7的制剂,其中抗体是抗STEAP-1抗体,其包括包含SEQ ID NO:16的氨基酸序列的HVR-H3。
9.权利要求8的制剂,其中抗STEAP-1抗体进一步包括选自下述的一个或多个HVRs:(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(d)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(e)包括SEQ ID NO:13的氨基酸序列的HVR-L3。
10.权利要求9的制剂,其中抗体包括(a)包括SEQ ID NO:14的氨基酸序列的HVR-H1;(b)包括SEQ ID NO:15的氨基酸序列的HVR-H2;(c)包括SEQ ID NO:16的氨基酸序列的HVR-H3;(d)包括SEQ ID NO:11的氨基酸序列的HVR-L1;(e)包括SEQ ID NO:12的氨基酸序列的HVR-L2;和(f)包括SEQ ID NO:13的氨基酸序列的HVR-L3。
11.权利要求8的制剂,其中抗体包括重链可变区(VH),其中所述VH包含与选自SEQ IDNOs:8-10的氨基酸序列至少90%氨基酸序列相同的氨基酸序列。
12.权利要求11的制剂,其中抗体还包括轻链可变区(VL),其中所述VL包含与选自SEQID NOs:5-6的氨基酸序列至少90%氨基酸序列相同的氨基酸序列。
13.权利要求8的制剂,其中抗体与细胞毒素剂缀合。
14.权利要求13的制剂,其中细胞毒素剂是auristatin。
15.权利要求13的制剂,其中细胞毒素剂是类美登素药物部分。
16.权利要求5-8中任一项的制剂,其中当在40℃贮存4周时,与在5℃贮存6个月比较,所述抗体显示≤25%的抗原结合丧失。
17.权利要求5-8中任一项的制剂,其包括20mM浓度的组氨酸-乙酸盐缓冲液。
18.权利要求5-8中任一项的制剂,其包括20mM浓度的组氨酸-盐酸盐缓冲液。
19.权利要求5-8中任一项的制剂,其包括以60mM-250mM量存在的选自海藻糖和蔗糖的糖。
20.权利要求5-8中任一项的制剂,其包括0.01%-0.1%量的聚山梨酸酯20。
21.治疗癌症的方法,所述方法包括给哺乳动物施用权利要求8的制剂。
22.抑制包括Asp-Asp基序的治疗蛋白质中的天冬氨酰异构化的方法,其中所述治疗蛋白质包含在制剂中,所述方法包括使所述制剂的pH升高至足以抑制天冬氨酰异构化的pH。
23.权利要求22的方法,其中所述治疗蛋白质是抗体。
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US11654108P | 2008-11-20 | 2008-11-20 | |
US61/116,541 | 2008-11-20 | ||
CN2009801548665A CN102281901A (zh) | 2008-11-20 | 2009-11-19 | 治疗性蛋白质制剂 |
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JP (1) | JP5726085B2 (zh) |
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CN (2) | CN102281901A (zh) |
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ES2636089T3 (es) | 2006-10-27 | 2017-10-05 | Genentech, Inc. | Anticuerpos e inmunoconjugados y usos para los mismos |
BR112012031727B1 (pt) * | 2010-06-15 | 2022-03-29 | Genmab A/S | Conjugado de droga-anticorpo, composição farmacêutica, e, uso do conjugado de droga- anticorpo |
EP2399604A1 (en) * | 2010-06-25 | 2011-12-28 | F. Hoffmann-La Roche AG | Novel antibody formulation |
SG11201401360XA (en) | 2011-10-25 | 2014-05-29 | Onclave Therapeutics Ltd | Antibody formulations and methods |
EP3148986A4 (en) * | 2014-05-27 | 2018-01-10 | Navigen, Inc. | Arf6 inhibitors and methods of synthesis and use thereof |
US20170096495A1 (en) * | 2015-10-02 | 2017-04-06 | Hoffmann-La Roche Inc. | Bispecific t cell activating antigen binding molecules |
CA3055132A1 (en) | 2017-04-03 | 2018-10-11 | F. Hoffmann-La Roche Ag | Antibodies binding to steap-1 |
JP6577683B2 (ja) * | 2017-09-22 | 2019-09-18 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
AR114722A1 (es) * | 2018-04-02 | 2020-10-07 | Amgen Inc | Composiciones de erenumab y usos de las mismas |
CR20210435A (es) | 2019-02-18 | 2021-09-20 | Lilly Co Eli | Formulación de anticuerpos terapéuticos |
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JP2003520828A (ja) * | 2000-01-27 | 2003-07-08 | ジェネティクス インスティテュート,エルエルシー | Ctla4(cd152)に対する抗体、これを含む結合体、およびその使用 |
JP5485489B2 (ja) * | 2000-08-11 | 2014-05-07 | 中外製薬株式会社 | 抗体含有安定化製剤 |
EP1391209A4 (en) * | 2001-05-30 | 2009-12-16 | Chugai Pharmaceutical Co Ltd | PROTEIN PREPARATION |
US20030113316A1 (en) * | 2001-07-25 | 2003-06-19 | Kaisheva Elizabet A. | Stable lyophilized pharmaceutical formulation of IgG antibodies |
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AU2003286003B2 (en) * | 2002-11-08 | 2011-05-26 | Ablynx N.V. | Stabilized single domain antibodies |
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IL211670A (en) | 2016-12-29 |
JP5726085B2 (ja) | 2015-05-27 |
EP2358393A1 (en) | 2011-08-24 |
HK1244426A1 (zh) | 2018-08-10 |
KR101676887B1 (ko) | 2016-11-16 |
US20120027772A1 (en) | 2012-02-02 |
CA2737045C (en) | 2017-11-14 |
US20160068607A1 (en) | 2016-03-10 |
BRPI0921947A2 (pt) | 2018-10-16 |
WO2010059787A1 (en) | 2010-05-27 |
MX2011004748A (es) | 2011-05-25 |
JP2012509344A (ja) | 2012-04-19 |
KR20110089141A (ko) | 2011-08-04 |
AU2009316592A1 (en) | 2010-05-27 |
CN102281901A (zh) | 2011-12-14 |
CA2737045A1 (en) | 2010-05-27 |
AU2009316592B2 (en) | 2016-01-07 |
IL211670A0 (en) | 2011-06-30 |
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