CN111868246A - 拴系白细胞介素-15和白细胞介素-21 - Google Patents
拴系白细胞介素-15和白细胞介素-21 Download PDFInfo
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- CN111868246A CN111868246A CN201980012443.3A CN201980012443A CN111868246A CN 111868246 A CN111868246 A CN 111868246A CN 201980012443 A CN201980012443 A CN 201980012443A CN 111868246 A CN111868246 A CN 111868246A
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Abstract
本申请公开了提供由宿主细胞共表达白细胞介素(IL)‑21和IL‑15的核酸和多肽，每种白细胞介素通过细胞膜锚定部分与细胞膜结合。还公开了相关的重组表达载体、宿主细胞、细胞群体、药物组合物以及治疗或预防癌症的方法。
Description
相关申请的交叉引用
本专利申请要求2018年2月9日提交的美国临时专利申请第62/628,454号的权益，将其在此通过引用以其整体并入。
关于联邦政府资助研究与开发的声明
本发明是由美国国立卫生研究院国家癌症研究所在政府支持下完成的，资助号是ZIABC011478。政府拥有本发明的某些权利。
通过引用并入电子提交的材料
通过引用以其整体并入本文的是随本文同时提交的并且如下确定的计算机可读的核苷酸/氨基酸序列表：名称为“741568_ST25.TXT”，日期为2019年2月7日的一份71,216字节ASCII(文本)文件。
发明背景
过继细胞疗法可有效治疗一些患者的癌症。然而，过继细胞疗法的总体成功的障碍仍然存在。例如，在一些情况下，在过继转移后，转移的T细胞的体内持久性、存活和抗肿瘤活性降低。尽管在过继细胞疗法领域进行了大量的研究，但仍然需要用于产生用于过继细胞疗法的细胞以及治疗和/或预防癌症的改进的方法和产品。
发明概述
本发明的实施方案提供了包含编码式I的氨基酸序列的核苷酸序列的核酸：
S1-N1-L1-C1 a-L2-S2-N2-L3-C2 b
(式I)，
其中：
S1和S2中的每一个独立地是信号序列；
N1和N2中的一个是白细胞介素(IL)-21氨基酸序列，并且N1和N2中的一个是IL-15氨基酸序列；
L1、L2和L3中的每一个独立地是接头序列；
C1和C2中的每一个独立地是跨膜-细胞内氨基酸序列或跨膜氨基酸序列；以及
a和b中的每一个独立地是0或1。
本发明的其它实施方案提供了相关的重组表达载体、多肽、宿主细胞、细胞群体、药物组合物以及治疗或预防癌症的方法。
附图中几个视图的简要说明
图1A是说明拴系(tethered)IL-15(TeIL-15)构建体的组成的示意图。每个TeIL-15构建体包含信号序列、IL-15成熟氨基酸序列、接头和细胞膜锚定部分(“锚”)。
图1B是说明拴系IL-21(TeIL-21)构建体的组成的示意图。每个TeIL-21构建体包含信号序列、IL-21成熟氨基酸序列、接头和细胞膜锚定部分(“锚”)。
图1C是说明拴系IL-21/拴系IL-15(TeIL-21/15)构建体的组成的示意图。每个TeIL-21/15构建体包含图1B的TeIL-21构建体、可切割的接头和图1A的TeIL-15构建体。
图2是显示用编码表2中的TeIL-15 Lr1、TeIL-15 Lr2、IL-15 RA、TeIL-15 Lr6或IL-15S构建体的载体转导细胞后7天，从培养基中撤掉IL-2后，在不同时间点(天数)测量的活细胞数量的图。未转导的(Un Tdx)细胞用作阴性对照。在外源性IL-15存在下培养的未转导细胞用作阳性对照。
图3是显示在输注未转导的(*)或转导的细胞(每组n＝5)后的指定天数，在荷瘤小鼠中测量的肿瘤大小(mm2)的图。用(i)DMF5 TCR和TeIL-15 Lr1Ar2(空心正方形)、(ii)DMF5 TCR和TeIL-21 Lr8Ar1(空心三角形)、(iii)DMF5 TCR和TeIL-21/15 E2A Ar1(空心菱形)、(iv)E7 TCR和TeIL-15 Lr1Ar2(实心正方形)、(v)E7 TCR和TeIL-21 Lr8Ar1(实心三角形)、(vi)E7 TCR和TeIL-21/15 E2A Ar1(实心菱形)、(vi)单独的DMF5 TCR(空心圆)、或(vii)单独的E7 TCR(实心圆)转导细胞。
图4A是显示在未转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4B是显示在用单独的E7 TCR转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4C是显示在用E7 TCR和TeIL-15转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4D是显示在用E7 TCR和TeIL-21转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4E是显示在用E7 TCR和TeIL-21/15转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4F是显示在用单独的DMF5 TCR转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4G是显示在用DMF5 TCR和TeIL-15转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4H是显示在用DMF5 TCR和TeIL-21转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图4I是显示在用DMF5 TCR和TeIL-21/15转导的T细胞输注后的指定天数，在5只荷瘤小鼠的每只中测量的肿瘤大小(mm2)的图。
图5A-5T是显示在用TeIL-21/15FurinA-P2A Ar2(正方形)或分泌的IL-21/15(sIL-21/15)(三角形)转导来自健康供体1-20(分别是图5A-5T)的细胞后，在指定的时间点(天数)存活的细胞浓度(细胞数/mL×106)的图。未处理的(UT)细胞(圆圈)用作对照。
图6A-6B是显示在用如下(i)-(v)之一转导的T细胞的上清液中测量的IL-15(6A)和IL-21(6B)的浓度(pg/mL)的图：(i)E7 TCR和TeIL-15 Lr1Ar2、(ii)E7 TCR和TeIL-21Lr8Ar2、(iii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2、(iv)E7 TCR和分泌的IL-21/15(sIL-21/15)或(v)单独的E7 TCR。未转导的(UTDX)T细胞用作对照。
图6C-6D是显示每种指定的肿瘤细胞系与用如下(i)-(v)之一转导的T细胞共培养物的上清液中测量的IL-15(6C)和IL-21(6D)的浓度(pg/mL)的图：(i)E7 TCR和TeIL-15Lr1Ar2、(ii)E7 TCR和TeIL-21 Lr8Ar2、(iii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2、(iv)E7 TCR和分泌的IL-21/15(sIL-21/15)、或(v)单独的E7 TCR。未转导的(UTDX)T细胞用作对照。
图7A-7B是显示在输注后的指定天数用未转导的细胞(UTDX)、HBSS(无Tx)或转导的细胞输注的健康NSG小鼠的血清中测量的IL-15(7A)和IL-21(7B)的浓度(pg/mL)的图。用如下(i)-(iii)之一转导细胞：(i)E7 TCR和TeIL-21/15 FurinA-P2A Ar2、(ii)E7 TCR和分泌的IL-21/15(sIL-21/15)、或(iii)单独的E7 TCR。
图7C-7D是显示在输注后的指定天数用未转导的细胞(UTDX)、HBSS(无Tx)或转导的细胞输注的荷瘤NSG小鼠的血清中测量的IL-15(7C)和IL-21(7D)的浓度(pg/mL)的图。用如下(i)-(v)之一转导细胞：(i)E7 TCR和TeIL-15 Lr1Ar2、(ii)E7 TCR和TeIL-21 Lr8Ar2、(iii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2、(iv)E7 TCR和分泌的IL-21/15(sIL-21/15)、或(v)单独的E7 TCR。
图8A-8G是显示在未转导的细胞(UTDX)、HBSS(无Tx)或转导的细胞输注后的指定天数，在荷瘤小鼠中观察到的IFN-γ、TNF-α、GM-CSF、IL-2、MIP-1α、IL-2Rα和IL-6(分别是8A-8G)的浓度(pg/mL)的图。用如下(i)-(v)之一转导T细胞：(i)E7 TCR和TeIL-15 Lr1Ar2、(ii)E7 TCR和TeIL-21 Lr8Ar2、(iii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2、(iv)E7 TCR和分泌的IL-21/15(sIL-21/15)、或(v)单独的E7 TCR。
图9是显示在HBSS(无Tx)(*)或转导的T细胞输注后的指定天数，在荷瘤小鼠中测量的肿瘤大小(mm2)的图。用如下(i)-(iv)之一转导输注的T细胞：(i)E7 TCR和NFAT.IL12(三角形)、(ii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2和NFAT.IL12(星形)、(iii)E7 TCR和TeIL-21/15 FurinA-P2A Ar2(菱形)、或(iv)单独的E7 TCR(对照)(圆圈)。n＝每次实验中小鼠的数量。
发明详述
本发明的实施方案提供了通过宿主细胞提供白细胞介素(IL)-21和IL-15共表达的核酸和多肽，每种白细胞介素通过细胞膜锚定部分与细胞膜结合。本发明的核酸和多肽可以提供多种优势中的任何一种或多种。这些优势可以包括，例如，膜结合IL-15和膜结合IL-21的高表达水平。与用单独的抗原特异性受体转导的细胞或者用抗原特异性受体以及IL-15或IL-21中不超过一种共转导的细胞相比，表达本发明核酸或多肽的细胞可以提供增强的功能(例如，增强的抗肿瘤功效)。不受特定理论或机制的束缚，还认为与含有IL-15Rα和IL-15核苷酸序列两者的核酸相比，本发明核酸中IL-15受体亚基α(IL-15Rα)的缺失有利地为例如IL-21核苷酸序列提供了更多的空间。
在一些情况下，IL-15和/或IL-21在过继转移T细胞的背景中的临床效用可能部分地受到剂量限制性毒性和需要重复施用的限制。本发明的核酸和多肽可以有利地通过由表达所述核酸或多肽的宿主细胞提供IL-15和IL-21的自分泌表达来改善这些限制。不受特定理论或机制的束缚，认为因为IL-15和IL-21分子被拴系于表达本发明核酸的细胞，所以该细胞向其自身提供IL-15和IL-21信号。认为，这种自分泌IL-15表达可以减少或避免在可溶性IL-15存在下可观察到的不期望的过度细胞生长。通过经由柔性接头将白细胞介素连接到细胞膜锚定部分，本发明的核酸和多肽可以降低可能由游离细胞因子分子引起的全身毒性。不受特定理论或机制的束缚，认为因为IL-15主要经由促细胞生长蛋白STAT5A/STAT5B发出信号，而IL-21主要经由促细胞死亡蛋白STAT1和STAT3发出信号，所以由本发明的核酸和多肽提供的IL-15和IL-21的共表达可以减少或避免在单独的IL-15存在下可观察到的不期望的过度细胞生长。
本发明的实施方案提供了包含编码式I的氨基酸序列的核苷酸序列的核酸：
S1-N1-L1-C1 a-L2-S2-N2-L3-C2 b
(式I)。
信号序列
在实施方案中，式I的S1和S2中的每一个独立地是信号序列。信号序列不受限制，并且可以是促进编码的多肽易位至细胞膜的任何序列。信号序列的实例是人粒细胞-巨噬细胞集落刺激因子(GM-CSF)受体信号序列、人催乳素信号序列和人IgE信号序列。优选地，信号序列是人IgE信号序列。人IgE信号序列可以包含MDWTWILFLVAAATRVHS(SEQ ID NO:1)的氨基酸序列，由其组成或基本上由其组成。人IgE信号序列可以包含NIKGSPWKGSLLLLLVSNLLLCQSVAP(SEQ ID NO:38)的氨基酸序列，由其组成或基本上由其组成。不受特定理论或机制的束缚，虽然认为信号序列可以促进细胞膜结合的白细胞介素的表达，但在表达的膜结合的白细胞介素中存在信号序列对于膜结合的白细胞介素发挥功能可能不是必需的。在本发明的实施方案中，在细胞表达膜结合的白细胞介素时，可以从膜结合的白细胞介素中切除信号序列。
白细胞介素
在实施方案中，式I中的N1和N2中的一个是白细胞介素(IL)-21氨基酸序列，并且N1和N2中的一个是IL-15氨基酸序列。虽然N1可以是IL-15氨基酸序列，并且N2可以是IL-21氨基酸序列，但在优选的实施方案中，N1是IL-21氨基酸序列，并且N2是IL-15氨基酸序列。
IL-21和IL-15是多效的四个α-螺旋束I型细胞因子。IL-21结合IL-21受体(IL-21R)和辅助受体(co-receptor)，常见的γ链(CD132)，并且IL-15结合IL-15受体α(IL-15Rα)和辅助受体，IL-2/IL-15受体β链(CD122)和CD132。在结合它们各自的受体和辅助受体时，IL-21和IL-15启动各种下游信号传导靶标中的一种或多种的活化，所述下游信号传导靶标包括例如JAK-STAT途径中的蛋白质，如JAK激酶(例如JAK1和JAK3)、STAT蛋白(例如STAT1、STAT3、STAT5A和STAT5B)以及磷酸肌醇3-激酶(PI3-激酶)和MAP激酶途径中的蛋白质。不受特定理论或机制的束缚，认为IL-21可以诱导某些免疫细胞(例如T细胞和NK细胞)的分化、死亡和活性中的一种或多种，并且IL-15可以诱导某些免疫细胞(例如T细胞和NK细胞)的分化、增殖和活性中的一种或多种。
在实施方案中，IL-21序列是人IL-21序列。人IL-21氨基酸序列包括Genbank登录号：AAU88182.1、EAX05226.1、CAI94500.1、CAJ47524.1、CAL81203.1、CAN87399.1、CAS03522.1、CAV33288.1、CBE74752.1、CBI70418.1、CBI85469.1、CBI85472.1、CBL93962.1、CCA63962.1、AAG29348.1、AAH66258.1、AAH66259.1、AAH66260.1、AAH66261.1、AAH66262.1、AAH69124.1和ABG36529.1。根据本发明可以使用其它人IL-21序列以及其它IL-21种类。在优选的实施方案中，IL-21氨基酸序列是成熟的人IL-21的氨基酸序列。成熟的人IL-21包含SEQ ID NO:2的氨基酸序列，由其组成或基本上由其组成。
在实施方案中，IL-15序列是人IL-15序列。人IL-15氨基酸序列包括Genbank登录号：NP_751915.1、NP_000576.1、AAI00963.1、AAI00964.1、AAI00962.1、CAA71044.1、AAH18149.1、AAB97518.1、CAA63914.1和CAA63913.1。根据本发明可以使用其它人IL-15序列以及其它IL-15种类。在优选的实施方案中，IL-15氨基酸序列是成熟的人IL-15的氨基酸序列。成熟的人IL-15包含SEQ ID NO:3的氨基酸序列，由其组成或基本上由其组成。
由本发明的核酸编码的IL-21和IL-15氨基酸序列可以分别包含成熟的IL-21或成熟的IL-15的任何功能部分。功能部分可以是包含其所来源的白细胞介素的连续氨基酸的任何部分，条件是所述功能部分特异性结合相应的白细胞介素受体。当用于提及白细胞介素时，术语“功能部分”是指白细胞介素的任何部分或片段，该部分或片段保留了其所来源的白细胞介素(亲本白细胞介素)的生物活性。功能部分涵盖，例如，白细胞介素的那些部分，其保留了与亲本白细胞介素相似的程度、相同的程度或更高的程度的特异性结合相应的白细胞介素受体，活化白细胞介素的下游靶标，和/或诱导免疫细胞(例如NK细胞和T细胞)的分化、增殖(或死亡)和活性中的一种或多种的能力。可以使用本领域已知的测定来测量白细胞介素的功能部分的生物活性。关于亲本白细胞介素，功能部分可以包含例如亲本白细胞介素的约60％、约70％、约80％、约90％、约95％或更多。
包括在本发明范围内的是本文所述的白细胞介素的功能变体。本文所用的术语“功能变体”是指与亲本白细胞介素具有大量的或显著的序列同一性或相似性的白细胞介素，该功能变体保留了变体所来源的白细胞介素的生物活性。功能变体涵盖，例如，本文所述的白细胞介素(亲本白细胞介素)的那些变体，其保留了与亲本白细胞介素相似的程度、相同的程度或更高的程度的特异性结合相应的白细胞介素受体，活化白细胞介素的下游靶标和/或诱导免疫细胞(例如T细胞和NK细胞)的分化、增殖(或死亡)和活性中的一种或多种的能力。关于亲本白细胞介素，功能变体可以与亲本白细胞介素的氨基酸序列例如至少约80％、约90％、约95％、约99％或更多相同。
功能变体可以例如包含具有至少一个保守氨基酸取代的亲本白细胞介素的氨基酸序列。可选地或另外地，功能变体可以包含具有至少一个非保守氨基酸取代的亲本白细胞介素的氨基酸序列。在这种情况下，优选非保守氨基酸取代不干扰或抑制功能变体的生物活性。非保守氨基酸取代可以增强功能变体的生物活性，使得与亲本白细胞介素相比，功能变体的生物活性增加。
白细胞介素的氨基酸取代优选是保守氨基酸取代。保守氨基酸取代是本领域已知的，并且包括其中具有某些物理和/或化学性质的一个氨基酸被交换为具有相同或相似化学或物理性质的另一氨基酸的氨基酸取代。例如，保守氨基酸取代可以是酸性/带负电荷的极性氨基酸取代另一酸性/带负电荷的极性氨基酸(例如Asp或Glu)，具有非极性侧链的氨基酸取代具有非极性侧链的另一氨基酸(例如Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Cys、Val等)，碱性/带正电荷的极性氨基酸取代另一碱性/带正电荷的极性氨基酸(例如Lys、His、Arg等)，具有极性侧链的不带电荷的氨基酸取代具有极性侧链的另一不带电荷的氨基酸(例如Asn、Gln、Ser、Thr、Tyr等)，具有β-支链侧链的氨基酸取代具有β-支链侧链的另一氨基酸(例如Ile、Thr和Val等)，具有芳香族侧链的氨基酸取代具有芳香族侧链的另一氨基酸(例如His、Phe、Trp和Tyr)等。
白细胞介素可以基本上由本文所述的指定氨基酸序列组成，使得其它组分，例如其它氨基酸，不会实质上改变功能变体的生物活性。
细胞膜锚定部分
本发明实施方案的核酸和多肽可以包含一个或多个细胞膜锚定部分。细胞膜锚定部分可以是将白细胞介素结合到细胞膜上的任何部分。每个细胞膜锚定部分可以独立地是氨基酸序列或不是氨基酸序列的部分(非肽细胞膜锚定部分)。在式I中，a和b中的每一个独立地是0或1。当a是1时，C1是细胞膜锚定部分，其是氨基酸序列(例如，跨膜-细胞内氨基酸序列或跨膜氨基酸序列)。当b是1时，C2是细胞膜锚定部分，其是氨基酸序列(例如，跨膜-细胞内氨基酸序列或跨膜氨基酸序列)。
在本发明的实施方案中，式I的C1和C2中的每一个独立地是跨膜-细胞内氨基酸序列或跨膜氨基酸序列。在本发明的实施方案中，式I的C1和C2中的每一个独立地是B7-1跨膜-细胞内氨基酸序列、B7-2跨膜-细胞内氨基酸序列、CD8α跨膜-细胞内氨基酸序列、B7-1跨膜氨基酸序列、B7-2跨膜氨基酸序列或CD8α跨膜氨基酸序列。在优选的实施方案中，式I的C1和C2中的每一个独立地是B7-1跨膜-细胞内氨基酸序列或CD8α跨膜氨基酸序列。在本发明的实施方案中，在式I中，a是1，b是1，并且C1和C2中的每一个独立地是CD8α跨膜氨基酸序列或B7-1跨膜-细胞内氨基酸序列，所述CD8α跨膜氨基酸序列包含IYIWAPLAGTCGVLLLSLVIT(SEQ ID NO:4)的氨基酸序列，由其组成或基本上由其组成，B7-1跨膜-细胞内氨基酸序列包含LLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV(SEQ ID NO:5)的氨基酸序列，由其组成或基本上由其组成。
在本发明的实施方案中，在式I中，a和b中的一个或两个独立地是0。当a是0时，L1编码的氨基酸序列还包含不是氨基酸序列的细胞膜锚定部分(非肽细胞膜锚定部分)。当b是0时，由L3编码的氨基酸序列还包含不是氨基酸序列的细胞膜锚定部分(非肽细胞膜锚定部分)。
非肽细胞膜锚定部分可以是糖脂，其可以在翻译后修饰期间连接至氨基酸序列的C-末端，并将白细胞介素结合到细胞膜上。这种糖脂的实例是糖磷脂酰肌醇(GPI)锚。因此，在本发明的实施方案中，非肽细胞膜锚定部分是GPI锚。GPI锚具有包括磷酸乙醇胺接头、聚糖核心和磷脂尾的结构。聚糖核心可以用侧链，如磷酸乙醇胺基团、甘露糖、半乳糖、唾液酸或其它糖进行各种修饰。GPI锚的实例描述于，例如，Paulick等人,Biochemistry,47:6991-7000(2008)中。
接头
在本发明的实施方案中，式I的L1、L2和L3中的每一个独立地是接头序列。接头序列的组成没有特别限制，并且可以是将白细胞介素结合到细胞膜锚定部分的任何接头序列。
在优选的实施方案中，式I的L2是可切割的接头序列。在这方面，本发明核酸编码的多肽可以被切割，从而产生两种多肽：第一多肽，其包含经由接头序列连接至细胞膜锚定部分的IL-21氨基酸序列；和第二多肽，其包含经由接头序列连接至细胞膜锚定部分的IL-15氨基酸序列。式I的接头序列L2的长度不受限制，并且可以是约20至约30个氨基酸残基，例如，约20、约21、约22、约23、约24、约25、约26、约27、约28、约29、约30个氨基酸残基或前述值中的任何两个之间的范围。
在实施方案中，可切割的接头序列包含“自我切割”2A肽。“自我切割”2A肽描述于，例如，Liu等人,Sci.Rep.,7(1):2193(2017)中。2A肽是在真核细胞中翻译期间介导多肽切割的病毒寡肽。名称“2A”是指病毒基因组的特定区域。不受特定理论或机制的束缚，认为2A介导的“自我切割”机制是2A肽的C-末端处甘氨酰-脯氨酰肽键形成的核糖体跳跃。不同的2A肽可以在C末端包含GDVEX1NPGP(SEQ ID NO:6)的共有氨基酸序列，其中SEQ ID NO:6中的X1是任何天然存在的氨基酸残基。在本发明的实施方案中，式I中的L2是猪捷申病毒-1 2A(P2A)氨基酸序列、马鼻炎A病毒(E2A)氨基酸序列、明脉扁刺蛾β四体病毒(thosea asignavirus)2A(T2A)氨基酸序列或口蹄疫病毒(F2A)氨基酸序列。在本发明的实施方案中，式I中的L2是2A肽氨基酸序列，其包含GSGATNFSLLKQAGDVEENPGP(P2A)(SEQ ID NO:7),GSGQCTNYALLKLAGDVESNPGP(E2A)(SEQ ID NO:8)或GSGEGRGSLLTCGDVEENPGP(T2A)(SEQ IDNO:9)的氨基酸序列，由其组成或者基本上由其组成。
在实施方案中，可切割的接头序列包含弗林蛋白酶(furin)可切割的序列。示例性的弗林蛋白酶切割序列描述于Duckert等人,Protein Engineering,Design&Selection,17(1):107-112(2004)和美国专利8,871,906中，其中的每一个通过引用并入本文。在本发明的实施方案中，弗林蛋白酶可切割的序列由式P4-P3-P2-P1(式II)表示，其中P4是氨基端的氨基酸残基，P1是羧基端的氨基酸残基，P1是精氨酸或赖氨酸残基，并且该序列在P1的羧基端可被弗林蛋白酶切割。在本发明的另一个实施方案中，式II的弗林蛋白酶可切割的序列(i)还包含在氨基端由P6-P5表示的氨基酸残基，(ii)还包含在羧基端由P1’-P2’表示的氨基酸残基，(iii)其中如果P1是精氨酸或赖氨酸残基，则P2’是色氨酸，并且P4是精氨酸、缬氨酸或赖氨酸，条件是如果P4不是精氨酸，则P6和P2是碱性残基，以及(iv)该序列在P1的羧基端可被弗林蛋白酶切割。在本发明的实施方案中，弗林蛋白酶切割序列包含R-X1-X2-R，其中X1是任何天然存在的氨基酸，并且X2是精氨酸或赖氨酸(SEQ ID NO:10)。
在本发明的实施方案中，可切割的接头序列包含2A肽序列和弗林蛋白酶可切割的序列。在本发明的实施方案中，式I中的L2是弗林蛋白酶可切割的-P2A氨基酸序列。弗林蛋白酶可切割的-P2A氨基酸序列可以包含RAKRSGSGATNFSLLKQAGDVEENPGP(SEQ ID NO:11)，由其组成或基本上由其组成。
在优选的实施方案中，式I的L1和L3中的每一个独立地是柔性接头。式I的L1和L3中的每一个的接头序列的长度不受限制，并且可以独立地是约10至约65个氨基酸残基、约18至约61个氨基酸残基或约25至约50个氨基酸残基。例如，式I的L1和L3中的每一个的接头序列的长度可以独立地是约10、约11、约12、约13、约14、约15、约16、约17、约18、约19、约20、约21、约22、约23、约24、约25、约26、约27、约28、约29、约30、约31、约32、约33、约34、约35、约36、约37、约38、约39、约40、约41、约42、约43、约44、约45、约46、约47、约48、约49、约50、约51、约52、约53、约54、约55、约56、约57、约58、约59、约60、约61、约62、约63、约64、约65个氨基酸残基或前述值中的任何两个之间的范围。在本发明的实施方案中，柔性接头主要包含甘氨酸和丝氨酸残基。例如，柔性接头可以包含G4S和G3S中一个或两个的一个或多个重复(例如，G4S和G3S的约3至约15或约5至约12个重复)。
在实施方案中，式I的L1和L3中的每一个独立地是(i)式III的多肽：X1 mX2 nX3 pX4 q(式III)(如下文进一步定义的)；(ii)式IV的多肽：X5 rX6 sX7 t(式IV)(如下文进一步定义的)；或(iii)独立地选自甘氨酸、丝氨酸、苏氨酸、赖氨酸、谷氨酸和脯氨酸的10至30个氨基酸残基selected。
在本发明的实施方案中，式I的L1和L3中的一个或两个是式III的多肽：X1 mX2 nX3 pX4 q(式III)，其中：
m、p和q中的每一个独立地是0或1；
n是20至65的整数；
X2是多个氨基酸残基，所述氨基酸残基中的每一个独立地选自甘氨酸和丝氨酸；以及
X1、X3和X4中的每一个独立地是任何一个天然存在的氨基酸残基。
在实施方案中，在式III中，n是20至60、25至60或25至50的整数。
在实施方案中，在式III中，m是0，n是25,p是1，并且q是1，其中X3是亮氨酸并且X4是谷氨酰胺。在这方面，式III的多肽可以包含SEQ ID NO:12的氨基酸序列(表3中的Lr1)或由其组成。
在实施方案中，在式III中，m是0，n是45，p是0，并且q是0。在这方面，式III的多肽可以包含SEQ ID NO:14的氨基酸序列(表3中的Lr6)或由其组成。
在实施方案中，在式III中，m是0,n是46,p是1，并且q是1，其中X3是亮氨酸并且X4是谷氨酰胺。在这方面，式III的多肽可以包含SEQ ID NO:16的氨基酸序列(表3中的Lr8)或由其组成。
在实施方案中，在式III中，m是1,n是58,p是1，并且q是1，其中X1是丙氨酸，X3是丙氨酸，并且X4是丝氨酸。在这方面，式III的多肽可以包含SEQ ID NO:17的氨基酸序列(表3中的Lr9)或由其组成。
在本发明的实施方案中，式I的L1和L3中的一个或两个是式IV的多肽：X5 rX6 sX7 t(式IV)，其中：
s是1；
r和t中的每一个独立地是20至25的整数；
每个X5和每个X7独立地是选自丙氨酸、赖氨酸和谷氨酸的多个氨基酸残基；以及
X6是任何一个天然存在的氨基酸残基。
在实施方案中，在式IV中，r是22,s是1，并且t是23，其中X6是亮氨酸。在这方面，式IV的多肽可以包含SEQ ID NO:15的氨基酸序列(表3中的Lr7)或由其组成。
在本发明的实施方案中，式I的L1和L3中的一个或两个是独立地选自甘氨酸、丝氨酸、苏氨酸、赖氨酸、谷氨酸和脯氨酸的10至30个氨基酸残基。在实施方案中，式I的L1和L3中的一个或两个是独立地选自甘氨酸、丝氨酸、苏氨酸、赖氨酸、谷氨酸和脯氨酸的10至20个，优选地，18个氨基酸残基。在这方面，式I的L1和L3中的一个或两个包含SEQ ID NO:13的氨基酸序列(表3中的Lr2)或由其组成。
核酸
在本发明的实施方案中，核酸包含编码与SEQ ID NO:32-37(表6A)中任一项的氨基酸序列至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列的核苷酸序列。例如，核酸可以包含与SEQ IDNOs:39-44(表6B)中任一项的核苷酸序列至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的核苷酸序列。
本文所用的术语“核酸”和“多核苷酸”是指任何长度的核苷酸(核糖核苷酸(RNA)或脱氧核糖核苷酸(DNA))的聚合形式。这些术语是指分子的一级结构，因此包括双链和单链DNA，双链和单链RNA以及双链DNA-RNA杂合体。该术语包括由核苷酸类似物和修饰的多核苷酸(如但不限于甲基化的和/或加帽的多核苷酸)制备的RNA或DNA的类似物作为等效物。合适的核苷酸类似物是已知的并且描述于例如美国专利申请公开2012/0101148和其中引用的参考文献中。在本发明的实施方案中，核酸是互补DNA(cDNA)。
本文所用的术语“核苷酸”是指由杂环碱基、糖和一个或多个磷酸基团组成的多核苷酸的单体亚基。天然存在的碱基(鸟嘌呤(G)、腺嘌呤(A)、胞嘧啶(C)、胸腺嘧啶(T)和尿嘧啶(U))通常是嘌呤或嘧啶的衍生物，尽管本发明包括使用天然和非天然存在的碱基类似物。天然存在的糖是戊糖(五碳糖)脱氧核糖(其形成DNA)或核糖(其形成RNA)，尽管本发明包括使用天然和非天然存在的糖类似物。核酸通常经由磷酸键连接以形成核酸或多核苷酸，尽管许多其它连键是本领域已知的(例如，硫代磷酸酯、硼烷磷酸酯等)。制备多核苷酸的方法在本领域普通技术范围内(Green和Sambrook,Molecular Cloning:A LaboratoryManual,(第4版)Cold Spring Harbor Laboratory Press,New York(2012))。
在一些实施方案中，核苷酸序列可以是密码子优化的。不受特定理论的束缚，认为核苷酸序列的密码子优化增加了mRNA转录物的翻译效率。核苷酸序列的密码子优化可以涉及用天然密码子取代另一密码子，所述密码子编码同一氨基酸，但可被细胞内更容易获得的tRNA翻译，从而提高翻译效率。核苷酸序列的密码子优化也可以减少干扰翻译的二级mRNA结构，从而提高翻译效率。在本发明的实施方案中，核苷酸序列经密码子优化用于在人组织中表达。
载体
在本发明的实施方案中，本发明的核酸被携带在重组表达载体中。因此，本发明的实施方案提供了重组表达载体，其包含相对于本发明的其它方面在此描述的任何本发明的核酸。
出于本文的目的，术语“重组表达载体”意指基因修饰的寡核苷酸或多核苷酸构建体，当构建体包含编码mRNA、蛋白质、多肽或肽的核苷酸序列，并且在足以在细胞内表达mRNA、蛋白质、多肽或肽的条件下载体与细胞接触时，所述基因修饰的寡核苷酸或多核苷酸构建体允许宿主细胞表达mRNA、蛋白质、多肽或肽。本发明的载体并非是整体天然存在的。然而，载体的一部分可以是天然存在的。重组表达载体可以包含任何类型的核苷酸，包括但不限于DNA和RNA，其可以是单链或双链的，合成的或部分从天然来源获得的，并且其可以含有天然的、非天然的或改变的核苷酸。重组表达载体可以包含天然存在的或非天然存在的核苷酸间连键或者这两种类型的连键。优选地，非天然存在的或改变的核苷酸或核苷酸间连键不会阻碍载体的转录或复制。载体可以含有提供本发明核酸表达的调控核酸序列。
重组表达载体可以是任何合适的重组表达载体。合适的载体包括设计以用于增殖和扩增或者用于表达或者用于这两种的那些载体，如质粒和病毒。例如，载体可以选自：pUC系列(Fermentas Life Sciences,Glen Burnie,MD)、pBluescript系列(Stratagene,LaJolla,CA)、pET系列(Novagen,Madison,WI)、pGEX系列(Pharmacia Biotech,Uppsala,Sweden)以及pEX系列(Clontech,Palo Alto,CA)。也可使用诸如λGT10、λGT11、λZapII(Stratagene)、λEMBL4和λNM1149的噬菌体载体。可以用于本发明背景中的植物表达载体的实例包括pBI01、pBI101.2、pBI101.3、pBI121和pBIN19(Clontech)。可以用于本发明背景中的动物表达载体的实例包括pEUK-Cl、pMAM和pMAMneo(Clontech)。
在一些实施方案中，重组表达载体是病毒载体。合适的病毒载体包括但不限于慢病毒载体、逆转录病毒载体、α病毒载体、牛痘病毒载体、腺病毒载体、腺相关病毒载体、疱疹病毒载体和禽痘病毒载体，并且优选具有转化T细胞的天然或工程改造的能力。
可以利用例如Green和Sambrook,Molecular Cloning:A Laboratory Manual,(第4版)Cold Spring Harbor Laboratory Press,New York(2012)中所述的标准重组DNA技术来制备重组表达载体。可以将环状或线性表达载体的构建体制备为含有在原核或真核宿主细胞中发挥功能的复制系统。复制系统可以来源于例如ColEl、2μ质粒、λ、SV40、牛乳头瘤病毒等。
重组表达载体可以包含调控序列，如转录和翻译起始和终止密码子，视情况而定并且考虑载体是基于DNA的还是基于RNA的，其对于待引入载体的宿主细胞的类型(例如细菌、真菌、植物或动物)具有特异性。
重组表达载体可以包含允许对转化或转染的宿主进行选择的一种或多种标志物基因。标志物基因包括抗微生物剂抗性(例如对抗生素、重金属等的抗性)，在营养缺陷型宿主中互补以提供原营养等。用于重组表达载体的合适的标志物基因包括，例如新霉素/G418抗性基因、潮霉素抗性基因、组氨醇抗性基因、四环素抗性基因以及氨苄西林抗性基因。
重组表达载体可以包含与编码式I的氨基酸序列的核酸可操作地连接的天然或非天然的启动子。优选地，启动子在T细胞中是有功能的。启动子的选择，例如强、弱、可诱导的、组织特异性的和发育特异性的，在本领域技术人员的普通技术内。类似地，核苷酸序列与启动子的组合也在本领域技术人员的技术内。启动子可以是非病毒启动子或病毒启动子，例如巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子或鼠干细胞病毒的长末端重复中存在的启动子。
可以将重组表达载体设计为瞬时表达、稳定表达或者设计为这两种。另外，可以将重组表达载体制备为组成型表达或诱导型表达。此外，可以将重组表达载体制备为包含自杀基因。
本文使用的术语“自杀基因”指导致表达自杀基因的细胞死亡的基因。自杀基因可以是赋予基因在其中表达的细胞针对试剂(例如药物)的敏感性的基因，并且当细胞与所述试剂接触或者暴露于所述试剂时引起细胞死亡。自杀基因是本领域已知的，并且包括例如单纯疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脱氨酶、嘌呤核苷磷酸化酶和硝基还原酶。
多肽
本发明的另一个实施方案提供了由本文所述的任何核酸编码的多肽。本文所用的术语“多肽”包含寡肽，并且是指通过一个或多个肽键连接的氨基酸的单链。
在本发明的实施方案中，多肽包含与SEQ ID NO:32-37(表6A)中任一项的氨基酸序列至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。
在式I中的L2是可切割接头的实施方案中，通过宿主细胞表达本发明核酸时产生的多肽可以被切割，从而产生两种多肽：第一多肽，其包含经由接头序列连接至细胞膜锚定部分的IL-21氨基酸序列；和第二多肽，其包含经由接头序列连接至细胞膜锚定部分的IL-15氨基酸序列。
在本发明的实施方案中，包含经由接头序列连接至细胞膜锚定部分的IL-21氨基酸序列的多肽可以包含与SEQ ID NO:24-30(表4-5)中任一项的氨基酸序列至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。
在本发明的实施方案中，包含经由接头序列连接至细胞膜锚定部分的IL-15氨基酸序列的多肽可以包含与SEQ ID NO:19、20、22和31(表2和5)中任一项的氨基酸序列至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。
宿主细胞及其群体
本发明的另一个实施方案还提供了包含本文所述的任一重组表达载体的宿主细胞。本发明的另一个实施方案提供了表达本文所述的任一核酸或者本文所述的一种或多种多肽的宿主细胞。如本文所用，术语“宿主细胞”是指可以含有本发明的重组表达载体的任何类型的细胞。宿主细胞可以是真核细胞，例如植物、动物、真菌或藻类；或者可以是原核细胞，例如细菌或原生动物。宿主细胞可以是培养的细胞或原代细胞，即直接由有机体如人分离到的细胞。宿主细胞可以是贴壁细胞或悬浮细胞，即悬浮生长的细胞。合适的宿主细胞是本领域已知的，并且包括，例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞等。出于扩增或复制重组表达载体的目的，宿主细胞优选是原核细胞，例如DH5α细胞。出于产生由本发明核酸编码的多肽的目的，宿主细胞优选是哺乳动物细胞。更优选地，宿主细胞是人细胞。尽管宿主细胞可以是任何类型的细胞、可以来源于任何类型的组织，并且可以处于任何发育阶段，但是宿主细胞优选是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。更优选地，宿主细胞是T细胞或自然杀伤(NK)细胞。
出于本文的目的，T细胞可以是任何T细胞，如培养的T细胞，例如原代T细胞；或者是来自培养的T细胞系的T细胞，例如Jurkat、SupT1等；或者是获自哺乳动物的T细胞。如果获自哺乳动物，T细胞可以获自多种来源，包括但不限于血液、骨髓、淋巴结、胸腺或者其它组织或液体。T细胞也可以是富集的或纯化的。优选地，T细胞是人T细胞。更优选地，T细胞是分离自人的T细胞。T细胞可以是任何类型的T细胞，并且可以处于任何发育阶段，包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD4+T细胞、CD8+T细胞(例如细胞毒性T细胞)、肿瘤浸润细胞(TIL)、记忆T细胞(例如，中心记忆T细胞和效应记忆T细胞)、初始T细胞等。
在本发明的实施方案中，宿主细胞包含(例如，表达)抗原特异性受体。在优选的实施方案中，抗原特异性受体对癌抗原具有抗原特异性。本文所用的短语“抗原特异的”和“抗原特异性”意指抗原特异性受体能特异性结合并免疫识别抗原或其表位，使得抗原特异性受体与抗原或其表位的结合引起免疫应答。
本文所用的术语“癌抗原”是指任何分子(例如蛋白质、多肽、肽、脂质、碳水化合物等)，其仅由或主要由肿瘤细胞或癌细胞表达或过表达，使得抗原与肿瘤或癌症相关。癌抗原可以另外地由正常的非肿瘤或非癌细胞表达。然而，在这种情况下，正常的非肿瘤或非癌细胞的癌抗原的表达不如肿瘤细胞或癌细胞的表达稳健。在这方面，与正常的非肿瘤或非癌细胞表达抗原相比，肿瘤或癌细胞可以过表达抗原或以显著较高的水平表达抗原。此外，癌抗原可以另外地由不同发育或成熟状态的细胞表达。例如，癌抗原可以另外地由胚胎期或胎儿期的细胞表达，这些细胞通常不存在于成年宿主中。可选地，癌抗原可以另外地由干细胞或前体细胞表达，这些细胞通常不存在于成年宿主中。癌抗原的实例包括但不限于间皮素、CD19、CD22、CD30、CD70、CD276(B7H3)、gp100、MART-1、表皮生长因子受体变体III(EGFRVIII)、血管内皮生长因子受体2(VEGFR-2)、TRP-1、TRP-2、酪氨酸酶、人乳头瘤病毒(HPV)16 E6、HPV 16 E7、HPV 18 E6、HPV 18 E7、KK-LC-1、NY-BR-1、NY-ESO-1(也称为CAG-3)、SSX-2、SSX-3、SSX-4、SSX-5、SSX-9、SSX-10、MAGE-A1、MAGE-A2、BRCA、MAGE-A3、MAGE-A4、MAGE-A5、MAGE-A6、MAGE-A7、MAGE-A8、MAGE-A9、MAGE-A10、MAGE-A11、MAGE-A12、HER-2等。在本发明的实施方案中，癌抗原可以是突变的抗原，其由肿瘤或癌细胞表达或过表达，并且其不由正常的非肿瘤或非癌细胞表达。这样的癌抗原的实例可以包括但不限于突变的KRAS和突变的p53。对癌抗原具有抗原特异性的T细胞可以有利地减少或避免与正常组织的交叉反应，诸如例如，使用对次要组织相容性抗原具有抗原特异性的T细胞可能发生的交叉反应。在优选的实施方案中，癌抗原是HPV 16 E7、HPV 18 E7或KK-LC-1。
癌抗原可以是由任何癌症或肿瘤(包括本文所述的癌症和肿瘤)的任何细胞表达的抗原。癌抗原可以是仅一种类型的癌症或肿瘤的癌抗原，使得所述癌抗原与仅一种类型的癌症或肿瘤相关或者是仅一种类型的癌症或肿瘤的特征。可选地，癌抗原可以是一种以上类型的癌症或肿瘤的癌抗原(例如，可以是特征性的)。例如，癌抗原可以由乳腺癌细胞和前列腺癌细胞表达，而完全不由正常的非肿瘤或非癌细胞表达。
在本发明的实施方案中，抗原特异性受体是外源性T细胞受体(TCR)。“外源性”意指TCR不是T细胞天然的(天然存在于T细胞上)。外源性TCR可以是重组TCR。重组TCR是通过重组表达一种或多种外源性TCRα-、β-、γ-和/或δ-链编码基因而产生的TCR。重组TCR可以包含完全衍生自单一哺乳动物物种的多肽链，或者重组TCR可以是包含衍生自来自两种不同哺乳动物物种的TCR的氨基酸序列的嵌合或杂合TCR。例如，TCR可以包含衍生自鼠TCR的可变区和人TCR的恒定区，使得TCR是“人源化的”。对癌抗原具有抗原特异性的任何外源性TCR可以用于本发明的方法和组合物中。TCR通常包含两条多肽(即多肽链)，如TCR的α链、TCR的β链、TCR的γ链、TCR的δ链或其组合。TCR的此类多肽链是本领域已知的。癌抗原特异性TCR可以包含任何氨基酸序列，前提是TCR能特异性结合并免疫识别癌抗原或其表位。可以用于本发明方法和组合物的外源性TCR的实例包括但不限于例如美国专利7,820,174；7,915,036；8,088,379；8,216,565；8,431,690；8,613,932；8,785,601；9,128,080；9,345,748；9,487,573；9,822,162；美国专利申请公开号2013/0116167；2014/0378389；2015/0246959；2017/0145070和国际专利申请公开号WO 2017/189254中公开的那些，上述中的每一个通过引用并入本文。在优选的实施方案中，外源性TCR是美国专利申请公开号2017/0145070中公开的抗HPV 16 E7 TCR或国际专利申请公开号WO 2017/189254中公开的抗KK-LC-1 TCR。
在本发明的实施方案中，抗原特异性受体是嵌合抗原受体(CAR)。通常，CAR包含与TCR的跨膜和细胞内结构域融合的抗体的抗原结合结构域，例如单链可变片段(scFv)。因此，本发明TCR的抗原特异性可以由特异性结合癌抗原或其表位的scFv编码。对癌抗原具有抗原特异性的任何CAR可以用于本发明的方法和组合物中。可以用于本发明的方法和组合物的CAR的实例包括但不限于在例如美国专利8,465,743；9,266,960；9,765,342；9,359,447；9,868,774和美国专利申请公开号2017/0107286中公开的那些，上述中的每一个通过引用并入本文。
在本发明的实施方案中，抗原特异性受体是内源性TCR。在一些实施方案中，包含内源性TCR的T细胞不包含(例如，表达)CAR或外源性TCR。在其它实施方案中，包含内源性癌抗原特异性TCR的T细胞也可以用编码外源性(例如重组)TCR或其它重组受体(例如CAR)的一种或多种核酸转化，例如转导或转染。这样的外源性受体，例如TCR，可以赋予转化的T细胞除内源性TCR具有天然特异性的抗原以外的另外的抗原的特异性。这可以但不必须导致具有双重抗原特异性的T细胞的产生。
在本发明的实施方案中，本发明的核酸、重组表达载体、多肽、宿主细胞及其群体可以是分离的或纯化的。本文所用的术语“分离的”意指已经从其天然环境中移出。本文所用的术语“纯化的”意指纯度增加，其中“纯度”是相对术语，并且不一定解释为绝对纯度。例如，纯度可以是至少约50％，可以大于约60％、约70％或约80％、约90％或可以是约100％。
药物组合物和治疗方法
本发明的核酸、重组表达载体、多肽，宿主细胞(及其群体)(下文称为“本发明的IL-21/15材料”)可以包含在诸如药物组合物的组合物中。在这方面，本发明提供了包含本文所述的任一本发明的IL-21/15材料和药学上可接受的载体的药物组合物。
优选地，载体是药学上可接受的载体。关于药物组合物，载体可以是常规用于施用细胞的那些载体中的任一种。这样的药学上可接受的载体是本领域技术人员众所周知的并且是公众容易获得的。优选药学上可接受的载体是在使用条件下没有有害副作用或毒性的载体。
载体的选择可以部分地由用于施用特定的本发明IL-21/15材料的具体方法决定。因此，存在多种合适的本发明的药物组合物的制剂。合适的制剂可以包括用于肠胃外、皮下、静脉内、肌肉内、动脉内、鞘内、瘤内或腹膜间施用的那些制剂中的任一种。可以使用多种途径来施用本发明的IL-21/15材料，并且在某些情况下，特定途径可以比另一途径提供更直接以及更有效的应答。
优选地，通过注射，例如静脉内注射施用本发明的IL-21/15材料。用于注射细胞的合适的药学上可接受的载体可以包括任何等张载体，诸如例如生理盐水(含约0.90％w/vNaCl的水，含约300mOsm/L NaCl的水，或者每升水约9.0g NaCl)、NORMOSOL R电解质溶液(Abbott,Chicago,IL)、PLASMA-LYTE A(Baxter,Deerfield,IL)、含约5％葡萄糖的水或者乳酸林格氏液。在实施方案中，用人血清白蛋白补充药学上可接受的载体。
出于本发明的目的，施用的本发明宿主细胞的剂量，例如数量应当足以在合理的时间框内在哺乳动物中产生例如治疗应答或预防应答。例如，施用的本发明宿主细胞的数量应当足以在距离施用时间约2小时或更长，例如12至24或者更多个小时的时间段内结合癌症抗原、或者治疗或预防癌症。在某些实施方案中，上述时间段甚至可能更长。施用的本发明宿主细胞的数量将由例如待施用的宿主细胞(例如T细胞)的特定群体的功效和哺乳动物(例如人)的情况以及待治疗的哺乳动物(例如人)的体重决定。
用于确定本发明宿主细胞的施用数量的许多测定法是本领域已知的。出于本发明的目的，可以使用如下的测定法来确定向哺乳动物施用的起始数量，所述测定法包括在一组哺乳动物(每只给予不同数量的T细胞)中向哺乳动物施用给定数量的此类T细胞时，比较靶细胞裂解、或者一种或多种细胞因子诸如例如IFN-γ和IL-2的分泌程度。可以通过本领域已知的方法来测定施用某一数量时，靶细胞裂解和/或细胞因子诸如例如IFN-γ和IL-2分泌的程度。细胞因子诸如例如IL-2的分泌还可以提供T细胞制备物的质量(例如表型和/或有效性)的指示。
施用的本发明宿主细胞的数量也将由可能伴随特定细胞群体的施用的任何不良副作用的存在、性质和程度来确定。通常，主治医师将考虑各种因素，如年龄、体重、一般健康状况、饮食、性别、施用途径和所治疗病况的严重程度，决定治疗每个个体患者的细胞的数量。例如且不旨在限制本发明，待施用的细胞数量可以是每次输注约10×106至约10×1011个细胞，每次输注约10×109至约10×1011个细胞，或每次输注10×107至约10×109个细胞。
预期本发明的IL-21/15材料可以用于治疗或预防哺乳动物中的癌症的方法中。在这方面，本发明提供了治疗或预防哺乳动物中癌症的方法，其包括以有效治疗或预防哺乳动物中癌症的量向哺乳动物施用本文所述的任一本发明IL-21/15材料或药物组合物。
可以将一种或多种另外的治疗剂共施用于哺乳动物。“共施用”意为在时间上足够接近地施用一种或多种另外的治疗剂和本发明的IL-21/15材料，以使本发明的IL-21/15材料可以增强所述一种或多种另外的治疗剂的作用，反之亦然。在这方面，可以首先施用本发明的IL-21/15材料，之后施用一种或多种另外的治疗剂，反之亦然。可选地，可以同时施用本发明的IL-21/15材料和一种或多种另外的治疗剂。可以增强本发明IL-21/15材料的功能的另外治疗剂可以包括例如一种或多种细胞因子或者一种或多种抗体(例如抑制PD-1功能的抗体)。可以与本发明IL-21/15材料共施用的示例性治疗剂是IL-2。不受特定理论或机制的束缚，认为IL-2可以增强本发明的宿主细胞群体的治疗效果。
本发明的实施方案还包括在施用本发明的IL-21/15材料前，对哺乳动物进行淋巴细胞清除。淋巴细胞清除的实例包括但可不限于：非骨髓根除性淋巴细胞清除化疗、骨髓根除性淋巴细胞清除化疗、全身辐射等。
本文使用的术语“治疗”和“预防”以及尤其衍生的词语不一定意指100％或完全的治疗或预防。而是，存在本领域普通技术人员认为具有潜在益处或治疗效果的不同程度的治疗或预防。在这方面，本发明的方法可以提供任何量任何水平的哺乳动物中癌症的治疗或预防。此外，本发明的方法提供的治疗或预防可以包括被治疗或预防的疾病(例如癌症)的一种或多种病况或症状的治疗或预防。另外，出于本文的目的，“预防”可以涵盖延迟疾病或其症状或病况的发作或复发。
出于施用细胞群体的本发明方法的目的，细胞可以是与哺乳动物同种异体的细胞或是其自体的细胞。优选地，细胞是哺乳动物自体的。
关于本发明的方法，癌症可以是任何癌症，包括白血病(例如，B细胞白血病)、肉瘤(例如，滑膜肉瘤、成骨肉瘤、子宫平滑肌肉瘤和肺泡横纹肌肉瘤)、淋巴瘤(例如，霍奇金淋巴瘤和非霍奇金淋巴瘤)、肝细胞癌、胶质瘤、头颈癌、急性淋巴细胞癌、急性髓性白血病、骨癌、脑癌、乳腺癌、肛门癌、肛管癌或肛门直肠癌、眼癌、肝内胆管癌、关节癌、颈癌、胆囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、外阴癌、慢性淋巴细胞白血病、慢性髓细胞癌、结肠癌症(colon cancer)(例如结肠癌(colon carcinoma))、食道癌、宫颈癌、胃肠类癌瘤、下咽癌、喉癌、肝癌、肺癌、恶性间皮瘤、黑色素瘤、多发性骨髓瘤、鼻咽癌、口咽癌、卵巢癌、胰腺癌、阴茎癌、腹膜癌、直肠癌、网膜癌和肠系膜癌、胰腺癌、咽癌、前列腺癌、直肠癌、肾癌、小肠癌、软组织癌、胃癌、睾丸癌、甲状腺癌、输尿管癌、阴道癌和膀胱癌中的任一种。
在癌症抗原是KK-LC-1的实施方案中，优选的癌症是膀胱癌、宫颈癌、胃癌、乳腺癌、肺癌、结肠癌、直肠癌或胰腺癌。特别优选的癌症是KK-LC-1-阳性癌症。尽管最常与KK-LC-1表达相关的癌症包括膀胱癌、宫颈癌、胃癌、乳腺癌、肺癌、结肠癌、直肠癌和胰腺癌，但该方法可以用于治疗任何KK-LC-1阳性癌症，包括在其它解剖区域发生的那些癌症。
在癌症抗原是HPV 16(E6或E7)的实施方案中，优选的癌症是宫颈癌、口咽癌、肛门癌、肛管癌、肛门直肠癌、阴道癌、外阴癌或阴茎癌。特别优选的癌症是HPV 16-阳性癌症。尽管最常与HPV 16感染相关的癌症包括宫颈癌、口咽癌、肛门癌、肛管癌、肛门直肠癌、阴道癌、外阴癌和阴茎癌，但该方法可以用于治疗任何HPV16阳性癌症，包括在其它解剖区域发生的那些癌症。
本发明的另一个实施方案提供了本文所述的核酸、多肽、重组表达载体、宿主细胞、细胞群体或药物组合物中的任一种，其用于治疗或预防哺乳动物中的癌症。
预期本文所述的本发明核酸、多肽、重组表达载体、宿主细胞、细胞群体或药物组合物中的任一种可以用作免疫治疗佐剂，例如疫苗佐剂。在这方面，本发明的实施方案提供了增强哺乳动物对免疫疗法(例如，疫苗)的免疫应答的方法，所述方法包括以有效增强哺乳动物对免疫疗法(例如，疫苗)的免疫应答的量向哺乳动物施用(i)疫苗和(ii)本文所述的本发明核酸、多肽、重组表达载体、宿主细胞、细胞群体或药物组合物中的任一种。
本发明的另一个实施方案提供了本文所述的本发明核酸、多肽、重组表达载体、宿主细胞、细胞群体或药物组合物中的任一种，其用于增强哺乳动物对免疫疗法(例如疫苗)的免疫应答。
以下实施例进一步说明本发明，但当然不应解释为以任何方式限制其范围。
实施例
在实施例1-8中描述的实验中采用以下材料和方法。
拴系IL-15和IL-21的设计和构建
制备了不同的IL-15构建体。这些包括拴系IL-15(TeIL-15)构建体(TeIL-15 Lr1、TeIL-15 Lr2和TeIL-15 Lr6)。每种TeIL-15构建体的结构由四个片段组成：信号序列、IL-15成熟氨基酸序列、柔性接头和细胞膜锚定部分(“锚”)(图1A)。信号序列是人IgE信号序列。锚Ar1是人CD8α跨膜氨基酸序列。
除了TeIL-15构建体，还制备了分泌的IL-15(IL-15S)构建体和IL-15RA构建体。IL-15RA构建体的结构由四个片段组成：人IgE信号序列、成熟的IL-15氨基酸序列、柔性接头和IL-15受体亚基α(IL-15Rα)序列。IL-15S构建体的结构由两个片段组成：人IgE信号序列和IL-15成熟氨基酸序列。
表1中示出了IL-15构建体中采用的各种组分的氨基酸序列。
表1
表2中示出了每种全长IL-15构建体的氨基酸序列。在表2中，IL-15氨基酸序列是加下划线的，锚序列(Ar1)以粗体显示，并且IL-15Rα是斜体的。
表2
制备了总共七种拴系IL-21(TeIL-21)构建体(TeIL-21 Lr1,TeIL-21 Lr2,TeIL-21 Lr6,TeIL-21 Lr7,TeIL-21 Lr8Ar1,TeIL-21 Lr9和eIL-21 Lr8Ar2)。每种TeIL-21构建体的结构由四个片段组成：信号序列、成熟的IL-21氨基酸序列、柔性接头和细胞膜锚定部分(图1B)。信号序列是人IgE信号序列。锚定序列是人CD8α跨膜氨基酸序列(Ar1)或人B7-1跨膜细胞内氨基酸序列(Ar2)。
表3中示出了TeIL-21构建体中采用的各种组分的氨基酸序列。
表3
表4中示出了每种全长TeIL-21构建体的氨基酸序列。在表4中，IL-21氨基酸序列是加下划线的，并且锚序列(Ar1或Ar2)以粗体显示。
表4
制备了五种拴系IL-21/拴系IL-15(TeIL-21/15)构建体(TeIL-21/15 P2A Ar1、TeIL-21/15 E2A、TeIL-21/15 T2A、TeIL-21/15 FurinA-P2A和TeIL-21/15 E2A Ar2)。一个TeIL-21构建体和一个TeIL-15构建体通过可切割的接头连接以产生每个TeIL-21/15构建体(图1C)。TeIL-21/15构建体的核苷酸序列来源于它们的氨基酸序列并针对人组织表达进行了密码子优化。
表5中示出了TeIL-21/15构建体的TeIL-21序列、TeIL-15序列和可切割的接头序列。在表5中，白细胞介素(IL15或IL-21)氨基酸序列是加下划线的，并且锚定序列(Ar1或Ar2)以粗体显示。
表5
表6A中示出了全长TeIL-21/15构建体的氨基酸序列。在表6A中，IL-21序列是加下划线的，IL-15序列以粗体显示，并且锚定序列(Ar1或Ar2)是斜体的。可切割的接头示于表6A的左栏。
表6A
表6B
病毒制备和T细胞转导
从血沉棕黄层分离人外周血单核细胞(PBMC)。转导前，将PBMC在T细胞培养基加50ng/mL抗CD3(OKT3,Miltenyi Biotech,Bergisch Gladbach,Germany)中培养2天。通过用TeIL-15载体和包装质粒(pREV/RSV,pMD.2,pRRE/LG)共转染293T细胞产生慢病毒上清液。转染后两天，收获慢病毒上清液。通过在硫酸鱼精蛋白(10μg/ml)存在下将5ml慢病毒上清液加入至1百万个T细胞中来进行转导。第二天，收获T细胞，并在正常T细胞培养基中培养。通过用拴系的细胞因子载体和RD114包装质粒共转染293GP细胞产生逆转录病毒上清液。转染后两天，收获逆转录病毒上清液。通过向包被有RETRONECTIN重组人纤连蛋白片段(Lonza,Basel,Switzerland)的六孔板的一个孔中加入5ml逆转录病毒上清液来进行转导，并在32℃下以2000g离心2小时。弃去逆转录病毒上清液，并加入1百万个T细胞。第二天，收获T细胞并在正常条件下培养。
T细胞增殖和活力
当从培养基中除去外源性IL-2时，在第0天以相同浓度接种用不同构建体转导的T细胞。使用CELLOMETER细胞计数仪机器(Nexcelom,Lawrence,MA)通过台盼蓝测定评估活细胞数。
流式细胞术
为了检测转导细胞中的TeIL-21，使用针对IL-21的藻红蛋白(PE)或别藻蓝蛋白(APC)缀合的抗体(Biolegend(San Diego,CA)或BD Biosciences(Franklin Lakes,NJ))标记细胞。为了检测TeIL-15，使用生物素缀合的IL-15(R&D Systems,Minneapolis,MN)加链霉亲和素-ALEXA FLUOR 647染料或链霉亲和素-ALEXA FLUOR 488染料(Thermo FischerScientific,Waltham,MA)标记转导的细胞。用BD FORTESSA或LSRII流式细胞仪(BDBiosciences)采集数据，并用FLOWJO软件(FlowJo,LLC,Ashland,OR)对其进行分析。
NSG小鼠中建立的肿瘤的治疗
动物研究方案由NIH动物护理和使用委员会批准。通过尾静脉注射人T细胞来治疗具有已建立的人宫颈癌肿瘤的NOD scidγ(NSG)小鼠(The Jackson Laboratory,BarHarbor,ME)。通过皮下注射1×106个CaSki肿瘤细胞引发肿瘤。在肿瘤细胞注射后第12天通过单次静脉注射进行T细胞输注。通过卡尺测量每个肿瘤的垂直直径来确定肿瘤大小，并将其报告为肿瘤面积。
实施例1
本实施例证实了与表2中的其它IL-15构建体相比，在外源性IL-2不存在下，用TeIL-15 Lr1转导的细胞表现出更优的增殖。
将PBMC在补充有IL-2(300IU/mL)和抗CD3抗体(OKT3,50ng/mL)的AIM V培养基中培养2天。然后用含有表2中的TeIL-15 Lr1、TeIL-15 Lr2、IL-15 RA、TeIL-15 Lr6或IL-15S构建体的慢病毒转导细胞。当在转导后第7天从培养基中撤出IL-2时，将用每种IL-15构建体转导的相同数量的细胞在第0天铺板(图2)。通过在图2所示的每个不同时间点使用台盼蓝测定法评估活细胞的总数量来评价转导细胞的增殖。未转导的细胞用作阴性对照。在外源性IL-15存在下培养的未转导细胞用作阳性对照。
结果显示在图2中。如图2所示，在外源性IL-2不存在下，用TeIL-15 Lr1构建体转导的T细胞显示出比其它构建体更好的增殖。
实施例2
本实施例证实了与用TeIL-15 Lr2、IL-15 RA或IL-15S构建体转导的细胞相比，用TeIL-15 Lr1构建体转导的细胞在细胞表面上显示出最高的IL-15表达水平。
如实施例1所述，用含有表2中的TeIL-15 Lr1、TeIL-15 Lr2、IL-15 RA或IL-15S构建体的慢病毒转导PBMC。通过流式细胞术分析细胞膜上表达的IL-15的存在。与用TeIL-15Lr2(53.2％)、IL-15 RA(23.5％)或IL-15S(33.2％)构建体转导的细胞相比，用TeIL-15Lr1构建体转导的细胞在细胞膜上显示出最高的IL-15表达水平(62.3％)。
实施例3
本实施例证实了用表4中的TeIL-21 Lr6、TeIL-21 Lr1或TeIL-21 Lr2构建体转导的293T细胞在细胞表面上表达IL-21。
用含有表4中的TeIL-21 Lr7、TeIL-21 Lr6、TeIL-21 Lr1或TeIL-21 Lr2构建体的慢病毒转导细胞(293T)。未染色的细胞和染色但未转导的细胞用作阴性对照。
通过流式细胞术分析TeIL-21表达。结果显示在表7中。如表7所示，超过30％的用TeIL-21 Lr6,、TeIL-21 Lr1或TeIL-21 Lr2转导的293T细胞表达IL-21。
表7
实施例4
本实施例证实了与用TeIL-21 Lr1或TeIL-21 Lr2构建体转导的细胞相比，用含有表4中的TeIL-21 Lr6构建体的慢病毒转导的人T细胞显示出最高的IL-21表达水平。
用含有表4中的TeIL-21 Lr6、TeIL-21 Lr1或TeIL-21 Lr2构建体的慢病毒转导人T细胞。未染色的细胞和染色但未转导的细胞用作阴性对照。
通过流式细胞术分析TeIL-21表达。结果显示在表8中。如表8所示，用TeIL-21 Lr6转导的细胞显示出最高的IL-21表达水平。
表8
实施例5
本实施例证实了与TeIL-21 Lr6或TeIL-21 Lr9构建体相比，用含有表4中的TeIL-21 Lr8Ar1构建体的逆转录病毒转导的人T细胞显示出最高的IL-21表达水平。
用含有表4中的TeIL-21 Lr6、TeIL-21 Lr8Ar1或TeIL-21 Lr9构建体的逆转录病毒转导人T细胞。染色但未转导的细胞用作阴性对照。
通过流式细胞术分析TeIL-21表达。结果显示在表9中。如表9所示，用TeIL-21Lr8Ar1转导的细胞显示出最高的IL-21表达水平。
表9
实施例6
本实施例证实了与TeIL-21 Lr8Ar1构建体相比，用含有表4中的TeIL-21 Lr8Ar2构建体的逆转录病毒转导的人T细胞显示出最高的IL-21表达水平。
用含有表4中的TeIL-21 Lr8Ar1或TeIL-21 Lr8Ar2构建体的逆转录病毒转导人T细胞。
通过流式细胞术分析TeIL-21表达。具有指定表型的细胞百分比显示在表10中。尽管与TeIL-21 Lr8Ar2相比，对于TeIL-21 Lr8Ar1，表10中表达IL-21的细胞的百分比略高，但观察到TeIL-21 Lr8Ar2的MFI(平均荧光强度)高于TeIL-21 Lr8Ar1的MFI，这表明在具有TeIL-21 Lr8Ar2的情况下，IL-21的蛋白表达水平更高。因此，得出结论，与TeIL-21 Lr8Ar1相比，用TeIL-21 Lr8Ar2转导的细胞显示出更高的IL-21表达。
表10
实施例7
本实施例证实了与TeIL-21/15 P2A、TeIL-21/15 T2A或TeIL-21/15 FurinA-P2A相比，用含有TeIL-21/15 E2A Ar1的逆转录病毒转导的人T细胞显示出较高的TeIL-21/15表达。
用含有表6中的TeIL-21/15 E2A Ar1、TeIL-21/15 P2A、TeIL-21/15 T2A或TeIL-21/15 FurinA-P2A构建体的逆转录病毒转导人T细胞。未转导的细胞用作阴性对照。用含有单独的TeIL-15 Lr1Ar2构建体(表5)或单独的TeIL-21 Lr8Ar1构建体(表5)的逆转录病毒转导的人T细胞用作对照。作为另一对照，将人T细胞与分开的TeIL-15 Lr1Ar2(表5)和TeIL-21 Lr8Ar1构建体共转导。
通过流式细胞术分析TeIL-21表达。结果显示在表11中。如表11所示，与TeIL-21/15 P2A、TeIL-21/15 E2A Ar1或TeIL-21/15 FurinA-P2A相比，用TeIL-21/15 T2A转导的细胞显示出较低的TeIL-21/15表达。
表11
实施例8
本实施例证实了将用E7 TCR和TeIL-21/15共转导的T细胞施用于荷瘤小鼠导致肿瘤的完全消退。
用1×106个CaSki宫颈肿瘤细胞皮下接种NSG小鼠。CaSki肿瘤细胞是HPV 16 E7阳性和MART-1阴性。两周后，单次静脉注射在汉克平衡盐溶液(Hank’s balanced saltsolution，HBSS)中0.5ml体积的一千万个未转导或转导的T细胞来处理具有建立的肿瘤的小鼠。用单独的抗-MART-1 TCR(DMF5)或单独的抗-HPV 16 E7 TCR(E7)转导T细胞，或者用如下(i)-(vi)之一共转导T细胞：
(i)DMF5 TCR和TeIL-15 Lr1Ar2，
(ii)DMF5 TCR和TeIL-21 Lr8Ar1，
(iii)DMF5 TCR和TeIL-21/15 E2A Ar1，
(iv)E7 TCR和TeIL-15 Lr1Ar2，
(v)E7 TCR和TeIL-21 Lr8Ar1或
(vi)E7 TCR和TeIL-21/15 E2A Ar1。
每3-4天使用数字卡尺测量肿瘤大小。结果显示在图3中。图3中评估的每只单独小鼠的肿瘤生长曲线显示在图4A-4I中。
在接受用E7 TCR和TeIL-21/15(图4E)共转导的T细胞的5只小鼠中的4只中以及在接受用E7 TCR和TeIL-21(图4D)共转导的T细胞的5只小鼠中的2只中观察到肿瘤的完全消退。接受用E7 TCR(图4B)转导的T细胞或用E7 TCR和TeIL-15(图4C)共转导的T细胞的小鼠仅显示出延迟的肿瘤进展。接受用不相关TCR(DMF5 TCR)(图4F)、DMF5 TCR和TeIL-15(图4G)、DMF5 TCR和TeIL-21(图4H)或DMF5 TCR和TeIL-21/15(Fig.4I)转导的T细胞的小鼠显示出与未接受治疗的对照小鼠(图4A)相似的肿瘤生长曲线。
实施例9
本实施例证实了用TeIL-21/15 FurinA-P2A Ar2体外转导的T细胞的生长曲线。
用TeIL-21/15 FurinA-P2A Ar2或分泌的IL-21/15(sIL-21/15)(用作对照)转导来自20个健康供体的T细胞。转导后第7天从培养基中撤掉外源性T细胞生长因子IL-2。在IL-2撤掉后的不同时间点对活细胞进行计数以评价转导的T细胞的存活。
来自每个健康供体的转导T细胞的生长曲线显示在图5A-5T中。如图5A-5T所示，来自20个健康供体中的18个中的TeIL-21/15 FurinA-P2A Ar2转导的T细胞在IL-2撤掉后6周死亡，表明组成型IL-15和IL-21信号传导不会将靶T细胞转化成永生细胞系。
实施例10
本实施例证实了与用分泌的IL-21/15转导的T细胞相比，用TeIL-21/15 FurinA-P2A Ar2转导的T细胞在体外释放较少的IL-15和IL-21。
用如下(i)-(v)之一转导来自健康供体的T细胞：
(i.)E7 TCR和TeIL-15 Lr1Ar2，
(ii.)E7 TCR和TeIL-21 Lr8Ar2，
(iii.)E7 TCR和TeIL-21/15 FurinA-P2A Ar2，
(iv.)E7 TCR和分泌的IL-21/15(sIL-21/15)(用作测定开发的阳性对照)或
(v.)单独的E7 TCR(对照)。
来自健康供体的未转导T细胞也用作对照。将转导的细胞培养7天。收获T细胞，并将其以相等数量接种在新鲜培养基中或与肿瘤细胞以1:1的比例共培养。收集培养物上清液并使用U-PLEX测定平台(Meso Scale Diagnostics,Rockville,MD)探测IL-15和IL-21。结果显示在图6A-6B中。
图6A-6B显示了在转导细胞的上清液中测量的IL-15(图6A)和IL-21(图6B)的水平。在用TeIL-15 Lr1Ar2(14.54pg/ml)和TeIL-21/15 FurinA-P2A Ar2(2.18pg/ml)转导的T细胞的上清液中几乎检测不到IL-15水平(图6A)，而在用TeIL-21 Lr8Ar2(2211.25pg/ml)和TeIL-21/15 FurinA-P2A Ar2(1234.02pg/ml)转导的T细胞的上清液中清晰地检测到IL-21水平(图6B)。与用分泌的IL-21/15(IL-15:988.37 pg/ml；IL-21:>13100.00 pg/ml)转导的T细胞相比，来自用拴系的细胞因子(TeIL-15 Lr1Ar2、TeIL-21 Lr8Ar2和TeIL-21/15FurinA-P2A Ar2)转导的T细胞的上清液中的IL-15水平和IL-21水平低得多(图6A-6B)。
图6C-6D显示了在转导的T细胞与靶肿瘤细胞系共培养物的上清液中测量的IL-15(图6C)和IL-21(图6D)的水平。如图6C-6D所示，可在转导的T细胞与靶肿瘤细胞系共培养物的上清液中检测到少量的IL-15(TeIL-15 Lr1Ar2:6.88-26.09 pg/ml；TeIL-21/15FurinA-P2A Ar2:0.71-12.87 pg/ml)和一些IL-21(TeIL-21 Lr8Ar2:152.41-1408.79pg/ml；TeIL-21/15 FurinA-P2A Ar2:146.23-1135.04pg/ml)。
实施例11
本实施例证实了与用分泌的IL-21/15转导的T细胞相比，用TeIL-21/15 FurinA-P2A Ar2转导的T细胞在体内释放较少的IL-15和IL-21。
用未转导的人T细胞、HBSS(无细胞)或用如下(i)-(iii)之一转导的人T细胞输注健康的NSG小鼠：
(i.)E7 TCR和TeIL-21/15 FurinA-P2A Ar2，
(ii.)E7 TCR和分泌的IL-21/15(sIL-21/15)(阳性对照)或
(iii.)单独的E7 TCR(对照)。
在图7A-7B所示的时间点收集血清，并使用U-PLEX测定平台测定IL-15和IL-21。结果显示在图7A-7B中。在每个时间点，测定两个小鼠血清样品。在用TeIL-21/15 FurinA-P2AAr2 T细胞输注的健康NSG小鼠的血清中，IL-15的浓度低于检测限(图7A)，而在同一血清中检测到低浓度的IL-21(图7B)。
在另一个实验中，用未转导的人T细胞、HBSS(无细胞)或用如下(i)-(v)之一转导的人T细胞输注携带来源于CaSki肿瘤细胞系的可触知肿瘤的NSG小鼠：
(i.)E7 TCR和Teil-15 Lr1Ar2,
(ii.)E7 TCR和Teil-21Lr8Ar2,
(iii.)E7 TCR和Teil-21/15 FurinA-P2A Ar2,
(iv.)E7 TCR和分泌的IL-21/15(sIL-21/15)(阳性对照)
(v.)单独的E7 TCR(对照)。
在图7C-7D所示的时间点收集血清，并使用U-PLEX测定平台测定IL-15和IL-21。结果示于图7C-7D中。在每个时间点，测定一个小鼠血清样品。在接受转导T细胞的荷瘤小鼠的血清中，在接受用E7 TCR和Teil-21/15 FurinA-P2A Ar2转导的T细胞的小鼠中，在早期时间点(T细胞输注后第8天和第9天)检测到痕量的IL-15，在接受用E7 TCR和Teil-15 Lr1Ar2转导的T细胞的小鼠中检测到少量的IL-15(图7C)。在用Teil-21/15FurinA-P2A Ar2 T细胞输注的小鼠血清中检测到少量IL-21(图7D)。
实施例12
该实施例证实了在用Teil-21/15 FurinA-P2A Ar2转导的细胞输注后，荷瘤小鼠中的血清炎性细胞因子图谱。
用未转导的人T细胞、HBSS(无细胞)或用如下(i)-(v)之一转导的人T细胞输注具有来源于CaSki肿瘤细胞系的可触知肿瘤的NSG小鼠：
(i.)E7 TCR和TeIL-15 Lr1Ar2，
(ii.)E7 TCR和TeIL-21 Lr8Ar2，
(iii.)E7 TCR和TeIL-21/15 FurinA-P2A Ar2，
(iv.)E7 TCR和分泌的IL-21/15(sIL-21/15)(阳性对照)或
(v.)单独的E7 TCR(对照)。
在四个时间点(T细胞输注后第8天、第9天、第15天和第29天)收集血清，并使用U-PLEX测定平台测定炎性细胞因子图谱。
结果显示在图8A-8G中。当与分别接受未转导的T细胞或用E7 TCR转导的T细胞的对照组鼠相比时，在接受用E7 TCR和TeIL-12/15 FurinA-P2A Ar2转导的T细胞的荷瘤小鼠的血清中，在所有时间点都观察到升高的细胞因子(包括IFN-γ、TNF-α、GM-CSF、IL-2、MIP-1α和IL-2Rα)水平(图8A-8F)。据报道，IL-6是CAR T细胞疗法中细胞因子风暴的主要因素。本文结果显示在用E7 TCR和TeIL-21/15 FurinA-P2A Ar2转导的T细胞输注的小鼠血清中，IL-6水平低于检测下限(图8G)。在T细胞输注后的第15天和第29天，在接受用E7 TCR和TeIL-15 Lr1Ar2转导的T细胞的小鼠血清中检测到IL-6略有增加(图8G)。
实施例13
本实施例证实了用E7 TCR和TeIL-21/15 FurinA-P2A Ar2共转导的T细胞处理的荷瘤小鼠经历肿瘤消退。
用2.5×106个CaSki肿瘤细胞皮下接种NSG小鼠。一周后，用单次静脉内注射在0.5ml HBSS中的5百万个T细胞来治疗具有建立肿瘤的小鼠。用如下(i)-(iv)之一转导注射的T细胞：
(i.)E7 TCR和NFAT.IL12(在活化T细胞核因子(NFAT)-应答性启动子控制下的IL-12)，
(ii.)E7 TCR和TeIL-21/15 FurinA-P2A Ar2及NFAT.IL12，
(iii.)E7 TCR和TeIL-21/15 FurinA-P2A Ar2或
(iv.)单独的E7 TCR(对照)。
将未处理的小鼠用作对照。每3-4天使用数字卡尺测量肿瘤大小。结果显示在图9中。接受用单独的E7 TCR转导的T细胞的小鼠显示出与未接受治疗的对照小鼠相似的肿瘤生长曲线。接受用E7 TCR和NFAT.IL12共转导的T细胞的小鼠仅显示出延迟的肿瘤进展。接受用E7 TCR和TeIL-21/15 FurinA-P2A Ar2共转导的T细胞的小鼠以及接受与E7 TCR和TeIL-21/15 FurinA-P2A Ar2及NFAT.IL12共转导的T细胞的小鼠在T细胞输注后的第51天显示出显著的肿瘤消退。在T细胞输注后的第63天，接受用E7 TCR和TeIL-21/15 FurinA-P2A Ar2共转导的T细胞的三只小鼠显示出完全肿瘤消退，而接受用E7 TCR和TeIL-21/15FurinA-P2A Ar2及NFAT.IL12共转导的T细胞的四只小鼠显示出小尺寸的肿瘤。
在此将本文引用的所有参考文献，包括出版物、专利申请和专利通过引用并入，其程度如同将各参考文献单独且明确指明通过引用并入，并且在本文整体示出一样。
术语“一个/一种(a)”和“一个/一种(an)”和“所述(the)”和至少一个(一种)以及类似的指代物在描述本发明的上下文中(特别是在下述权利要求的上下文中)的使用被解释为既涵盖单数又涵盖复数，除非本文另外指明或者上下文明显矛盾。术语“至少一种/一个”之后一项或多项列举(例如，“A和B中的至少一种/一个”)的使用应被解释为意指选自列出的项中的一项(A或B)或两个或更多个列出的项的组合(A和B)，除非本文另外指出或与上下文明显矛盾。术语“包含(comprising)”、“具有(having)”、“包括(including)”以及“含有(containing)”被解释为开放式术语(即，意为“包括但不限于”)，除非另外标注。本文数值范围的叙述仅意图作为单独指落入范围内的各独立数值的速记法，除非本文另外指明，并且各独立的数值并入说明书如同本文单独对其进行叙述一样。可以以任何合适的顺序实施本文所述的所有方法，除非本文另外指明或者在其它方面与上下文明显矛盾。本文提供的任何或所有实施例或者示例性语言(例如“如”)的使用仅意图更好地阐明本发明，并且不对本发明的范围构成限制，除非另外声明。说明书中的语言均不应被解释为指示任何未要求保护的元素对于本发明的实践是必要的。
本文描述了本发明的优选实施方案，包括发明人已知的实施本发明的最佳方式。经阅读前述描述，那些优选实施方案的改变对于本领域普通技术人员而言可以变得显而易见。发明人期望本领域技术人员视情况应用此类改变，并且发明人意图以与本文具体所述的不同的方式实践本发明。因此，如适用的法律所允许的，本发明包括在此所附的权利要求中所述的主题的所有修饰和等同物。此外，本发明涵盖以上所述元素的所有可能的改变的任何组合，除非本文另外指明或者在其它方面与上下文明显矛盾。
序列表
<110> 美国卫生和人力服务部
克里斯蒂安·S·欣里西斯
本杰明·Y·金
<120> 拴系白细胞介素-15和白细胞介素-21
<130> 741568
<150> US 62/628,454
<151> 2018-02-09
<160> 44
<170> PatentIn version 3.5
<210> 1
<211> 18
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser
<210> 2
<211> 133
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile
1 5 10 15
Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu
20 25 30
Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser
35 40 45
Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu
50 55 60
Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser
65 70 75 80
Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys
85 90 95
Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys
100 105 110
Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His
115 120 125
Gly Ser Glu Asp Ser
130
<210> 3
<211> 114
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr Ser
<210> 4
<211> 21
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr
20
<210> 5
<211> 46
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly Ile Phe
1 5 10 15
Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu Arg
20 25 30
Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
35 40 45
<210> 6
<211> 9
<212> PRT
<213> 猪捷申病毒-1 2A(porcine teschovirus-1 2A)
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> X是任何天然存在的氨基酸残基。
<400> 6
Gly Asp Val Glu Xaa Asn Pro Gly Pro
1 5
<210> 7
<211> 22
<212> PRT
<213> 猪捷申病毒-1 2A(porcine teschovirus-1 2A)
<400> 7
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 8
<211> 23
<212> PRT
<213> 马鼻炎A病毒2a(equine rhinitis A virus 2a)
<400> 8
Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp
1 5 10 15
Val Glu Ser Asn Pro Gly Pro
20
<210> 9
<211> 21
<212> PRT
<213> 明脉扁刺蛾β四体病毒2A (thosea asigna virus 2A)
<400> 9
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 10
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X是任何天然存在的氨基酸。
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> X是精氨酸或赖氨酸。
<400> 10
Arg Xaa Xaa Arg
1
<210> 11
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 11
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
1 5 10 15
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
20 25
<210> 12
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 12
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln
20 25
<210> 13
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 13
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 14
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 14
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
<210> 15
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 15
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
35 40 45
<210> 16
<211> 48
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 16
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln
35 40 45
<210> 17
<211> 61
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 17
Ala Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser
50 55 60
<210> 18
<211> 237
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 18
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val
65 70 75 80
Thr Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly
85 90 95
Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr
100 105 110
Thr Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro
115 120 125
Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr
130 135 140
Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser
145 150 155 160
His Gln Pro Pro Gly Val Tyr Pro Gln Gly His Ser Asp Thr Thr Val
165 170 175
Ala Ile Ser Thr Ser Thr Val Leu Leu Cys Gly Leu Ser Ala Val Ser
180 185 190
Leu Leu Ala Cys Tyr Leu Lys Ser Arg Gln Thr Pro Pro Leu Ala Ser
195 200 205
Val Glu Met Glu Ala Met Glu Ala Leu Pro Val Thr Trp Gly Thr Ser
210 215 220
Ser Arg Asp Glu Asp Leu Glu Asn Cys Ser His His Leu
225 230 235
<210> 19
<211> 180
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 19
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln Ile
145 150 155 160
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
165 170 175
Leu Val Ile Thr
180
<210> 20
<211> 171
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 20
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly
130 135 140
Glu Gly Ser Thr Lys Gly Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
145 150 155 160
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
165 170
<210> 21
<211> 396
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 21
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln Ile
145 150 155 160
Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys
165 170 175
Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe
180 185 190
Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys
195 200 205
Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg
210 215 220
Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr
225 230 235 240
Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly Lys
245 250 255
Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr Thr
260 265 270
Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro Ser
275 280 285
Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr Pro
290 295 300
Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser His
305 310 315 320
Gln Pro Pro Gly Val Tyr Pro Gln Gly His Ser Asp Thr Thr Val Ala
325 330 335
Ile Ser Thr Ser Thr Val Leu Leu Cys Gly Leu Ser Ala Val Ser Leu
340 345 350
Leu Ala Cys Tyr Leu Lys Ser Arg Gln Thr Pro Pro Leu Ala Ser Val
355 360 365
Glu Met Glu Ala Met Glu Ala Leu Pro Val Thr Trp Gly Thr Ser Ser
370 375 380
Arg Asp Glu Asp Leu Glu Asn Cys Ser His His Leu
385 390 395
<210> 22
<211> 198
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 22
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
180 185 190
Leu Ser Leu Val Ile Thr
195
<210> 23
<211> 132
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 23
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser
130
<210> 24
<211> 199
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 24
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
165 170 175
Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
180 185 190
Leu Leu Ser Leu Val Ile Thr
195
<210> 25
<211> 190
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 25
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro
145 150 155 160
Gly Ser Gly Glu Gly Ser Thr Lys Gly Ile Tyr Ile Trp Ala Pro Leu
165 170 175
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
180 185 190
<210> 26
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 26
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
165 170 175
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
180 185 190
Gly Gly Gly Ser Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
195 200 205
Val Leu Leu Leu Ser Leu Val Ile Thr
210 215
<210> 27
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 27
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ala Glu Ala Ala Ala Lys Glu Ala Ala
145 150 155 160
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Leu Glu Ala
165 170 175
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
180 185 190
Ala Ala Ala Lys Ala Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
195 200 205
Gly Val Leu Leu Leu Ser Leu Val Ile Thr
210 215
<210> 28
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 28
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly
195 200 205
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
210 215 220
<210> 29
<211> 233
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 29
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ala Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
165 170 175
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
180 185 190
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
195 200 205
Gly Ser Ala Ser Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
210 215 220
Val Leu Leu Leu Ser Leu Val Ile Thr
225 230
<210> 30
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 30
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu
195 200 205
Ile Ser Val Asn Gly Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe
210 215 220
Ala Pro Arg Cys Arg Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu
225 230 235 240
Ser Val Arg Pro Val
245
<210> 31
<211> 205
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 31
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
20 25 30
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
35 40 45
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
50 55 60
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
65 70 75 80
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
85 90 95
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
100 105 110
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
115 120 125
Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln Leu
145 150 155 160
Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly Ile Phe Val
165 170 175
Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu Arg Arg
180 185 190
Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
195 200 205
<210> 32
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 32
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly
195 200 205
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Gly Ser Gly Ala
210 215 220
Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro
225 230 235 240
Gly Pro Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr
245 250 255
Arg Val His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
260 265 270
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
275 280 285
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
290 295 300
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
305 310 315 320
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
325 330 335
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
340 345 350
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
355 360 365
Met Phe Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu
385 390 395 400
Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly Ile
405 410 415
Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu
420 425 430
Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
435 440 445
<210> 33
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 33
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly
195 200 205
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Gly Ser Gly Gln
210 215 220
Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
225 230 235 240
Pro Gly Pro Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala
245 250 255
Thr Arg Val His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
260 265 270
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
275 280 285
Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
290 295 300
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
305 310 315 320
His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
325 330 335
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
340 345 350
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
355 360 365
Gln Met Phe Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
385 390 395 400
Leu Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly
405 410 415
Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg
420 425 430
Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
435 440 445
<210> 34
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 34
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly
195 200 205
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Gly Ser Gly Glu
210 215 220
Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly
225 230 235 240
Pro Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg
245 250 255
Val His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
260 265 270
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
275 280 285
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
290 295 300
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
305 310 315 320
Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
325 330 335
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
340 345 350
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met
355 360 365
Phe Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln
385 390 395 400
Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly Ile Phe
405 410 415
Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu Arg
420 425 430
Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
435 440 445
<210> 35
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 35
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly
195 200 205
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ala Lys Arg
210 215 220
Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp
225 230 235 240
Val Glu Glu Asn Pro Gly Pro Met Asp Trp Thr Trp Ile Leu Phe Leu
245 250 255
Val Ala Ala Ala Thr Arg Val His Ser Asn Trp Val Asn Val Ile Ser
260 265 270
Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala
275 280 285
Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala
290 295 300
Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly
305 310 315 320
Asp Ala Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn
325 330 335
Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu
340 345 350
Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe
355 360 365
Val His Ile Val Gln Met Phe Ile Asn Thr Ser Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Ser Leu Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile
405 410 415
Ser Val Asn Gly Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala
420 425 430
Pro Arg Cys Arg Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser
435 440 445
Val Arg Pro Val
450
<210> 36
<211> 473
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 36
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu
195 200 205
Ile Ser Val Asn Gly Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe
210 215 220
Ala Pro Arg Cys Arg Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu
225 230 235 240
Ser Val Arg Pro Val Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu
245 250 255
Lys Leu Ala Gly Asp Val Glu Ser Asn Pro Gly Pro Met Asp Trp Thr
260 265 270
Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val His Ser Asn Trp
275 280 285
Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser
290 295 300
Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser
305 310 315 320
Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile
325 330 335
Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu Asn Leu
340 345 350
Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu
355 360 365
Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu
370 375 380
Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn Thr Ser
385 390 395 400
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
405 410 415
Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln Leu Leu Pro Ser Trp
420 425 430
Ala Ile Thr Leu Ile Ser Val Asn Gly Ile Phe Val Ile Cys Cys Leu
435 440 445
Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu Arg Arg Arg Asn Glu Arg
450 455 460
Leu Arg Arg Glu Ser Val Arg Pro Val
465 470
<210> 37
<211> 477
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 37
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile
20 25 30
Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu
35 40 45
Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala
50 55 60
Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn
65 70 75 80
Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro
85 90 95
Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro
100 105 110
Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg
115 120 125
Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg
130 135 140
Thr His Gly Ser Glu Asp Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
165 170 175
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Leu Gln Leu Leu Pro Ser Trp Ala Ile Thr Leu
195 200 205
Ile Ser Val Asn Gly Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe
210 215 220
Ala Pro Arg Cys Arg Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu
225 230 235 240
Ser Val Arg Pro Val Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn
245 250 255
Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
260 265 270
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
275 280 285
His Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
290 295 300
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
305 310 315 320
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
325 330 335
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
340 345 350
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
355 360 365
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
370 375 380
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
385 390 395 400
Ile Asn Thr Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
405 410 415
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln Leu
420 425 430
Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly Ile Phe Val
435 440 445
Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg Glu Arg Arg
450 455 460
Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
465 470 475
<210> 38
<211> 27
<212> PRT
<213> 智人(Homo sapiens)
<400> 38
Asn Ile Lys Gly Ser Pro Trp Lys Gly Ser Leu Leu Leu Leu Leu Val
1 5 10 15
Ser Asn Leu Leu Leu Cys Gln Ser Val Ala Pro
20 25
<210> 39
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 39
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcagatc 600
tatatttggg cccctctggc cggaacatgt ggcgtgttgc tgctgtctct ggttatcacc 660
ggcagcggcg ccacaaattt cagcctgctg aaacaggccg gcgacgtgga agagaatcct 720
ggacctatgg actggacttg gatactcttt ctggtcgctg ccgccacacg ggtgcactct 780
aattgggtca acgtgatcag cgacctgaag aagatcgagg acctgatcca gagcatgcac 840
atcgacgcca cactgtacac cgagtccgat gtgcacccta gctgcaaagt gaccgccatg 900
aagtgctttc tgctggaact gcaagtgatc agcctggaaa gcggcgacgc cagcatccac 960
gataccgtgg aaaatctgat catcctggcc aacaacagcc tgtccagcaa cggcaatgtg 1020
accgagagcg gctgcaaaga gtgcgaggaa ctggaagaga agaacatcaa agagtttctg 1080
cagagcttcg tccacatcgt gcagatgttc atcaacacct catcaggcgg cggtggtagt 1140
ggaggcggag gctcaggcgg cggaggttcc ggaggtggcg gttccggcgg aggatctctt 1200
caattgctgc ctagctgggc catcacactg atctccgtga acggcatctt cgtgatctgc 1260
tgcctgacct actgcttcgc ccctagatgc agagagcgga gaagaaacga gcggctgaga 1320
agagaaagcg tgcggcctgt g 1341
<210> 40
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 40
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcagatc 600
tatatttggg cccctctggc cggaacatgt ggcgtgttgc tgctgtctct ggttatcacc 660
ggctccggcc agtgtaccaa ttacgccctg cttaaactgg ccggcgacgt ggaatccaat 720
cctggaccta tggactggac ttggatactc tttctggtcg ctgccgccac acgggtgcac 780
tctaattggg tcaacgtgat cagcgacctg aagaagatcg aggacctgat ccagagcatg 840
cacatcgacg ccacactgta caccgagtcc gatgtgcacc ctagctgcaa agtgaccgcc 900
atgaagtgct ttctgctgga actgcaagtg atcagcctgg aaagcggcga cgccagcatc 960
cacgataccg tggaaaatct gatcatcctg gccaacaaca gcctgtccag caacggcaat 1020
gtgaccgaga gcggctgcaa agagtgcgag gaactggaag agaagaacat caaagagttt 1080
ctgcagagct tcgtccacat cgtgcagatg ttcatcaaca cctcatcagg cggcggtggt 1140
agtggaggcg gaggctcagg cggcggaggt tccggaggtg gcggttccgg cggaggatct 1200
cttcaattgc tgcctagctg ggccatcaca ctgatctccg tgaacggcat cttcgtgatc 1260
tgctgcctga cctactgctt cgcccctaga tgcagagagc ggagaagaaa cgagcggctg 1320
agaagagaaa gcgtgcggcc tgtg 1344
<210> 41
<211> 1338
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 41
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcagatc 600
tatatttggg cccctctggc cggaacatgt ggcgtgttgc tgctgtctct ggttatcacc 660
ggttctggcg aaggcagagg ctctctgctt acttgtggcg acgtggaaga gaatcctgga 720
cctatggact ggacttggat actctttctg gtcgctgccg ccacacgggt gcactctaat 780
tgggtcaacg tgatcagcga cctgaagaag atcgaggacc tgatccagag catgcacatc 840
gacgccacac tgtacaccga gtccgatgtg caccctagct gcaaagtgac cgccatgaag 900
tgctttctgc tggaactgca agtgatcagc ctggaaagcg gcgacgccag catccacgat 960
accgtggaaa atctgatcat cctggccaac aacagcctgt ccagcaacgg caatgtgacc 1020
gagagcggct gcaaagagtg cgaggaactg gaagagaaga acatcaaaga gtttctgcag 1080
agcttcgtcc acatcgtgca gatgttcatc aacacctcat caggcggcgg tggtagtgga 1140
ggcggaggct caggcggcgg aggttccgga ggtggcggtt ccggcggagg atctcttcaa 1200
ttgctgccta gctgggccat cacactgatc tccgtgaacg gcatcttcgt gatctgctgc 1260
ctgacctact gcttcgcccc tagatgcaga gagcggagaa gaaacgagcg gctgagaaga 1320
gaaagcgtgc ggcctgtg 1338
<210> 42
<211> 1356
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 42
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcagatc 600
tatatttggg cccctctggc cggaacatgt ggcgtgttgc tgctgtctct ggttatcacc 660
agggccaaaa gaagcggcag cggcgccaca aatttcagcc tgctgaaaca ggccggcgac 720
gtggaagaga atcctggacc tatggactgg acttggatac tctttctggt cgctgccgcc 780
acacgggtgc actctaattg ggtcaacgtg atcagcgacc tgaagaagat cgaggacctg 840
atccagagca tgcacatcga cgccacactg tacaccgagt ccgatgtgca ccctagctgc 900
aaagtgaccg ccatgaagtg ctttctgctg gaactgcaag tgatcagcct ggaaagcggc 960
gacgccagca tccacgatac cgtggaaaat ctgatcatcc tggccaacaa cagcctgtcc 1020
agcaacggca atgtgaccga gagcggctgc aaagagtgcg aggaactgga agagaagaac 1080
atcaaagagt ttctgcagag cttcgtccac atcgtgcaga tgttcatcaa cacctcatca 1140
ggcggcggtg gtagtggagg cggaggctca ggcggcggag gttccggagg tggcggttcc 1200
ggcggaggat ctcttcaatt gctgcctagc tgggccatca cactgatctc cgtgaacggc 1260
atcttcgtga tctgctgcct gacctactgc ttcgccccta gatgcagaga gcggagaaga 1320
aacgagcggc tgagaagaga aagcgtgcgg cctgtg 1356
<210> 43
<211> 1419
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 43
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcaattg 600
ctgcctagct gggccatcac actgatctcc gtgaacggca tcttcgtgat ctgctgcctg 660
acctactgct tcgcccctag atgcagagag cggagaagaa acgagcggct gagaagagaa 720
tctgtgcggc ctgttggctc cggccagtgt acaaattatg ccctgctgaa gctggccggc 780
gacgtggaat ctaatcctgg acctatggac tggacttgga tactctttct ggtcgctgcc 840
gccacacggg tgcactctaa ttgggtcaac gtgatcagcg acctgaagaa gatcgaggac 900
ctgatccaga gcatgcacat cgacgccaca ctgtacaccg agtccgatgt gcaccctagc 960
tgcaaagtga ccgccatgaa gtgctttctg ctggaactgc aagtgatcag cctggaaagc 1020
ggcgacgcca gcatccacga taccgtggaa aatctgatca tcctggccaa caacagcctg 1080
tccagcaacg gcaatgtgac cgagagcggc tgcaaagagt gcgaggaact ggaagaaaag 1140
aacatcaaag agtttctgca gagcttcgtc cacatcgtgc agatgttcat caacacctca 1200
tcaggtggcg gtggaagcgg aggtggcggt agtggcggcg gaggctcagg cggcggaggt 1260
tccggcggag gatctcttca gctcctgcca tcttgggcta tcaccctgat tagtgtgaat 1320
gggatctttg tcatctgttg tctcacgtac tgtttcgctc cccggtgcag agagagaagg 1380
cgcaacgaaa gactgcggag agaaagcgtc agacccgtg 1419
<210> 44
<211> 1431
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 44
atggattgga cctggattct gttcctggtg gccgctgcca caagagtgca tagccagggc 60
caagaccggc acatgatccg gatgagacag ctgatcgaca tcgtggacca gctgaagaac 120
tacgtgaacg acctggtgcc tgagttcctg cctgctcctg aggacgtgga aacaaattgc 180
gagtggtccg ccttcagctg cttccagaag gcccagctga aaagcgccaa caccggcaac 240
aacgagcgga tcatcaacgt gtccatcaag aagctgaagc ggaagcctcc tagcaccaat 300
gccggaagaa ggcagaagca cagactgacc tgtcctagct gcgacagcta cgagaagaag 360
cctccaaaag agttcctgga acggttcaag agcctgctgc agaagatgat ccaccagcac 420
ctgagcagca gaacccacgg ctctgaagat tctagcggag gcggaggaag tggtggcgga 480
ggttctggtg gcggtggatc aggcggtggc ggatctggcg gcggaggcag tggcggaggt 540
ggaagcggtg gtggtggctc tggcggaggc ggtagcggcg gaggcggatc tcttcaattg 600
ctgcctagct gggccatcac actgatctcc gtgaacggca tcttcgtgat ctgctgcctg 660
acctactgct tcgcccctag atgcagagag cggagaagaa acgagcggct gagaagagaa 720
tctgtgcggc ctgttagagc caagagatct ggaagcggcg ccaccaactt tagcctgctg 780
aaacaggctg gcgacgtgga agagaaccct ggacctatgg actggacttg gatactcttt 840
ctggtcgctg ccgccacacg ggtgcactct aattgggtca acgtgatcag cgacctgaag 900
aagatcgagg acctgatcca gagcatgcac atcgacgcca cactgtacac cgagtccgat 960
gtgcacccta gctgcaaagt gaccgccatg aagtgctttc tgctggaact gcaagtgatc 1020
agcctggaaa gcggcgacgc cagcatccac gataccgtgg aaaatctgat catcctggcc 1080
aacaacagcc tgtccagcaa cggcaatgtg accgagagcg gctgcaaaga gtgcgaggaa 1140
ctggaagaaa agaacatcaa agagtttctg cagagcttcg tccacatcgt gcagatgttc 1200
atcaacacct catcaggtgg cggtggaagc ggaggtggcg gtagtggcgg cggaggctca 1260
ggcggcggag gttccggcgg aggatctctt cagctcctgc catcttgggc tatcaccctg 1320
attagtgtga atgggatctt tgtcatctgt tgtctcacgt actgtttcgc tccccggtgc 1380
agagagagaa ggcgcaacga aagactgcgg agagaaagcg tcagacccgt g 1431
Claims (24)
1.核酸，其包含编码式I的氨基酸序列的核苷酸序列：
S1-N1-L1-C1 a-L2-S2-N2-L3-C2 b
(式I)，
其中：
S1和S2中的每一个独立地是信号序列；
N1和N2中的一个是白细胞介素(IL)-21氨基酸序列，并且N1和N2中的一个是IL-15氨基酸序列；
L1和L3中的每一个独立地是接头序列；
L2是可切割的接头序列；
C1和C2中的每一个独立地是跨膜-细胞内氨基酸序列或跨膜氨基酸序列；以及
a和b中的每一个独立地是0或1。
2.如权利要求1所述的核酸，其中L1和L3中的每一个独立地是10至65个氨基酸残基。
3.如权利要求1或2所述的核酸，其中L2是20至30个氨基酸残基。
4.如权利要求1-3中任一项所述的核酸，其中L1和L3中的每一个独立地是
(i)式III的多肽：X1 mX2 nX3 pX4 q(式III)，其中：
m、p和q中的每一个独立地是0或1；
n是20至65的整数；
X2是多个氨基酸残基，所述氨基酸残基中的每一个独立地选自甘氨酸和丝氨酸；以及
X1、X3和X4中的每一个独立地是任何一个天然存在的氨基酸残基；
(ii)式IV的多肽：X5 rX6 sX7 t(式IV)，其中：
s是1；
r和t中的每一个独立地是20至25的整数；
X5和X7中的每一个独立地是多个氨基酸残基，所述氨基酸残基中的每一个独立地选自丙氨酸、赖氨酸和谷氨酸；以及
X6是任何一个天然存在的氨基酸残基；或者
(iii)10至30个氨基酸残基，其独立地选自甘氨酸、丝氨酸、苏氨酸、赖氨酸、谷氨酸和脯氨酸。
5.如权利要求1-4中任一项所述的核酸，其中L2是(i)猪捷申病毒-1 2A(P2A)氨基酸序列、(ii)马鼻炎A病毒(E2A)氨基酸序列、(iii)明脉扁刺蛾β四体病毒2A(T2A)氨基酸序列、(iv)口蹄疫病毒(F2A)氨基酸序列或(v)弗林蛋白酶可切割的-P2A氨基酸序列。
6.如权利要求1-5中任一项所述的核酸，其中C1和C2中的每一个独立地是B7-1跨膜-细胞内氨基酸序列、B7-2跨膜-细胞内氨基酸序列、CD8α跨膜-细胞内氨基酸序列、B7-1跨膜氨基酸序列、B7-2跨膜氨基酸序列或CD8α跨膜氨基酸序列。
7.如权利要求1-6中任一项所述的核酸，其中C1和C2中的每一个独立地是IYIWAPLAGTCGVLLLSLVIT(SEQ ID NO:4)或LLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV(SE Q ID NO:5)。
8.如权利要求1-7中任一项所述的核酸，其中N1是IL-21氨基酸序列，以及N2是IL-15氨基酸序列。
9.如权利要求1-8中任一项所述的核酸，其包含编码与SEQ ID NO:32-37中任一项至少85％相同的氨基酸序列的核苷酸序列。
10.一种或多种多肽，其由权利要求1-9中任一项所述的核酸编码。
11.如权利要求10所述的一种或多种多肽，其中：
当a是0时，L1还包含非肽细胞膜锚定部分，以及
当b是0时，L3还包含非肽细胞膜锚定部分。
12.如权利要求11所述的一种或多种多肽，其中所述非肽细胞膜锚定部分是糖磷脂酰肌醇(GPI)锚定。
13.重组表达载体，其包含权利要求1-9中任一项所述的核酸。
14.宿主细胞，其包含权利要求13所述的重组表达载体。
15.宿主细胞，其表达权利要求1-9中任一项所述的核酸或者权利要求10-12中任一项所述的一种或多种多肽。
16.如权利要求14或15所述的宿主细胞，其中所述宿主细胞包含抗原特异性受体。
17.如权利要求16所述的宿主细胞，其中所述抗原特异性受体是嵌合抗原受体(CAR)。
18.如权利要求16所述的宿主细胞，其中所述抗原特异性受体是内源性T细胞受体(TCR)。
19.如权利要求16所述的宿主细胞，其中所述抗原特异性受体是外源性TCR。
20.如权利要求14-19中任一项所述的宿主细胞，其中所述抗原特异性受体对癌抗原具有抗原特异性。
21.细胞群体，其包含权利要求14-20中任一项所述的宿主细胞。
22.药物组合物，其包含药学上可接受的载体和权利要求1-9中任一项所述的核酸、权利要求10-12中任一项所述的一种或多种多肽、权利要求13所述的重组表达载体、权利要求14-20中任一项所述的宿主细胞、或者权利要求21所述的细胞群体。
23.权利要求1-9中任一项所述的核酸、权利要求10-12中任一项所述的一种或多种多肽、权利要求13所述的重组表达载体、权利要求14-20中任一项所述的宿主细胞、权利要求21所述的细胞群体或者权利要求22所述的药物组合物，其用于治疗或预防哺乳动物中的癌症。
24.权利要求1-9中任一项所述的核酸、权利要求10-12中任一项所述的一种或多种多肽、权利要求13所述的重组表达载体、权利要求14-20中任一项所述的宿主细胞、权利要求21所述的细胞群体或者权利要求22所述的药物组合物，其用于增强哺乳动物对疫苗的免疫应答。
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| AU2020408017A1 (en) | 2019-12-20 | 2022-07-14 | Instil Bio (Uk) Limited | Devices and methods for isolating tumor infiltrating lymphocytes and uses thereof |
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| KR102393402B1 (ko) * | 2021-03-26 | 2022-05-04 | (주)와이디생명과학 | 세포 내 존재 단백질과 세포 외부로 분비되는 단백질을 동시 발현하는 이중발현벡터를 포함하는 암의 예방 또는 치료용 조성물 |
| BR112023021665A2 (pt) | 2021-04-19 | 2023-12-19 | Iovance Biotherapeutics Inc | Método para tratar um câncer, e, composição |
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| US20210052647A1 (en) | 2021-02-25 |
| US20230355677A1 (en) | 2023-11-09 |
| CA3090512A1 (en) | 2019-08-15 |
| EP3749770A1 (en) | 2020-12-16 |
| AU2019218785A1 (en) | 2020-09-03 |
| WO2019157130A1 (en) | 2019-08-15 |
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