CN103951753B - 抗‑gitr抗体 - Google Patents
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- CN103951753B CN103951753B CN201410047532.0A CN201410047532A CN103951753B CN 103951753 B CN103951753 B CN 103951753B CN 201410047532 A CN201410047532 A CN 201410047532A CN 103951753 B CN103951753 B CN 103951753B
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Abstract
本发明涉及抗‑GITR抗体。具体地，提供了针对人GITR的抗体及其应用，例如，用于治疗增生性障碍和免疫障碍。
Description
本申请是申请日为2010年8月31日的中国专利申请201080049756.5“抗-GITR抗体”的分案申请。
技术领域
本发明概括地涉及对糖皮质激素诱导的TNF受体(GITR)特异性的抗体及其应用。更具体地，本发明涉及识别人GITR并调节其活性的人源化抗体，所述活性尤其为在免疫障碍和增生性障碍中的活性。
背景技术
糖皮质激素诱导的TNFR相关蛋白(GITR，TNFR超家族的一个成员)在先天性和适应性免疫系统的许多组分中表达(参见，例如，Hanabuchi等人(2006)Blood107：3617-3623；和Nocentini和Riccardi(2005)Eur.J.Immunol.2005.35：1016-1022)。在T细胞活化后，它的膜表达增加(Hanabuchi，同上；和Nocentini和Riccardi，同上)；它的触发会共活化效应性T淋巴细胞，并调节调节性T细胞(Treg)活性(参见，例如，McHugh，等人(2002)Immunity2002.16：311-323；Shimizu，等人(2002)Nat.Immunol..3：135-142；Ronchetti，等人(2004)Eur.J.Immunol.34：613-622；和Tone，等人(2003)Proc.Natl.Acad.Sci.USA100：15059-15064)。
GITR会被GITR配体(GITRL)活化，所述配体主要在APC上表达，且已经提出，其通过它的细胞质结构域来递送信号，尽管需要进一步研究来确定生化信号传递(Nocentini，同上；Ronchetti，同上；Suvas，等人(2005)J.Virol.79：11935-11942；和Shin，等人(2002)Cytokine19：187-192)。
GITR活化会增加对肿瘤和病毒感染的抗性，参与自身免疫过程／炎症性过程，并调节白细胞外渗(Nocentini同上；Cuzzocrea，等人(2004)J.Leukoc.Biol.76：933-940；Shevach等人(2006)Nat.Rev.Immunol.6：613-618；Cuzzocrea，等人(2006)J.Immunol.177：631-641；和Cuzzocrea等人(2007)FASEBJ.21：117-129)。
需要改进的用于治疗免疫障碍和增生性障碍(例如，肿瘤和癌症)的方法和组合物，其中使用调节GITR活性的试剂。优选地，这样的激动剂对它的靶分子具有高亲和力，且能够在相对低剂量时刺激GITR信号传递。优选地，这样的方法和组合物对GITR是高度特异性的，且不会干扰其它受体的活性。优选地，这样的方法和组合物采用这样的激动剂：所述激动剂适用于修饰细胞毒性的有效负载向靶细胞的递送，而且也适用于非细胞毒性的应用。优选地，这样的方法和组合物采用这样的抗体：所述抗体被修饰成，当施用给有此需要的受试者时，会限制它们的抗原性。
附图说明
图1显示了DTA-1(对mGITR特异性的；参见，例如，Shimizu，等人(2002)NatureImmunol.3：135-142)和局部辐照的联合治疗的协同效应。“CR”是指完全消退。
图2显示了通过Naismith和Sprang(1998)Trends Biochem.Sci.23：74-79所述的方法测得的GITR的模块。粗体残基指示如下测定的构象DTA-1-样表位。
具体实施方式
通过提供GITR的激动剂，例如人源化的抗-GITR抗体，本发明满足了本领域的这些需要和其它需要。
在一个方面，本发明提供了结合人GITR的结合化合物，诸如抗体或其片段，包括人源化的或嵌合的重组抗体，其包含：抗体轻链可变结构域或其抗原结合片段，其具有至少一个或多个选自SEQ ID NO：56-88的CDR；和重链可变结构域，其具有至少一个或多个选自SEQIDNO：23-55的CDR。
在其它实施方案中，本发明的结合化合物包含前述2个段落中描述的轻链可变结构域和重链可变结构域或其抗原结合片段。
在有些实施方案中，结合化合物包含框架区，其中所述框架区的氨基酸序列是所有的或基本上所有的人免疫球蛋白氨基酸序列。
在有些实施方案中，所述轻链可变结构域包含选自SEQ ID NO：12-22的序列或其变体。在有些实施方案中，所述重链可变结构域包含选自SEQ ID NO：1-11的序列。在另一个实施方案中，结合化合物包含在本段中描述的轻链可变结构域和重链可变结构域或其抗原结合片段。
在其它实施方案中，本发明的结合化合物包含：基本上由选自SEQ ID NO：91、93、95、97、99、101、103、105、107、109、111的序列组成的轻链可变结构域或其抗原结合片段，和／或基本上由选自SEQ ID NO：90、92、94、96、98、100、102、104、106、108、110的序列组成的重链可变结构域或其抗原结合片段。
在一个实施方案中，本发明涉及抗体，所述抗体能够在交叉阻断试验中阻断本发明的结合化合物与人GITR的结合。在不同的实施方案中，所述抗体能够阻断人GITR与包含本文公开的抗体36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5或31H6的CDR序列的抗体的结合。在另一个实施方案中，本发明涉及结合化合物，其能够阻断 GITR-介导的活性，这样的活性包括、但不限于：原初CD4+T细胞增殖试验的共刺激。
在有些实施方案中，本发明的结合化合物另外包含重链恒定区，其中所述重链恒定区包括γ1、γ2、γ3或γ4人重链恒定区或其变体。在不同的实施方案中，所述轻链恒定区包括λ或κ人轻链恒定区。
在不同的实施方案中，本发明的结合化合物是多克隆的、单克隆的、嵌合的、人源化的或全人抗体或其片段。本发明也预见到，所述抗原结合片段是选自Fab、Fab’、Fab’-SH、Fv、scFv、F(ab’)2和双体的抗体片段。
本发明包括一种增强人受试者的免疫应答的方法，所述方法包括：给有此需要的受试者施用有效地刺激GITR信号传递的量的对GITR特异性的抗体(或其抗原结合片段)。在有些实施方案中，对GITR特异性的抗体是人源化的或嵌合的抗体。在其它实施方案中，所述免疫应答是抗感染应答或抗病毒应答。在某些实施方案中，所述GITR抗体或其抗原结合片段与TGFβ抗体或局部辐射共同施用。
本发明包括一种分离的核酸，其编码本发明的结合化合物的抗体实施方案的多肽序列。所述核酸可以是在表达载体中，其可操作地连接至所述载体转染的宿主细胞识别的控制序列上。也包括包含所述载体的宿主细胞和生产多肽的方法，所述方法包括：在表达所述核酸序列的条件下培养宿主细胞，从而生产多肽，并从宿主细胞或培养基回收多肽。
本发明提供了由保藏在美国典型培养物保藏中心(ATCC)的杂交瘤生产的抗体或其抗原结合片段，其中所述杂交瘤选自：PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
本发明包括结合人GITR蛋白的抗体或抗原结合片段，其中所述抗体或抗原结合片段会识别跨人GITR蛋白(SEQ ID NO：89)的模块3和模块4的表位。在某些实施方案中，所述表位包含Gly57、Arg65、His67、Lys80、Phe81、Ser82和Gln86。在还其它实施方案中，所述抗体会交叉阻断由选自下述的杂交瘤生产的抗体或抗体片段中的至少一种：PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
详细描述
如本文(包括附加权利要求)所使用的，单词的单数形式如“一个”、“一种”和“该”包括其相应的复数含义，除非上下文另有明确说明。下面的表15提供了在本申请中使用的序列标识符的列表。本文引用的所有参考文献都通过引用并入，其程度如同每个单独的出版物、数据库登录项(例如Genbank序列或GeneID登录项)、专利申请或专利明确地且单独地被 指出通过引用并入。在本文中对参考文献的引用并不意味着承认前述中的任一种是有关的现有技术，也不意味着它构成关于这些出版物或文件的内容或日期的任何承认。
I.定义
术语“GITR”、“糖皮质激素诱导的TNFR相关蛋白”、“活化可诱导的TNFR家族受体”、“AITR”、“肿瘤坏死因子受体超家族成员18”和“TNFSF18”是本领域众所周知的。在WO98／06842中公开了人和小鼠GITR核苷酸和多肽序列。人GITR氨基序列(Q9Y5U5)和小鼠GITR核酸和氨基酸序列(AF109216)的保藏品也是可得到的。
“增殖活性”包括对于例如正常细胞分裂以及癌症、肿瘤、发育异常、细胞转化、转移或血管发生可促进、必需或特异性相关的活性。
“施用”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“施用”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“施用”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。“处理”在应用于人、兽医学或研究受试者或者细胞、组织或器官时，包括试剂与动物受试者、细胞、组织、生理区室或生理流体的接触。“细胞的处理”还包括其中试剂接触GITR(例如在流体相或胶体相中)的情况，而且包括其中激动剂或拮抗剂不接触细胞或受体的情况。
本文使用的术语“抗体”是指表现出所需生物学活性的任何形式的抗体。因此，它以最广义使用，具体地涵盖：单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)、嵌合抗体、人源化抗体、全人抗体等。只要它们表现出所需生物学活性。
本文使用的术语“GITR结合片段”、“其结合片段”或“其抗原结合片段”包括抗体的片段或衍生物，其仍然基本上保留它的诱导GITR信号传递的生物学活性，在本文中称作“GITR诱导活性”。术语“抗体片段”或GITR结合片段是指全长抗体的一部分，通常是其抗原区或可变区。抗体片段的实例包括：Fab、Fab′、F(ab′)2和Fv片段；双体；线性抗体；单链抗体分子，例如sc-Fv；和由抗体片段形成的多特异性抗体。通常，结合片段或衍生物保留它的GITR激动剂活性的至少10％。优选地，结合片段或衍生物保留它的GITR激动剂活性的至少25％、50％、60％、70％、80％、90％、95％、99％或100％(或更多)，尽管 具有足以产生所需生物学效应的亲和力的任意结合片段都是有用的。还预期，GITR结合片段可以包括这样的变体，其具有基本上不改变其生物学活性的保守氨基酸置换。
本文使用的术语“单克隆抗体”是指得自基本上均质抗体群体的抗体，即，除了可以以小量存在的可能天然发生的突变以外，构成群体的个体抗体是相同的。单克隆抗体是高度特异性的，针对单个抗原表位。相比之下，常规(多克隆)抗体制剂一股包括针对不同表位(或对其特异性)的许多抗体。修饰词“单克隆”指得自基本上均质的抗体群体的抗体特征，并且不应被解释为需要通过任何具体方法生产抗体。例如，依照本发明使用的单克隆抗体可以通过首先由Kohler等(1975)Nature256：495描述的杂交瘤方法制备，或可以通过重组DNA法(参见，例如，美国专利号4,816,567)制备。“单克隆抗体”还可以使用例如Clackson等(1991)Nature352：624-628和Marks等(1991)J.Mol.Biol.222：581-597中描述的技术从噬菌体抗体文库中分离。
本文的单克隆抗体具体包括“嵌合”抗体(免疫球蛋白)，其中重链和／或轻链的部分与源于特定物种或属于特定抗体类或亚类的抗体的相应序列相同或同源，而一条或多条链的其余部分与源于另一物种或属于另一抗体类或亚类的抗体的相应序列相同或同源，以及此种类抗体的片段，只要它们具有所需生物学活性。美国专利号4,816,567；Morrison等人(1984)Proc.Natl.Acad.Sci.USA81：6851-6855。
“结构域抗体”为仅含有重链可变区或轻链可变区的免疫功能性免疫球蛋白片段。在某些情况下，两个或更多个VH区与肽接头共价连接，产生二价结构域抗体。二价结构域抗体的两个VH区可靶向相同的或不同的抗原。
“二价抗体”包含2个抗原结合位点。在某些情况下，2个结合部位具有相同抗原特异性。然而，二价抗体可以是双特异性的(参见下文)。
本文使用的术语“单链Fv”或“scFv抗体”是指包含抗体的VH和VL结构域的抗体片段，其中这些结构域存在于单条多肽链上。通常，Fv多肽另外包含在VH和VL结构域之间的多肽接头，其使scFv能够形成抗原结合所需的结构。关于scFv的综述，参见Pluckthun(1994)The Pharmacology of Monoclonal Antibodies，第113卷，Rosenburg和Moore编辑，Springer-Verlag，New York，第269-315页。
本文的单克隆抗体还包括骆驼源化单结构域抗体。参见，例如，Muyldermans等(2001)Trends Biochem.Sci.26：230；Reichmann等(1999)J.Immunol.Methods231：25；WO94／04678；WO94／25591；美国专利号6,005,079。在一个实施方案中，本发明提供了包含修饰的2个VH结构域以致于形成单结构域抗体的单结构域抗体。
本文使用的术语“双体(diabody)”是指具有2个抗原结合位点的小抗体片段，所述片段在相同多肽链中包含与轻链可变结构域(VL)连接的重链可变结构域(VH)(VH-VL或VL-VH)。通过使用太短而不允许相同链上的2个结构域之间配对的接头，迫使结构域与另一条链的互补结构域配对，并产生2个抗原结合位点。在例如EP404,097；WO93／11161；和Holliger等(1993)Proc.Natl.Acad.Sci.USA90：6444-6448中更充分地描述了双体。关于工程改造的抗体变体的综述，一股参见Holliger和Hudson(2005)Nat.Biotechnol.23：1126-1136。
本文使用的术语“人源化抗体”是指包含来自非人(例如，鼠)抗体以及人抗体的序列的抗体形式。这样的抗体含有源自非人免疫球蛋白的微小序列。一股而言，人源化抗体将包含基本上所有的至少1个且通常是2个可变结构域，其中所有的或基本上所有的高变环均对应于非人免疫球蛋白的那些，所有的或基本上所有的FR区都是人免疫球蛋白序列的那些。人源化抗体任选地还包含免疫球蛋白恒定区(Fc)的至少一部分，所述恒定区通常是人免疫球蛋白的恒定区。当需要将人源化抗体与母体啮齿动物抗体区分开时，将前缀“hum”、“hu”或“h”添加在抗体克隆名称上。啮齿动物抗体的人源化形式通常包含母体啮齿动物抗体的相同CDR序列，尽管可能包括某些氨基酸置换来增加亲和力、增加人源化抗体的稳定性或为了其它原因。
本发明的抗体还包括具有修饰的(或阻断的)Fc区以提供改变的效应子功能的抗体。参见，例如，美国专利号5,624,821；WO2003／086310；WO2005／120571；WO2006／0057702；Presta(2006)Adv.DrugDelivery Rev.58：640-656。此种修饰可用于增强或抑制免疫系统的各种反应，在诊断和治疗中具有可能有益的作用。Fc区的改变包括氨基酸变化(置换、缺失和插入)、糖基化或去糖基化和添加多个Fc。Fc的变化还可以改变治疗抗体的抗体半衰期，更长的半衰期会导致更低频率的给药，并增加方便性和减少材料使用。参见Presta(2005)J.Allergy Clin.Immunol.116：731在734-35。
本发明的抗体也包括具有提供完全效应子功能的完整Fc区的抗体，例如同种型IgG1的抗体，其在靶向的细胞中诱导补体依赖性的细胞毒性(CDC)或抗体依赖性的细胞的细胞毒性(ADCC)。
本发明的抗体也包括与细胞毒性的有效负载(诸如细胞毒性剂或放射性核素)缀合的抗体。这样的抗体缀合物可以与抗-GITR治疗联合地用于免疫疗法中，以选择性地靶向和杀死在它们的表面上表达某些抗原的细胞。示例性的细胞毒性剂包括：蓖麻蛋白、长春花生物碱、甲氨蝶呤、假单胞菌外毒素、皂草素、白喉毒素、顺铂、多柔比星、相思豆毒蛋白毒素、白树毒素和美洲商陆抗病毒蛋白。与本发明的抗体一起用于免疫疗法中的示例性的放射性核素包括：125I、131I、90Y、67Cu、211At、177Lu、143pr和213Bi。参见，例如，美国专利申请公开号2006／0014225。
术语“全人抗体”是指只包含人免疫球蛋白序列的抗体。如果全人抗体在小鼠、小鼠细胞或衍生自小鼠细胞的杂交瘤中生产，那么全人抗体可以包含小鼠碳水化合物链。类似地，“小鼠抗体”或“大鼠抗体”是指分别只包含小鼠或大鼠免疫球蛋白序列的抗体。全人抗体可以在人类中、在具有人免疫球蛋白种系序列的转基因动物中制备，通过噬菌体展示或其它分子生物学方法来制备。
本文使用的术语“高变区”是指负责抗原结合的抗体氨基酸残基。高变区包含来自“互补决定区”或“CDR”的氨基酸残基(例如，轻链可变结构域中的残基24-34(CDRL1)、50-56(CDRL2)和89-97(CDRL3)，和重链可变结构域中的残基31-35(CDRH1)、50-65(CDRH2)和95-102(CDRH3)；Kabat等(1991)Sequences of Proteins of Immunological Interest，第5版，Public Health Service，National Institutes of Health，Bethesda，Md.)和／或来自“高变环”的那些残基(例如，轻链可变结构域中的残基26-32(L1)、50-52(L2)和91-96(L3)，和重链可变结构域中的残基26-32(H1)、53-55(H2)和96-101(H3)；Chothia和Lesk(1987)J.Mol.Biol.196：901-917)。本文使用的术语“框架”或“FR”残基是指除本文定义为CDR残基的高变区残基外的那些可变结构域残基。上面的残基编号遵循Kabat编号系统，且不一定详细地对应附随的序列表中的序列编号。
“结合化合物”是指能够与靶标结合的分子、小分子、大分子、多肽、抗体或其片段或类似物、或可溶性受体。“结合化合物”还可以指能够与靶标结合的分子复合物(例如非共价复合物)、电离分子以及共价或非共价修饰的分子(例如通过磷酸化、酰化、交联、环化或有限分裂修饰的分子)。当关于抗体使用时，术语“结合化合物”是指抗体和其抗原结合片段。“结合”是指结合组合物与靶标的结合，其中在结合组合物可以溶解或悬浮于溶液中的情况下，所述结合导致结合组合物的正常布朗运动减少。“结合组合物”是指与稳定剂、赋形剂、盐、缓冲剂、溶剂或添加剂相组合的、能够结合靶标的分子，例如结合化合物。
“保守修饰的变体”或“保守置换”是指本领域技术人员已知的氨基酸置换，且经常甚至在多肽的必需区域中进行，而不改变得到的分子的生物学活性。此种示例性置换优选依照如下表1中所示的那些来进行：
表1示例性的保守氨基酸置换
本领域技术人员知晓，一股而言，多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性。参见，例如，Watson等(1987)Molecular Biology of the Gene，TheBenjamin／Cummings Pub.Co.，第224页，(第4版)。
整个说明书和权利要求书中使用的短语“基本上由……组成”或其变形表示包括所有所述元件或元件组，并且任选包括与所述元件类似或不同性质的其它元件，所述其它元件非显著改变指定给药方案、方法或组合物的基本性质或新性质。作为非限制性实例，基本上由所提及的氨基酸序列组成的结合化合物还可以包括一种或多种氨基酸(包括一种或多种氨基酸残基的置换)，其不显著影响结合化合物的性质。
“有效量”包含足以改善或预防医学病症的征状或病征的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。参见，例如，美国专利号5,888,530。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。效果将导致诊断测量或参数改善至少5％、通常至少10％、更通常至少20％、最通常至少30％、优选至少40％、更优选至少50％、最优选至少60％、理想地至少70％、更理想地至少80％和最理想地至少90％，其中100％被定义为由正常受试者显示的诊断参数。参见，例如，Maynard等(1996)A Handbook of SOPs for Good Clinical Practice，InterpharmPress，Boca Raton，FL；Dent(2001)Good Laboratory and Good Clinical Practice，UrchPubl.，London，UK。
“免疫病症”或“免疫障碍”包括例如病理性炎症、炎性病症和自身免疫性病症或疾病。“免疫病症”还指感染、持续感染和增生性病症，例如癌症、肿瘤和血管发生，包括抗免疫系统根除的感染、肿瘤和癌症。“癌性病症”包括例如癌症、癌细胞、肿瘤、血管发生和癌变前病症，例如发育异常。
术语“免疫障碍”指哺乳动物中由哺乳动物免疫系统成分引起、介导、或以其它方式促成发病的疾病。还包括刺激或干预免疫应答对疾病发展具有改善作用的疾病。该术语包括自身免疫病、免疫介导的炎性疾病、非免疫介导的炎性疾病、传染病和免疫缺陷病。可依照本发明治疗的免疫相关疾病和炎性疾病的实例(其中有些是免疫或T细胞介导的)包括：系统性红斑狼疮、类风湿性关节炎、幼年型慢性关节炎、脊椎关节病、系统性硬化病(硬皮病)、特发性炎性肌病(皮肌炎、多肌炎)、干燥综合征、系统性血管炎、结节病、自身免疫性溶血性贫血(免疫性全血细胞减少症、阵发性夜间血红蛋白尿)、自身免疫性血小板减少症(特发性血小板减少性紫癜、免疫介导的血小板减少症)、甲状腺炎(格雷夫斯氏病、桥本甲状腺炎、幼年型淋巴细胞性甲状腺炎、萎缩性甲状腺炎)、糖尿病、免疫介导的肾病(肾小球肾炎、肾小管间质性肾炎)、中枢和周围神经系统的脱髓鞘病诸如多发性硬化病、特发性脱髓鞘多神经病或格-巴二氏(Guillain-Barre)综合征、和慢性炎性脱髓鞘多神经病、肝胆病诸如传染性肝炎(甲型、乙型、丙型、丁型、戊型和其它非嗜肝病毒肝炎)、自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、和硬化性胆管炎、炎性和纤维化肺病诸如炎性肠病(溃疡性结肠炎：克罗恩病)、麸胶敏感性肠病、和惠普尔氏(Whipple)病、自身免疫性或免疫介导的皮肤病包括大疱性皮肤病、多形红斑和接触性皮炎、银屑病、变应性疾病诸如哮喘、变应性鼻炎、特应性皮炎、食物超敏反应和荨麻疹、肺的免疫学疾病诸如嗜曙红细胞性肺炎、特发性肺纤维化和超敏感性肺炎、移植相关疾病包括移植物排斥和移植物抗宿主疾病。传染病包括AIDS(HIV感染)、甲型、乙型、丙型、丁型和戊型肝炎、细菌感染、真菌感染、原生动物感染和寄生虫感染。
术语“癌症”、“肿瘤”、“癌性的”和“恶性的”是指或描述哺乳动物中特征通常为细胞生长不受调节的生理状况。癌症的实例包括、但不限于：癌，包括腺癌、淋巴瘤、母细胞瘤、黑素瘤、肉瘤和白血病。此类癌症的更具体实例包括：鳞状细胞癌、小细胞肺癌、非小细胞肺癌、胃肠癌、何杰金氏和非何杰金氏淋巴瘤、胰腺癌、胶质母细胞瘤、神经胶质 瘤、宫颈癌、卵巢癌、肝癌诸如肝的癌和肝细胞瘤、膀胱癌、乳癌、结肠癌、结肠直肠癌、子宫内膜癌、骨髓瘤(诸如多发性骨髓瘤)、唾液腺癌、肾癌诸如肾细胞癌和威尔曼瘤、基底细胞癌、黑素瘤、前列腺癌、外阴癌、甲状腺癌、睾丸癌、食管癌、及各种类型的头颈癌。
随着癌性细胞生长和倍增，它们形成癌性组织块，这就是肿瘤，其侵入和破坏正常的邻近组织。恶性肿瘤是癌症。恶性肿瘤经常可以切除，但是它们可能再生。来自恶性肿瘤的细胞可以侵入和破坏附近的组织和器官。另外，癌细胞可以脱离恶性肿瘤，并进入血流或淋巴系统，这是癌细胞从原发肿瘤(即，最初的癌)扩散以在其它器官中形成新肿瘤的途径。癌症在体内的扩散被称作转移(What You Need to Know About Cancer-an Overview,NIH公开号00-1566；2000年9月26日公布，2002年9月16日更新(2002))。
本文使用的术语“实体瘤”是指异常的组织生长或块，其通常不含有囊肿或液体区。实体瘤可以是良性的(非癌性的)或恶性的(癌性的)。不同类型的实体瘤根据形成它们的细胞的类型来命名。实体瘤的实例是：肉瘤、癌和淋巴瘤。白血病(血癌)通常不形成实体瘤(National Cancer Institute，Dictionary of Cancer Terms)。
本文使用的术语“原发癌”是指最初的肿瘤或首个肿瘤。癌症可以开始于身体的任何器官或组织。它通常根据它起源的身体部分或细胞类型而命名(Metastatic Cancer：Questions and Answers，Cancer Facts6.20，National Cancer Institute，2004年9月1日综述(2004))。
本文使用的术语“原位癌”是指这样的癌性细胞：其仍然被包含在它们开始生长的组织内，且尚未变成侵入性的，或尚未扩散至身体的其它部分。
本文使用的术语“癌”是指上皮细胞的癌症，所述上皮细胞是覆盖身体的表面、产生激素和构成腺体的细胞。癌的实例是皮肤、肺、结肠、胃、乳腺、前列腺和甲状腺的癌症。
本文使用的术语“分离的核酸分子”是指这样的核酸分子：其从所述抗体核酸的天然来源中通常伴随的至少一种污染核酸分子中鉴别和分离出来。分离的核酸分子不同于它在自然界中发现的形式或场所。分离的核酸分子因此不同于在天然细胞中存在的核酸分子。但是，分离的核酸分子包括在通常表达抗体的细胞中含有的核酸分子，例如，其中所述核酸分子是在不同于天然细胞的染色体位置中。
表述“控制序列”是指在特定宿主生物中表达可操作地连接的编码序列所必需的DNA序列。适合于原核生物的控制序列例如包括启动子、任选的操纵子序列和核糖体结合位点。已知真核细胞利用启动子、多腺苷酸化信号和增强子。
当将核酸置于与另一个核酸序列的功能性关系之中时，它是“可操作地连接的”。例如，如果前序列或分泌前导序列的DNA被表达为参与多肽分泌的前蛋白，则该DNA与多肽的DNA可操作地连接；如果启动子或增强子影响序列的转录，则其与编码序列可操作地连接；或者如果核糖体结合位点的位置使得利于翻译，则其与编码序列可操作地连接。一股地，“可操作地连接的”意指被连接的DNA序列是邻接的，并且对分泌前导序列而言，是邻接的并在读码框中。然而，增强子不必是邻接的。通过在方便的限制位点上连接来实现相连。如果此种位点不存在，那么依照常规实践使用合成寡核苷酸连接物或接头。
本文使用的表述“细胞”、“细胞系”和“细胞培养物”可互换使用，并且所有这类名称都包括后代。因此，单词“转化体”和“转化细胞”包括原代受试细胞和由其衍生的培养物，而不考虑转移数目。还应当理解的是，由于故意或非有意的突变，所有后代在DNA含量方面不可能精确相同。包括具有与最初转化细胞中筛选的相同的功能或生物学活性的突变后代。在意指不同名称的情况下，其由上下文清楚可见。
本文使用的“聚合酶链式反应”或“PCR”是指其中微量的特定部分的核酸、RNA和／或DNA如在例如美国专利号4,683,195中所述扩增的程序或技术。一股来说，需要获得来自目标区域末端或之外的序列信息，使得可以设计寡核苷酸引物；这些引物在序列方面与待扩增模板的对应链相同或相似。2个引物的5’末端核苷酸可以与扩增材料的末端一致。PCR可用于扩增特定的RNA序列、来自总基因组DNA的特定DNA序列和由总细胞RNA转录的cDNA、噬菌体或质粒序列等。一股参见Mullis等(1987)Cold Spring Harbor Symp.Quant.Biol.51：263；Erlich编辑，(1989)PCR Technology(Stockton Press，N.Y.)。本文使用的PCR被视为用于扩增核酸测试样品的核酸聚合酶反应法的一个实例，但不是唯一的实例，所述方法包括使用作为引物的已知核酸和核酸聚合酶，以扩增或产生核酸的特定部分。
本文使用的术语“种系序列”是指未重新排列的免疫球蛋白DNA序列的一个序列，包括啮齿动物(例如小鼠)和人种系序列。可以使用未重新排列的免疫球蛋白DNA的任意合适的来源。例如，可以从种系数据库(在美国国立卫生研究院的国家关节炎和肌肉骨骼及皮肤病研究所网站上)，得到人种系序列。例如，可以如在Giudicelli等人(2005)NucleicAcidsRes.33：D256-D261中所述，得到小鼠种系序列。
为了检查GITR活性的增强程度，例如，用潜在的活化剂或抑制剂处理包含给定的例如蛋白、基因、细胞或生物体的样品或试验，并且与不使用所述试剂的对照样品比较。对照样品，即不用所述试剂处理的样品，被指定100％的相对活性值。当相对于对照的活性值为 约90％以下、典型地85％以下、更典型地80％以下、最典型地75％以下、一股地70％以下、更一股地65％以下、最一股地60％以下、典型地55％以下、通常50％以下、更通常45％以下、最通常40％以下、优选35％以下、更优选30％以下、再更优选25％以下和最优选小于20％时，实现抑制。当相对于对照的活性值为约110％、一股至少120％、更一股至少140％、更一股至少160％、通常至少180％、更通常至少2倍、最通常至少2.5倍、经常至少5倍、更经常至少10倍、优选至少20倍、更优选至少40倍和最优选高于40倍时，实现活化。
活化或抑制的终点可以如下进行监测。例如细胞、生理学流体、组织、器官和动物或人受试者的活化、抑制和对处理的应答可以通过终点进行监测。终点可以包括预定量或百分比的例如炎症、致癌性或细胞脱粒或分泌的标记，例如细胞因子、有毒氧或蛋白酶的释放。终点可以包括例如预定量的离子流或运输；细胞迁移；细胞粘附；细胞增殖；转移潜力；细胞分化；和表型变化，例如，涉及炎症、凋亡、转化、细胞周期或转移的基因表达的变化(参见，例如，Knight(2000)Ann.Clin.Lab.Sci.30：145-158；Hood和Cheresh (2002)NatureRev.Cancer2：91-100；Timme等，(2003)Curr.Drug Targets4：251-261；Robbins和Itzkowitz(2002)Med.Clin.North Am.86：1467-1495；Grady和Markowitz(2002)Annu.Rev.Genomics Hum.Genet.3：101-128；Bauer等，(2001)Glia36：235-243；Stanimirovic和Satoh(2000)BrainPathol.10：113-126)。
抑制终点一股是对照的75％以下、优选对照的50％以下、更优选对照的25％以下和最优选对照的10％以下。一股地，活化终点为对照的至少150％、优选对照的至少2倍、更优选对照的至少4倍和最优选对照的至少10倍。
“小分子”被定义为分子量小于10kD、通常小于2kD、优选小于1kD的分子。小分子包括、但不限于：无机分子、有机分子、含无机组分的有机分子、含放射性原子的分子、合成分子、肽模拟物和抗体模拟物。作为治疗剂，小分子可以比大分子更能透过细胞、对降解更不易感和更不易于引发免疫应答。已描述了小分子，例如抗体和细胞因子的肽模拟物，以及小分子毒素。参见，例如，Casset等人(2003)Biochem.Biophys.Res.Commun.307：198-205；Muyldermans(2001)J.Biotechnol.74：277-302；Li(2000)Nat.Biotechnol.18：1251-1256；Apostolopoulos等人(2002)Curr.Med.Chem.9：411-420；Monfardini等人(2002)Curr.Pharm.Des.8：2185-2199；Domingues等人(1999)Nat.Struct.Biol.6：652-656；Sato和Sone(2003)Biochem.J.371：603-608；美国专利号6,326,482。
“特异性地”或“选择性地”结合在指配体／受体、抗体／抗原或其它结合对时，指决定蛋白和其它生物产品的异质群体中的蛋白存在情况的结合反应。因此，在指定条件下，指定配体与特定受体结合，并且不以显著量与样品中存在的其它蛋白结合。如果本文使用的抗体结合包含GITR序列的多肽、但是不结合缺少GITR序列的蛋白，则称作它特异性地结合包含给定序列的多肽(在该情况下，GITR)。例如，特异性地结合包含GITR的多肽的抗体，可能结合-标记形式的GITR，但是不会结合其它-标记的蛋白。
预期方法的抗体或衍生自抗体的抗原结合位点的结合组合物与其抗原结合的亲和力，是与无关抗原的亲和力的至少2倍、优选至少10倍、更优选至少20倍和最优选至少100倍。在一个优选的实施方案中，所述抗体将具有大于约109升／mol的亲和力，例如通过Scatchard分析测定。Munsen等人(1980)Analyt.Biochem.107：220-239。
本文使用的“慢性病毒感染”或“持续的病毒感染”是指人或其它动物的病毒感染，其能够感染宿主，并在宿主细胞内长时间繁殖——通常数周、数月或数年，而不致死。根据本发明可以治疗的、会造成慢性感染的病毒包括：人乳头瘤病毒(HPV)、单纯疱疹和其它疱疹病毒、乙型肝炎病毒和丙型肝炎病毒(HBV和HCV)以及其它肝炎病毒、麻疹病毒(它们都会产生重大临床疾病)和HIV。长期感染最终可能导致对患者致命的疾病的诱发，例如，在丙型肝炎病毒的情况下，所述疾病可能是肝癌。根据本发明可以治疗的其它慢性病毒感染包括：EB病毒(EBV)以及其它病毒，诸如可能与肿瘤有关的那些，或在动物的情况下，各种兽病毒疾病，例如家养宠物或在农业上重要的农用动物的那些。
术语“抗病毒活性”是指：抑制病毒向未感染的细胞传递，抑制病毒的复制，预防病毒在宿主中确立自身地位，或改善或减轻由病毒感染造成的疾病的征状。这些效果可以由病毒载量的减少或死亡率和／或发病率的降低来证实，它们的测定如下文所述。抗病毒剂或药物具有抗病毒活性，且可单独地或作为多药物联合治疗的一部分用于治疗持久的或慢性的病毒感染。
II.概述
本发明提供了工程化的抗-GITR抗体，及其用于治疗免疫障碍、尤其是受损的对感染性疾病(包括病毒感染)和癌症的应答的应用。
GITR(也称作TNFRSF18)是属于TNR-R超家族的一种受体。迄今为止，不可得到人或小鼠GITR的晶体结构，但是，基于例如在Naismith和Sprang(1998)TrendsBiochem.Sci.23：74-79中所述的研究，可以建立所述分子的分子结构。图2表明，人GITR可以分成6个模块。从下面的研究可知，某些具有激动剂活性的抗体可能具有跨模块3和4的构象表位。
III.GITR特异性抗体的制备
可以使用任何适于产生单克隆抗体的方法。例如，可以用GITR或其片段免疫受体。可以使用任何合适的免疫接种方法。这类方法可以包括佐剂、其它免疫刺激剂、重复的加强免疫接种以及使用一种或多种免疫接种途径。GITR的任意合适的来源可以用作免疫原，用于制备本文公开的组合物和方法中的非人抗体。这样的形式包括、但不限于：通过本领域已知的重组方法、合成方法、化学方法或酶降解方法制备的完整蛋白、肽和表位。在优选的实施方案中，所述免疫原包含GITR的胞外部分。
任意形式的抗原可以用于制备足以产生生物活性抗体的抗体。因而，引发抗原可以是单个表位、多个表位或整个蛋白，它们是单独的或与本领域已知的一种或多种免疫原性增强剂相组合。引发抗原可以是分离的全长蛋白、细胞表面蛋白(例如，用被所述抗原的至少一部分转染的细胞免疫接种)或可溶性蛋白(例如，仅用所述蛋白的胞外结构域部分免疫接种)。可以在遗传修饰的细胞中生产所述抗原。编码所述抗原的DNA可以是基因组的或非基因组的(例如，cDNA)，且编码胞外结构域的至少一部分。本文使用的术语“一部分”是指，适当地构成目标抗原的免疫原性表位的最小数目的氨基酸或核酸。可以采用适合转化目标细胞的任何遗传载体，包括、但不限于腺病毒载体、质粒和非病毒载体，诸如阳离子脂质。
任何合适的方法都可以用于激发具有所需生物学性质的抗体，以增强GITR信号传递。希望从不同的哺乳动物宿主(例如小鼠、大鼠、其它啮齿动物、人类、其它灵长类动物等)中制备单克隆抗体(mAb)。用于制备这样的单克隆抗体的技术的描述，可以参见，例如，Stites等人(编)Basic and Clinical Immunology(第4版)Lange Medical Publications，Los Altos，CA，以及其中引用的参考文献；Harlow和Lane(1988)Antibodies：ALaboratoryManual CSH Press；Goding(1986)Monoclonal Antibodies：Principles and Practice(第2版)Academic Press，New York，NY。因此，单克隆抗体可以通过本领域研究人员熟悉的多种技术获得。通常，来自用所需抗原免疫的动物的脾细胞通常通过与骨髓瘤细胞融合而永生化。参见Kohler和Milstein(1976)Eur.J.Immunol.6：511-519。永生化的替代方法包括用EB病毒、癌基因或逆转录酶病毒或本领域已知的其它方法转化。参见，例如，Doyle等(编辑)(1994和周期增刊)Cell and Tissue Culture：Laboratory Procedures，John Wiley andSons，New York，NY。关于对抗原具有所需特异性和亲和力的抗体的生产，筛选产生于单一永生化细胞的集落，这类细胞生产的单克隆抗体的得率可以通过各种技术得到提高，包括注射入脊椎动物宿主的腹腔内。或者，通过根据例如Huse等人(1989)Science246：1275-1281所述的一股方案，筛 选来自人B细胞的DNA文库，可以分离出编码单克隆抗体或其抗原结合片段的DNA序列。
其它合适的技术涉及在噬菌体或相似载体中选择抗体文库。参见，例如，Huse等人同上；和Ward等人(1989)Nature341：544-546。本发明的多肽和抗体可以经修饰或不经修饰使用，包括嵌合的或人源化的抗体。经常，通过共价地或非共价地连接提供可检测信号的物质来标记多肽和抗体。多种多样的标记和缀合技术是已知的，并且在科学文献和专利文献中广泛报道。合适的标记包括放射性核素、酶、底物、辅因子、抑制剂、荧光部分、化学发光部分、磁性颗粒等。教导此类标记使用的专利包括：美国专利号3,817,837；3,850,752；3,939,350；3,996,345；4,277,437；4,275,149；和4,366,241。另外，可以生产重组免疫球蛋白，参见Cabilly的美国专利号4,816,567；和Queen等(1989)Proc.Nat′l Acad.Sci.USA86：10029-10033；或可以在转基因小鼠中制备，参见Mendez等人(1997)Nature Genetics15：146-156。还参见Abgenix和Medarex的技术。
或者，通过富集从用人GITR免疫接种的动物(例如，小鼠、大鼠、兔等)的脾分离出的B细胞的克隆群体，可以生产单克隆抗体(参见，例如，WO2008045140、US5627052和US20030186327)。
通过用多肽、片段、肽或表位与载体蛋白的缀合物免疫接种动物，可以产生针对预先确定的GITR片段的抗体或结合组合物。单克隆抗体从分泌所需抗体的细胞制备。可筛选这些抗体与正常或缺陷型GITR的结合。这些单克隆抗体通常将以至少约1μM、更通常至少约300nM、30nM、10nM、3nM、1nM、300pM、100pM、30pM或更好的Kd结合，所述Kd通常通过ELISA或Biacore来测定。还可以使用下文实施例5和6中描述的生物学测定，鉴定合适的非人抗体。
在布达佩斯条约要求下，在2009年3月25日，将与克隆3D6、36E5、61G6、6H6和61F6相对应的杂交瘤保藏在美国典型培养物保藏中心(“ATCC”)，其保藏号分别为PTA-9889、PTA-9890、PTA-9891、PTA-9892和PTA-9893，其分类命名分别为Hybridoma Cell Line JL5-3D6、Hybridoma Cell Line TC97-36E5.A5、Hybridoma Cell Line TC97.61G6.B6、Hybridoma Cell Line TC97-6H6.C3和Hybridoma Cell Line TC97-61F6.B9。
根据布达佩斯条约要求，在2009年8月20日，将与克隆17F10、9E5、31H6、1D8、49A1、和35D8相对应的杂交瘤保藏在ATCC，其保藏号分别为PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291，其分类命名分别为Mouse hybridoma：TCl09-17F10.B1、Mouse hybridoma：TC108-9E5.C1、Mouse hybridoma：TC108-31H6.B7、Mousehybridoma：TC109-1D8.35、Mouse hybridoma：TC109-49A1.B1和Mouse hybridoma：TC109-35D8.B10。
IV.GITR特异性抗体的人源化
任何合适的非人抗体都可以用作高变区的来源。非人抗体的来源包括、但不限于：鼠(例如小家鼠(Mus musculus))、大鼠(例如褐家鼠(Rattus norveglcus))、兔类动物(包括兔)、 牛和灵长类动物。在极大程度上，人源化抗体是这样的人免疫球蛋白(受体抗体)：其中受体的高变区残基被来自具有所需特异性、亲和力和能力的非人物种(供体抗体)的高变区残基替换，所述非人物种例如为小鼠、大鼠、兔或非人灵长类动物。在某些情况下，人免疫球蛋白的Fv框架区(FR)残基被对应的非人残基替换。而且，人源化抗体可以包含在受体抗体或供体抗体中不存在的残基。进行这些修饰，以进一步精修所需生物学活性的抗体性能。关于进一步的细节，参见Jones等人(1986)Nature321：522-525；Reichmann等人(1988)Nature332：323-329；和Presta(1992)Culr.Op.Struct.Biol.2：593-596。
已经描述了用于重组改造和生产抗体的方法，例如，Boss等人(美国专利号4,816,397)，Cabilly等人(美国专利号4,816,567)，Law等人(欧洲专利申请公开号438310)和Winter(欧洲专利申请公开号239400)。
通过将合适的核苷酸变化引入人源化的抗-GITR抗体DNA内，或通过肽合成，制备人源化的抗-GITR抗体的氨基酸序列变体。这样的变体包括，例如，在人源化的抗-GITR抗体的所示氨基酸序列内的残基的缺失和／或插入和／或置换。可造成缺失、插入和置换的任何组合，以获得最终构建体，前提是，最终构建体具有所需特征。氨基酸变化还可以改变人源化的抗-GITR抗体的翻译后加工，例如改变糖基化位点的数目或位置。
用于鉴定为诱变优选位置的人源化的抗-GITR抗体多肽的某些残基或区域的一种有用方法，被称为“丙氨酸扫描诱变”，其描述在Cunningham和Wells(1989)Science244：1081-1085。在这里，鉴定一个残基或一组靶残基(例如带电残基，如Arg、Asp、His、Lys和Glu)，并被中性或带负电的氨基酸(最优选丙氨酸或聚丙氨酸)替换，以影响氨基酸与GITR抗原的相互作用。随后通过在置换部位处导入另外的或其它的变体，改进显示出对置换的功能敏感性的氨基酸残基。因而，尽管预先确定了用于导入氨基酸序列变化的部位，突变的性质本身不需要预先确定。例如，为了分析在给定部位处的突变的性能，在靶密码子或区域处进行Ala扫描或随机诱变，并筛选表达的人源化的抗-GITR抗体变体的所需活性。
氨基酸序列插入包括长度为1个残基至包含100个以上残基的多肽的氨基和／或羧基末端融合体，以及单个或多个氨基酸残基的序列内插入。末端插入的实例包括：具有N-末端甲硫氨酰残基的人源化的抗-GITR抗体或与表位标签融合的抗体。人源化的抗-GITR抗体分子的其它插入变体包括：增加抗体的血清半衰期的酶或多肽与人源化的抗-GITR抗体的N-末端或C-末端的融合体。
另一类变体是氨基酸置换变体。这些变体在人源化的抗-GITR抗体分子中去除了至少一个氨基酸残基，并在其位置中插入不同残基。最令人感兴趣的置换诱变位点包括高变环， 但也预见到FR改变。
抗体的另一类氨基酸变体会改变抗体的最初糖基化模式。改变是指，消除抗体中的一个或多个碳水化合物部分，和／或添加一个或多个在抗体中不存在的糖基化位点。抗体的糖基化一股是N-连接的或O-连接的。N-连接的是指碳水化合物部分与天冬酰胺残基侧链相连。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸外的任何氨基酸)是碳水化合物部分与天冬酰胺侧链的酶促连接的识别序列。因而，这些三肽序列中的任一个在多肽中的存在，会产生潜在的糖基化位点。O-连接的糖基化是指糖类N-乙酰基半乳糖胺、半乳糖或木糖与羟氨基酸、最通常为丝氨酸或苏氨酸的连接，尽管还可以使用5-羟脯氨酸或5-羟赖氨酸。
通过改变氨基酸序列，使得它含有一个或多个上述的三肽序列，可以方便地向抗体添加糖基化位点(对于N-连接的糖基化位点)。通过向原始抗体的序列添加或置换一个或多个丝氨酸或苏氨酸残基，也可以做出改变(对于O-连接的糖基化位点)。
另一类氨基酸变体是残基的置换，以提供最终人源化抗体的更大化学稳定性。例如，可以改变天冬酰胺(N)残基，以减小在啮齿动物CDR内的任意NG序列处形成异天冬氨酸酯的可能性。类似的问题可能出现在DG序列处。Reissner和Aswad(2003)Cell.Mol.LifeSci.60：1281。异天冬氨酸酯形成可能弱化或完全消除抗体与它的靶抗原的结合。Presta(2005)J.Allergy Clin.Immunol.116：731在734。在一个实施方案中，将天冬酰胺改成谷氨酰胺(Q)。另外，可以改变啮齿动物CDR中的甲硫氨酸残基，以减小甲硫氨酸硫氧化的可能性，所述氧化会减小抗原结合亲和力，并且还促进最终的抗体制品中的分子异质性。同上。在一个实施方案中，将甲硫氨酸改成丙氨酸(A)。随后筛选具有这类置换的抗体，以确保所述置换没有降低GITR结合亲和力至不可接受的水平。
通过本领域已知的多种方法，制备编码人源化的GITR特异性抗体的氨基酸序列变体的核酸分子。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)，或通过人源化的抗-GITR抗体的早前制备的变体或非变体形式的寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
通常，人源化的抗-GITR抗体的氨基酸序列变体所具有的氨基酸序列与重链或轻链的原始人源化抗体氨基酸序列具有至少75％、更优选至少80％、更优选至少85％、更优选至少90％和最优选至少95％、98％或99％氨基酸序列同一性。相对于该序列的同一性或同源性在本文中被定义为：在比对序列(在必要时引入空位，以达到最大序列同一性百分比，并且不将任何保守置换视为序列同一性的组成部分)后，候选序列中与人源化的抗-GITR残基相 同的氨基酸残基的百分比。抗体序列的N末端、C末端或内部延伸、缺失或插入，都不被认为会影响序列同一性或同源性。
人源化抗体可以选自任何种类的免疫球蛋白，包括IgM、IgG、IgD、IgA和IgE。优选地，抗体是IgG抗体。可以使用IgG的任何同种型，包括IgG1、IgG2、IgG3和IgG4。还预见到IgG同种型的变体。人源化抗体可以包含来自一个以上的种类或同种型的序列。通过用实施例中描述的生物学测定筛选抗体易于实现必需恒定结构域序列的最优化，以产生所需生物学活性。
同样，任一类轻链都可以在本文的组合物和方法中使用。具体地说，κ、λ或其变体在本发明的组合物和方法中是有用的。
可以使用来自非人抗体的CDR序列的任何适宜部分。通过置换、插入或缺失至少一个残基，使得CDR序列不同于采用的人和非人抗体序列，可以诱变CDR序列。预见到，这类突变是最小的。典型地，至少75％的人源化抗体残基将对应于非人CDR残基的那些残基，更通常90％，最优选大于95％。
可以使用来自人抗体的FR序列的任何适宜部分。通过置换、插入或缺失至少一个残基，使得FR序列不同于采用的人和非人抗体序列，可以诱变FR序列。预见到，这类突变是最小的。典型地，至少75％的人源化抗体残基将对应于人FR残基的那些残基，更通常90％，最优选大于95％、98％或99％。
根据Kabat的标准序列定义，确定CDR和FR残基。Kabat等人(1987)Sequences ofProteins of Immunological Interest，National Institutes of Health.Bethesda Md。SEQ ID NO：1-11显示了不同啮齿动物抗-人GITR抗体的重链可变结构域序列，SEQ ID NO：12-22描绘了轻链可变结构域序列。
表2重链序列和结构域
表3轻链序列和结构域
在一个实施方案中，CDR包括本文公开的任意单个序列CDR(SEQ ID NO：23-88)的变体，其中所述变体相对于公开的序列包含1、2、3、4、5、6、7、8、9、10或更多个保守氨基酸置换，如使用表1的数据所确定的。
也预见到嵌合抗体。如上面所指出的，典型的嵌合抗体包含重链和／或轻链的一部分，所述部分与源自特定物种或属于特定抗体类别或子类的抗体中的对应序列相同或同源，同时所述链的剩余部分与源自另一个物种或属于另一个抗体类别或子类的抗体中的对应序列相同或同源，以及这样的抗体的片段，只要它们表现出所需生物学活性。参见美国专利号4,816,567；和Morrison等人(1984)Proc.Natl.Acad.Sci.USA81：6851-6855。
双特异性抗体也可用于本发明的方法和组合物中。本文使用的术语“双特异性抗体”是指对至少2种不同抗原表位具有结合特异性的抗体。在一个实施方案中，表位来自相同抗原。在又一个实施方案中，表位来自2种不同抗原。用于制备双特异性抗体的方法是本领域已知的。例如，双特异性抗体可以使用2个免疫球蛋白重链／轻链对的共表达来重组生产。参见，例如，Milstein等(1983)Nature305：537-39。或者，双特异性抗体可以使用化学连接来制备。参见，例如，Brennan等人(1985)Science229：81。双特异性抗体包括双特异性抗体片段。参见，例如，Holliger等人(1993)Proc.Natl.Acad.Sci.U.S.A.90：6444-48，Gruber等人(1994)J.Immunol.152：5368。
在其它的实施方案中，可以给源自本文提供的CDR的人源化的VL和VH区附加不同的恒定结构域。例如，如果本发明的抗体(或片段)的特定预期用途要求改变的效应子功能，那么可以使用除IgG1外的重链恒定结构域。尽管IgG1抗体提供长半衰期和效应子功 能，例如补体活化和抗体依赖性细胞毒性，但此种活性可能不是抗体的所有用途所需要的。在此类情况下可以使用例如IgG4或IgG2恒定结构域。
本发明的抗体的母体形式和工程化形式也可以与化学部分缀合。除了别的以外，所述化学部分可以是聚合物、放射性核素或细胞毒性因子。优选地，所述化学部分是增加抗体分子在受试者体内的半衰期的聚合物。合适的聚合物包括、但不限于：聚乙二醇(PEG)(例如，分子量为2kDa、5kDa、10kDa、12kDa、20kDa、30kDa或40kDa的PEG)、葡聚糖和单甲氧基聚乙二醇(mPEG)。Lee等人，(1999)(Bioconi.Chem.10：973-981)公开了PEG缀合的单链抗体。Wen等人，(2001)(Bioconi.Chem.12：545-553)公开了含有PEG的缀合抗体，所述PEG连接在放射性金属螯合剂(二亚乙基三胺五乙酸(DTPA))上。
也可以用标记缀合本发明的抗体和抗体片段或GITR可溶性蛋白或其片段，所述标记例如99Tc、90y、111in、32P、14C、125I、3H、131I、11C、15O、13N、18F、35S、51Cr、57To、 226Ra、60Co、59Fe、57Se、152Eu、67CU、217Ci、211At、212Pb、47Sc、109pd、234Th和40K、 157Gd、55Mn、52Tr和56Fe。
也可以用荧光标记或化学发光标记缀合本发明的抗体和抗体片段或GITR可溶性蛋白或其片段，所述标记包括：荧光团，诸如稀土螯合物、荧光素和它的衍生物、罗丹明和它的衍生物、异硫氰酸酯、藻红蛋白、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛、荧光胺、152Eu、丹磺酰、伞形酮、萤光素、鲁米诺标记、异鲁米诺标记、芳族吖啶酯标记、咪唑标记、吖啶盐标记、草酸酯标记、水母荧光素标记、2，3-二氢酞嗪二酮、生物素／抗生物素蛋白、旋转标记和稳定自由基。
可以采用本领域已知的将本发明的抗体分子或蛋白分子缀合到不同部分上的任意方法，包括在下述文献中描述的那些方法：Hunter等人，(1962)Nature144：945；David等人，(1974)Biochemistry13：1014；Pain等人，(1981)J.Immunol.Meth.40：219；和Nygren，J.，(1982)Histochem.and Cytochem.30：407。用于缀合抗体和蛋白的方法是本领域常规的且众所周知的。
V.人源化的抗-GITR抗体的生物学活性
可以关于体外抑制性生物活性或合适的结合亲和力，筛选具有在本文中鉴别为人源化的抗-GITR抗体所希望的特征的抗体。使用在实施例5中提供的生物学试验，可以将激动剂抗体与拮抗剂抗体区分开。表现出激动剂活性的抗体不会阻断GITR的活性，但是相反会刺激通常由GITR信号传递介导的应答。
为了筛选与在人GITR(其被目标抗体结合，所述目标抗体例如阻断GITR的结合的那些)上的表位结合的抗体，可以进行常规的交叉阻断试验，诸如在下述文献中描述的试验：Antibodies，A Laboratory Manual，Cold Spring Harbor Laboratory，Harlow和DavidLane编(1988)。结合相同表位的抗体可能在这样的试验中交叉阻断，但是并非所有交叉阻断抗体必然地精确地结合相同表位，因为交叉阻断可能源自结合在重叠表位或甚至附近的非重叠表位处的抗体的抗体结合位阻。
或者，可以进行表位作图，例如，在Champe等人(1995)J.Biol.Chem.270：1388-1394中所述的表位作图，以确定所述抗体是否结合目标表位。也可以使用由Cunningham和Wells(1989)Science244：1081-1085描述的“丙氨酸扫描诱变”或人GITR中的氨基酸残基的一些其它形式的点诱变，以确定本发明的抗-GITR抗体的功能表位。但是，诱变研究也可能揭示这样的氨基酸残基：所述残基对于GITR的总体三维结构而言是重要的，但是不直接参与抗体-抗原接触，因而可能需要其它方法来证实使用该方法确定的功能表位。
通过评估抗体与包含人GITR的片段(SEQ ID NO：41)的肽的结合，也可以确定被特定抗体结合的表位。可以合成一系列包括GITR序列的重叠肽，并筛选其结合，例如在直接ELISA、竞争性ELISA(其中评估所述肽的阻止抗体与结合在微孔滴定板的孔上的GITR相结合的能力)中或在芯片上。这样的肽筛选方法可能不能够检测一些不连续的功能表位，即涉及沿着GITR多肽链的基本序列不连续的氨基酸残基的功能表位。
通过结构方法，诸如X-射线晶体结构测定(例如，WO2005／044853)、分子建模和核磁共振(NMR)波谱学，包括GITR(当游离时，和当结合在与目标抗体的复合物中时)中的不稳定酰胺氢的H-D交换率的NMR测定，也可以测定本发明的抗体所结合的表位(Zinn-Justin等人(1992)Biochemistry31：11335-11347；Zinn-Justin等人(1993)Biochemistry32：6884-6891)。
关于X-射线晶体学，使用本领域已知方法中的任一种(例如Giege等人(1994)ActaCrystallogr：D50：339-350；McPherson(1990)Eur.J.Biochem.189：1-23)，包括微批(microbatch)(例如Chayen(1997)Structure5：1269-1274)、悬滴蒸汽扩散(例如McPherson(1976)J.Biol.Chem.251：6300-6303)、引晶和透析，可以实现结晶。理想地，使用浓度为至少约1mg／mL、优选约10mg／mL至约20mg／mL的蛋白制品。在沉淀剂溶液中可以最好地实现结晶，所述沉淀剂溶液含有聚乙二醇1000-20,000(PEG；平均分子量范围为约1000至约20,000Da)、优选约5000至约7000Da、更优选约6000Da，浓度范围为约10％至约30％(w／v)。也可能希望包括蛋白稳定剂，例如浓度范围为约0.5％至约20％的甘油。也可能希望在沉淀剂溶液中含有合适的盐，诸如氯化钠、氯化锂或柠檬酸钠，优选地其 浓度范围为约1mM至约1000mM。优选地将沉淀剂缓冲至约3.0至约5.0、优选约4.0的pH。可用于沉淀剂溶液中的具体缓冲剂可以变化，且是本领域众所周知的。Scopes，Protein Purification：Principlesand Practice，第3版，(1994)Springer-Verlag，New York。有用的缓冲剂的实例包括、但不限于：HEPES、Tris、MES和乙酸盐。晶体可以在宽温度范围生长，包括2℃、4℃、8℃和26℃。
使用众所周知的X-射线衍射技术，可以研究抗体：抗原晶体，且可以使用计算机软件诸如X-PLOR(Yale University，1992，由Molecular Simulations，Inc.发布；参见，例如，Blundell & Johnson(1985)Meth.Enzymol.114&115，H.W Wyckoff等人编，AcademicPress；美国专利申请公开号2004／0014194)和BUSTER(Bricogne(1993)Acta Cryst.D49：37-60；Bricogne(1997)Meth.Enzymol.276A：361-423，Carter & Sweet，编；Roversi等人(2000)Acta Cryst.D56：1313-1323)来精化。
可以得到结合与本发明的抗体相同的表位的其它抗体，例如，通过筛选针对GITR产生的抗体与所述表位的结合，或通过用包含人GITR片段(其包含所述表位序列)的肽免疫接种动物。可能预期，结合相同功能表位的抗体会表现出类似的生物学活性，诸如阻断受体结合，且这样的活性可以通过所述抗体的功能试验来证实。
使用标准分析，可以测定抗体亲和力。优选的人源化抗体是以下述Kd值结合人GITR的那些：不超过约1x10-7；优选地不超过约1x10-8；更优选地不超过约1x10-9；最优选地不超过约1x10-10或甚至1x10-11M。
可用于本发明的组合物和方法中的抗体和其片段是生物学上有活性的抗体和片段。本文使用的术语“生物学上有活性的”是指这样的抗体或抗体片段：其能够结合所需抗原表位，并且直接或间接发挥生物学作用。本文使用的术语“特异性”是指抗体与靶抗原表位的选择性结合。通过在一组给定条件下比较与GITR的结合和与无关抗原或抗原混合物的结合，可以测试抗体的结合特异性。如果抗体与GITR结合的亲和力是其对无关抗原或抗原混合物的亲和力的至少10倍、优选50倍，那么该抗体被视为特异性的。“特异性地结合”GITR的抗体不结合不含GITR衍生序列的蛋白，即，本文使用的“特异性”涉及GITR特异性，而不涉及可能存在于所研究的蛋白中的任何其它序列。例如，本文使用的“特异性地结合”包含GITR的多肽的抗体通常会结合-GITR(它是包含GITR和肽标签的融合蛋白)，但是它不会结合肽标签(单独的，或当它与非GITR的蛋白融合时)。
本发明的GITR-特异性的结合化合物，诸如激动性的GITR特异性抗体，可以以任意方式增强它的生物学活性，所述方式包括、但不限于增加对微生物感染的免疫应答。
VI.药物组合物
为了制备药用的或无菌的包含GITR抗体的组合物，将细胞因子类似物或突变蛋白、针对它们的抗体或它们的核酸与药学上可接受的载体或赋形剂相混合。参见，例如，Remington′sPharmaceutical Sciences和U.S.Pharmacopeia：National Formulary，MackPublishing Company，Easton，PA(1984)。
治疗剂和诊断剂的制剂可以通过与例如冻干粉末、淤浆、水溶液或混悬液形式的生理学上可接受的载体、赋形剂或稳定剂混合来制备。参见，例如，Hardman等，(2001)Goodman and Gilman’s The Pharmacological Basis of Therapeutics，McGraw-Hill，New York，NY；Gennaro(2000)Remington：The Science and Practice of Pharmacy，Lippincott，Williams 和Wilkins，New York，NY；Avis等，(编辑)(1993)PharmaceuticalDosage Forms：Parenteral Medications，Marcel Dekker，NY；Lieberman等，(编辑)(1990)Pharmaceutical Dosage Forms：Tablets，Marcel Dekker，NY；Lieberman等，(编辑)(1990)Pharmaceutical Dosage Forms：Disperse Systems，Marcel Dekker，NY；Weiner和Kotkoskie(2000)Excipient Toxicity and Safety，Marcel Dekker，Inc.，New York，NY。
单独或与免疫抑制剂组合施用的抗体组合物的毒性和疗效可以通过细胞培养或实验动物的标准药学程序来测定，例如用于测定LD50(对50％的群体致死的剂量)和ED50(在50％的群体中治疗上有效的剂量)的标准药学程序。毒性和疗效之间的剂量比是治疗指数，它可以表示为LD50与ED50之比。优选显示高治疗指数的抗体。由这些细胞培养测定和动物研究获得的数据可以用于配制用于人使用的一系列剂量。这类组合物的剂量优选处于包括基本没有或没有毒性的ED50的循环浓度范围内。剂量可根据使用的剂型和给药途径在此范围内变化。
给药方式不是特别重要的。合适的给药途径可以包括例如，经口、直肠、透粘膜或肠内给药；肠胃外递送，包括肌内、皮下、髓内注射，以及鞘内、直接心室内、静脉内、腹膜内、鼻内或眼内注射。在药物组合物中使用的或用于实践本发明方法的抗体的给药，可以以多种常规方式进行，例如经口摄食、吸入、局部应用或皮肤、皮下、腹膜内、胃肠外、动脉内或静脉内注射。
或者，人们可以以局部而不是全身方式施用抗体，例如，将抗体直接注射到关节炎的关节或特征在于免疫病理学的病原体诱导的病灶内，通常以贮存或持续释放制剂。而且，人们可以施用在靶向药物递送系统中的抗体，例如，在用组织特异性抗体包被的脂质体中，靶 向例如关节炎的关节或特征在于免疫病理学的病原体诱导的病灶。脂质体将被靶向受害组织并被受害组织选择性吸收。
为治疗剂选择给药方案取决于几种因素，包括实体的血清或组织周转率、征状水平、实体的免疫原性和生物基质中靶细胞的可接近性。优选地，给药方案会使递送给患者的治疗剂的量最大化，并与可接受的副作用水平相一致。因此，递送的生物制剂的量部分地取决于特定实体和待治疗病症的严重性。选择合适剂量的抗体、细胞因子和小分子的指引是可获得的。参见，例如，Wawrzynczak(1996)Antibody Therapy，Bios Scientific Pub.Ltd，Oxfordshire，UK；Kresina(ed.)(1991)Monoclonal Antibodies，Cytokines andArthritis，Marcel Dekker，New York，NY；Bach(ed.)(1993)Monoclonal Antibodies andPeptide Therapy in Autoimmune Diseases，Marcel Dekker，New York，NY；Baert等人(2003)New Engl.J.Med.348：601-608；Milgrom等人(1999)New Engl.J.Med.341：1966-1973；Slamon等人(2001)New Engl.J.Med.344：783-792；Beniaminovitz等人(2000)NewEngl.J.Med.342：613-619；Ghosh等人(2003)New Engl.J.Med.348：24-32；Lipsky等人(2000)New Engl.J.Med.343：1594-1602。
合适剂量的确定由临床医生进行，例如，使用本领域已知或怀疑影响治疗预测会影响治疗的参数或因素。一股地，剂量以略微小于最佳剂量的量开始，其后通过小增量增加，直至相对于任何负面副作用达到所需或最佳作用。重要的诊断测量包括例如产生的那些炎症征状或产生的炎性细胞因子水平。优选地，将要使用的生物制剂基本上源自与治疗靶向的动物相同的物种(例如用于治疗人受试者的人源化抗体)，从而使针对试剂的任何免疫应答最小化。
抗体、抗体片段和细胞因子可以通过连续输注或通过间隔给药来提供，所述间隔给药例如1天1次、1-7次／周、1周1次、2周1次、1月1次、2月1次等。可以静脉内地、皮下地、局部地、经口地、鼻地、直肠地、肌内地、大脑内地、椎管内地或通过吸入，提供剂量。一个优选的剂量方案是，包括最大剂量或给药频率的方案，其避免显著的不希望的副作用。每周总剂量通常为至少0.05μg／kg、0.2μg／kg、0.5μg/kg、1μg／kg、10μg／kg、100μg／kg、0.2mg／kg、1.0mg／kg、2.0mg／kg、10mg／kg、25mg／kg、50mg／kg体重或更高。参见，例如，Yang等人(2003)New Engl.J.Med.349：427-434；Herold等人(2002)New Engl.J.Med.346：1692-1698；Liu等人(1999)J.Neurol.Neurosurg.Psych.67：451-456；Portielji等人(20003)CancerImmunol.Immunother.52：133-144。小分子治疗剂(例如，肽模仿物、天然产物或有机化学试剂)的所需剂量与抗体或多肽的剂量大致相同 (以摩尔／kg为基础)。
本文使用的“抑制”或“治疗”或“处理”包括：与自身免疫病或病原体诱发的免疫病理学相关的征状发展的延缓，和／或将会或预期会发展的此种征状的严重性的降低。该术语进一步包括：改善现有的不受控的或不希望的自身免疫相关的或病原体诱发的免疫病理学征状，预防另外的征状，和改善或预防这类征状的潜在原因。因此，该术语指已赋予脊椎动物受试者的有益结果，所述受试者具有自身免疫或病原体诱发的免疫病理学疾病或征状，或可能发生此种疾病或征状。
本文使用的术语“治疗有效量”或“有效量”是指GITR-特异性的结合化合物(例如和抗体)的量，其在单独或与另外的治疗剂组合施用给细胞、组织或受试者时，可有效预防或改善自身免疫病或病原体诱发的免疫病理学相关的疾病或病症或疾病的进程。治疗有效剂量进一步指这样的化合物的量：其足以使征状改善，例如治疗、治愈、预防或改善相关医学病症，或治疗、治愈、预防或改善这类病症的比率增加。当应用于单独施用的单个活性成分时，治疗有效剂量是指单独的该成分。当应用于组合时，治疗有效剂量是指产生疗效的活性成分的组合量，无论是组合、顺次还是同时施用。治疗剂的有效量会使征状减少通常至少10％、通常至少20％、优选至少约30％、更优选至少40％、最优选至少50％。
与第二种治疗剂(例如，细胞因子、抗体、类固醇、化学治疗剂、抗生素、抗病毒剂或辐射)共同施用或治疗的方法，是本领域众所周知的，参见，例如，Hardman等人(编)(2001)Goodman和Gilman的The Pharmacological Basis of Therapeutics，第10版，McGraw-Hill，New York，NY；Poole和Peterson(编)(2001)Pharmacotherapeutics for AdvancedPractice：A Practical Approach，Lippincott，Williams & Wilkins，Phila.，PA；Chabner和Longo(编)(2001)Cancer Chemotherapy and Biotherapy，Lippincott，Williams &Wilkins，Phila.，PA。
化学治疗剂包括：烷化剂类，诸如塞替派和环磷酰胺；烷基磺酸酯类，诸如白消安、英丙舒凡和哌泊舒凡；氮丙啶类，诸如苯佐替派、卡波醌、美妥替派和乌瑞替派；乙烯亚胺类和甲基蜜胺类(methylamelamines)，包括六甲蜜胺、曲他胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲蜜胺(trimethylolomelamine)；番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone))；喜树碱(包括合成类似物托泊替康)；苔藓抑素；callystatin；CC-1065(包括它的阿多来新、卡折来新和比折来新合成类似物)；隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8)；多拉司他汀；多卡米星(包括合成类似物，KW-2189和CB1-TM1)；软珊瑚醇；pancratistatin；sarcodictyin；海绵抑素；氮芥类，诸如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、氮芥、盐酸氧化氮芥、美法仑、新氮芥、泼尼氮芥、曲磷胺、乌拉莫司汀；亚硝脲类，诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀；抗生素类，诸如烯二炔类抗生素(例如，加利车霉素，尤其是加利车霉素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，包括达内霉素A；二膦酸盐类，诸如氯膦酸盐；埃斯波霉素；以及新制癌素发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素、放线菌素、氨茴霉素、偶氮丝氨酸、博来霉素、放线菌素C、卡柔比星、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-二氮杂-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素，嘌罗霉素，三铁阿霉素，罗多比星，链黑霉素，链佐星，杀结核菌素，乌苯美司，净司他丁，佐柔比星；抗代谢物诸如甲氨蝶呤和5-氟尿嘧啶(5-FU)；叶酸类似物诸如二甲叶酸，甲氨蝶呤，蝶罗呤，三甲曲沙；嘌呤类似物诸如氟达拉滨，6-巯嘌呤，硫咪嘌呤，硫鸟嘌呤；嘧啶类似物诸如安西他滨，阿扎胞苷，6-氮杂尿苷，卡莫氟，阿糖胞苷，二脱氧尿苷，去氧氟尿苷，依诺他滨，氮尿苷；雄激素类诸如卡普睾酮，丙酸屈他雄酮，环硫雄醇，美雄烷，睾内酪；抗肾上腺药诸如氨鲁米特，米托坦，曲洛司坦；叶酸补充剂，诸如亚叶酸(frolinic acid)；醋葡醛内酯；醛磷酰胺糖苷；氨基乙酰丙酸；恩尿嘧啶；安吖啶；bestrabucil；比生群；依达曲沙(edatraxate)；地磷酰胺(defofamine)；秋水仙胺；地吖醌；elfomithine；依利醋铵；埃博霉素；依托格鲁；硝酸镓；羟基脲；香菇多糖；氯尼达明(lonidainine)；美登木素生物碱类(maytansinoids)，诸如美坦辛和安丝菌素；米托胍腙；米托蒽醌；莫哌达醇(mopidanmol)；硝氨丙吖啶(nitracrine)；喷司他丁；蛋氨氮芥；吡柔比星；洛索蒽醌；鬼臼酸；2-乙基酰肼；丙卡巴肼；多糖复合物(JHS Natural Products，Eugene，OR)；雷佐生；根霉素；西左非兰；锗螺胺；替奴佐酸；三亚胺醌；2，2′，2″-三氯三乙胺；单端孢霉烯类(尤其是T-2毒素、疣孢菌素A、杆孢菌素A和蛇行菌素(anguidine))；乌拉坦；长春地辛；达卡巴嗪；甘露莫司汀；二溴甘露醇；二溴卫矛醇；哌泊溴烷；gacytosine；阿糖胞苷(“Ara-C”)；环磷酰胺；塞替派；紫杉烷类，例如，泰素紫杉醇(Bristol-Myers Squibb Oncology，Princeton，N.J.)、ABRAxANETM(不含克列莫佛)、白蛋白改造的紫杉醇纳米颗粒制剂(AmericanPharmaceutical Partners，Schaumberg，Ill.)和泰索帝多西紫杉醇(-PoulencRorer，Antony，France)；苯丁酸氮芥(chloranbucil)； 吉西他滨；6-硫鸟嘌呤；巯嘌呤；甲氨蝶呤；铂类似物，诸如顺铂和卡铂；长春碱；铂；依托泊苷(VP-16)；异环磷酰胺；米托蒽醌；长春新碱；长春瑞滨；能灭瘤；替尼泊苷；依达曲沙；道诺霉素；氨基蝶呤；希罗达卡培他滨；伊班膦酸盐；CPT-11；拓扑异构酶抑制剂RFS2000；二氟甲基鸟氨酸(DMFO)；维生素A酸类，诸如维A酸；及任何上述物质的药学上可接受的盐、酸或衍生物。
还包括作用为调节或抑制激素对肿瘤的作用的抗激素剂，诸如抗雌激素类和选择性雌激素受体调节剂(SERM)，他莫昔芬(包括他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、那洛昔芬(keoxifene)、LY117018、奥那司酮和托瑞米芬；抑制调节肾上腺中的雌激素生成的芳香酶的芳香酶抑制剂，例如，4(5)-咪唑、氨鲁米特，醋酸甲地孕酮、依西美坦、福美坦(formestanie)、法倔唑、伏氯唑、来曲唑和阿那曲唑；抗雄激素类，诸如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林；以及曲沙他滨(1，3-二氧戊环核苷胞嘧啶类似物)；反义寡核苷酸，特别是抑制涉入异常细胞增殖中的信号传递途径的基因表达的那些，例如PKC-α、Ralf和H-Ras；核酶，诸如VEGF表达抑制剂(例如，核酶)和HER2表达抑制剂；疫苗，诸如基因疗法疫苗，例如 疫苗、疫苗和疫苗；rIL-2； 拓扑异构酶1抑制剂；rmRH；及上述任一种的药学上可接受的盐、酸或衍生物。
具体地，转化生长因子(TGF)-B在细胞功能方面(诸如增殖、体内稳态、血管生成和伤口愈合)显示出一系列的多效作用。TGF-β功能的异常调节会促进癌症进展。大多数癌症的特征在于，肿瘤过量生产转化生长因子-β，后者可以促进肿瘤生长并介导上皮-至-间质转变。TGF-β也在免疫系统中起关键作用，其通过调节淋巴细胞增殖、分化和存活来维持耐受性。已经证实，TGF-β是增强Treg功能和降低肿瘤免疫的重要抑制元件。预见到TGF-β抑制剂与GITR激动剂(例如，抗体)的联合施用。
也预见到与抗病毒治疗剂的共同施用。抗病毒剂包括破坏病毒的任何药物。抗病毒剂可以包括起抑制病毒复制功能的干扰素、蛋白酶抑制剂和逆转录酶抑制剂或在HIV的高效抗逆转录病毒治疗(HAART)组合中包含的试剂。
典型的医用动物的(veterinary)、实验性的或研究性的受试者包括：猴、狗、猫、大鼠、小鼠、兔、豚鼠、马和人。
VII.抗体生产
在一个实施方案中，为了重组生产本发明的抗体，分离出编码2条链的核酸，并插入一个或多个可复制的载体中，用于进一步克隆(DNA扩增)或用于表达。使用常规程序(例如通过使用能够与编码抗体的重链和轻链的基因特异性结合的寡核苷酸探针)易于分离并测序编码单克隆抗体的DNA。许多载体是可用的。载体组分一股包括、但不限于以下的一种或多种：信号序列、复制起点、一个或多个标记基因、增强子元件、启动子和转录终止序列。在一个实施方案中，本发明的人源化的抗-GITR抗体的轻链和重链这两者由相同载体例如质粒或腺病毒载体表达。
本发明的抗体可以通过本领域已知的任何方法生产。在一个实施方案中，抗体在培养的哺乳动物或昆虫细胞中表达，例如中国仓鼠卵巢(CHO)细胞、人胚肾(HEK)293细胞、小鼠骨髓瘤NSO细胞、幼仓鼠肾(BHK)细胞、草地夜蛾(Spodoptera frugiperda)卵巢(Sf9)细胞。在一个实施方案中，由CHO细胞分泌的抗体被回收并通过标准层析法进行纯化，例如A蛋白、阳离子交换、阴离子交换、疏水作用和羟磷灰石层析。所获抗体被浓缩并贮存于20mM乙酸钠pH5.5中。
在又一个实施方案中，本发明的抗体根据WO2005／040395中所述方法在酵母中进行生产。简言之，将编码目标抗体的单独轻链或重链的载体引入不同的酵母单倍体细胞内，例如不同交配型的酵母巴斯德毕赤氏酵母(Pichia pastoris)，所述酵母单倍体细胞任选地为互补营养缺陷体。转化的单倍体酵母细胞随后可以进行交配或融合，以产生能够生产重链和轻链这两者的二倍体酵母细胞。二倍体菌株随后能够分泌完全装配的和生物学活性的抗体。2条链的相对表达水平例如可如下优化：使用具有不同拷贝数的载体、使用不同强度的转录启动子或由驱动编码1条或2条链的基因转录的诱导型启动子诱导表达。
在一个实施方案中，将多种不同的抗-GITR抗体(“原始”抗体)各自的重链和轻链引入酵母单倍体细胞内，以产生表达多条轻链的一种交配型的单倍体酵母菌株文库，和表达多条重链的不同交配型的单倍体酵母菌株文库。这些单倍体菌株文库可以进行交配(或融合为原生质球)，以生产表达包含轻链和重链的各种可能排列的抗体组合文库的一系列二倍体酵母细胞。随后可以筛选抗体组合文库，以确定任一个抗体是否具有优于(例如对GITR的更高亲和力)原始抗体的性质。参见，例如，WO2005／040395。
在又一个实施方案中，本发明的抗体是其中抗体可变结构域的部分以分子量约13kDa的多肽连接的人结构结构域抗体。参见，例如，美国专利公开号2004／0110941。就合成的容易性、稳定性和给药途径而言，这样的单结构域、低分子量物质提供了众多优点。
VIII.应用
本发明提供了使用抗-GITR抗体和其片段治疗和诊断增生性或炎性障碍和病症的方法。
本发明提供了用于诊断微生物感染或癌症的存在的方法，其中分析实验细胞、组织或体液中的GITR的表达水平，并与来自对照的细胞、组织或体液(优选相同类型)中的GITR水平相对比。如本文所证实的，例如，与对照相比患者中GITR表达水平的增加与癌症的存在有关。
通常，对于定量诊断试验，指示受测患者具有癌症或传染性疾病的阳性结果是这样的：其中所述细胞、组织或体液的GITR表达水平升高了至少2倍、5倍、10倍、15倍、20倍、25倍。
可以用于测定本发明的基因和蛋白(诸如GITR)在源自宿主的样品中的表达水平的测定技术是本领域技术人员众所周知的。这样的测定方法包括：放射免疫测定法、逆转录酶PCR(RT-PCR)测定法、定量实时PCR测定法、免疫组织化学测定法、原位杂交测定法、竞争性结合测定法、蛋白印迹测定法、ELISA测定法和流式细胞计测定法，例如，肿瘤相关的巨噬细胞的M2表型相对于M1表型的双色FACS分析(Mantovani等人，(2002)TRENDS inImmunology23：549-555)。
ELISA测定法最初包括制备对GITR特异性的本发明的抗体，优选36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5和31H6(统一称作“GITR抗体”)。另外，通常制备报告抗体，其特异性地结合GITR。将所述报告抗体连接到可检测的试剂诸如放射性试剂、荧光试剂或酶试剂(例如辣根过氧化物酶或碱性磷酸酶)上。
为了进行ELISA，在固体支持物(例如，结合抗体的聚苯乙烯盘子)上温育至少一种上述的GITR抗体。然后通过用非特异性的蛋白(诸如牛血清白蛋白)温育，覆盖盘子上的任何游离的蛋白结合位点。接着，在盘子中温育要分析的样品，在这期间，GITR会结合连接在聚苯乙烯盘子上的特异性GITR抗体。用缓冲液洗掉未结合的样品。将特异性地针对GITR并连接到辣根过氧化物酶上的报告抗体放入盘子中，导致所述报告抗体与GITR所结合的任何单克隆抗体的结合。然后洗掉未结合的报告抗体。然后将用于测定过氧化物酶活性的试剂(包括比色法底物)加入盘子中。固定化的过氧化物酶(与GITR抗体相连)产生有色的反应产物。在给定的时间段中形成的颜色的量与样品中存在的GITR蛋白的量成比例。通常通过参照标准曲线，得到定量结果。
可以采用竞争测定法，其中将对GITR特异性的抗体连接到固体支持物上，并使标记的GITR和源自宿主的样品在固体支持物上面经过，检测到的与固体支持物连接的标记的量可以与样品中GITR的量相关联。
可以在从患者得到的多种细胞、体液和／或组织提取物(诸如匀浆物或溶解组织)所衍生出的样品上，进行上述实验。常规地，从组织活组织检查和尸体剖检材料得到组织提取物。可用于本发明中的体液包括：血液、尿、唾液或任意其它身体排泄物或它们的衍生物。术语“血液”意在包括全血、血浆、血清或血液的任意衍生物。
本发明的抗体可以用于治疗病毒感染。HIV感染的特征在于，中枢记忆细胞的产生和维持的缺陷。与对照相比，在HIV-感染的个体中，CD8+中枢记忆细胞具有更短的半衰期和更低的丰度。另外，在开始高效抗逆转录病毒治疗(HAART)以后，CD4+和CD8+HIV-特异性的T细胞的频率快速降低。抗-GITR对CD4+的共刺激，可以提供增加记忆性CD8+应答并促进病毒的清除的机制。已经证实，用抗-GITR抗体治疗Friend病毒持久感染的小鼠(以改善Tregs的抑制)，会显著提高CD8+T细胞的IFN-γ生产，并会显著减少病毒载量(Dittmer等人，(2004)Immunity20：293-303)。
HIV感染的另一个特征是，从HIV感染早期开始的CD4+T细胞的大量细胞凋亡。CD4T细胞的渐进性细胞凋亡性去除，会促进减弱的HIV-特异性的细胞免疫应答和AIDS的发展。已经证实，GITR共刺激会通过保护T细胞免于细胞凋亡而增加鼠抗原-特异性的细胞因子分泌。Lahey等人(2007)J InfectDis.196：43-49)证实，HIV-特异性的CD4+T细胞的抗-GITR治疗会增加它们的细胞因子表达，并保护它们免于细胞凋亡。
对于由病毒原因导致的感染，可以在施用治疗病毒感染的标准疗法的同时、之前或之后，联合施用本发明的抗体。这类标准疗法随病毒的类型而变化，尽管在几乎所有情况下，施用含有对所述病毒特异性的抗体(例如，IgA、IgG)的人血清可能是有效的。
流感感染会导致发烧、咳嗽、肌痛、头痛及全身乏力，其常见于季节性流行病中。流感也与许多传染后障碍有关，所述障碍例如：脑炎、心肌心包炎、肺出血肾炎综合征和瑞氏综合征。流感感染也会抑制正常的肺抗细菌防御，使得流感康复的患者具有增加的发展细菌性肺炎的风险。
流感病毒表面蛋白表现出显著的抗原性变异，所述变异源自突变和重组。因而，溶细胞性的T淋巴细胞是宿主在感染后消除病毒的主要媒介物。流感被分类为3大类：A、B和C。A型流感的独特之处在于，它感染人类和许多其它动物(例如，猪、马、禽类和海豹)，且是大流行流感的主要原因。另外，当细胞被2种不同的A型流感株感染时，2个亲本病毒类型的片段化的RNA基因组在复制过程中混合以建立杂种复制子(replicant)，产生新的传染株。B型流感不在动物中复制，因而具有更少的遗传变异，C型流感仅具有单个血清型。
最常规的疗法是由感染引起的征状的姑息剂，同时宿主的免疫应答实际上清除该疾病。但是，某些株(例如，A型流感)可以造成更严重的疾病和死亡。通过施用环胺类抑制剂金刚烷胺和金刚乙胺(它们抑制病毒复制)，可以在临床上和预防性地治疗A型流感。但是，这些药物的临床实用性受到限制，这是由于不良反应的相对高发率、它们的狭窄抗病毒谱(仅A型流感)和病毒变得抗性的倾向。施用针对主要流感表面蛋白、血凝素和神经氨酸酶的血清IgG抗体，可以预防肺感染，而需要用粘膜IgA来预防上呼吸道和气管的感染。流感的目前最有效的治疗是，通过使用用福尔马林或β-丙内酯灭活的病毒进行疫苗接种。
在9-11天的潜伏期以后，被麻疹病毒感染的宿主会形成发热、咳嗽、鼻炎和结膜炎。在1-2天内，出现红斑性的斑丘疹，其迅速地扩散至全身。因为感染也会抑制细胞免疫，所述宿主处于更大的形成细菌重叠感染(包括中耳炎、肺炎和感染后脑脊髓炎)的风险中。急性感染伴有高发病率和死亡率，特别是在营养不良的青少年中。
麻疹的治疗包括：被动性施用混合的人IgG，其可以预防无免疫性的受试者的感染，即使在暴露后多达1周施用。
但是，用活的减毒病毒事先免疫接种，是最有效的治疗，且会在超过95％的免疫接种人群中预防疾病。由于该病毒存在一种血清型，单次免疫或感染通常会导致免于以后感染的终生保护。
在低比例的受感染宿主中，麻疹可以发展成SSPE，这是由中枢神经系统的持续性感染导致的一种慢性渐进性神经学障碍。SSPE由麻疹病毒的克隆变异体造成，所述变异体具有干扰病毒粒子装配和芽殖的缺陷。对于这些患者，希望用本发明的抗体重新活化T-细胞，从而促进病毒清除。
乙型肝炎病毒(HB-V)是最有传染性的已知的血液传染的病原体。它是急性和慢性肝炎和肝癌以及终生慢性感染的主要原因。在感染后，所述病毒在肝细胞中复制，它们随后也脱落表面抗原HBsAg。血清中过度的HBsAg水平的检测，被用作诊断乙型肝炎感染的标准方法。急性感染可以消退，或它可以发展成慢性持续性感染。
慢性HBV的现有治疗包括：α-干扰素，其会增加I类人白细胞抗原(HLA)在肝细胞表面上的表达，从而促进细胞毒性的T淋巴细胞对它们的识别。另外，核苷类似物更昔洛韦、泛昔洛韦和拉米夫定也已经在临床试验中在HBV感染的治疗方面表现出某些效力。HBV的其它治疗包括：聚乙二醇化的α-干扰素、阿德福韦(adenfovir)、恩替卡韦和替比夫定。尽管通过抗-HBsAg血清抗体的肠胃外施用可以赋予被动免疫，用灭活的或重组的HBsAg进行疫苗接种，也会赋予对感染的抗性。本发明的抗体可以与乙型肝炎感染的常规 治疗相组合，实现治疗益处。
丙型肝炎病毒(HC-V)感染可能导致慢性形式的肝炎，导致肝硬化。尽管征状与乙型肝炎引起的感染类似，与HB-V明显不同的是，被感染的宿主可以不出现征状达10-20年。HC-V感染的治疗包括：施用α-干扰素和利巴韦林的组合。HC-V感染的一种有前途的潜在治疗是，蛋白酶抑制剂特拉匹韦(VX-960)。其它治疗包括：抗-PD-1抗体(MDX-1106，Medarex)、巴维昔单抗(一种以B2-糖蛋白I依赖性的方式结合阴离子性磷脂磷脂酰丝氨酸的抗体，Peregrine Pharmaceuticals)、抗-HPV病毒外壳蛋白E2抗体(例如，ATL6865-Ab68+Ab65，XTL Pharmaceuticals)和(多克隆抗-HCV人免疫球蛋白)。本发明的抗体可以与丙型肝炎感染的这些治疗中的一种或多种相组合，实现治疗益处。
参考下面的实施例，会最好地理解本发明的宽广范围，所述实施例无意将本发明限制为具体实施方案。本文描述的具体实施方案仅为了举例而提供，本发明由随附权利要求的条款连同此权利要求授权的等同方案的全部范围限定。
实施例
实施例1
一股方法
分子生物学的标准方法已有描述。Maniatis等，(1982)Molecular Cloning，ALaboratory Manual，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NY；Sambrook和Russell(2001)Molecular Cloning，第3版，Cold Spring Harbor LaboratoryPress，Cold Spring Harbor，NY；Wu(1993)Recombinant DNA，第217卷，Academic Press，San Diego，CA。标准方法还见于Ausbel等，(2001)Current Protocols in MolecularBiology，第1-4卷，John Wiley and Sons，Inc.New York，NY其描述了在细菌细胞中克隆和DNA诱变(第1卷)、在哺乳动物细胞和酵母中克隆(第2卷)、复合糖和蛋白表达(第3卷)，以及生物信息学(第4卷)。
蛋白纯化的方法，包括免疫沉淀、层析、电泳、离心和结晶，已有描述(Coligan等，(2000)Current Protocols in Protein Science，第1卷，John Wiley and Sons，Inc.，NewYork)。描述了化学分析、化学修饰、翻译后修饰、融合蛋白的生产、蛋白糖基化。参见，例如，Coligan等，(2000)Current Protocols in Protein Science，第2卷，John Wiley andSons，Inc.，New York；Ausubel等，(2001)Current Protocols in Molecular Biology，第3卷，John Wiley and Sons，Inc.，NY，NY，第16.0.5-16.22.17页；Sigma-Aldrich，Co.(2001)Products for Life Science Research，St.Louis，MO；第45-89页；Amersham PharmaciaBiotech(2001)BioDirectory，Piscataway，N.J.，第384-391页。多克隆抗体和单克隆抗体的生产、纯化和片段 化已有描述。Coligan等，(2001)Current Protcols in Immunology，第1卷，John Wiley and Sons，Inc.，New York；Harlow和Lane(1999)UsingAntibodies，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NY；Harlow和Lane，出处同上。用于表征配体／受体相互作用的标准技术是可用的。参见，例如，Coligan等，(2001)Current Protcols in Immunology，第4卷，John Wiley，Inc.，New York。
用于流式细胞术的方法，包括荧光活化细胞分选检测系统是可用的。参见，例如，Owens等，(1994)Flow Cytometry Principles for Clinical LaboratoryPractice，John Wiley and Sons，Hoboken，NJ；Givan(2001)Flow Cytometry，第2版；Wiley-Liss，Hoboken，NJ；Shapiro(2003)Practical Flow Cytometry，John Wiley andSons，Hoboken，NJ。适于修饰核酸(包括核酸引物和探针)、多肽和抗体以及适合用作例如诊断试剂的荧光试剂是可用的。Molecular Probes(2003)Catalogue，Molecular Probes，Inc.，Eugene，OR；Sigma-Aldrich(2003)Catalogue，St.Louis，MO。
描述了免疫系统组织学的标准方法。参见，例如，Muller-Harmelink(编辑)(1986)Human Thymus.Histopathology and Pathology，Springer Verlag，New York，NY；Hiatt等，(2000)Color Atlas of Histology，Lippincott，Williams和Wilkins，Phila，PA；Louis等，(2002)Basic Histology：Text andA tlas，McGraw-Hill，New York，NY。
用于测定例如抗原片段、前导序列、蛋白折叠、功能结构域、糖基化位点和序列比对的软件包和数据库是可用的。参见，例如，GenBank，VectorSuite(Informax，Inc，Bethesda，MD)；GCG Wisconsin Package(Accelrys，Inc.，San Diego，CA)；(TimeLogic Corp.，Crystal Bay，Nevada)；Menne等，(2000)Bioinformatics16：741-742；Menne等，(2000)Bioinformatics Applications Note16：741-742；Wren等，(2002)Comput.Methods Programs Biomed.68：177-181；von Heijne(1983)Eur.J.Biochem.133：17-21；von Heijne(1986)NucleicAcidsRes.14：4683-4690。
实施例2
抗-人GITR抗体的人源化
抗体的人源化通常描述在，例如，PCT专利申请公开WO2005／047324和WO2005／047326。
简而言之，将非人VH结构域的氨基酸序列(例如SEQ ID NO：1-11)与一组5条人VH种系氨基酸序列相对比：1条代表亚组IGHV1，1条代表IGHV4，3条代表亚组IGHV3。VH亚组列于：M.-P.Lefranc(2001)“Nomenclature of the human Immunoglobulin Heavy(IGH)Genes”，Experimental and Clinical Immunogenetics，18：100-116。使用具有最接近匹配的人种系序列的框架序列，构建人源化的VH结构域。
在本文中公开的啮齿动物抗-huGITR抗体都属于VL的κ亚类。将非人VL结构域的氨基酸序列(例如SEQ ID NO：12-22)与一组4条人VLκ种系氨基酸序列相对比。该组4条由来自4个确定的人VL亚组中的每一个的一个代表组成，所述人VL亚组列于：V.Barbie & M.-P.Lefranc(1998)“The Human Immunoglobulin Kappa Variable(IGKV)Genes andJoining(IGKJ)Segments”，Experimental and Clinical Immunogenetics15：171-183和M.-P.Lefranc(2001)“Nomenclature of the Human Immunoglobulin Kappa(IGK)Genes”，Experimental and Clinical Immunogenetics18：161-174。所述4个亚组也对应于在下述文献中列出的4个亚组：Kabat等人(1991-第5版)“Sequences of Proteins ofImmunological Interest”，U.S.Department of Health and Human Services，NIHPub.91-3242，第103-130页。使用具有最接近匹配的人种系序列的框架序列，构建人源化的VL结构域。
一旦确定可变重链和轻链的靶氨基酸序列，可以制备编码全长人源化抗体的质粒。使用Kunkel诱变(参见，例如，Kunkel T A.(1985)Proc.Natl.Acad.Sci.U.S.A82：488-492)，可以改变质粒序列，以将DNA序列改变成靶人源化抗体序列。同时，可以进行密码子优化，以提供可能最佳的表达。
使用鉴别人源化抗体的受体种系序列的方法，可以将本发明的抗体人源化，所述方法包括下述步骤：a)鉴别具有所需生物学活性的非人抗体；b)测定非人抗体VH和VL结构域的氨基酸序列；和c)将非人抗体序列与一组人种系序列相对比，其中所述对比包括下述子步骤：1)根据Kabat(同上)，指定非人V序列残基编号；2)根据Kabat(同上)，描绘序列中的CDR和FR区；3)在非人和人抗体种系序列的相同的特定残基位置处，指定预定数字记分；和4)累加所有残基记分，以建立每个人种系序列的总记分；和d)将具有最高总残基记分的人种系序列鉴别为受体种系序列。在一个实施方案中，所述方法另外包括下述子步骤：5)对于在子步骤(3)中没有记分的、非人和人抗体种系序列的相同的每个FR残基位置，指定1的数字记分，以得到在子步骤(4)以后具有相同总残基记分的种系序列；6)累加所有残基记分，以建立每个人种系序列的总记分。在一个具体的实施方案中，所述非人抗体对GITR是特异性的，并增强GITR的生物学活性。本文也提供了通过上述方法制备的抗体。
在一个实施方案中，使用下述方法，将GITR抗体人源化。首先，克隆GITR抗体的非人VL和VH结构域，测序，并测定氨基酸序列。然后，将非人VH序列与一组3条人VH 种系氨基酸序列相对比。该组含有来自亚组IGHV1、IGHV3和IGHV4中的每一个的一个代表。VH亚组列于：M.-P.Lefranc，Exp.Clin.Immunogenetics，18：100-116(2001)。具体地，所述3个种系序列的对比，从根据Kabat编号系统给非人VH序列指定残基编号开始。参见Kabat，等人，美国卫生和人类服务部(U.S.Department of Health and Human Services)，NIH Pub.91-3242(第5版，1991)。然后将非人VH序列与3个人种系序列中的每一个相比对。由于V基因仅包含VH残基1-94，在比对中仅考虑这些残基。接着，描绘序列中的互补性决定区(CDR)和框架区(FR)。根据在Kabat，等人，美国卫生和人类服务部，NIH Pub.91-3242(第5版，1991)，和C.Chothia & A.M.Lesk，J.Mol.Biol.，196：901-917(1987)中提供的定义的组合，描绘CDR和FR。因此，使用的CDR定义是：残基26-35(对于VH结构域的CDR1)、残基50-65(对于VH结构域的CDR2)、残基95-102(对于VH结构域的CDR3)。下一步包括，在鉴别出的非人和人序列的相同的残基位置处，指定数字记分。该记分的一个实例如下表4所示。
*表示影响CDR构象，见C.Chothia等人，Nature342：877-883(1989)。
在给残基位置指定数字记分以后，累加所有残基记分。受体种系序列是具有最高总 记分的序列。对于两个或更多个种系序列具有相同记分的情况，则对于下述FR残基中非人和人序列相同的每个位置，向总记分增加1：1-23、25、36、38-47、66、68、70、72、74、75、77和79-93(最大60)。再次累加残基记分，受体种系序列是具有最高总记分的序列。如果两个或更多个种系序列仍具有相同记分，则任一个都可用作受体种系序列。
如果VL序列是VL的κ亚类的成员，则将来自GITR特异性抗体的非人VL序列与一组4条人VLκ种系氨基酸序列相对比。4条序列包括来自4个已确定的人VL亚组中的每一个的一个代表，所述人VL亚组列于：V.Barbie & M.-P.Lefranc，Exp.Clin.Immunogenetics 15：171-183(1998)和M.-P.Lefranc，Exp.Clin.Immunogenetics18：161-174(2001)。4个序列还对应于在Kabat等人，美国卫生和人类服务部，NIH Pub.91-3242，第103-130页(第5版，1991)中列出的4个亚组。所述非人序列与4个种系序列的对比，从根据Kabat等人，美国卫生和人类服务部，NIH Pub.91-3242(第5版，1991)给非人VL序列残基指定残基编号开始。然后将非人VL序列与4个人种系序列中的每一个相比对。由于V基因仅包含VL残基1-95，在比对中仅考虑这些残基。接着，描绘序列中的互补性决定区(CDR)和框架区(FR)。根据在Kabat等人，美国卫生和人类服务部，NIH Pub.91-3242(第5版1991)，和C.Chothia & A.M.Lesk，J.Mol.Biol.，196：901-917(1987)中提供的定义的组合，描绘CDR和FR。因此，使用的CDR定义是：残基24-34(对于VL结构域的CDR1)、残基50-56(对于VL结构域的CDR2)、残基89-97(对于VL结构域的CDR3)。下一步包括，在鉴别出的非人和人序列的相同的残基位置处，指定数字记分。该记分的一个实例如下表5所示。
*表示影响CDR构象，见C.Chothia等人，Nature342：877-883(1989)。
在给残基位置指定数字记分以后，累加所有残基记分。受体种系序列是具有最高总记分的序列。对于两个或更多个种系序列具有相同记分的情况，则对于下述FR残基中非人 和人序列相同的每个位置，向总记分增加1：1-3、5-23、35-42、44-49、57、59-88(最大67)。再次累加残基记分，受体种系序列是具有最高总记分的序列。如果两个或更多个种系序列仍具有相同记分，则任一个都可用作受体种系序列。
使用该方法，将上述亲本单克隆抗体人源化。SEQ ID NO：90、92、94、96、98、100、102、104、106、108和110是可变重链多肽的序列，SEQ ID NO：91、93、95、97、99、101、103、105、107、109和111是可变轻链的序列。
实施例3
使用KinExA技术测定抗-人GITR抗体的平衡解离常数(Kd)
使用KinExA3000仪器(Sapidyne Instruments Inc.，Boise Idaho，USA)，测定抗人GITR抗体的平衡解离常数(Kd)。KinExA使用动态排除测定法(Kinetic Exclusion Assaymethod)的原理，其基于测量抗体、抗原和抗体-抗原复合物的混合物中未复合抗体的浓度。通过使混合物接触固相固定化的抗原非常短暂的时间段，测量游离抗体的浓度。在实践中，这通过使溶液相抗原-抗体混合物流经流动池中捕获的抗原包被的颗粒来完成。由该仪器产生的数据使用定制软件进行分析。使用数学理论基于下述假定计算平衡常数：
1.结合遵循关于平衡的可逆结合等式：
kon[Ab][Ag]=koff[AbAg]
2.抗体和抗原1∶1结合，且总抗体等于抗原-抗体复合物加游离抗体
3.仪器信号与游离抗体浓度线性相关。
按照Sapidyne“Protocol for coating PMMA particles with biotinylatedligands having short or nonexistent linker arms.”，用生物素化的GITR(或其片段，诸如胞外结构域)包被PMMA颗粒(Sapidyne，目录号440198)。按照生产商的推荐(Piercebulletin0874)，使用EZ-link TFP PEO-生物素(Pierce，目录号21219)进行GITR的生物素化。
实施例4
使用BIAcore技术测定人源化的抗-人GITR抗体的平衡解离常数(Kd)
基本上如共同未决的、共同转让的美国专利申请号11／511,635(2006年8月29日提交)的实施例4所述，进行BIAcore测定。简而言之，使用标准的胺偶联规程，将结合配偶体固定化在BIAcore CM5传感器芯片上。使用BIAevaluation软件3.1，确定不同相互作用的动力学常数。使用计算的解离速率常数和结合速率常数，确定Kd。
GITR抗体36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5和31H6具有下述Kd值：
表6：GITR抗体的亲和力测量
实施例5
用于评估抗-GITR抗体的活化的生物测定法
通过对原初T细胞的增殖的影响(参见，例如，Ito等人，(2006)PNAS103(35)：13138-43)，评估了单克隆抗体在生物学上增强GITR活性的能力。通过蔗聚糖离心，随后使用原初CD4T细胞分离试剂盒(购自STEMCELL Technologies)，从外周血单核细胞(PBMC)中分离出原初CD4+T细胞。
在平底96-孔组织培养板(其已经用抗-CD3预包被)中，在有抗-hGITR抗体或同种型对照存在下，与辐照过的表达CD32的L细胞共培养共2x104个新鲜纯化的原初CD4T细胞。
表7A和7B显示了不同剂量的抗-GITR抗体对原初CD4+T细胞的增殖的影响(KM4-R63是同种型对照抗体)。
实施例5
用TGF-β和GITR抗体治疗肿瘤
以前的研究揭示，4T1肿瘤的基因表达已经增加了TGF-βmRNA的水平。据假设，与免疫抑制的去除(通过抑制TGF-β信号传递)相组合的抗-GITR激动剂的免疫共刺激，会诱导协同的抗肿瘤效力。
为了验证该假设，将1.5x1054T1肿瘤细胞皮下地植入在Balb／C小鼠的右胁腹。在肿瘤植入后4或7天，以100μg／200μL，将针对鼠TGF-β的中和抗体(1D11；Bioexpress)皮下地注射在颈部，每3天重复1次，共7剂。在第7、14和21天，以500μg／200μL，注射抗-小鼠GITR激动剂抗体DTA-1。每3天测量肿瘤体积。如下面表8所示，单独的DTA-1或抗-TGF-β本身几乎不具有效果。在抗-TGF-β治疗开始(肿瘤植入后第4天或第7天)后任一天，联合治疗会诱导协同效应。值是肿瘤体积(mm3)。
实施例6
CT26肿瘤的抗体-辐射联合治疗
将CT26肿瘤细胞(3x105)皮下地植入在Balb／c小鼠的左胁腹。在观察到单独的DTA-1不具有杀死肿瘤效力以后，将局部辐照(10Gy)施用于生长至300mm3的肿瘤。在辐照后1天，将DTA-1(500ug)皮下地注射在颈部，每周重复1次，共3剂。每2-5天测量肿瘤体积。在接受局部辐照和DTA-1联合治疗的10只小鼠组中，5只小鼠完全排斥肿瘤，并存活了多达3个月。单独的DTA-1或辐照没有表现出肿瘤排斥(参见，例如，图1)。
实施例7
GITR抗体的表位作图
如上面所指出的，DTA-1是针对小鼠GITR产生的激动剂抗体(参见，例如，Shimizu，等人同上)。已经证实，DTA-1在癌症的小鼠模型中具有有效的抗肿瘤活性(参见，例如，Cohen，等人(2006)Cancer Res.66：4904-4912；Ramirez-Montagut，等人(2006)J.Immunol.176：6434-6442；Zhou，等人(2007)J.Immunol.179：7365-7375；和Ko，等人(2005)J.Exp.Med.202：885-891)。
为了确定上述抗体是否结合在人GITR蛋白上的DTA-1-样表位，首先在小鼠GITR蛋白上绘制DTA-1表位的图谱。由于不可得到人或小鼠GITR的晶体结构，使用标准的定位诱变技术(参见，例如，Kunkel(1985)Proc.Natl.Acad.Sci.82：488-492)和TNF-受体家族的模块性的一股原理(参见，例如，Naismith和Sprang，同上)，测定DTA-1表位。
一旦确定被DTA-1识别的小鼠GITR表位，将在人GITR上的对应残基改变成小鼠残基，从而将DTA-1结合性赋予人GITR。由此可以确定，在人GITR上的DTA-1-样表位跨模块3和4(参见图2)，被上面鉴别出的抗体中的2种识别的人GITR(SEQ ID NO：89)表位包含Gly57、Arg65、His67、Lys80、Phe81、Ser82和Gln86。
实施例8
用抗-GITR抗体治疗病毒感染
HIV感染的特征在于，中枢记忆细胞的产生和维持的缺陷。与对照相比，在HIV-感染的个体中，CD8+中枢记忆细胞具有更短的半衰期和更低的丰度。另外，在开始高效抗逆转录病毒治疗(HAART)以后，CD4+和CD8+HIV-特异性的T细胞的频率快速降低。抗-GITR对CD4+的共刺激，可以提供增加记忆性CD8+应答并促进病毒的清除的机制。已经证实，用抗-GITR抗体治疗Friend病毒持久感染的小鼠(以改善Tregs的抑制)，会显著提高CD8+T细胞的IFN-γ生产，并会显著减少病毒载量(Dittmer等人，(2004)Immunity20：293-303)。
HIV感染的另一个特征是，从HIV感染早期开始的CD4+T细胞的大量细胞凋亡。CD4T细胞的渐进性细胞凋亡性去除，会促进减弱的HIV-特异性的细胞免疫应答和AIDS的发展。已经证实，GITR共刺激会通过保护T细胞免于细胞凋亡而增加鼠抗原-特异性的细胞因子分泌。Lahey等人(2007)J InfectDis.196：43-49)证实，HIV-特异性的CD4+T细胞的抗-GITR治疗会增加它们的细胞因子表达，并保护它们免于细胞凋亡。
对于由病毒原因导致的感染，可以在施用治疗病毒感染的标准疗法的同时、之前或之后，联合施用本发明的抗体。这类标准疗法随病毒的类型而变化，尽管在几乎所有情况下，施用含有对所述病毒特异性的抗体(例如，IgA、IgG)的人血清可能是有效的。
流感感染会导致发烧、咳嗽、肌痛、头痛及全身乏力，其常见于季节性流行病中。流感也与许多传染后障碍有关，所述障碍例如：脑炎、心肌心包炎、肺出血肾炎综合征和瑞氏综合征。流感感染也会抑制正常的肺抗细菌防御，使得流感康复的患者具有增加的发展细菌性肺炎的风险。
流感病毒表面蛋白表现出显著的抗原性变异，所述变异源自突变和重组。因而，溶细胞性的T淋巴细胞是宿主在感染后消除病毒的主要媒介物。流感被分类为3大类：A、B和C。A型流感的独特之处在于，它感染人类和许多其它动物(例如，猪、马、禽类和海豹)，且是大流行流感的主要原因。另外，当细胞被2种不同的A型流感株感染时，2个亲本病毒类型的片段化的RNA基因组在复制过程中混合以建立杂种复制子(replicant)，产生新的传染株。B型流感不在动物中复制，因而具有更少的遗传变异，C型流感仅具有单个血清型。
最常规的疗法是由感染引起的征状的姑息剂，同时宿主的免疫应答实际上清除该疾病。但是，某些株(例如，A型流感)可以造成更严重的疾病和死亡。通过施用环胺类抑制剂金刚烷胺和金刚乙胺(它们抑制病毒复制)，可以在临床上和预防性地治疗A型流感。但是，这些药物的临床实用性受到限制，这是由于不良反应的相对高发率、它们的狭窄抗病毒谱(仅A型流感)和病毒变得抗性的倾向。施用针对主要流感表面蛋白、血凝素和神经氨酸酶的血清IgG抗体，可以预防肺感染，而需要用粘膜IgA来预防上呼吸道和气管的感染。流感的目前最有效的治疗是，通过使用用福尔马林或β-丙内酯灭活的病毒进行疫苗接种。
在9-11天的潜伏期以后，被麻疹病毒感染的宿主会形成发热、咳嗽、鼻炎和结膜炎。在1-2天内，出现红斑性的斑丘疹，其迅速地扩散至全身。因为感染也会抑制细胞免疫，所述宿主处于更大的形成细菌重叠感染(包括中耳炎、肺炎和感染后脑脊髓炎)的风险中。急性感染伴有高发病率和死亡率，特别是在营养不良的青少年中。
麻疹的治疗包括：被动性施用混合的人IgG，其可以预防无免疫性的受试者的感染，即使在暴露后多达1周施用。
但是，用活的减毒病毒事先免疫接种，是最有效的治疗，且会在超过95％的免疫接种人群中预防疾病。由于该病毒存在一种血清型，单次免疫或感染通常会导致免于以后感染的终生保护。
在低比例的受感染宿主中，麻疹可以发展成SSPE，这是由中枢神经系统的持续性感染导致的一种慢性渐进性神经学障碍。SSPE由麻疹病毒的克隆变异体造成，所述变异体具有干扰病毒粒子装配和芽殖的缺陷。对于这些患者，希望用本发明的抗体重新活化T-细胞，从而促进病毒清除。
乙型肝炎病毒(HB-V)是最有传染性的已知的血液传染的病原体。它是急性和慢性肝炎和肝癌以及终生慢性感染的主要原因。在感染后，所述病毒在肝细胞中复制，它们随后也脱落表面抗原HBsAg。血清中过度的HBsAg水平的检测，被用作诊断乙型肝炎感染的标准方法。急性感染可以消退，或它可以发展成慢性持续性感染。
慢性HBV的现有治疗包括：α-干扰素，其会增加I类人白细胞抗原(HLA)在肝细胞表面上的表达，从而促进细胞毒性的T淋巴细胞对它们的识别。另外，核苷类似物更昔洛韦、泛昔洛韦和拉米夫定也已经在临床试验中在HBV感染的治疗方面表现出某些效力。HBV的其它治疗包括：聚乙二醇化的α-干扰素、阿德福韦(adenfovir)、恩替卡韦和替比夫定。尽管通过抗-HBsAg血清抗体的肠胃外施用可以赋予被动免疫，用灭活的或重组的HBsAg进行疫苗接种，也会赋予对感染的抗性。本发明的抗-GITR抗体可以与乙型肝炎感染的常规治疗相组合，实现治疗益处。
丙型肝炎病毒(HC-V)感染可能导致慢性形式的肝炎，导致肝硬化。尽管征状与乙型肝炎引起的感染类似，与HB-V明显不同的是，被感染的宿主可以不出现征状达10-20年。HC-V感染的治疗包括：施用α-干扰素和利巴韦林的组合。HC-V感染的一种有前途的潜在治疗是，蛋白酶抑制剂特拉匹韦(VX-960)。其它治疗包括：抗-PD-1抗体(MDX-1106，Medarex)、巴维昔单抗(一种以B2-糖蛋白I依赖性的方式结合阴离子性磷脂磷脂酰丝氨酸的抗体，Peregrine Pharmaceuticals)、抗-HPV病毒外壳蛋白E2抗体(例如，ATL6865-Ab68+Ab65，XTL Pharmaceuticals)和(多克隆抗-HCV人免疫球蛋白)。本发明的抗-GITR抗体可以与丙型肝炎感染的这些治疗中的一种或多种相组合，实现治疗益处。
表9提供了序列表中的序列的简单描述。
序列表
<110> Schebye, Xiao-Min
Ermakov, Grigori
Hodges, Douglas J.
Presta, Leonard G.
<120> 抗-GITR抗体
<130> BP2009.6860WO
<150> 61/239,667
<151> 2009-09-03
<150> 61/307,767
<151> 2010-02-24
<150> 61/313,955
<151> 2010-03-15
<160> 111
<170> PatentIn version 3.5
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<213> 小家鼠
<400> 6
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Leu Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Val Arg Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 7
<211> 117
<212> PRT
<213> 小家鼠
<400> 7
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Gln
85 90 95
Arg Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 8
<211> 120
<212> PRT
<213> 小家鼠
<400> 8
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Gly Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Ser Gln Tyr Tyr Leu
65 70 75 80
Gln Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 9
<211> 120
<212> PRT
<213> 小家鼠
<400> 9
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Phe Glu Tyr Met
35 40 45
Gly Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Phe Leu
65 70 75 80
His Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 10
<211> 121
<212> PRT
<213> 褐家鼠
<400> 10
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser
50 55 60
Leu Ile His Arg Leu Thr Val Ser Lys Asp Thr Ser Asn Asn Gln Ala
65 70 75 80
Phe Leu Lys Ile Thr Asn Val Asp Thr Ala Glu Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Pro Gly Thr Met Val Ser Val Ser Ser
115 120
<210> 11
<211> 121
<212> PRT
<213> 褐家鼠
<400> 11
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Ala
65 70 75 80
Phe Leu Lys Ile Thr Asn Val Asp Thr Ala Glu Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Pro Gly Thr Met Val Ser Val Ser Ser
115 120
<210> 12
<211> 113
<212> PRT
<213> 小家鼠
<400> 12
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Val Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Thr Lys
85 90 95
Glu Val Thr Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 13
<211> 113
<212> PRT
<213> 褐家鼠
<400> 13
Asp Val Val Met Thr Gln Thr Pro Val Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Asn Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Gly Asn Thr Phe Leu Ser Trp Tyr Phe Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Ala Ser Asn Arg Phe Ser Gly Val Ser
50 55 60
Asn Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Pro Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln His
85 90 95
Thr His Leu Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 14
<211> 108
<212> PRT
<213> 小家鼠
<400> 14
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Asn Ser Thr Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Cys Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Ser Asn Pro Pro Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Arg Arg Ala
100 105
<210> 15
<211> 110
<212> PRT
<213> 小家鼠
<400> 15
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Thr Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105 110
<210> 16
<211> 113
<212> PRT
<213> 小家鼠
<400> 16
Asp Ile Val Val Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 17
<211> 118
<212> PRT
<213> 小家鼠
<400> 17
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Ala Asp Ala Ala Pro
115
<210> 18
<211> 113
<212> PRT
<213> 小家鼠
<400> 18
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Ser Leu Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Asn Leu Asp Gln
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly His Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 19
<211> 114
<212> PRT
<213> 小家鼠
<400> 19
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ala Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg Ala Asp Ala
100 105 110
Ala Pro
<210> 20
<211> 114
<212> PRT
<213> 小家鼠
<400> 20
Val Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Ile Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Arg Ala Leu Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gly Gly Thr Asn Leu Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro
<210> 21
<211> 113
<212> PRT
<213> 褐家鼠
<400> 21
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Phe Cys Arg Ala Ser Gln Gly Val Asn Asn Phe
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Phe Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 22
<211> 113
<212> PRT
<213> 褐家鼠
<400> 22
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Phe Cys Arg Ala Ser Gln Gly Val Asn Asn Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Phe Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 23
<211> 10
<212> PRT
<213> 小家鼠
<400> 23
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 褐家鼠
<400> 24
Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ala
1 5 10
<210> 25
<211> 11
<212> PRT
<213> 小家鼠
<400> 25
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala Trp Asn
1 5 10
<210> 26
<211> 10
<212> PRT
<213> 小家鼠
<400> 26
Gly Tyr Thr Phe Ser Arg Tyr Trp Ile Glu
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 小家鼠
<400> 27
Gly Tyr Thr Phe Thr Ser Tyr Thr Met His
1 5 10
<210> 28
<211> 12
<212> PRT
<213> 小家鼠
<400> 28
Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly
1 5 10
<210> 29
<211> 10
<212> PRT
<213> 小家鼠
<400> 29
Gly Phe Thr Val Arg Asn Tyr Ala Met Ser
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 小家鼠
<400> 30
Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 31
<211> 10
<212> PRT
<213> 小家鼠
<400> 31
Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 32
<211> 12
<212> PRT
<213> 褐家鼠
<400> 32
Gly Phe Ser Leu Ser Thr Tyr Gly Val Gly Val Gly
1 5 10
<210> 33
<211> 12
<212> PRT
<213> 褐家鼠
<400> 33
Gly Phe Ser Leu Ser Thr Tyr Gly Val Gly Val Gly
1 5 10
<210> 34
<211> 16
<212> PRT
<213> 小家鼠
<400> 34
Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 35
<211> 17
<212> PRT
<213> 褐家鼠
<400> 35
Tyr Ile His Ala Asn Gly Gly Ser Thr Tyr Tyr Arg Asp Ser Val Arg
1 5 10 15
Gly
<210> 36
<211> 16
<212> PRT
<213> 小家鼠
<400> 36
Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 37
<211> 17
<212> PRT
<213> 小家鼠
<400> 37
Glu Ile Leu Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 38
<211> 17
<212> PRT
<213> 小家鼠
<400> 38
Tyr Ile Asn Pro Arg Ser Val Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 39
<211> 16
<212> PRT
<213> 小家鼠
<400> 39
His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 40
<211> 16
<212> PRT
<213> 小家鼠
<400> 40
Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys Gly
1 5 10 15
<210> 41
<211> 16
<212> PRT
<213> 小家鼠
<400> 41
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly
1 5 10 15
<210> 42
<211> 16
<212> PRT
<213> 小家鼠
<400> 42
Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg Ser
1 5 10 15
<210> 43
<211> 16
<212> PRT
<213> 褐家鼠
<400> 43
Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser Leu Ile His
1 5 10 15
<210> 44
<211> 16
<212> PRT
<213> 褐家鼠
<400> 44
Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
<210> 45
<211> 10
<212> PRT
<213> 小家鼠
<400> 45
Val Gly Gly Tyr Tyr Asp Ser Met Asp Tyr
1 5 10
<210> 46
<211> 14
<212> PRT
<213> 褐家鼠
<400> 46
Gly Ser Phe Met Tyr Ala Ala Asp Tyr Tyr Ile Met Asp Ala
1 5 10
<210> 47
<211> 9
<212> PRT
<213> 小家鼠
<400> 47
Gln Leu Gly Leu Arg Phe Phe Asp Tyr
1 5
<210> 48
<211> 9
<212> PRT
<213> 小家鼠
<400> 48
Lys Val Tyr Tyr Tyr Ala Met Asp Phe
1 5
<210> 49
<211> 10
<212> PRT
<213> 小家鼠
<400> 49
Leu Gly Gly Tyr Tyr Asp Thr Met Asp Tyr
1 5 10
<210> 50
<211> 23
<212> PRT
<213> 小家鼠
<400> 50
Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly
1 5 10 15
Thr Ser Val Thr Val Ser Ser
20
<210> 51
<211> 20
<212> PRT
<213> 小家鼠
<400> 51
Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu Val
1 5 10 15
Thr Val Ser Ala
20
<210> 52
<211> 23
<212> PRT
<213> 小家鼠
<400> 52
Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln Gly
1 5 10 15
Thr Leu Val Thr Val Ser Ala
20
<210> 53
<211> 23
<212> PRT
<213> 小家鼠
<400> 53
Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln Gly
1 5 10 15
Thr Leu Val Thr Val Ser Ala
20
<210> 54
<211> 22
<212> PRT
<213> 褐家鼠
<400> 54
Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly Pro Gly Thr
1 5 10 15
Met Val Ser Val Ser Ser
20
<210> 55
<211> 22
<212> PRT
<213> 褐家鼠
<400> 55
Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly Pro Gly Thr
1 5 10 15
Met Val Ser Val Ser Ser
20
<210> 56
<211> 15
<212> PRT
<213> 小家鼠
<400> 56
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Val Ser Phe Met Asn
1 5 10 15
<210> 57
<211> 16
<212> PRT
<213> 褐家鼠
<400> 57
Arg Ser Ser Gln Ser Leu Leu His Ser Asp Gly Asn Thr Phe Leu Ser
1 5 10 15
<210> 58
<211> 10
<212> PRT
<213> 小家鼠
<400> 58
Ser Ala Asn Ser Thr Val Asn Tyr Met Tyr
1 5 10
<210> 59
<211> 12
<212> PRT
<213> 小家鼠
<400> 59
Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Phe His
1 5 10
<210> 60
<211> 15
<212> PRT
<213> 小家鼠
<400> 60
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn
1 5 10 15
<210> 61
<211> 16
<212> PRT
<213> 小家鼠
<400> 61
Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 62
<211> 11
<212> PRT
<213> 小家鼠
<400> 62
Arg Ala Ser Gln Asp Ile Asn Asn Phe Leu Asn
1 5 10
<210> 63
<211> 11
<212> PRT
<213> 小家鼠
<400> 63
Lys Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 64
<211> 11
<212> PRT
<213> 小家鼠
<400> 64
Lys Ala Ser Gln Asp Val Ile Ser Ala Val Ala
1 5 10
<210> 65
<211> 11
<212> PRT
<213> 褐家鼠
<400> 65
Arg Ala Ser Gln Gly Val Asn Asn Phe Leu Thr
1 5 10
<210> 66
<211> 11
<212> PRT
<213> 褐家鼠
<400> 66
Arg Ala Ser Gln Gly Val Asn Asn Tyr Leu Thr
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 小家鼠
<400> 67
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 68
<211> 7
<212> PRT
<213> 褐家鼠
<400> 68
Leu Ala Ser Asn Arg Phe Ser
1 5
<210> 69
<211> 7
<212> PRT
<213> 小家鼠
<400> 69
Leu Thr Ser Asn Leu Ala Ser
1 5
<210> 70
<211> 7
<212> PRT
<213> 小家鼠
<400> 70
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 71
<211> 7
<212> PRT
<213> 小家鼠
<400> 71
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 72
<211> 7
<212> PRT
<213> 小家鼠
<400> 72
Lys Val Ser Lys Arg Phe Ser
1 5
<210> 73
<211> 7
<212> PRT
<213> 小家鼠
<400> 73
Tyr Thr Ser Lys Leu His Ser
1 5
<210> 74
<211> 7
<212> PRT
<213> 小家鼠
<400> 74
Trp Ala Ser Thr Arg His Thr
1 5
<210> 75
<211> 7
<212> PRT
<213> 小家鼠
<400> 75
Trp Ala Ser Thr Arg His Thr
1 5
<210> 76
<211> 7
<212> PRT
<213> 褐家鼠
<400> 76
Tyr Thr Ser Asn Leu Gln Ser
1 5
<210> 77
<211> 7
<212> PRT
<213> 褐家鼠
<400> 77
Tyr Thr Ser Asn Leu Gln Ser
1 5
<210> 78
<211> 9
<212> PRT
<213> 小家鼠
<400> 78
Gln Gln Thr Lys Glu Val Thr Trp Thr
1 5
<210> 79
<211> 9
<212> PRT
<213> 褐家鼠
<400> 79
Phe Gln His Thr His Leu Pro Leu Thr
1 5
<210> 80
<211> 9
<212> PRT
<213> 小家鼠
<400> 80
Gln Gln Trp Asn Ser Asn Pro Pro Thr
1 5
<210> 81
<211> 9
<212> PRT
<213> 小家鼠
<400> 81
His Gln Tyr His Arg Ser Pro Arg Thr
1 5
<210> 82
<211> 9
<212> PRT
<213> 小家鼠
<400> 82
Gln Gln Ser Lys Glu Val Pro Phe Thr
1 5
<210> 83
<211> 9
<212> PRT
<213> 小家鼠
<400> 83
Ser Gln Ser Thr His Val Pro Pro Thr
1 5
<210> 84
<211> 9
<212> PRT
<213> 小家鼠
<400> 84
Gln Gln Gly His Thr Leu Pro Pro Thr
1 5
<210> 85
<211> 10
<212> PRT
<213> 小家鼠
<400> 85
Gln Gln His Ser Tyr Thr Pro Pro Trp Thr
1 5 10
<210> 86
<211> 10
<212> PRT
<213> 小家鼠
<400> 86
Gln Gln His Ser Tyr Thr Pro Pro Trp Thr
1 5 10
<210> 87
<211> 9
<212> PRT
<213> 褐家鼠
<400> 87
Gln Gln Tyr His Gly Phe Pro Asn Thr
1 5
<210> 88
<211> 9
<212> PRT
<213> 褐家鼠
<400> 88
Gln Gln Tyr His Gly Phe Pro Asn Thr
1 5
<210> 89
<211> 241
<212> PRT
<213> 智人
<220>
<221> 信号
<222> (1)..(25)
<400> 89
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys
165 170 175
Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu
180 185 190
Arg Ser Gln Cys Met Trp Pro Arg Glu Thr Gln Leu Leu Leu Glu Val
195 200 205
Pro Pro Ser Thr Glu Asp Ala Arg Ser Cys Gln Phe Pro Glu Glu Glu
210 215 220
Arg Gly Glu Arg Ser Ala Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp
225 230 235 240
Val
<210> 90
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是A或F
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是F或L
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是R或K
<220>
<221> 变体
<222> (75)..(75)
<223> 可以是N或T
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是L或V
<220>
<221> 变体
<222> (98)..(98)
<223> 可以是A或V
<400> 90
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Val Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Arg Xaa Thr Ile Ser Xaa Asp Xaa Ser Lys Asn Thr Xaa
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Xaa Arg Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 91
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 91
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 92
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (97)..(97)
<223> 可以是A或T
<220>
<221> 变体
<222> (98)..(98)
<223> 可以是R或T
<400> 92
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile His Ala Asn Gly Gly Ser Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Arg Gly 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
Xaa Xaa Gly Ser Phe Met Tyr Ala Ala Asp Tyr Tyr Ile Met Asp Ala
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 93
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 93
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Gly Asn Thr Phe Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Ala Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln His
85 90 95
Thr His Leu Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 94
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是M或I
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或A
<220>
<221> 变体
<222> (70)..(70)
<223> 可以是M或F
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是T或A
<400> 94
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Xaa Thr Xaa Thr Xaa Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Val Tyr Tyr Tyr Ala Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 95
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是L或W
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是F或Y
<400> 95
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Xaa
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 96
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是V或F
<220>
<221> 变体
<222> (50)..(50)
<223> 可以是I或L
<220>
<221> 变体
<222> (51)..(51)
<223> 可以是G或A
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是V或L
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是I或V
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是V或K
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是F或A
<220>
<221> 变体
<222> (99)..(99)
<223> 可以是R或Q
<400> 96
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Xaa Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Xaa Xaa Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser
50 55 60
Leu Ile His Arg Xaa Thr Xaa Ser Xaa Asp Thr Ser Lys Asn Gln Xaa
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Xaa Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 97
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或P
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是Y或F
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 97
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Phe
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Xaa Leu Ile
35 40 45
Xaa Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 98
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是V或F
<220>
<221> 变体
<222> (50)..(50)
<223> 可以是I或L
<220>
<221> 变体
<222> (51)..(51)
<223> 可以是G或A
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是V或L
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是V或K
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是F或A
<220>
<221> 变体
<222> (99)..(99)
<223> 可以是R或Q
<400> 98
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Xaa Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Xaa Xaa Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Xaa
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Xaa Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 99
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或P
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是Y或F
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 99
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Xaa Leu Ile
35 40 45
Xaa Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 100
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或Q
<400> 100
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 101
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 101
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 102
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (47)..(47)
<223> 可以是W或Y
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是I或M
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是V或R
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或S
<400> 102
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Xaa Xaa
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Gly Arg Val Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 103
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 103
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 104
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 104
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Val Gly Gly Tyr Tyr Asp Ser Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 105
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (31)..(31)
<223> 可以是N或Q
<220>
<221> 变体
<222> (57)..(57)
<223> 可以是N或Q
<400> 105
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Xaa Tyr
20 25 30
Gly Val Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Xaa Gln Gly Ser Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys
85 90 95
Glu Val Thr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 106
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (47)..(47)
<223> 可以是W或Y
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是I或M
<220>
<221> 变体
<222> (67)..(67)
<223> 可以是V或I
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是V或R
<220>
<221> 变体
<222> (78)..(78)
<223> 可以是F或Y
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或S
<400> 106
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Xaa Xaa
35 40 45
Gly Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Ser Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Xaa Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (1)..(1)
<223> 可以是D或V
<400> 107
Xaa Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asp Val Ile Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 108
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是M或I
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或A
<220>
<221> 变体
<222> (70)..(70)
<223> 可以是M或L
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是T或A
<220>
<221> 变体
<222> (74)..(74)
<223> 可以是T或K
<400> 108
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Tyr Ile Asn Pro Arg Ser Val Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Xaa Thr Xaa Thr Xaa Asp Xaa Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Gly Tyr Tyr Asp Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 109
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 109
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 110
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是I或M
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或I
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是V或R
<400> 110
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Xaa Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Gly Leu Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 111
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (45)..(45)
<223> 可以是L或P
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或C
<400> 111
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Asn Ser Thr Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Xaa Xaa Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Asn Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
Claims (15)
1.一种特异性结合人GITR的分离的抗体，其包含：
a)轻链免疫球蛋白可变区，其包含SEQ ID NO:105中描述的氨基酸序列所示的轻链免疫球蛋白可变区的CDR-L1、CDR-L2和CDR-L3，其中氨基酸31是Q，并且氨基酸57是Q；和
b)重链免疫球蛋白可变区，其包含SEQ ID NO:104中描述的氨基酸序列所示的重链免疫球蛋白可变结构区的CDR-H1、CDR-H2和CDR-H3。
2.一种分离的核酸，其编码如权利要求1所述的分离的抗体的轻链可变区和重链可变区。
3.一种表达载体，其包含如权利要求2所述的核酸，所述核酸可操作地连接到当用所述载体转染宿主细胞时所述宿主细胞识别的控制序列上。
4.一种宿主细胞，其包含如权利要求3所述的表达载体。
5.一种生产抗体的方法，所述方法包括：
在表达核酸序列的条件下，在培养基中培养如权利要求4所述的宿主细胞，从而生产包含轻链和重链可变区的抗体；和
从宿主细胞或培养基回收抗体。
6.如权利要求1所述的分离的抗体，其另外包含重链恒定区，所述重链恒定区包含γ1人重链恒定区或其变体，其中所述恒定区变体包含最多20个保守修饰的氨基酸置换。
7.如权利要求1所述的分离的抗体，其另外包含重链恒定区，所述重链恒定区包含γ4人重链恒定区或其变体，其中所述恒定区变体包含最多20个保守修饰的氨基酸置换。
8.如权利要求1所述的分离的抗体，其是包含人重链恒定区和人轻链恒定区的人源化抗体。
9.如权利要求1所述的分离的抗体在制备用于治疗人对象中选自增生性障碍和病毒感染的疾病的药物中的用途。
10.如权利要求9所述的用途，其中所述分离的抗体与抗-TGFβ抗体共同施用。
11.如权利要求10所述的用途，其中所述分离的抗体与局部辐射共同施用。
12.如权利要求9所述的用途，其中所述疾病是增生性障碍。
13.如权利要求9所述的用途，其中所述疾病是病毒感染。
14.一种药物组合物，其包含如权利要求1所述的分离的抗体和药学上可接受的载体。
15.一种由保藏在美国典型培养物保藏中心（ATCC）的杂交瘤生产的抗体，其中所述杂交瘤是PTA-9890。
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| CN2010800497565A CN102574924A (zh) | 2009-09-03 | 2010-08-31 | 抗-gitr抗体 |
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