CN110372792A - 抑制vegf的稳定和可溶的抗体 - Google Patents
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Abstract
本发明涉及包含来自兔单克隆抗体的CDR的可溶和稳定的抗VEGF免疫结合剂。所述抗体经设计用于诊断和/或治疗VEGF介导的病症。还公开了用于表达本发明的重组抗体的杂交瘤、核酸、载体和宿主细胞、用于分离其的方法和所述抗体在医药中的用途。
Description
本申请是2009年6月25日提交的同名发明专利申请201510205513.0(原始母案申请号为200980124313.5)的分案申请。
相关信息
本申请要求2008年6月25日提交的US61/133,212、2008年6月25日提交的US61/075,697、2009年2月24日提交的US61/155,041和2008年6月25日提交的US61/075,692的优先权。
在整个本说明书中引用的任何专利、专利申请和参考资料的内容以其全文通过引用合并入本文。
发明背景
血管生成牵涉许多种病症的发病机制，所述病症包括实体瘤、眼内新生血管综合征例如增殖性视网膜病或年龄相关性黄斑变性(AMD)、类风湿性关节炎和银屑病(Folkman等人J.Biol.Chem.267:10931-10934(1992)；Klagsbrun等人Annu.Rev.Physiol.53:217-239(1991)；和Garner A，Vascular diseases.In:Pathobiology of ocular disease.Adynamic approach.Garner A，Klintworth G K，Eds.第2版Marcel Dekker，NY，pp 1625-1710(1994))。在实体瘤中，新脉管系统(vasculture)的生长和血管生成允许肿瘤存活，并且已证明肿瘤切片中微血管的密度与乳腺癌和其他癌症的患者存活之间的关系(Weidner等人N Engl J Med 324:1-6(1991)；Horak等人Lancet 340:1120-1124(1992)；和Macchiarini等人Lancet 340:145-146(1992))。
血管内皮生长因子(VEGF)是血管生成和新生血管形成(neovascularization)的已知的调节剂，并且已显示为与肿瘤和眼内病症相关的新生血管形成的至关重要的介体(Ferrara等人Endocr.Rev.18:4-25(1997))。VEGF mRNA在许多人肿瘤中过表达，并且眼液(eye fluid)中VEGF的浓度与糖尿病性和其他缺血相关视网膜病变患者的血管的活跃增殖的存在高度相关(Berkman等人，J Clin Invest91:153-159(1993)；Brown等人HumanPathol.26:86-91(1995)；Brown等人Cancer Res.53:4727-4735(1993)；Mattern等人Brit.J.Cancer.73:931-934(1996)；和Dvorak等人Am J.Pathol.146:1029-1039(1995)；Aiello等人N.Engl.J.Med.331:1480-1487(1994))。此外，最近的研究已显示在受AMD影响的患者的脉络膜新生血管膜中存在局域性VEGF(Lopez等人Invest.Ophtalmo.Vis.Sci.37:855-868(1996))。抗VEGF中和抗体可用于在裸鼠中抑制多种人肿瘤细胞系的生长并且还可在缺血性视网膜病的模型中抑制眼内血管生成(Kim等人Nature 362:841-844(1993)；Warren等人J.Clin.Invest 95:1789-1797(1995)；Borgstrom等人Cancer Res.56:4032-4039(1996)；和Melnyk等人Cancer Res.56:921-924(1996))(Adamis等人Arch.Opthalmol.114:66-71(1996))。
因此，需要能够用于治疗实体瘤和各种新生血管眼内疾病的抗VEGF单克隆抗体。
发明概述
本发明提供了包含来自兔单克隆抗体的CDR的可溶和稳定的抗VEGF免疫结合剂。所述抗体经设计用于诊断和/或治疗VEGF介导的病症。还公开了用于表达本发明的重组抗体的杂交瘤、核酸、载体和宿主细胞、用于分离其的方法和所述抗体在医药中的用途。
附图概述
图1举例说明了使用Biacore产生的所选择的scFv对hVEGF165的结合动力学(hVEGF165)。图1a显示获得的关于511max的数据:Ka(l/Ms)：6.59E+05；SE(ka):1.10E+03；kd(l/s):4.40E-05；SE(kd)：6.30E-07；KD(M)：6.67E-1l。图1b显示获得的关于578max的数据：Ka(l/Ms)：7.00E+05；SE(ka)：1.40E+03；kd(l/s)：3.07E-04；SE(kd)：8.50E-07；KD(M)：4.39E-10。
图2通过显示578max对人、小鼠和大鼠VEGF的结合动力学举例说明了种特异性。图2a显示获得的关于人VEGF165的数据：Ka(l/Ms)：7.00E+05；SE(ka)：1.40E+03；kd(l/s)：3.07E-04；SE(kd)：8.50E-07；KD(M)：4.39E-10。图2b显示获得的关于小鼠VEGF164的数据：Ka(l/Ms)：1.03E+06；SE(ka)：2.30E+03；kd(l/s)：4.40E-04；SE(kd)：9.40E-07；KD(M)：4.29E-10。图2c显示获得的关于大鼠VEGF164的数据：Ka(l/Ms)：8.83E+05；SE(ka)：2.50E+03；kd(l/s)：5.28E-04；SE(kd)：1.20E-06；KD(M)：5.98E-10。
图3举例说明578max对VEGF同种型(hVEGF121和hVEGF110)的结合动力学。图3a显示获得的关于人VEGF165的数据：Ka(l/Ms)：7.00E+05；SE(ka)：1.4E+03；kd(l/s)：3.07E-04；SE(kd)：8.50E-07；KD(M)：4.39E-10。图3b显示获得的关于人VEGF121的数据：Ka(1/Ms)：5.87E+05；SE(ka)：1.20E+03；kd(l/s)：5.58E-04；SE(kd)：9,60E-07；KD(M)：9.50E-11。
图4描述了578max、578minmax和578wt对hVEGF165的结合动力学。图4a显示获得的关于578max的数据：Ka(1/Ms)：7.00E+05；SE(ka)：1.40E+03；kd(l/s)：3.07E-04；SE(kd)：8.50E-07；KD(M)：4.39E-10。图4b显示获得的关于578minmax的数据：Ka(1/Ms)：8.06E+05；SE(ka)：2.10E+03；kd(l/s)：5.04E-04；SE(kd)：1.10E-06；KD(M)：6.25E-10。图4c显示获得的关于578wt-His的数据：Ka(1/Ms)：8.45E+05；SE(ka)：1.60E+03；kd(l/s)：l.69E-04；SE(kd)：7.60E-07；KD(M)：2.00E-10。
图5举例说明578max、578minmax和578minmax_DHP的热稳定性(通过FT-IR测量去折叠)。图5a：578minmax(ESBA903)：Tm＝71.1℃；图5b：578minmax_DHP(#961)：Tm＝70.2℃；图5c：578max(#821)：Tm＝70.4℃。
图6举例说明在热胁迫(图6a：50℃，图6b：60℃，图6c：70℃)30分钟后578衍生物的变性和沉淀。
图7举例说明578max、578minmax和578minmax_DHP的溶解性(通过硫酸铵沉淀法进行测定)。图7a：578max(#821)。V50为27.24％。图7b：578minmax(ESBA903)。V50为28.13。图7c：578minmax_DHP(#961)。V50为32.36％。
图8举例说明VEGFR2竞争性ELISA和HUVEC测定(作为测量潜能的方法)。图8a：VEGFR2竞争性ELISA中Lucentis与511max(#802)的比较。Lucentis的R2：0.9417；ESBA802的R2：0.9700。Lucentis的EC50：7.137nM；#802的EC50：0.8221nM。图8b：VEGFR2竞争性ELISA中Lucentis与578max(#821)的比较。图8c：HUVEC测定中Lucentis、511maxC-his和534max的比较。Lucentis的R2：0.9399；EP511maxC-his的R2：0.9313，EP534max的R2：0.7391。Lucentis的EC50：0.08825nM，511maxC-his的EC50：0.7646nM，534max的EC50：63.49nM。图8d：HUVEC测定中Lucentis、578min和578max的比较。Lucentis的R2：0.9419，EP578min的R2：0.8886，EP578max的R2：0.9274。Lucentis的EC50：0.1529nM，578min的EC50：1.528nM，578max的EC50：0.1031nM。
图9举例说明578minmax对由hVEGF165诱导的HUVEC增殖的影响。测定的参数如下：hVEGF165浓度：0.08nM(3ng/ml)；与VEGF和测试项目的温育：96小时。EC50为0.08959nM(对于Lucentis)和0.05516nM(对于578minmax)，而R2为0.9066(对于Lucentis)和0.9622(对于578minmax)。
图10举例说明578minmax对由小鼠VEGF164和大鼠VEGF164诱导的HUVEC增殖的影响。测定的参数如下：小鼠VEGF164浓度：0.08nM(3ng/ml)；大鼠VEGF164浓度：0.3nM(11.3ng/ml)。在VEGF诱导HUVEC增殖的EC90处选择两个浓度；与VEGF和测试项目的温育：96小时。图10a举例说明获得的小鼠VEGF的数据。EC50为0.1196nM(对于V1253)和0.06309nM(对于578minmax)，而R2为0.02744(对于Lucentis)、0.9348(对于V1253)和0.9767(对于EP578minmax)。Lucentis不抑制由小鼠VEGF诱导的HUVEC增殖。图10b举例说明获得的大鼠VEGF的数据。EC50为1.597nM(对于V1253)和0.06974nM(对于578minmax)，而R2为00,7664(对于V1253)和0.6635(对于578minmax)。
图11举例说明在裸豚鼠中使用Miles测定的功效研究(第I部分)。给裸豚鼠静脉内施用染料阿尔玛蓝(almar blue)1。在染料注射后1小时，分别将hVEGF(2.61nM)和Lucentis、ESBA903或#802的预混合物2注射入动物3的皮肤。在注射溶液后1小时，对动物3实施安乐死，收集、清洁毛皮并且使用入射光和透射光对其进行数码拍照。使用Image J评估渗入注射位置的伊文斯蓝(Evans Blue)染料的面积，并且对剂量-面积保留(dose-arearetention)作图。
图12举例说明在裸豚鼠中使用Miles测定的功效研究(第II部分)。图12a显示获得的关于#803(511max)的结果。EC50为5.990nM并且具有2.060至17.41nM的统计展布(statistical spread)，而R2为0.5800。图12b显示获得的关于ESBA903(578minmax)的结果。EC50为3.989并且具有1.456至10.93nM的统计展布，而R2为0.3920。图12c显示Lucentis的染料渗漏面积。由于曲线的较差的拟合性，无法计算Lucentis的EC50。
图13举例说明在大鼠中使用改进的miles测定的功效研究(预先混合hVEGF165和578minmax(ESBA903))。图13a举例说明阿瓦斯丁(Avastin)对大鼠中VEGF诱导的视网膜血管渗漏的抗渗透性功效-剂量响应。阿瓦斯丁抑制hVEGF-诱导的视网膜血管渗透性。注射之前进行预混合。大约等摩尔量、3倍或10倍过量。＊p<0.05(VEGF对BSA)，＊＊p<0.05(阿瓦斯丁处理的对VEGF)。图13b显示ESBA903对大鼠中VEGF诱导的视网膜血管渗漏的抗渗透性功效。剂量响应(预先混合的，ivt)。ESBA903完全抑制hVEGF诱导的视网膜血管渗透性。注射之前进行预混合。大约等摩尔量、3倍或10倍过量。＊p<0.05(VEGF对BSA)，＊＊p<0.05(ESBA903处理的对VEGF)。
图14举例说明在大鼠中使用改进的miles测定的功效研究(局部施用578minmax(ESBA903))。在局部施用后测试AL-51287(ESBA903)对大鼠中VEGF诱导的视网膜血管渗漏的抗渗透性功效。5天的预处理，4滴/天(使用10ng/ml ESBA903制剂)。＊p<0.05(VEGF对BSA)，＊＊p<0.05(VEGF对AL-51287)，＊＊＊p＝0.060(AL-51287对AL-52667)，＊＊＊＊(VEGF对AL-39324)；p<0.05(AL-39324对媒介物参照对照)。AL-51287：ESBA903；AL-52657：局部媒介物参照对照；AL-39324：小分子RTK抑制剂。
图15举例说明本文中使用的VH的CDR1的界定。
发明详述
本发明提供了包含来自兔单克隆抗体的CDR的可溶和稳定的抗VEGF免疫结合剂。所述免疫结合剂经设计用于诊断和/或治疗VEGF介导的病症。还公开了用于表达本发明的重组抗体的杂交瘤、核酸、载体和宿主细胞、用于分离其的方法和所述抗体在医药中的用途。
定义
为了可更容易地理解本发明，如下定义某些术语。另外的定义示于本说明书的上下文中。
术语“VEGF”是指165个氨基酸的血管内皮细胞生长因子和相关的121、189和206个氨基酸的血管内皮细胞生长因子(如由Leung等人，Science 246:1306(1989)，和Houck等人，Mol.Endocrin.5:1806(1991)描述的)和这些生长因子的天然存在的等位基因形式和加工的形式。
术语“VEGF受体”或“VEGFr”是指VEGF的细胞受体(通常在血管内皮细胞上发现的细胞表面受体)以及保持结合hVEGF的能力的其变体。VEGF受体的一个实例是fms样酪氨酸激酶(flt)，酪氨酸激酶家族的跨膜受体。DeVries等人，Science 255:989(1992)；Shibuya等人，Oncogene5:519(1990)。flt受体包含胞外结构域、跨膜结构域和具有酪氨酸激酶活性的胞内结构域。胞外结构域参与VEGF的结合，而胞内结构域参与信号转导。VEGF受体的另一个实例是flk-1受体(也称为KDR)。Matthews等人，Proc.Nat.Acad.Sci.88:9026(1991)；Terman等人，Oncogene6:1677(1991)；Terman等人，Biochem.Biophys.Res.Commun.187:1579(1992)。VEGF对flt受体的结合导致形成至少2个高分子量复合物(具有205,000和300,000道尔顿的表观分子量)。300,000道尔顿的复合物据信为包含结合至单个VEGF分子的两个受体分子的二聚体。
如本文中使用的，术语“兔”是指属于兔科(leporidae)的动物。
本文中使用的术语“抗体”是“免疫球蛋白”的同义词。根据本发明的抗体可以是完整的免疫球蛋白或其片段，其包括免疫球蛋白的至少一个可变结构域，例如单个可变结构域，Fv(Skerra A.和Pluckthun，A.(1988)Science 240：1038-41)，scFv(Bird，R.E.等人(1988)Science 242：423-26；Huston，J.S.等人(1988)Proc.Natl.Acad.Sci.USA85：5879-83)，Fab，(Fab')2或本领域技术人员熟知的其他片段。
术语“CDR”是指抗体的可变结构域内主要促成抗原结合的6个高变区之一。所述6个CDR的最常用的定义之一由Kabat E.A.等人，(1991)Sequences of proteins ofimmunological interest.NIH Publication91-3242)提供。如本文中使用的，CDR的Kabat定义只应用于轻链可变结构域的CDR1、CDR2和CDR3(CDR L1、CDR L2、CDR L3或L1、L2、L3)，以及重链可变结构域的CDR2和CDR3(CDR H2、CDR H3或H2、H3)。然而，如本文中使用的，根据下列残基(Kabat编号)定义重链可变结构域的CDR1(CDR H1或H1)：其始于位置26并且终止于位置36之前。这基本上是由Kabat和Chotia分别定义的CDR H1的融合物(关于示例说明，也参见图15)。
本文中使用的术语“抗体构架”或有时仅称为“构架”，是指可变结构域VL或VH的一部分，其用作该可变结构域的抗原结合环(CDR)的支架。从本质上讲，其是不具有CDR的可变结构域。
术语“单链抗体”、“单链Fv”或“scFv”意指包含通过接头连接的抗体重链可变结构域(或区域；VH)和抗体轻链可变结构域(或区域；VL)的分子。此类scFv分子可具有一般结构：NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。
如本文中所使用的，“同一性”是指两个多肽、分子之间或两个核酸之间匹配的序列。当两个进行比较的序列中的位置都被相同的碱基或氨基酸单体亚单元占据(例如，如果两个DNA分子的每一个中的位置都被腺嘌呤占据，或两个多肽的每一个中的位置都被赖氨酸占据)时，各个分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置的数目除以进行比较的位置的数目再乘以100的函数。例如，如果两个序列的10个位置中有6个匹配，那么这两个序列具有60％的同一性。例如，DNA序列CTGACT和CAGGTT共有50％的同一性(总共6个位置中有3个位置匹配)。通常，在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过使用，例如，通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行的Needleman等(1970)J.Mol.Biol.48：443-453的方法来提供。还可使用已整合入ALIGN程序(版本2.0)的E.Meyers和W.Miller的算法(Comput.ApplBiosci.，4:11-17(1988))，使用PAM120权重残基表(weight residue table)、12的缺口长度罚分和4的缺口罚分来测定两个氨基酸序列之间的百分比同一性。此外，可使用已整合入GCG软件包(可在www.gcg.com上获得)中的GAP程序的Needleman和Wunsch(J.Mol.Biol.48:444-453(1970))算法，使用Blossum62矩阵或PAM250矩阵以及16，14，12，10，8，6或4的缺口权重和1，2，3，4，5或6的长度权重来测定两个氨基酸序列之间的百分比同一性。
“相似的”序列是当比对时共有相同和相似氨基酸残基的序列，其中相似的残基是进行比对的参照序列中的相应氨基酸残基的保守置换。在这点上，参照序列中的残基的“保守置换”是用在物理或功能上与相应的参照残基相似(例如具有相似大小、形状、电荷、化学性质，包括形成共价键或氢键的能力等)的残基进行的置换。因此，“经保守置换修饰的”序列是与参照序列或野生型序列相异在于存在一个或多个保守置换的序列。两个序列之间的“百分数相似性”是包含由两个序列共有的匹配残基或保守置换的位置的数目除以进行比较的位置的数目x 100的函数。例如，如果两个序列的10个位置中有6个匹配以及10个位置中有2个包含保守置换，那么这两个序列具有80％的正相似性。
如本文中使用的，术语“保守的序列修饰”意指不会不利地影响或改变包含氨基酸序列的抗体的结合特征的氨基酸修饰。此类保守的序列修饰包括核苷酸和氨基酸置换、添加和缺失。例如，可通过本领域内已知的标准技术例如定点诱变和PCR介导的诱变引入修饰。保守氨基酸置换包括其中用具有相似侧链的氨基酸残基替代氨基酸残基的置换。已在本领域内定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如，赖氨酸、精氨酸和组氨酸)、酸性侧链(例如，天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如，甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如，丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β分支侧链(例如，苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如，酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此，优选用来自相同侧链家族的另一个氨基酸残基替代人抗VEGF抗体中的预测的非必需氨基酸残基。鉴定不消除抗原结合作用的核苷酸和氨基酸保守置换的方法在本领域内是熟知的(参见，例如，Brummell等人，Biochem.32:1180-1187(1993)；Kobayashi等人Protein Eng.12(10):879-884(1999)；和Burks等人Proc.Natl.Acad.Sci.USA94:412-417(1997))。
本文中使用的“氨基酸共有序列”是指可使用至少两个，优选更多的进行比对的氨基酸序列的矩阵产生的氨基酸序列(允许在比对中出现缺口)，其使得可能确定各位置上出现频率最高的氨基酸残基。共有序列是包含在各位置上出现频率最高的氨基酸的序列。如果两个或更多个氨基酸等同地出现在单个位置上，那么共有序列包括两个或所有此类氨基酸。
可在不同水平上分析蛋白质的氨基酸序列。例如，可在单个残基水平、多个残基水平、具有缺口的多个残基水平等上展示保守性或变异性。残基可展示相同残基的保守性或可在种类水平上保守。氨基酸种类的实例包括具有下列的氨基酸种类：极性的但不带电荷的R基团(丝氨酸、苏氨酸、天冬酰胺和谷氨酰胺)；带正电荷的R基团(赖氨酸、精氨酸和组氨酸)；带负电荷的R基团(谷氨酸和天冬氨酸)；疏水R基团(丙氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、色氨酸、缬氨酸和酪氨酸)；以及特殊氨基酸种类(半胱氨酸、甘氨酸和脯氨酸)。其他种类对于本领域技术人员来说是已知的并且可使用结构测定法或其他数据来定义以估量可置换性。在该意义上，可置换的氨基酸可以指可在该位置上进行置换并且保持功能保守性的任何氨基酸。
然而，将认识到，相同种类的氨基酸在它们的生物物理性质上可具有一定程度的不同。例如，将认识到，某些疏水性R基团(例如，丙氨酸、丝氨酸或苏氨酸)比其他疏水性R基团(例如，缬氨酸或亮氨酸)更加亲水(即，具有更高的亲水性或更低的疏水性)。相对亲水性或疏水性可使用本领域公知的方法(参见，例如，Rose等人,Science,229:834-838(1985)和Cornette等人,J.Mol.Biol.,195:659-685(1987))来测定。
如本文中所使用的，当一个氨基酸序列(例如，第一VH或VL序列)与一个或多个另外的氨基酸序列(例如，数据库中的一个或多个VH或VL序列)比对时，可将一个序列(例如，第一VH或VL序列)中的氨基酸位置与一个或多个另外的氨基酸序列中的“相应位置”相比较。如本文中所使用的，“相应位置”表示当对序列进行最优比对时，即当序列进行比对以获得最高百分数同一性或百分数相似性时进行比较的序列中的等同位置。
如本文中所使用的，术语“抗体数据库”是指两个或更多个抗体氨基酸序列(“多个”序列)的集合，通常是指数十个、数百个或甚至数千个抗体氨基酸序列的集合。抗体数据库可存储例如抗体VH区、抗体VL区或两者的集合的氨基酸序列，或可存储由VH和VL区域组成的scFv序列的集合。优选，可将数据库存储在可检索的、固定的介质中，例如计算机上可检索的计算机程序中。在一个实施方案中，抗体数据库是包含或由种系抗体序列组成的数据库。在另一个实施方案中，抗体数据库是包含或由成熟(即，表达的)抗体序列组成的数据库(例如，成熟抗体序列的Kabat数据库，例如KBD数据库)。在另一个实施方案中，抗体数据库包含或由功能性选择的序列(例如，根据QC测定选择的序列)组成。
术语“免疫结合剂”是指分子，所述分子包含抗体的全部或部分抗原结合位置，例如重链和/或轻链可变结构域的全部或一部分，这样免疫结合剂能够特异性识别靶抗原。免疫结合剂的非限定性实例包括全长免疫球蛋白分子和scFv，以及抗体片段，包括但不限于(i)Fab片段，由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，包含通过铰链区上的二硫桥连接的两个Fab片段的二价片段，(iii)Fab'片段，其基本上是具有铰链区的一部分的Fab(参见,Fundamental Immunology(Paul编辑，3.sup.rd ed.1993)；(iv)由VH和CH1结构域组成的Fd片段；(v)由抗体的单臂的VL和VH结构域组成的Fv片段；(vi)单结构域抗体例如Dab片段(Ward等人,(1989)Nature 341：544-546)，其由VH或VL结构域组成，Camelid(参见Hamers-Casterman等人，Nature 363：446-448(1993)和Dumoulin等人，ProteinScience11：500-515(2002))或Shark抗体(例如，shark Ig-NARs)；和(vii)纳米抗体(Nanobody)，包含可变结构域和两个恒定结构域的重链区。
如本文中所使用的，术语“功能性质”是例如为了提高多肽的生产性质或治疗功效，其提高(例如相对于常规多肽)对于本领域技术人员来说是期望的和/或有利的多肽(例如，免疫结合剂)的性质。在一个实施方案中，功能性质是稳定性(例如，热稳定性)。在另一个实施方案中，功能性质是溶解性(例如，在细胞条件下)。在另一个实施方案中，功能性质是非聚集性。在另一个实施方案中，功能性质是蛋白质表达(例如，在原核细胞中)。在另一个实施方案中，功能性质是在相应的纯化方法中内含体溶解后的重折叠效率。在某些实施方案中，抗原结合亲和力不是期望提高的功能性质。
术语“表位”或“抗原决定簇”是指抗原(例如，VEGF)上免疫球蛋白或抗体特异性结合的部位。表位通常以独特的空间构象包括至少3，4，5，6，7，8，9，10，11，12，13，14或15个连续或非连续的氨基酸。参见，例如，Epitope Mapping Protocols in Methods inMolecular Biology，第66卷，G.E.Morris，Ed.(1996)。
术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。通常，抗体以大约小于10-7 M，例如大约小于10-8 M、10-9 M或10-10 M或更小的亲和力(KD)结合。
术语“KD”或“Kd”是指特定抗体-抗原相互作用的解离平衡常数。通常，本发明的抗体以小于大约10-7 M，例如小于大约10-8 M、10-9 M或10-10 M或更小的解离平衡常数(KD)结合VEGF，例如，如使用表面等离子体共振(SPR)技术在BIACORE仪中测定的。
术语“中和VEGF”、“抑制VEGF”和“阻断VEGF”可互换使用，表示本发明的抗体阻止VEGF与一个或多个VEGF受体例如VEGFR-1和/或VEGFR-2相互作用(从而例如引发信号转导)的能力。
本文中使用的“重组免疫结合剂”是指通过从重组DNA表达而产生的免疫结合剂。
如本文中使用的，"嵌合的"免疫结合剂具有与来源于特定物种或属于特定抗体种类或亚类的抗体中的相应序列同一或同源的重链和/或轻链的部分，同时链的其余部分与来源于另一物种或属于另一抗体种类或亚类的抗体以及此类抗体的片段中的相应序列同一或同源。本文中使用的人源化抗体是一种嵌合抗体。
如本文中使用的，"人源化抗体"是使用重组DNA技术合成以规避对外来抗原的免疫应答的免疫结合剂。人源化是用于减少异种来源的单克隆抗体的免疫原性的良好建立的技术。这包括受体构架的选择(优选人受体构架)、待插入受体构架的来自供体免疫结合剂的CDR的范围和来自供体构架的残基至受体构架内的置换。用于将CDR移植入人受体构架的一般方法已由Winter在美国专利5,225,539(其以其全文通过引用合并入本文)中公开。US6,407,213(其教导以其全文通过引用合并入本文)公开了构架的许多氨基酸位置，其中来自供体免疫结合剂的置换是优选的。
术语“核酸分子”是指DNA分子和RNA分子。核酸分子可以是单链或双链的，但优选是双链DNA。当将核酸与另一个核酸序列置于功能关系中时，核酸是“有效连接的”。例如，如果启动子或增强子影响编码序列的转录，那么启动子或增强子有效地连接至所述编码序列。
术语“载体”是指能够运输已与其连接的另一个核酸的核酸分子。一种类型的载体是“质粒”，其是指可将另外的DNA区段连接至其中的环状双链DNA环。另一种类型的载体是病毒载体，其中可将另外的DNA区段连接至病毒基因组中。某些载体(例如，具有细菌复制起点的细菌载体和附加型哺乳动物载体)能够在已将它们引入其中的宿主细胞中自主复制。其他载体(例如，非附加型哺乳动物载体)可在引入宿主细胞后整合入宿主细胞的基因组，从而它们可随宿主基因组一起复制。
术语“宿主细胞”是指已向其中引入了表达载体的细胞。宿主细胞可包括细菌、微生物、植物或动物细胞。易于转化的细菌包括肠杆菌科(enterobacteriaceae)的成员，例如大肠杆菌(Escherichia coli)或沙门氏菌(Salmonella)的菌株；芽孢杆菌科(Bacillaceae)例如枯草芽孢杆菌(Bacillus subtilis)；肺炎球菌(Pneumococcus)；链球菌(Streptococcus)和流感嗜血菌(Haemophilus influenzae)。适当的微生物包括酿酒酵母(Saccharomyces cerevisiae)和毕赤酵母(Pichia pastoris)。适当的动物宿主细胞系包括CHO(中国仓鼠卵巢细胞系)和NS0细胞。
术语“治疗”、“疗法”和“医治”是指本文中描述的治疗性或预防性措施。“治疗”的方法利用给有此治疗需要的受试者(例如，患有VEGF介导的病症的受试者或最终可能获得这样的病症的受试者)施用本发明的抗体以预防、治愈、延迟、减轻病症或复发性病症的严重度或改善其一个或多个症状，或以延长在这样的治疗不存在的情况下所预期的受试者的存活。
术语"VEGF-介导的病症"是指其症状或疾病状态的发作、进展或持续需要VEGF的参与的任何病症。示例性VEGF介导的病症包括但不限于，年龄相关黄斑变性、新生血管性青光眼、糖尿病性视网膜病变、早产儿视网膜病变、晶体后纤维增生症、乳腺癌、肺癌、胃癌、食管癌、结肠直肠癌、肝癌、卵巢癌、昏迷、男性细胞瘤(arrhenoblastoma)、宫颈癌、子宫内膜癌、子宫内膜增生、子宫内膜异位、纤维肉瘤、绒毛膜癌、头颈癌、鼻咽癌、喉癌、肝母细胞瘤、卡波西肉瘤(Kaposi's sarcoma)、黑素瘤、皮肤癌、血管瘤、海绵状血管瘤、血管母细胞瘤、胰腺癌、视网膜母细胞瘤、星形细胞瘤、胶质母细胞瘤、神经鞘瘤、少突胶质细胞瘤、髓母细胞瘤、神经母细胞瘤、横纹肌肉瘤、成骨肉瘤、平滑肌肉瘤、泌尿道癌、甲状腺癌、肾母细胞瘤(Wilm's tumor)、肾细胞癌、前列腺癌、与斑痣性错构瘤病(phakomatoses)相关的异常血管增生、水肿(edema)(例如与脑肿瘤相关的水肿)、麦格综合征(Meigs'syndrome)、类风湿性关节炎、银屑病和动脉粥样硬化。
术语"有效剂量"或"有效给药量"是指足以获得或至少部分获得期望的效果的量。术语“治疗有效剂量”定义为足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。对于该用途有效的量将取决于待治疗的病症的严重度和患者自己的免疫系统的总体状态。
术语“受试者”是指任何人或非人动物。例如，本发明的方法和组合物可用于治疗患有VEGF介导的病症的受试者。
如本文中使用的，术语"Min-graft"或"min"是指通过将来自兔可变结构域的兔CDR移植入天然存在的人受体构架(FW1.4，SEQ ID No.172)而产生的人源化的可变结构域。在构架区中不进行改变。就期望的功能性质(溶解性和稳定性)预先选择构架本身。
如本文中使用的，术语"Max-graft"或"max"是指通过将来自兔可变结构域的兔CDR移植入“兔源化的(rabbitized)”人受体构架"RabTor"(rFW1.4，SEQ ID No.173)或移植入称为rFW1.4(v2)的其衍生物(SEQ ID No.174)而产生的人源化的可变结构域。通过整合通常参与兔可变结构域结构和稳定性的构架位置处的保守兔残基(另外其在其他物种中是高度可变的)来制备"RabTor"构架，目的在于产生可通用的构架，所述构架几乎接受任何兔CDR组而无需移植供体构架残基(除了在这样的位置上，所述位置在它们的假定祖先序列中不同，例如在体细胞高度突变过程中被改变从而可能促进抗原结合)。假定的祖先序列定义为最接近的兔种系对应物，并且在不能确定最接近的种系对应物的情况下，定义为兔亚型共有序列或具有高相似性百分数的兔序列的共有序列。
如本文中使用的，术语"Min-Max"或"minmax"是指包含"Min-graft"可变轻链与"Max-graft"可变重链的人源化可变结构域。
如本文中使用的，术语"Max-Min"或"maxmin"是指包含"Max-graft"可变轻链与"Min-graft"可变重链的人源化可变结构域。
不同的命名法被用于产生的免疫结合剂。此类免疫结合剂通常利用编号(例如#578)来标识。在使用前缀例如EP或Epi的情况下(例如，EP 578，其与Epi 578相同)，表示相同的免疫结合剂。有时，免疫结合剂接受由前缀"ESBA"标识的第二名称。例如ESBA903表示与578minmax或EP578minmax或Epi578minmax相同的免疫结合剂。
除非另外指出，本文中使用的所有技术和科学术语具有与本发明所属领域内的技术人员通常理解的意义相同的意义。虽然与本文中描述的方法和材料相似或等同的方法和材料可用于本发明的实践或试验中，但下面描述了适当的方法和材料。在矛盾的情况下，以本说明书(包括定义)为准。此外，材料、方法和实施例只是举例说明性的而非限定性的。
在下列部分更详细地描述本发明的多个方面。应理解，可随意组合不同实施方案、参数和范围。此外，取决于具体的实施方案，可不使用选择的定义、实施方案或范围。
抗VEGF免疫结合剂
在一个方面，本发明提供了结合VEGF，从而适合于在体内阻断VEGF的功能的免疫结合剂。此类免疫结合剂的CDR来源于从用人VEGF和/或其片段(SEQ ID NO.1)免疫的兔获得的兔抗VEGF单克隆抗体。就我们所知，这是首次从兔获得单克隆抗VEGF抗体并且对其进行了详尽地表征。令人惊讶地，发现亲和力(Kd)极高。
在某些实施方案中，本发明提供了特异性结合VEGF的免疫结合剂，其包含CDRH1、CDRH2、CDRH3、CDRL1、CDRL2或CDRL3氨基酸序列中的至少一个。用于本发明的免疫结合剂的示例性CDR氨基酸序列示于SEQ ID No：2-72(表1-6)中。
表1.本发明的抗VEGF免疫结合剂的CDR H1氨基酸序列。
| 序列标识符 | CDR-H1 | SEQ ID No. |
| 60-11-4 | GFPFSSGYWVC | 2 |
| 60-11-6 | GFSFSSGYWIC | 3 |
| 435 | GFSLNTNYWMC | 4 |
| 453 | GFSFSRSYYIY | 5 |
| 375 | GFSFTTTDYMC | 6 |
| 610 | GIDFSGAYYMG | 7 |
| 578 | GFSLTDYYYMT | 8 |
| 534 | GFSLSYYYMS | 9 |
| 567 | GFSLSDYYMC | 10 |
| 509 | GFSLSSYYMC | 11 |
| 511 | GFSLNTYYMN | 12 |
| 509maxII | GFSLSSYYMS | 13 |
| 共有序列 | GFSLSSGYYMC | 14 |
表2.本发明的抗VEGF免疫结合剂的CDR H2氨基酸序列。
| 序列标识符 | CDR-H2 | SEQ ID No. |
| 60 | CIYAGSSGSTYYASWAKG | 15 |
| 435 | CMYTGSYNRAYYASWAKG | 16 |
| 453 | CIDAGSSGILVYANWAKG | 17 |
| 375 | CILAGDGSTYYANWAKG | 18 |
| 610 | YIDYDGDRYYASWAKG | 19 |
| 578 | FIDPDDDPYYATWAKG | 20 |
| 534 | IIGPGDYTDYASWAKG | 21 |
| 567 | CLDYFGSTDDASWAKG | 22 |
共有序列
| 509 | CLDYVGDTDYASWAKG | 23 |
| 511 | IIAPDDTTYYASWAKS | 24 |
| 509maxII | ILDYVGDTDYASWAKG | 25 |
| Consensus | CIDAGSDGDTYYASWAKG | 26 |
表3.本发明的抗VEGF免疫结合剂的CDR H3氨基酸序列。
| 序列标识符 | CDR-H3 | SEQ ID No. |
| 60 | GNNYYIYTDGGYAYAGLEL | 27 |
| 435 | GSNWYSDL | 28 |
| 453 | GDASYGVDSFMLPL | 29 |
| 375 | SDPASSWSFAL | 30 |
| 610 | SDYSSGWGTDI | 31 |
| 578 | GDHNSGWGLDI | 32 |
| 534 | GDDNSGWGEDI | 33 |
| 567 | TDDSRGWGLNI | 34 |
| 509 | TDDSRGWGLNI | 35 |
| 511 | SGDTTAWGADI | 36 |
| 共有序列 | GDDSSGYTDGGYAYWGLDI | 37 |
表4.本发明的抗VEGF免疫结合剂的CDR L1氨基酸序列。
表5.本发明的抗VEGF免疫结合剂的CDR L2氨基酸序列。
| 序列标识符 | CDR-L2 | SEQ ID No. |
| 60 | KASTLAS | 50 |
| 435 | TAANLAS | 51 |
| 453 | YASTLAS | 52 |
| 375 | QASKLAS | 53 |
| 610 | QASTLAS | 54 |
| 578 | LASTLAS | 55 |
| 534 | KESTLAS | 56 |
| 567 | KASTLES | 57 |
| 509 | KASTLES | 58 |
| 511 | RASTLAS | 59 |
| 共有序列 | KASTLAS | 60 |
表6.本发明的抗VEGF免疫结合剂的CDR L3氨基酸序列。
| 序列标识符 | CDR-L3 | SEQ ID No. |
| 60 | QSNYGGSSSDYGNP | 61 |
| 435 | QNFATSDTVT | 62 |
| 453 | AGGYSSTSDNT | 63 |
| 375 | QNNYSYNRYGAP | 64 |
| 610 | QNNYGFRSYGGA | 65 |
| 578 | QNVYLASTNGAN | 66 |
| 534 | QNNYDSGNNGFP | 67 |
| 567 | QNNAHYSTNGGT | 68 |
| 509 | QNNAHYSTNGGT | 69 |
| 511 | QANYAYSAGYGAA | 70 |
| 共有序列 | QNNYHYSSSTNGGT | 71 |
在一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：14，SEQ ID NO：26，SEQ ID NO：37，SEQ ID NO：49，SEQ ID NO：60和SEQ ID NO：71的共有序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：14，SEQ ID NO：26和SEQ ID NO：37组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：49，SEQ ID NO：60和SEQ ID NO：71组成的组中的CDR。优选，CDR选自SEQ ID NO：2至SEQ IDNO：13，SEQ ID NO：15至SEQ ID NO：25，SEQ ID NO：27至SEQ ID NO：36，SEQ ID NO：38至SEQID NO：48，SEQ ID NO：50至SEQ ID NO：59和SEQ ID NO：61至SEQ ID NO：70。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：2，SEQ ID NO：3，SEQ ID NO：15，SEQ ID NO：27，SEQ ID NO：38，SEQ ID NO：50和SEQ IDNO：61的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：2，SEQ ID NO：15和SEQ ID NO：27组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：38，SEQ ID NO：50和SEQ ID NO：61组成的组中的CDR。在另一个优选的实施方案中，所述免疫结合剂的VH包含由SEQ ID NO：3，SEQ ID NO：15和SEQ ID NO：27组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：38，SEQ ID NO：50和SEQ ID NO：61组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：4，SEQ ID NO：16，SEQ ID NO：28，SEQ ID NO：39，SEQ ID NO：51和SEQ ID NO：62的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：4，SEQ ID NO：16和SEQ ID NO：28组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：39，SEQID NO：51和SEQ ID NO：62组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：5，SEQ ID NO：17，SEQ ID NO：29，SEQ ID NO：40，SEQ ID NO：52和SEQ ID NO：63的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：5，SEQ ID NO：17和SEQ ID NO：29组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：40，SEQID NO：52和SEQ ID NO：63组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：6，SEQ ID NO：18，SEQ ID NO：30，SEQ ID NO：41，SEQ ID NO：53和SEQ ID NO：64的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：6，SEQ ID NO：18和SEQ ID NO：30组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：41，SEQID NO：53和SEQ ID NO：64组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：7，SEQ ID NO：19，SEQ ID NO：31，SEQ ID NO：42，SEQ ID NO：54和SEQ ID NO：65的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：7，SEQ ID NO：19和SEQ ID NO：31组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：42，SEQID NO：54和SEQ ID NO：65组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：8，SEQ ID NO：20，SEQ ID NO：32，SEQ ID NO：43，SEQ ID NO：55和SEQ ID NO：66的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：8，SEQ ID NO：20和SEQ ID NO：32组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：43，SEQID NO：55和SEQ ID NO：66组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：9，SEQ ID NO：21，SEQ ID NO：33，SEQ ID NO：44，SEQ ID NO：56和SEQ ID NO：67的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：9，SEQ ID NO：21和SEQ ID NO：33组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：44，SEQID NO：56和SEQ ID NO：67组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：10，SEQ ID NO：22，SEQ ID NO：34，SEQ ID NO：45，SEQ ID NO：57和SEQ ID NO：68的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：10，SEQ ID NO：22和SEQ ID NO：34组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：45，SEQID NO：57和SEQ ID NO：68组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：11，SEQ ID NO：13，SEQ ID NO：23，SEQ ID NO：25，SEQ ID NO：35，SEQ ID NO：46，SEQ IDNO：58和SEQ ID NO：69的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQID NO：11，SEQ ID NO：23和SEQ ID NO：35组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：46，SEQ ID NO：58和SEQ ID NO：69组成的组中的CDR。备选地，所述免疫结合剂的VH包含由SEQ ID NO：13，SEQ ID NO：25和SEQ ID NO：35组成的组中的CDR和/或所述免疫结合剂的VL的CDR包含由SEQ ID NO：46，SEQ ID NO：58和SEQ ID NO：69组成的组中的CDR。
在另一个实施方案中，本发明提供了免疫结合剂，其包含至少一个与选自SEQ IDNO：12，SEQ ID NO：24，SEQ ID NO：36，SEQ ID NO：47，SEQ ID NO：48，SEQ ID NO：59和SEQID NO：70的序列具有至少75％的相似性，优选至少75％的同一性，更优选至少80％，85％，90％，95％，更优选100％的同一性的CDR。优选，所述免疫结合剂的VH包含由SEQ ID NO：12，SEQ ID NO：24和SEQ ID NO：36组成的组中的CDR。另外或备选地，所述免疫结合剂的VL包含由SEQ ID NO：47，SEQ ID NO：48，SEQ ID NO：59和SEQ ID NO：70组成的组(例如SEQ ID NO：47，SEQ ID NO：59和SEQ ID NO：70；或SEQ ID NO：48，SEQ ID NO：59和SEQ ID NO：70)中的CDR。
在非常优选的实施方案中，本文中公开的免疫结合剂中和人VEGF并且与大鼠/小鼠VEGF或其部分交叉反应。
免疫结合剂可包含抗体或能够容纳CDR的任何可选择的结合支架。可使用任何本领域公认的方法(参见，例如，Riechmann，L.等人(1998)Nature 332:323-327；Jones，P.等人(1986)Nature 321:522-525；Queen，C.等人(1989)Proc.Natl.Acad.参见U.S.A.86:10029-10033；属于Winter的美国专利5,225,539，和Queen等人的美国专利5,530,101；5,585,089；5,693,762和6,180,370)将SEQ ID No：2-72中所示的CDR移植至任何适当的结合支架上。然而，优选人源化本文中公开的免疫结合剂，从而使其适合于治疗应用。
在抗体的情况下，可将SEQ ID No:2-72中所示的兔CDR移植入来自任何物种的任何抗体的构架区。然而，之前已发现，包含在所谓的“质量控制”筛选(WO0148017)中鉴定的构架的抗体或抗体衍生物的特征在于普遍较高的稳定性和/或溶解性，从而其还可用于细胞外应用例如中和人VEGF的背景中。此外，还已发现此类VL(可变轻链)和VH(可变重链)的可溶和稳定的构架的一个特定组合特别适合于容纳兔CDR。因此，在一个实施方案中，将SEQID No:2-72中所示的CDR移植入通过EP 1479694中公开的“质量控制”筛选而产生的人抗体构架。用于本发明的示例性构架的氨基酸序列示于SEQ ID No:172至174中。令人惊讶地发现，在移植入所述构架或其衍生物后，许多种兔CDR的环构象可得到完全保持，且很大程度上不依赖于供体构架的序列。此外，与兔野生型单链相反，包含不同兔CDR的所述构架或其衍生物得到良好表达和产生，并且仍然几乎完全保持原始供体兔抗体的亲和力。
因此，在优选实施方案中，本文中公开的CDR和/或CDR基序存在于重链可变区构架序列，所述构架序列与SEQ ID NO：169的序列具有至少80％的序列同一性，更优选至少85％、90％、95％,更优选100％的同一性。在优选实施方案中，重链可变区构架序列包含SEQID NO：170或SEQ ID NO：171。
在优选实施方案中，本文中公开的CDR和/或CDR基序存在于轻链可变区构架序列中，所述构架序列与SEQ ID NO：167的序列具有至少85％的序列同一性，更优选至少90％、95％，更优选100％的同一性，更优选包含SEQ ID NO：167或SEQ ID NO：168。
在兔抗体中，CDR可包含变成连接至抗体构架中的半胱氨酸残基的二硫键的半胱氨酸残基。因此，当将包含半胱氨酸残基的兔CDR移植入非兔构架区时，可能必需通过例如诱变将半胱氨酸残基引入非兔构架以通过二硫键促进兔CDR的稳定。
在其他实施方案中，本发明提供了特异性结合VEGF的免疫结合剂，其包含VL或VH氨基酸序列中的至少一个。用于本发明的免疫结合剂的示例性VH或VL氨基酸序列分别示于SEQ ID No：72-106和107-166。
在优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：107，SEQ ID NO：108，SEQ ID NO：118，SEQ ID NO：119，SEQ ID NO：130和SEQ IDNO：131(分别地VH60-11-4，VH60-11-6，VH60-11-4min，VH60-11-6min，VH60-11-4max和VH60-11-6max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：72，SEQ ID NO:82和SEQ ID NO：93(分别地VL60，VL60min，VL60max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：109，SEQ ID NO：120和SEQ ID NO：132(分别地VH 435，VH 435min和VH435max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：73，SEQ ID NO:83和SEQ ID NO：94(分别地VL 435，VL 435min和VL435max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
优选，所述免疫结合剂与SEQ ID NO：175(435max)具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：110，SEQ ID NO：121和SEQ ID NO：133(分别地VH 453，VH 453min和VH453max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：74，SEQ ID NO:84和SEQ ID NO：95(分别地VL 453，VL 453min和VL453max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：111，SEQ ID NO：122和SEQ ID NO：134(分别地VH 375，VH 375min和VH375max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：75，SEQ ID NO:85和SEQ ID NO：96(分别地VL 375，VL 375min和VL375max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：112，SEQ ID NO：123和SEQ ID NO：135(分别地VH 610，VH 610min和VH610max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：76，SEQ ID NO:86和SEQ ID NO：97(分别地VL 610，VL 610min和VL610max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：113，SEQ ID NO：124，SEQ ID NO：129，SEQ ID NO：136，SEQ ID NO：142，SEQID NO：144，SEQ ID NO：146，SEQ ID NO：147，SEQ ID NO：148，SEQ ID NO：149，SEQ ID NO：150，SEQ ID NO：151，SEQ ID NO：152，SEQ ID NO：153，SEQ ID NO：154，SEQ ID NO：155，SEQID NO：156，SEQ ID NO：157，SEQ ID NO：158，SEQ ID NO：159，SEQ ID NO：160，SEQ ID NO：161，SEQ lD NO：162，SEQ ID NO：163，SEQ ID NO：164，SEQ ID NO：165和SEQ ID NO：166(VH578和其变体)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：77，SEQ ID NO：87，SEQ ID NO：92，SEQ ID NO：98，SEQ ID NO：103，SEQ ID NO：104和SEQ ID NO：105(VL 578和其变体)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
优选，所述免疫结合剂与SEQ ID NO：178(578min)，SEQ ID NO：179(578max)或SEQID NO：180(578minmax)具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：114，SEQ ID NO：125和SEQ ID NO：137(分别地VH 534，VH 534min和VH534max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：78，SEQ ID NO:88和SEQ ID NO：99(分别地VL 534，VL 534min和VL534max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：115，SEQ ID NO：126，SEQ ID NO：138和SEQ ID NO：143(分别地VH 567，VH567min和VH567max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：79，SEQ ID NO:89和SEQ ID NO：100(分别地VL 567，VL567min和VL 567max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
优选，所述免疫结合剂与SEQ ID NO：177(567min)具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：116，SEQ ID NO：127，SEQ ID NO：139和SEQ ID NO：140(分别地VH 509，VH509min，VH509max和VH 509maxII)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：80，SEQ ID NO:90和SEQ ID NO：101(分别地VL509，VL 509min和VL 509max)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在另一个优选实施方案中，本发明提供了包含VH和/或VL的免疫结合剂，所述VH与选自SEQ ID NO：117，SEQ ID NO：128，SEQ ID NO：141和SEQ ID NO：145(分别地VH 511，VH511min，VH511max和VH 511maxDHP)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性；所述VL与选自SEQ ID NO：81，SEQ ID NO:91，SEQ ID NO:102和SEQ IDNO：106(分别地VL511，VL 511min，VL 511max和VL 511minC41L)的序列具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
优选，所述免疫结合剂与SEQ ID NO：176(511_max)具有至少80％，更优选至少85％，90％，95％，最优选100％的同一性。
在某些实施方案中，本发明还提供了特异性结合VEGF的免疫结合剂，其包含与SEQID No：2-166和SEQ ID No：175-180中所示的氨基酸序列具有大体上的相似性的氨基酸序列，并且其中所述免疫结合剂基本上保持或提高本发明的抗VEGF免疫结合剂的期望的功能性质。优选的百分数相似性包括但不限于至少50％，60％，70％，75％，80％，85％，90％或95％的同一性。
在某些实施方案中，本发明还提供了特异性结合VEGF的免疫结合剂，其包含与SEQID No：2-166和SEQ ID No：175-180中所示的氨基酸序列具有大体上的同一性的氨基酸序列，并且其中所述免疫结合剂保持或提高本发明的抗VEGF免疫结合剂的期望的功能性质。优选的百分数同一性包括但不限于至少50％，60％，70％，75％，80％，85％，90％或95％的同一性。
在某些实施方案中，本发明还提供了特异性结合VEGF的免疫结合剂，其包含具有相对于SEQ ID No：2-166和SEQ ID No：175-180中所示的氨基酸序列的保守置换的氨基酸序列，并且其中所述免疫结合剂保持或提高本发明的抗VEGF免疫结合剂的期望的功能性质。
在某些实施方案中，本发明还提供了特异性结合人VEGF并且与其他物种的VEGF分子(例如，小鼠VEGF、大鼠VEGF、兔VEGF或豚鼠VEGF)交叉反应的免疫结合剂。在特定的实施方案中，抗VEGF免疫结合剂可特异性结合人和大鼠/小鼠VEGF。
在一些实施方案中，本发明提供了特异性结合人VEGF并且不与其他物种的VEGF分子(例如小鼠VEGF、大鼠VEGF、兔VEGF或豚鼠VEGF)交叉反应的免疫结合剂。
在一些实施方案中，本发明提供了特异性结合人VEGF的免疫结合剂，其中所述免疫结合剂是亲和力成熟的。
在一个实施方案中，本发明的抗体和抗体片段是单链抗体(scFv)或Fab片段。在scFv抗体的情况下，可利用柔性接头以任一方向将选择的VL结构域连接至选择的VH结构域。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成。在本发明的优选实施方案中，使用具有SEQ ID No:181中所示的氨基酸序列的(GGGGS)4接头，但也可使用1-3个重复的变体(Holliger等人(1993)，Proc.Natl.Acad.Sci.USA90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995)，Protein Eng.8:725-731，Choi等人(2001)，Eur.J.Immunol.31:94-106，Hu等人(1996)，Cancer Res.56:3055-3061，Kipriyanov等人(1999)，J.Mol.Biol.293:41-56和Roovers等人(2001)，Cancer Immunol.Immunother.50:51-59描述。排列可以是VL-接头-VH或VH-接头-VL，前者的方向是优选的方向。然而，还预期单个VH或VL结构域的抗体。在Fab片段的情况下，将选择的轻链可变结构域VL融合至人Igκ链的恒定区，同时将适当的重链可变结构域VH融合至人IgG的第一(N-末端)恒定结构域CH1。可在恒定结构域的C末端或在可变或恒定结构域的其他位置形成链间二硫桥。可选择地，还可通过柔性接头连接两条链，从而导致单链Fab抗体。
本发明的抗体或抗体衍生物可具有对人VEGF的亲和力，且解离常数Kd在10-14 M-10-5 M的范围内。在本发明的优选实施方案中，Kd≤1nM。可使用适当的方法(Berzofsky等"Antibody-Antigen Interactions"，Fundamental Immunology，Paul，W.E.，Ed，RavenPress:New York，NY(1992)；Kuby，J.Immunology，W.H.Freeman and Company:New York，NY)和本文中描述的方法通过实验测定抗体对抗原的亲和力。
Epitomics公司出售为兔单克隆抗体的抗VEGF抗体(VEGF(C-term)RabbitAntibody,Cat.no.1909-1)。所述抗体抗人VEGF的C端上的残基，从而不能够中和VEGF。因此，所述抗体不适合于治疗应用。此外，所述单克隆IgG不是人源化抗体，而是天然兔全长免疫球蛋白。此外，已显示该抗体不识别VEGF的天然形式。
结合VEGF上的相同表位的免疫结合剂
在另一个方面，本发明提供了结合被包含SEQ ID No2-211中所示的氨基酸序列中的任一序列的抗体识别的VEGF上的表位的抗体。此类抗体可基于它们在标准VEGF结合测定(包括但不限于ELISA)中与包含SEQ ID No2-211中所示的任一个或多个氨基酸序列的抗体交叉竞争的能力来进行鉴定。测试抗体抑制包含SEQ ID No2-211中所示的任一个或多个氨基酸序列的抗体与人VEGF结合的能力证明：所述测试抗体可交叉竞争，从而可和与包含SEQID No2-211中所示的任一个或多个氨基酸序列的抗体识别的人VEGF上的表位交叠的表位相互作用。
另外或可选择地，还可使用标准表位作图技术来鉴定此类抗体，从而确定它们是否结合相同的肽免疫原。还可将结构建模技术用于进一步确定抗体/VEGF相互作用的精确分子决定簇，包括但不限于NMR、X射线晶体学、基于计算机的建模或蛋白质层析成像(tomography)(Banyay等人，2004ASSAY and Drug Development Technologies(2)，5，Page516-567)。事实上，已解析了VEGF的晶体结构，并且已知参与VEGFr结合的表面氨基酸残基(Fuh等人，2006，J.Biol.Chem.，281，6625-6631)。因此，鉴于肽免疫原的氨基酸序列和VEGF的结构知识在本领域内是可获得的，鉴定结合被包含SEQ ID No 2-211中所示的任一个或多个氨基酸序列的抗体识别的VEGF上的表位的抗体完全在本领域技术人员的能力之内。
在一些实施方案中，结合被包含SEQ ID No 2-211中所示的任一个或多个氨基酸序列的抗体识别的VEGF上的表位的抗体以至少107M-1，例如至少107 M-1、至少108 M-1、至少109 M-1、至少1010 M-1、至少1011 M-1、至少1012 M-1或至少1013 M-1的亲和力结合VEGF。
在一些实施方案中，结合被包含SEQ ID No 2-211中所示的任一个或多个氨基酸序列的抗体识别的VEGF上的表位的抗体特异性结合人VEGF并且不与其他物种的VEGF分子例如小鼠VEGF、大鼠VEGF、兔VEGF或豚鼠VEGF交叉反应。
在一些实施方案中，结合被包含SEQ ID No 2-211中所示的任一个或多个氨基酸序列的抗体识别的VEGF上的表位的抗体与其他物种的VEGF分子例如小鼠VEGF、大鼠VEGF或兔VEGF交叉反应。
经优化的变体
可就增强的功能性质例如增强的溶解性和/或稳定性进一步优化本发明的抗体。
在某些实施方案中，按照2008年3月12日提交的PCT申请系列号PCT/EP2008/001958(名称为"Sequence Based Engineering and Optimization of Single ChainAntibodies"，其通过引用合并入本文)中公开的“功能共有序列”方法优化本发明的抗体。例如，可将本发明的VEGF免疫结合剂与功能性选择的scFv的数据库进行比较以鉴定比VEGF免疫结合剂中的相应位置更耐受变异性或更不耐受变异性的氨基酸残基位置，从而表明此类鉴定的残基位置可适合用于改造以改善功能性例如稳定性和/或溶解性。
用于置换的示例性构架位置描述于2008年6月25日提交的PCT申请PCT/CH2008/000285(名称为"Methods of Modifying Antibodies，and Modified Antibodies withImproved Functional Properties")和2008年6月25日提交的PCT申请PCT/CH2008/000284(名称为"Sequence Based Engineering and Optimization of Single ChainAntibodies")中。例如，可在本发明的免疫结合剂的重链可变区中在氨基酸位置(对于下文列出的每一个氨基酸位置参照AHo编号)上引入一个或多个下列置换：
(a)氨基酸位置1处的Q或E；
(b)氨基酸位置6处的Q或E；
(c)氨基酸位置7处的T、S或A，更优选T或A，更优选T；
(d)氨基酸位置10处的A、T、P、V或D，更优选T、P、V或D，
(e)氨基酸位置12处的L或V，更优选L，
(f)氨基酸位置13处的V、R、Q、M或K，更优选V、R、Q或M，
(g)氨基酸位置14处的R，M，E，Q或K，更优选R，M，E或Q，更优选R或E；
(h)氨基酸位置19处的L或V，更优选L；
(i)氨基酸位置20处的R，T，K或N，更优选R，T或N，更优选N；
(j)氨基酸位置21处的I，F，L或V，更优选I，F或L，更优选I或L；
(k)氨基酸位置45处的R或K，更优选K；
(l)氨基酸位置47处的T，P，V，A或R，更优选T，P、V或R，更优选R；
(m)氨基酸位置50处的K，Q、H或E，更优选K、H或E，更优选K；
(n)氨基酸位置55处的M或I，更优选I；
(o)氨基酸位置77处的K或R，更优选K；
(p)氨基酸位置78处的A、V、L或I，更优选A、L或I，更优选A；
(q)氨基酸位置82处的E，R，T或A，更优选E，T或A，更优选E；
(r)氨基酸位置86处的T，S，I或L，更优选T，S或L，更优选T；
(s)氨基酸位置87处的D，S，N或G，更优选D，N或G，更优选N；
(t)氨基酸位置89处的A，V，L或F，更优选A，V或F，更优选V；
(u)氨基酸位置90处的F，S，H，D或Y，更优选F，S，H或D；
(v)氨基酸位置92处的D，Q或E，更优选D或Q，更优选D；
(w)氨基酸位置95处的G，N，T或S，更优选G，N或T，更优选G；
(x)氨基酸位置98处的T，A，P，F或S，更优选T，A，P或F，更优选F；
(y)氨基酸位置103处的R，Q，V，I、M，F或L，更优选R，Q，I，M，F或L，更优选Y，更优选L；和
(z)氨基酸位置107处的N，S或A，更优选N或S，更优选N。
另外地或可选择地，可将一个或多个下列置换引入本发明的免疫结合剂的轻链可变区：
(aa)氨基酸位置1处的Q，D，L，E，S或I，更优选L，E，S或I，更优选L或E；
(bb)氨基酸位置2处的S，A，Y，I，P或T，更优选A，Y，I，P或T，更优选P或T；
(cc)氨基酸位置3处的Q，V，T或I，更优选V，T或I，更优选V或T；
(dd)氨基酸位置4处的V，L，I或M，更优选V或L；
(ee)氨基酸位置7处的S，E或P，更优选S或E，更优选S；
(ff)氨基酸位置10处的T或I，更优选I；
(gg)氨基酸位置11处的A或V，更优选A；
(hh)氨基酸位置12处的S或Y，更优选Y；
(ii)氨基酸位置14处的T，S或A，更优选T或S，更优选T；
(jj)氨基酸位置18处的S或R，更优选S；
(kk)氨基酸位置20处的T或R，更优选R；
(ll)氨基酸位置24处的R或Q，更优选Q；
(mm)氨基酸位置46处的H或Q，更优选H；
(nn)氨基酸位置47处的K，R或I，更优选R或I，更优选R；
(oo)氨基酸位置50处的R，Q，K，E，T或M，更优选Q，K，E，T或M；
(pp)氨基酸位置53处的K，T，S，N，Q或P，更优选T，S，N，Q或P；
(qq)氨基酸位置56处的I或M，更优选M；
(rr)氨基酸位置57处的H，S，F或Y，更优选H，S或F；
(ss)氨基酸位置74处的I，V或T，更优选V或T，R，更优选T；
(tt)氨基酸位置82处的R，Q或K，更优选R或Q，更优选R；
(uu)氨基酸位置91处的L或F，更优选F；
(vv)氨基酸位置92处的G，D，T或A，更优选G，D或T，更优选T；
(xx)氨基酸位置94处的S或N，更优选N；
(yy)氨基酸位置101处的F，Y或S，更优选Y或S，更优选S；和
(zz)氨基酸位置103处的D，F，H，E，L，A，T，V、S，G或I，更优选H，E，L，A，T，V，S，G或I，更优选A或V。
AHo编号系统进一步描述于Honegger，A.和Pluckthun，A.(2001)J.Mol.Biol.309:657-670)中。可选择地，可使用如在Kabat等人(Kabat，E.A.,等人(1991)Sequences ofProteins of Immunological Interest，第5版，U.S.Department of Health and HumanServices，NIH Publication No.91-3242)中进一步描述的Kabat编号系统。用于确定抗体重链和轻链可变区中氨基酸残基位置的两个不同编号系统的换算表提供于A.Honegger，J.Mol.Biol.309(2001)657-670中。
在其他实施方案中，本发明的免疫结合剂包含一个或多个2008年6月25日提交的美国临时申请系列号61/075,692(名称为“Solubility Optimization ofimmunobinders”)中描述的溶解性和/或稳定性增强突变。在某些优选实施方案中，免疫结合剂在选自由12、103和144(AHo编号约定)组成的重链氨基酸位置的氨基酸位置处包含溶解性增强突变。在一个优选实施方案中，免疫结合剂包含一个或多个选自下列的置换：(a)重链氨基酸位置12处的丝氨酸(S)；(b)重链氨基酸位置103处的丝氨酸(S)或苏氨酸(T)；和(c)重链氨基酸位置144处的丝氨酸(S)或苏氨酸(T)。在另一个实施方案中，免疫结合剂包含下列置换：(a)重链氨基酸位置12处的丝氨酸(S)；(b)重链氨基酸位置103处的丝氨酸(S)或苏氨酸(T)；和(c)重链氨基酸位置144处的丝氨酸(S)或苏氨酸(T)。
表达兔抗VEGF抗体的杂交瘤
在另一个方面，本发明提供了表达包含SEQ ID No 72-81和SEQ ID No 107-117中所示的任一个或多个氨基酸序列的单克隆抗体的杂交瘤。用于从兔B细胞产生杂交瘤的方法在本领域内是熟知的并且公开于例如美国专利申请2005/0033031中。
抗VEGF免疫结合剂的产生
可使用重组遗传学领域内的常规技术产生本发明的抗体或抗体衍生物。在已知多肽的序列的情况下，可通过基因合成(www.genscript.com)产生编码其的cDNA。可将此类cDNA克隆入适当的载体质粒。一旦获得编码VL和/或VH结构域的DNA，便可进行定点诱变(例如使用诱变引物通过PCR进行的定点诱变)以获得各种衍生物。可基于VL和/或VH序列中期望的改变的数目来选择最佳“起始”序列。
用于将CDR整合入或移植入构架区的方法包括例如Riechmann，L.等人(1998)Nature 332:323-327；Jones，P.等人(1986)Nature 321:522-525；Queen，C.等人(1989)Proc.Natl Acad.See.U.S.A.86:10029-10033；属于Winter的美国专利5,225,539和属于Queen等人的美国专利5,530,101；5,585,089；5,693,762和6,180,370中所示的方法以及于2008年6月25日提交的、名称为"Humanization of Rabbit Antibodies Using UniversalAntibody Frameworks"的美国临时申请系列号61/075,697中公开的方法。
可使用本领域技术人员熟知的标准克隆和诱变技术来连接接头、改组结构域或构建用于产生Fab片段的融合物。公开本发明的一般方法的基本方案描述于MolecularCloning，A Laboratory Manual(Sambrook&Russell，第3版，2001)和Current Protocolsin Molecular Biology(Ausubel等人，1999)中。
将具有编码scFv多肽的基因的DNA序列，或在Fab片段的情况下，编码两个分开的基因或包含VL-Cκ和VH-CH1融合物的两个基因的双顺反子操纵子的DNA序列克隆入适当的表达载体，优选具有诱导型启动子的表达载体。必须注意，在各基因之前存在适当的核糖体结合位点以确保翻译。应当理解，本发明的抗体包含公开的序列而非由公开的序列组成。例如，克隆策略可要求制备从其产生在N末端具有一个或一些另外的残基的抗体的构建体。具体地，来源于起始密码子的甲硫氨酸可存在于终蛋白质中(在其中其在翻译后未被切割的情况下)。大多数scFv抗体的构建体在N末端产生另外的丙氨酸。在本发明的优选实施方案中，选择用于大肠杆菌的周质表达的表达载体(Krebber，1997)。所述载体在可切割的信号序列之前包含启动子。然后将抗体肽的编码序列符合读框地融合至可切割的信号序列。这允许将表达的多肽靶向在其中信号序列被切割的细菌周质。然后折叠抗体。在Fab片段的情况下，必须将VL-Cκ和VH-CH1融合肽都连接至输出信号。在肽到达周质后在C末端半胱氨酸上形成共价S-S键。如果抗体的细胞质表达是优选的，那么通常可以以高产量从内含体获得所述抗体，所述内含体可容易地与其他细胞片段和蛋白质分离。在该情况下，将内含体溶解在变性剂例如盐酸胍(GndHCl)中，然后利用本领域技术人员熟知的复性方法使其重折叠。
将表达scFv或Fab多肽的质粒引入适当的宿主细胞，优选细菌、酵母或哺乳动物细胞，最优选适当的大肠杆菌菌株，如例如JM83(用于周质表达)或BL21(用于在内含体中表达)。可从周质或内含体收获多肽并且使用本领域技术人员已知的标准技术例如离子交换层析、反相层析、亲和层析和/或凝胶过滤来纯化所述多肽。
可就产量、体外溶解性和稳定性表征本发明的抗体或抗体衍生物。可使用WO9729131中描述的重组人VEGF，利用ELISA或表面等离子体共振(BIACore)体外测试对VEGF，优选对人VEGF的结合能力，后一种方法还允许测定koff速率常数，其优选应当小于10-3s-1。Kd值≤10nM是优选的。
除了对于人VEGF具有强的结合亲和力的抗体外，还期望选择在治疗方面具有其他有益性质的抗VEGF抗体。例如，抗体可以是抑制响应VEGF的HUVEC细胞生长的抗体(参见实施例3)。在一个实施方案中，抗体能够抑制响应VEGF的接近最大有效浓度(0.08nM)的HUVEC细胞增殖。优选，抗体在该“内皮细胞生长测定”中具有不超过大约5nM，优选不超过大约1nM，优选不超过大约1nM，优选不超过大约0.5nM和最优选不超过大约0.06nM的抑制VEGF诱导的内皮细胞增殖的有效剂量50(ED50)值，即在这些浓度上，抗体能够体外抑制例如50％或更多的VEGF诱导的内皮细胞生长。
双特异性分子
在另一个方面，本发明表征了包含本发明的抗VEGF抗体或其片段的双特异性分子。可将本发明的抗体或其抗原结合部分衍生或连接至另一种功能性分子例如另一种肽或蛋白质(例如，受体的另一种抗体或配体)以产生结合至少两个不同的结合位点或靶分子的双特异性分子。可将本发明的抗体衍生或连接至超过一个的其他功能性分子以产生结合超过两个不同的结合位点和/或靶分子的多特异性分子；此类多特异性分子也意欲包括在本文中使用的术语“双特异性分子”中。为了产生本发明的双特异性分子，可将本发明的抗体功能性地连接(例如，通过化学偶联、基因融合、非共价结合或其他方法)至一个或多个其他结合分子例如另一个抗体、抗体片段、肿瘤特异性或病原体特异性抗原、肽或结合模拟物，以便产生双特异性分子。因此，本发明包括包含至少一个对于VEGF具有特异性的第一结合分子和对于一个或多个另外的靶表位具有特异性的第二结合分子的双特异性分子。
在一个实施方案中，本发明的双特异性分子包含至少一个抗体或其抗体片段(包括例如Fab、Fab'、F(ab')2、Fv或单链Fv)的结合特异性。抗体还可以是轻链或重链二聚体，或其任何最小片段例如Fv或单链构建体，如Ladner等人的美国专利4,946,778(其内容通过引用合并入本文)中所描述的。
虽然人单克隆抗体是优选的，但可用于本发明的双特异性分子的其他抗体是鼠单克隆抗体、嵌合单克隆抗体和人源化单克隆抗体。
本发明的双特异性分子可通过使用本领域已知的方法缀合组分结合特异性来制备。例如，可分开地产生双特异性分子的各结合特异性，然后将其彼此缀合。当结合特异性是蛋白质或肽时，可将多种偶联或交联剂用于共价缀合。交联剂的实例包括蛋白A、碳二亚胺、N-琥珀酰亚胺基-S-乙酰基-硫代乙酸酯(SATA)、5,5'-二硫代双(2-硝基苯甲酸)(DTNB)、邻-苯二马来酰亚胺(oPDM)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)和4-(N-马来酰亚胺甲基)环己烷-1-羧酸磺基琥珀酰亚胺酯(磺基-SMCC)(参见例如，Karpovsky等人(1984)J.Exp.Med.160:1686；Liu，MA等人(1985)Proc.Natl.Acad.SciUSA82:8648)。其他方法包括Paulus(1985)Behring Ins.Mitt.No.78，118-132；Brennan等人(1985)Science 229:81-83)，和Glennie等人(1987)J.Immunol.139：2367-2375)中描述的方法。优选的缀合剂是SATA和磺基-SMCC，两者都可从Pierce Chemical Co.(Rockford，IL)获得。
当结合特异性是抗体时，可通过巯基键合，例如经由两个重链的C端铰链区或其他位置(无论是天然存在的还是人工引入的)来缀合它们。在特别优选的实施方案中，修饰铰链区以在缀合前包含奇数个(优选1个)巯基残基。
可选择地，可在相同的载体中编码两个结合特异性，并且在相同的宿主细胞中进行表达和装配。该方法在双特异性是mAb x mAb、mAb x Fab、Fab x F(ab')2或配体x Fab融合蛋白的情况下特别有用。本发明的双特异性分子可以是包含一个单链抗体和结合决定簇的单链分子，或包含两个结合决定簇的单链双特异性分子。双特异性分子可包含至少两个单链分子。此外，双特异性分子可以是特异性结合第一靶的scFv，其中将所述scFv的VH和VL与包含提供对第二靶的特异性结合的结构域的柔性接头连接。合适的接头描述于美国临时申请60/937,820。用于制备双特异性分子的方法描述于例如美国专利5,260,203；美国专利5,455,030；美国专利4,881,175；美国专利5,132,405；美国专利5,091,513；美国专利5,476,786；美国专利5,013,653；美国专利5,258,498和美国专利5,482,858。
双特异性分子对它们的特异性靶的结合可通过例如酶联免疫吸附测定(ELISA)、放射性免疫测定(RIA)、FACS分析、生物测定(例如，生长抑制)或通过免疫印迹测定来确认。每一种此类测定通常通过利用特异于目的复合物的标记试剂(例如，抗体)来检测特定目的蛋白质-抗体复合物的存在。例如，可使用例如识别并且特异性结合抗体-VEGF复合物的酶联抗体或抗体片段检测VEGF-抗体复合物。可选择地，可使用多种其他的免疫测定的任一种检测复合物。例如，可放射性标记抗体并且将其用于放射免疫测定(RIA)(参见，例如，Weintraub，B.，Principles of Radioimmunoassays，Seventh Training Course onRadioligand Assay Techniques，The Endocrine Society，March，1986，其通过引用合并入本文)。可通过这样的方法如使用γ计数器或闪烁计数器或通过放射自显影检测放射性同位素。
免疫缀合物
在另一个方面，本发明表征了缀合至治疗性部分例如细胞毒素、药物(例如，免疫抑制剂)或放射性毒素的抗VEGF抗体或其片段。此类缀合物在本文中称为“免疫缀合物”。包括一个或多个细胞毒素的免疫缀合物称为“免疫毒素”。细胞毒素或细胞毒性剂(cytotoxicagent)包括对细胞有害(例如，杀死细胞)的任意试剂。实例包括泰素、细胞松弛素B、短杆菌肽D、溴乙啶、吐根碱、丝裂霉素、依托泊苷、鬼臼噻吩甙、长春新碱、长春碱、秋水仙碱、多柔比星、柔红霉素、二羟基蒽二酮(dihydroxy anthracin dione)、米托蒽醌、光辉霉素、放线菌素D、1-去氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔和嘌呤霉素以及其类似物或同源物。治疗剂还包括例如抗代谢物(例如，甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶达卡巴嗪)、烷化剂(例如，氮芥、thioepa苯丁酸氮芥、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲霉素、丝裂霉素C和顺-二氯二胺铂(II)(DDP)顺铂)、蒽环类(例如，柔红霉素(以前称为道诺霉素)和多柔比星)、抗生素类(例如，放线菌素D(以前称为放线菌素)、博来霉素、光辉霉素和氨茴霉素(AMC))以及抗有丝分裂剂(例如，长春新碱和长春碱)。
可缀合至本发明的抗体的治疗性细胞毒素的其他优选的实例包括多卡米星、卡奇霉素(calicheamicin)、美坦辛和auristatin及其衍生物。卡奇霉素抗体缀合物的实例是可商购获得的(MylotargTM；Wyeth-Ayerst)。
可使用可在本领域内获得的接头技术将细胞毒素缀合至本发明的抗体。已用于将细胞毒素缀合至抗体的接头类型的实例包括但不限于腙类、硫醚、酯类、二硫化物类和包含肽的接头。可选择例如对溶酶体区室中的低pH导致的切割易感或对蛋白酶例如肿瘤组织中优先表达的蛋白酶例如组织蛋白酶类(例如，组织蛋白酶B、C、D)导致的切割易感的接头。
关于细胞毒素的类型、将治疗剂缀合至抗体的接头和方法的论述，也参见Saito，G.等人(2003)Adv.Drug Deliv.Rev.55:199-215；Trail，P.A.等人(2003)CancerImmunol.Immunother.52:328-337；Payne，G.(2003)Cancer Cell3:207-212；Allen，T.M.(2002)Nat.Rev.Cancer 2:750-763；Pastan，I.和Kreitman，R.J.(2002)Curr.Opin.Investig.Drugs3:1089-1091；Senter，P.D.和Springer，CJ.(2001)Adv.DrugDeliv.Rev.53:247-264。
还可将本发明的抗体缀合至放射性同位素以产生也称为放射免疫缀合物的细胞毒性放射性药物。可被缀合至用于诊断或治疗的抗体的放射性同位素的实例包括但不限于碘131、铟111、钇90和镥177。本领域已建立了用于制备免疫缀合物的方法。放射免疫缀合物的实例是可商购获得的，包括ZevalinTM(IDEC Pharmaceuticals)和BexxarTM(CorixaPharmaceuticals)，并且可使用相似的方法，使用本发明的抗体来制备放射免疫缀合物。
本发明的抗体缀合物可用于改变给定的生物学应答，并且药物部分不被解释为限定于经典的化学治疗剂。例如，药物部分可以是具有期望的生物学活性的蛋白质或多肽。此类蛋白质可包括例如酶促活性毒素或其活性片段，例如相思豆毒蛋白、蓖麻蛋白A、假单胞菌外毒素或白喉毒素；蛋白质例如肿瘤坏死因子或干扰素-γ；或生物应答调节剂例如淋巴因子、白细胞介素-1("IL-1")、白细胞介素-2("IL-2")、白细胞介素-6("IL-6")、粒细胞-巨噬细胞集落刺激因子("GM-CSF")、粒细胞集落刺激因子("G-CSF")或其他生长因子。
用于将此类治疗性部分缀合至抗体的技术是熟知的，参见，例如，Arnon等人，"Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy"，inMonoclonal Antibodies And Cancer Therapy，Reisfeld等人(eds.)，pp.243-56(AlanR.Liss，Inc.1985)；Hellstrom等人，"Antibodies For Drug Delivery"，in ControlledDrug Delivery(第2版)，Robinson等人(eds.)，pp.623-53(Marcel Dekker，Inc.1987)；Thorpe，"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy：A Review"，inMonoclonal Antibodies'84：Biological And Clinical Applications，Pinchera等人(eds.)，pp.475-506(1985)；"Analysis，Results，And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy"，in MonoclonalAntibodies For Cancer Detection And Therapy，Baldwin等人(eds.)，pp.303-16(Academic Press 1985)，和Thorpe等人，"The Preparation And Cytotoxic PropertiesOf Antibody-Toxin Conjugates"，Immunol.Rev.，62:119-58(1982)。
抗VEGF抗体的用途
对于治疗性应用，以药学上可接受的剂型例如本文中论述的剂型(包括可以以推注的形式静脉内或通过在一段时间内的持续输注，通过局部、眼内、肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内、口服或吸入途径给人施用的剂型)给哺乳动物优选人施用本发明的抗VEGF抗体。还可以适当地通过瘤内、肿瘤旁、损伤内(intralesional)或损伤周围(perilesional)途径施用抗体以产生局部及全身性治疗效应。预期腹膜内途径在例如卵巢肿瘤的治疗中是特别有用的。
为了预防或治疗疾病，适当的抗体剂量将取决于待治疗的疾病的类型(如上所定义的)、疾病的严重度和进程、是为了预防目的还是为了治疗目的施用抗体、以前的治疗、患者的临床史和对抗体的应答以及主治医生的判断。适当地在一次或在一系列治疗中给患者施用抗体。
抗VEGF抗体可用于治疗本文中描述的VEGF介导的疾病。例如年龄相关性黄斑变性(AMD)是老年人群中严重视力丧失的首要原因。AMD的渗出形式的特征在于脉络膜新生血管化和视网膜色素上皮细胞脱离。因为脉络膜新生血管化与预后的急剧恶化相关联，因此本发明的VEGF抗体在减轻AMD的严重度中特别有用。该治疗的进展可通过常规技术包括眼底镜检查、眼底显微镜检查和眼计算机层析成像来容易地监控。
考虑适合用于Lucentis的所有FDA批准的剂量和给药方案。其他的剂量和给药方案描述于2008年6月25日提交的美国临时申请系列号61/075,641(名称为"ImprovedImmunobinder Formulations And Methods For Adminstration")和美国临时申请号61/058,504(将其明确地合并入本文)中。
根据本发明的其他实施方案，可通过连续施用抗体或与对于此类目的有效的另一种试剂组合施用抗体来提高抗体预防或治疗疾病的功效，所述另一种试剂例如肿瘤坏死因子(TNF)、能够抑制或中和酸性或碱性成纤维细胞生长因子(FGF)或肝细胞生长因子(HGF)的血管生成活性的抗体、能够抑制或中和组织因子、蛋白质C或蛋白质S的凝血剂活性的抗体(参见Esmon等人，1991年2月21日公开的PCT专利公开案WO 91/01753)、能够结合HER2受体的抗体(参见Hudziak等人，1989年7月27日公开的PCT专利公开案89/06692)或一个或多个常规治疗剂例如烷化剂、光凝固剂(photocoagulant)(例如维替泊芬)、叶酸拮抗剂、核酸代谢的抗代谢物、抗生素类、嘧啶类似物，5-氟尿嘧啶、顺铂、嘌呤核苷、胺、氨基酸、三唑核苷或皮质类固醇。此类其他试剂可存在于将要施用的组合物中或可分开施用。此外，适当地连续或与放射治疗(无论是照射还是施用放射性物质)组合施用抗体。
本发明的抗体可用作亲和纯化剂。在该方法中，使用本领域内熟知的方法将抗体固定在固相例如Sephadex树脂或滤纸上。将固定的抗体与待纯化的包含VEGF蛋白(或其片段)的样品接触，然后用基本上除去样品中的所有物质(除了结合至固定的抗体的VEGF蛋白外)的适当的溶剂洗涤支持物。最后，用使VEGF蛋白从抗体释放的另一种适当的溶剂例如甘氨酸缓冲液pH5.0洗涤支持物。
抗VEGF抗体还可用于VEGF蛋白的诊断测定，例如检测其在特定细胞、组织或血清中的表达。此类诊断法可用于癌症诊断。
对于诊断应用，通常用可检测的部分标记抗体。许多标记是可获得的，其通常可分类为以下类别：
(a)放射性同位素例如111In、99Tc、14C、131I、125I、3H、32P或35S。可使用例如CurrentProtocols in Immunology，第1和2卷，Coligen等人，Ed.Wiley-Interscience，New York，N.Y.，Pubs.(1991)中描述的技术用放射性同位素标记抗体，并且可使用闪烁计数测量放射性。
(b)荧光标记例如稀土螯合物(铕螯合物)或荧光素和其衍生物、罗丹明和其衍生物、丹(磺)酰、丽丝胺(Lissamine)、藻红蛋白和德克萨斯红是可获得的。可使用例如Current Protocols in Immunology(同上)中公开的技术将荧光标记缀合至抗体。可使用荧光计定量荧光。
(c)各种酶-底物标记是可获得的，美国专利4,275,149提供了一些此类标记的综述。酶通常催化生色底物的化学变化，所述化学变化可使用各种技术测量。例如，酶可催化底物的颜色变化，所述颜色变化可通过分光光度计测量。可选择地，酶可改变底物的荧光或化学发光。用于定量荧光的变化的技术描述于上文中。化学发光底物通过化学反应被电子激发，然后可发射可测量的(例如使用化学发光仪(chemiluminometer)或给荧光受体提供能量的光。酶标记的实例包括萤光素酶(例如，萤火虫萤光素酶和细菌萤光素酶；美国专利4,737,456)、萤光素、2,3-二氢酞嗪二酮、苹果酸脱氢酶、尿素酶、过氧化物酶例如辣根过氧化物酶(HRPO)、碱性磷酸酶、β半乳糖苷酶、葡糖淀粉酶、溶菌酶、糖氧化酶(例如葡糖氧化酶、半乳糖氧化酶和6-磷酸葡糖脱氢酶)、杂环氧化酶(例如尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。用于将酶缀合至抗体的技术描述于O'Sullivan等人，Methodsfor the Preparation of Enzyme-Antibody Conjugates for use in EnzymeImmunoassay，in Methods in Enzym.(ed J.Langone&H.Van Vunakis)，Academic press，New York，73:147-166(1981)中。酶-底物组合的实例包括例如：
(i)辣根过氧化物酶(HRPO)和过氧化氢酶(作为底物)，其中过氧化氢酶氧化染料前体(例如，邻苯二胺(OPD)或盐酸3,3',5,5'-四甲基联苯胺(TMB))；
(ii)碱性磷酸酶(AP)和对-硝基苯基磷酸盐(作为生色底物)；和
(iii)β-D-半乳糖苷酶(β-D-Gal)和生色底物(例如，对-硝基苯基-β-D-半乳糖苷酶)或荧光底物4-甲基伞形基-β-D-半乳糖苷酶。
在本发明的另一个实施方案中，不必标记抗VEGF抗体，并且可使用结合VEGF抗体的标记抗体检测其存在。
本发明的抗体可用于任何已知的测定方法，例如竞争性结合测定、直接和间接夹心测定以及免疫沉淀测定。Zola，Monoclonal Antibodies:A Manual of Techniques，pp.147-158(CRC Press，Inc.1987)。
竞争性结合测定依赖于标记的标准品与测试样品分析物竞争与有限量的抗体的结合的能力。测试样品中VEGF蛋白的量与结合至抗体的标准品的量成反比。为了帮助测定结合的标准品的量，通常在竞争之前或之后使抗体不溶解，以便可方便地将结合至抗体的标准品和分析物与保持未结合的标准品和分析物分开。
夹心测定涉及两种抗体(各自能够结合待检测的蛋白质的不同免疫原性部分或表位)的使用。在夹心测定中，测试样品分析物被固定在固体支持物上的第一抗体结合，然后第二抗体结合分析物，从而形成不溶性三部分复合物。参见，例如美国专利4,376,110。第二抗体本身可用可检测的部分标记(直接夹心测定)或可使用用可检测的部分标记的抗免疫球蛋白抗体测量(间接夹心测定)。例如，一种类型的夹心测定是ELISA测定，在该情况下可检测的部分是酶。
对于免疫组织化学，肿瘤样品可以是新鲜的或冷冻的或可包埋在石蜡中和用防腐剂例如福尔马林固定。
抗体还可用于体内诊断测定。通常，用放射性核素(例如111In、99Tc、14C、131I、125I、3H、32P或35S)标记抗体，以便能够使用免疫闪烁成像(immunoscintiography)定位肿瘤。
本发明的抗体还可提供于试剂盒(预先确定量的试剂与用于进行诊断测定的说明书的包装组合)中。在用酶标记抗体的情况下，试剂盒可包括酶所需的底物和辅因子(例如提供可检测的生色团或荧光团的底物前体)。此外，可包括其他添加剂例如稳定剂、缓冲剂(例如，封闭缓冲剂或裂解缓冲剂)等。各种试剂的相对量可广泛地变化以在溶液中提供显著优化测定的灵敏性的试剂的浓度。特别地，可以以包含赋形剂的无水粉剂(通常冻干的)的形式提供试剂，当其溶解时将提供具有适当浓度的试剂溶液。
药物制剂
在一个方面，本发明提供了含有用于治疗VEGF介导的疾病的抗VEGF抗体的药物制剂。术语"药物制剂"是指以这样的形式存在的制剂，所述形式允许抗体或抗体衍生物的生物学活性明确有效，并且所述制剂不包含对将给其施用所述制剂的受试者有毒的另外的成分。“药学上可接受的”赋形剂(媒介物、添加剂)是可适当地给受试哺乳动物施用以提供有效剂量的使用的活性成分的那些。
“稳定的”制剂是其中的抗体或抗体衍生物在贮存时基本上保持其物理稳定性和/或化学稳定性和/或生物学活性的制剂。用于测量蛋白质稳定性的各种分析技术在本领域内是可获得的并且综述于例如Peptide and Protein Drug Delivery，247-301，VincentLee Ed.，Marcel Dekker，Inc.，New York，N.Y.，Pubs.(1991)和Jones，A.Adv.DrugDelivery Rev.10:29-90(1993)中。可在选择的温度下测量稳定性，并进行选择的时间。优选，制剂在室温(大约30℃)或在40℃下稳定至少1周和/或在大约2-8℃下稳定至少3个月至2年。此外，制剂优选在制剂的冷冻(至例如，-70℃)和解冻后稳定。
如果抗体或抗体衍生物在颜色和/或澄清度的目测检查时或如通过UV光散射或通过尺寸排阻层析或其他适当的本领域公认的方法所测量的，满足定义的关于聚集、降解、沉淀和/或变性的释放规格，那么其在药物制剂中“保持其物理稳定性”。
如果在给定的时间上化学稳定性是使蛋白质被认为仍然保持其生物学活性(如下文中所定义的)的化学稳定性，那么抗体或抗体衍生物在药物制剂中“保持其化学稳定性”。可通过检测和定量蛋白质的化学改变的形式来估量化学稳定性。化学变化可包括大小改变(例如，剪切(clipping))，其可使用例如尺寸排阻层析、SDS-PAGE和/或基质辅助激光解吸附电离/飞行时间质谱(MALDI/TOF MS)来评估。其他类型的化学变化包括可通过例如离子交换层析来评估的电荷变化(例如，由于脱酰胺作用而发生的)。
如果在给定的时间上抗体的生物学活性在制备药物制剂时所展示的生物学活性的大约10％内(在测定的误差内)(如在例如抗原结合测定中所测定的)，那么抗体或抗体衍生物在药物制剂中“保持其生物学活性”。在下文中详尽地阐述抗体的其他“生物学活性”测定。
“等渗的”意指目的制剂具有与人血液大体上相同的渗透压。等渗制剂通常具有大约250至350mOsm的渗透压。可使用例如蒸汽压或冰冷冻型渗透计(ice-freezing typeosmometer)测量等渗性。
“多元醇”是具有多个羟基的物质，其包括糖(还原性和非还原性糖)、糖醇和糖酸。本文中优选的多元醇具有小于大约600kD(例如，在大约120至大约400kD的范围内)的分子量。“还原性糖”是包含可还原金属离子或与蛋白质中的赖氨酸和其他氨基共价反应的半缩醛基团的糖，“非还原性糖”是不具有还原性糖的此类性质的糖。还原性糖的实例是果糖、甘露糖、麦芽糖、乳糖、阿拉伯糖、木糖、核糖、鼠李糖、半乳糖和葡萄糖。非还原性糖包括蔗糖、海藻糖、山梨糖、松三糖和棉子糖。甘露糖醇、木糖醇、赤藻糖醇、苏糖醇、山梨糖醇和甘油是糖醇的实例。至于糖酸，其包括L-葡糖酸和其金属盐。在期望制剂是冷冻-融化稳定的情况下，多元醇优选是在冷冻温度(例如-20℃)下不结晶(结晶使得制剂中的抗体不稳定)的多元醇。非还原性糖例如蔗糖和海藻糖是本文中优选的多元醇，并且由于海藻糖的优良的溶液稳定性，海藻糖优于蔗糖。
如本文中使用的，“缓冲液”是指通过其酸碱共轭成分的作用抗pH变化的经缓冲的溶液。本发明的缓冲液具有范围在大约4.5至大约8.0、优选大约5.5至大约7内的pH。可控制pH在该范围内的缓冲液的实例包括乙酸盐(例如，乙酸钠)、琥珀酸盐(例如琥珀酸钠)、葡糖酸盐、组氨酸、柠檬酸盐和其他有机酸缓冲液。在期望冷冻-融化稳定的制剂的情况下，缓冲液优选不是磷酸盐。
在药理学意义上，在本发明的背景中，抗体或抗体衍生物的“治疗有效量”是指在预防或治疗病症(所述抗体或抗体衍生物对于其的治疗是有效的)中有效的量。“疾病/病症”是可受益于使用抗体或抗体衍生物的治疗的任何病况。其包括慢性和急性病症或疾病，包括使哺乳动物易患所述病症的那些病理学状况。
“防腐剂”是可包含在制剂中以显著减弱其中的细菌作用，从而有助于例如多用途制剂的产生的化合物。可能的防腐剂的实例包括十八烷基二甲基苄基氯化铵、氯己双铵、苯扎氯铵(其中烷基是长链化合物的烷基苄基二甲基氯化铵的混合物)和苄索氯铵。其他类型的防腐剂包括芳香醇例如酚、丁基和苯甲醇、对羟苯甲酸烷基酯例如对羟基苯甲酸甲酯或丙酯、儿茶酚、间苯二酚、环己醇、3-戊醇和间-甲酚。本文中最优选的防腐剂是苯甲醇。
本发明还提供了包含一种或多种抗体或抗体衍生物化合物以及至少一种生理上可接受的载体或赋形剂的药物组合物。药物组合物可包含例如水、缓冲液(例如，中性缓冲盐溶液或磷酸缓冲盐溶液)、乙醇、矿物油、植物油、二甲基亚砜、碳水化合物(例如，葡萄糖、甘露糖、蔗糖或葡聚糖)、甘露糖醇、蛋白质、佐剂、多肽或氨基酸例如甘氨酸、抗氧化剂、螯合剂例如EDTA或谷胱甘肽和/或防腐剂中的一种或多种。如上文中所指出的，其他活性成分可以(但不是必须)包含在本文提供的药物组合物中。
载体是可在施用给患者前与抗体或抗体衍生物结合的物质(通常用于控制化合物的稳定性或生物利用度)。用于此类制剂中的载体通常是生物相容性的，并且还可以是生物可降解的。载体包括例如单价或多价分子例如血清白蛋白(例如，人或牛)、卵白蛋白、肽、多聚赖氨酸和多糖例如氨基葡聚糖和聚酰胺胺(polyamidoamine)。载体还可包括固体支持材料例如包含例如聚乳酸聚乙醇酸、聚(丙交酯-共-乙交酯)、聚丙烯酸酯、胶乳、淀粉、纤维素或葡聚糖的珠粒和微粒。载体可以以多种方式(包括共价结合(直接地或经由接头基团)、非共价相互作用或混合)携带化合物。
可配制药物组合物以用于任何适当的施用方式，包括例如局部、眼内、口服、经鼻、直肠或胃肠外施用。在某些实施方案中，以适合于局部使用的形式(例如滴眼液)存在的组合物是优选的。其他形式包括例如丸剂、片剂、糖锭、锭剂、水性或油性悬浮剂、可分散粉剂或粒剂、乳剂、硬或软胶囊或糖浆剂或酏剂。在其他实施方案中，可将本文提供的组合物配制为冻干剂(lyophilizate)。本文中使用的术语胃肠外包括皮下、皮内、血管内(例如，静脉内)、肌内、经脊柱、颅内、鞘内和腹膜内注射以及任何相似的注射或输注技术。
可将药物组合物配制为无菌注射水性或油性悬浮液，其中取决于所用的媒介物和浓度，将调节剂悬浮或溶解在媒介物中。还可按照现有技术，使用适当的分散剂、湿润剂和/或混悬剂例如上文提及的那些来配制这样的组合物。其中可使用的可接受的媒介物和溶剂是水、1,3-丁二醇、林格氏溶液和等渗氯化钠溶液。此外，无菌不挥发性油可用作溶剂或悬浮介质。为此，可使用任何非刺激性的不挥发性油，包括合成的甘油一酯或甘油二酯。此外，可将脂肪酸例如油酸用于制备可注射的组合物，并且可将佐剂例如局部麻醉药、防腐剂和/或缓冲剂溶解于媒介物中。
还可将药物组合物配制为持续释放制剂(即，在施用后进行调节剂的缓慢释放的制剂例如胶囊)。通常可使用熟知的技术制备此类制剂，并且可通过例如口服、直肠或皮下植入，或通过在期望的靶位置植入来施用所述制剂。用于此类制剂中的载体是生物相容性的，并且还可以是生物可降解的；优选地制剂提供相对恒定水平的调节剂释放。持续释放制剂中包含的抗体或抗体衍生物的量取决于例如植入的位置、释放的速率和预期的持续时间以及待治疗或预防的疾病/病症的性质。
通常以在体液(例如，血液、血浆、血清、CSF、滑液、淋巴、细胞间隙液、眼泪或尿)中获得足以可检测地结合VEGF以及预防或抑制VEGF介导的疾病/病症的浓度的量施用本文中提供的抗体或抗体衍生物。如果剂量导致如本文中描述的可辨别的患者益处，则其被认为是有效的。优选全身性剂量的范围是大约0.1mg至大约140mg/千克体重/天(大约0.5mg至大约7g/患者/天)，且口服剂量通常为静脉内剂量的约5至20倍。可与载体材料组合以产生单个剂型的抗体或抗体衍生物的量将随治疗的宿主和具体的施用模式的变化而变化。剂量单位形式通常可包含大约1mg至大约500mg的活性成分。
可包装药物组合物以治疗响应抗VEGF的抗体或抗体衍生物的病症。包装的药物组合物可包括容器(其装有有效量的至少一种本文中所述的抗体或抗体衍生物)和说明书(例如，标签)(其说明包含的组合物将用于治疗响应一种抗体或抗体衍生物(在施用给患者后)的疾病/病症)。
还可化学修饰本发明的抗体或抗体衍生物。优选的修饰基团是聚合物，例如任选地取代的直链或支链聚烯烃、polyalkenylene或聚氧烯烃聚合物或分支或不分支的多糖。此类效应物基团可增加抗体的体内半衰期。合成的聚合物的具体实例包括任选地取代的直链或支链聚(乙二醇)(PEG)、聚(丙二醇)、聚(乙烯醇)或其衍生物。特定的天然存在的聚合物包括乳糖、直链淀粉、葡聚糖、糖原或其衍生物。需要时可改变聚合物的大小，但其平均分子量通常在500 Da至50000 Da的范围内。对于其中抗体设计用于渗透组织的局部应用，聚合物的优选分子量是约5000 Da。可将聚合物分子连接至抗体，特别是经由WO0194585中所述的共价连接的铰链肽连接至Fab片段重链的C末端。关于PEG部分的连接，参见“Poly(ethyleneglycol)Chemistry，Biotechnological and Biomedical Applications”，1992，J.Milton Harris(ed)，Plenum Press，New York和“Bioconjugation Protein CouplingTechniques for the Biomedical Sciences”，1998，M.Aslam和A.Dent，GrovePublishers，New York。
在如上所述制备目的抗体或抗体衍生物后，制备包含其的药物制剂。待配制的抗体未经历在前的冷冻干燥并且本文中的目的制剂是水性制剂。优选制剂中的抗体或抗体衍生物是抗体片段，例如scFv。通过考虑例如期望的剂量容积和施用模式来确定存在于制剂中的抗体的治疗有效量。大约0.1mg/ml至大约50mg/ml，优选大约0.5mg/ml至大约40mg/ml和最优选大约10mg/ml至大约20mg/ml是制剂中的示例性抗体浓度。
在pH缓冲剂中制备包含抗体或抗体衍生物的水性制剂。本发明的缓冲剂具有大约4.5至大约8.0，优选大约5.5至大约7的pH。可控制pH在该范围内的缓冲剂的实例包括乙酸盐(例如，乙酸钠)、琥珀酸盐(例如琥珀酸钠)、葡糖酸盐、组氨酸、柠檬酸盐和其他有机酸缓冲剂。缓冲剂的浓度可以是大约1mM至大约50mM，优选大约5mM至大约30mM，取决于例如缓冲剂和制剂的期望的等渗性。
将可用作张力剂(tonicifier)和可稳定抗体的多元醇包含在制剂中。在优选实施方案中，制剂不包含紧张(tonicifying)量的盐例如氯化钠，因为这可引起抗体或抗体衍生物沉淀和/或可导致在低pH下的氧化作用。在优选实施方案中，多元醇是非还原性糖例如蔗糖或海藻糖。以可根据制剂的期望的等渗性而变化的量向制剂中加入多元醇。优选水性制剂是等渗的，在该情况下制剂中适当的多元醇浓度在例如大约1％至大约15％w/v的范围内，优选在大约2％至大约10％whv的范围内。然而，高渗或低渗制剂也可以是合适的。加入的多元醇的量还根据多元醇的分子量而改变。例如，与二糖(例如海藻糖)相比较，可加入更低量的单糖(例如，甘露醇)。
还可向抗体或抗体衍生物制剂中加入表面活性剂。示例性表面活性剂包括非离子型表面活性剂例如聚山梨醇酯(例如，聚山梨醇酯20，80等)或泊洛沙姆(例如泊洛沙姆188)。加入的表面活性剂的量是使其减少配制的抗体/抗体衍生物的聚集和/或使制剂中颗粒的形成降至最低和/或减少吸附的量。例如，表面活性剂可以以大约0.001％至大约0.5％，优选大约0.005％至大约0.2％和最优选大约0.01％至大约0.1％的量存在于制剂中。
在一个实施方案中，制剂包含上文中鉴定的试剂(即，抗体或抗体衍生物、缓冲剂、多元醇和表面活性剂)并且基本上不含一种或多种防腐剂，例如苯甲醇、苯酚、间-甲酚、氯丁醇和苄索氯铵。在另一个实施方案中，可在制剂中包含防腐剂，特别是在制剂为多剂量制剂的情况下。防腐剂的浓度可在大约0.1％至大约2％，最优选大约0.5％至大约1％的范围内。可在制剂中包含一种或多种其他药学上可接受的载体、赋形剂或稳定剂例如Remington's Pharmaceutical Sciences第21版，Osol，A.Ed.(2006)中描述的试剂，只要其不会不利地影响期望的制剂特征。可接受的载体、赋形剂或稳定剂在使用的剂量和浓度上对接受者无毒，并且包括：另外的缓冲剂；共溶剂；抗氧化剂包括抗坏血酸和甲硫氨酸；螯合剂例如EDTA；金属复合物(例如Zn-蛋白质复合物)；生物可降解的聚合物例如聚酯；和/或形成盐的抗衡离子例如钠。
用于体内施用的制剂必须是无菌的。这可通过在配制制剂之前或之后利用无菌滤膜进行过滤来容易地实现。
按照已知的方法，例如以推注的形式静脉内施用或通过在一段时间内的持续输注，通过肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内、口服、局部或吸入途径给需要使用所述抗体的治疗的哺乳动物优选人施用制剂。在优选实施方案中，通过将滴眼剂局部施用至眼表面来给哺乳动物施用制剂。为此，可使用例如滴眼剂施用器来施用制剂。
抗体的适当剂量(“治疗有效量”)将取决于例如待治疗的病症、疾病的严重度和进程、是为了预防目的还是为了治疗目的而施用抗体、以前的治疗、患者的临床史和对抗体的应答、使用的抗体类型以及主治医生的判断。适当地在一次或在一系列治疗中给患者施用抗体或抗体衍生物，并且可在诊断后任何时间给患者施用抗体或抗体衍生物。抗体或抗体衍生物还可作为单一治疗或与用于治疗所述病症的其他药物或治疗剂结合进行施用。
作为一般建议，施用的抗体或抗体衍生物的治疗有效量可在大约0.1至大约50mg/kg患者体重的范围内(无论通过一次还是多次施用)，且使用的抗体的常见范围为例如大约0.3至大约20mg/kg，更优选大约0.3至大约15mg/kg(每天施用一次)。然而，可以使用其他给药方案。可通过常规技术容易地监控该治疗的进展。
考虑适合用于Lucentis的FDA批准的剂量和给药方案。
其他的剂量和给药方案描述于2008年6月25日提交的美国临时申请系列号61/075,641(名称为"Improved Immunobinder Formulations And Methods ForAdminstration")(将其明确地合并入本文)中。
制品
在本发明的另一个实施方案中，提供了包含容器的制品，所述容器装有本发明的水性药物制剂，并且任选地提供关于其使用的说明书。适当的容器包括例如瓶子、小瓶、滴眼剂施用器和注射器。容器可由多种材料例如塑料或玻璃制成。示例性容器是3-20cc的一次性玻璃或塑料小瓶。可选择地，对于多剂量制剂，容器可以是3-100cc的玻璃小瓶。容器装有制剂，并且在其上或与其结合的标签可标明使用指导。制品还可包括从商业和用户立场来看期望的其他材料，包括其他缓冲剂、稀释剂、滤器、针、注射器和具有使用说明的产品说明书。
实施例
本公开内容还通过下列实施例来举例说明，所述实施例不应当解释为进一步限定。本申请中提及的所有图和所有参考资料、专利和公开的专利申请的内容以它们的全文通过引用明确地合并入本文。
在整个实施例中，除非另外指出，否则使用下列材料和方法。
一般材料和方法
一般而言，除非另外指出，否则本发明的实施使用化学、分子生物学、重组DNA技术、免疫学(尤其是例如抗体技术)的常规技术和多肽制备的标准技术。参见，例如，Sambrook，Fritsch和Maniatis，Molecular Cloning:Cold Spring Harbor LaboratoryPress(1989)；Antibody Engineering Protocols(Methods in Molecular Biology)，510，Paul，S.，Humana Pr(1996)；Antibody Engineering:A Practical Approach(PracticalApproach Series，169)，McCafferty，Ed.，Irl Pr(1996)；Antibodies:A LaboratoryManual，Harlow等人，C.S.H.L.Press，Pub.(1999)；和Current Protocols in MolecularBiology，eds.Ausubel等人，John Wiley&Sons(1992)。
热稳定性的测量
在Tensor Bruker中使用FT-IR Bio-ATR cell获得各种单链和衍生物分子的衰减全反射傅里叶变换IR(FTIR-ATR)光谱。将分子浓缩直至3mg/ml并且在4℃下对PBS，pH6.5透析过夜，收集缓冲液流过物(flow through)作为空白对照。通过对分子实施广泛温度范围(25-95℃)的热攻击(以5℃为梯度)来获得变性曲线图。使用OPUS软件进行所有光谱操作。从蛋白质光谱扣除主要的缓冲液和瞬时大气(CO2和H2O)背景。然后对所得的蛋白质光谱进行基线修正，根据预期区域中最宽的可分辨峰的宽度测定蛋白质酰胺I光谱。使用三次多项式函数和光滑函数获得酰胺I带光谱的二阶导数光谱。通过酰胺I二阶导数分析来估计蛋白质结构的变化，使用线性校准曲线进行初始曲线拟合计算(假定对于3个更低的测量值，0％的变性和对于3个更高的测量值，100％的变性)。通过应用玻尔兹曼S形模型，将变性曲线图用于估计每种变体的热去折叠转变的中点(TM)。
溶解性测量
在硫酸铵存在的情况下增加蛋白质聚集和沉淀后测量各种scFv分子的相对溶解性。向蛋白质水溶液中加入硫酸铵以在终混合物盐-蛋白质中产生5％的饱和增量。凭经验确定沉淀的动态范围，将该范围中的饱和间隔减少至终混合物中的2.5％间隔饱和。在加入硫酸铵后，将样品轻轻混合，以6000rpm离心30分钟。就每一个硫酸铵饱和百分数回收上清液中剩余的蛋白质。使用NanoDropTM 1000分光光度计通过UV-VIS测量来测量上清液中的蛋白质浓度从而测定溶解性曲线。对上清液中剩余的可溶性蛋白质的测量值进行标准化，并通过应用玻尔兹曼S形模型将其用于评估每种变体的相对溶解性的中点。
短期稳定性测试
在40℃下温育2周后就可溶性聚集体和降解产物的存在检查scFv分子。将具有10mg/ml浓度的蛋白质在4℃下对具有广泛pH范围(3.5，4.5，5.5，6.5，7.0，7.5和8.5)的PBS透析过夜。将在标准缓冲液PBS(pH6.5)中具有相同浓度的对照分子在-80℃下贮存2周。在t＝0和t＝14天的时间点上通过SDS-PAGE测定降解条带，在SEC-HPLC中估量可溶性聚集物。使用Biacore测定于40℃下进行2周后的剩余活性。
实施例1：产生抗VEGF抗体的免疫策略。
在本实施例中，描述了使用新型抗原性VEGF衍生的肽来产生能够识别人、小鼠和兔VEGFA的抗体的免疫策略。
根据在Genentech进行的丙氨酸扫描诱变研究，已知对于与VEGFr的高亲和力相互作用是至关重要的VEGFA的残基(Fuh，G.等人，(2006)J.Biol Chem.281，6625-6631)。虽然受体结合位置可能代表构象表位，但大多数至关重要的残基存在于α螺旋上，在成熟VEGFA的前10个氨基酸上。
当与人序列相比较时，兔VEGFA在α螺旋中包含3个氨基酸变化；相反地，小鼠VEGFA在该区域与人相同。因此，为了产生小鼠-人交叉反应性抗体，兔提供了用于免疫的合适物种。此外，与小鼠免疫相比，兔免疫可导致具有更高的亲和力的Ab。
如上所概述的，与VEGFA的N-末端α螺旋上的残基的相互作用似乎对于与VEGFR1的结合是最关键的。因此，该10个氨基酸长的区段可用作免疫的表位。可选择地，可注射全长VEGFA，然而，VEGFA上的其他肽区段更具免疫原性，因此降低了产生中和抗体的概率。该假说得到下述事实的支持：两个不同的肽(两者都位于靠近VEGFA的C端)潜在地具有免疫原性(如通过Johnson和Wolf的方法预测的)。该方法预测N末端α螺旋只有较小的免疫原性潜能。因此，使用只构成α螺旋的肽的免疫可比使用全长VEGFA的免疫更直接。引发强免疫应答的概率可通过将肽融合或化学偶联至钥孔血蓝蛋白(KLH)进一步增加。
如下进行4个免疫策略。
A.用全长人VEGFA165预免疫兔以增加获得构象结合剂的概率。然后用来自aa区段16-KFMDVYQRDYCHP-28(下划线：受体相互作用；双下划线，兔中的趋异进化，根据晶体结构，Cys参与二硫键)的肽进行二次加强。可将肽序列中包含的Cys用于偶联至KLH，从而其可不暴露为游离Cys。最终的肽如下：KFMDVYQRSY-Cys-KLH。
B.使用全长VEGFA165预免疫小鼠以增加获得构象结合剂的概率。然后用来自aa区段16-KFMDVYQRSYCHP-28(根据晶体结构，Cys参与二硫键)的肽进行二次加强。可将肽序列中包含的Cys用于偶联至KLH，从而其可不暴露为游离Cys。最终的肽如下：KFMDVYQRSY-Cys-KLH。
C.使用来自aa区段16-KFMDVYQRSYCHP-28的肽(最终的肽：KFMDVYQRSY-Cys-KLH)预免疫兔/小鼠。然后用全长VEGFA165进行二次加强以增加获得构象结合剂的概率。
D.在兔中用全长VEGFA165进行免疫。
实施例2
单克隆兔抗VEGF抗体的CDR移植和功能性人源化。
兔CDR的移植
与使用与非人供体抗体共有最大序列同源性的人抗体受体构架的常规人源化方法不同，将兔CDR移植入构架FW1.4(SEQ ID No.172)以产生Min-graft，或将其移植入“兔源化的(rabbitized)”构架rFW1.4(SEQ ID No.173)或其变体rFW1.4(v2)(SEQ ID No.174)以产生Max-graft。最初就期望的功能性质(溶解性和稳定性)、容纳多种兔CDR的结构适合性和与兔可变结构域共有序列的适当的同源性选择两种构架。构架rFW1.4是被进一步改造(目的在于用作几乎任意组兔CDR的通用受体构架)的FW1.4的衍生物。虽然稳定且可溶的构架序列FW1.4展示与兔抗体的高度同源性，但其不是可获得的最同源的序列。
可能参与结合的残基的鉴定
对于各个兔可变结构域序列，鉴定最接近的兔种系对应物。如果不能确定最接近的种系，那么将序列与亚型共有序列或具有高相似性百分数的兔序列的共有序列相比较。稀有构架残基被认为是体细胞高度突变的可能的结果，从而在抗原结合中起着重要作用。因此，考虑将此类残基移植至受体构架rFW1.4或rFW1.4(v2)上以产生Max-graft。特别地，移植潜在参与直接抗原接触或影响VL和VH的排布的残基。需要时置换被描述为影响CDR结构的其他残基。当将CDR移植至FW1.4(Min-graft)上时不进行构架置换。
例如为了产生578minmax，将rFW1.4的残基VH94(H94)突变成供体序列中相应的残基。兔抗体578在H94上包含Gly，然而最同源的种系和兔共有序列在位置H94处都包含Arg。Gly具有对于其他氨基酸未发现的独特的柔性(正Φ角)。这表明在主链扭转角中的作用和对牵涉活性的环构象的可能的强影响。被移植以获得本文中公开的Max-graft的构架位置的另外的实例可通过进行rFW1.4、rFW1.4(v2)的构架区与本文中提供的目的scFv序列的序列比对来鉴定。本领域内已知的网络工具可以例如用于所述目的(例如，在2009年6月23日在http://www.ebi.ac.uk/Tools/clustalw2/index.html上可获得的ClustalW或在2009年6月23日在http://bioinfo.genotoul.fr/multalin上可获得的MultiAlin)。在其上rFW1.4和rFW1.4(v2)包含相同残基并且在其上目的scFv显示不同残基的所有构架位置是被移植以获得Max-graft的构架位置。
结构域改组
将Min-graft的可变轻链与Max-graft的可变重链组合以鉴定就生物物理性质(溶解性和稳定性)和活性而言最佳的组合。
scFv的克隆和表达
如下产生本文中描述和表征的scFv。通过SEQ ID NO.181的接头将人源化的VL序列(SEQ ID No:82-106)连接至人源化的VH序列(SEQ ID No:118-166)以产生下列方向的scFv：NH2-VL-接头-VH-COOH。在许多情况下，由服务提供商Entelechon GmbH(www.entelechon.com)从头合成编码各个scFv的DNA序列。通过分别在scFv DNA序列的5'和3'末端上引入的NcoI和HindIII限制性位点将所得的DNA插入物克隆入细菌表达载体pGMP002。BamHI限制性位点位于VL结构域与VH结构域的DNA序列之间。在一些情况下，不从头合成编码scFv的DNA，而通过结构域改组来克隆表达scFv的构建体。因此，切取VL结构域并且通过NcoI和BamHI限制性位点将其引入新构建体，通过BamHI和HindIII限制性位点将VH结构域引入新构建体。在其他情况下，使用现有技术组装PCR法将点突变引入VH和/或VL结构域。GMP002的克隆描述于WO2008006235的实施例1中。与WO2008006235的实施例1中对于ESBA105的描述类似，产生scFv。
实施例3：抗VEGF SCFV的BIACORE结合分析
在本实施例中，测定scFv的Biacore结合能力，利用BIAcoreTM-T100使用示例性表面等离子体共振法测量结合亲和力。在本实施例和后面的实施例中，就此类scFv候选物的结合而进行测试的VEGF蛋白包括纯化的大肠杆菌(Escherichia coli)表达的重组人VEGF165(PeproTech EC Ltd.)、重组人VEGF121(PeproTech EC Ltd.)、重组人VEGF110(ESBATech AG)、重组小鼠VEGF164(PeproTech EC Ltd.)、重组大鼠VEGF164(Biovision)、重组兔VEGF110(ESBATech AG)和重组人PLGF(PeproTech EC Ltd.)。关于表面等离子体共振实验，按照制造商的说明书用盐酸N-乙基-N'-(3-二甲基氨基丙基)碳二亚胺和N-羟基琥珀酰亚胺活化羧甲基化的葡聚糖生物传感器芯片(CM4，GE Healthcare)。使用标准胺-偶联方法，将上文中举例说明的6个不同的VEGF形式的每一个形式偶联至CM4传感器芯片上的4个不同的流动池之一。在偶联和封闭后，使用这些固定的VEGF分子获得的响应的范围是大约250-500响应单位(RU)(对于hVEGF165)、大约200 RU(对于hVEGF110、hVEGF121、鼠VEGF164、大鼠VEGF164和兔VEGF110)和大约400 RU(对于PLGF)。除了在封闭之前不固定蛋白质外，类似地处理各芯片的第4流动池，并且将该流动池用作内联参照。将不同浓度的在HBS-EP缓冲液(0.01 M HEPES，pH7.4或5，0.15 M NaCl，3mM EDTA，0.005％表面活性剂P20)中的抗VEGFscFv(例如90nM，30nM，10nM，3.33nM，1.11nM，0.37nM，0.12nM和0.04nM)以30μl/分钟的流速注射入流动池，进行5分钟。让抗VEGF scFv与CM4芯片上的VEGF在25℃下解离10分钟。在进行内联参照池修正，然后扣除缓冲液样品后，产生各抗VEGF scFv样品的传感图。使用一对一Langmuir结合模型(one-to-one Langmuir binding model)利用BIAcore T100评估软件版本1.1计算表观解离速率常数(kd)、表观结合速率常数(ka)和表观解离平衡常数(KD)。
作为一个示例性结果，一些前导抗VEGF scFv候选物列于显示它们对hVEGF165的结合亲和力的表7中。在后面的实施例中描述的使用VEGFR竞争性ELISA和/或HUVEC测定测量的它们作为VEGF抑制剂的潜能也示于表7中。图1中举例说明就它们对hVEGF165的结合而言，一些示例性前导候选物例如511max和578max的动力学曲线。还测定了它们的亲和常数(kd，ka和KD)。一些前导候选物在它们对不同来源的不同VEGF蛋白的结合中还展示了物种特异性。例如，使用小鼠和大鼠VEGF164作为结合伴侣在pH5下测量的一些亲和力数据示于表8a和b中。示例性前导scFv候选物578minmax在pH5下在对小鼠和大鼠VEGF164的结合中分别具有5.76E-10 M和7.48E-10M的KD(表8a和b)以及在pH7.4下分别具有2.73E-11和2.19E-11的KD(数据未显示)。在图4中在关于578minmax与人、小鼠或大鼠VEGF蛋白之间的结合的动力学曲线和亲和力数据中进一步举例说明了该物种特异性。
除了在它们对来自不同生物的VEGF的结合中的物种特异性外，许多前导scFv候选物还展示对不同VEGF同种型的差异结合亲和力。例如，表9中比较了在pH5.0下测量的一些scFv候选物对人VEGF165、VEGF121和VEGF110的结合的亲和力数据。在相同的实验中，PIGF蛋白也用作对此类scFv候选物不具有结合能力的阴性对照。此外，关于578Max与VEGF同种型之间的结合的差异动力学曲线和亲和力数据举例说明于图3中。
本发明还公开了源于上文提及的前导抗VEGF scFv候选物的衍生物。就它们的亲和力和潜能(在pH5.0下测量的)举例说明候选物578和511的一些前导衍生物，如表10中所列的。在本实验中，将Biacore用于测量此类衍生物对hVEGF165的亲和力，而将hVEGFR2竞争性ELISA和/或HUVEC测定用于确定它们抑制VEGF的潜能(表10)。在图4中在它们的关于对hVEGF165的结合的动力学曲线和亲和力数据中进一步举例说明3个衍生物578max、578minmax和578wt-His。
关于前导候选物的衍生物，在图5-7和表11中测定和举例说明它们的生物物理特征。如表11中举例说明的，此类特征包括：通过FTIR测定的Tm、在60℃下温育30分钟后β折叠或蛋白质丧失的百分数、通过硫酸铵沉淀测定的溶解性、在产生过程中重折叠的产量和大肠杆菌中的表达水平。在通过FT-IR测量的它们针对不同温度的去折叠曲线中就它们的热稳定性表征了3种衍生物，578max、578minmax和578minmax_DHP(图5)。
在热胁迫(例如，在50℃，60℃或70℃下)30分钟后就它们的变性和沉淀比较图6中所列的一些衍生物。就它们的溶解性(通过硫酸铵沉淀法进行测定)进一步举例说明578max，578minmax和578minmax_DHP。如图7中所示，比较在不同浓度的硫酸铵下这些衍生物的可溶性蛋白质的百分数。
表12a：在50℃下温育30分钟后的抗VEGF结合剂
| 样品名称 | β折叠％ | Nanodrop(mg/ml) |
| 950 | 100,8 | 81,2 |
| 978 | 100,9 | 85,1 |
| 980 | 99,9 | 100,3 |
| 991 | 99,4 | 99,2 |
| 802 | 100,4 | 96,7 |
| 821 | 100,6 | 93,5 |
| 903 | 99,5 | 99,4 |
| 961 | 98,7 | 101,7 |
| 997 | 99,9 | 76,39 |
表12a：在60℃下温育30分钟后的抗VEGF结合剂
| 样品名称 | β折叠％ | Nanodrop(mg/ml) |
| 950 | 45,9 | 2 |
| 978 | 102,3 | 52 |
| 980 | 100,8 | 61 |
| 991 | 99,9 | 80 |
| 802 | 101,5 | 96 |
| 821 | 101,9 | 84 |
| 903 | 100,5 | 89 |
| 961 | 100,1 | 85 |
| 997 | 49,1 | 2 |
表12a：在70℃下温育30分钟后的抗VEGF结合剂
| 样品名称 | β折叠％ | Nanodrop(mg/ml) |
| 950 | 43,1 | 1,0 |
| 978 | 13,4 | 2,7 |
| 980 | 4,5 | 0,2 |
| 991 | 21,5 | 1,4 |
| 802 | 100,4 | 80,8 |
| 821 | 58,4 | 3,3 |
| 903 | 81,9 | 0,7 |
| 961 | 46,3 | 1,1 |
| 997 | 0,0 | 0,3 |
实施例4：VEGF受体阻断测定
对于本发明中公开的抗VEGF scFv候选物或其衍生物，除了实施例3中测量的它们对VEGF的结合亲和力外，还测量它们作为VEGF抑制剂的潜能。测量其潜能的方法包括例如VEGFR竞争性ELISA(如本实施例中举例说明的)和HUVEC测定(图8)。
VEGFR竞争性ELISA测定包括例如VEGFR2受体阻断测定和VEGFR1受体阻断测定。关于VEGFR2受体阻断测定，将人VEGF165以0.05μg/ml(于PBS中)涂铺在96孔Maxisorp ELISA板(Nunc)上，然后使用含有0.1％ BSA和0.2％ Tween20的PBS(PBST)进行封闭。首先将500ng/ml重组人VEGFR2/Fc嵌合体(R&D Systems Inc.)(由融合至6x组氨酸标记的人IgG1的Fc的人VEGFR2的胞外结构域的氨基酸残基1-764组成)与在PBST中3倍系列稀释的抗VEGF scFv一起温育。在于室温下温育30-60分钟后，将混合物转移至固定了人VEGF165的板并且温育90分钟。用偶联至辣根过氧化物酶的山羊(Fab2)抗人IgG Fcγ(Jackson ImmunoResearch)，然后用底物(BM Blue POD底物，Roche Diagnostics)检测VEGFR2/Fc嵌合体对固定的VEGF165的结合。使用Sunrise酶标仪(Tecan)测量450nm处的光密度(OD 450nm)。使用4参数逻辑曲线拟合分析数据，然后根据scFv的剂量-响应曲线计算EC50值。通过VEGFR2受体阻断测定测量的前导候选物或其衍生物的示例性潜能列于表7和9中。
关于VEGFR1受体阻断测定，将0.0125μg/ml的在PBS中的人VEGF165涂铺在96孔Maxisorp ELISA板(Nunc)上，然后使用含有0.4％BSA和0.1％Tween20的PBS进行封闭。首先将100ng/ml的重组人VEGFR1/Fc嵌合体(R&D Systems Inc.)(其由融合至6x组氨酸标记的人IgG1的Fc的人VEGFR1的胞外结构域的氨基酸残基1-687组成)与在PBST中3倍系列稀释的抗VEGF scFv一起温育。在于室温下温育30-60分钟后，将混合物转移至固定了人VEGF165的板中并且温育90分钟。使用偶联至辣根过氧化物酶的山羊(Fab2)抗人IgG Fcγ(JacksonImmunoResearch)，然后使用底物(BM Blue POD底物，Roche Diagnostics)检测VEGFR1/Fc嵌合体对固定的VEGF165的结合。使用Sunrise酶标仪(Tecan)测量450nm处的光密度(OD450nm)。如上分析数据，然后根据scFv的剂量-响应曲线计算EC50值。通过VEGFR1受体阻断测定测量的前导候选物的示例性潜能列于表7中。
实施例5：VEGF抑制的HUVEC测定
本实施例举例说明HUVEC测定，其是测量公开的抗VEGF scFv候选物或其衍生物作为VEGF抑制剂的潜能的另一方法。
使用从几个供体汇集的第2代至第14代的人脐静脉内皮细胞(HUVEC)(Promocell)。将细胞以1000个细胞/孔接种于50μl完全内皮细胞生长培养基(ECGM)(Promocell)，该培养基含有0.4％ECGS/H，2％胎牛血清，0.1ng/ml表皮生长因子，1μg/ml氢化可的松，1ng/ml碱性成纤维细胞因子和1％青霉素/链霉素(Gibco)。7至8小时后，向细胞中加入50μl饥饿培养基(不含含有0.5％热灭活的FCS和1％青霉素/链霉素的补充物的ECGM)，将细胞饥饿15至16小时。在饥饿培养基中制备抗VEGF scFv的3倍系列稀释物(0.023-150nM)和下列之一：重组人VEGF165(0.08nM)、重组小鼠VEGF164(0.08nM)或重组大鼠VEGF164(0.3nM)，并且在室温下预温育30-60分钟。不同浓度的VEGF用于补偿它们的不同的相对生物学活性。使用刺激次最大VEGF诱导的增殖的浓度(EC90)。向含有HUVEC悬浮液的96孔组织培养板中加入100μl混合物，并于37℃/5％CO2潮湿的培养箱中温育4天。在加入20μl/孔的WST-1细胞增殖试剂(Roche)后，使用Sunrise酶标仪(Tecan)通过测量450nm处的吸光度(620nm用作参照波长)来估量HUVEC的增殖。使用4参数逻辑曲线拟合来分析数据，根据抑制曲线推算出抑制50％的HUVEC增殖所需的抗VEGF scFv的浓度(EC50)。
通过HUVEC测定测量的前导候选物或其衍生物的示例性潜能列于表7中。此外，在图9中举例说明了前导候选物的一个衍生物578minmax对hVEGF165诱导的HUVEC增殖的抑制。578minmax对hVEGF165诱导的细胞增殖的抑制的EC50测定为0.06nM(图9)。578minmax作为VEGF抑制剂的潜能是Lucentis的大约1.6倍。578minmax对小鼠或大鼠VEGF164诱导的HUVEC增殖的抑制也举例说明于图10中。578minmax对小鼠和大鼠VEGF164诱导的细胞增殖的抑制的EC50分别为0.06nM和0.07nM(图10)。因此，就被示例性衍生物(578minmax)抑制而言，小鼠和大鼠VEGF与人VEGF是等效的。在本实验中，还发现Lucentis不抑制由啮齿类动物VEGF诱导的增殖。
实施例6：抗VEGF SCFV对无毛豚鼠中HVEGF165诱导的血管渗透性的作用
在本实施例中，使用Miles测定在豚鼠中估量抗VEGF scFv对人VEGF165诱导的血管渗透性的作用。使用永不褪色标记物在无毛雄性豚鼠的背部标记30个施用位置/动物。在处理当天，在全身麻醉下用1ml1％伊文斯蓝染料溶液静脉内施用每一只动物。在染料注射后1小时，将0.1ml含有2.61nM重组人VEGF165(PeproTech EC Ltd.)和不同浓度的抗VEGF scFv(0nM，0.085nM，0.256nM，0.767nM，2.3nM，6.9nM，20.7nM，62.1nM；n＝7只动物/测试项目)的测试溶液以一式三份注射入背部的标记位置(每个测试项目浓度3个注射)。在所有动物中，PBS的注射用作阴性对照。作为另外的对照，在所有动物中注射6.9nM Lucentis(Novartis)。
在测试溶液注射后1小时，对动物施用安乐死，收集、清洗毛皮，使用入射光和透射光对其进行数码拍照。使用Image J评估渗入注射位置的伊文斯蓝染料的面积。对于每一只动物，使用4参数逻辑曲线拟合来分析抗VEGF scFv浓度对染料渗漏面积。根据抑制曲线推算出抑制50％的血管渗漏所需的抗VEGF scFv的浓度(EC50)。
图11中举例说明了实验方案。此外，图11中还举例说明了scFv候选物、ESBA903(578minmax)和802(511max)抑制hVEGF的功效，如由包含从血管系统渗漏入皮肤的伊文斯蓝染料的面积的不同大小表示的。903和802的功效数据示于图12中。在6.9nM上，903和802在所有测试动物中都显示与Lucentis相比更强的对VEGF诱导的至皮肤内的血管渗漏的抑制(图12)。
实施例7：局部抗VEGF SCFV治疗对大鼠中HVEGF165诱导的视网膜血管渗漏的作用
在本实施例中，使用改进的Miles测定显示578minmax的局部功效。此类改进包括例如使用scFv的玻璃体内注射和局部应用进行的预混合研究。
通过单次玻璃体内注射施用预混合的不同浓度的抗VEGF scFv(相对于VEGF，10、3和1倍摩尔过量)和VEGF(500ng)。将阿瓦斯丁(Roche)(相对于VEGF，10、3和1倍摩尔过量)用作阳性对照。将用于578minmax的媒介物(柠檬酸盐缓冲液，20mM Na-Citrate，125mM NaCl，pH7)用作阴性对照。如图13中所举例说明的，与hVEGF165的预混合促进578minmax(ESBA903)完全抑制hVEGF诱导的视网膜血管渗透性。在本实施例中，578minmax(ESBA903)的抑制作用比阿瓦斯丁更显著。
对于局部应用，在VEGF刺激前5天，成年Sprague-Dawley大鼠通过每天四次(4滴/天)双侧局部给药接受578minmax(1％＝10mg/ml)直至灌注当天(第6天)。用于578minmax的媒介物(局部给药)和Alcon RTKi(10mg/kg/d，经口强饲)用作阴性和阳性对照。在第5天，麻醉大鼠，使其瞳孔扩大。所有动物双眼接受500ng hrVEGF(10μl)的玻璃体内注射。在VEGF注射后24小时，在全身麻醉期间对所有动物进行3％伊文斯蓝染料的静脉内输注。在染料循环90分钟后，对大鼠实施安乐死。收集血液样品，然后用无菌盐溶液灌注大鼠，然后立即摘取每一只大鼠的双眼，使用外科显微镜收获视网膜。对于两个视网膜和血浆样品，使用分光光度计在620/740nm处将60μL的上清液用于测量伊文斯蓝染料吸光度(ABS)。将通过染料吸光度测量的血液-视网膜屏障瓦解和随后的视网膜血管渗透性计算为净ABS/湿重/血浆ABS的平均值±s.e.m.。使用单因素方差分析测定处理方法之间的总体差异，其中P≤0.05被认为是显著的。如图14中所举例说明的，578minmax(903)的局部施用(5天的预处理，4滴/天)显著抑制hVEGF诱导的视网膜血管渗透性。这是可用于治疗眼内疾病的局部有效抗体的首次证明。
等同物
根据前述说明，本发明的许多变化和备选实施方案对于本领域技术人员来说是显然的。因此，本说明书被解释为仅示例性的并且是用于教导本领域技术人员的用于进行本发明的最佳模式。结构的细节可显著改变而不背离本发明的精神，并且保留落在所附权利要求的范围内的所有变化的排他性使用。本发明意欲只限定至所附权利要求和适用的法律法规要求的程度。
本说明书中引用的所有文献和类似材料包括专利、专利申请、文章、书籍、论文、学术论文、网页、图和/或附件，无论此类文献和类似材料的形式如何，都以其全文通过引用明确地合并入本文。如果一个或多个合并的文献和类似材料与本说明书不同或相矛盾，包括定义的术语、术语的用法、描述的技术等，那么以本说明书为准。
本文中使用的章节标题仅为了组织目的，并且不被理解为以任何方式限定所述主题。
虽然已结合多种实施方案和实施例描述了本发明，但本教导无意限定于此类实施方案或实施例。相反，本发明包括各种备选方案、变化和等同物，如本领域技术人员所理解的。
除非另外指出，否则权利要求不应当理解为限定于所描述的顺序或元素。应当理解，可进行形式和内容上的各种变化而不背离所附权利要求的范围。因此，要求保护落在下列权利要求的范围和精神内的所有实施方案和其等同物。
序列表
SEQ ID NO：1
肽免疫原
KFMDVYQRSYC
VL序列：
SEQ ID NO.72：60
SEQ ID NO.73：435
SEQ ID NO.74：453
SEQ ID NO.75：375
SEQ ID NO.76：610
SEQ ID NO.77：578
SEQ ID NO.78：534
SEQ ID NO.79：567
SEQ ID NO.80：509
SEQ ID NO.81：511
SEQ ID NO.82：60min
SEQ ID NO.83：435min
SEQ ID NO.84：453min
SEQ ID NO.85：375min
SEQ ID NO.86：610min
SEQ ID NO.87：578min
SEQ ID NO.88：534min
SEQ ID NO.89：567min
SEQ ID NO.90：509min
SEQ ID NO.91：511min
SEQ ID NO.92：578min_Pref subst
SEQ ID NO.93：60max
SEQ ID NO.94：435max
SEQ ID NO.95：453max
SEQ ID NO.96：375max
SEQ ID NO.97：610max
SEQ ID NO.98：578max
SEQ ID NO.99：534max
SEQ ID NO.100：567max
SEQ ID NO.101：509max
SEQ ID NO.102：511max
SEQ ID NO.103：578max_Pref subst
SEQ ID NO.104：578min VL：E1D
SEQ lD NO.105：578min VL：12V
SEQ ID NO.106：511min VL：C41L
VH序列：
SEQ ID NO.107：60-11-4
SEQ ID NO.108：60-11-6
SEQ ID NO.109：435
SEQ ID NO.110：453
SEQ ID NO.111：375
SEQ ID NO.112：610
SEQ ID NO.113：578
SEQ ID NO.114：534
SEQ ID NO.115：567
SEQ ID NO.116：509
SEQ ID NO.117：511
SEQ lD NO.118：60-11-4min
SEQ ID NO.119：60-11-6min
SEQ ID NO.120：435min
SEQ ID NO.121：453min
SEQ ID NO.122：375min
SEQ ID NO.123：610min
SEQ ID NO.124：578min
SEQ ID NO.125：534min
SEQ ID NO.126：567min
SEQ ID NO.127：509min
SEQ ID NO.128：511min
SEQ ID NO.129：578min_Pref subst
SEQ ID NO.130：60-11-4max
SEQ ID NO.131：60-11-6max
SEQ ID NO.132：435max
SEQ ID NO.133：453max
SEQ ID NO.134：375max
SEQ ID NO.135：610max
SEQ ID NO.136：578max
SEQ ID NO.137：534max
SEQ ID NO.138：567max
SEQ ID NO.139：509max
SEQ ID NO.140：509maxII
SEQ ID NO.141：511max
SEQ ID NO.142：578max_Pref subst
SEQ ID NO.143：567minDHP
SEQ ID NO.144：578maxDHP
SEQ ID NO.145：511maxDHP
SEQ ID NO.146：578max_Pref subst_DHP
SEQ ID NO.147：578max VH：E1_
SEQ ID NO.148：578max VH：V2Q
SEQ ID NO.149：578max VH：Q46L
SEQ ID NO.150：578max VH：W54Y
SEQ ID NO.151：578max VH：V55I
SEQ ID NO.152：578max VH：D83A
SEQ ID NO.153：578max VH：N87A
SEQ ID NO.154：578max VH：Y105F
SEQ ID NO.155：578max VH：D83_
SEQ ID NO.156：578max VH：N87_
SEQ lD NO.157：578max VH：T84N
SEQ ID NO.158：578max VH：V89L
SEQ ID NO.159：578max VH：V89A
SEQ ID NO.160：578maxDHP VH：T84N
SEQ ID NO.161：578maxDHP VH：V89L
SEQ ID NO.162：578maxDHP VH：V89A
SEQ ID NO.163：578max VH：T84N，V89A
SEQ ID NO.164：578max VH：T84N，V89L
SEQ ID NO.165：578maxDHP VH：T84N，V89A
SEQ ID NO.166：578maxDHP VH：T84N，V89L
构架序列(X残基是CDR插入位置并且可以是任何天然存在的氨基酸。可存在至少3个且直至50个氨基酸)：
SEQ ID NO.167：可变轻链FW1.4和rFW1.4
SEQ ID NO.168：可变轻链rFW1.4变体2(v2)
SEQ ID NO.169：可变重链FW1.4
SEQ ID NO.170：可变重链rFW1.4
SEQ ID NO.171：可变重链rFW1.4变体2(v2)
scFv构架序列：
SEQ ID NO.172：FW1.4
SEQ ID NO.173：rFW1.4
SEQ ID NO.174：rFW1.4变体2(v2)
ScFv抗VEGF序列：
SEQ ID NO.175：435_max
SEQ ID NO.176：511_max
SEQ ID NO.177：567_min
SEQ ID NO.178：578min
SEQ ID NO.179：578max
SEQ ID NO.180：578minmax(ESBA903)
SEQ ID NO.181：接头
本说明书还包括下列内容：
1.中和人VEGF并且包含兔CDR的重组免疫结合剂，其包含可变重链(VH)和/或可变轻链(VL)。
2.实施方式1的免疫结合剂，其为嵌合免疫结合剂。
3.前述实施方式的任一项的免疫结合剂，其为人源化的。
4.前述实施方式的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：14，SEQ ID NO：26，SEQ ID NO：37，SEQ ID NO：49，SEQ ID NO：60和SEQ ID NO：71的共有序列具有至少80％的相似性的CDR。
5.前述实施方式的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：2，SEQ ID NO：3，SEQ ID NO：15，SEQ ID NO：27，SEQ ID NO：38，SEQ ID NO：50和SEQ ID NO：61的序列具有至少80％的相似性的CDR。
6.实施方式5的免疫结合剂，其中所述VH包含由SEQ ID NO：2，SEQ ID NO：15和SEQID NO：27组成的组中的CDR和/或其中所述VL包含由SEQ ID NO：38，SEQ ID NO：50和SEQ IDNO：61组成的组中的CDR。
7.实施方式5的免疫结合剂，其中所述VH包含由SEQ ID NO：3，SEQ ID NO：15和SEQID NO：27组成的组中的CDR和/或所述VL包含由SEQ ID NO：38，SEQ ID NO：50和SEQ ID NO：61组成的组中的CDR。
8.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：4，SEQ ID NO：16，SEQ ID NO：28，SEQ ID NO：39，SEQ ID NO：51和SEQ ID NO：62的序列具有至少80％的相似性的CDR。
9.实施方式8的免疫结合剂，其中所述VH包含由SEQ ID NO：4，SEQ ID NO：16，SEQID NO：28组成的组中的CDR和/或所述VL包含由SEQ ID NO：39，SEQ ID NO：51和SEQ ID NO：62组成的组中的CDR。
10.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：5，SEQ ID NO：17，SEQ ID NO：29，SEQ ID NO：40，SEQ ID NO：52和SEQ ID NO：63的序列具有至少80％的相似性的CDR。
11.实施方式10的免疫结合剂，其中所述VH包含由SEQ ID NO：5，SEQ ID NO：17，SEQ ID NO：29组成的组中的CDR和/或所述VL包含由SEQ ID NO：40，SEQ ID NO：52和SEQ IDNO：63组成的组中的CDR。
12.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：6，SEQ ID NO：18，SEQ ID NO：30，SEQ ID NO：41，SEQ ID NO：53和SEQ ID NO：64的序列具有至少80％的相似性的CDR。
13.实施方式12的免疫结合剂，其中所述VH包含由SEQ ID NO：6，SEQ ID NO：18和SEQ ID NO：30组成的组中的CDR和/或所述VL包含由SEQ ID NO：41，SEQ ID NO：53和SEQ IDNO：64组成的组中的CDR。
14.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：7，SEQ ID NO：19，SEQ ID NO：31，SEQ ID NO：42，SEQ ID NO：54和SEQ ID NO：65的序列具有至少80％的相似性的CDR。
15.实施方式14的免疫结合剂，其中所述VH包含由SEQ ID NO：7，SEQ ID NO：19和SEQ ID NO：31组成的组中的CDR和/或所述VL包含由SEQ ID NO：42，SEQ ID NO：54和SEQ IDNO：65组成的组中的CDR。
16.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：8，SEQ ID NO：20，SEQ ID NO：32，SEQ ID NO：43，SEQ ID NO：55和SEQ ID NO：66的序列具有至少80％的相似性的CDR。
17.实施方式16的免疫结合剂，其中所述VH包含由SEQ ID NO：8，SEQ ID NO：20和SEQ ID NO：32组成的组中的CDR和/或所述VL包含由SEQ ID NO：43，SEQ ID NO：55和SEQ IDNO：66组成的组中的CDR。
18.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：9，SEQ ID NO：21，SEQ ID NO：33，SEQ ID NO：44，SEQ ID NO：56和SEQ ID NO：67的序列具有至少80％的相似性的CDR。
19.实施方式18的免疫结合剂，其中所述VH包含由SEQ ID NO：9，SEQ ID NO：21和SEQ ID NO：33组成的组中的CDR和/或所述VL包含由SEQ ID NO：44，SEQ ID NO：56和SEQ IDNO：67组成的组中的CDR。
20.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：10，SEQ ID NO：22，SEQ ID NO：34，SEQ ID NO：45，SEQ ID NO：57和SEQ ID NO：68的序列具有至少80％的相似性的CDR。
21.实施方式20的免疫结合剂，其中所述VH包含由SEQ ID NO：10，SEQ ID NO：22和SEQ ID NO：34组成的组中的CDR和/或所述VL包含由SEQ ID NO：45，SEQ ID NO：57和SEQ IDNO：68组成的组中的CDR。
22.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：11，SEQ ID NO：13，SEQ ID NO：23，SEQ ID NO：25，SEQ ID NO：35，SEQ ID NO：46，SEQ ID NO：58和SEQ ID NO:69的序列具有至少80％的相似性的CDR。
23.实施方式22的免疫结合剂，其中所述VH包含(i)由SEQ ID NO：11，SEQ ID NO：23和SEQ ID NO：35组成的组中的CDR；(ii)由SEQ ID NO：11，SEQ ID NO：25和SEQ ID NO：35组成的组中的CDR；(iii)由SEQ ID NO：13，SEQ ID NO：23和SEQ ID NO：35组成的组中的CDR；或(iv)由SEQ ID NO：13，SEQ ID NO：25和SEQ ID NO：35组成的组中的CDR。
24.实施方式23的免疫结合剂，其中所述VL包含由SEQ ID NO：46，SEQ ID NO：58和SEQ ID NO：69组成的组中的CDR。
25.实施方式1至4的任一项的免疫结合剂，其包含至少一个与选自SEQ ID NO：12，SEQ ID NO：24，SEQ ID NO：36，SEQ ID NO：47，SEQ ID NO：48，SEQ ID NO：59和SEQ ID NO：70的序列具有至少80％的相似性的CDR。
26.实施方式25的免疫结合剂，其中所述VH包含由SEQ ID NO：12，SEQ ID NO：24和SEQ ID NO：36组成的组中的CDR和/或所述VL包含(i)由SEQ ID NO：47，SEQ ID NO：59和SEQID NO：70组成的组中的CDR；或(ii)由SEQ ID NO：48，SEQ ID NO：59和SEQ ID NO：70组成的组中的CDR。
27.前述实施方式的任一项的免疫结合剂，其包含与SEQ ID NO：169的序列具有至少80％的序列同一性的重链可变区构架序列。
28.实施方式27的免疫结合剂，其中所述重链可变区构架是SEQ ID NO：170或SEQID NO：171。
29.前述实施方式的任一项的免疫结合剂，其在根据AHo编号系统的重链可变区的位置1、83或87处具有缺失。
30.前述实施方式的任一项的免疫结合剂，其在根据AHo编号系统的重链可变区的位置2，12，24，25，46，54，55，83，84，87，89，103，105，108或144的至少一个位置处具有置换。
31.实施方式30的免疫结合剂，其中所述置换选自：
(a)位置2处的谷氨酰胺；
(b)位置12处的丝氨酸；
(c)位置24处的苏氨酸；
(d)位置25处的缬氨酸；
(e)位置46处的亮氨酸；
(f)位置54处的酪氨酸；
(g)位置55处的异亮氨酸；
(h)位置83处的丙氨酸；
(i)位置84处的天冬酰胺；
(j)位置87处的丙氨酸或亮氨酸；
(k)位置89处的丙氨酸或亮氨酸；
(1)位置103处的丝氨酸或苏氨酸；
(m)位置105处的苯丙氨酸；
(n)位置108处的精氨酸；和
(o)位置144处的丝氨酸或苏氨酸。
32.前述实施方式的任一项的免疫结合剂，其包含与SEQ ID NO：167的序列具有至少85％的序列同一性的轻链可变区构架序列。
33.实施方式30的免疫结合剂，其中所述轻链可变区构架是SEQ ID NO：167或SEQID NO：168。
34.前述实施方式的任一项的免疫结合剂，其在根据AHo编号系统的轻链可变区的位置1、2或15的至少一个位置处具有置换。
35.实施方式34的免疫结合剂，其中所述置换选自：
(a)位置1处的天冬氨酸；
(b)位置2处的缬氨酸；
(c)位置15处的苏氨酸。
36.实施方式5-7或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：107至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：72至少80％相似的轻链可变区。
37.实施方式8-9或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：109至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：73至少80％相似的轻链可变区。
38.实施方式10-11或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：110至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：74至少80％相似的轻链可变区。
39.实施方式12-13或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：111至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：75至少80％相似的轻链可变区。
40.实施方式14-15或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：112至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：76至少80％相似的轻链可变区。
41.实施方式16-17或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：113至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：77至少80％相似的轻链可变区。
42.实施方式41的免疫结合剂，其与SEQ ID NO：178，SEQ ID NO：179或SEQ ID NO：180具有至少80％的同一性。
43.实施方式18-19或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：114至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：78至少80％相似的轻链可变区。
44.实施方式20-21或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：115至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：79至少80％相似的轻链可变区。
45.实施方式44的免疫结合剂，其与SEQ ID NO：177具有至少80％的同一性。
46.实施方式22-24或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：116至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：80至少80％相似的轻链可变区。
47.实施方式25-26或27-35的任一项的免疫结合剂，其包含含有与SEQ ID NO：117至少80％相似的氨基酸序列的重链可变区和/或与SEQ ID NO：81至少80％相似的轻链可变区。
48.实施方式47的免疫结合剂，其与SEQ ID NO：176具有至少80％的同一性。
49.与前述实施方式的任一项的免疫结合剂竞争对人VEGF的结合的免疫结合剂。
50.一种免疫结合剂，其以至少107 M-1的亲和力结合被前述实施方式的任一项的免疫结合剂识别的人VEGF上的表位。
51.前述实施方式的任一项的免疫结合剂，其特异性结合人和大鼠/小鼠VEGF。
52.前述实施方式的任一项的免疫结合剂，其是抗体、scFv、Fab或Dab。
53.包含前述实施方式的任一项的免疫结合剂和药学上可接受的载体的组合物。
54.编码前述实施方式的任一项的免疫结合剂的分离的核酸分子。
55.包含实施方式54的核酸分子的表达载体。
56.包含实施方式55的表达载体的宿主细胞。
57.治疗或预防受试者中的人VEGF介导的疾病的方法，其包括给受试者施用前述实施方式的任一项的免疫结合剂以便治疗所述受试者的VEGF介导的疾病。
58.实施方式57的方法，其中局部施用所述免疫结合剂。
59.实施方式57或58的方法，其中所述VEGF介导的疾病选自：年龄相关黄斑变性、新生血管性青光眼、糖尿病性视网膜病变、早产儿视网膜病变、晶体后纤维增生症、乳腺癌、肺癌、胃癌、食管癌、结肠直肠癌、肝癌、卵巢癌、昏迷、男性细胞瘤、宫颈癌、子宫内膜癌、子宫内膜增生、子宫内膜异位、纤维肉瘤、绒毛膜癌、头颈癌、鼻咽癌、喉癌、肝母细胞瘤、卡波西肉瘤、黑素瘤、皮肤癌、血管瘤、海绵状血管瘤、血管母细胞瘤、胰腺癌、视网膜母细胞瘤、星形细胞瘤、胶质母细胞瘤、神经鞘瘤、少突胶质细胞瘤、髓母细胞瘤、神经母细胞瘤、横纹肌肉瘤、成骨肉瘤、平滑肌肉瘤、泌尿道癌、甲状腺癌、肾母细胞瘤、肾细胞癌、前列腺癌、与斑痣性错构瘤病相关的异常血管增生、水肿(例如与脑肿瘤相关的水肿)、麦格综合征、类风湿性关节炎、银屑病和动脉粥样硬化。
60.产生包含SEQ ID No60-166和SEQ ID No.175-180中所示的任一个氨基酸序列的抗体的杂交瘤。
61.适合用于产生或鉴定与大鼠/小鼠和人VEGF或其部分交叉反应的免疫结合剂的免疫原。
62.实施方式61的免疫原，其具有SEQ ID No.1。
63.制备与大鼠/小鼠和人VEGF交叉反应的免疫结合剂的方法，其中所述方法使用实施方式61的免疫原。
序列表
<110> ESBATEch AG
<120> 抑制VEGF的稳定和可溶的抗体
<130> VEGF binders
<140> Us61/133,212
<141> 2008-06-25
<160> 180
<170> PatentIn version 3.5
<210> 1
<211> 11
<212> PRT
<213> 智人
<400> 1
Lys Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys
1 5 10
<210> 2
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 2
Gly Phe Pro Phe Ser Ser Gly Tyr Trp Val Cys
1 5 10
<210> 3
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 3
Gly Phe Ser Phe Ser Ser Gly Tyr Trp Ile Cys
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 4
Gly Phe Ser Leu Asn Thr Asn Tyr Trp Met Cys
1 5 10
<210> 5
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 5
Gly Phe Ser Phe Ser Arg Ser Tyr Tyr Ile Tyr
1 5 10
<210> 6
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 6
Gly Phe Ser Phe Thr Thr Thr Asp Tyr Met Cys
1 5 10
<210> 7
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 7
Gly Ile Asp Phe Ser Gly Ala Tyr Tyr Met Gly
1 5 10
<210> 8
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 8
Gly Phe Ser Leu Thr Asp Tyr Tyr Tyr Met Thr
1 5 10
<210> 9
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 9
Gly Phe Ser Leu Ser Tyr Tyr Tyr Met Ser
1 5 10
<210> 10
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 10
Gly Phe Ser Leu Ser Asp Tyr Tyr Met Cys
1 5 10
<210> 11
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 11
Gly Phe Ser Leu Ser Ser Tyr Tyr Met Cys
1 5 10
<210> 12
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 12
Gly Phe Ser Leu Asn Thr Tyr Tyr Met Asn
1 5 10
<210> 13
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 13
Gly Phe Ser Leu Ser Ser Tyr Tyr Met Ser
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 14
Gly Phe Ser Leu Ser Ser Gly Tyr Tyr Met Cys
1 5 10
<210> 15
<211> 18
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 15
Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 16
<211> 18
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 16
Cys Met Tyr Thr Gly Ser Tyr Asn Arg Ala Tyr Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 17
<211> 18
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 17
Cys Ile Asp Ala Gly Ser Ser Gly Ile Leu Val Tyr Ala Asn Trp Ala
1 5 10 15
Lys Gly
<210> 18
<211> 17
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 18
Cys Ile Leu Ala Gly Asp Gly Ser Thr Tyr Tyr Ala Asn Trp Ala Lys
1 5 10 15
Gly
<210> 19
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 19
Tyr Ile Asp Tyr Asp Gly Asp Arg Tyr Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 20
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 20
Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala Lys Gly
1 5 10 15
<210> 21
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 21
Ile Ile Gly Pro Gly Asp Tyr Thr Asp Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 22
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 22
Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 23
<211> 16
<212> PRT
<213> 人工序列
<400> 23
Cys Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 24
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 24
Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Ser
1 5 10 15
<210> 25
<211> 16
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 25
Ile Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 26
<211> 18
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 26
Cys Ile Asp Ala Gly Ser Asp Gly Asp Thr Tyr Tyr Ala Ser Trp Ala
1 5 10 15
Lys Gly
<210> 27
<211> 19
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 27
Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr Ala Tyr Ala Gly
1 5 10 15
Leu Glu Leu
<210> 28
<211> 8
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 28
Gly Ser Asn Trp Tyr Ser Asp Leu
1 5
<210> 29
<211> 14
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 29
Gly Asp Ala Ser Tyr Gly Val Asp Ser Phe Met Leu Pro Leu
1 5 10
<210> 30
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 30
Ser Asp Pro Ala Ser Ser Trp Ser Phe Ala Leu
1 5 10
<210> 31
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 31
Ser Asp Tyr Ser Ser Gly Trp Gly Thr Asp Ile
1 5 10
<210> 32
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 32
Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile
1 5 10
<210> 33
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 33
Gly Asp Asp Asn Ser Gly Trp Gly Glu Asp Ile
1 5 10
<210> 34
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 34
Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile
1 5 10
<210> 35
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 35
Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile
1 5 10
<210> 36
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 36
Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile
1 5 10
<210> 37
<211> 19
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 37
Gly Asp Asp Ser Ser Gly Tyr Thr Asp Gly Gly Tyr Ala Tyr Trp Gly
1 5 10 15
Leu Asp Ile
<210> 38
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 38
Gln Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ser
1 5 10
<210> 39
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 39
Gln Ala Ser Gln Ser Ile Gly Ser Ser Leu Ala
1 5 10
<210> 40
<211> 13
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 40
Gln Ser Ser Gln Ser Val Trp Asn Asn Asn Arg Leu Ala
1 5 10
<210> 41
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 41
Gln Ala Ser Glu Asn Ile Asn Ile Trp Leu Ser
1 5 10
<210> 42
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 42
Gln Ala Ser Gln Ser Ile Ser Ser Trp Leu Ser
1 5 10
<210> 43
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 43
Gln Ala Ser Glu Ile Ile His Ser Trp Leu Ala
1 5 10
<210> 44
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 44
Gln Ala Ser Gln Ser Ile Asn Ile Trp Leu Ser
1 5 10
<210> 45
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 45
Gln Ala Asp Gln Ser Ile Tyr Ile Trp Leu Ser
1 5 10
<210> 46
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 46
Gln Ala Ser Gln Asn Ile Arg Ile Trp Leu Ser
1 5 10
<210> 47
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 47
Gln Ala Ser Gln Ser Ile Asn Ile Trp Cys Ser
1 5 10
<210> 48
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 48
Gln Ala Ser Gln Ser Ile Asn Ile Trp Leu Ser
1 5 10
<210> 49
<211> 13
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 49
Gln Ala Ser Gln Ser Ile Asn Ile Asn Asn Trp Leu Ser
1 5 10
<210> 50
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 50
Lys Ala Ser Thr Leu Ala Ser
1 5
<210> 51
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 51
Thr Ala Ala Asn Leu Ala Ser
1 5
<210> 52
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 52
Tyr Ala Ser Thr Leu Ala Ser
1 5
<210> 53
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 53
Gln Ala Ser Lys Leu Ala Ser
1 5
<210> 54
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 54
Gln Ala Ser Thr Leu Ala Ser
1 5
<210> 55
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 55
Leu Ala Ser Thr Leu Ala Ser
1 5
<210> 56
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 56
Lys Glu Ser Thr Leu Ala Ser
1 5
<210> 57
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 57
Lys Ala Ser Thr Leu Glu Ser
1 5
<210> 58
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 58
Lys Ala Ser Thr Leu Glu Ser
1 5
<210> 59
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 59
Arg Ala Ser Thr Leu Ala Ser
1 5
<210> 60
<211> 7
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 60
Lys Ala Ser Thr Leu Ala Ser
1 5
<210> 61
<211> 14
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 61
Gln Ser Asn Tyr Gly Gly Ser Ser Ser Asp Tyr Gly Asn Pro
1 5 10
<210> 62
<211> 10
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 62
Gln Asn Phe Ala Thr Ser Asp Thr Val Thr
1 5 10
<210> 63
<211> 11
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 63
Ala Gly Gly Tyr Ser Ser Thr Ser Asp Asn Thr
1 5 10
<210> 64
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 64
Gln Asn Asn Tyr Ser Tyr Asn Arg Tyr Gly Ala Pro
1 5 10
<210> 65
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 65
Gln Asn Asn Tyr Gly Phe Arg Ser Tyr Gly Gly Ala
1 5 10
<210> 66
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 66
Gln Asn Val Tyr Leu Ala Ser Thr Asn Gly Ala Asn
1 5 10
<210> 67
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 67
Gln Asn Asn Tyr Asp Ser Gly Asn Asn Gly Phe Pro
1 5 10
<210> 68
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 68
Gln Asn Asn Ala His Tyr Ser Thr Asn Gly Gly Thr
1 5 10
<210> 69
<211> 12
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 69
Gln Asn Asn Ala His Tyr Ser Thr Asn Gly Gly Thr
1 5 10
<210> 70
<211> 13
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 70
Gln Ala Asn Tyr Ala Tyr Ser Ala Gly Tyr Gly Ala Ala
1 5 10
<210> 71
<211> 14
<212> PRT
<213> 未知
<220>
<223> 源自兔抗体的CDR
<400> 71
Gln Asn Asn Tyr His Tyr Ser Ser Ser Thr Asn Gly Gly Thr
1 5 10
<210> 72
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 72
Glu Val Val Met Ala Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Gly Gly Ser Ser
85 90 95
Ser Asp Tyr Gly Asn Pro Phe Gly Gly Gly Thr Glu Ala Val Val Lys
100 105 110
<210> 73
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 73
Ala Phe Glu Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Arg Gly
50 55 60
Ser Arg Ser Gly Ala Ala Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Phe Ala Thr Ser Asp Thr
85 90 95
Val Thr Phe Gly Gly Gly Thr Glu Val Val Val Thr
100 105
<210> 74
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 74
Ala Val Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Ser Ile Ser Cys Gln Ser Ser Gln Ser Val Trp Asn Asn
20 25 30
Asn Arg Leu Ala Trp Phe Gln Gln Lys Ser Gly Gln Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Lys Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Val
65 70 75 80
Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Ser Ser
85 90 95
Thr Ser Asp Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 75
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 75
Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Thr Val Gly
1 5 10 15
Gly Thr Ile Thr Ile Asn Cys Gln Ala Ser Glu Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Ser Tyr Asn Arg
85 90 95
Tyr Gly Ala Pro Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 76
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 76
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Pro Arg Ser Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Phe Cys Gln Asn Asn Tyr Gly Phe Arg Ser
85 90 95
Tyr Gly Gly Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 77
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 77
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Ile Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 78
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 78
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Asp Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Ser Gly Gln Pro Pro Lys Leu Leu Val
35 40 45
Tyr Lys Glu Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Asp Ser Gly Asn
85 90 95
Asn Gly Phe Pro Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 79
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 79
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Asp Thr Val Thr Ile Asn Cys Gln Ala Asp Gln Ser Ile Tyr Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 80
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 80
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Asp Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Arg Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 81
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 81
Glu Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Cys Ser Trp Tyr Gln Gln Lys Pro Gly His Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ala Asn Tyr Ala Tyr Ser Ala
85 90 95
Gly Tyr Gly Ala Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 82
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 82
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Gly Gly Ser Ser
85 90 95
Ser Asp Tyr Gly Asn Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu
100 105 110
Gly
<210> 83
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 83
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Phe Ala Thr Ser Asp Thr
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105
<210> 84
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 84
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ser Ser Gln Ser Val Trp Asn Asn
20 25 30
Asn Arg Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Ser Ser
85 90 95
Thr Ser Asp Asn Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 85
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 85
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Ser Tyr Asn Arg
85 90 95
Tyr Gly Ala Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 86
<211> 111
<212> PRT
<213> 人工序列
<400> 86
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Gly Phe Arg Ser
85 90 95
Tyr Gly Gly Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 87
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 87
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 88
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 88
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Glu Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Asp Ser Gly Asn
85 90 95
Asn Gly Phe Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 89
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 89
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Asp Gln Ser Ile Tyr Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 90
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 90
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 91
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 91
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Cys Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ala Asn Tyr Ala Tyr Ser Ala
85 90 95
Gly Tyr Gly Ala Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 92
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 92
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Ser Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 93
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 93
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Gly Gly Ser Ser
85 90 95
Ser Asp Tyr Gly Asn Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu
100 105 110
Gly
<210> 94
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 94
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Phe Ala Thr Ser Asp Thr
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105
<210> 95
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 95
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ser Ser Gln Ser Val Trp Asn Asn
20 25 30
Asn Arg Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Ser Ser
85 90 95
Thr Ser Asp Asn Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 96
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 96
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Ser Tyr Asn Arg
85 90 95
Tyr Gly Ala Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 97
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 97
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Gly Phe Arg Ser
85 90 95
Tyr Gly Gly Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 98
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 98
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 99
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 99
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Glu Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Tyr Asp Ser Gly Asn
85 90 95
Asn Gly Phe Pro Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 100
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 100
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Asp Gln Ser Ile Tyr Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 101
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 101
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 102
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 102
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ala Asn Tyr Ala Tyr Ser Ala
85 90 95
Gly Tyr Gly Ala Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 103
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 103
Glu Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Ser Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 104
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 104
Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 105
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 105
Glu Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 106
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL序列
<400> 106
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ala Asn Tyr Ala Tyr Ser Ala
85 90 95
Gly Tyr Gly Ala Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 107
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 107
Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Pro Phe Ser Ser Gly Tyr
20 25 30
Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr
65 70 75 80
Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr Ala Tyr
100 105 110
Ala Gly Leu Glu Leu Trp Gly Pro Gly Ile Leu Val Thr Val Ser Ser
115 120 125
<210> 108
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 108
Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr
20 25 30
Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr
65 70 75 80
Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr Ala Tyr
100 105 110
Ala Gly Leu Glu Leu Trp Gly Pro Gly Ile Leu Val Thr Val Ser Ser
115 120 125
<210> 109
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 109
Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Ala Ser
1 5 10 15
Leu Thr Leu Thr Cys Lys Val Ser Gly Phe Ser Leu Asn Thr Asn Tyr
20 25 30
Trp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Cys Met Tyr Thr Gly Ser Tyr Asn Arg Ala Tyr Tyr Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ser Ser Lys Thr Ser Ser Thr Thr Val Thr
65 70 75 80
Leu Glu Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Gly Ser Asn Trp Tyr Ser Asp Leu Trp Gly Pro Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 110
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 110
Gln Glu Arg Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly
1 5 10 15
Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Ser Phe Ser Arg Ser
20 25 30
Tyr Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Ala Cys Ile Asp Ala Gly Ser Ser Gly Ile Leu Val Tyr Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val
65 70 75 80
Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe
85 90 95
Cys Ala Arg Gly Asp Ala Ser Tyr Gly Val Asp Ser Phe Met Leu Pro
100 105 110
Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 111
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 111
Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser
1 5 10 15
Leu Thr Leu Thr Cys Lys Ala Ser Gly Phe Ser Phe Thr Thr Thr Asp
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Cys Ile Leu Ala Gly Asp Gly Ser Thr Tyr Tyr Ala Asn Trp Ala
50 55 60
Lys Gly Arg Phe Thr Gly Ser Lys Thr Ser Ser Thr Thr Val Asp Leu
65 70 75 80
Lys Met Thr Gly Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys Ala
85 90 95
Arg Ser Asp Pro Ala Ser Ser Trp Ser Phe Ala Leu Trp Gly Pro Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 112
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 112
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Ile Asp Phe Ser Gly Ala Tyr
20 25 30
Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Tyr Asp Gly Asp Arg Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser
85 90 95
Asp Tyr Ser Ser Gly Trp Gly Thr Asp Ile Trp Gly Pro Gly Thr Leu
100 105 110
Val Thr Val Ser Leu
115
<210> 113
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 113
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr Tyr
20 25 30
Tyr Met Thr Trp Val Arg Leu Ala Pro Gly Lys Gly Leu Glu Tyr Ile
35 40 45
Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Val Asn Leu Lys Met
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Gly Gly
85 90 95
Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Pro Gly Thr Leu
100 105 110
Val Thr Val Ser Leu
115
<210> 114
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 114
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Tyr Tyr Tyr
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Gly Pro Gly Asp Tyr Thr Asp Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Gly Arg Gly Asp
85 90 95
Asp Asn Ser Gly Trp Gly Glu Asp Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 115
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 115
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Ala Pro
1 5 10 15
Leu Thr Leu Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asp Tyr Tyr
20 25 30
Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Ile Gly
35 40 45
Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Ala Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Thr Asp
85 90 95
Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 116
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 116
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr Tyr
20 25 30
Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Cys Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Ala Ser Thr Thr Val Asp Leu Lys Ile Thr
65 70 75 80
Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Thr Asp
85 90 95
Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Leu
115
<210> 117
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 117
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Thr Tyr Tyr
20 25 30
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Ser
50 55 60
Arg Ser Thr Ile Thr Arg Asp Thr Asn Glu Asn Thr Val Thr Leu Lys
65 70 75 80
Met Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
85 90 95
Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Leu
115
<210> 118
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 118
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 Ala Ser Gly Phe Pro Phe Ser Ser Gly
20 25 30
Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Lys Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr
100 105 110
Ala Tyr Ala Gly Leu Glu Leu Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 119
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 119
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 Ala Ser Gly Phe Ser Phe Ser Ser Gly
20 25 30
Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Lys Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr
100 105 110
Ala Tyr Ala Gly Leu Glu Leu Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 120
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 120
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 Ala Ser Gly Phe Ser Leu Asn Thr Asn
20 25 30
Tyr Trp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Cys Met Tyr Thr Gly Ser Tyr Asn Arg Ala Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Lys Gly Ser Asn Trp Tyr Ser Asp Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 121
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 121
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 Ala Ser Gly Phe Ser Phe Ser Arg Ser
20 25 30
Tyr Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Cys Ile Asp Ala Gly Ser Ser Gly Ile Leu Val Tyr Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Lys Gly Asp Ala Ser Tyr Gly Val Asp Ser Phe Met Leu
100 105 110
Pro Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 122
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 122
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 Ala Ser Gly Phe Ser Phe Thr Thr Thr
20 25 30
Asp Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Cys Ile Leu Ala Gly Asp Gly Ser Thr Tyr Tyr Ala Asn Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Lys Ser Asp Pro Ala Ser Ser Trp Ser Phe Ala Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 123
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 123
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 Ala Ser Gly Ile Asp Phe Ser Gly Ala
20 25 30
Tyr Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Tyr Ile Asp Tyr Asp Gly Asp Arg Tyr Tyr Ala Ser Trp Ala
50 55 60
Lys 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
Ala Lys Ser Asp Tyr Ser Ser Gly Trp Gly Thr Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 124
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 124
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 Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys 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
Ala Lys Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 125
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 125
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 Ala Ser Gly Phe Ser Leu Ser Tyr Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ile Ile Gly Pro Gly Asp Tyr Thr Asp Tyr Ala Ser Trp Ala 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
Lys Gly Asp Asp Asn Ser Gly Trp Gly Glu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 126
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 126
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 Ala Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser Trp Ala 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
Lys Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 127
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 127
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 Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Cys Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala 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
Lys Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 128
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 128
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 Ala Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Ser 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
Lys Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 129
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 129
Gln Val Gln Leu Val Gln Thr Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 130
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 130
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 Thr Ala Ser Gly Phe Pro Phe Ser Ser Gly
20 25 30
Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr
100 105 110
Ala Tyr Ala Gly Leu Glu Leu Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 131
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 131
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 Thr Ala Ser Gly Phe Ser Phe Ser Ser Gly
20 25 30
Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Tyr Ala Gly Ser Ser Gly Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Gly Asn Asn Tyr Tyr Ile Tyr Thr Asp Gly Gly Tyr
100 105 110
Ala Tyr Ala Gly Leu Glu Leu Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 132
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 132
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 Lys Val Ser Gly Phe Ser Leu Asn Thr Asn
20 25 30
Tyr Trp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Met Tyr Thr Gly Ser Tyr Asn Arg Ala Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ser Ser Lys Asp Thr Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Lys Gly Ser Asn Trp Tyr Ser Asp Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 133
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 133
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 Lys Ala Ser Gly Phe Ser Phe Ser Arg Ser
20 25 30
Tyr Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Asp Ala Gly Ser Ser Gly Ile Leu Val Tyr Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Gly Asp Ala Ser Tyr Gly Val Asp Ser Phe Met Leu
100 105 110
Pro Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 134
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 134
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 Lys Ala Ser Gly Phe Ser Phe Thr Thr Thr
20 25 30
Asp Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Cys Ile Leu Ala Gly Asp Gly Ser Thr Tyr Tyr Ala Asn Trp
50 55 60
Ala Lys Gly Arg Phe Thr Gly Ser Lys Asp Thr Ser Lys Asn Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Asp Pro Ala Ser Ser Trp Ser Phe Ala Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 135
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 135
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 Thr Ala Ser Gly Ile Asp Phe Ser Gly Ala
20 25 30
Tyr Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Asp Tyr Asp Gly Asp Arg Tyr Tyr Ala Ser Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr Val 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 Ser Asp Tyr Ser Ser Gly Trp Gly Thr Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 136
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 136
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 137
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 137
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 Thr Ala Ser Gly Phe Ser Leu Ser Tyr Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Gly Pro Gly Asp Tyr Thr Asp Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr Val 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 Gly Asp Asp Asn Ser Gly Trp Gly Glu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 138
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 138
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 Ser Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr Val 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 Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 139
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 139
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 Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Cys Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Ala Ser Lys Asn Thr Val 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 Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 140
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 140
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 Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Leu Asp Tyr Val Gly Asp Thr Asp Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Ala Ser Lys Asn Thr Val 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 Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 141
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 141
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 Thr Val Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 142
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 142
Gln Val Gln Leu Val Gln Thr Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 143
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser Trp Ala 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 Thr Tyr Tyr Cys Ala
85 90 95
Lys Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 144
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 144
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 145
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 145
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 146
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 146
Gln Val Gln Leu Val Gln Thr Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 147
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 147
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr Tyr
20 25 30
Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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
Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 148
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 148
Glu Gln Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 149
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 149
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Leu Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 150
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 150
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 151
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 151
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 152
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 152
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Ala Thr Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 153
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 153
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Ala Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 154
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 154
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 155
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 155
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Thr Ser Lys Asn Thr Val 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
Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 156
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 156
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Thr Val 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
Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 157
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 157
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 158
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 158
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 159
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 159
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Ala 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 160
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 160
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 161
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 161
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 162
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 162
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 163
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 163
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala 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 Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 164
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 164
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 Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys 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
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 165
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 165
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 166
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH序列
<400> 166
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys 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 Thr Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 167
<211> 381
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL受体序列
<220>
<221> CDR
<222> (24)..(123)
<223> 可存在至少3个和直至50个氨基酸
<220>
<221> CDR
<222> (139)..(238)
<223> 可存在至少3个和直至50个氨基酸
<220>
<221> CDR
<222> (271)..(370)
<223> 可存在至少3个和直至50个氨基酸
<400> 167
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Tyr Gln Gln Lys
115 120 125
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Xaa Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
370 375 380
<210> 168
<211> 381
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VL受体序列
<220>
<221> CDR
<222> (24)..(123)
<223> 可存在至少3个和直至50个氨基酸
<220>
<221> CDR
<222> (139)..(238)
<223> 可存在至少3个和直至50个氨基酸
<220>
<221> CDR
<222> (271)..(370)
<223> 可存在至少3个和直至50个氨基酸
<400> 168
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Tyr Gln Gln Lys
115 120 125
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Xaa Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
370 375 380
<210> 169
<211> 382
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH受体序列
<220>
<221> CDR
<222> (26)..(125)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (140)..(239)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (272)..(371)
<223> 可存在至少3个和直至50个氨基酸.
<400> 169
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 Ala Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val Arg
115 120 125
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg
225 230 235 240
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
245 250 255
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
370 375 380
<210> 170
<211> 381
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH受体序列
<220>
<221> CDR
<222> (26)..(125)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (140)..(239)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (272)..(371)
<223> 可存在至少3个和直至50个氨基酸.
<400> 170
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 Thr Ala Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val Arg
115 120 125
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg
225 230 235 240
Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu Gln Met
245 250 255
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser
370 375 380
<210> 171
<211> 382
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv - VH受体序列
<220>
<221> CDR
<222> (26)..(125)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (140)..(239)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (272)..(371)
<223> 可存在至少3个和直至50个氨基酸.
<400> 171
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 Thr Val Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val Arg
115 120 125
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg
225 230 235 240
Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr Val Tyr Leu Gln Met
245 250 255
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
370 375 380
<210> 172
<211> 783
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv -受体序列
<220>
<221> CDR
<222> (24)..(123)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (139)..(238)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (271)..(370)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (427)..(526)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (541)..(640)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (673)..(772)
<223> 可存在至少3个和直至50个氨基酸.
<400> 172
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Tyr Gln Gln Lys
115 120 125
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Xaa Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val
515 520 525
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
645 650 655
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
770 775 780
<210> 173
<211> 783
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv -受体序列
<220>
<221> CDR
<222> (24)..(123)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (139)..(238)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (271)..(370)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (427)..(526)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (541)..(640)
<223> 可存在至少3个和直至50个氨基酸.
<220>
<221> CDR
<222> (673)..(772)
<223> 可存在至少3个和直至50个氨基酸.
<400> 173
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Tyr Gln Gln Lys
115 120 125
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Xaa Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val
515 520 525
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu Gln
645 650 655
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
770 775 780
<210> 174
<211> 783
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv -受体序列
<220>
<221> CDR
<222> (24)..(123)
<223> 可存在至少3个和直至50个氨基酸。
<220>
<221> CDR
<222> (139)..(238)
<223> 可存在至少3个和直至50个氨基酸。
<220>
<221> CDR
<222> (271)..(370)
<223> 可存在至少3个和直至50个氨基酸。
<220>
<221> CDR
<222> (427)..(526)
<223> 可存在至少3个和直至50个氨基酸。
<220>
<221> CDR
<222> (541)..(640)
<223> 可存在至少3个和直至50个氨基酸。
<220>
<221> CDR
<222> (673)..(772)
<223> 可存在至少3个和直至50个氨基酸。
<400> 174
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75 80
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105 110
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Tyr Gln Gln Lys
115 120 125
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Xaa Xaa Xaa Xaa Xaa Xaa
130 135 140
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
145 150 155 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
165 170 175
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
195 200 205
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
210 215 220
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Val
225 230 235 240
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
245 250 255
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Thr Val Ser Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Val
515 520 525
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Arg Phe Thr Ile Ser Lys Asp Thr Ser Lys Asn Thr Val Tyr Leu Gln
645 650 655
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
770 775 780
<210> 175
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 175
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Phe Ala Thr Ser Asp Thr
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Phe Ser Leu Asn Thr
145 150 155 160
Asn Tyr Trp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Val Gly Cys Met Tyr Thr Gly Ser Tyr Asn Arg Ala Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ser Ser Lys Asp Thr Ser Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Lys Gly Ser Asn Trp Tyr Ser Asp Leu Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser
245
<210> 176
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 176
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ala Asn Tyr Ala Tyr Ser Ala
85 90 95
Gly Tyr Gly Ala Ala Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Phe Ser
145 150 155 160
Leu Asn Thr Tyr Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Gly Ile Ile Ala Pro Asp Asp Thr Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Ser Arg Ser Thr Ile Ser Arg Asp Thr Ser Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Ser Gly Asp Thr Thr Ala Trp Gly Ala Asp Ile
225 230 235 240
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 177
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 177
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Asp Gln Ser Ile Tyr Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Asn Ala His Tyr Ser Thr
85 90 95
Asn Gly Gly Thr Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu
145 150 155 160
Ser Asp Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
165 170 175
Glu Trp Val Ser Cys Leu Asp Tyr Phe Gly Ser Thr Asp Asp Ala Ser
180 185 190
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
195 200 205
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Lys Thr Asp Asp Ser Arg Gly Trp Gly Leu Asn Ile Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 178
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 178
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu
145 150 155 160
Thr Asp Tyr Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Ser Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala
180 185 190
Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Lys Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile
225 230 235 240
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 179
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 179
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu
145 150 155 160
Thr Asp Tyr Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala
180 185 190
Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile
225 230 235 240
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 180
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 重组scFv
<400> 180
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser Thr
85 90 95
Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu
145 150 155 160
Thr Asp Tyr Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala
180 185 190
Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile
225 230 235 240
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
Claims (34)
1.人源化抗体或其抗原结合片段，其包含可变重链(VH)和可变轻链(VL)，
其中
VH包含：
SEQ ID NO：8所示的CDRH1，
SEQ ID NO：20所示的CDRH2，和
SEQ ID NO：32所示的CDRH3，且
VL包含：
SEQ ID NO：43所示的CDRL1，
SEQ ID NO：55所示的CDRL2，和
SEQ ID NO：66所示的CDRL3，并且
其中所述抗体或其抗原结合片段以≤1×10-9M的亲和力(Kd)结合人VEGF165。
2.权利要求1的抗原结合片段，其中所述片段是scFv、Fab片段、Fab'片段或F(ab')2片段。
3.组合物，其包含权利要求1的人源化抗体或抗原结合片段和药学上可接受的载体。
4.权利要求3的组合物，其配制用于局部、眼内、口腔、鼻腔、直肠或肠胃外施用。
5.权利要求1的人源化抗体或抗原结合片段，其包含与SEQ ID NO：164的序列具有至少95％序列同一性的重链可变区可变区框架序列。
6.权利要求5的人源化抗体或抗原结合片段，其中所述重链可变区框架包含与SEQ IDNO：164具有100％同一性的序列。
7.权利要求1的人源化抗体或抗原结合片段，其包含与SEQ ID NO：87的序列具有至少95％序列同一性的轻链可变区框架序列。
8.权利要求7的人源化抗体或抗原结合片段，其中所述轻链可变区框架包含与SEQ IDNO：87具有100％同一性的序列。
9.在患有人VEGF介导的疾病的受试者中抑制人VEGF介导的内皮细胞增殖和血管通透性的方法，其包括给受试者施用权利要求1的人源化抗体或抗原结合片段，使得受试者接受治疗VEGF介导的疾病。
10.分离的核酸分子，其编码包含可变重链(VH)和可变轻链(VL)的抗体或其抗原结合片段，其中
(A)所述VH包含由SEQ ID NO：2、SEQ ID NO：15和SEQ ID NO：27组成的组的CDR，且
所述VL包含由SEQ ID NO：38、SEQ ID NO：50和SEQ ID NO：61组成的组的CDR；
(B)所述VH包含由SEQ ID NO：3、SEQ ID NO：15和SEQ ID NO：27组成的组的CDR，且
所述VL包含由SEQ ID NO：38、SEQ ID NO：50和SEQ ID NO：61组成的组的CDR；
(C)所述VH包含由SEQ ID NO：4、SEQ ID NO：16、SEQ ID NO：28组成的组的CDR，且
所述VL包含由SEQ ID NO：39、SEQ ID NO：51和SEQ ID NO：62组成的组的CDR；
(D)所述VH包含由SEQ ID NO：5、SEQ ID NO：17、SEQ ID NO：29组成的组的CDR，且
所述VL包含由SEQ ID NO：40、SEQ ID NO：52和SEQ ID NO：63组成的组的CDR；
(E)所述VH包含由SEQ ID NO：6、SEQ ID NO：18和SEQ ID NO：30组成的组的CDR，且
所述VL包含由SEQ ID NO：41、SEQ ID NO：53和SEQ ID NO：64组成的组的CDR；
(F)所述VH包含由SEQ ID NO：7、SEQ ID NO：19和SEQ ID NO：31组成的组的CDR，且
所述VL包含由SEQ ID NO：42、SEQ ID NO：54和SEQ ID NO：65组成的组的CDR；
(G)所述VH包含由SEQ ID NO：8、SEQ ID NO：20和SEQ ID NO：32组成的组的CDR，且
所述VL包含由SEQ ID NO：43、SEQ ID NO：55和SEQ ID NO：66组成的组的CDR；
(H)所述VH包含由SEQ ID NO：9、SEQ ID NO：21和SEQ ID NO：33组成的组的CDR，且
所述VL包含由SEQ ID NO：44、SEQ ID NO：56和SEQ ID NO：67组成的组的CDR；
(I)所述VH包含由SEQ ID NO：10、SEQ ID NO：22和SEQ ID NO：34组成的组的CDR，且
所述VL包含由SEQ ID NO：45、SEQ ID NO：57和SEQ ID NO：68组成的组的CDR；
(J)所述VH包含：
(i)由SEQ ID NO：11、SEQ ID NO：23和SEQ ID NO：35组成的组的CDR；
(ii)由SEQ ID NO：11、SEQ ID NO：25和SEQ ID NO：35组成的组的CDR；
(iii)由SEQ ID NO：13、SEQ ID NO：23和SEQ ID NO：35组成的组的CDR；或
(iv)由SEQ ID NO：13、SEQ ID NO：25和SEQ ID NO：35组成的组的CDR；且
所述VL包含由SEQ ID NO：46、SEQ ID NO：58和SEQ ID NO：69组成的组的CDR；或者
(K)所述VH包含由SEQ ID NO：12、SEQ ID NO：24和SEQ ID NO：36组成的组的CDR，且
所述VL包含：
(i)由SEQ ID NO：47、SEQ ID NO：59和SEQ ID NO：70组成的组的CDR；或
(ii)由SEQ ID NO：48、SEQ ID NO：59和SEQ ID NO：70组成的组的CDR。
11.权利要求10的分离的核酸分子，
其中所述抗体或抗原结合片段包含可变重链，所述可变重链具有与SEQ ID NO：164的序列至少95％相同的氨基酸序列，并且
其中所述抗体或抗原结合片段包含可变轻链，所述可变轻链具有与SEQ ID NO：87的序列至少95％相同的氨基酸序列。
12.权利要求11的分离的核酸分子，其中
所述可变重链包含SEQ ID NO：164的氨基酸序列，且
所述可变轻链包含SEQ ID NO：87的氨基酸序列。
13.权利要求12的分离的核酸分子，其中所述重链可变区和轻链可变区通过SEQ IDNO：181的序列连接。
14.表达载体，其包含权利要求10的核酸分子。
15.表达载体，其包含权利要求11的核酸分子。
16.表达载体，其包含权利要求12的核酸分子。
17.宿主细胞，其包含权利要求14的表达载体。
18.宿主细胞，其包含权利要求15的表达载体。
19.宿主细胞，其包含权利要求16的表达载体。
20.权利要求1的人源化抗体或抗原结合片段，
其中所述抗体或抗原结合片段包含可变重链，所述可变重链包含SEQ ID NO：164的序列，并且
其中所述抗体或抗原结合片段包含可变轻链，所述可变轻链包含SEQ ID NO：87的序列。
21.权利要求20的人源化抗体或抗原结合片段，其还包含连接所述重链可变区和轻链可变区的接头序列，所述接头序列具有SEQ ID NO：181的序列。
22.权利要求21的抗原结合片段，其是单链抗体(scFv)。
23.权利要求22的抗原结合片段，其包含衍生自存在于表达载体的起始密码子的N-末端甲硫氨酸，所述表达载体表达抗原结合片段。
24.权利要求1、5、6、7、8、20、21、22或23的人源化抗体或抗原结合片段，其中所述抗体或其抗原结合片段以≤1×10-10M的亲和力(Kd)结合人VEGF165。
25.组合物，其包含权利要求24的人源化抗体或抗原结合片段、及药学上可接受的载体。
26.药物制剂，其包含浓度为约0.1mg/ml～约50mg/ml的重组抗VEGF抗体或其抗原结合片段，所述抗体或其抗原结合片段包含可变重链(VH)和可变轻链(VL)，其中
重链可变区包含SEQ ID NO：164的氨基酸序列，且
轻链可变区包含SEQ ID NO：87的氨基酸序列。
27.权利要求26的药物制剂，其中所述抗原结合片段是Fab、F(ab')2或Fab'。
28.权利要求26的药物制剂，其中所述抗原结合片段是scFv。
29.权利要求28的药物制剂，其中所述重链可变区和轻链可变区通过SEQ ID NO：181的序列连接。
30.权利要求26的药物制剂，其中所述重组抗体或其抗原结合片段的浓度为0.5mg/ml～约40mg/ml。
31.制品，其包括容纳权利要求26的药物制剂的容器。
32.权利要求26～30之任一项的药物制剂，其配制用于全身、肿瘤内、肿瘤周围、病灶内、病灶周围、局部、眼内、口腔、鼻腔、直肠或肠胃外施用。
33.治疗受试者的人VEGF介导的疾病的方法，其包括给受试者施用权利要求26～30和32之任一项的药物制剂，使得受试者接受VEGF介导的疾病。
34.权利要求33的方法，其中所述VEGF介导的疾病选自：年龄相关黄斑变性、新生血管性青光眼、糖尿病性视网膜病变、早产儿视网膜病变、晶体后纤维增生症、乳腺癌、肺癌、胃癌、食管癌、结肠直肠癌、肝癌、卵巢癌、男性细胞瘤、宫颈癌、子宫内膜癌、子宫内膜增生、子宫内膜异位、纤维肉瘤、绒毛膜癌、头颈癌、鼻咽癌、喉癌、肝母细胞瘤、卡波西肉瘤、黑素瘤、皮肤癌、血管瘤、血管母细胞瘤、胰腺癌、视网膜母细胞瘤、星形细胞瘤、胶质母细胞瘤、神经鞘瘤、少突胶质细胞瘤、髓母细胞瘤、神经母细胞瘤、横纹肌肉瘤、成骨肉瘤、平滑肌肉瘤、泌尿道癌、甲状腺癌、肾母细胞瘤、肾细胞癌、前列腺癌、与斑痣性错构瘤病相关的异常血管增生、水肿、麦格综合征、类风湿性关节炎、银屑病和动脉粥样硬化。
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