CN116003600A - 人抗vegfr-2/kdr抗体 - Google Patents
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- CN116003600A CN116003600A CN202211207207.7A CN202211207207A CN116003600A CN 116003600 A CN116003600 A CN 116003600A CN 202211207207 A CN202211207207 A CN 202211207207A CN 116003600 A CN116003600 A CN 116003600A
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Abstract
本发明涉及人抗VEGFR‑2/KDR抗体。本发明涉及结合于VEGFR‑2的抗体。所述抗体用于治疗肿瘤性疾病、过度增生病症和血管生成病症,并且可将其单独使用或与其它药剂组合使用。
Description
本申请是申请日为2013年10月7日的中国专利申请201811092472.9“人抗VEGFR-2/KDR抗体”的分案申请。
技术领域
本发明涉及结合VEGFR-2的抗体。所述抗体被用于治疗肿瘤性疾病和过度增生病症,并且可将其单独使用或与其它药剂组合使用。
相关申请的交叉引用
本申请要求2012年10月5日提交的美国申请No.61/710,420的优先权,该美国申请通过引用以其整体并入本文。
背景技术
血管生成是高度复杂的形成新血管的过程,其牵涉毛细血管内皮细胞的增生,以及其从预先存在的血管的迁移和组织浸润,细胞至管状结构的组配,新形成的管状组装体形成闭路循环血管系统的联接或新形成的毛细血管的成熟。
血管生成在正常生理过程包括胚胎发育、卵泡生长和伤口愈合中是非常重要的。过度的血管生成还导致肿瘤性疾病和非肿瘤性疾病诸如年龄相关性黄斑变性、糖尿病性视网膜病和新生血管性青光眼中的新血管形成。利用雷珠单抗(乐明睛,Lucentis)靶向血管内皮细胞生长因子(VEGF)的抗血管生成疗法已被证明在延缓AMD的进展中是有效的。然而,新血管形成是复杂的,并且多血管生成机制有可能作出贡献。但仍然需要开发用于治疗与新血管形成相关的疾病的药剂和疗法。
发明内容
本发明提供了结合VEGFR-2(KDR)的人抗体及其片段。在一些实施方案中,所述抗体阻断配体(例如,VEGF-A、VEGF-C、VEGF-D或VEGF-E的一种或多种)对VEGFR-2的结合。在一些实施方案中,所述抗体中和VEGFR-2的激活。所述抗体用于治疗肿瘤性疾病,包括,例如实体瘤和非实体瘤,以及过度增生病症。因此,本发明提供了中和KDR的激活的方法,抑制肿瘤生长(包括抑制肿瘤相关血管生成)的抑制的方法,以及治疗血管生成相关病症的方法。本发明提供了具有结合于VEGR受体的人抗体或抗体片段的试剂盒。
在一个实施方案中,本发明提供了包含CDR-1H、CDR-2H和CDR-3H序列的分离的重链可变区,其中:
(i)CDR-1H序列为GFTFSWYX1MX2(SEQ ID NO:185),其中X1为V或I,X2为G或L,
(ii)CDR-2H序列为SIX1X2SGGX3TX4YADSVKG(SEQ ID NO:186),其中X1为Y或G,X2为P或S,X3为A或F,X4为N或D,以及
(iii)CDR-3H序列为GNYFDY(SEQ ID NO:3)或GLAAPRS(SEQ ID NO:11)。
在一个实施方案中,本发明提供了包含CDR-1L、CDR-2L和CDR-3L的分离的轻链可变区,其中
(i)CDR-1L序列为:X1GX2X3LX4X5X6X7X8S(SEQ ID NO:187),其中X1为S、Q,或T,X2为D、E或Q,X3为K、S、N、I或A,X4为G或R,X5为D、S、H、E或N,X6为E、Y、Q、R或N,X7为Y、F或S以及X8为A或S;或SGSX1SNX2X3X4X5X6X7X8(SEQ ID NO:188),其中X1为S或T,X2为I或L,X3为E或G,X4为T、S或N,X5为N或Y,X6为T、P、A或Y,X7为V或L以及X8为N、I或Y;或X1GX2SX3DX4GX5YDYVS(SEQ IDNO:189),其中X1为A或T,X2为S或T,X3为H、S或N,X4为I或V以及X5为S或A,
(ii)CDR-2L序列为X1X2X3X4X5PS(SEQ ID NO:190),其中X1为Q、D、T、Y、S或A,X2为D、N、S、T、V或V,X3为D、N、S、T或Y,X4为Q、K、N或L以及X5为R或L,以及
(iii)其中CDR-3L序列为:QX1WX2X3X4X5X6X7X8(SEQ ID NO:191),其中X1为A或T,X2为D或G,X3为R或无氨基酸,X4为S、F或N,X5为S、T或N,X6为S、T或P,X7为A、V、L、I或Y以及X8为V或L;或AX1WDDX2LX3X4X5X6(SEQ ID NO:192),其中X1为A、S或T,X2为N或S,X3为N、I或G,X4为G或S,X5为P、W或V以及X6为V或L;或MYSTITX1LL(SEQ ID NO:193),其中X1为A或T。
在一个实施方案中,本发明提供了包含CDR-1L、CDR-2L和CDR-3L的分离的轻链可变区,其中
(i)CDR-1L序列为RASX1X2X3X4X5X6X7YX8X9(SEQ ID NO:194),其中X1为Q、E或H,X2为S、R或N,X3为V、I或L,X4为S、R、G或N,X5为S或N,X6为S、N、W或D,X7为G或无氨基酸,X8为L或F以及X9为A、G、M或S,
(ii)CDR-2L序列为GASX1RAT(SEQ ID NO:195),其中X1为S、T、I或N,以及
(iii)CDR-3L序列为QQX1X2X3X4X5X6X7X8(SEQ ID NO:196),其中X1为F或Y,X2为D、G或Y,X3为S、T或N,X4为S、L或W,X5为P或无氨基酸,X6为P或T,X7为L、I、V、P、W或Y以及X8为T或S。
在本发明的实施方案中,所述抗体为表2中显示的抗体。在本发明的实施方案中,所述抗体包含具有SEQ ID NO:4的重链可变结构域。在本发明的实施方案中,所述抗体包含具有SEQ ID NO:28的轻链可变结构域。在本发明的另一个实施方案中,所述抗体包含具有SEQ ID NO:32的轻链可变结构域。
在本发明的实施方案中,所述抗体用于中和VEGFR2的激活的方法,包括将细胞有有效量的所述抗体接触。
在本发明的另一个实施方案中,所述抗体用于抑制受试者的血管生成的方法,包括施用有效量的抗体。在某些这样的实施方案中,将所述抗体与有效量的rho相关激酶2(ROCK2)拮抗剂一起施用。
在本发明的另一个实施方案中,所述抗体用于治疗受试者的赘生物或减少肿瘤生长的方法,所述方法包括施用有效量的所述抗体。在某些这样的实施方案中,将所述抗体与有效量的表皮生长因子受体(EGFR)拮抗剂一起施用。在某些这样的实施方案中,将所述抗体与有效量的fms-样酪氨酸激酶受体(flt-1)拮抗剂一起施用。在其它这样的实施方案中,将所述抗体与有效量的rho相关激酶(ROCK)拮抗剂一起施用。在其它这样的施用方案中,将所述抗体与有效量的基质金属蛋白酶拮抗剂一起施用。
附图说明
图1A-C分别显示通过噬菌体展示鉴定的本发明的抗VEGFR2抗体的人重链、λ轻链和κ轻链可变区序列。
图2显示本发明的抗体对hVEGFR2(顶)的结合以及含有hVEGFR2的结构域2和3的构建体(中)。底图框显示配体(VEGF165)阻断。
图3显示本发明的Mab 101和102抑制过表达KDR(人VEGFR2)的猪主动脉内皮(PAE)细胞中的VEGFR2、AKT和MAPK的VEGFA-刺激的磷酸化。
图4显示Mab 104、105、106和108阻断hVEGFR2和VEGF165配体的结合。在单独的实验中对于Mab 103、107、109和110获得相似的结果。这些Mab含有与不同轻链可变结构域重组的Mab101的重链可变结构域。
图5显示本发明的Mab 105和106抑制过表达KDR(人VEGFR2)的猪主动脉内皮(PAE)细胞中的VEGFR2、AKT和MAPK的VEGFA-刺激的磷酸化。
详述
在一个方面,本发明提供了新型VEGFR2抗体或应用对于抑制VEGFR2依赖性信号转导是有效的这样的抗体的抗原结合片段。如本文中所用,“抑制受体”意指消除和/或灭活受体的固有激酶活性以转导信号。用于VEGFR2抑制的可靠测定是受体磷酸化的减少。
本发明不受VEGFR2抑制的任何特定机制限制。被一种抗体所遵循的机制不一定与被另一种抗体所遵循的机制相同。一些可能的机制包括阻止VEGF配体对VEGFR2的细胞外结合结构域的结合和阻止受体的二聚化或寡聚化。然而不能排除其它机制。
抗体是识别并结合特定抗原或物质的蛋白质。在优选实施方案中,本发明的抗体结合KDR至少与结合天然配体一样强。由抗原与抗体的解离的平衡常数(Kd)表示的亲和力测量抗原决定簇与抗体结合位点之间的结合强度。亲合力是抗体与其抗原之间的结合强度的量度。亲合力涉及抗原决定簇与抗体上的抗原结合位点之间的亲和力和每抗体结合位点(效价)的数目。例如,单价抗体(例如,Fab)具有一个针对特定表位的结合位点。IgG抗体具有2个抗原结合位点。K的典型值(解离常数Kd的倒数)为105至1011升/mol。任何比104升/mol弱的K被认为表示为非特异性的结合。
本发明的抗体抑制VEGFR2的激活。VEGFR2抑制的一个量度为降低的受体的酪氨酸激酶活性。酪氨酸激酶抑制可使用公知的方法来测量,诸如测量受体的自磷酸化水平。还可通过天然或合成VEGFR2底物以及VEGFR2信号转导途径的其它组分的磷酸化事件的抑制或调控来观察VEGFR2的抑制。还可例如在ELISA测定中或western印迹上使用对于磷酸酪氨酸是特异性的抗体检测磷酸化。用于酪氨酸激酶活性的一些测定描述于Panek等,J.Pharmacol.Exp.Thera.,283:1433-44(1997)和Batley等,Life Sci.,62:143-50(1998)中。
还可使用体内测定。例如,可在抑制剂存在和不存在的情况下使用利用受体配体刺激的细胞系,通过有丝分裂测定来观察受体酪氨酸激酶的抑制。例如,利用VEGF刺激的HUVEC细胞(ATCC)可用于测定VEGFR抑制。另一种方法包括使用例如注射入小鼠的人肿瘤细胞测试表达VEGF的肿瘤细胞的生长的抑制。参见,美国专利No.6,365,157(Rockwell等人)。
本发明提供了抗VEGFR2抗体,包括编码这样的抗体的核酸和包含这样的抗体的组合物。在一个实施方案中,本发明提供了包含CDR-1H、CDR-2H和CDR-3H序列的分离的抗体重链可变区,其中:
(i)CDR-1H序列为GFTFSWYX1MX2(SEQ ID NO:185),其中X1为V或I,X2为G或L,
(ii)CDR-2H序列为SIX1X2SGGX3TX4YADSVKG(SEQ ID NO:186),其中X1为Y或G,X2为P或S,X3为A或F,X4为N或D以及
(iii)CDR-3H序列为GNYFDY(SEQ ID NO:3)或GLAAPRS(SEQ ID NO:11)。
在一个实施方案中,本发明提供了包含CDR-L1、CDR-L2和CDR-L3的分离的轻链可变区,其中
(i)CDR-L1序列为:X1GX2X3LX4X5X6X7X8S(SEQ ID NO:187),其中X1为S、Q或T,X2为D、E或Q,X3为K、S、N、I或A,X4为G或R,X5为D、S、H、E或N,X6为E、Y、Q、R或N,X7为Y、F或S,以及X8为A或S;或SGSX1SNX2X3X4X5X6X7X8(SEQ ID NO:188),其中X1为S或T,X2为I或L,X3为E或G,X4为T、S或N,X5为N或Y,X6为T、P、A或Y,X7为V或L,以及X8为N、I或Y;或X1GX2SX3DX4GX5YDYVS(SEQ IDNO:189),其中X1为A或T,X2为S或T,X3为H、S或N,X4为I或V以及X5为S或A,
(ii)CDR-L2序列为X1X2X3X4X5PS(SEQ ID NO:190),其中X1为Q、D、T、Y、S或A,X2为D、N、S、T或V,X3为D、N、S、T或Y,X4为Q、K、N或L,以及X5为R或L,以及
(iii)其中CDR-L3序列为:QX1WX2X3X4X5X6X7X8(SEQ ID NO:191),其中X1为A或T,X2为D或G,X3为R或无氨基酸,X4为S、F或N,X5为S、T或N,X6为S、T或P,X7为A、V、L、I或Y,以及X8为V或L;或AX1WDDX2LX3X4X5X6(SEQ ID NO:192,其中X1为A、S或T,X2为N或S,X3为N、I或G,X4为G或S,X5为P、W或V,以及X6为V或L;或MYSTITX1LL(SEQ ID NO:193),其中X1为A或T。
在一个实施方案中,本发明提供了包含CDR-L1、CDR-L2和CDR-L3的分离的轻链可变区,其中
(i)CDR-L1序列为RASX1X2X3X4X5X6X7YX8X9(SEQ ID NO:194),其中X1为Q、E或H,X2为S、R或N,X3为V、I或L,X4为S、R、G或N,X5为S或N,X6为S、N、W或D,X7为G或无氨基酸,X8为L或F以及X9为A、G、M或S,
(ii)CDR-L2序列为GASX1RAT(SEQ ID NO:195),其中X1为S、T、I或N,以及
(iii)CDR-L3序列为QQX1X2X3X4X5X6X7X8(SEQ ID NO:196),其中X1为F或Y,X2为D、G或Y,X3为S、T或N,X4为S、L或W,X5为P或无氨基酸,X6为P或T,X7为L、I、V、P、W或Y以及X8为T或S。
在本发明的实施方案中,提供了抗体,所述抗体包含含有上文中所示的1、2、3、4、5或6个轻链可变结构域和重链可变结构域CDR序列。
提供了VEGFF2结合抗体序列的非限定性实例。如本文中所述,从人Fab噬菌体展示文库鉴定了2种中和抗体,所述抗体结合人VEGFR2,阻断配体VEGFA对hVEGFR2的结合,以及抑制VEGFR2磷酸化和通过VEGFA刺激的下游信号转导。表1显示所述抗体的CDR和可变结构域的氨基酸序列。Mab 101和Mab 102的Kd分别为约6.6mM和1.7nM。
利用κ轻链基因(κ-文库)和λ轻链基因(λ-文库)改组Mab 101的重链。通过针对人VEGFR2和小鼠VEGFR2淘选λ-文库发现了20个独特的λ轻链变体。通过针对人VEGFR2和小鼠VEGFR2淘选κ-文库发现了22个独特κ轻链变体。表2显示轻链的CDR和可变结构域的氨基酸序列。Mab 105、106和107的Kd增加约10倍(分别地0.24nM、0.22nM和0.12nM)。与亲代抗体一样,这些抗体结合VEGFR2,阻断VEGFA对VEGFR2的结合以及抑制VEGFR2、AKT和MAPK的VEGFA刺激的磷酸化。(图4)。
几种抗体,包括Mab 138、139、140和146,也与小鼠VEGFR2交叉反应。这些抗体还抑制VEFGR2和下游信号转导分子包括MAPK的VEGFA刺激的磷酸化。
本发明提供了分离的VEGFR2抗体和其VEGFR2结合片段,所述抗体或其结合片段包含选自表1和表2中所示的1、2或3个重链CDR和1、2或3个轻链CDR。在本发明的抗体中,当超过1个CDR选自表1和表2中所示的序列时,不同的CDR无需选自这些表中所示的相同单克隆抗体,但可选自表中所示的2个或更多个抗体可变结构域。具体实施方案包括但不限于下列实施方案。在本发明的实施方案中,分离的VEGFR2抗体包含1、2或3个具有SEQ ID NO:1、SEQID NO:2和SEQ ID NO:3的重链CDR。在本发明的实施方案中,所述抗体包含1、2或3个具有SEQ ID NO:5、SEQ ID NO:6和SEQ ID NO:7的轻链CDR。在另一个实施方案中,所述抗体包含1、2或3个具有表1或2中所示的序列的轻链CDR。非限定性实例包括含有SEQ ID NO:25、SEQID NO:26和SEQ ID NO:27的一个或多个、SEQ ID NO:29、SEQ ID NO:30和SEQ ID NO:31的一个或多个或SEQ ID NO:33、SEQ ID NO:34和SEQ ID NO:35的一个或多个的轻链可变区。在某些实施方案中,VEGFR2抗体包含含有SEQ ID NO:4或SEQ ID NO:12的重链可变结构域。在某些实施方案中,VEGFR2抗体包含含有SEQ ID NO:8、SEQ ID NO:16、SEQ ID NO:27、SEQID NO:31或SEQ ID NO:35的轻链可变结构域。在某些实施方案中,所述抗体包含上述重链可变结构域之一和上述轻链可变结构域之一。在某些实施方案中,所述VEGFR2抗体或其结合片段包含1个或多个CDR或1个或多个具有与表1或2中所示的CDR和可变结构域序列具有至少85%、至少90%、至少95%、至少97%、至少98%或至少99%的同一性的氨基酸序列的可变结构域。
“同一性”是指在考虑需要被引入以最佳比对两个序列的缺口的数目或每一个缺口的长度的情况下,由两个氨基酸或核酸序列共有的相同位置的数目或百分比。“大体上相同”意指相异仅在于保守氨基酸置换,例如,一个氨基酸对另一个相同种类的氨基酸(例如,缬氨酸对甘氨酸、精氨酸对赖氨酸等)的置换,或在于一个或多个位于氨基酸序列的位置上的不破坏所述蛋白质的功能的非保守置换、缺失或插入的氨基酸序列。优选地,氨基酸序列与另一个氨基酸序列具有至少80%,更优选至少85%和最优选至少90%的相似性。用于测定序列相似性的方法和计算机程序是公开可用的,包括,但不限于GCG程序包(Devereux等,Nucleic Acids Research 12:387,1984)、BLASTP、BLASTN、FASTA(Altschul等,J.Mol.Biol.215:403(1990))和ALIGN程序(2.0版)。公知的Smith Waterman算法也可以用于测定相似性。BLAST程序是可从NCBI和其它来源公开获得的(BLAST Manual,Altschul等,NCBI NLM NIH,Bethesda,Md.20894;http://www.ncbi.nlm.nih.gov/blast/上的BLAST2.0)。在比较序列中,这些方法考虑各种置换、缺失和其它修饰。保守置换通常包括在下列组内的置换:甘氨酸、丙氨酸;缬氨酸、异亮氨酸、亮氨酸;天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺;丝氨酸、苏氨酸;赖氨酸、精氨酸;以及苯丙氨酸、酪氨酸。
本发明的抗体还包括已通过直接突变、亲和力成熟、噬菌体展示或链改组的方法发送其结合特征的那些抗体。可通过突变CDR和筛选具有期望的特征的抗原结合位点来修饰或提高亲和力和特异性。以多种方法突变CDR。一种方法是随机化单个残基或残基的组合,以便在一组另外地相同的抗原结合位点中,在特定位置上发现所有20种氨基酸。或者,可通过易错PCR法(参见,例如,Hawkins等,J.Mol.Biol.,226:889-896(1992))在许多CDR残基上诱导突变。例如,可在大肠杆菌(E.coli)的增变株中扩增含有重链和轻链可变区基因的噬菌体展示载体(参见,例如,Low等,J.Mol.Biol.,250:359-368(1996))。这些诱变方法是本领域普通技术人员已知的许多方法的举例说明。
为了使结合VEGF受体的抗体的免疫原性降至最低,本发明提供了包含人可变和恒定结构域序列的抗体。所述抗体可以是任何免疫球蛋白种类诸如IgG、IgM、IgA、IgD或IgE及其亚类的成员或可组成所述种员。所述抗体种类可被选择用于最优化天然抗体的效应子功能(例如,补体依赖性细胞毒性(CDC)和抗体依赖性细胞毒性(ADCC))。
本发明的某些实施方案包括VEGFR2-结合抗体片段的用途。Fv是含有完全重链和轻链可变结构域的最小片段,包括所有6个高变环(CDR)。由于不存在恒定结构域,因此所述可变结构域是非共价缔合的。可使用允许VH和VL结构域结合以形成抗原结合位点的接头来将重链和轻链连接成单个多肽链(“单链Fv”或“scFv”)。在本发明的实施方案中,所述接头为(Gly-Gly-Gly-Gly-Ser)3。由于scFv片段缺乏完整抗体的恒定结构域,因此它们被认为小于完整抗体。scFv片段也无在某些实施方案中可能不想要的重链恒定结构域与其它生物分子的正常相互作用。
还可使用含有VH、VL和任选地CL、CH1或其它恒定结构域的抗体的片段。通过木瓜蛋白酶消化生成的抗体的单价片段称为Fab并且缺乏重链铰链区。通过胃蛋白酶消化生成的片段称为F(ab’)2,其保留重链铰链并且是二价的。这样的片段还可重组地产生。许多其它有用的抗原-结合抗体片段在本领域中是已知的,包括,但不限于双抗体、三抗体、单结构域抗体或其它单价和多价形式。
本发明还提供了多价抗原结合蛋白,其可以以(但不限于)抗体、其抗原结合片段和包含抗体的抗原结合部分的全部或部分的蛋白的形式存在。多价抗原结合蛋白可以是单特异性的、双特异性的或多特异性的。术语特异性是指特定分子可结合的不同类型的抗原决定簇的数目。如果免疫球蛋白分子仅结合一种类型的抗原决定簇,那么所述免疫球蛋白分子为单特异性的。如果免疫球蛋白分子结合不同类型的抗原决定簇,则所述免疫球蛋白为多特异性的。
例如,双特异性多价单链抗体允许识别两个不同类型的表位。两个表位可以在相同的抗原(例如,VEGFR2)上。或者,一个表位可以在一个抗原(例如,VEGFR2)上并且第二表位在不同的抗原上。
在一个实施方案中,多价单链抗体包括连接于可变重链片段的可变轻链片段(类似于scFv),其通过另一个肽接头被进一步连接于至少一个其它抗原结合结构域。通常地,所述肽接头由约15个氨基酸残基组成。在优选实施方案中,VL和VH结构域的数目相等。例如,可如下表示双价单链抗体:VL-L1-VH–L2-VL-L3-VH或VL-L1-VH-L2-VH–L3-VL或VH–L1-VL-L2-VH–L3-VL或VH-Ll-VL-L2-VL–L3-VH。作为三价或更多价的多价单链抗体具有一个或多个通过另外的肽接头连接于双价单链抗体的抗体片段。三价单链抗体的一个实例是VL-L1-VH-L2-VL-LI-VH-L2-VL-LI-VH。
可组合两个单链抗体以形成双抗体,也称为二价二聚体。双抗体具有两条链。双抗体的每一条链包括通过约5-10个氨基酸残基的短接头例如(Gly-Gly-Gly-Gly-Ser),(Gly-Gly-Gly-Gly-Ser)2连接于VL结构域的VH结构域。这样的接头短至足以阻止相同链上的结构域之间的链内配对,从而驱动不同链上的互补结构域之间的链间配对,并且重新产生两个抗原结合位点。双抗体结构是刚性的和致密的,抗体结合位点位于分子的相对末端。双抗体可以是单特异性的或双特异性的。
可将3个单链抗体组合以形成三抗体,也称为三价三聚体。在一些实施方案中,利用直接融合于(即无任何接头序列)VH或VL的氨基末端的VL或VH结构域的羧基末端构建三抗体。三抗体具有3个Fv头,所述多肽以环状头-对-尾方式排列。三抗体分子的可能构象是平面的,3个结合位点以彼此成120度的角位于平面中。三抗体可以是单特异性的、双特异性的或三特异性的。
应理解,本发明的抗VEGFR2抗体,当出于预防或治疗目的而用于哺乳动物时,以额外地包含药学上可接受的载体的组合物的形式进行施用。适合的药学上可接受的载体包括例如水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇等的一种或多种及其组合。药学上可接受的载体还可包含少量辅助物质诸如湿润剂或乳化剂、防腐剂或缓冲剂,其增加抗体的货架期或功效。
在本发明的方法中,向有此需要的哺乳动物施用治疗有效量的本发明的抗体。如本文中所用,术语“施用”意指通过可实现寻求的结果的任何方法将本发明的抗体递送至哺乳动物。可以例如静脉内或肌内施用它们。尽管本发明的人抗体特别适用于对人施用,但也可将它们施用给其它哺乳动物。如本文中所用,术语“哺乳动物”意谷包括,但不限于,人、实验室动物、家养宠物和农场动物。“治疗有效量”意指当向哺乳动物施用时,在产生期望的治疗效应诸如抑制激酶活性中是有效的本发明的抗体的量。例如,取决于疾病,对于抗体,这可需要0.1、1.0、3.0、6.0或10.0mg/Kg。对于具有150,000g/摩尔的分子量的IgG(两个结合位点),这些剂量对应于约18nM、180nM、540nM、1.08μM和1.8μM的结合位点(对于5L血体积)。
本发明的抗体用于抑制肿瘤生长、与肿瘤生长相关的血管生成或与血管生成相关的其它病理状况。可治疗的肿瘤包括原发性肿瘤、转移性肿瘤和难治性肿瘤。难治性肿瘤包括不能响应利用单独的化学治疗剂、单独的抗体、单独的辐射或其组合的治疗或抗所述治疗的肿瘤。难治性肿瘤还包括似乎被利用这样的药剂的治疗抑制,但在中断治疗后长达5年,有时长达10年或更长时间复发的肿瘤。所述抗体对于治疗血管化肿瘤和未被血管化或基本上尚未血管化的肿瘤是有效的。
可相应地治疗的实体瘤的实例包括乳腺癌、肺癌、结肠直肠癌、胰腺癌、神经胶质瘤和淋巴瘤。这样的肿瘤的一些实例包括表皮样瘤、鳞状肿瘤诸如头颈肿瘤、结肠直肠肿瘤、前列腺肿瘤、乳腺肿瘤、肺肿瘤,包括小细胞和非小细胞肺肿瘤、胰腺肿瘤、甲状腺肿瘤、卵巢肿瘤和肝肿瘤。其它实例包括卡波西氏肉瘤、CNS肿瘤、神经母细胞瘤、毛细血管母细胞瘤、脑膜瘤、脑转移瘤、黑色素瘤、胃肠道和肾脏癌及肉瘤,横纹肌肉瘤、胶质母细胞瘤,优选地胶质母细胞瘤和平滑肌肉瘤。本发明的拮抗剂对于其是有效的血管化皮肤癌的实例包括鳞状细胞癌、基底细胞癌和可以通过抑制恶性角质形成细胞,诸如人恶性角质形成细胞的生长来治疗的皮肤癌。
非实体肿瘤的实例包括白血病、多发性骨髓瘤和淋巴瘤。白血病的一些实例包括急性骨髓性白血病(AML)、慢性髓细胞性白血病(CML)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、红细胞白血病或单核细胞白血病。淋巴瘤的一些实例包括何杰金氏和非何杰金氏淋巴瘤。
本发明的抗体也可用于治疗或预防特征在于过度血管生成的病理状况,包括,例如,血管形成和/或炎症,诸如动脉粥样硬化,类风湿关节炎(RA),血管瘤,血管纤维瘤和牛皮癣。非肿瘤性血管生成疾病的其它非限制性实例是早产儿视网膜病(晶状体后纤维形成)、角膜移植排斥、胰岛素依赖性糖尿病、多发性硬化症、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发型超敏反应、炎性肠病、败血性休克、骨质疏松症、骨关节炎、由神经炎症诱发的认知缺陷、奥-韦综合征、再狭窄以及真菌,寄生虫和病毒感染,包括巨细胞病毒感染。
特征在于过度血管生成的眼疾病包括新生血管性青光眼、增生性视网膜病,包括增生性糖尿病性视网膜病和黄斑变性。本发明提供了用于治疗眼疾病和病症的方法和化合物。在一个实施方案中,本发明提供了用于治疗以“干”和“湿”的形式存在的年龄相关黄斑变性(AMD)的方法和化合物。AMD的“湿”形式引发因异常血管生长(血管新生)而导致的视力丧失。从这些视网膜血管的出血、渗漏和瘢痕形成最终引发光感受器的不可逆损伤。干形式因视网膜色素上皮细胞层的萎缩而引起,其通过眼中心部分中的光感受器(杆和视锥细胞)的丢失而引发视力丧失。在另一个实施方案中,本发明提供了治疗脉络膜新生血管形成(CNV)的方法。脉络膜新生血管形成是其中新血管在脉络膜中生长,穿过Bruch膜和侵入视网膜下空间的过程,其为,除其它原因以外,年龄相关性黄斑变性、近视和眼外伤的症状。在另一个实施方案中,本发明提供了治疗糖尿病性黄斑水肿(DME)的方法。在另一个实施方案中,本发明提供了治疗继发于视网膜分支静脉阻塞(BRVO)或视网膜中央静脉阻塞(CRVO)的黄斑水肿的方法。可根据本发明治疗的其它疾病包括,但不限于,虹膜新血管形成、葡萄膜炎、新生血管性青光眼和早产儿视网膜炎(ROP)。治疗的方法可以是预防性的,诸如避开角膜移植后角膜新生血管形成,或在小梁切除手术中调节伤口愈合过程。
可有利地向有此需要的受试者施用本发明的抗体和抗原结合片段与第二药剂。例如,在一些实施方案中,向受试者施用本发明的VEGFR-2抗体与抗肿瘤剂。在一些实施方案中,向受试者施用VEGFR-2抗体与第二血管生成抑制剂。在一些实施方案中,施用本发明的VEGFR-2抗体与抗炎剂或免疫抑制剂。
抗肿瘤剂包括抗肿瘤剂包括细胞毒性化学治疗剂,靶向小分子以及生物分子和辐射。化学治疗剂的非限制性实例包括顺铂、达卡巴嗪(DTIC)、更生霉素、伊立替康、氮芥(氮芥(nitrogen mustard))、链佐星、环磷酰胺、卡莫司汀(BCNU)、洛莫司汀(CCNU)、多柔比星(阿霉素)、柔红霉素、丙卡巴肼、丝裂霉素、阿糖胞苷、依托泊苷、氨甲蝶呤、5-氟尿嘧啶、长春碱、长春新碱、博来霉素、紫杉醇(泰素)、多西紫杉醇(泰索帝)、阿地白介素、天冬酰胺酶、白消安、卡铂、克拉屈滨、达卡巴嗪、氟尿苷、氟达拉滨、羟基脲、异环磷酰胺、干扰素α、亮丙瑞林、甲地孕酮、美法仑、巯基嘌呤、普卡霉素、米托坦、培门冬酶、喷司他丁、哌泊溴烷、普卡霉素、链佐星、他莫昔芬、替尼泊苷、睾内酯、硫鸟嘌呤、塞替派、乌拉莫司汀、长春瑞滨、苯丁酸氮芥、紫杉醇及其组合。
靶向小分子和生物分子包括,但不限于,信号转导途径的组分诸如酪氨酸激酶的调节剂的抑制剂,以及受体酪氨酸激酶和结合肿瘤特异性抗原的药剂的抑制剂。参与肿瘤发生的生长因子受体的非限制性实例是受体血小板衍生生长因子(PDGFR)、胰岛素样生长因子(IGFR)、神经生长因子(NGFR)和成纤维细胞生长因子(FGFR)的受体以及表皮生长因子受体家族的受体,包括EGFR(erbB1)、HER2(erbB2)、erbB3和erbB4。
EGFR拮抗剂包括结合于EGFR或EGFR配体并且抑制配体结合和/或受体激活的抗体。例如,所述药剂可阻断受体二聚体或与其它EGFR家族成员的异二聚体的形成。EGFR的配体包括,例如,EGF、TGF-α双调蛋白、肝素结合EGF(HB-EGF)和βrecullulin。EGFR拮抗剂可在外部结合EGFR的细胞外部分,其可以抑制或可以不抑制配体的结合,或在内部结合于酪氨酸激酶结构域。EGFR拮抗剂还包括例如通过抑制EGFR信号转导途径的组分的功能来抑制EGFR依赖性信号转导的药剂。结合EGFR的EGFR拮抗剂包括,但不限于,对于EGFR和小分子诸如直接作用于EGFR的细胞质结构域的合成的激酶抑制剂是特异性的生物分子,诸如抗体(及其功能等同物)。
小分子和生物抑制剂包括表皮生长因子受体(EGFR)的抑制剂,包括吉非替尼、埃罗替尼和西妥昔单抗、HER2的抑制剂(例如,曲妥单抗、曲妥单抗emtansine(曲妥单抗DM1;T-DM1)和帕妥珠单抗)、抗VEGF抗体和片段(例如,贝伐单抗)、抑制CD20的抗体(例如,利妥昔单抗、替伊莫单抗),抗VEGFR抗体(例如,雷莫芦单抗(IMC-1121B)、IMC-1C11和CDP791)、抗PDGFR抗体和伊马替尼。小分子激酶抑制剂可以是对于特定酪氨酸激酶是特异性的或可以是两种或更多种激酶的抑制剂。例如,化合物N-(3,4-二氯-2-氟苯基)-7-({[(3aR,6aS)-2-甲基八氢环戊烯并[c]吡咯-5-基]甲基}氧基)-6-(甲氧基)喹唑啉-4-胺(也称为XL647、EXEL-7647和KD-019)是几种受体酪氨酸激酶(RTK),包括EGFR、EphB4、KDR(VEGFR)、Flt4(VEGFR3)和ErbB2的抑制剂,并且也为SRC激酶的抑制剂,其牵涉导致肿瘤对某些TKI的无反应的途径。在本发明的实施方案中,治疗有此需要的受试者包括施用式I的rho激酶抑制剂和施用KD-019。
达沙替尼(BMS-354825;Bristol-Myers Squibb,New York)为另一种口服生物可用的ATP位点竞争性Src抑制剂。达沙替尼还靶向Bcr-Abl(FDA批准的用于慢性髓细胞性白血病(CML)或费城染色体阳性(Ph+)急性淋巴细胞性白血病(ALL)患者的)以及c-Kit、PDGFR、c-FMS、EphA2和SFK。Src和Bcr-Abl的两个其它口服酪氨酸激酶抑制剂是波舒替尼(SKI-606)和沙拉替尼(AZD0530)。
虽然VEGFR2在血管生成中介导VEGF的大多数下游效应,它可有利施用第二血管生成抑制剂。可将本发明的抗VEGFR-2抗体与中和参与肿瘤生长或血管形成的其它受体的抗体一起施用。
VEGF结合剂的非限制性实例包括VEGF抗体和VEGF陷阱(即,VEGF受体的配体结合结构域)。抗体(包括VEGF结合抗体片段)的两个例子是贝伐单抗(阿瓦斯丁)(一种结合于VEGF-A的抗体)和雷珠单抗(乐明睛)(一种从贝伐单抗衍生的Fab)。通常地,VEGF陷阱为包含一种或多种VEGF受体蛋白的VEGF结合结构域的蛋白。VEGF-陷阱包括,但不限于,可溶性VEGFR-1、可溶性神经菌毛素1(NRP1)、可溶性VEGFR-3(其结合VEGF-C和VEGF-D)和阿柏西普(Zaltrap;Eylea;VEGF陷阱R1R2),由融合于人IgG1的恒定区(Fc)的人血管内皮细胞生长因子受体VEGFR1和VEGFR2的细胞外结构域的区段组成。Conbercept(KH902)为含有融合于人IgG1的Fc部分的VEGFR-1(Flt-1)的胞外域2和VEGFR-2(KDR)的细胞外结构域3、4的融合蛋白。以各种组合含有KDR和FLT-1Ig-样结构域的几个VEGF陷阱公开于美国专利8,216,575中。DARPin(设计的锚蛋白重复蛋白的缩写)是通常展现高特异性和高亲和力靶蛋白结合的基因工程抗体模拟蛋白。MP0112是血管内皮生长因子(VEGF)抑制剂,并且已进入湿性黄斑变性和糖尿病性黄斑水肿的治疗的临床试验。
根据本发明,可靶向VEGF表达。例如,VEGF抑制剂PTC299通过选择性结合VEGF信使RNA(mRNA)的5'-和3'-非翻译区(UTR)来转录后靶向VEGF,从而阻止VEGF的翻译。哌加他尼(Macugen)为针对VEGF-165的RNA适体。
胎盘生长因子(PlGF)牵涉病理性血管生成。PlGF在结构上与VEGF相关并且也是VEGFR-1的配体。因此,包含VEGFR1的细胞外结构域的VEGF陷阱(参见上文)适用于靶向PlGF。抗血管生成剂还包括结合于VEGFR-1/Flt-1受体的那些抗血管生成剂。在某些实施方案中,结合于VEGFR-1的细胞外结构域的抗原结合蛋白阻断其配体VEGF和PlGF的一个或两个的结合,和/或中和VEGFR-1的VEGF诱导的或PlGF诱导的激活。
PDGF由形成同二聚体PDGF-AA、BB、CC和DD的以及异二聚体PDGF-AB的4条多肽链组成。PDGF受体(PDGFR)-α和-β介导PDGF功能。具体地,PDGFRα结合于PDGF-AA、-BB、-AB和-CC,而PDGFRβ与PDGFR-BB和-DD相互作用。PDGF-结合剂的非限定性实例包括抗PDGF抗体和PDGF陷阱。靶向PDGF的药剂包括FovistaTM(E10030,Ophthotech)、靶向PDGF-B和AX102的PEG化适体(Sennino等,2007,Cancer Res.75(15):7359-67)、结合PDGF-B的DNA寡核苷酸适体。
靶向PDGF受体的药剂包括雷莫芦单抗(IMC-3G3,人IgG1)(一种抗PDGFRα抗体)、crenolanib(CP-868596)(PDGFRα(IC50=0.9nM)和PDGFRβ(IC50=1.8nM)的选择性抑制剂)和尼洛替尼(一种PDGFRα和PDGFRβ以及其它酪氨酸激酶的抑制剂)。
血管生成抑制剂包括阻断由例如VEGF、PDGF、VEGF或PDGF受体的配体或补体介导的信号转导的细胞内药剂。抑制血管生成抑制剂抑制的细胞内药剂包括下列药剂,但不限于其。舒尼替尼(Sutent;SU11248)是VEGFR1–VEGFR3、PDGFRα和PDGFRβ、干细胞因子受体(cKIT)、Flt-3和集落刺激因子-1受体(CSF-1R)的泛特异性小分子抑制剂。阿西替尼(AG013736;Inlyta)为抑制VEGFR-1-VEGFR-3、PDGFR和cKIT的另一种小分子酪氨酸激酶抑制剂。西地尼布(AZD2171)为VEGFR-1-VEGFR-3、PDGFRβ和cKIT的抑制剂。索拉非尼(Nexavar)为几种酪氨酸蛋白激酶,包括VEGFR、PDGFR和Raf激酶的另一种小分子抑制剂。帕唑帕尼(Votrient;(GW786034)抑制VEGFR-1、-2和-3、cKIT和PDGFR。Foretinib(GSK1363089;XL880)抑制VEGFR2和MET,卡博替尼(Cometriq;XL184)亦如此。泊那替尼(Iclusig;AP24534)抑制VEGFR、PDGFR和c kit。Tivozanib(AV-951)在皮摩尔浓度上抑制VEGFR-1、VEGFR-2和VEGFR-3。CP-547632为VEGFR-2和碱性成纤维细胞生长因子(FGF)激酶的强效抑制剂。E-3810((6-(7-((1-氨基环丙基)甲氧基)-6-甲氧基喹啉-4-基氧基)-N-甲基-1-萘甲酰胺)在纳摩尔范围内抑制VEGFR-1、-2和-3以及FGFR-1和-2激酶。Brivanib(BMS-582664)为也抑制FGF受体信号转导的VEGFR-2抑制剂。CT-322(Adnectin)为基于人纤连蛋白结构域的小蛋白,其结合于VEGFR2并抑制其激活。凡德他尼(Caprelas;Zactima;ZD6474)为VEGFR2、EGFR和RET酪氨酸激酶的抑制剂。X-82(Xcovery)为通过生长因子受体VEGFR和PDGFR进行信号转导的小分子吲哚酮抑制剂。
在某些实施方案中,将本发明的抗VEGFR抗体抑制剂与基质金属蛋白酶抑制剂共施用。基质金属蛋白酶(MMP)诸如MMP-14、MMP-16和MMP-24切割细胞外基质(ECM)和基底膜的组分,从而允许癌细胞穿透和渗润下方的间质状基质。此外,许多生长因子受体、细胞粘附分子、趋化因子、细胞因子、细胞凋亡配体和血管生成因子是MMP的底物。因此,MMP活性可导致生长因子的激活,肿瘤细胞凋亡的抑制,通过宿主免疫应答形成的趋化因子梯度的破坏,或血管生成因子的释放。MMP可通过促进细胞增生因子诸如结合于特定结合蛋白(IGFBP)的胰岛素样生长因子的释放来促进肿瘤生长(Manes等,1997J.Biol.Chem.272:25706-25712)。
已在黑素瘤中以及在结肠癌、乳腺癌、肺癌、前列腺癌和膀胱癌中发现升高的水平的胶原酶,包括MMP-2。通常地,这些升高的水平与较高的肿瘤分级和侵袭性相关。MMP-2的水平在转移性肺癌患者的血清中显著升高,在具有高水平的那些患者中,对化疗的反应消失。切割前MMP-2以释放活性MMP-2的MMP-14在许多癌症中升高,并且可促成肿瘤的生长、肿瘤栓塞和移动性、癌症的侵袭和转移(例如,CNS肿瘤(例如,神经胶质瘤)、头颈部癌、口腔癌、喉癌、软骨肉瘤、乳腺癌)。MMP-16和MMP-24也在许多癌症中升高并且可促成肿瘤的生长和癌症的侵袭和转移(例如,乳房癌、喉癌、卵巢癌、睾丸癌、黑素瘤、脑肿瘤(例如,星形细胞瘤、胶质母细胞瘤、神经胶质瘤)。
在某些实施方案中,将本发明的抗VEGFR抗体与MMP-14拮抗剂(包括但不限于美国专利7,745,587和8,106,168中公开的抗MMP-14抗体)共施用。在一个实施方案中,所述抗体为人单克隆抗体DX-2400(Dyax Corp)。与这样的抗体的共施用适合用于治疗人癌症,包括但不限于,子宫颈肿瘤、胃肿瘤、肺肿瘤、乳腺肿瘤、结肠肿瘤、头颈肿瘤、恶性脑肿瘤和黑色素瘤。
在另一个实施方案中,可将本发明的VEGFR2抗体与一种或多种适合的佐剂,诸如,例如,细胞因子(例如,IL-10和IL-13)或其它免疫刺激剂组合施用。然而,应当理解,仅抗KDR抗体的施用足以以治疗上有效的方式预防、抑制或减缓肿瘤的进展。
抗炎剂和免疫抑制剂包括类固醇药物,诸如糖皮质激素(例如,地塞米松)、FK506(他克莫司)、环孢素、芬戈莫德、干扰素,诸如IFNβ或IFNγ、肿瘤坏死因子-α(TNF-α)结合蛋白诸如英利昔单抗(Remicade)、依那西普(Enbrel)或阿达木单抗(Humira)和霉酚酸。
些实施方案包括施用本发明的抗体和如下的第二药剂:用于实体瘤(包括乳腺癌和泌尿道癌以及肾癌症)的多西他赛、紫杉醇(实体瘤、胃腺癌)、用于结肠直肠癌的FOLFRI(即伊立替康、亚叶酸酸、5-氟尿嘧啶)、卡培他滨(乳腺癌)、FOLFOX(即,奥沙利铂、甲酰四氢叶酸、5-氟尿嘧啶)(胃癌、食道癌、胃食管癌),艾立布林(乳腺癌)、FOLFIRI(即,依立替康、左亚叶酸盐、5-氟尿嘧啶)(结直肠癌)、卡铂(NSCLC)、米托蒽醌和强的松(前列腺癌)、OFF(奥沙利铂、亚叶酸、5-氟尿嘧啶)(结直肠癌)、伊立替康和西妥昔单抗(结直肠癌)和达卡巴嗪(恶性黑色素瘤)。
可将本发明的抗体和抗原结合片段缀合于药剂,例如细胞毒性药物、细胞毒素酶或放射性同位素。该方法包括向需要这样的治疗的受试者施用单独的或附接于药剂(例如,细胞毒性药物)的结合蛋白。例如,VEGFR2抗体或其片段可用于将含药剂诸如毒素的纳米颗粒递送至VEGFR2结合的细胞或组织,例如肿瘤。
可将VEGFR2结合蛋白在体内直接用于通过补体依赖性细胞毒性(CDC)或抗体依赖性细胞毒性(ADCC)消除表达抗原的细胞。本文中描述的结合蛋白可包括补体结合效应子结构域,诸如来自IgG1、-2或-3的Fc部分或结合补体的IgM的相应部分。
当将本发明的VEGFR-2抗体与第二药剂一起施用时,可相继地或同时地施用所述第一和第二药剂。可以以单份或多份剂量施用每一种药剂,以及可按任何时间安排,包括,但不限于每天2次、每天1次、每周1次、每2周1次或每月1次施用剂量。
本发明还包括佐剂施用。佐剂施用意指除了已被施用以治疗疾病或疾病症状的第一药剂外还向患者施用第二药剂。在一些实施方案中,佐剂施用包括向其中第一药剂的施用不能治疗,或不足以治疗疾病或疾病症状的患者施用第二药剂。在其它实施方案中,佐剂施用包括向其疾病已通过第一药剂的施用有效治疗的患者施用第二药剂。
在本发明的一个实施方案中,通过注射施用抗体或其抗原结合片段,口服施用小分子。在一个这样的实施方案中,每周1次或每月1次或2次施用抗体,每天1次施用小分子。
在本发明的实施方案中,通过注射施用抗体或其抗原结合片段,通过口服施用ROCK2抑制剂。在优选实施方案中,每天一次施用所述药剂。根据本发明,当向受试者施用ROCK抑制剂或VEGFR2抗体以治疗眼疾病时,可向所述受试者施用TGF-β拮抗剂以减少或防止疤痕形成。例如,在本发明的实施方案中,当施用ROCK抑制剂以治疗眼病症时,还施用TGF-β拮抗剂。在另一个实施方案中,当向受试者施用VEGF拮抗剂以治疗眼病症时,还施用TGF-β拮抗剂。在本发明的另一个实施方案中,当向受试者施用ROCK抑制剂和VEGF拮抗剂时以治疗眼病症时,还施用TGF-β拮抗剂。在牵涉新血管形成的眼疾病中,在新血管渗漏后形成疤痕(例如,盘状疤痕)。本发明包括向受试者施用TGF-β拮抗剂以及VEGF拮抗剂和ROCK2抑制剂,以治疗眼疾病的新血管形成。
有用的TGF-β拮抗剂包括,但不限于,下列拮抗剂:(i)抗TGF-β抗体及其抗原结合片段,诸如泛-TGF-β抗体GC-1008(Genzyme)、抗TGF-β1抗体美替木单抗(CAT-192)(Cambridge Antibody Technology)和这些抗体的抗原结合片段,(ii)可溶性TGF-β受体或其配体结合片段,诸如P144,一种包含TGF-βIII型受体的近膜端配体结合结构域的氨基酸730-743的合成肽(Esparza-López等,2001,J.Biol.Chem.276(18):14588-96)和II型TGF-β受体–Fc(IgG1)融合物(Smith,J.等,1999,CirculationRes.84:1212-22),(iii)结合TGF-β受体,阻断TGF-β的一个或多个同种型的肽,诸如来自由Huang等,1997,J.Biol.Chem.272:27155-59公开的TGF-β1、TGF-β2和TGF-β3,结合于TGF-β受体的25个氨基酸的肽,和(iv)抑制TGF-β合成的反义药剂,诸如曲贝德生(Antisense Pharma GmbH)(一种抑制TGF-β2的合成的寡核苷酸)。另外的拮抗剂公开于WO2006/052568、WO 02/094833、WO 04/048382、WO 04/048381、WO 04/050659、WO 04/021989、WO 04/026871和WO 04/026307中。
在某些实施方案中,每天1次、每隔1天1次、每2天1次、或每隔2天1次、每周1次、每周2次、每周3次或每两周1次向受试者施用一个剂量的化合物或组合物。在其它实施方案中,每天1次、每2天1次、每隔2天1次、每周1次或每2周1次向受试者施用2、3或4剂化合物或组合物。在一些实施方案中,施用一个剂量的化合物或组合物,维持2天、3天、5天、7天、14天或21天。在某些实施方案中,施用一个剂量的化合物或组合物,维持1个月、1.5个月、2个月、2.5个月、3个月、4个月、5个月、6个月或更多个月。
施用方法包括但不限于肠胃外、皮内、玻璃体内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外、口服、舌下、鼻内、脑内、阴道内、经皮、经粘膜、直肠、通过吸入或局部给药(特别是对耳鼻、眼或皮肤)施用。施用模式留给医生判断。在大多数情况下,施用将导致化合物至血流中的释放。对于眼疾病的治疗,生物药剂的玻璃体内施用是优选的。
在具体实施方案中,可期望局部施用化合物。这可例如通过或不通过限制,通过局部输注、局部施用,通过注射、借助于导管,或通过植入物来实现,所述植入物是多孔的、无孔的或凝胶状的材料,包括膜,诸如硅橡胶膜或纤维。在这样的情况下,施用可选择性靶向局部组织而基本上不将化合物释放至血液中。
还可例如通过使用吸入器或喷雾器和具有雾化剂的制剂,或通过在碳氟化合物或合成肺表面活性剂中的灌流来应用肺施用。在某些实施方案中,利用常规粘合剂和媒介物诸如甘油三酯将化合物为配制为栓剂。
在另一个实施方案中,在小囊泡,具体地脂质体(参见Langer,1990,Science 249:1527-1533;Treat等,于Liposomes inthe Therapy of Infectious Disease andBacterial infection,Lopez-Berestein和Fidler(编辑),Liss,New York,第353-365页(1989);Lopez Berestein,如上,第317-327页中;一般参见上文)中递送化合物。
在另一个实施方案中,在受控释放系统(参见,例如,Goodson,于MedicalApplications ofControlledRelease,同上,第2卷,第115-138页(1984)中)中递送化合物。可使用由Langer,1990,Science 249:1527-1533在综述中讨论的受控释放系统的实例。在一个实施方案中,可使用泵(参见Langer,同上;Sefton,1987,CRCCrit.Ref.Biomed.Eng.14:201;Buchwald等,1980,Surgery 88:507;Saudek等,1989,N.Engl.J.Med.321:574)。在另一个实施方案中,可使用聚合物材料(参见MedicalApplications of Controlled Release,Langer和Wise(编辑),CRC Pres.,Boca Raton,Florida(1974);Controlled Drug Bioavailability,Drug Product Design andPerformance,Smolen和Ball(编辑),Wiley,New York(1984);Ranger和Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61;也参见Levy等,1985,Science 228:190;During等,1989,Ann.Neurol.25:351;Howard等,1989,J.Neurosurg.71:105)。
上述施用方案被提供来仅用于举例说明目的,并且不应当被认为是限制。本领域普通技术人员将容易地理解所有剂量在本发明的范围内。
应当理解和预期,本文中公开的本发明的原理的变化可由本领域普通技术人员产生,并且这样的修改意欲包括在本发明的范围内。
在整个本申请中,参考各种出版物。这些出版物由此通过引用以其整体并入本申请以更全面描述本申请所属领域的现有技术水平。下列实施例进一步举例说明本发明,但不应当被解释为以任何方式限制本发明的范围。
本发明还涉及以下实施方案:
1.一种结合于人VEGFR2的分离的抗体或其片段,其包含重链可变结构域,所述重链可变结构域包含CDR-1H、CDR-2H和CDR-3H序列,其中:
(i)所述CDR-1H序列为GFTFSWYX1MX2(SEQ ID NO:185),其中X1为V或I,X2为G或L,
(ii)所述CDR-2H序列为SIX1X2SGGX3TX4YADSVKG(SEQ ID NO:186),其中X1为Y或G,X2为P或S,X3为A或F,X4为N或D,以及
(iii)所述CDR-3H序列为GNYFDY(SEQ ID NO:3)或GLAAPR S(SEQ ID NO:11)。
2.根据实施方案1所述的抗体,其中所述抗体包含CDR-1L、CDR-2L和CDR-3L,其中
(i)所述CDR-1L序列为:X1GX2X3LX4X5X6X7X8S(SEQ ID NO:187),其中X1为S、Q或T,X2为D、E或Q,X3为K、S、N、I或A,X4为G或R,X5为D、S、H、E或N,X6为E、Y、Q、R或N,X7为Y、F或S以及X8为A或S;或SGSX1SNX2X3X4X5X6X7X8(SEQ ID NO:188),其中X1为S或T,X2为I或L,X3为E或G,X4为T、S或N,X5为N或Y,X6为T、P、A或Y,X7为V或L以及X8为N、I或Y;或X1GX2SX3DX4GX5YDYVS(SEQ IDNO:189),其中X1为A或T,X2为S或T,X3为H、S或N,X4为I或V以及X5为S或A,
(ii)所述CDR-2L序列为X1X2X3X4X5PS(SEQ ID NO:190),其中X1为Q、D、T、Y、S或A,X2为D、N、S、T、V或V,X3为D、N、S、T或Y,X4为Q、K、N或L以及X5为R或L,以及
(iii)所述CDR-3L序列为:QX1WX2X3X4X5X6X7X8(SEQ ID NO:191),其中X1为A或T,X2为D或G,X3为R或无氨基酸,X4为S、F或N,X5为S、T或N,X6为S、T或P,X7为A、V、L、I或Y以及X8为V或L;或AX1WDDX2LX3X4X5X6(SEQ ID NO:192),其中X1为A、S或T,X2为N或S,X3为N、I或G,X4为G或S,X5为P、W或V以及X6为V或L;或MYSTITX1LL(SEQ ID NO:193),其中X1为A或T。
3.根据实施方案1所述的抗体,其中所述抗体包含CDR-1L、CDR-2L和CDR-3L,其中
(i)所述CDR-1L序列为RASX1X2X3X4X5X6X7YX8X9(SEQ ID NO:194),其中X1为Q、E或H,X2为S、R或N,X3为V、I或L,X4为S、R、G或N,X5为S或N,X6为S、N、W或D,X7为G或无氨基酸,X8为L或F以及X9为A、G、M或S,
(ii)所述CDR-2L序列为GASX1RAT(SEQ ID NO:195),其中X1为S、T、I或N,以及
(iii)所述CDR-3L序列为QQX1X2X3X4X5X6X7X8(SEQ ID NO:196),其中X1为F或Y,X2为D、G或Y,X3为S、T或N,X4为S、L或W,X5为P或无氨基酸,X6为P或T,X7为L、I、V、P、W或Y以及X8为T或S。
4.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:1的CDR-1H、具有SEQ ID NO:2的CDR-2H和具有SEQ ID NO:3的CDR-3H。
5.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:5的CDR-1L、具有SEQ ID NO:6的CDR-2L和具有SEQ ID NO:7的CDR-3L。
6.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:4的重链可变结构域。
7.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:8的轻链可变结构域。
8.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:9的CDR-1H、具有SEQ ID NO:10的CDR-2H和具有SEQ ID NO:11的CDR-3H。
9.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:13的CDR-1L、具有SEQ ID NO:14的CDR-2L和具有SEQ ID NO:15的CDR-3L。
10.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:12的重链可变结构域。
11.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:16的轻链可变结构域。
12.根据实施方案1所述的抗体,其中所述抗体为表2中显示的抗体之一。
13.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:25的CDR-1L、具有SEQ ID NO:26的CDR-2L和具有SEQ ID NO:27的CDR-3L。
14.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:28的轻链可变结构域。
15.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:29的CDR-1L、具有SEQ ID NO:30的CDR-2L和具有SEQ ID NO:31的CDR-3L。
16.根据实施方案1所述的抗体,其中所述抗体包含具有SEQ ID NO:32的轻链可变结构域。
17.根据实施方案1至16中任一项所述的抗体,其中所述抗体阻断VEGF对hVEGFR2的结合。
18.一种中和VEGFR2的激活的方法,其包括将细胞与有效量的根据实施方案1至16中任一项所述的抗体接触。
19.一种抑制血管生成的方法,其包括施用有效量的根据实施方案1至16中任一项所述的抗体。
20.一种减少肿瘤生长的方法,其包括施用有效量的根据实施方案1至16中任一项所述的抗体。
21.根据实施方案20所述的方法,其还包括施用有效量的表皮生长因子受体(EGFR)拮抗剂。
22.根据实施方案20所述的方法,其还包括施用有效量的fms-样酪氨酸激酶受体(flt-1)拮抗剂。
23.根据实施方案20所述的方法,其还包括施用有效量的rho相关激酶2(ROCK2)拮抗剂。
24.根据实施方案20所述的方法,其还包括施用有效量的基质金属蛋白酶拮抗剂。
具体实施方式
实施例
实施例1
结合VEGFR结构域2和3并且阻断配体结合的抗体的鉴定。
从人Fab噬菌体文库分离表1中鉴定的结合人VEGFR2并中和其的两种抗体。所述抗体阻断配体VEGFA对hVEGFR2的结合(图2)。所述抗体还结合表达KDR的猪主动脉内皮(PAE)细胞和抑制VEGFR2、AKT和MAPK的VEGFA刺激的磷酸化(图3)。表1显示所述抗体的CDR和可变结构域的氨基酸序列。Mab 101和Mab 102的Kd分别为约6.6mM和1.7nM。
利用κ轻链基因(κ-文库)和λ轻链基因(λ-文库)改组利用Mab 101的重链。通过针对人VEGFR2和小鼠VEGFR2淘选λ-文库发现20个独特的λ轻链变体。通过针对人VEGFR2和小鼠VEGFR2淘选κ-文库发现22个独特的κ轻链变体。表2显示轻链的CDR和可变结构域的氨基酸序列。Mab 105、106和107的Kd增加约10倍(分别地,0.24nM、0.22nM和0.12nM)(表3)。这些抗体和它们所源自的抗体Mab101结合VEGFR的结构域2和3以及含有这些结构域的构建体。
与亲代抗体一样,这些抗体结合VEGFR2和阻断VEGFA对VEGFR2的结合(图4),以及抑制VEGFR2、AKT和MAPK的VEGFA刺激的磷酸化(图5)。
几种抗体,包括Mab 138、139、140和146也与小鼠VEGFR2交叉反应。
Mab 138、139和140抑制VEGFR2的VEGFA刺激的磷酸化以及下游信号转导分子,包括MAPK。
实施例2
体内肿瘤生长的抑制
以约0.9Gy/分钟的剂量率利用来自137Csγ-射线源的3.5Gy辐射6至8周龄的性别匹配的(雌性)NOD-SCID小鼠,利用2x107个HL60细胞静脉内接种所述小鼠。在肿瘤接种后3天,每周2次用不同剂量的Mab 106处理小鼠的组,记录其存活时间。
所有未处理的小鼠在约2周内死亡。即使对于高肿瘤负荷,利用10mg/kg Mab 106处理的小鼠的存活时间被延长至多至28天。
实施例3
人患者的结肠癌的治疗
将经诊断患有结肠癌的人受试者分成治疗组,并给予标准化学治疗方案。两个患者组每周1次利用5mg/kg/周或15mg/kg/周治疗,持续4个月。对照组仅给予标准化学治疗方案。通过磁共振成像(MRI)定期评估肿瘤负荷。相较于对照组,预期已每周接受抗体治疗的患者显示肿瘤生长或肿瘤尺寸的显著减小,相较于不接受所述抗体治疗的患者增加的进展延迟或延长的存活期。
Claims (14)
1.一种结合于人VEGFR2的分离的抗体或其片段,其包含重链可变结构域和轻链可变结构域,所述重链可变结构域包含CDR-1H、CDR-2H和CDR-3H序列,所述轻链可变结构域包含CDR-1L、CDR-2L和CDR-3L序列,其中:
(i) 所述CDR-1H序列为GFTFSWYIML;
(ii) 所述CDR-2H序列为SIGSSGGFTDYADSVKG;
(iii) 所述CDR-3H序列为GLAAPRS (SEQ ID NO:11);
(iv) 所述CDR-1L序列为SEQ ID NO:13的序列;
(v) 所述CDR-2L序列为SEQ ID NO:14的序列;和
(vi) 所述CDR-3L序列为SEQ ID NO:15的序列。
2.根据权利要求1所述的分离的抗体或其片段,其中所述抗体包含具有SEQ ID NO:12的重链可变结构域。
3.根据权利要求1所述的分离的抗体或其片段,其中所述抗体包含具有SEQ ID NO:16的轻链可变结构域。
4.编码根据权利要1-3中任一项所述的抗体或其片段的分离的多核苷酸。
5.编码结合于人VEGFR2的抗体或其片段的分离的多核苷酸,所述抗体或其片段包含重链可变结构域和轻链可变结构域,所述重链可变结构域包含CDR-1H、CDR-2H和CDR-3H序列,所述轻链可变结构域包含CDR-1L、CDR-2L和CDR-3L序列,其中:
(i) 所述CDR-1H序列为GFTFSWYIML;
(ii) 所述CDR-2H序列为SIGSSGGFTDYADSVKG;
(iii) 所述CDR-3H序列为GLAAPRS (SEQ ID NO:11);
(iv) 所述CDR-1L序列为SEQ ID NO:13的序列;
(v) 所述CDR-2L序列为SEQ ID NO:14的序列;和
(vi) 所述CDR-3L序列为SEQ ID NO:15的序列。
6.根据权利要求5所述的分离的多核苷酸,其中所述抗体包含具有SEQ ID NO:12的重链可变结构域。
7.根据权利要求5所述的分离的多核苷酸,其中所述抗体包含具有SEQ ID NO:16的轻链可变结构域。
8.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸在制备用于中和VEGFR2的激活的方法的药物中的用途,所述方法包括将细胞与有效量的根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸接触。
9.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸在制备用于抑制血管生成的方法的药物中的用途,所述方法包括施用有效量的根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸。
10.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸在制备用于减少肿瘤生长的方法的药物中的用途,所述方法包括施用有效量的根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸。
11.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸与有效量的表皮生长因子受体(EGFR)拮抗剂的组合在制备用于减少肿瘤生长的方法的药物中的用途。
12.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸与有效量的fms-样酪氨酸激酶受体(flt-1)拮抗剂的组合在制备用于减少肿瘤生长的方法的药物中的用途。
13.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸与有效量的rho相关激酶2(ROCK2)拮抗剂的组合在制备用于减少肿瘤生长的方法的药物中的用途。
14.根据权利要求1-3中任一项所述的分离的抗体或其片段或根据权利要求4-7中任一项所述的分离的多核苷酸与有效量的基质金属蛋白酶拮抗剂的组合在制备用于减少肿瘤生长的方法的药物中的用途。
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TW201718641A (zh) * | 2015-06-30 | 2017-06-01 | 偉東 姜 | 抗血管內皮生長因子受體2(vegfr2)抗體 |
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EP3685855C0 (en) | 2023-11-22 |
US10023640B2 (en) | 2018-07-17 |
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EA032679B1 (ru) | 2019-07-31 |
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EP2903647A4 (en) | 2016-08-17 |
EP3685855A1 (en) | 2020-07-29 |
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