CN110198724A - 改变的病毒 - Google Patents
改变的病毒 Download PDFInfo
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- CN110198724A CN110198724A CN201880006355.8A CN201880006355A CN110198724A CN 110198724 A CN110198724 A CN 110198724A CN 201880006355 A CN201880006355 A CN 201880006355A CN 110198724 A CN110198724 A CN 110198724A
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Abstract
本发明涉及编码CTLA‑4抑制剂诸如抗‑CTLA‑4抗体或其抗原结合片段的溶瘤病毒。
Description
发明领域
本发明涉及溶瘤性免疫治疗剂和该溶瘤性免疫治疗剂在治疗癌症中的用途。
发明背景
病毒具有以高效率进入细胞的独特能力。进入细胞后，表达病毒基因并且病毒复制。这通常导致受感染细胞的死亡和细胞的抗原成分的释放，因为当细胞死亡时细胞破裂。因此，病毒介导的细胞死亡倾向于导致针对这些细胞组分(包括源自宿主细胞的那些组分和由病毒本身编码或掺入其中的那些组分)并且由于所谓的损伤相关分子模式(DAMP)(其有助于激活免疫反应)的宿主识别而增强的免疫反应。
病毒还与先天免疫反应的各种介质结合，作为宿主对病毒感染的识别(通过例如Toll样受体和cGAS/STING信号传导)和病原体相关分子模式(PAMP)的识别的反应的一部分，导致干扰素反应和炎症的激活，这也是针对宿主的免疫原性信号。这些免疫反应可以对癌症患者产生免疫原性益处，使得对肿瘤抗原的免疫反应提供全身性的总体益处，从而导致治疗未感染病毒的肿瘤(包括微转移性疾病)，并提供针对复发的疫苗接种。
病毒的组合直接(‘溶瘤’)效应和针对肿瘤抗原(包括非自身“新抗原”，即源自个体肿瘤中的特定突变基因)的免疫反应被称为“溶瘤性免疫疗法”。
病毒也可用作递送媒介物(‘载体’)以在感染的细胞中表达插入病毒基因组中的异源基因。这些特性使病毒可用于各种生物技术和医学应用。例如，表达异源治疗性基因的病毒可用于基因疗法。在溶瘤性免疫疗法的背景下，递送的基因可包括编码特定肿瘤抗原的基因、旨在诱导免疫反应或在病毒复制和细胞死亡后增加释放的抗原的免疫原性的基因、旨在塑造所产生的免疫反应的基因、增加肿瘤的一般免疫激活状态的基因或增加病毒的直接溶瘤特性(即细胞毒性作用)的基因。重要的是，病毒具有递送编码的分子的能力，所述编码的分子旨在帮助直接或选择性地启动、增强或塑造对肿瘤的全身性抗肿瘤免疫反应，这可能具有例如以下益处：与这些相同分子的全身性施用或靶向同一途径的其他分子的全身性施用相比，毒性降低或将有益效应聚焦在肿瘤(包括未被病毒感染的那些)上而不是将脱靶效应聚焦在正常(即非癌性)组织上。
已经证明，包括例如单纯疱疹病毒(HSV)在内的许多病毒可用于癌症的溶瘤治疗。必须将用于癌症的溶瘤治疗的HSV失能，使其不再致病，但仍可进入肿瘤细胞并杀死其。已经鉴定了许多针对HSV的失能突变，包括对编码ICP34.5、ICP6和/或胸苷激酶的基因的破坏，所述致残突变不能阻止病毒在培养物中或在体内肿瘤组织中复制，但其阻止了在正常组织中的显著复制。其中仅有ICP34.5基因被破坏的HSV在体外在许多肿瘤细胞类型中复制，并且在小鼠肿瘤模型中选择性地在肿瘤组织中复制，但不在周围组织中复制。缺失ICP34.5或者缺失ICP34.5和ICP6的HSV的临床试验也显示出在人的肿瘤组织中的安全性和选择性复制。
如上所述，包括HSV在内的溶瘤病毒也可用于在癌症治疗中递送治疗基因。还在临床试验中测试了额外缺失了ICP47并且编码GM-CSF的异源基因的这种类型的缺失ICP34.5的病毒，所述临床试验包括在黑素瘤中进行的3期试验，其中显示了在人中的安全性和有效性。GM-CSF是一种促炎细胞因子，其具有多种功能，包括刺激单核细胞离开循环并迁移到组织中，它们在所述组织中增殖并成熟为巨噬细胞和树突状细胞。GM-CSF对抗原呈递细胞的增殖和成熟很重要，其活性是激活抗肿瘤免疫反应所需的。试验数据表明，在注射肿瘤中可以看到肿瘤反应，在未注射肿瘤中可以看到较小程度的肿瘤反应。反应往往是高度持久的(数月-数年)，并且在响应患者中似乎实现了生存益处。除了直接溶瘤作用以外，这些中的每一个还表明免疫系统参与癌症治疗。然而，溶瘤病毒的这个和其他数据一般表明并非所有肿瘤都对治疗有反应，并且并非所有患者都能获得生存优势。因此，显然需要改进溶瘤治疗领域。
最近已经表明，溶瘤性免疫疗法可以与免疫共抑制途径阻断(即免疫检查点途径的抑制或‘拮抗作用’，也称为免疫共抑制途径)一起导致累加或协同治疗效应。免疫共抑制途径阻断旨在阻断宿主免疫抑制机制，其通常用于防止自身免疫的发生。然而，在癌症患者中，这些机制还可用于抑制针对肿瘤诱导的任何免疫反应的诱导或阻断所述免疫反应的所述潜在有益作用。
靶向细胞毒性T淋巴细胞相关分子-4(CTLA-4)、PD-1或PD-L1的药剂对这些途径的系统性阻断已在许多肿瘤类型包括黑素瘤和肺癌中显示出功效。然而，不出所料，基于作用机制，脱靶毒性可由于自身免疫的诱导而发生。即便如此，这些药剂也足以容许提供相当大的临床效用。针对其的药剂(主要是抗体)处于开发中的其他免疫共抑制途径和相关靶标包括LAG-3、TIM-3、VISTA、CSF1R、IDO、CEACAM1、CD47。由于作用机制，这些药剂(例如PD1、PDL1、LAG-3、TIM-3、VISTA、CSF1R、IDO、CD47、CEACAM1)的最佳临床活性可能需要全身性施用或存在于所有肿瘤中，即包括靶向免疫效应细胞与肿瘤的界面或肿瘤中/肿瘤的其他免疫抑制机制。在某些情况下，在例如仅在一些肿瘤中或在一些淋巴结中更加局部的存在也可以是最佳有效的，例如靶向CTLA-4的药剂。
增加癌症患者的抗肿瘤免疫反应的替代方法是靶向(激活)免疫共刺激途径，即与抑制免疫共抑制途径相反。这些途径将激活信号发送到T细胞和其他免疫细胞中，这通常由抗原呈递细胞(APC)上的相关配体与T细胞和其他免疫细胞表面上的相关受体的相互作用导致。取决于配体/受体，这些信号可导致T细胞和/或APC和/或NK细胞和/或B细胞(包括特定亚型)的活化增加，T细胞的分化和增殖增加和/或APC和/或NK细胞和/或B细胞(包括特定亚型)的分化和增殖增加，或免疫抑制性T细胞诸如调节性T细胞的活性的抑制。因此预期这些途径的激活会导致增强的抗肿瘤免疫反应，但也可预期这些途径的系统性激活(即一般性激活免疫反应而不是特异性或选择性地抗肿瘤免疫反应)将在非肿瘤组织中导致相当大的脱靶毒性，此类脱靶毒性的程度取决于所靶向的特定免疫共刺激途径。然而，靶向免疫共刺激途径(主要是激动性抗体，或者不太常见地是针对所述受体的可溶性配体)(包括靶向GITR、4-1-BB、OX40、CD40或ICOS的药剂)并且打算用于全身性使用(即静脉内递送)的药剂处于临床开发中或已被建议进行临床开发。
为了使靶向免疫共抑制或共抑制途径的这些方法中的许多方法成功，需要预先存在的对肿瘤的免疫反应，即使得预先存在的免疫反应可得以加强或针对抗肿瘤免疫反应的阻断可得以递送。还需要存在发炎的肿瘤微环境(这表明这种持续的反应)。对肿瘤新抗原的预先存在的免疫反应对于免疫共抑制途径阻断和相关药物的活性似乎特别重要。只有一些患者可能对肿瘤抗原(包括新抗原和/或发炎的肿瘤微环境，这两者都是这些药物的最佳活性所必需的)具有持续的免疫反应。因此，可诱导针对肿瘤抗原(包括新抗原)的免疫反应和/或可诱导发炎的肿瘤微环境的溶瘤剂对于与免疫共抑制途径阻断和免疫增强药物组合使用是有吸引力的。这可能解释了迄今为止观察到的溶瘤剂和免疫共抑制途径阻断在小鼠和人中的有希望的联合抗肿瘤作用。
上述讨论表明，对于改善溶瘤剂以及利用溶瘤剂、抗肿瘤免疫反应和靶向免疫共抑制或共刺激途径的药物的癌症疗法仍有很大的余地。
发明概述
本发明提供了表达CTLA-4的抑制剂的溶瘤病毒。所述病毒还可包含其他免疫调节剂。特别地，病毒可包含GM-CSF和/或至少一种靶向免疫共刺激途径的分子。CTLA-4抑制剂用于阻断共抑制途径，即干扰CTLA-4与B7之间的相互作用。GM-CSF有助于诱导炎性肿瘤微环境并刺激抗原呈递细胞(包括树突状细胞)的增殖和成熟，有助于诱导抗肿瘤免疫反应。这些免疫反应可通过使用也由溶瘤病毒递送的一种或多种免疫共刺激途径激活分子激活一种或多种免疫共刺激途径来放大。
溶瘤病毒在肿瘤内复制，引起肿瘤细胞裂解和肿瘤抗原释放，结合局部炎症和先天性免疫反应的激活，所有这些都有益于抗肿瘤免疫反应的激活和CTLA-4/B7相互作用的抑制剂的活性。
将抑制CTLA-4/B7相互作用的分子直接递送至免疫反应引发肿瘤(包括其中预期会流向引流淋巴结)中，将通过抑制剂产生的免疫增强集中在肿瘤上，从而集中在存在于其内的肿瘤抗原上，降低全身毒性并阻断调节性T细胞(Treg)的活化，所述调节性T细胞(Treg)的活化可以其他方式在免疫反应引发部位抑制T细胞活化。使用溶瘤病毒将靶向CTLA-4的分子以及任选地靶向免疫共刺激途径的分子递送至肿瘤将免疫效应的放大集中于抗肿瘤免疫反应，并减少了针对非肿瘤抗原的免疫反应的放大。因此，肿瘤和肿瘤引流淋巴结中的免疫细胞一般受到病毒表达的分子而非免疫细胞的选择性影响。这导致免疫细胞刺激的效力增强，并且还可导致脱靶毒性降低。将组合的系统免疫共抑制途径阻断和免疫共刺激途径激活的效应集中于肿瘤(即，使得从其释放共抑制性阻断的放大的免疫反应是抗肿瘤免疫反应而不是针对非肿瘤抗原的反应)也是重要的。
本发明利用以下事实：当由溶瘤病毒递送时，CTLA-4阻断和任选地共刺激途径激活和GM-CSF表达的作用位点在肿瘤和/或肿瘤引流淋巴结中，但这种激活(放大的全身抗肿瘤免疫反应)的结果是全身性的。这通常靶向肿瘤，而不仅仅是溶瘤病毒已将一种或多种免疫调节分子递送至其的肿瘤。因此，本发明的溶瘤病毒通过产生改善的集中于肿瘤的免疫反应来提供改善的癌症治疗。本发明的溶瘤病毒还提供改善的抗肿瘤免疫刺激作用，使得免疫介导的对未被溶瘤作用破坏的肿瘤(包括微转移性疾病)的作用得以增强，导致对这些肿瘤的更有效破坏和更有效的长期抗肿瘤疫苗接种，以防止未来复发和提高整体存活率。
当本发明的溶瘤病毒用作单一药剂时以及当将病毒与其他抗癌方式组合使用时，抗肿瘤效力得以提高，所述其他抗癌方式包括化学疗法、利用靶向药剂的治疗、辐照以及在优选实施方案中，免疫检查点阻断药物(即免疫共抑制途径的拮抗剂，例如针对PD1或PD-L1的抗体)和/或免疫共刺激途径的激动剂。
因此，本发明提供了编码CTLA-4抑制剂的溶瘤病毒。CTLA-4抑制剂优选为抗-CTLA-4抗体或抗体样分子，或其抗原结合片段。
病毒还可包含：(i)GM-CSF编码基因；和/或(ii)免疫共刺激途径激活分子或免疫共刺激途径激活分子编码基因。该病毒可编码不止一种免疫共刺激途径激活分子/基因。
免疫共刺激途径激活分子优选为GITRL、4-1-BBL、OX40L、ICOSL或CD40L或其任何经修饰的形式。经修饰的形式的实例包括分泌而不是膜结合的共刺激途径的激动剂，和/或经修饰而使得形成蛋白质的多聚体的激动剂。
该病毒可以是经修饰的临床分离株，诸如经修饰的病毒临床分离株，其中所述临床分离株比相同种病毒的一种或多种参照临床分离株更快速地和/或以更低剂量体外杀死两种或更多种肿瘤细胞系。
病毒优选是单纯疱疹病毒(HSV)，诸如HSV1。HSV通常不表达功能性ICP34.5和/或功能性ICP47和/或将US11基因表达为立即早期基因。
本发明还提供：
-包含本发明病毒和药学上可接受的载体或稀释剂的药物组合物；
-用于通过疗法治疗人体或动物体的方法的本发明的病毒；
-用于治疗癌症的方法的本发明的病毒，其中该方法任选地包括施用另外的抗癌剂；
-在无菌小瓶、安瓿或注射器中包含本发明的病毒的制品；
-治疗癌症的方法，其包括向有此需要的患者施用治疗有效量的本发明的病毒或药物组合物，其中所述方法任选地包括施用另外的抗癌剂；
-本发明的病毒在制备用于治疗癌症的方法的药物中的用途，其中所述方法任选地包括施用另外的抗癌剂。
附图简述
图1描绘了用于构建本发明的示例性病毒的病毒的结构，所述示例性病毒包含抗小鼠或抗人CTLA-4构建体，所述构建体是与人或小鼠IgG1 Fc区连接的密码子优化的分泌的scFv分子。scFv含有通过15-mer[G4S]3(GGGGSGGGGSGGGGS)连接的来自9D9(最初用于验证CTLA-4的初始小鼠抗体；WO2007/123737：小鼠形式)或来自伊匹木单抗(WO2014/066532；人形式)的可变轻链和可变重链。病毒是毒株HSV1RH018A(临床株18)的经修饰的形式。ICP34.5和ICP47基因在病毒中是失活的。通过缺失ICP47启动子将US11基因置于ICP47立即早期基因启动子的控制之下。将表达盒插入ICP34.5基因座。在病毒17中，表达盒包含在CMV启动子控制下的人GM-CSF基因和在RSV启动子控制下的GALV基因。除包含人GM-CSF而非小鼠GM-CSF外，病毒16与病毒17相同。除它们各自在表达盒中另外包含在MMLV启动子的控制下的GFP基因外，病毒25和29分别与病毒16和17相同。除GFP基因分别被小鼠抗-CTLA4和人抗-CTLA4替代外，病毒27和31分别与病毒25和29相同。
图2描绘了用于构建本发明的示例性病毒的质粒的结构。
图3显示了抗小鼠或人CTLA-4构建体的结构，所述抗小鼠或人CTLA-4是与人或小鼠IgG1Fc区连接的密码子优化的分泌的scFv分子。所述scFv含有连接的([G4S]3)来自9D9(最初用于验证CTLA-4的初始小鼠抗体；US2011044953：小鼠形式)或来自伊匹木单抗(US20150283234；人形式)的可变轻链和可变重链。还显示了CTLA-4抑制剂的所得结构。
图4是证明抗小鼠CTLA-4由病毒27表达的蛋白质印迹。使用的凝胶是还原的变性PVDF膜tris-甘氨酸凝胶。使用碱性磷酸酶标记的抗小鼠IgG1抗体检测抗-CTLA-4。第1泳道：系列宽范围梯状条带(spectra broad range ladder)；泳道2：病毒27的纯净上清液；泳道3：以1:2稀释的病毒27上清液；泳道4：以1:4稀释的病毒27上清液；泳道5：以1:8稀释的病毒27上清液；泳道6：以1:16稀释的病毒27上清液；泳道7：以1:32稀释的病毒27上清液；泳道8：阴性对照病毒(纯净上清液)。抗-CTLA-4(还原的)的预期大小是57kDa。
图5显示了与不表达CTLA-4的在其它方面相同的病毒(病毒16)相比，表达抗mCTLA-4(病毒27)的病毒在未注射肿瘤中的优异肿瘤控制和收缩。使用的病毒剂量为5x104pfu(每种情况下50ul的1x106pfu/ml)，在一周内给予三次。对于病毒16的未注射肿瘤，该剂量水平的病毒是亚治疗的，这使得可以清楚地看到病毒27编码的另外分子的递送的益处。
图6显示了与不表达CTLA-4的在其他方面相同的病毒(病毒16)相比，表达抗mCTLA-4的病毒(病毒27)的注射和未注射肿瘤中的优异肿瘤控制和收缩。与不表达CTLA-4的病毒(病毒16)相比，一周内进入表达抗mCTLA-4的病毒(病毒27)的右侧肿瘤中的所用病毒的剂量为5x104pfu。每条线代表不同的小鼠。
图7显示了使用抗PD1和表达mGM-CSF、GALVR和抗mCTLA-4的病毒27联合治疗双侧小鼠A20肿瘤的效果。上图显示了单独的抗PD1对注射(右侧)和未注射(左侧)肿瘤的效果。中图显示单独的病毒27对注射(右侧)和未注射(左侧)肿瘤的效果。下图显示了当将抗PD1和病毒27都注射到右侧肿瘤中时实现的优异的肿瘤控制和收缩。在注射(右侧)和未注射(左侧)肿瘤中观察到联合治疗的改善的抗肿瘤效果。每条线代表不同的鼠标。
图8显示了在表达人CTLA-4的敲入小鼠中在小鼠MC38肿瘤中，与仅表达hGM-CSF和GALVR的病毒17相比表达hGM-CSF、GALVR和抗人CTLA-4的病毒31的优异的肿瘤控制和收缩效果。当单独施用病毒或将其与抗PD1组合施用时，观察到病毒31的抗肿瘤效果。与不表达抗人CTLA-4、但在其它方面相同的病毒相比，利用表达抗人CTLA-4的病毒31获得了注射肿瘤的优异肿瘤控制和收缩(左图)。当将利用病毒的治疗与抗PD1治疗组合时，这种效果得以进一步增强。当将利用任一病毒的治疗与抗PD1治疗组合时，在未注射的肿瘤(右图)中也观察到优异的肿瘤控制和收缩。与不表达抗CTLA-4的病毒17相比，对于表达抗CTLA-4的病毒31，这种改善更加明显。每条线代表不同的鼠标。
序列表简述
SEQ ID NO:1是实施例中使用的人CTLA-4抗体的轻链可变区氨基酸序列。
SEQ ID NO:2是完整轻链氨基酸序列，其包含实施例中使用的人CTLA-4抗体的轻链可变区氨基酸序列。
SEQ ID NO:3是实施例中使用的人CTLA-4抗体的重链可变区氨基酸序列。
SEQ ID NO:4是实施例中使用的人CTLA-4抗体的重链CH1氨基酸序列。
SEQ ID NO:5是实施例中使用的人CTLA-4抗体的重链CH2/3氨基酸序列。
SEQ ID NO:6是实施例中使用的人CTLA-4抗体的完整重链氨基酸序列。
SEQ ID NO:7是实施例的CTLA-4抗体中存在的信号肽的氨基酸序列。
SEQ ID NO:8是存在于实施例的CTLA-4抗体中的轻链可变区与重链可变区之间的接头的氨基酸序列。
SEQ ID NO:9是实施例的人scFv CTLA-4抗体的氨基酸序列。
SEQ ID NO:10是实施例的人scFv CTLA-4抗体的核苷酸序列。
SEQ ID NO:11是实施例中使用的鼠CTLA-4抗体的轻链可变区氨基酸序列。
SEQ ID NO:12是实施例中使用的鼠CTLA-4抗体的重链可变区氨基酸序列。
SEQ ID NO:13是实施例中使用的鼠CTLA-4抗体的完整重链氨基酸序列。
SEQ ID NO:14是实施例的鼠scFv CTLA-4抗体的氨基酸序列。
SEQ ID NO:15是实施例的鼠scFv CTLA-4抗体的核苷酸序列。
SEQ ID NO:16是具有位于N和C末端的用于克隆目的的插入限制性位点的实施例的鼠scFv CTLA-4抗体的核苷酸序列，其存在于示例性病毒中。限制性位点是序列的前六个和后八个核苷酸。
SEQ ID NO:17是具有位于N和C末端的用于克隆目的的插入限制性位点的实施例的人scFv CTLA-4抗体的核苷酸序列，其存在于示例性病毒中。限制性位点是序列的前六个和后八个核苷酸。
SEQ ID NO:18是小鼠GM-CSF的核苷酸序列。
SEQ ID NO:19是小鼠GM-CSF的密码子优化形式的核苷酸序列。
SEQ ID NO:20是人GM-CSF的核苷酸序列。
SEQ ID NO:21是人GM-CSF的密码子优化形式的核苷酸序列。
SEQ ID NO:22是小鼠GM-CSF的氨基酸序列。
SEQ ID NO:23是人GM-CSF的氨基酸序列。
SEQ ID NO:24是GALV-R-的核苷酸序列。
SEQ ID NO:25是GALV-R-的密码子优化形式的核苷酸序列。
SEQ ID NO:26是GALV-R-的氨基酸序列。
SEQ ID NO:27是CD40L的人/小鼠杂交膜结合形式的密码子优化形式的核苷酸序列。
SEQ ID NO:28是CD40L的人/小鼠杂交膜结合形式的氨基酸序列。
SEQ ID NO:29是人CD40L的多聚体分泌形式的密码子优化形式的核苷酸序列。
SEQ ID NO:30是人CD40L的多聚体分泌形式的氨基酸序列。
SEQ ID NO:31是小鼠CD40L的多聚体分泌形式的密码子优化形式的核苷酸序列。
SEQ ID NO:32是小鼠CD40L的多聚体分泌形式的氨基酸序列。
SEQ ID NO:33是野生型人CD40L的核苷酸序列。
SEQ ID NO:34是野生型人CD40L的氨基酸序列。
SEQ ID NO:35是野生型小鼠CD40L的核苷酸序列。
SEQ ID NO:36是野生型小鼠CD40L的氨基酸序列。
SEQ ID NO:37是CMV启动子的核苷酸序列。
SEQ ID NO:38是RSV启动子的核苷酸序列。
SEQ ID NO:39是BGH polyA的核苷酸序列。
SEQ ID NO:40是SV40晚期polyA的核苷酸序列。
SEQ ID NO:41是兔β-球蛋白polyA的核苷酸序列。
SEQ ID NO:42是GFP的核苷酸序列。
SEQ ID NO:43是来自MMLV的逆转录病毒LTR的核苷酸序列。
SEQ ID NO:44是EF1a启动子的核苷酸序列。
SEQ ID NO:45是SV40启动子的核苷酸序列。
SEQ ID NO:46是HGH polyA的核苷酸序列。
发明详述
溶瘤病毒
本发明的病毒是溶瘤性的。溶瘤病毒是感染肿瘤细胞并在肿瘤细胞中复制，从而杀死肿瘤细胞的病毒。因此，本发明的病毒具有复制能力。优选地，病毒具有在肿瘤中选择性复制的能力。如果病毒在肿瘤组织中比在非肿瘤组织中更有效地复制，则病毒具有在肿瘤组织中选择性复制的能力。可以使用本领域的标准技术确定病毒在不同组织类型中复制的能力。
本发明的病毒可以是具有这些特性的任何病毒，包括疱疹病毒、痘病毒、腺病毒、逆转录病毒、弹状病毒、副粘病毒或呼肠孤病毒，或这些较大组中的任何种或株。本发明的病毒可以是野生型(即与亲本病毒物种相比未改变的)，或具有基因破坏或基因添加。至于属于这些中的哪种情况，将取决于要使用的病毒种类。优选地，病毒是疱疹病毒的种类，更优选是HSV的毒株，包括HSV1和HSV2的毒株，并且最优选是HSV1的毒株。在特别优选的实施方案中，本发明的病毒基于待使用的病毒种类的临床分离株。可基于其具有用于治疗癌症的特别有利特性来选择临床分离株。
该病毒可以是经修饰的临床分离株，其中临床分离株相较于相同病毒种类的一种或多种参照临床分离株更快速地和/或以更低的剂量体外杀死两种或更多种肿瘤细胞系。通常，临床分离株将在感染复数(MOI)小于或等于0.1的感染的48小时内，优选24小时内杀死两种或更多种肿瘤细胞系。优选地，临床分离株将杀死广泛的肿瘤细胞系，诸如以下人肿瘤细胞系中的2种、3种、4种、5种、6种、7种、8种、9种、10种肿瘤细胞系或例如所有细胞系：U87MG(神经胶质瘤)、HT29(结直肠癌)、LNCaP(前列腺癌)、MDA-MB-231(乳腺癌)、SK-MEL-28(黑素瘤)、Fadu(鳞状细胞癌)、MCF7(乳腺癌)、A549(肺癌)、MIAPACA-2(胰腺癌)、CAPAN-1(胰腺癌)、HT1080(纤维肉瘤)。
在一个优选实施方案中，本发明的病毒是选自以下的病毒株：
RH018A株，登录号为ECCAC 16121904；
RH004A株，登录号为ECCAC 16121902；
RH031A株，登录号为ECCAC 16121907；
RH040B株，登录号为ECCAC 16121908；
RH015A株，登录号为ECCAC 16121903；
RH021A株，登录号为ECCAC 16121905；
RH023A株，登录号为ECCAC 16121906；和
RH047A株，登录号为ECCAC 16121909。
更优选地，本发明的病毒是选自以下的病毒株：
RH018A株，登录号ECCAC 16121904；
RH004A株，登录号为ECCAC 16121902；
RH031A株，登录号为ECCAC 16121907；
RH040B株，登录号为ECCAC 16121908；和
RH015A株，登录号为ECCAC 16121903。
最优选地，本发明的病毒是登录号为EACC 16121904的RH018A株。可以如本文所定义修饰任何一种保藏的病毒株。
本发明的HSV能够在肿瘤(诸如人肿瘤)中选择性地复制。通常，HSV在靶肿瘤中高效复制，但在非肿瘤组织中不能高效复制。该HSV可在一种或多种病毒基因中包含一种或多种突变，所述突变抑制正常组织中的复制但仍允许在肿瘤中复制。例如，突变可以是阻止HSV表达功能性ICP34.5、ICP6和/或胸苷激酶的突变。
在一个优选实施方案中，突变ICP34.5编码基因以赋予HSV以选择性的溶瘤活性。在Chou等(1990)Science 250:1262-1266,Maclean等(1991)J.Gen.Virol.72:631-639和Liu等(2003)Gene Therapy 10:292-303(其通过引用并入本文)中描述了阻止功能性ICP34.5表达的ICP34.5编码基因的突变。还可使ICP6编码基因和/或胸苷激酶编码基因失活，同样可使其他基因失活，只要这种失活不会阻止病毒感染肿瘤或在其中复制即可。
HSV可含有增强HSV在肿瘤中的复制的另外的突变。由此导致的病毒在肿瘤中的复制增强不仅导致病毒对肿瘤细胞的直接“溶瘤性”杀伤增强，而且还提高了异源(即插入病毒的基因，在本发明的病毒的情况下，编码CTLA-4抑制剂、GM-CSF和/或免疫共刺激途径激活分子的基因)基因表达的水平并且增加肿瘤细胞死亡时释放的肿瘤抗原的量，这两者均也可改善用癌症治疗的疗法的免疫原性性质。例如，在本发明的一个优选实施方案中，以使US11基因置于通常控制ICP47编码基因表达的立即早期启动子控制下的方式缺失ICP47编码基因导致在肿瘤中的复制增强(参见Liu等，2003，其通过引用并入本文)。
还可向本发明的病毒中引入将US11编码序列(其为HSV晚期基因)置于不依赖于病毒复制的启动子控制下的其他突变。此类突变允许在HSV复制发生之前表达US11并增强肿瘤中的病毒复制。特别地，此类突变增强了缺乏功能性ICP34.5编码基因的HSV的复制。
因此，在一个实施方案中，本发明的HSV包含与启动子可操作地连接的US11基因，其中启动子的活性不依赖于病毒复制。启动子可以是在哺乳动物(优选人)肿瘤细胞中具有活性的立即早期(IE)启动子或非HSV启动子。启动子可以是例如真核启动子，诸如源自哺乳动物(优选人)的基因组的启动子。启动子可以是普遍存在的启动子(诸如β-肌动蛋白或微管蛋白的启动子)或细胞特异性启动子，者如肿瘤特异性启动子。启动子可以是病毒启动子，诸如莫洛尼鼠白血病病毒长末端重复序列(MMLV LTR)启动子或人或小鼠巨细胞病毒(CMV)IE启动子。HSV立即早期(IE)启动子是本领域公知的。HSV IE启动子可以是驱动ICP0、ICP4、ICP22、ICP27或ICP47表达的启动子。
可通过任何合适的方法，例如通过缺失或取代基因的全部或部分和/或基因的控制序列，或通过将一个或多个核酸插入或替代基因和/或基因的控制序列而使上述基因(其功能失活为病毒提供了肿瘤选择性的性质)功能失活。例如，本领域标准的同源重组方法可用于产生本发明的病毒。或者，可使用基于细菌人工染色体(BAC)的方法。
如本文所用，术语“基因”旨在表示编码蛋白质的核苷酸序列，即基因的编码序列。通过突变基因本身或基因侧翼的控制序列，例如启动子序列，可使上述各种基因失去功能。缺失可以去除基因的一个或多个部分、整个基因或整个基因以及全部或一些控制序列。例如，可以仅缺失基因内的一个核苷酸，导致移码。然而，可以进行更大的缺失，例如总编码序列和/或非编码序列的至少约25％，更优选至少约50％。在一个优选实施方案中，缺失待进行功能失活的基因。例如，可以从病毒中除去整个基因和任选地一些侧翼序列。当病毒基因组中存在两个或更多个基因拷贝时，使基因的两个拷贝都丧失功能活性。
可通过取代其他序列，例如通过用异源基因和任选地启动子序列取代全部或部分内源基因来使基因失活。在没有启动子序列被取代的情况下，可以插入异源基因，使得其被待进行功能失活的基因的启动子控制。在本发明的HSV中，优选通过将一种或多种异源基因和与其可操作地连接的一个或多个启动子序列或任选地其他调节元件(诸如多腺苷酸化序列)插入每个ICP34.5编码基因的基因座来使ICP34.5编码基因失去功能。
本发明的病毒用于在肿瘤中表达CTLA-4抑制剂和任选地GM-CSF和/或免疫共刺激途径激活分子。这通常通过在有选择性复制能力的病毒的基因组中插入编码CTLA-4抑制剂的异源基因和任选地编码GM-CSF的异源基因和/或编码免疫共刺激途径激活分子的异源基因来实现，其中每个基因都在启动子序列的控制下。由于这种病毒的复制将在肿瘤组织中选择性发生，因此病毒对CTLA-4抑制剂的表达以及如果存在的话GM-CSF和/或免疫共刺激激活蛋白的表达在肿瘤组织中与在体内的非肿瘤组织中相比得以增强。在与身体的其他组织相比在肿瘤中表达更高的情况下，发生增强的表达。由溶瘤病毒表达的蛋白质也预期存在于溶瘤病毒感染的肿瘤引流淋巴结中，包括由于表达的蛋白质和病毒从肿瘤至抗原呈递细胞中或其上的运输而导致的。因此，本发明提供了CTLA-4抑制剂和任何共表达的GM-CSF和/或免疫共刺激途径激活分子在肿瘤和肿瘤引流淋巴结中的选择性表达与由溶瘤病毒复制提供的抗肿瘤作用组合的益处。
本发明的病毒包含CTLA-4抑制剂。CTLA-4抑制剂是通常为与CTLA-4结合并减少或阻断通过CTLA-4的信号传导的肽或蛋白质的分子。通过减少CTLA-4信号传导，该抑制剂减少或除去CTLA-4对免疫刺激途径的阻断。
CTLA-4抑制剂优选为抗体或其抗原结合片段。
本文提及的术语“抗体”包括完整抗体和其任何抗原结合片段(即“抗原结合部分”)或单链。抗体是指包含通过二硫键相互连接的至少两条重(H)链和两条轻(κ)(L)链的糖蛋白，或其抗原结合部分。每条重链由重链可变区(本文中缩写为VH)和重链恒定区组成。每条轻链由轻链可变区(本文中缩写为VL)和轻链恒定区组成。重链和轻链的可变区含有与抗原相互作用的结合结构域。VH和VL区可以进一步细分为高变区，称为互补决定区(CDR)，散布有更保守的区域，称为框架区(FR)。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子(包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分(Clq))的结合。
抗体通常是单克隆抗体。抗体可以是嵌合抗体。抗体优选为人源化抗体，更优选为人抗体。
术语抗体的“抗原结合片段”是指保留与CTLA-4特异性结合的能力的抗体的一个或多个片段。抗原结合片段还保留抑制CTLA-4，从而减少或消除刺激性免疫反应的CTLA-4阻断的能力。合适片段的实例包括Fab片段、F(ab')2片段、Fab'片段、Fd片段、Fv片段、dAb片段和分离的互补决定区(CDR)。单链抗体诸如scFv和重链抗体诸如VHH和骆驼抗体也旨在包涵在术语抗体的“抗原结合部分”内。在一个优选实施方案中，抗体是scFv。合适的scFv分子的实例公开于例如WO2007/123737和WO2014/066532(其通过引用并入本文)中。
抗体编码序列通常编码具有N末端信号序列的抗体或抗体片段。信号序列可以具有SEQ ID NO:7中所示的氨基酸序列。例如，该信号序列包含在具有SEQ ID NO:9中所示的并由SEQ ID NO:10中所示的核苷酸序列编码的氨基酸序列的scFv中，以及具有SEQ ID NO:14中所示的并由SEQ ID NO:15中所示的核苷酸序列编码的氨基酸序列的scFv中。
在抗体或抗体片段中，轻链和重链序列可以通过氨基酸接头连接。接头通常包含约15至约25个氨基酸，诸如约18或20个氨基酸。可以使用任何合适的接头，诸如包含甘氨酸和丝氨酸残基(例如SEQ ID NO:8中所示的氨基酸序列)的接头。例如，该接头包含在具有SEQ ID NO:9中所示的并由SEQ ID NO:10中所示的核苷酸序列编码的氨基酸序列的scFv中，和具有SEQ ID NO:14中所示的并由SEQ ID NO:15中所示的核苷酸序列编码的氨基酸序列的scFv中。两者均为用于本发明的优选抗体片段。
具有相似结构的其他抗体片段也是优选的。因此，本发明的病毒可以编码包含轻链可变区、接头、重链可变区、重链CH1结构域、重链CH2结构域和重链CH3结构域或基本上由其组成的抗体或片段。病毒还可编码抗体N末端处的信号序列。
本发明的抗体或抗体片段可以优选包含Fc区，其为IgG1、IgG2、IgG3或IgG4区，更优选IgG1区。优选地，抗体是其中scFv与IgG重链CH2和CH3结构域连接的scFv抗体。
优选的CTLA-4抗体或片段包含SEQ ID NO:3中所示的重链可变区和/或SEQ IDNO:1中所示的轻链可变区或SEQ ID NO:11中所示的重链可变区和/或SEQ ID NO:12中所示的轻链可变区。抗体可包含具有SEQ ID NO:4中所示的氨基酸序列的重链CH1结构域和/或SEQ ID NO:5中所示的CH2/CH3结构域。抗体可包含SEQ ID NO:2中所示的轻链氨基酸序列。本发明的抗体可以可选地包含这些重链或轻链可变区或CDR序列之一的变体。例如，变体可以是任何上述氨基酸序列的取代、缺失或添加变体。
变体抗体可包含来自上文论述的特定序列和片段的1个、2个、3个、4个、5个、至多10个、至多20个、至多30个或更多个氨基酸取代和/或缺失，同时保持本文所述抗体的活性。“缺失”变体可包含例如1个、2个、3个、4个或5个单个氨基酸或者一个或多个小组的氨基酸(诸如2个、3个、4个或5个氨基酸)的缺失。“取代”变体优选包括用相同数量的氨基酸替代一个或多个氨基酸并产生保守氨基酸取代。例如，氨基酸可被具有相似性质的替代氨基酸(例如，另一种碱性氨基酸、另一种酸性氨基酸、另一种中性氨基酸、另一种带电荷的氨基酸、另一种亲水性氨基酸、另一种疏水性氨基酸、另一种极性氨基酸、另一种芳香族氨基酸或另一种脂肪族氨基酸)取代。
本发明的病毒包含编码CTLA-4抑制剂的一种或多种多核苷酸序列。多核苷酸序列在合适的启动子的控制下。病毒可包含编码抗体重链可变区的第一多核苷酸序列和编码抗体轻链可变区的第二多核苷酸。第一多核苷酸可编码全长重链和/或第二多核苷酸可编码全长轻链。第一和第二多核苷酸可在单个启动子的控制下，任选地具有IRES，或者可在两个分开的启动子的控制下。分开的启动子可以相同或不同。
第一多核苷酸可包含SEQ ID NO:9中所示的重链可变区编码序列、基本上由其组成或由其组成，和/或第二多核苷酸可包含SEQ ID NO:10中所示的重链可变区编码序列、基本上由其组成或由其组成。第一多核苷酸可包含SEQ ID NO:19中所示的重链可变区编码序列、基本上由其组成或由其组成，和/或第二多核苷酸可包含SEQ ID NO:20中所示的重链可变区编码序列、基本上由其组成或由其组成。
第一和/或第二多核苷酸序列可以是SEQ ID NO:9、10、19或20的变体。例如，变体可以是这些核酸序列中的任一个的取代、缺失或添加变体。变体多核苷酸可包含来自SEQID NO:9、10、19或20的1个、2个、3个、4个、5个、至多10个、至多20个、至多30个、至多40个、至多50个、至多75个或更多个核酸取代和/或缺失。
合适的变体可以与本文公开的核酸序列中的任一种的多核苷酸具有至少70％的同源性，优选与其具有至少80％或90％，更优选至少95％、97％或99％的同源性。优选地，至少对于多核苷酸的编码区，存在这些水平的同源性和同一性。测量同源性的方法是本领域熟知的，并且本领域技术人员将理解，在本说明书中，基于核酸同一性计算同源性。这种同源性可以存在于至少15个，优选至少30个，例如至少40个、60个、100个、200个或更多个连续核苷酸的区域上。这种同源性可存在于未修饰的多核苷酸序列的整个长度上。
测量多核苷酸同源性或同一性的方法是本领域已知的。例如，UWGCG包提供BESTFIT程序，其可用于计算同源性(例如，在其默认设置下使用)(Devereux等(1984)Nucleic Acids Research 12，第387-395页)。
PILEUP和BLAST算法也可用于计算同源性或排列序列(通常在其默认设置下)，例如如Altschul S.F.(1993)J Mol Evol 36:290-300；Altschul,S,F等(1990)J Mol Biol215:403-10中所述的。
用于进行BLAST分析的软件可通过国家生物技术信息中心(http://www.ncbi.nlm.nih.gov/)公开获得。该算法涉及首先通过鉴定查询序列中长度为W的短字(short words)来鉴定高评分序列对(HSP)，所述短字在与数据库序列中的相同长度的字对齐时匹配或满足某一正值阈值分数T。T被称为邻域字得分阈值(neighbourhood wordscore threshold)(Altschul等，同上)。这些初始邻域字命中用作种子用于启动搜索以找到包含它们的HSP。只要可以增加累积比对分数，就将所述字命中沿着每个序列在两个方向上延伸。当在以下情况下时，停止每个方向上的字命中的延伸：由于一个或多个负评分残基比对的累积，累积比对评分变为零或更低；或达到任一序列的末端。BLAST算法参数W、T和X确定比对的灵敏度和速度。BLAST程序将字长(W)为11、BLOSUM62评分矩阵(参见Henikoff和Henikoff(1992)Proc.Natl.Acad.Sci.USA 89:10915-10919)、比对(B)为50、期望值(E)为10、M＝5、N＝4以及两条链的比较用作默认值。
BLAST算法对两个序列之间的相似性进行统计分析；参见，例如，Karlin和Altschul(1993)Proc.Natl.Acad.Sci.USA90:5873-5787。BLAST算法提供的一种相似性度量是最小总和概率(P(N))，其提供了两个核苷酸或氨基酸序列之间偶然发生匹配的概率的指示。例如，如果第一序列与第二序列的比较中最小总和概率小于约1，优选地小于约0.1，更优选地小于约0.01，最优选地小于约0.001，则认为序列与另一序列相似。
在一个实施方案中，由于遗传密码的冗余性，变体序列可以与序列表中给出的特定序列不同。DNA代码具有4个主要核酸残基(A、T、C和G)，并使用这些残基“拼写”三字母密码子，其代表生物体基因中编码的蛋白质中的氨基酸。沿着DNA分子的密码子的线性序列被翻译成由这些基因编码的蛋白质中的氨基酸的线性序列。该密码是高度简并的，其中61个密码子编码20个天然氨基酸，3个密码子代表“终止”信号。因此，大多数氨基酸由不止一个密码子编码-实际上几种氨基酸由四个或更多个不同密码子编码。因此，本发明的变体多核苷酸可编码与本发明的另一种多核苷酸编码的多肽序列相同的多肽序列，但由于使用不同的密码子编码相同的氨基酸，因此可具有不同的核酸序列。可以优化密码子以与使用未改变的序列相比，提高编码的蛋白质在靶细胞中的表达水平。
本发明的病毒优选包含GM-CSF。可对编码GM-CSF的基因的序列进行密码子优化，以便与使用未改变的序列的情况相比，提高相应蛋白质在靶细胞中的表达水平。
本发明的病毒优选包含一种或多种免疫共刺激途径激活分子和/或一种或多种编码免疫共刺激途径激活分子的基因。免疫共刺激途径激活分子包括蛋白质和核酸分子(例如适体序列)。免疫共刺激途径激活分子的实例包括CD40配体、GITR配体、4-1-BB配体、OX40配体、ICOS配体、flt3配体、TL1A、CD30配体、CD70和靶向这些分子(CD40、GITR、4-1-BB、OX40、ICOS、flt3、DR3、CD30、CD27)的各自受体的单链抗体。
免疫共刺激途径的激活剂包括突变体或野生型、可溶性、分泌性和/或膜结合型的配体，以及包括单链抗体在内的激动性抗体。本发明的病毒优选编码CD40L、ICOSL、4-1-BBL、GITRL或OX40L中的一种或多种。
本发明的病毒可编码一种或多种免疫共刺激途径激活分子，优选1种、2种、3种或4种免疫共刺激途径激活分子，更优选1种或2种免疫共刺激途径激活分子。
可对编码免疫共刺激活化分子的基因的序列进行密码子优化，以便与在使用未改变的序列时相比，升高相应蛋白质在靶细胞中的表达水平。
除了CTLA-4抑制剂和GM-CSF和/或免疫共刺激途径激活分子以外，本发明的病毒还可包含一种或多种另外的异源基因。在一个优选实施方案中，病毒还可包含促融合蛋白，诸如GALVR-。
促融合蛋白可以是能够促进被本发明的病毒感染的细胞与另一细胞融合的任何异源蛋白质。促融合蛋白，优选野生型或经修饰的病毒糖蛋白(即经修饰以增加其促融合特性)是能够诱导其中表达其的细胞的细胞间融合(合胞体形成)的蛋白质。促融合糖蛋白的实例包括VSV-G、合胞素-1(来自人内源性逆转录病毒-W(HERV-W))或合胞素-2(来自HERVFRDE1)、副粘病毒SV5-F、麻疹病毒-H、麻疹病毒-F、RSV-F、来自逆转录病毒或慢病毒的糖蛋白，诸如长臂猿白血病病毒(GALV)、鼠白血病病毒(MLV)、Mason-Pfizer猴病毒(MPMV)和马传染性贫血病毒(EIAV)的糖蛋白(其中R跨膜肽被去除(R-形式))。在一个优选实施方案中，促融合蛋白来自GALV并且已去除了R-肽(GALV-R-)。
本发明的病毒可任选地包含促融合蛋白编码基因的多个拷贝，优选1或2个拷贝。病毒可包含两种或更多种不同的促融合蛋白，包括上文列出的任何促融合蛋白。
任选由本发明的病毒表达的促融合蛋白可以与天然存在的蛋白质相同，或者可以是经修饰的蛋白质。
促融合蛋白编码基因(促融合基因)可以具有天然存在的核酸序列或经修饰的序列。例如，可以修饰促融合基因的序列以增加编码的蛋白质的促融合特性，或提供密码子优化，从而提高编码的蛋白质的表达效率。
本发明还提供了表达至少三种异源基因的病毒，诸如痘病毒或HSV，优选HSV1，其中三种异源基因中的每一种均由不同的启动子驱动，所述启动子选自：CMV启动子、RSV启动子、EF1a启动子、SV40启动子和逆转录病毒LTR启动子。例如，病毒可以表达四种异源基因，其中四种异源基因中的每一种都由不同的启动子驱动，所述启动子选自CMV启动子、RSV启动子、EF1a启动子、SV40启动子和逆转录病毒LTR启动子。逆转录病毒LTR优选来自MMLV。异源基因可通过多腺苷酸化序列终止。多腺苷酸化序列可以相同或不同。优选地，每个异源基因由不同的多腺苷酸化序列终止，所述多腺苷酸化序列优选选自BGH、SV40、HGH和RBG多腺苷酸化序列。本发明还提供病毒，诸如痘病毒或HSV，优选HSV1，其表达至少三种异源基因，其中三种异源基因中的每一种都被不同的多腺苷酸化序列终止，所述多腺苷酸化序列选自BGH、SV40、HGH和RBG多腺苷酸化序列。例如，病毒可以分别表达由BGH、SV40、HGH和RBG多腺苷酸化序列中的每一种终止的四个异源基因。
所述至少三种异源基因可以例如选自CTLA-4抑制剂、编码GM-CSF的基因、编码免疫共刺激途径激活分子的基因和促融合基因。三种异源基因的实例是CTLA-4抑制剂、编码GM-CSF的基因和编码免疫共刺激途径激活分子的基因；CTLA-4抑制剂、编码GM-CSF的基因和促融合基因；以及CTLA-4抑制剂、编码免疫共刺激途径激活分子的基因和促融合基因。例如，所述四种异源基因可以是CTLA-4抑制剂、编码GM-CSF的基因、编码免疫共刺激途径激活分子的基因和融合基因。所述三个或四个异源基因可包括，例如，编码免疫共刺激途径激活分子的两种或更多种基因和/或两种或更多种促融合基因。
在一个实施方案中，控制所述三种异源基因表达的启动子是CMV、RSV和MMLV启动子。例如，一种优选病毒可包含在CMV启动子控制下的GM-CSF基因、在RSV启动子控制下的GALV基因和在MMLV启动子控制下的CTLA-4抑制剂。
在一个实施方案中，终止所述至少三种异源基因的多腺苷酸化序列是SV40、BGH和RBG多腺苷酸化序列。控制所述三种异源基因的表达的是CMV、RSV和MMLV启动子。例如，一种优选病毒可包括由BGH多腺苷酸化序列终止的GM-CSF基因、由SV40多腺苷酸化序列终止的GALV基因和由RGB多腺苷酸化序列终止的CTLA-4抑制剂。
可将各种启动子和聚腺苷酸化序列的任意组合与任何异源基因一起使用。例如，一种优选的病毒可以包含在CMV启动子控制下并且由BGH多腺苷酸化序列终止的GM-CSF基因、在RSV启动子控制下并且由SV40多腺苷酸化序列终止的GALV基因，以及在MMLV启动子控制下并且由RGB多腺苷酸化序列终止的CTLA-4抑制剂。
病毒的产生
使用本领域公开的方法构建本发明的病毒。例如，可通过标准分子生物学技术构建编码待包装的病毒基因组(包括在适当的调节控制下的编码促融合分子和免疫刺激分子的基因)的质粒(用于较小的病毒以及单个和多个基因组组分RNA病毒)或BAC(用于较大的DNA病毒，包括疱疹病毒)，并将其转染至可从其回收重组病毒的允许细胞中。
或者，在一个优选实施方案中，可构建含有位于预期插入位点侧翼的DNA区域的质粒，然后将其与病毒基因组DNA共转染至允许细胞中，使得质粒中靶插入位点侧翼区域与亲本病毒中的相同区域之间发生同源重组。然后可通过功能(通过用于修饰的质粒插入或缺失的，例如标记基因诸如来自亲本病毒的GFP或lacZ在预期插入位点的插入或缺失)的丢失或添加来选择和纯化重组病毒。在一个最优选实施方案中，插入位点是HSV的ICP34.5基因座，因此用于操作的质粒含有位于该插入位点侧翼的HSV序列，其间是编码GM-CSF和免疫共刺激途径激活分子的表达盒。在这种情况下，亲本病毒可含有编码替代ICP34.5的GFP的盒，并且通过GFP表达的丧失来选择重组病毒噬菌斑。在一个最优选实施方案中，HSV的US11基因也表达为IE基因。这可通过缺失ICP47编码区或通过其他方式来实现。
将CTLA-4抑制剂和任选地GM-CSF编码序列以及免疫共刺激途径激活分子编码序列和/或另外的蛋白质编码序列(诸如编码促融合蛋白诸如GALVR-的序列)在适当的调节控制下插入病毒基因组中。根据物种和插入位点，这可在所用的本发明病毒种类的天然启动子的调节控制之下，或者优选在异源启动子的控制下。合适的异源启动子包括哺乳动物启动子，诸如IEF2a启动子或肌动蛋白启动子。更优选的是强病毒启动子诸如CMV IE启动子、RSV LTR、MMLV LTR、其他逆转录病毒LTR启动子或源自SV40的启动子。优选地，每个外源基因(例如编码GM-CSF和免疫共刺激途径激活分子)将在分开的启动子控制下，但也可以从单个RNA转录物表达，例如通过在蛋白质编码序列之间插入内部核糖体进入位点(IRES)。源自每个启动子的RNA通常使用多腺苷酸化序列(例如哺乳动物序列，诸如牛或人生长激素(BGH)poly A序列、合成的多腺苷酸化序列、兔β珠蛋白多腺苷酸化序列，或病毒序列诸如SV40早期或晚期多腺苷酸化序列)来终止。
病毒中的每种异源基因通常都在启动子的控制下。控制异源基因表达的启动子可以相同或不同。例如，抗-CTLA-4以及GM-CSF、促融合基因和免疫共刺激途径激活分子编码基因中的一种或多种可以各自在CMV启动子、RSV启动子、EF1a启动子、SV40启动子或逆转录病毒LTR启动子的控制下。或者，例如，抗-CTLA-4可以在逆转录病毒LTR启动子诸如MMLV启动子的控制下，GM-CSF基因可以在CMV启动子的控制下和/或促融合基因诸如GALVR-可在RSV启动子的控制下。
药物组合物
本发明提供了包含病毒和药学上可接受的载体或稀释剂的药物组合物。合适的载体和稀释剂包括等渗盐水溶液，例如磷酸盐缓冲盐水。该组合物还可包含其他成分，诸如糖或蛋白质，以改善性质，诸如产品的稳定性。或者，可使用冻干制剂，在使用前将其在药学上可接受的载体或稀释剂中复原。
如果需要，载体的选择通常是组合物递送途径的函数。在本发明中，组合物可被配制成用于任何合适的施用途径和方式。药学上可接受的载体或稀释剂是可用于适于肿瘤内施用、静脉内/动脉内施用、大脑内施用或至体腔(例如膀胱、胸膜腔或通过腹膜内施用)内施用的组合物中的那些载体或稀释剂。组合物可以任何合适的形式，优选以液体形式施用。
本发明还提供了在无菌小瓶、安瓿或注射器中包含本发明病毒的制品。
医疗用途/治疗方法
本发明提供了本发明的病毒，其用于通过疗法治疗人体或动物体，特别是用于治疗癌症的方法。癌症通常存在于哺乳动物中，优选存在于人中。病毒通过裂解和通过使受感染的肿瘤细胞彼此融合来杀死受感染的肿瘤细胞。本发明的病毒还引发全身性抗肿瘤免疫反应，通过CTLA-4抑制剂和任选地GM-CSF以及免疫共刺激途径激活分子的表达而增强，所述免疫共刺激途径激活分子也杀死癌细胞。
本发明还提供了治疗癌症的方法，该方法包括向有此需要的个体施用治疗有效量的本发明的病毒。
本发明另外提供了本发明的病毒在制备用于治疗癌症的药物中的用途。
本发明的病毒特别适用于治疗任何实体瘤，包括任何腺癌、癌、黑素瘤或肉瘤。例如，本发明的病毒可用于治疗头颈癌、前列腺癌、乳腺癌、卵巢癌、肺癌、肝癌、子宫内膜癌、膀胱癌、胆囊癌、胰腺癌、结肠癌、肾癌、胃/胃(gastric)癌、食道癌或宫颈癌、间皮瘤、黑素瘤或其他皮肤癌、淋巴瘤、神经胶质瘤或神经系统的其他癌症，或肉瘤诸如软组织肉瘤。
本发明的病毒可用于治疗恶性肿瘤，包括已从原始肿瘤部位转移的肿瘤。在该实施方案中，可将病毒施用于原发性肿瘤或一种或多种继发性肿瘤。
可将本发明的病毒与其他治疗剂(包括化学疗法、靶向疗法、免疫疗法(包括免疫检查点阻断，即施用免疫共抑制途径的一种或多种拮抗剂，和/或免疫共刺激途径的一种或多种激动剂))组合施用，和/或与放射疗法组合施用和/或与这些疗法的任意组合组合施用。治疗剂优选为抗癌剂。
可将本发明的病毒与第二病毒诸如第二溶瘤病毒组合施用。
例如，治疗剂可包含免疫原(包括重组或天然存在的抗原，包括这样的抗原或以其中编码它/它们的DNA或RNA递送的抗原的组合)，以进一步刺激针对肿瘤细胞，特别是肿瘤新抗原的免疫反应，诸如细胞或体液免疫反应。治疗剂可以是旨在增加或增强免疫反应的药剂，诸如细胞因子、旨在抑制免疫检查点途径或刺激免疫增强途径的药剂或抑制调节性T细胞(Treg)或髓源性抑制细胞(MDSC)的活性的药剂。
治疗剂可以是已知用于现有癌症治疗处理的药剂。治疗剂可以是放射疗法或化学治疗剂。治疗剂可选自环磷酰胺、烷化剂诸如顺铂或美法仑、植物生物碱和萜类化合物诸如长春新碱或紫杉醇(泰素)、抗代谢物诸如5-氟尿嘧啶、拓扑异构酶抑制剂I型或II型诸如喜树碱或多柔比星、细胞毒性抗生素诸如放线菌素、蒽环霉素诸如表柔比星、糖皮质激素诸如曲安西龙、蛋白质、DNA和/或RNA合成的抑制剂诸如甲氨蝶呤和达卡巴辛、组蛋白去乙酰化酶(HDAC)抑制剂或任何其他化学治疗剂。
治疗剂可以是免疫治疗剂或免疫调节剂中的一种或其组合，诸如TLR激动剂；下调T-调节性细胞的药物，诸如环磷酰胺；或旨在阻断免疫检查点或刺激免疫增强途径的药剂，包括但不限于单克隆抗体，诸如CTLA-4抑制剂、PD-1抑制剂、PD-L1抑制剂、LAG-3抑制剂、TIM-3抑制剂、VISTA抑制剂、CSF1R抑制剂、IDO抑制剂、CEACAM1抑制剂、GITR激动剂、4-1-BB激动剂、KIR抑制剂、SLAMF7抑制剂、OX40激动剂、CD40激动剂、ICOS激动剂或CD47抑制剂。在一个优选实施方案中，治疗剂是CTLA-4抑制剂，诸如抗-CTLA-4抗体、PD1抑制剂，诸如抗PD-1抗体或PD-L1抑制剂，诸如抗PD-L1抗体。可通过本领域已知的标准方法产生和测试此类抑制剂、激动剂和抗体。
免疫治疗剂还可包括双特异性抗体、基于树突状细胞、NK细胞或工程化T细胞(诸如CAR-T细胞或表达工程化T细胞受体的T细胞)的细胞基疗法。免疫治疗剂还包括靶向肿瘤中发生的特定遗传突变的药剂、旨在诱导针对特定肿瘤抗原或肿瘤抗原的组合(包括新抗原)的免疫反应的药剂和/或旨在激活STING/cGAS途径、TLR或其他先天免疫反应和/或炎症途径的药剂，包括肿瘤内药剂。
例如，可将本发明的病毒与达卡巴嗪、BRAF抑制剂和/或PD1或PD-L1阻断剂组合使用以治疗黑素瘤；与紫杉醇、多柔比星、长春瑞滨、环磷酰胺和/或吉西他滨组合使用以治疗乳腺癌；与5-氟尿嘧啶和任选地甲酰四氢叶酸、伊立替康和/或奥沙利铂组合使用以治疗结直肠癌；与泰素、卡铂、长春瑞滨和/或吉西他滨、PD-1或PD-L1阻断组合使用以治疗肺癌；与顺铂和/或放射疗法组合使用以治疗头颈癌。
治疗剂可以是吲哚胺2,3-双加氧酶(IDO)途径的抑制剂。IDO抑制剂的实例包括epacadostat(INCB024360)、1-甲基-色氨酸、吲哚酰莫德(indoximod)(1-甲基-D-色氨酸)、GDC-0919或F001287。
IDO在抑制抗肿瘤免疫反应中的作用机制也可以抑制溶瘤病毒治疗后产生的免疫反应。IDO表达由Toll样受体(TLR)激活和干扰素-γ(这两者都可由溶瘤病毒感染引起)诱导。使用溶瘤病毒疗法治疗癌症的一个实施方案包括溶瘤病毒，和任选地GM-CSF和/或免疫共刺激途径激活分子和/或一种或多种另外的蛋白质编码序列(诸如编码促融合蛋白质诸如GALVR-的序列)(包括表达CTLA-4抑制剂的病毒)与IDO途径的抑制剂和任选地免疫共抑制途径的另一种拮抗剂和/或免疫共刺激途径的一种或多种激动剂(包括靶向PD-1和/或PD-L1的那些激动剂)的组合。
当将治疗剂和/或放射疗法与本发明的病毒结合使用时，病毒和治疗剂和/或放射疗法的施用可以是同时的或是按时间分开的。可以在治疗剂或放射疗法之前、与之同时或之后施用本发明的组合物。治疗癌症的方法可包括多次施用本发明的病毒和/或治疗剂和/或放射疗法。在优选实施方案中，在与免疫检查点阻断或其他免疫增强剂组合的情况下，施用本发明的病毒一次或多次，然后同时施用免疫检查点阻断剂或之后施用一种或多种其他免疫增强剂，或者在不事先施用本发明的病毒的情况下，将本发明的病毒与免疫检查点阻断剂或一种或多种其他免疫增强剂同时施用。
可通过任何合适的途径向受试者施用本发明的病毒。通常，通过直接肿瘤内注射施用本发明的病毒。肿瘤内注射包括直接注射到浅表皮肤、皮下或淋巴结肿瘤，以及成像引导(包括CT、MRI或超声)注射到更深或更难定位的部位中，包括在内脏器官和其他地方中。可将病毒施用到体腔中，例如施用到胸膜腔、膀胱中或通过腹膜内施用。病毒可能被注射到血管(优选地供应肿瘤的血管)中。
可使用多种已知途径和技术向人或动物受试者体内施用可以与本发明的病毒组合的治疗剂。例如，组合物可以作为注射液、悬浮液或乳液提供，并使用常规针头和注射器或使用液体喷射注射系统通过肠胃外、皮下、口腔、表皮、皮内、肌内、动脉内、腹膜内、静脉内注射施用。可将组合物局部施用至皮肤或粘膜组织(诸如经鼻、气管内、肠内、舌下、经直肠或经阴道)，或以适于呼吸或肺部施用的微细分散的喷雾剂提供。在优选实施方案中，通过静脉内输注、口服或直接进入肿瘤中来施用组合物。
可以以与治疗上有效的剂量组合物相容的量向受试者施用病毒和/或治疗剂。本发明病毒的施用是为了“治疗”目的。如本文中所用，术语“治疗的”或“治疗”包括以下任一种或多种作为其目标：预防任何转移或进一步的转移发生；减轻或消除症状；减少或完全消除肿瘤或癌症，增加达到患者癌症进展的时间；治疗后至复发的时间增加；或者延长生存时间。
可在手术干预之前或之后(即在手术后肿瘤复发或其不完全切除后)，优选在任何手术干预(以切除原发性或复发性/转移性疾病)之前，或在手术后或在不完全手术切除疾病(即残留肿瘤时)后复发后，可对I、II、III或IV期癌症，优选II、III或IV期，更优选III或IV期癌症施用治疗性治疗。
在将病毒组合物直接注射到可以是肿瘤的靶组织中、体腔或血管中后，可进行治疗性治疗。作为指导，在HSV的情况下施用的病毒量在104至1010pfu，优选105至109pfu的范围内。在HSV的情况下，可向患者施用初始较低剂量(例如104至107pfu)以对对于HSV呈血清阴性的患者进行血清转化，并在呈血清阳性的那些患者中加强免疫，然后此后施用更高剂量(例如106至109pfu)。通常，可将高达20ml的基本上由病毒和药学上可接受的合适的载体或稀释剂组成的药物组合物用于直接注射到肿瘤中，或者将高达50ml用于施用到体腔中(可在施用前将所述组合物进一步稀释至适当的稀释剂中)或血流中。然而，对于一些溶瘤疗法应用，也可以使用更大或更小的体积，这取决于肿瘤以及给药途径和部位。
所描述的施用途径和剂量仅旨在作为指导，因为熟练的从业者将能够容易地确定最佳给施用径和剂量。剂量可根据各种参数，尤其是根据肿瘤的位置、肿瘤的大小、待治疗的患者的年龄、体重和状况以及施用途径来确定。优选地，通过直接注射到肿瘤中或体腔中来施用病毒。还可通过直接注射到血管中来施用病毒。最佳施用途径将取决于肿瘤的位置和大小。可能需要多个剂量来实现免疫学或临床效果，如果需要，通常间隔2天至12周，优选间隔3天至3周施用所述剂量。可给予长达5年或更长时间的重复剂量，优选长达一个月至两年，这取决于所治疗的肿瘤类型的反应速度和特定患者的反应以及还可能给出的任何组合疗法。
以下实施例说明了本发明。
实施例1.本发明的病毒的构建
用于举例说明本发明的病毒种类是HSV，特别是HSV1。
所使用的质粒的图示于图2中。病毒的图示于图1中。所有病毒均使用HSV1毒株RH018A构建。用于病毒构建的质粒是由GenscriptInc.进行的基因合成和亚克隆的组合产生的。
通过将质粒77与病毒16DNA共转染以将GFP插入病毒16(通过选择表达GFP的噬菌斑)以产生病毒25，来构建表达抗小鼠CTLA4以及小鼠GM-CSF和GALV的病毒。然后通过将病毒25DNA与质粒119共转染来将GFP从病毒25中敲除。这产生病毒27。
通过将质粒78与病毒17DNA共转染以将GFP插入病毒17(通过选择表达GFP的噬菌斑)以产生病毒29，来构建表达抗人CTLA4以及人GM-CSF和GALV的病毒。然后通过将病毒29DNA与质粒122共转染来将GFP从病毒29中敲除。这产生病毒31。
通过将在小鼠GM-CSF编码序列与抗小鼠CTLA-4编码序列之间编码由SV40启动子驱动的GFP的质粒与病毒27共转染，来构建表达抗小鼠CTLA-4和共刺激配体以及小鼠GM-CSF和GALV的病毒。然后用编码每种单独的小鼠共刺激配体的质粒替代GFP来将GFP从所得病毒中敲除。
通过将在人GM-CSF编码序列与抗人CTLA-4编码序列之间编码由SV40启动子驱动的GFP的质粒与病毒31共转染，来构建表达抗人CTLA-4和共刺激配体以及人GM-CSF和GALV的病毒。然后用编码每种单独的人共刺激配体的质粒替代GFP来将GFP从所得病毒中敲除。
图4显示证明来自病毒27的抗小鼠CTLA-4表达的蛋白质印迹。
实施例2.来自溶瘤病毒的GALV、GM-CSF和抗-CTLA4的组合表达的效果
以下列方式演示本发明的效用。将A20细胞施用于Balb/c小鼠的两侧肋腹，并使A20肿瘤生长至直径约0.5cm。
然后向小鼠的组施用(每周3次，仅向每只小鼠的一侧肋腹(右侧肿瘤)中施用，持续1周)以下治疗：
-50μl媒介物(1组)；
-50μl的106pfu/ml的仅插入小鼠GM-CSF和GALVR-的HSV(病毒16)；
-50μl的106pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV(病毒27)；
然后观察对肿瘤生长的影响长达一个月。所使用的病毒剂量为5x104pfu(在每种情况下为50ul，1x106pfu/ml)，在一周内施用三次。对于病毒16的未注射肿瘤，该病毒剂量水平是亚治疗性的，这使得可以清楚地看到病毒27编码的其他分子的递送益处。图5和图6显示了与不表达CTLA-4的病毒16相比，具有表达抗-CTLA-4的病毒的未注射肿瘤中的优异肿瘤控制和收缩。
实施例3.来自溶瘤病毒的GALV、GM-CSF和抗-CTLA4与抗-PD-1的组合表达的效果
向Balb/c小鼠的两侧肋腹施用A20细胞，并使A20肿瘤生长至直径约0.5cm。
然后向小鼠的组(每组10只)施用(每周3次，仅向每只小鼠的一侧肋腹中施用，持续1周)以下治疗：
-50μl媒介物；
-腹膜内抗小鼠PD1(Bioxcell RMP-1-14 10mg/kg，每三天一次)；
-50μl的107pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV(病毒27)
-50μl的107pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体(病毒27)以及腹膜内抗小鼠PD1(每3天10mg/kg)的HSV(3组)。
然后观察对肿瘤生长的影响长达80天。当将利用病毒的治疗与抗PD1联合治疗时，注射和未注射肿瘤中均存在优异的肿瘤控制和收缩。该数据如图7所示。
实施例4.来自溶瘤病毒的GALV、GM-CSF和抗人CTLA4的组合表达单独地以及其与抗PD-1组合的效果
向通过基因编辑工程化以表达人CTLA-4而非小鼠CTLA-4的C57BL/6小鼠的两侧肋腹施用MC38细胞。这使得小鼠易受抗人CTLA-4抗体诸如伊匹木单抗影响。使MC38肿瘤生长至直径约0.5cm。
然后向小鼠的组(每组10只)施用(每周3次，仅向每只小鼠的一侧肋腹中施用，持续2周)以下治疗：
-50μl媒介物；
-50μl的108pfu/ml的病毒17(即表达hGM-CSF和GALV)；
-50μl的108pfu/ml的病毒31(即表达hGM-CSF、GALV和抗人CTLA-4)；
-50μl的108pfu/ml的病毒17以及腹膜内抗小鼠PD1(每3天10mg/kg)；
-50μl的108pfu/ml的病毒31以及腹膜内抗小鼠PD1(每3天10mg/kg)。
然后观察对肿瘤生长的影响长达35天。在具有表达抗人CTLA-4的病毒的注射肿瘤中观察到优异肿瘤控制和收缩，该效果在与抗PD1组合时得以进一步增强。当将利用任一种病毒的治疗与抗PD1治疗组合时，在未注射肿瘤中观察到优异的肿瘤控制和收缩。对表达抗CTLA4的病毒，改善更为明显。该数据示于图8中。
实施例5.来自溶瘤病毒的GALV、GM-CSF和抗-CTLA4与抗-PD-1的组合表达的效果
向Balb/c小鼠的两侧肋腹施用A20细胞，并使A20肿瘤生长至直径约0.5cm。
然后向小鼠的组(每组10只)施用(每周3次，仅向每只小鼠的一侧肋腹中施用，持续2周)以下治疗：
-50μl媒介物(1组)；
-腹膜内抗小鼠PD1(Bioxcell RMP-1-14 10mg/kg，每三天一次)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的仅插入小鼠GM-CSF和GALVR-的HSV(3组)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的仅插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的仅插入小鼠GM-CSF和GALVR-的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)。
然后观察对肿瘤生长的影响长达一个月。与观察另一组相比，包括通过改善的剂量反应曲线，观察到具有表达抗-CTLA-4的病毒的注射和未注射肿瘤中的优异肿瘤控制和收缩，当与抗PD1联合治疗时所述肿瘤控制和收缩得以进一步增强。
实施例6.来自溶瘤病毒的GALV、GM-CSF和抗人CTLA4的组合表达本身以及其与抗PD-1组合的效果
向通过基因编辑工程化以表达人CTLA-4而非小鼠CTLA-4的C57BL/6小鼠的两侧肋腹施用MC38细胞。这使得小鼠易受抗人CTLA-4抗体诸如伊匹木单抗影响。使MC38肿瘤生长至直径约0.5cm。
然后向小鼠的组(每组10只)施用(每周3次，仅向每只小鼠的一侧肋腹中施用，持续2周)以下治疗：
-50μl媒介物(1组)；
-腹膜内抗小鼠PD1(Bioxcell RMP-1-14 10mg/kg，每三天一次)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的仅插入小鼠GM-CSF和GALVR-的HSV(3组)；
-50μl 105pfu/ml、106pfu/ml或107pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)；
-50μl的105pfu/ml、106pfu/ml或107pfu/ml的仅插入小鼠GM-CSF和GALVR-的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)；
-50μl 105pfu/ml、106pfu/ml或107pfu/ml的插入GALVR-、小鼠GM-CSF和抗小鼠CTLA-4抗体的HSV以及腹膜内抗小鼠PD1(10mg/kg，每三天一次)(3组)。
然后观察对肿瘤生长的影响长达一个月。与观察另一组相比，包括通过改善的剂量反应曲线，观察到具有表达抗-CTLA-4的病毒的注射和未注射肿瘤中的优异的肿瘤控制和收缩，当与抗PD1联合治疗时所述肿瘤控制和收缩得以进一步增强。
实施例7.来自溶瘤病毒的GALV、GM-CSF、抗-CTLA4和免疫共刺激途径激活分子的组合表达的效果
重复上述实施例3中的实验，但给小鼠服用另外表达免疫共刺激途径配体以及表达GALV、mGM-CSF和抗-CTLA4的病毒。
更具体地说，小鼠的组接受：
(1)媒介物；
(2)腹膜内抗小鼠PD1；
(3)如实施例2中那样插入mGM-CSF、GALVR-和抗-CTLA4的HSV；
(4)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠CD40L的HSV；
(5)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠4-1BBL的HSV；
(6)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠GITRL的HSV；
(7)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠OX40L的HSV；
(8)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠ICOSL的HSV；
(9)如实施例2中那样插入mGM-CSF、GALVR-和抗-CTLA4的HSV以及腹膜内抗-PD1；
(10)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠CD40L的HSV以及腹膜内抗-PD1；
(11)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠4-1BBL的HSV以及腹膜内抗-PD1；
(12)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠GITRL的HSV以及腹膜内抗-PD1；
(13)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠OX40L的HSV以及腹膜内抗-PD1；或
(14)插入mGM-CSF、GALVR-、抗-CTLA4和小鼠ICOSL的HSV以及腹膜内抗-PD1。
对表表达免疫共刺激配体的病毒观察到优异的肿瘤控制。
保藏信息
以下HSV1株由Replimune Limited于2016年12月19日保藏于ECACC,CultureCollections,Public Health England,Porton Down,Salisbury,SP4 0JG,UnitedKingdom，并被分配指定的登录号：
RH004A–登录号16121902
RH015A–登录号16121903
RH018A–登录号16121904
RH021A–登录号16121905
RH023A–登录号16121906
RH031A–登录号16121907
RH040B–登录号16121908
RH047A–登录号16121909
序列表
<110> Replimune Limited
<120> 改变的病毒
<130> N409771WO
<140>
<141> 2018-01-09
<150> GB 1700350.0
<151> 2017-01-09
<160> 46
<170> PatentIn version 3.5
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Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu
1 5 10 15
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
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Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 2
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<212> PRT
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
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<210> 3
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
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Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
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Leu Val Thr Val Ser Ser
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Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
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Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
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Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys
100
<210> 5
<211> 227
<212> PRT
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Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 6
<211> 448
<212> PRT
<213> 人
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
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 Ile Tyr Tyr Cys
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Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
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Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
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Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 7
<211> 21
<212> PRT
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<400> 7
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20
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<223> (Gly4Ser)3 连接子
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
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Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
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Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
165 170 175
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
180 185 190
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
195 200 205
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
210 215 220
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
225 230 235 240
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
245 250 255
Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
260 265 270
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
275 280 285
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
290 295 300
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
305 310 315 320
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
325 330 335
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
340 345 350
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
355 360 365
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
370 375 380
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
385 390 395 400
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
405 410 415
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
420 425 430
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
435 440 445
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
450 455 460
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
465 470 475 480
Lys Ser Leu Ser Leu Ser Pro Gly Lys
485
<210> 10
<211> 1470
<212> DNA
<213> 人
<400> 10
atggaaactg acaccctgct gctgtgggtc ctgctgctgt gggtgcctgg atccaccggc 60
gatatcgtgc tgacccagtc tcctggcaca ctgagtctgt caccagggga gcgagcaaca 120
ctgtcttgta gagccagcca gtctgtggga agctcctacc tggcttggta tcagcagaag 180
ccaggccagg cacccaggct gctgatctac ggagccttca gccgggccac tggcattcca 240
gacaggttct ctggaagtgg ctcagggacc gacttcaccc tgaccatcag ccgactggag 300
cccgaagact tcgccgtgta ctattgccag cagtacggct ctagtccttg gacttttgga 360
cagggcacca aagtggagat caagcgcggc gggggaggct ctgggggagg cgggagtgga 420
ggcgggggat cacaggtcca gctggtggaa agcggcgggg gagtggtcca gccaggccgg 480
agcctgcggc tgagctgcgc cgcttcagga ttcacatttt caagctatac catgcactgg 540
gtccggcagg caccagggaa gggactggag tgggtgacct tcatcagcta tgacggcaac 600
aacaagtatt acgctgattc cgtgaaaggg aggtttacca ttagccgcga caactccaaa 660
aatacactgt acctgcagat gaacagcctg cgggccgagg atactgctat ctactattgc 720
gcaagaaccg ggtggctggg acccttcgac tattggggcc aggggactct ggtcaccgtg 780
tcctctgata agacacacac atgccctccc tgtcctgcac cagagctgct gggcgggcca 840
tccgtgttcc tgtttccacc caagcctaaa gacaccctga tgatcagccg gacacctgaa 900
gtcacttgcg tggtcgtgga cgtgagtcac gaggatccag aagtcaagtt taactggtac 960
gtggatggcg tcgaggtgca taatgccaag accaaacctc gcgaggaaca gtacaatagc 1020
acatatcgag tcgtgtccgt cctgactgtg ctgcatcagg attggctgaa cggcaaagag 1080
tataagtgca aagtgagcaa taaggcactg cctgccccaa tcgagaaaac aatttccaag 1140
gctaaaggcc agcccaggga acctcaggtg tacactctgc ctccaagtcg cgaggaaatg 1200
accaagaacc aggtgagcct gacctgtctg gtgaaagggt tctatccatc agacattgca 1260
gtggagtggg aaagcaatgg acagcccgaa aacaattaca agaccacacc ccctgtgctg 1320
gacagcgatg gctccttctt tctgtattct aagctgactg tggataaaag tcgctggcag 1380
caggggaacg tctttagctg ttccgtgatg catgaggctc tgcacaatca ttacacacag 1440
aagtctctga gtctgtcacc cggcaaatga 1470
<210> 11
<211> 127
<212> PRT
<213> 小鼠
<400> 11
Ile Arg Arg Ala Asp Ile Val Met Thr Gln Thr Thr Leu Ser Leu Pro
1 5 10 15
Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
20 25 30
Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys
35 40 45
Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe
50 55 60
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
65 70 75 80
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr
85 90 95
Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys
100 105 110
Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Gly Ser
115 120 125
<210> 12
<211> 134
<212> PRT
<213> 小鼠
<400> 12
Glu Ala Lys Leu Gln Glu Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Ile Thr Val Ser Thr Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Arg Ser Ser Arg
130
<210> 13
<211> 356
<212> PRT
<213> 小鼠
<400> 13
Glu Ala Lys Leu Gln Glu Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Ile Thr Val Ser Thr Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Arg Ser Ser Arg Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
130 135 140
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
145 150 155 160
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
165 170 175
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
180 185 190
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
195 200 205
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
210 215 220
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
225 230 235 240
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
245 250 255
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
260 265 270
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
275 280 285
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
290 295 300
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
305 310 315 320
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
325 330 335
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
340 345 350
Ser Pro Gly Lys
355
<210> 14
<211> 519
<212> PRT
<213> 小鼠
<400> 14
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Arg Arg Ala Asp Ile Val Met Thr Gln Thr
20 25 30
Thr Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys
35 40 45
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
50 55 60
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys
65 70 75 80
Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
85 90 95
Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp
100 105 110
Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe
115 120 125
Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr
130 135 140
Val Ser Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Glu Ala Lys Leu Gln Glu Ser Gly Pro Val Leu Val Lys
165 170 175
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
180 185 190
Thr Asp Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu
195 200 205
Glu Trp Ile Gly Val Ile Asn Pro Tyr Asn Gly Asp Thr Ser Tyr Asn
210 215 220
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
225 230 235 240
Thr Ala Tyr Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val
245 250 255
Tyr Tyr Cys Ala Arg Tyr Tyr Gly Ser Trp Phe Ala Tyr Trp Gly Gln
260 265 270
Gly Thr Leu Ile Thr Val Ser Thr Ala Lys Thr Thr Pro Pro Ser Val
275 280 285
Tyr Pro Leu Ala Pro Arg Ser Ser Arg Gly Cys Lys Pro Cys Ile Cys
290 295 300
Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys
305 310 315 320
Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val
325 330 335
Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp
340 345 350
Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe
355 360 365
Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp
370 375 380
Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe
385 390 395 400
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys
405 410 415
Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys
420 425 430
Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp
435 440 445
Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys
450 455 460
Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser
465 470 475 480
Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr
485 490 495
Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser
500 505 510
Leu Ser His Ser Pro Gly Lys
515
<210> 15
<211> 1560
<212> DNA
<213> 小鼠
<400> 15
atggaaactg atactctgct gctctgggtg ctgctcctct gggtgcctgg ttcaactggg 60
gacattcgac gggctgacat tgtgatgacc cagaccacac tgagcctgcc cgtgtccctg 120
ggcgaccagg ccagcatctc ctgccggagc tcccagtcta tcgtgcacag caacggaaac 180
acatacctgg agtggtatct gcagaagcct ggccagtccc caaagctgct gatctacaag 240
gtgtccaaca ggttcagcgg cgtgcctgac cgcttttctg gaagcggctc cggaacagat 300
ttcaccctga agatcagcag ggtggaggct gaggacctgg gcgtgtacta ctgcttccag 360
ggatcccacg tgccttacac ctttggcgga ggcacaaagc tggagatcaa gagagccgat 420
gctgctccaa ccgtgtctgg aagcggaggc gggggttctg gaggcggtgg gagcggtggc 480
ggagggtctg aggctaagct gcaggagagc ggccccgtgc tggtgaagcc tggagccagc 540
gtgaagatgt cctgtaaggc ttctggatac accttcacag actactacat gaactgggtg 600
aagcagagcc acggcaagtc cctggagtgg atcggagtga tcaaccctta caacggcgac 660
acctcttaca accagaagtt taagggcaag gccaccctga cagtggataa gtctagctcc 720
accgcttaca tggagctgaa cagcctgaca tccgaggatt ctgccgtgta ctactgtgct 780
aggtactacg gaagctggtt cgcctactgg ggccagggaa cactgatcac cgtgtccaca 840
gccaagacca caccccctag cgtgtacccc ctggctccta ggtctagcag aggctgcaag 900
ccatgcatct gtaccgtgcc cgaggtgagc agcgtgttca tctttccacc caagcccaag 960
gacgtgctga ccatcacact gacccctaag gtgacatgcg tggtggtgga tatcagcaag 1020
gacgatccag aggtgcagtt ctcctggttt gtggacgatg tggaggtgca caccgcccag 1080
acacagccaa gggaggagca gttcaactcc acctttagat ccgtgtctga gctgcccatc 1140
atgcaccagg actggctgaa cggaaaggag ttcaagtgcc gggtgaactc cgccgctttt 1200
cctgctccaa tcgagaagac catctctaag acaaagggcc gcccaaaggc tccacaggtg 1260
tacaccatcc ctccacccaa ggagcagatg gctaaggata aggtgagcct gacctgtatg 1320
atcacagact tctttcccga ggatatcaca gtggagtggc agtggaacgg acagcctgcc 1380
gagaactaca agaacaccca gccaatcatg gacacagatg gctcttactt cgtgtacagc 1440
aagctgaacg tgcagaagtc taactgggag gctggcaaca ccttcacctg cagcgtgctg 1500
cacgaaggtc tccataatca ccacaccgaa aagagcctca gtcacagccc tgggaaatga 1560
<210> 16
<211> 1574
<212> DNA
<213> 小鼠
<400> 16
cttaagatgg aaactgatac tctgctgctc tgggtgctgc tcctctgggt gcctggttca 60
actggggaca ttcgacgggc tgacattgtg atgacccaga ccacactgag cctgcccgtg 120
tccctgggcg accaggccag catctcctgc cggagctccc agtctatcgt gcacagcaac 180
ggaaacacat acctggagtg gtatctgcag aagcctggcc agtccccaaa gctgctgatc 240
tacaaggtgt ccaacaggtt cagcggcgtg cctgaccgct tttctggaag cggctccgga 300
acagatttca ccctgaagat cagcagggtg gaggctgagg acctgggcgt gtactactgc 360
ttccagggat cccacgtgcc ttacaccttt ggcggaggca caaagctgga gatcaagaga 420
gccgatgctg ctccaaccgt gtctggaagc ggaggcgggg gttctggagg cggtgggagc 480
ggtggcggag ggtctgaggc taagctgcag gagagcggcc ccgtgctggt gaagcctgga 540
gccagcgtga agatgtcctg taaggcttct ggatacacct tcacagacta ctacatgaac 600
tgggtgaagc agagccacgg caagtccctg gagtggatcg gagtgatcaa cccttacaac 660
ggcgacacct cttacaacca gaagtttaag ggcaaggcca ccctgacagt ggataagtct 720
agctccaccg cttacatgga gctgaacagc ctgacatccg aggattctgc cgtgtactac 780
tgtgctaggt actacggaag ctggttcgcc tactggggcc agggaacact gatcaccgtg 840
tccacagcca agaccacacc ccctagcgtg taccccctgg ctcctaggtc tagcagaggc 900
tgcaagccat gcatctgtac cgtgcccgag gtgagcagcg tgttcatctt tccacccaag 960
cccaaggacg tgctgaccat cacactgacc cctaaggtga catgcgtggt ggtggatatc 1020
agcaaggacg atccagaggt gcagttctcc tggtttgtgg acgatgtgga ggtgcacacc 1080
gcccagacac agccaaggga ggagcagttc aactccacct ttagatccgt gtctgagctg 1140
cccatcatgc accaggactg gctgaacgga aaggagttca agtgccgggt gaactccgcc 1200
gcttttcctg ctccaatcga gaagaccatc tctaagacaa agggccgccc aaaggctcca 1260
caggtgtaca ccatccctcc acccaaggag cagatggcta aggataaggt gagcctgacc 1320
tgtatgatca cagacttctt tcccgaggat atcacagtgg agtggcagtg gaacggacag 1380
cctgccgaga actacaagaa cacccagcca atcatggaca cagatggctc ttacttcgtg 1440
tacagcaagc tgaacgtgca gaagtctaac tgggaggctg gcaacacctt cacctgcagc 1500
gtgctgcacg aaggtctcca taatcaccac accgaaaaga gcctcagtca cagccctggg 1560
aaatgaggcg cgcc 1574
<210> 17
<211> 1484
<212> DNA
<213> 人
<400> 17
cttaagatgg aaactgacac cctgctgctg tgggtcctgc tgctgtgggt gcctggatcc 60
accggcgata tcgtgctgac ccagtctcct ggcacactga gtctgtcacc aggggagcga 120
gcaacactgt cttgtagagc cagccagtct gtgggaagct cctacctggc ttggtatcag 180
cagaagccag gccaggcacc caggctgctg atctacggag ccttcagccg ggccactggc 240
attccagaca ggttctctgg aagtggctca gggaccgact tcaccctgac catcagccga 300
ctggagcccg aagacttcgc cgtgtactat tgccagcagt acggctctag tccttggact 360
tttggacagg gcaccaaagt ggagatcaag cgcggcgggg gaggctctgg gggaggcggg 420
agtggaggcg ggggatcaca ggtccagctg gtggaaagcg gcgggggagt ggtccagcca 480
ggccggagcc tgcggctgag ctgcgccgct tcaggattca cattttcaag ctataccatg 540
cactgggtcc ggcaggcacc agggaaggga ctggagtggg tgaccttcat cagctatgac 600
ggcaacaaca agtattacgc tgattccgtg aaagggaggt ttaccattag ccgcgacaac 660
tccaaaaata cactgtacct gcagatgaac agcctgcggg ccgaggatac tgctatctac 720
tattgcgcaa gaaccgggtg gctgggaccc ttcgactatt ggggccaggg gactctggtc 780
accgtgtcct ctgataagac acacacatgc cctccctgtc ctgcaccaga gctgctgggc 840
gggccatccg tgttcctgtt tccacccaag cctaaagaca ccctgatgat cagccggaca 900
cctgaagtca cttgcgtggt cgtggacgtg agtcacgagg atccagaagt caagtttaac 960
tggtacgtgg atggcgtcga ggtgcataat gccaagacca aacctcgcga ggaacagtac 1020
aatagcacat atcgagtcgt gtccgtcctg actgtgctgc atcaggattg gctgaacggc 1080
aaagagtata agtgcaaagt gagcaataag gcactgcctg ccccaatcga gaaaacaatt 1140
tccaaggcta aaggccagcc cagggaacct caggtgtaca ctctgcctcc aagtcgcgag 1200
gaaatgacca agaaccaggt gagcctgacc tgtctggtga aagggttcta tccatcagac 1260
attgcagtgg agtgggaaag caatggacag cccgaaaaca attacaagac cacaccccct 1320
gtgctggaca gcgatggctc cttctttctg tattctaagc tgactgtgga taaaagtcgc 1380
tggcagcagg ggaacgtctt tagctgttcc gtgatgcatg aggctctgca caatcattac 1440
acacagaagt ctctgagtct gtcacccggc aaatgaggcg cgcc 1484
<210> 18
<211> 426
<212> DNA
<213> 小鼠
<400> 18
atgtggctgc agaatttact tttcctgggc attgtggtct acagcctctc agcacccacc 60
cgctcaccca tcactgtcac ccggccttgg aagcatgtag aggccatcaa agaagccctg 120
aacctcctgg atgacatgcc tgtcacattg aatgaagagg tagaagtcgt ctctaacgag 180
ttctccttca agaagctaac atgtgtgcag acccgcctga agatattcga gcagggtcta 240
cggggcaatt tcaccaaact caagggcgcc ttgaacatga cagccagcta ctaccagaca 300
tactgccccc caactccgga aacggactgt gaaacacaag ttaccaccta tgcggatttc 360
atagacagcc ttaaaacctt tctgactgat atcccctttg aatgcaaaaa accagtccaa 420
aaatga 426
<210> 19
<211> 426
<212> DNA
<213> 小鼠
<400> 19
atgtggctcc agaacctcct cttcctcggt atcgtcgtgt attcactctc cgcacctact 60
cgctcaccta tcactgtcac cagaccctgg aagcacgtgg aggccatcaa ggaggctctg 120
aacctgctgg acgatatgcc agtgaccctg aacgaggagg tggaggtggt gagcaacgag 180
ttctccttta agaagctgac ctgcgtgcag acaaggctga agatcttcga gcagggcctg 240
agaggaaact ttaccaagct gaagggcgcc ctgaacatga ccgcttctta ctaccagaca 300
tactgccccc ctacccccga gacagactgt gagacacagg tgaccacata cgccgacttc 360
attgatagcc tgaaaacatt cctgaccgac attccatttg agtgtaagaa gcccgtccag 420
aagtaa 426
<210> 20
<211> 435
<212> DNA
<213> 人
<400> 20
atgtggctgc agagcctgct gctcttgggc actgtggcct gcagcatctc tgcacccgcc 60
cgctcgccca gccccagcac gcagccctgg gagcatgtga atgccatcca ggaggcccgg 120
cgtctcctga acctgagtag agacactgct gctgagatga atgaaacagt agaagtcatc 180
tcagaaatgt ttgacctcca ggagccgacc tgcctacaga cccgcctgga gctgtacaag 240
cagggcctgc ggggcagcct caccaagctc aagggcccct tgaccatgat ggccagccac 300
tacaagcagc actgccctcc aaccccggaa acttcctgtg caacccagat tatcaccttt 360
gaaagtttca aagagaacct gaaggacttt ctgcttgtca tcccctttga ctgctgggag 420
ccagtccagg agtga 435
<210> 21
<211> 435
<212> DNA
<213> 人
<400> 21
atgtggctgc agtccctgct gctgctgggc accgtcgcct gttctatttc cgcacccgca 60
aggtcaccaa gtccatctac tcagccttgg gagcacgtga acgcaatcca ggaggcacgg 120
cggctgctga acctgagccg ggacaccgcc gccgagatga acgagacagt ggaagtgatc 180
agcgagatgt tcgatctgca ggagcccacc tgcctgcaga caaggctgga gctgtacaag 240
cagggcctgc gcggctctct gaccaagctg aagggcccac tgacaatgat ggccagccac 300
tataagcagc actgcccccc tacccccgag acaagctgtg ccacccagat catcacattc 360
gagtccttta aggagaacct gaaggatttt ctgctggtca ttccatttga ttgttgggag 420
cccgtccagg agtaa 435
<210> 22
<211> 141
<212> PRT
<213> 小鼠
<400> 22
Met Trp Leu Gln Asn Leu Leu Phe Leu Gly Ile Val Val Tyr Ser Leu
1 5 10 15
Ser Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His
20 25 30
Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val
35 40 45
Thr Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys
50 55 60
Lys Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu
65 70 75 80
Arg Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser
85 90 95
Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr
100 105 110
Gln Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu
115 120 125
Thr Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
130 135 140
<210> 23
<211> 144
<212> PRT
<213> 人
<400> 23
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
20 25 30
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
35 40 45
Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
50 55 60
Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
65 70 75 80
Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
85 90 95
Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
100 105 110
Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
115 120 125
Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
130 135 140
<210> 24
<211> 2010
<212> DNA
<213> 长臂猿白血病病毒
<400> 24
atggtattgc tgcctgggtc catgcttctc acctcaaacc tgcaccacct tcggcaccag 60
atgagtcctg ggagctggaa aagactgatc atcctcttaa gctgcgtatt cggcggcggc 120
gggacgagtc tgcaaaataa gaacccccac cagcccatga ccctcacttg gcaggtactg 180
tcccaaactg gagacgttgt ctgggataca aaggcagtcc agcccccttg gacttggtgg 240
cccacactta aacctgatgt atgtgccttg gcggctagtc ttgagtcctg ggatatcccg 300
ggaaccgatg tctcgtcctc taaacgagtc agacctccgg actcagacta tactgccgct 360
tataagcaaa tcacctgggg agccataggg tgcagctacc ctcgggctag gactagaatg 420
gcaagctcta ccttctacgt atgtccccgg gatggccgga ccctttcaga agctagaagg 480
tgcggggggc tagaatccct atactgtaaa gaatgggatt gtgagaccac ggggaccggt 540
tattggctat ctaaatcctc aaaagacctc ataactgtaa aatgggacca aaatagcgaa 600
tggactcaaa aatttcaaca gtgtcaccag accggctggt gtaaccccct taaaatagat 660
ttcacagaca aaggaaaatt atccaaggac tggataacgg gaaaaacctg gggattaaga 720
ttctatgtgt ctggacatcc aggcgtacag ttcaccattc gcttaaaaat caccaacatg 780
ccagctgtgg cagtaggtcc tgacctcgtc cttgtggaac aaggacctcc tagaacgtcc 840
ctcgctctcc cacctcctct tcccccaagg gaagcgccac cgccatctct ccccgactct 900
aactccacag ccctggcgac tagtgcacaa actcccacgg tgagaaaaac aattgttacc 960
ctaaacactc cgcctcccac cacaggcgac agactttttg atcttgtgca gggggccttc 1020
ctaaccttaa atgctaccaa cccaggggcc actgagtctt gctggctttg tttggccatg 1080
ggcccccctt attatgaagc aatagcctca tcaggagagg tcgcctactc caccgacctt 1140
gaccggtgcc gctgggggac ccaaggaaag ctcaccctca ctgaggtctc aggacacggg 1200
ttgtgcatag gaaaggtgcc ctttacccat cagcatctct gcaatcagac cctatccatc 1260
aattcctccg gagaccatca gtatctgctc ccctccaacc atagctggtg ggcttgcagc 1320
actggcctca ccccttgcct ctccacctca gtttttaatc agactagaga tttctgtatc 1380
caggtccagc tgattcctcg catctattac tatcctgaag aagttttgtt acaggcctat 1440
gacaattctc accccaggac taaaagagag gctgtctcac ttaccctagc tgttttactg 1500
gggttgggaa tcacggcggg aataggtact ggttcaactg ccttaattaa aggacctata 1560
gacctccagc aaggcctgac aagcctccag atcgccatag atgctgacct ccgggccctc 1620
caagactcag tcagcaagtt agaggactca ctgacttccc tgtccgaggt agtgctccaa 1680
aataggagag gccttgactt gctgtttcta aaagaaggtg gcctctgtgc ggccctaaag 1740
gaagagtgct gtttttacat agaccactca ggtgcagtac gggactccat gaaaaaactc 1800
aaagaaaaac tggataaaag acagttagag cgccagaaaa gccaaaactg gtatgaagga 1860
tggttcaata actccccttg gttcactacc ctgctatcaa ccatcgctgg gcccctatta 1920
ctcctccttc tgttgctcat cctcgggcca tgcatcatca ataagttagt tcaattcatc 1980
aatgatagga taagtgcagt taaaatttaa 2010
<210> 25
<211> 2013
<212> DNA
<213> 长臂猿白血病病毒
<400> 25
accatggtcc tgctgcctgg gtctatgctg ctgacttcta acctgcacca cctgcgacac 60
cagatgtctc ccggctcatg gaaacggctg atcatcctgc tgagctgcgt gttcggagga 120
ggaggcacct ccctgcagaa caagaatcct caccagccaa tgaccctgac atggcaggtg 180
ctgtcccaga caggcgacgt ggtgtgggat accaaggcag tgcagccacc ttggacatgg 240
tggcccaccc tgaagcctga cgtgtgcgcc ctggccgcct ccctggagtc ttgggacatc 300
cccggcacag acgtgagcag cagcaagagg gtgagaccac ccgactctga ttatacagcc 360
gcctacaagc agatcacctg gggcgccatc ggctgtagct atcctcgggc ccgcacaagg 420
atggccagct ccacctttta cgtgtgccca cgcgacggaa ggaccctgtc tgaggcaagg 480
agatgtggcg gcctggagag cctgtattgc aaggagtggg attgtgagac cacaggcaca 540
ggctactggc tgtctaagtc tagcaaggac ctgatcaccg tgaagtggga tcagaacagc 600
gagtggacac agaagttcca gcagtgccac cagaccggct ggtgtaatcc cctgaagatc 660
gactttacag ataagggcaa gctgtccaag gactggatca ccggcaagac atggggcctg 720
agattctacg tgtctggcca ccctggcgtg cagtttacaa tccggctgaa gatcaccaac 780
atgccagcag tggcagtggg accagacctg gtgctggtgg agcagggacc tccacgcacc 840
tccctggccc tgccccctcc actgccccct agggaggccc caccccctag cctgcccgat 900
tctaacagca cagccctggc cacctccgcc cagaccccta cagtgcgcaa gaccatcgtg 960
acactgaata ccccaccccc taccacaggc gacaggctgt tcgatctggt gcagggcgcc 1020
tttctgacac tgaacgccac caatcctggc gcaaccgaga gctgctggct gtgcctggct 1080
atgggcccac cctactatga ggcaatcgcc tcctctggag aggtggcata ttccacagac 1140
ctggatagat gcagatgggg cacccagggc aagctgaccc tgacagaggt gtctggccac 1200
ggcctgtgca tcggcaaggt gccattcaca caccagcacc tgtgcaacca gaccctgagc 1260
atcaatagct ccggcgacca ccagtacctg ctgccaagca accactcctg gtgggcatgc 1320
tccacaggac tgaccccatg tctgagcacc agcgtgttca accagaccag agacttttgt 1380
atccaggtgc agctgatccc tcggatctac tattacccag aggaggtgct gctgcaggcc 1440
tatgataatt cccacccaag aacaaagagg gaggccgtgt ctctgaccct ggccgtgctg 1500
ctgggactgg gaatcacagc aggaatcggc acaggcagca ccgccctgat caagggacca 1560
atcgacctgc agcagggact gacctccctg cagatcgcca tcgacgccga tctgagagcc 1620
ctgcaggaca gcgtgtccaa gctggaggat tctctgacct ctctgagcga ggtggtgctg 1680
cagaacagga ggggcctgga cctgctgttc ctgaaggagg gaggactgtg cgccgccctg 1740
aaggaggagt gctgttttta tatcgaccac tctggcgccg tgcgggatag catgaagaag 1800
ctgaaggaga agctggataa gcgccagctg gagaggcaga agagccagaa ttggtacgag 1860
ggctggttca acaattcccc ctggtttacc acactgctgt ctaccatcgc aggacctctg 1920
ttattactgc tgctgctgct gatcctgggc ccatgtatca tcaacaagct ggtgcagttt 1980
atcaacgacc gaatctccgc agtgaaaatc taa 2013
<210> 26
<211> 669
<212> PRT
<213> 长臂猿白血病病毒
<400> 26
Met Val Leu Leu Pro Gly Ser Met Leu Leu Thr Ser Asn Leu His His
1 5 10 15
Leu Arg His Gln Met Ser Pro Gly Ser Trp Lys Arg Leu Ile Ile Leu
20 25 30
Leu Ser Cys Val Phe Gly Gly Gly Gly Thr Ser Leu Gln Asn Lys Asn
35 40 45
Pro His Gln Pro Met Thr Leu Thr Trp Gln Val Leu Ser Gln Thr Gly
50 55 60
Asp Val Val Trp Asp Thr Lys Ala Val Gln Pro Pro Trp Thr Trp Trp
65 70 75 80
Pro Thr Leu Lys Pro Asp Val Cys Ala Leu Ala Ala Ser Leu Glu Ser
85 90 95
Trp Asp Ile Pro Gly Thr Asp Val Ser Ser Ser Lys Arg Val Arg Pro
100 105 110
Pro Asp Ser Asp Tyr Thr Ala Ala Tyr Lys Gln Ile Thr Trp Gly Ala
115 120 125
Ile Gly Cys Ser Tyr Pro Arg Ala Arg Thr Arg Met Ala Ser Ser Thr
130 135 140
Phe Tyr Val Cys Pro Arg Asp Gly Arg Thr Leu Ser Glu Ala Arg Arg
145 150 155 160
Cys Gly Gly Leu Glu Ser Leu Tyr Cys Lys Glu Trp Asp Cys Glu Thr
165 170 175
Thr Gly Thr Gly Tyr Trp Leu Ser Lys Ser Ser Lys Asp Leu Ile Thr
180 185 190
Val Lys Trp Asp Gln Asn Ser Glu Trp Thr Gln Lys Phe Gln Gln Cys
195 200 205
His Gln Thr Gly Trp Cys Asn Pro Leu Lys Ile Asp Phe Thr Asp Lys
210 215 220
Gly Lys Leu Ser Lys Asp Trp Ile Thr Gly Lys Thr Trp Gly Leu Arg
225 230 235 240
Phe Tyr Val Ser Gly His Pro Gly Val Gln Phe Thr Ile Arg Leu Lys
245 250 255
Ile Thr Asn Met Pro Ala Val Ala Val Gly Pro Asp Leu Val Leu Val
260 265 270
Glu Gln Gly Pro Pro Arg Thr Ser Leu Ala Leu Pro Pro Pro Leu Pro
275 280 285
Pro Arg Glu Ala Pro Pro Pro Ser Leu Pro Asp Ser Asn Ser Thr Ala
290 295 300
Leu Ala Thr Ser Ala Gln Thr Pro Thr Val Arg Lys Thr Ile Val Thr
305 310 315 320
Leu Asn Thr Pro Pro Pro Thr Thr Gly Asp Arg Leu Phe Asp Leu Val
325 330 335
Gln Gly Ala Phe Leu Thr Leu Asn Ala Thr Asn Pro Gly Ala Thr Glu
340 345 350
Ser Cys Trp Leu Cys Leu Ala Met Gly Pro Pro Tyr Tyr Glu Ala Ile
355 360 365
Ala Ser Ser Gly Glu Val Ala Tyr Ser Thr Asp Leu Asp Arg Cys Arg
370 375 380
Trp Gly Thr Gln Gly Lys Leu Thr Leu Thr Glu Val Ser Gly His Gly
385 390 395 400
Leu Cys Ile Gly Lys Val Pro Phe Thr His Gln His Leu Cys Asn Gln
405 410 415
Thr Leu Ser Ile Asn Ser Ser Gly Asp His Gln Tyr Leu Leu Pro Ser
420 425 430
Asn His Ser Trp Trp Ala Cys Ser Thr Gly Leu Thr Pro Cys Leu Ser
435 440 445
Thr Ser Val Phe Asn Gln Thr Arg Asp Phe Cys Ile Gln Val Gln Leu
450 455 460
Ile Pro Arg Ile Tyr Tyr Tyr Pro Glu Glu Val Leu Leu Gln Ala Tyr
465 470 475 480
Asp Asn Ser His Pro Arg Thr Lys Arg Glu Ala Val Ser Leu Thr Leu
485 490 495
Ala Val Leu Leu Gly Leu Gly Ile Thr Ala Gly Ile Gly Thr Gly Ser
500 505 510
Thr Ala Leu Ile Lys Gly Pro Ile Asp Leu Gln Gln Gly Leu Thr Ser
515 520 525
Leu Gln Ile Ala Ile Asp Ala Asp Leu Arg Ala Leu Gln Asp Ser Val
530 535 540
Ser Lys Leu Glu Asp Ser Leu Thr Ser Leu Ser Glu Val Val Leu Gln
545 550 555 560
Asn Arg Arg Gly Leu Asp Leu Leu Phe Leu Lys Glu Gly Gly Leu Cys
565 570 575
Ala Ala Leu Lys Glu Glu Cys Cys Phe Tyr Ile Asp His Ser Gly Ala
580 585 590
Val Arg Asp Ser Met Lys Lys Leu Lys Glu Lys Leu Asp Lys Arg Gln
595 600 605
Leu Glu Arg Gln Lys Ser Gln Asn Trp Tyr Glu Gly Trp Phe Asn Asn
610 615 620
Ser Pro Trp Phe Thr Thr Leu Leu Ser Thr Ile Ala Gly Pro Leu Leu
625 630 635 640
Leu Leu Leu Leu Leu Leu Ile Leu Gly Pro Cys Ile Ile Asn Lys Leu
645 650 655
Val Gln Phe Ile Asn Asp Arg Ile Ser Ala Val Lys Ile
660 665
<210> 27
<211> 759
<212> DNA
<213> 人工序列
<220>
<223> 人-小鼠杂合体
<400> 27
atgatcgaga cctacaatca gacaagccca cggtccgccg caaccggact gcctatcagc 60
atgaagatct tcatgtacct gctgaccgtg tttctgatca cacagatgat cggctccgcc 120
ctgttcgccg tgtatctgca caggagactg gacaagatcg aggatgagcg caatctgcac 180
gaggacttcg tgtttatgaa gaccatccag cggtgcaaca caggcgagag gagcctgtct 240
ctgctgaatt gtgaggagat caagtcccag ttcgagggct ttgtgaagga tatcatgctg 300
aacaaggagg agacaaagaa ggacgaggat ccacagatcg cagcacacgt ggtgtccgag 360
gcaaactcta atgccgccag cgtgctgcag tgggccaaga agggctacta taccatgaag 420
tctaacctgg tgacactgga gaatggcaag cagctgaccg tgaagaggca gggcctgtac 480
tatatctatg cccaggtgac attctgctct aacagagagg caagctccca ggcacccttc 540
atcgtgggac tgtggctgaa gccctctagc ggcagcgaga ggatcctgct gaaggccgcc 600
aatacccact cctctagcca gctgtgcgag cagcagtcca tccacctggg aggcgtgttc 660
gagctgcagc ctggagccag cgtgttcgtg aacgtgacag acccatctca ggtgagccac 720
ggcaccggct tcacaagctt tggcctgctg aagctgtga 759
<210> 28
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> 人-小鼠杂合体
<400> 28
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Asp Glu Asp Pro Gln
100 105 110
Ile Ala Ala His Val Val Ser Glu Ala Asn Ser Asn Ala Ala Ser Val
115 120 125
Leu Gln Trp Ala Lys Lys Gly Tyr Tyr Thr Met Lys Ser Asn Leu Val
130 135 140
Thr Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr
145 150 155 160
Tyr Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser
165 170 175
Gln Ala Pro Phe Ile Val Gly Leu Trp Leu Lys Pro Ser Ser Gly Ser
180 185 190
Glu Arg Ile Leu Leu Lys Ala Ala Asn Thr His Ser Ser Ser Gln Leu
195 200 205
Cys Glu Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro
210 215 220
Gly Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His
225 230 235 240
Gly Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu
245 250
<210> 29
<211> 1416
<212> DNA
<213> 人
<400> 29
atgctgccct ttctgagcat gctggtgctg ctggtgcagc ctctgggaaa cctgggagcc 60
gagatgaaga gcctgtccca gagatctgtg cctaacacct gcacactggt catgtgcagc 120
cccaccgaga atggactgcc tggaagggac ggaagggatg gaagggaggg ccctcggggc 180
gagaagggcg acccaggact gcctggacca atgggactga gcggactgca gggaccaaca 240
ggacctgtgg gaccaaaggg agagaacgga tccgccggag agccaggccc taagggcgag 300
aggggcctgt ctggcccccc tggcctgcca ggcatcccag gccccgccgg caaggagggc 360
ccatccggca agcagggcaa tatcggcccc cagggcaagc ctggcccaaa gggcgaggca 420
ggaccaaagg gagaagtggg agcacctggc atgcagggat ccaccggagc aaagggatct 480
acaggaccaa agggcgagcg cggcgcccca ggcgtgcagg gcgcccccgg caatgcagga 540
gcagcaggac cagcaggacc tgcaggccca cagggcgccc ctggctctag gggcccaccc 600
ggcctgaagg gcgacagggg agtgcctggc gataggggca tcaagggaga gagcggactg 660
ccagattccg ccgccctgag gcagcagatg gaggccctga agggcaagct gcagaggctg 720
gaggtggcct tctcccacta ccagaaggcc gccctgtttc cagacggcca caggagactg 780
gacaagatcg aggatgagcg caacctgcac gaggatttcg tgtttatgaa gaccatccag 840
agatgcaaca caggcgagcg gtctctgagc ctgctgaatt gtgaggagat caagtctcag 900
ttcgagggct ttgtgaagga catcatgctg aacaaggagg agaccaagaa ggagaatagc 960
ttcgagatgc agaagggcga tcagaatccc cagatcgcag cacacgtgat cagcgaggca 1020
agctccaaga ccacatccgt gctgcagtgg gccgagaagg gctactatac catgtccaac 1080
aatctggtga cactggagaa cggcaagcag ctgaccgtga agagacaggg cctgtactat 1140
atctatgccc aggtgacatt ctgctctaat cgggaggcct ctagccaggc cccttttatc 1200
gcctctctgt gcctgaagag cccaggcaga ttcgagcgga tcctgctgag ggccgccaac 1260
acccactcct ctgccaagcc atgcggacag cagagcatcc acctgggagg cgtgttcgag 1320
ctgcagccag gagcctccgt gtttgtgaat gtgacagacc catcccaggt gtctcacgga 1380
accggcttca catcctttgg cctgctgaag ctgtga 1416
<210> 30
<211> 471
<212> PRT
<213> 人
<400> 30
Met Leu Pro Phe Leu Ser Met Leu Val Leu Leu Val Gln Pro Leu Gly
1 5 10 15
Asn Leu Gly Ala Glu Met Lys Ser Leu Ser Gln Arg Ser Val Pro Asn
20 25 30
Thr Cys Thr Leu Val Met Cys Ser Pro Thr Glu Asn Gly Leu Pro Gly
35 40 45
Arg Asp Gly Arg Asp Gly Arg Glu Gly Pro Arg Gly Glu Lys Gly Asp
50 55 60
Pro Gly Leu Pro Gly Pro Met Gly Leu Ser Gly Leu Gln Gly Pro Thr
65 70 75 80
Gly Pro Val Gly Pro Lys Gly Glu Asn Gly Ser Ala Gly Glu Pro Gly
85 90 95
Pro Lys Gly Glu Arg Gly Leu Ser Gly Pro Pro Gly Leu Pro Gly Ile
100 105 110
Pro Gly Pro Ala Gly Lys Glu Gly Pro Ser Gly Lys Gln Gly Asn Ile
115 120 125
Gly Pro Gln Gly Lys Pro Gly Pro Lys Gly Glu Ala Gly Pro Lys Gly
130 135 140
Glu Val Gly Ala Pro Gly Met Gln Gly Ser Thr Gly Ala Lys Gly Ser
145 150 155 160
Thr Gly Pro Lys Gly Glu Arg Gly Ala Pro Gly Val Gln Gly Ala Pro
165 170 175
Gly Asn Ala Gly Ala Ala Gly Pro Ala Gly Pro Ala Gly Pro Gln Gly
180 185 190
Ala Pro Gly Ser Arg Gly Pro Pro Gly Leu Lys Gly Asp Arg Gly Val
195 200 205
Pro Gly Asp Arg Gly Ile Lys Gly Glu Ser Gly Leu Pro Asp Ser Ala
210 215 220
Ala Leu Arg Gln Gln Met Glu Ala Leu Lys Gly Lys Leu Gln Arg Leu
225 230 235 240
Glu Val Ala Phe Ser His Tyr Gln Lys Ala Ala Leu Phe Pro Asp Gly
245 250 255
His Arg Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp
260 265 270
Phe Val Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser
275 280 285
Leu Ser Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe
290 295 300
Val Lys Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser
305 310 315 320
Phe Glu Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val
325 330 335
Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu
340 345 350
Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly
355 360 365
Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln
370 375 380
Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile
385 390 395 400
Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu
405 410 415
Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser
420 425 430
Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe
435 440 445
Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr
450 455 460
Ser Phe Gly Leu Leu Lys Leu
465 470
<210> 31
<211> 1412
<212> DNA
<213> 小鼠
<400> 31
atgctgccct tcctgagcat gctggtgctg ctggtgcagc ctctgggcaa tctgggcgcc 60
gagatgaagt ccctgtctca gaggagcgtg ccaaacacct gcacactggt catgtgctct 120
ccaaccgaga atggactgcc aggaagggac ggaagagatg gaagggaggg accaagggga 180
gagaagggcg accctggact gcctggacca atgggactgt ccggactgca gggaccaaca 240
ggccctgtgg gaccaaaggg agagaatgga agcgccggag agccaggacc taagggagag 300
aggggcctgt ccggcccccc tggcctgcct ggcatcccag gccccgccgg caaggagggc 360
ccttctggca agcagggcaa catcggacca cagggcaagc ctggaccaaa gggagaggca 420
ggaccaaagg gagaagtggg agcacccggc atgcagggca gcaccggagc aaagggatcc 480
accggcccta agggagagag aggagcacct ggagtgcagg gcgccccagg caatgcagga 540
gcagcaggac cagcaggacc tgcaggccca cagggcgccc caggcagccg gggcccaccc 600
ggcctgaagg gcgacagggg agtgccaggc gataggggca tcaagggaga gtccggactg 660
ccagactctg ccgccctgag gcagcagatg gaggccctga agggcaagct gcagaggctg 720
gaggtggcct tctcccacta ccagaaggcc gccctgtttc cagacggaca caggagactg 780
gataaggtgg aggaggaggt gaacctgcac gaggatttcg tgttcatcaa gaagctgaag 840
aggtgcaaca agggcgaggg cagcctgtcc ctgctgaatt gtgaggagat gcggcgccag 900
ttcgaggacc tggtgaagga tatcaccctg aacaaggagg agaagaagga gaattctttt 960
gagatgcaga ggggcgacga ggatcctcag atcgcagcac acgtggtgtc cgaggcaaac 1020
tctaatgccg ccagcgtgct gcagtgggcc aagaagggct actataccat gaagtctaac 1080
ctggtcatgc tggagaatgg caagcagctg acagtgaaga gagagggcct gtactacgtg 1140
tacacccagg tgacattctg cagcaacaga gagcccagct cccagcggcc ttttatcgtg 1200
ggcctgtggc tgaagccctc tatcggaagc gagaggatcc tgctgaaggc agccaatacc 1260
cactctagct cccagctgtg cgagcagcag tccgtgcacc tgggaggcgt gttcgagctg 1320
caggcaggag caagcgtgtt cgtgaacgga cagaggccag ccaggtcatc cacagagtgg 1380
gcttctctag ctttggcctg ctgaagctgt ga 1412
<210> 32
<211> 470
<212> PRT
<213> 小鼠
<400> 32
Met Leu Pro Phe Leu Ser Met Leu Val Leu Leu Val Gln Pro Leu Gly
1 5 10 15
Asn Leu Gly Ala Glu Met Lys Ser Leu Ser Gln Arg Ser Val Pro Asn
20 25 30
Thr Cys Thr Leu Val Met Cys Ser Pro Thr Glu Asn Gly Leu Pro Gly
35 40 45
Arg Asp Gly Arg Asp Gly Arg Glu Gly Pro Arg Gly Glu Lys Gly Asp
50 55 60
Pro Gly Leu Pro Gly Pro Met Gly Leu Ser Gly Leu Gln Gly Pro Thr
65 70 75 80
Gly Pro Val Gly Pro Lys Gly Glu Asn Gly Ser Ala Gly Glu Pro Gly
85 90 95
Pro Lys Gly Glu Arg Gly Leu Ser Gly Pro Pro Gly Leu Pro Gly Ile
100 105 110
Pro Gly Pro Ala Gly Lys Glu Gly Pro Ser Gly Lys Gln Gly Asn Ile
115 120 125
Gly Pro Gln Gly Lys Pro Gly Pro Lys Gly Glu Ala Gly Pro Lys Gly
130 135 140
Glu Val Gly Ala Pro Gly Met Gln Gly Ser Thr Gly Ala Lys Gly Ser
145 150 155 160
Thr Gly Pro Lys Gly Glu Arg Gly Ala Pro Gly Val Gln Gly Ala Pro
165 170 175
Gly Asn Ala Gly Ala Ala Gly Pro Ala Gly Pro Ala Gly Pro Gln Gly
180 185 190
Ala Pro Gly Ser Arg Gly Pro Pro Gly Leu Lys Gly Asp Arg Gly Val
195 200 205
Pro Gly Asp Arg Gly Ile Lys Gly Glu Ser Gly Leu Pro Asp Ser Ala
210 215 220
Ala Leu Arg Gln Gln Met Glu Ala Leu Lys Gly Lys Leu Gln Arg Leu
225 230 235 240
Glu Val Ala Phe Ser His Tyr Gln Lys Ala Ala Leu Phe Pro Asp Gly
245 250 255
His Arg Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp
260 265 270
Phe Val Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser
275 280 285
Leu Ser Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu
290 295 300
Val Lys Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asn Ser Phe
305 310 315 320
Glu Met Gln Arg Gly Asp Glu Asp Pro Gln Ile Ala Ala His Val Val
325 330 335
Ser Glu Ala Asn Ser Asn Ala Ala Ser Val Leu Gln Trp Ala Lys Lys
340 345 350
Gly Tyr Tyr Thr Met Lys Ser Asn Leu Val Met Leu Glu Asn Gly Lys
355 360 365
Gln Leu Thr Val Lys Arg Glu Gly Leu Tyr Tyr Val Tyr Thr Gln Val
370 375 380
Thr Phe Cys Ser Asn Arg Glu Pro Ser Ser Gln Arg Pro Phe Ile Val
385 390 395 400
Gly Leu Trp Leu Lys Pro Ser Ile Gly Ser Glu Arg Ile Leu Leu Lys
405 410 415
Ala Ala Asn Thr His Ser Ser Ser Gln Leu Cys Glu Gln Gln Ser Val
420 425 430
His Leu Gly Gly Val Phe Glu Leu Gln Ala Gly Ala Ser Val Phe Val
435 440 445
Asn Val Thr Glu Ala Ser Gln Val Ile His Arg Val Gly Phe Ser Ser
450 455 460
Phe Gly Leu Leu Lys Leu
465 470
<210> 33
<211> 786
<212> DNA
<213> 人
<400> 33
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 34
<211> 261
<212> PRT
<213> 人
<400> 34
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 35
<211> 783
<212> DNA
<213> 小鼠
<400> 35
atgatagaaa catacagcca accttccccc agatccgtgg caactggact tccagcgagc 60
atgaagattt ttatgtattt acttactgtt ttccttatca cccaaatgat tggatctgtg 120
ctttttgctg tgtatcttca tagaagattg gataaggtcg aagaggaagt aaaccttcat 180
gaagattttg tattcataaa aaagctaaag agatgcaaca aaggagaagg atctttatcc 240
ttgctgaact gtgaggagat gagaaggcaa tttgaagacc ttgtcaagga tataacgtta 300
aacaaagaag agaaaaaaga aaacagcttt gaaatgcaaa gaggtgatga ggatcctcaa 360
attgcagcac acgttgtaag cgaagccaac agtaatgcag catccgttct acagtgggcc 420
aagaaaggat attataccat gaaaagcaac ttggtaatgc ttgaaaatgg gaaacagctg 480
acggttaaaa gagaaggact ctattatgtc tacactcaag tcaccttctg ctctaatcgg 540
gagccttcga gtcaacgccc attcatcgtc ggcctctggc tgaagcccag cagtggatct 600
gagagaatct tactcaaggc ggcaaatacc cacagttcct cccagctttg cgagcagcag 660
tctgttcact tgggcggagt gtttgaatta caagctggtg cttctgtgtt tgtcaacgtg 720
actgaagcaa gccaagtgat ccacagagtt ggcttctcat cttttggctt actcaaactc 780
tga 783
<210> 36
<211> 260
<212> PRT
<213> 小鼠
<400> 36
Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly
1 5 10 15
Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val
50 55 60
Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys
85 90 95
Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asn Ser Phe Glu Met
100 105 110
Gln Arg Gly Asp Glu Asp Pro Gln Ile Ala Ala His Val Val Ser Glu
115 120 125
Ala Asn Ser Asn Ala Ala Ser Val Leu Gln Trp Ala Lys Lys Gly Tyr
130 135 140
Tyr Thr Met Lys Ser Asn Leu Val Met Leu Glu Asn Gly Lys Gln Leu
145 150 155 160
Thr Val Lys Arg Glu Gly Leu Tyr Tyr Val Tyr Thr Gln Val Thr Phe
165 170 175
Cys Ser Asn Arg Glu Pro Ser Ser Gln Arg Pro Phe Ile Val Gly Leu
180 185 190
Trp Leu Lys Pro Ser Ser Gly Ser Glu Arg Ile Leu Leu Lys Ala Ala
195 200 205
Asn Thr His Ser Ser Ser Gln Leu Cys Glu Gln Gln Ser Val His Leu
210 215 220
Gly Gly Val Phe Glu Leu Gln Ala Gly Ala Ser Val Phe Val Asn Val
225 230 235 240
Thr Glu Ala Ser Gln Val Ile His Arg Val Gly Phe Ser Ser Phe Gly
245 250 255
Leu Leu Lys Leu
260
<210> 37
<211> 632
<212> DNA
<213> 人工序列
<220>
<223> CMV 启动子
<400> 37
gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 60
gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 120
ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 180
ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 240
atcaagtgta tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg 300
cctggcatta tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg 360
tattagtcat cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat 420
agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 480
tttggcacca aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc 540
aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctctc tggctaacta 600
gagaacccac tgcttactgg cttatcgaaa tt 632
<210> 38
<211> 394
<212> DNA
<213> 人工序列
<220>
<223> RSV 启动子
<400> 38
tgtacgggcc agatatacgc gtatctgagg ggactagggt gtgtttaggc gaaaagcggg 60
gcttcggttg tacgcggtta ggagtcccct caggatatag tagtttcgct tttgcatagg 120
gagggggaaa tgtagtctta tgcaatacac ttgtagtctt gcaacatggt aacgatgagt 180
tagcaacatg ccttacaagg agagaaaaag caccgtgcat gccgattggt ggaagtaagg 240
tggtacgatc gtgccttatt aggaaggcaa cagacaggtc tgacatggat tggacgaacc 300
actgaattcc gcattgcaga gataattgta tttaagtgcc tagctcgata caataaacgc 360
catttgacca ttcaccacat tggtgtgcac ctcc 394
<210> 39
<211> 188
<212> DNA
<213> 人工序列
<220>
<223> BGH polyA
<400> 39
ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 60
tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 120
tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 180
gggaagac 188
<210> 40
<211> 249
<212> DNA
<213> 人工序列
<220>
<223> SV40晚期polyA
<400> 40
gacatgataa gatacattga tgagtttgga caaaccacaa ctagaatgca gtgaaaaaaa 60
tgctttattt gtgaaatttg tgatgctatt gctttatttg tgaaatttgt gatgctattg 120
ctttatttgt aaccattata agctgcaata aacaagttaa caacaacaat tgcattcatt 180
ttatgtttca ggttcagggg gaggtgtggg aggtttttta aagcaagtaa aacctctaca 240
aatgtggta 249
<210> 41
<211> 99
<212> DNA
<213> 人工序列
<220>
<223> 兔beta-球蛋白polyA
<400> 41
gacctctggc taataaagga aatttatttt cattgcaata gtgtgttgga attttttgtg 60
tctctcactc ggaaggacat atgggagggc aaatcattt 99
<210> 42
<211> 723
<212> DNA
<213> 人工序列
<220>
<223> GFP
<400> 42
accatggtga gcaagggcga ggagctgttc accggggtgg tgcccatcct ggtcgagctg 60
gacggcgacg taaacggcca caagttcagc gtgtccggcg agggcgaggg cgatgccacc 120
tacggcaagc tgaccctgaa gttcatctgc accaccggca agctgcccgt gccctggccc 180
accctcgtga ccaccctgac ctacggcgtg cagtgcttca gccgctaccc cgaccacatg 240
aagcagcacg acttcttcaa gtccgccatg cccgaaggct acgtccagga gcgcaccatc 300
ttcttcaagg acgacggcaa ctacaagacc cgcgccgagg tgaagttcga gggcgacacc 360
ctggtgaacc gcatcgagct gaagggcatc gacttcaagg aggacggcaa catcctgggg 420
cacaagctgg agtacaacta caacagccac aacgtctata tcatggccga caagcagaag 480
aacggcatca aggtgaactt caagatccgc cacaacatcg aggacggcag cgtgcagctc 540
gccgaccact accagcagaa cacccccatc ggcgacggcc ccgtgctgct gcccgacaac 600
cactacctga gcacccagtc cgccctgagc aaagacccca acgagaagcg cgatcacatg 660
gtcctgctgg agttcgtgac cgccgccggg atcactctcg gcatggacga gctgtacaag 720
taa 723
<210> 43
<211> 454
<212> DNA
<213> 人工序列
<220>
<223> MoMuLV LTR
<400> 43
ttaattaagt aacgccattt tgcaaggcat ggaaaaatac ataactgaga atagagaagt 60
tcagatcaag gtcaggaaca gatggaacag ctgaatatgg gccaaacagg atatctgtgg 120
taagcagttc ctgccccggc tcagggccaa gaacagatgg aacagctgaa tatgggccaa 180
acaggatatc tgtggtaagc agttcctgcc ccggctcagg gccaagaaca gatggtcccc 240
agatgcggtc cagccctcag cagtttctag agaaccatca gatgtttcca gggtgcccca 300
aggacctgaa atgaccctgt gccttatttg aactaaccaa tcagttcgct tctcgcttct 360
gttcgcgcgc ttctgctccc cgagctcaat aaaagagccc acaacccctc actcggggcg 420
ccagtcctcc gattgactga gtcgcccgct taag 454
<210> 44
<211> 1349
<212> DNA
<213> 人工序列
<220>
<223> EF1alpha 启动子
<400> 44
ttaattaaga gtaattcata caaaaggact cgcccctgcc ttggggaatc ccagggaccg 60
tcgttaaact cccactaacg tagaacccag agatcgctgc gttcccgccc cctcacccgc 120
ccgctctcgt catcactgag gtggagaaga gcatgcgtga ggctccggtg cccgtcagtg 180
ggcagagcgc acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac 240
cggtgcctag agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg 300
cctttttccc gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct 360
ttttcgcaac gggtttgccg ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc 420
tggcctcttt acgggttatg gcccttgcgt gccttgaatt acttccacgc ccctggctgc 480
agtacgtgat tcttgatccc gagcttcggg ttggaagtgg gtgggagagt tcgaggcctt 540
gcggttaagg agccccttcg cctcgtgctt gagttgaggc ctggcttggg cgctggggcc 600
gccgcgtgcg aatctggtgg caccttcgcg cctgtctcgc tgctttcgat aagtctctag 660
ccatttaaaa tttttgatga cctgctgcga cgcttttttt ctggcaagat agtcttgtaa 720
atgcgggcca agatctgcac actggtattt cggtttttgg ggccgcgggc ggcgacgggg 780
cccgtgcgtc ccagcgcaca tgttcggcga ggcggggcct gcgagcgcgg ccaccgagaa 840
tcggacgggg gtagtctcaa gctggccggc ctgctctggt gcctggcctc gcgccgccgt 900
gtatcgcccc gccctgggcg gcaaggctgg cccggtcggc accagttgcg tgagcggaaa 960
gatggccgct tcccggccct gctgcaggga gctcaaaatg gaggacgcgg cgctcgggag 1020
agcgggcggg tgagtcaccc acacaaagga aaagggcctt tccgtcctca gccgtcgctt 1080
catgtgactc cacggagtac cgggcgccgt ccaggcacct cgattagttc tcgagctttt 1140
ggagtacgtc gtctttaggt tggggggagg ggttttatgc gatggagttt ccccacactg 1200
agtgggtgga gactgaagtt aggccagctt ggcacttgat gtaattctcc ttggaatttg 1260
ccctttttga gtttggatct tggttcattc tcaagcctca gacagtggtt caaagttttt 1320
ttcttccatt tcaggtgtcg tgacttaag 1349
<210> 45
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> SV40 增强子启动子
<400> 45
gctgtggaat gtgtgtcagt tagggtgtgg aaagtcccca ggctccccag caggcagaag 60
tatgcaaagc atgcatctca attagtcagc aaccaggtgt ggaaagtccc caggctcccc 120
agcaggcaga agtatgcaaa gcatgcatct caattagtca gcaaccatag tcccgcccct 180
aactccgccc atcccgcccc taactccgcc cagttccgcc cattctccgc cccatggctg 240
actaattttt tttatttatg cagaggccga ggccgcctcg gcctctgagc tattccagaa 300
gtagtgagga ggcttttttg gaggcctagg cttttgcaaa aagct 345
<210> 46
<211> 481
<212> DNA
<213> 人工序列
<220>
<223> HGH polyA
<400> 46
gacgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 60
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 120
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggca agttgggaag 180
acaacctgta gggcctgcgg ggtctattgg gaaccaagct ggagtgcagt ggcacaatct 240
tggctcactg caatctccgc ctcctgggtt caagcgattc tcctgcctca gcctcccgag 300
ttgttgggat tccaggcatg catgaccagg ctcagctaat ttttgttttt ttggtagaga 360
cggggtttca ccatattggc caggctggtc tccaactcct aatctcaggt gatctaccca 420
ccttggcctc ccaaattgct gggattacag gcgtgaacca ctgctccctt ccctgtcctt 480
t 481
Claims (53)
1.一种编码CTLA-4抑制剂的溶瘤病毒。
2.权利要求1的病毒，其中所述CTLA-4抑制剂是抗-CTLA-4抗体，或其抗原结合片段。
3.权利要求2的病毒，其中所述片段包含scFv分子。
4.权利要求2的病毒，其中所述片段是与一个或多个IgG1恒定区连接的scFv分子。
5.权利要求2至4中任一项的病毒，其中所述抗体或片段包含与IgG重链连接的轻链可变区序列。
6.权利要求2至5中任一项的病毒，其中所述抗体或片段包含(a)SEQ ID NO:1中所示的轻链可变区序列和SEQ ID NO:3中所示的重链可变区序列；或(b)SEQ ID NO:11中所示的轻链可变区序列和SEQ ID NO:12中所示的重链可变区序列。
7.权利要求6的病毒，其中所述抗体或片段包含(a)SEQ ID NO:9的氨基酸序列；或(b)SEQ ID NO:14的氨基酸序列。
8.权利要求7的病毒，其中所述抗体或片段由(a)SEQ ID NO:10的核苷酸序列或(b)SEQID NO:15的核苷酸序列编码。
9.前述权利要求中任一项的病毒，其中所述病毒还包含GM-CSF编码基因。
10.前述权利要求中任一项的病毒，其中所述病毒还包含免疫共刺激途径激活分子或免疫共刺激途径激活分子编码基因。
11.权利要求10的病毒，其中所述免疫共刺激途径激活分子编码基因编码CD40配体(CD40L)、ICOS配体、GITR配体、4-1-BB配体、OX40配体、TL1A、CD30配体、CD27或flt3配体或这些配体中的任一种的修饰形式。
12.权利要求10或11的病毒，其中所述免疫共刺激途径激活分子编码基因编码CD40配体、GITR配体、4-1-BB配体、OX40配体、ICOS配体或这些配体中的任一种的修饰形式。
13.前述权利要求中任一项的病毒，其还包含促融合蛋白编码基因。
14.权利要求13的病毒，其中所述促融合蛋白选自水泡性口炎病毒(VSV)G蛋白、合胞素-1、合胞素-2、猿猴病毒5(SV5)F蛋白、麻疹病毒(MV)H蛋白、MV F蛋白、呼吸道合胞病毒(RSV)F蛋白和已从其缺失R肽的来自长臂猿白血病病毒(GALV)、鼠白血病病毒(MLV)、Mason-Pfizer猴病毒(MPMV)或马传染性贫血病毒(EIAV)的糖蛋白。
15.权利要求13或14的病毒，其中所述促融合蛋白是来自长臂猿白血病病毒(GALV)的糖蛋白，并且R跨膜肽已被突变或去除(GALV-R-)。
16.前述权利要求中任一项的病毒，其编码超过一种免疫共刺激途径激活分子。
17.前述权利要求中任一项的病毒，其源自病毒的临床分离株。
18.前述权利要求中任一项的病毒，其为病毒的经修饰的临床分离株，其中所述临床分离株相较于相同病毒种类的一种或多种参照临床分离株更快速地和/或以更低的剂量体外杀死两种或更多种肿瘤细胞系。
19.前述权利要求中任一项的病毒，其选自疱疹病毒、痘病毒、腺病毒、逆转录病毒、弹状病毒、副粘病毒和呼肠孤病毒。
20.前述权利要求中任一项的病毒，其为单纯疱疹病毒(HSV)。
21.权利要求20的病毒，其为HSV1。
22.权利要求21的病毒，其中所述HSV：
(a)不表达功能性ICP34.5；
(b)不表达功能性ICP47；和/或
(c)将US11基因表达为立即早期基因。
23.权利要求20至22中任一项的病毒，其中已通过插入、部分缺失或完全缺失将抗-CTLA-4抑制蛋白编码基因插入到ICP34.5编码基因座中。
24.权利要求23的病毒，其中所述抗-CTLA-4抑制蛋白编码基因包含在盒中，所述盒还包含一种或多种免疫刺激基因诸如GM-CSF和/或免疫共刺激途径激活分子编码基因和/或促融合蛋白编码基因。
25.前述权利要求中任一项的病毒，其中所述编码CTLA-4抑制剂的序列、编码GM-CSF的序列、编码免疫共刺激途径激活分子的序列和/或编码促融合蛋白的序列被密码子优化以提高靶细胞中的表达水平。
26.前述权利要求中任一项的病毒，其表达三种异源基因，其中所述三种异源基因中的每一种均由不同的启动子驱动，所述启动子选自CMV启动子、RSV启动子、SV40启动子(SEQID)和逆转录病毒LTR启动子。
27.权利要求26的病毒，其表达分别由CMV启动子、RSV启动子、SV40启动子和逆转录病毒LTR启动子中的每一种驱动的四种异源基因。
28.权利要求26或27的病毒，其中所述逆转录病毒LTR来自MMLV(SEQ ID)。
29.前述权利要求中任一项的病毒，其表达三种异源基因，其中所述三种异源基因中的每一种被不同的多腺苷酸化序列中止，所述多腺苷酸化序列选自BGH、SV40、HGH和RBG多聚腺苷酸化序列。
30.权利要求29的病毒，其表达分别由BGH、SV40、HGH和RBG多聚腺苷酸化序列中的每一种终止的四种异源基因。
31.权利要求26至30中任一项的病毒，其为痘病毒。
32.一种药物组合物，其包含根据权利要求1至31中任一项的病毒和药学上可接受的载体或稀释剂。
33.权利要求1至31中任一项的病毒，其用于通过疗法治疗人体或动物体的方法。
34.权利要求1至31中任一项的病毒，其用于治疗癌症的方法中。
35.一种用于根据权利要求34的用途的病毒，其中所述方法包括施用另外的抗癌剂。
36.一种用于根据权利要求35的用途的病毒，其中所述另外的抗癌剂选自靶向免疫共抑制或免疫共刺激途径的药剂、辐照和/或化学疗法、靶向肿瘤中发生的特定遗传突变的药剂、旨在诱导对一种或多种肿瘤抗原或新抗原的免疫反应的药剂、源自T细胞或NK细胞的细胞产物、旨在刺激STING、cGAS、TLR或其他先天性免疫反应和/或炎性途径的药剂、第二病毒，任选地为溶瘤病毒，及其组合。
37.一种用于根据权利要求36的用途的病毒，其中所述靶向免疫共抑制途径的药剂是PD-1抑制剂、PD-L1抑制剂、LAG-3抑制剂、TIM-3抑制剂、VISTA抑制剂、CSF1R抑制剂、IDO抑制剂、KIR抑制剂、SLAMF7抑制剂、CEACAM1抑制剂或CD47抑制剂，和/或靶向免疫共刺激途径的药剂是GITR激动剂、4-1-BB激动剂、OX40激动剂、CD40激动剂或ICOS激动剂。
38.一种用于根据权利要求35至37中任一项的用途的病毒，其中所述另外的抗癌剂是抗体。
39.一种用于根据权利要求35至38中任一项的用途的病毒，其中所述方法包括施用吲哚胺2,3-双加氧酶(IDO)途径的抑制剂以及免疫共抑制途径的另一拮抗剂或免疫共刺激途径的激动剂。
40.一种用于根据权利要求34至39中任一项的用途的病毒，其中分开施用所述病毒和所述另外的抗癌剂。
41.一种用于根据权利要求34至39中任一项的用途的病毒，其中同时施用所述病毒和所述另外的抗癌剂。
42.一种用于根据权利要求34至41中任一项的用途的病毒，其中所述癌症是实体瘤。
43.一种制品，其在无菌小瓶、安瓿或注射器中包含根据权利要求1至31中任一项的病毒。
44.一种治疗癌症的方法，其包括向有此需要的患者施用治疗有效量的权利要求1至31中任一项的病毒或根据权利要求32的药物组合物。
45.权利要求44的方法，其还包括向有此需要的患者施用治疗有效量的另外的抗癌剂。
46.权利要求45的方法，其中所述另外的抗癌剂选自靶向免疫共抑制或免疫共刺激途径的药剂、辐照和/或化学疗法、靶向肿瘤中发生的特定遗传突变的药剂、旨在诱导对一种或多种肿瘤抗原或新抗原的免疫反应的药剂、源自T细胞或NK细胞的细胞产物、旨在刺激STING、cGAS、TLR或其他先天性免疫反应和/或炎性途径的药剂、第二病毒，任选地为溶瘤病毒，及其组合。
47.权利要求46的方法，其中所述靶向免疫共抑制途径的药剂是PD-1抑制剂、PD-L1抑制剂、LAG-3抑制剂、TIM-3抑制剂、VISTA抑制剂、CSF1R抑制剂、IDO抑制剂、KIR抑制剂、SLAMF7抑制剂、CEACAM1抑制剂或CD47抑制剂，和/或所述靶向免疫共刺激途径的药剂为GITR激动剂、4-1-BB激动剂、OX40激动剂、CD40激动剂或ICOS激动剂。
48.权利要求45至47中任一项的方法，其中所述另外的抗癌剂包括抗体。
49.权利要求45至48中任一项的方法，其中分开施用所述病毒和所述另外的抗癌剂。
50.权利要求45至48中任一项所述的方法，其中同时施用所述病毒和所述另外的抗癌剂。
51.权利要求44-50中任一项的方法，其中所述癌症是实体瘤。
52.权利要求1至31中任一项的病毒在制备用于治疗癌症的方法的药物中的用途。
53.权利要求52的用途，其中所述方法包括施用另外的抗癌剂。
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| GB1700350.0 | 2017-01-09 | ||
| PCT/GB2018/050048 WO2018127713A1 (en) | 2017-01-09 | 2018-01-09 | Altered virus |
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| BR112019000015A2 (pt) | 2016-06-30 | 2019-04-24 | Oncorus, Inc. | distribuição por vírus oncolítico pseudotipado de polipeptídeos terapêuticos |
| EP3658165A4 (en) | 2017-07-26 | 2021-09-01 | Oncorus, Inc. | ONCOLYTIC VIRUS VECTORS AND USES THEREOF |
| BR122021015266B1 (pt) | 2017-08-03 | 2023-01-24 | Amgen Inc. | Conjugado compreendendo muteína de il-21 e anticorpo anti-pd, kit e composição farmacêutica |
| ES2928576T3 (es) | 2017-09-08 | 2022-11-21 | Amgen Inc | Inhibidores de KRAS G12C y métodos de uso de los mismos |
| US11865081B2 (en) | 2017-12-29 | 2024-01-09 | Virogin Biotech Canada Ltd. | Oncolytic viral delivery of therapeutic polypeptides |
| JP2019122373A (ja) | 2018-01-12 | 2019-07-25 | アムジエン・インコーポレーテツド | 抗ｐｄ−１抗体及び治療方法 |
| CN109762068A (zh) * | 2018-08-09 | 2019-05-17 | 源道隆（苏州）医学科技有限公司 | 一种可靶向ctla4和pd-1的单基因双特异性抗体及其应用 |
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| EP3565568A1 (en) | 2019-11-13 |
| US20190343903A1 (en) | 2019-11-14 |
| AU2018205763A1 (en) | 2019-06-20 |
| BR112019013215A2 (pt) | 2019-12-10 |
| CA3049496A1 (en) | 2018-07-12 |
| JP2020503871A (ja) | 2020-02-06 |
| IL267949A (en) | 2019-09-26 |
| MX2019008146A (es) | 2019-10-09 |
| WO2018127713A1 (en) | 2018-07-12 |
| KR20190104055A (ko) | 2019-09-05 |
| GB201700350D0 (en) | 2017-02-22 |
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