CN114787181A - 用抗pd-1/il-15免疫细胞因子靶向pd-1的新型免疫疗法 - Google Patents
用抗pd-1/il-15免疫细胞因子靶向pd-1的新型免疫疗法 Download PDFInfo
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Abstract
发明人现在提供新的IL‑15/IL‑15受体α(IL‑15Rα)融合蛋白。此外，作为抗PD‑1疗法的补充，发明人开发了一系列抗PD‑1/IL‑15/IL‑15受体α(IL‑15Rα)免疫细胞因子，能够同时靶向免疫激活过程中的多个步骤。所述免疫细胞因子的开发提供了与单独施用抗PD‑1抗体和IL‑15相关的潜在益处，并具有几个明显的优势。这些包括相对于IL‑15疗法显著延长的体内半衰期、预先形成的IL‑15/IL‑15Rα复合物的施用将排除IL‑15Rα反式呈递的需要、高活性导致的低靶向治疗剂量和靶向递送IL‑15到高PD‑1细胞的区域，这将限制脱靶不良事件。
Description
技术领域
本发明属于医学领域，特别是免疫学、肿瘤学和病毒学领域。
背景技术
靶向PD-1的抗体是肿瘤学的金标准免疫治疗策略，数百项临床试验正在进行中，以确定更有效和/或更广泛适用于不同形式癌症的联合疗法。治疗可以在三个特定的免疫增强步骤中产生抗肿瘤作用。这些通常是为了：1)促进足够数量和多样性的肿瘤引发的T细胞，2)确保适当的运输和穿透肿瘤，以及，3)防止抑制肿瘤特异性T细胞反应。针对免疫介导的抗肿瘤反应中不同限制步骤的治疗组合预计具有协同治疗效果。这一假设在将纳武单抗(Opdivo)抗PD-1疗法与伊匹单抗(Ipilimumab)联合使用以减轻肿瘤特异性CD8+T细胞功能衰竭的试验中得到证实，伊匹单抗(Ipilimumab)通过CTLA-4阻断作用以增强T细胞通过抗原呈递细胞的启动。尽管观察到几种癌症的治疗益处，但患者也面临着不利事件的显著增加，这限制了这种免疫治疗组合的使用。因此，免疫治疗组合在增强抗肿瘤免疫反应方面具有巨大潜力，但这些组合的安全性是一个重要的考虑因素。
治疗性疫苗和免疫调节剂通常用于增强HIV-1特异性细胞介导的免疫反应和抑制病毒复制。虽然前者对刺激HIV-1-特异性T-细胞反应很重要，但后者可能支持受刺激的病毒特异性T细胞的扩增，并使它们对病毒清除具有更强的细胞毒性。最近靶向PD-1的免疫疗法在癌症领域的成功为开发有效的组合疗法提供了科学基础，以增强免疫反应，从而更有效地控制病毒复制。
WO/2007/046006公开了IL-15/IL-15受体α(IL-15Rα)融合蛋白，与抗PD-1疗法相比，它可以通过多种不同的方式促进肿瘤清除。这些方式包括NK细胞的激活和诱导增殖、抗原特异性CD8+T细胞的诱导增殖、CD8+T细胞的溶细胞活性增强和长期抗原经历的CD8+CD44hi记忆T细胞的诱导。另一个好处是，与IL-2相比，IL-15不会诱导对肿瘤特异性CTL的扩增产生抑制作用的调节细胞(Tregs)的增殖。已使用小鼠体内肿瘤模型显示支持抗PD-1Abs与所述IL-15/IL-15受体α(IL-15Rα)融合蛋白联合使用，相比于单独施用任一单一疗法，其中接受联合疗法治疗的动物的肿瘤生长速度显著降低、生存期延长(Desbois,Mélanie,et al."IL-15trans-signaling with the superagonist RLI promoteseffector/memory CD8+T cell responses and enhances antitumor activity of PD-1antagonists."The Journal of Immunology 197.1(2016):168-178.)。与这种协同作用相关的机制部分原因是T细胞信号通路的免疫增强，促进抗原特异性刺激、细胞增殖和细胞存活。尽管有这些好处，但由于一些限制，IL-15/IL-15受体α(IL-15Rα)融合蛋白在临床上的应用有限。这些限制包括：1)体内半衰期短(<1小时；Stoklasek et al.2006)导致高峰浓度(Cmax)值，2)由血管渗漏综合征等不良事件引起的低剂量限制性毒性，3)在肿瘤微环境中，对IL-15Rα反式表达的需求经常被下调，4)PD-1在T细胞上的快速上调，当用作单一疗法时导致自限性免疫反应，和5)由于使用的高治疗剂量，导致严重但可逆的中性粒细胞减少症。
WO20012/175222公开了一种免疫细胞因子，其包括(a)缀合物，和(b)通过共价直接或间接连接至所述缀合物的抗体或其片段，其中所述缀合物包含(i)包含白细胞介素15或其衍生物的氨基酸序列的多肽，以及包含IL-15Rα或其衍生物的sushi结构域的氨基酸序列的多肽。然而，现有技术没有公开抗PD-1/IL-15免疫细胞因子。
发明内容
如权利要求所定义，本发明涉及新的IL-15/IL-15受体α(IL-15Rα)融合蛋白，包括所述融合蛋白的免疫细胞因子和所述免疫细胞因子用于治疗癌症和病毒感染的用途。
发明详述：
本发明人现在提供了新的IL-15/IL-15受体α(IL-15Rα)融合蛋白。此外，作为对抗PD-1治疗的补充，发明人开发了一系列抗PD-1/IL-15/IL-15受体α(IL-15Rα)免疫细胞因子，其能够同时靶向免疫激活过程中的多个步骤。所述免疫细胞因子的开发提供了与单独施用抗PD-1抗体和IL-15相关的潜在益处，并具有几个明显的优势。这些包括相对于IL-15疗法显著延长的体内半衰期、施用预先形成的IL-15/IL-15Rα复合物，其能够排除IL-15Rα反式呈递需要、高活性导致低靶向治疗剂量和IL-15靶向输送到具有高PD-1细胞的区域，从而限制非靶向不良事件。
最重要的是，本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白与WO007046006中描述的融合蛋白的不同之处在于连接子的性质。本发明的连接子序列(“Flex序列”)不遵从WO007046006的教导提出的特征。实际上，WO007046006教导，为了促进与功能性蛋白质结构域的相互作用，连接子序列应具有最小的疏水性或带电性，并且优选地包含甘氨酸(G)、天冬酰胺(N)和丝氨酸(S)。在此，发明人出人意料地表明，本发明的连接子主要由疏水性(例如丙氨酸A、缬氨酸V、脯氨酸P和亮氨酸L)或带电氨基酸(例如天冬氨酸D和谷氨酸E)组成且不包含甘氨酸(G)、天冬酰胺(N)和丝氨酸(S)，但导致获得功能性融合蛋白。
主要定义：
如本文所用，术语“PD-1”在本领域具有其一般含义并且是指程序性细胞死亡蛋白1(也称为CD279)。PD-1作为一个免疫检查点，在与其配体之一PD-L1或PD-L2结合后，Shp2能够使CD28去磷酸化并抑制T细胞的活化。
如本文所用，术语“CD40”在本领域具有其一般含义并且是指人CD40多肽受体。在一些实施方案中，CD40是UniProtKB-P25942(也称为人TNR5)报道的人规范序列的同种型。
如本文所用，术语“白细胞介素15”在本领域具有其一般含义并且是指与IL-2结构相似的细胞因子(GRABSTEIN et al.,Science,vol.264(5161),p:965-968,1994)。这种细胞因子也称为IL-15、IL15或MGC9721。这种细胞因子和IL-2共享许多生物活性，并且发现它们可以结合常见的造血素受体亚基。因此，它们可能会竞争相同的受体，从而负面地调节彼此的活动。已经证实IL-15调节T细胞和自然杀伤细胞的活化和增殖，并且CD8+记忆T细胞的数量受该细胞因子和IL-2之间的平衡控制。IL-15的活性可以通过测定其对kit225细胞系的增殖诱导来测量(HORI et al.,Blood,vol.70(4),p:1069-72,1987)。
如本文所用，术语“IL-15Rα的sushi结构域”在本领域具有其一般含义并且是指从IL-15Rα的信号肽之后的第一个半胱氨酸残基(C1)开始，到所述信号肽之后的第四个半胱氨酸残基(C4)结束的结构域。与IL-15Rα的细胞外区域的一部分相对应的所述sushi结构域是与IL-15的结合所必需的(WEI et al.,J Immunol.,vol.167(1),p:277-282,2001)。
如本文所用，术语“肽”、“多肽”和“蛋白质”可互换使用，并且是指由通过肽键共价连接的氨基酸残基组成的化合物。多肽不限于特定长度：它必须包含至少两个氨基酸，并且不限制可以构成多肽序列的氨基酸的最大数量。肽、寡肽和蛋白质包括在多肽的定义内，除非另有特别说明，否则这些术语在本文中可以互换使用。如本文所用，该术语既指短链，其在本领域中也通常被称为肽、寡肽和寡聚体，也指更长链，在本领域中通常称为蛋白质，其有多种类型。在本文使用的一个实施方案中，术语“肽”是指通过肽键连接在一起的氨基酸线性聚合物，优选具有小于约50个氨基酸残基的链长；“多肽”是指至少50个氨基酸通过肽键连接在一起的线性聚合物；蛋白质特指由一种或多种肽或可选地糖基化的多肽和可选地非多肽辅因子形成的功能实体。而且该术语不包括多肽的表达后修饰，例如糖基化、乙酰化、磷酸化等，以及本领域已知天然存在和非天然存在的其他修饰。多肽可以是完整的蛋白质或其子序列。“多肽”包括例如生物活性片段、基本上同源的多肽、寡肽、同二聚体、异二聚体、多肽的变体、修饰的多肽、衍生物、类似物、融合蛋白等。多肽包括天然肽、重组肽或其组合。在本发明的上下文中感兴趣的特定多肽是包含CDRs并且能够结合抗原的氨基酸子序列。
如本文所用，术语“融合蛋白”指包含至少一条通过基因融合获得或可获得的多肽链的重组蛋白，例如通过至少两个编码不同蛋白质的独立功能域的基因片段的基因融合。因此，术语“融合蛋白”是指其中两个多肽直接融合或通过连接子融合的构建体。
如本文所用，术语“直接地”是指第一多肽的末端(N或C末端)的(第一个或最后一个)氨基酸与第二多肽末端(N或C末端)的(第一或最后一个)氨基酸融合。换句话说，在本实施方案中，所述多肽的C末端的最后一个氨基酸通过共价键直接连接到所述异源多肽的N末端的第一个氨基酸，或者所述多肽N末端的第一个氨基酸通过共价键直接连接到所述异源多肽C末端的最后一个氨基酸。
如本文所用，术语“连接子”具有其在本领域中的一般含义并且是指长度足以确保蛋白质形成适当的二级和三级结构的氨基酸序列。在一些实施方案中，连接子是包含至少一个但少于30个氨基酸的肽连接子，例如包含2-30个氨基酸、优选10-30个氨基酸、更优选15-30个氨基酸、更优选19-27个氨基酸、最优选20-26个氨基酸的肽连接子。在一些实施方案中，连接子具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30个氨基酸残基。通常，连接子是那些允许化合物采用适当构象(即允许通过IL-15Rβ/γ信号通路进行适当的信号转导活动的构象)的连接子。通常，最合适的连接子序列(1)将采用灵活的扩展构象，(2)不会表现出可与融合蛋白功能域相互作用的有序二级结构的倾向，以及(3)具有可促进与功能蛋白域相互作用的最小疏水性或带电性。
如本文所用，术语“核酸”或“多核苷酸”是指通过磷酸二酯键共价连接的核苷酸聚合物，例如单链或双链形式的脱氧核糖核酸(DNA)或核糖核酸(RNA)。除非特别限定，否则该术语包括含有已知天然核苷酸类似物的核酸，其具有与参考核酸类似的结合性质，并以类似于天然核苷酸的方式代谢。通常，本发明的核酸是密码子优化的。如本文所用，术语“优化的”是指核苷酸序列已经被改变，以使用生产细胞或生物体(通常为真核细胞，例如中国仓鼠卵巢细胞(CHO)或人类细胞)中优选的密码子来编码氨基酸序列。优化的核苷酸序列被设计成完全或尽可能多地保留起始核苷酸序列最初编码的氨基酸序列。通过优化的核苷酸序列编码的氨基酸序列也称为优化的。
如本文所用，术语“编码”指多核苷酸中特定核苷酸序列的固有特性，例如基因、cDNA或mRNA，用作生物过程中合成其他聚合物和大分子的模板，这些聚合物和大分子具有规定的核苷酸序列(例如rRNA、tRNA和mRNA)或规定的氨基酸序列以及由此产生的生物特性。因此，如果与该基因对应的mRNA的转录和翻译在细胞或其他生物系统中产生蛋白质，则基因、cDNA或RNA编码蛋白质。编码链(其核苷酸序列与mRNA序列相同并且通常在序列列表中提供)和非编码链(用作基因或cDNA转录的模板)都可以称为编码该基因或cDNA的蛋白质或其他产物。除非另有说明，否则“编码氨基酸序列的核苷酸序列”包括所有核苷酸序列，所述核苷酸序列是彼此的简并形式且编码相同氨基酸序列。短语“编码蛋白质或RNA的核苷酸序列”也可能包括内含子，以致编码蛋白质的核苷酸序列在某些形式中可能包含内含子。
如本文所用，术语“载体”、“克隆载体”和“表达载体”是指可以将DNA或RNA序列(例如外源基因)导入宿主细胞的载体，从而转化宿主并促进所导入序列的表达(例如转录和翻译)。
如本文所用，术语“启动子/调节序列”是指通过细胞的合成机器识别的核酸序列(例如DNA序列)，或引入合成机器所需要得启动多核苷酸序列的特定转录，从而允许可操作地连接到启动子/调节序列的基因产物的表达。在某些情况下，该序列可能是核心启动子序列，在其他情况下，该序列还可能包括增强子序列和表达基因产物所需的其他调节元件。启动子/调节序列可以是例如组织特异性方式表达基因产物的序列。
如本文所用，术语“可操作连接”或“转录控制”是调控序列和导致后者表达的异源核酸序列之间的功能连接。例如，当第一核酸序列与第二核酸序列处于功能关系时，第一核酸序列可操作地与第二核酸序列连接。例如如果启动子影响编码序列的转录或表达，则启动子可操作地连接到编码序列。可操作地连接的DNA序列彼此连续，例如在需要连接两个蛋白质编码区时，它们位于同一阅读框中。
如本文所用，术语“转化”是指将“外源”(即外来的或细胞外的)基因、DNA或RNA序列引入宿主细胞，以便宿主细胞将表达所引入的基因或序列以产生所需物质，通常是由所引入的基因或序列编码的蛋白质或酶。接受并表达引入的DNA或RNA的宿主细胞已被“转化”。
如本文所用，术语“表达系统”指在适当条件下的宿主细胞和兼容载体，例如用于表达由载体携带并引入宿主细胞的外源DNA编码的蛋白质。
如本文所用，两个序列之间的“同一性百分比”是序列共享的相同位置的数量的函数(即同一性％＝相同位置的数量/位置的总数×100)，考虑到间隙的数量和每个间隙的长度，需要引入这些以实现两个序列的最佳比对。如下所述，序列的比对和确定两个序列之间的同一性百分比可以使用数学算法完成。两个氨基酸序列之间的同一性百分比可以使用Needleman和Wunsch算法(NEEDLEMAN和Wunsch)确定。两个核苷酸或氨基酸序列之间的同一性百分比也可以使用例如EMBOSS Needle(成对比对；可在www.ebi.ac.uk上获得)等算法来确定。例如，EMBOSS Needle可与BLOSUM62矩阵一起使用，“间隙开放罚分”为10，“间隙延伸罚分”为0.5，“末端间隙罚分”为假，“末端间隙开放罚分”为10，“末端间隙延伸罚分”为0.5。通常，“同一性百分比”是匹配位置数除以比较位置数并乘以100的函数。例如如果比对后两个对比序列之间的10个序列位置中有6个是相同的，则同一性为60％。同一性％通常在执行分析的查询序列的整个长度上确定。两个具有相同一级氨基酸序列或核酸序列的分子是完全相同的，与是否进行任何化学和/或生物修饰无关。
根据本发明，与第二氨基酸序列具有至少80％同一性的第一氨基酸序列意味着第一序列具有与第二个氨基酸序列80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100％的同一性。
如本文所用，术语“抗体”具有本领域的一般含义，并且是指免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即包含与抗原免疫特异性结合的抗原结合位点的分子。在啮齿动物和灵长类动物的天然抗体中，两条重链通过二硫键相互连接，而每条重链通过二硫键连接到一条轻链。有两种类别的轻链，λ(1)和κ(k)。有五种主要的重链类别(或同型)决定抗体分子的功能活性：IgM、IgD、IgG、IgA和IgE。每条链包含不同的序列域。在典型的IgG抗体中，轻链包括两个结构域，一个可变结构域(VL)和一个恒定结构域(CL)。重链包括四个结构域，一个可变结构域(VH)和三个恒定结构域(CH1、CH2和CH3，统称为CH)。轻链(VL)和重链(VH)的可变区域决定了对抗原的结合识别和特异性。轻链(CL)和重链(CH)的恒定区域赋予重要的生物学特性，如抗体链结合、分泌、跨胎盘迁移、补体结合和与Fc受体(FcR)的结合。Fv片段是免疫球蛋白Fab片段的N端部分，由一条轻链和一条重链的可变部分组成。抗体的特异性在于抗体结合位点和抗原决定簇之间的结构互补性。抗体结合位点由主要来自高变区或互补决定区(CDR)的残基组成。偶尔，来自非高变区或框架区(FR)的残基可以参与抗体结合位点，或影响整体结构域结构，从而影响结合位点。互补决定区或CDRs是指共同定义天然免疫球蛋白结合位点的天然Fv区的结合亲和力和特异性的氨基酸序列。免疫球蛋白的轻链和重链各有三个CDRs，分别命名为L-CDR1、L-CDR2、L-CDR3和H-CDR1、H-CDR2、H-CDR3。因此，抗原结合位点通常包括六个CDRs，包括来自重链V区和轻链V区中每一个的CDRs组。框架区(FRs)指插入CDRs之间的氨基酸序列。因此，轻链和重链的可变区通常包括以下序列的4个框架区和3个CDRs：FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。抗体可变结构域中的残基通常根据Kabat等人设计的系统进行编号。该系统载于Kabat等人，1987年在美国国家卫生研究院，美国卫生与公共服务部(Kabat et al.，1992，以下简称“Kabat et al.”)提出的《具有免疫学意义的蛋白质序列》中。Kabat残基名称并不总是与SEQ ID序列中氨基酸残基的线性编号直接对应。实际的线性氨基酸序列可能比严格的Kabat编号包含更少或更多的氨基酸，对应于基本可变结构域结构的结构成分，无论是框架还是互补决定区(CDR)的缩短或插入。通过将抗体序列中的同源残基与“标准”Kabat编号序列对齐，可以确定给定抗体的正确Kabat残基编号。根据Kabat编号系统，重链可变结构域的CDRs位于残基31-35(H-CDR1)、残基50-65(H-CDR2)和残基95-102(H-CDR3)。根据Kabat编号系统，轻链可变结构域的CDRs位于残基24-34(L-CDR1)、残基50-56(L-CDR2)和残基89-97(L-CDR3)。对于下文描述的激动剂抗体，已使用www.bioinf.com上的CDR查找算法确定CDRs-请参阅抗体页面中题为《如何通过查看序列识别CDRs》的部分。
如本文所用，术语“IgG Fc区”用于定义免疫球蛋白重链的C端区域，包括天然序列Fc区和变异Fc区。人IgG重链Fc区通常定义为包含从位置C226或从P230到IgG抗体羧基末端的氨基酸残基。Fc区域的残基编号是欧盟Kabat索引的编号。例如，在抗体的生产或纯化过程中，可去除Fc区域的C-末端赖氨酸(残基K447)。因此，本发明抗体的组合物可包括去除了所有K447残基的抗体群、未去除K447残基的抗体群，以及含有和不含有K447残基的抗体混合物的抗体群。
如本文所用，本文所用术语“单克隆抗体”、“单克隆Ab”、“单克隆抗体组合物”、“mAb”等指具有单分子组合物的抗体分子的制剂。单克隆抗体是从基本上同质的抗体群体中获得的，即除了可能存在少量的自然发生的突变外，群体中包含的单个抗体是相同的。单克隆抗体组合物显示出对特定表位的单一结合特异性和亲和力。单克隆抗体可以使用Kohler和Milstein(Nature,256:495,1975)的方法产生。为了制备在本发明中有用的单克隆抗体，以适当的时间间隔(例如每周两次、每周、每月两次或每月一次)用适当的抗原形式(即PD-1多肽)对小鼠或其他合适的宿主动物进行免疫。动物可能会在处死后一周内接受最后一次抗原“增强”。在免疫过程中通常需要使用免疫佐剂。合适的免疫佐剂包括弗氏完全佐剂(Freund's complete adjuvant)、弗氏不完全佐剂(Freund's incompleteadjuvant)、明矾、Ribi佐剂、Hunter's Titermax、皂苷佐剂(如QS21或Quil A)，或含有CpG的免疫刺激性寡核苷酸。其他合适的佐剂在本领域是众所周知的。动物可通过皮下、腹腔、肌肉内、静脉内、鼻内或其他途径进行免疫。特定的动物可以通过多种途径用多种形式的抗原进行免疫。然而，修饰物“单克隆”不应被解释为需要通过任何特定方法生产抗体。例如，单克隆抗体也可通过Kohler等人.,Nature,256:495(1975)首次描述的杂交瘤方法制备，或可在细菌、真核动物或植物细胞中使用重组DNA方法制备(参阅，例如，U.S.Pat.No.4,816,567)。也可以使用例如Clackson等人.,Nature,352:624-628(1991)和Marks et al.,J.Mol.Biol.,222:581-597(1991)中描述的技术，从噬菌体抗体库中分离“单克隆抗体”。
如本文所用，术语“嵌合抗体”是指包含非人类抗体的VH结构域和VL结构域，以及人类抗体的CH结构域和CL结构域的抗体。在一个实施方案中，“嵌合抗体”是一种抗体分子，其中(a)恒定区(即重链和/或轻链)或其一部分被改变、替换或交换，以使抗原结合位点(可变区)连接到不同或改变的类别、效应器功能和/或物种的恒定区，或赋予嵌合抗体新特性的完全不同的分子，例如酶、毒素、激素、生长因子、药物等；或(b)可变区或其一部分被改变、替换或交换为具有不同或改变的抗原特异性的可变区。嵌合抗体还包括灵长类抗体，尤其是人源化抗体。此外，嵌合抗体可包含在受体抗体或供体抗体中未发现的残基。这些修改是为了进一步改善抗体性能。有关详细信息，请参阅Jones et al.,Nature 321:522-525(1986)；Riechmann et al.,Nature 332:323-329(1988)；和Presta,Curr.Op.Struct.Biol.2:593-596(1992).(请参阅U.S.Pat.No.4,816,567；and Morrisonet al.,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。
如本文所用，术语“人源化抗体”包括具有小鼠抗体的6个CDRs，但具有人源化框架和恒定区域的抗体。更具体地说，本文使用的术语“人源化抗体”可包括其中衍生自另一哺乳动物物种(例如小鼠)的种系的CDR序列已被移植到人类框架序列上的抗体。
如本文所用，术语“人类单克隆抗体”旨在包括具有衍生自人类免疫球蛋白序列的可变和恒定区域的抗体。本发明的人类抗体可包括不是由人类免疫球蛋白序列编码的氨基酸残基(例如，通过体外随机或位点特异性突变或通过体内体细胞突变引入的突变)。然而，在一个实施方案中，如本文所用的术语“人类单克隆抗体”不包括衍生自另一哺乳动物物种(例如小鼠)的种系的CDR序列已被移植到人类框架序列上的抗体。
如本文所用，术语“Kassoc”或“Ka”意指特定抗体-抗原相互作用的结合率，而如本文所用的术语“Kdis”或“Kd”意指特定抗体-抗原相互作用的解离率。
如本文所用，术语“KD”意指解离常数，由Kd与Ka之比(即Kd/Ka)获得并表示为摩尔浓度(M)。本领域已知测定抗体KD的方法，包括但不限于在BIAcore 3000仪器中使用抗原的可溶性形式作为配体，抗体作为分析物的表面等离子体共振(SPR)技术。
(GEHealthcare，Piscaataway，NJ)是多种表面等离子体共振分析方法中之一，通常用于对单克隆抗体的bin面板进行表位。抗体的亲和力可以使用其他常规技术容易地确定，例如Scatchard等人所述的技术(Ann.N.Y.Acad.Sci.USA 51:660(1949))。抗体与抗原、细胞或组织的结合特性通常可以使用免疫检测方法来确定和评估，包括例如基于免疫荧光的分析，例如免疫组织化学(IHC)和/或荧光激活细胞分选(FACS)。通常，抗体以与KD相对应的亲和力结合到预定抗原，该亲和力比结合到非特异性抗原(例如BSA、酪蛋白)的KD低至少十倍，例如低至少100倍，例如低至少1000倍，例如低至少10000倍，例如低至少100000倍，该非特异性抗原与预定抗原不完全相同或不密切相关。当抗体的KD非常低(即抗体具有高亲和力)时，与抗原结合的KD通常比非特异性抗原的KD低至少10000倍。如果不能检测(例如，在BIAcore 3000仪器中使用等离子体共振(SPR)技术，使用可溶性抗原作为配体，抗体作为分析物)到抗原或表位的结合，或者比该抗体和具有不同化学结构或氨基酸序列的抗原或表位检测到的结合少100倍、500倍、1000倍或1000倍以上，则称抗体基本上不结合抗原或表位。
如本文所用，术语“结合特异性”是指抗体可检测地结合抗原重组多肽(例如重组PD-1多肽)的能力，其通过表面等离子体共振(SPR)测得的KD为100nM或更小、10nM或更小、5nM或更小。
如本文所用，术语“特异性”指抗体可检测地结合抗原上呈现的表位的能力，例如PD-1或CD40，同时与非PD-1或CD40蛋白质具有相对较小的可检测反应性。特异性可通过结合或竞争性结合分析相对确定，如本文其他地方所述，使用例如Biacore仪器。特异性可通过例如约10:1、约20:1、约50:1、约100:1、10.000:1或更大比例的亲和力/亲合力与其他无关分子的非特异性结合来表现(在这种情况下，特异性抗原为PD-1或CD40)。本文使用的术语“亲和力”是指抗体与表位结合的强度。抗体的亲和力由解离常数Kd给出，定义为[Ab]×[抗原]/[Ab-抗原]，其中[Ab-抗原]是抗体-抗原复合物的摩尔浓度，[Ab]是未结合抗体的摩尔浓度，[抗原]是未结合抗原的摩尔浓度。亲和常数Ka定义为1/Kd。确定mAb亲和力的优选方法可见Harlow,et al.,Antibodies:ALaboratory Manual,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1988),Coligan et al.,eds.,CurrentProtocols in Immunology,Greene Publishing Assoc.和Wiley Interscience,N.Y.,(1992,1993),and Muller,Meth.Enzymol.92:589-601(1983)，这些参考文献通过引用完全并入本文。本领域已知的一种确定mAb亲和力的优选标准方法是使用Biacore仪器。
如本文所用，术语“表位”指位于抗体结合的一种或多种蛋白质上的氨基酸的特定排列。表位通常由氨基酸或糖侧链等具有化学活性的表面分子组成，具有特定的三维结构特征和特定的电荷特征。表位可以是线性的或构象的，即在抗原的不同区域涉及两个或多个氨基酸序列，这些区域可能不一定是连续的。
如本文所用，术语“免疫细胞因子”指通过共价直接或间接连接到细胞因子或其衍生物的抗体。所述抗体和所述细胞因子可通过连接子连接。
如本文所用，术语“T细胞”在本领域中具有其一般含义，并且代表免疫系统的重要组成部分，在细胞介导免疫中起核心作用。T细胞被称为常规淋巴细胞，因为它们通过TCR(抗原的T细胞受体)识别抗原，并受到复杂的主要组织相容性分子的呈递或限制。有几个T细胞亚群，每个亚群都有不同的功能，如CD8+T细胞、CD4+T细胞、γδT细胞和Tregs。
如本文所用，术语“CD8+T细胞”在本领域中具有其一般含义，并指在其表面表达CD8的T细胞的亚群。它们是MHC I类限制性细胞，具有细胞毒性T细胞的功能。“CD8+T细胞”也称为细胞毒性T淋巴细胞(CTL)、T杀伤细胞、溶细胞性T细胞或杀伤性T细胞。CD8抗原是免疫球蛋白表基因家族的成员，是主要组织相容性复合体I类限制性相互作用中的结合识别元件。如本文所用，术语“肿瘤浸润性CD8+T细胞”指患者的CD8+T细胞池，其已离开血流并已迁移到肿瘤中。
如本文所用，术语“CD4+T细胞”(也称为辅助性T细胞或TH细胞)是指在其表面表达CD4糖蛋白并在免疫过程中协助其他白细胞的T细胞，包括B细胞成熟为浆细胞和记忆性B细胞，以及细胞毒性T细胞和巨噬细胞的激活。当CD4+T细胞被表达在抗原呈递细胞(APCs)表面的MHC II类分子呈递肽抗原时，CD4+T细胞被激活。一旦被激活，它们会迅速分裂并分泌调节或协助主动免疫反应的细胞因子。这些细胞可以分化为几种亚型之一，包括TH1、TH2、TH3、TH17、TH9、TFH或Treg，它们分泌不同的细胞因子以促进不同类型的免疫反应。来自APC的信号引导T细胞进入特定的亚型。除CD4外，本领域已知的TH细胞表面生物标记物包括CXCR3(Th1)、CCR4、Crth2(Th2)、CCR6(Th17)、CXCR5(Tfh)以及细胞因子和转录因子的亚型特异性表达，包括T-bet、GATA3、EOMES、RORγT、BCL6和FoxP3。
如本文所用，术语“γδT细胞”在本领域中具有其一般含义。γδT细胞通常占健康个体(人、猴)外周血淋巴细胞的1％至5％。它们参与启动保护性免疫反应，并且已经证明，它们通过与抗原的直接相互作用识别抗原配体，而无需抗原呈递细胞的MHC分子进行任何呈递。γ9δ2T细胞(有时也称为γ2δ2T细胞)是带有可变结构域Vγ9和Vδ2的TCR受体的γδT细胞。它们形成人体血液中的大部分γδT细胞。当被激活时，γδT细胞发挥有效的、非MHC限制的细胞毒活性，尤其能有效地杀死各种类型的细胞，特别是致病细胞。这些可能是被病毒感染的细胞(Poccia et al.,J.Leukocyte Biology,1997,62:1-5)或其他细胞内寄生虫，例如分枝杆菌(Constant et al.,Infection and Immunity,December 1995,vol.63,no.12:4628-4633)或原生动物(Behr et al.,Infection and Immunity,1996,vol.64,no.8:2892-2896)。它们也可以是癌细胞(Poccia et al.,J.Immunol.,159:6009-6015；Fournie and Bonneville,Res.Immunol.,第66届免疫学论坛,147:338-347)。因此，在体外、离体或体内调节所述细胞的活性的可能性将为治疗各种疾病提供新的、有效的治疗方法，例如传染病(尤其是病毒性或寄生虫性)、癌症、过敏，甚至自身免疫和/或炎性疾病。
如本文所用，术语“CAR-T细胞”是指经过基因工程以表达CAR的T淋巴细胞。CAR T细胞的定义包括T淋巴细胞的所有类别和亚类，包括CD4+、CD8+T细胞、γδT细胞以及效应T细胞、记忆T细胞、调节性T细胞等。基因修饰的T淋巴细胞可以从将接受使用基因修饰的T细胞治疗的受试者“衍生”或“获得”，也可以从不同的受试者“衍生”或“获得”。
如本文所用，术语“嵌合抗原受体”或可选的“CAR”是指一组多肽，在最简单的实施例中通常为两种，当在免疫效应细胞中时，其为细胞提供对靶细胞的特异性，靶细胞通常为癌细胞，并产生细胞内信号。在一些实施方案中，CAR至少包括细胞外抗原结合域、跨膜域和细胞质信号域(在本文中也称为“细胞内信号域”)，其包括衍生自以下定义的刺激分子和/或共刺激分子的功能信号域。在某些方面，这组多肽彼此邻接。在一些实施方案中，该组多肽包括二聚化开关，二聚化开关可在二聚化分子存在时将多肽彼此偶联，例如可将抗原结合域偶联至细胞内信号传导结构域。在一些实施方案中，刺激分子是与T细胞受体复合物相关联的ζ(zeta)链。在一些实施方案中，细胞质信号传导结构域还包括一个或多个衍生自以下定义的至少一个共刺激分子的功能信号结构域。在一些实施方案中，共刺激分子选自本文所述的共刺激分子，例如4-1BB(即CD137)、CD27和/或CD28。在一些实施方案中，CAR包含嵌合融合蛋白，该嵌合融合蛋白包含细胞外抗原结合结构域、跨膜结构域和细胞内信号结构域，所述细胞内信号结构域包含衍生自刺激分子的功能性信号结构域。在一些实施方案中，CAR包含嵌合融合蛋白，该嵌合融合蛋白包含细胞外抗原结合结构域、跨膜结构域和细胞内信号结构域，所述细胞内信号结构域包含衍生自共刺激分子的功能性信号结构域和衍生自刺激分子的功能性信号结构域。在一些实施方案中，CAR包含嵌合融合蛋白，该嵌合融合蛋白包含细胞外抗原结合结构域、跨膜结构域和细胞内信号结构域，该细胞内信号结构域包含两个衍生自一个或多个共刺激分子的功能信号结构域和衍生自刺激分子的功能信号结构域。在一些实施方案中，CAR包含嵌合融合蛋白，该嵌合融合蛋白包含细胞外抗原结合结构域、跨膜结构域和细胞内信号结构域，所述细胞内信号结构域包含源自一个或多个共刺激分子的至少两个功能信号域和源自刺激分子的功能信号结构域。在一些实施方案中，CAR包含CAR融合蛋白氨基末端(N-ter)处的可选的先导序列。在一些实施方案中，CAR进一步包含位于细胞外抗原结合结构域N末端的先导序列，其中，在CAR细胞处理和定位到细胞膜期间，先导序列任选地从抗原结合结构域(例如单链抗体scFv)切割。在特定方面，CARs包括来自单克隆抗体的单链可变片段(scFv)的融合物，融合到CD3-zeta跨膜结构域和内结构域。在一些实施方案中，CARs包含用于额外共刺激信号的结构域，例如CD3-zeta、FcR、CD27、CD28、CD137、DAP10和/或OX40。在一些实施方案中，分子可与CAR共表达，包括共刺激分子、用于成像的报告基因(例如用于正电子发射断层扫描)、在添加前药后有条件地消融T细胞的基因产物、归巢受体、趋化因子、趋化因子受体、细胞因子和细胞因子受体。
如本文所用，术语“T细胞衰竭”是指T细胞功能障碍的状态。T细胞衰竭通常发生在许多慢性感染和癌症期间。T细胞衰竭可通过不良的效应器功能、抑制性受体持续的表达和/或不同于功能性效应器或记忆T细胞的转录状态来定义。T细胞衰竭通常会阻止对感染和肿瘤的最佳控制。参阅例如Wherry E J,Nat Immunol.(2011)12:492-499，了解关于T细胞衰竭的更多信息。通常，T细胞衰竭是由PD-1与其配体PD-L1和PD-L2的结合引起的。
如本文所用，“树突细胞”或“DCs”是指在淋巴组织或非淋巴组织中发现的形态相似的细胞类型的不同群体中的任何成员。这些细胞以其独特的形态和高水平的表面MHC II类表达为特征。这些细胞可以从许多组织来源中分离出来，也可以方便地从外周血中分离出来，如下面的实施例中所述。
如本文所用，“疗法”或“治疗”是一种获得有益或预期结果(包括临床结果)的方法。就本发明而言，有益的或期望的临床结果包括但不限于以下一种或多种：减轻由疾病引起的一种或多种症状、减轻疾病的程度、稳定疾病(例如预防或延迟疾病的恶化)、预防或延缓疾病的传播(例如转移)、预防或延缓疾病复发、延缓或减缓疾病进展、改善疾病状态、缓解(部分或全部)疾病、减少治疗疾病所需的一种或多种其他药物的剂量、延缓疾病进展、提高生活质量和/或延长生存期。“疗法”还包括减少癌症的病理后果。本发明的方法考虑了这些治疗的任何一个或多个方面。在一个实施方案中，术语“治疗”或“疗法”指的是治疗性疗法和预防性或预防性措施；其中目的是预防或减缓(减轻)目标疾病。因此，在一个实施方案中，需要治疗的人可以包括已经患有该疾病的人、易于患有该疾病的人或要预防该疾病的人。
如本文所用，术语“癌症”在本领域中具有其一般含义，包括但不限于实体瘤和血源性肿瘤。术语癌症包括皮肤、组织、器官、骨、软骨、血管疾病。术语“癌症”还进一步包括原发性和转移性癌症。可通过本发明的方法和组合物治疗的癌症的实例包括但不限于来自膀胱、血液、骨、骨髓、脑、乳腺、结肠、食管、胃肠道、牙龈、头部、肾脏、肝脏、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、睾丸、舌头或子宫的癌细胞。此外，该癌症可能属于以下组织学类型，但不限于以下类型：恶性的肿瘤、癌、未分化癌、巨细胞和梭形细胞癌、小细胞癌、乳头状癌、鳞状细胞癌、淋巴上皮癌、基底细胞癌、毛母细胞癌、移行细胞癌、乳头状移行细胞癌、腺癌、恶性胃泌素瘤、胆管癌、肝细胞癌、合并肝细胞癌和胆管癌、小梁腺癌、腺样囊性癌、腺瘤性息肉中的腺癌、腺癌、家族性结肠息肉病、实体癌、恶性类癌、鳃肺泡腺癌、乳头状腺癌、嫌色细胞癌、嗜酸细胞癌、嗜氧腺癌、嗜碱性粒细胞癌、透明细胞腺癌、颗粒细胞癌、滤泡腺癌、乳头状和滤泡状腺癌、非包膜硬化性癌、肾上腺皮质癌、子宫内膜癌、皮肤附件癌、顶泌腺癌、皮脂腺癌、耵聍的(ceruminous)、腺癌、粘液表皮样癌、囊腺癌、乳头状囊腺癌、乳头状浆液性囊腺癌、粘液性囊腺癌、粘液腺癌、印戒细胞癌、浸润性导管癌、髓样癌、小叶癌、炎性癌、乳腺佩吉特病、腺泡细胞癌、腺鳞癌、腺癌伴鳞状化生、恶性胸腺瘤、恶性卵巢间质瘤、恶性卵泡膜瘤、恶性颗粒细胞瘤、恶性成纤维细胞瘤、支持细胞癌、恶性间质细胞瘤、恶性脂质细胞瘤、恶性副神经节瘤、恶性乳腺外副神经节瘤、嗜铬细胞瘤、血管肉瘤、恶性黑色素瘤、无色素性黑色素瘤、浅表扩散性黑色素瘤、巨大色素痣中的恶性黑色素瘤、上皮样细胞黑色素瘤、恶性蓝色痣、肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、黏液肉瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、间质肉瘤、恶性混合瘤、苗勒氏管混合瘤、肾母细胞瘤、肝母细胞瘤、癌肉瘤、恶性间叶瘤、恶性布伦纳(brenner)肿瘤、恶性叶状肿瘤、滑膜肉瘤、恶性间皮瘤、无性细胞瘤、胚胎癌、恶性畸胎瘤、恶性卵巢甲状腺肿、绒毛膜癌、恶性中肾瘤、血管肉瘤、恶性血管内皮瘤、卡波西(kaposi's)肉瘤、恶性血管外皮细胞瘤、淋巴管肉瘤、骨肉瘤、皮质旁骨肉瘤、软骨肉瘤、恶性软骨母细胞瘤、间充质软骨肉瘤、骨巨细胞瘤、尤因氏(ewing's)肉瘤、恶性牙源性肿瘤、成釉细胞性牙肉瘤、恶性成釉细胞瘤、成釉细胞纤维肉瘤、恶性松果体瘤、脊索瘤、恶性胶质瘤、室管膜瘤、星形细胞瘤、原生质性星形细胞瘤、纤维状星形细胞瘤、星形母细胞瘤、胶质母细胞瘤、少突胶质细胞瘤、少突胶质母细胞瘤、原始神经外胚层、小脑肉瘤、神经节神经母细胞瘤、神经母细胞瘤、视网膜母细胞瘤、嗅觉神经源性肿瘤、恶性脑膜瘤、神经纤维肉瘤、恶性神经鞘瘤、恶性颗粒细胞瘤、恶性淋巴瘤、NK白血病或NK淋巴瘤，例如结外和非结外NK/T淋巴瘤、NK细胞源性恶性肿瘤、和急性NK白血病、霍奇金(Hodgkin's)病、霍奇金(Hodgkin's)淋巴瘤、副肉瘤、恶性淋巴瘤、小淋巴细胞瘤、弥漫性大细胞恶性淋巴瘤、滤泡性恶性淋巴瘤、蕈样肉芽肿、其他特定的非霍奇金(Hodgkin's)淋巴瘤、恶性组织细胞增生症、多发性骨髓瘤、肥大细胞肉瘤、免疫增殖性小肠疾病、白血病、淋巴白血病、浆细胞白血病、红白血病、淋巴肉瘤细胞白血病、髓系白血病、嗜碱性白血病、嗜酸性白血病、单核细胞白血病、肥大细胞白血病、巨核母细胞白血病、髓样肉瘤和毛细胞白血病。
如本文所用，术语“传染病”包括由病毒、细菌、原生动物、霉菌或真菌引起的任何感染。在一些实施方案中，病毒感染包括由一种或多种选自以下的病毒感染组成的组：沙粒病毒科(Arenaviridae)、星状病毒科(Astroviridae)、鸟病毒科(Birnaviridae)、溴病毒科(Bromoviridae)、布尼亚病毒科(Bunyaviridae)、杯状病毒科(Caliciviridae)、梭状病毒科(Closteroviridae)、共病毒科(Comoviridae)、囊状病毒科(Cystoviridae)、黄病毒科(Flaviviridae)、弯曲病毒科(Flexiviridae)、肝炎病毒(Hepevirus)、列维病毒科(Leviviridae)、黄体病毒科(Luteoviridae)、单内病毒(Mononegavirales)、花叶病毒(Mosaic Viruses)、巢状病毒(Nidovirales)、野病毒科(Nodaviridae)、正粘病毒科(Orthomyxoviridae)、短小核糖核酸病毒(Picobirnavirus)、小核糖核酸病毒科(Picornaviridae)、马铃薯Y病毒(Potyviridae)、呼肠孤病毒科(Reoviridae)、逆转录病毒科(Retroviridae)、菊科病毒科(Sequiviridae)、细纹病毒(Tenuivirus)、披膜病毒科(Togaviridae)、汤姆布斯病毒科(Tombusviridae)、细胞病毒科(Totiviridae)、鼠疫病毒科(Tymoviridae)、肝炎病毒科(Hepadnaviridae)、疱疹病毒科(Herpesviridae)、副粘病毒科(Paramyxoviridae)或乳头瘤病毒科病毒(Papillomaviridae viruses)。RNA病毒的相关分类家族包括但不限于：星病毒科(Astroviridae)、鸟病毒科(Birnaviridae)、溴病毒科(Bromoviridae)、杯状病毒科(Caliciviridae)、梭状病毒科(Closteroviridae)、共病毒科(Comoviridae)、囊状病毒科(Cystoviridae)、黄病毒科(Flaviviridae)、弯曲病毒科(Flexiviridae)、肝炎病毒(Hepevirus)、列维病毒科(Leviviridae)、黄体病毒科(Luteoviridae)、单内病毒科(Mononegavirales)、花叶病毒(Mosaic Viruses)、雀巢病毒(Nidovirales)、野病毒科(Nodaviridae)、正粘病毒科(Orthomyxoviridae)、短小核糖核酸病毒(Picobirnavirus)、小核糖核酸病毒科(Picornaviridae)、病毒科(Potyviridae)、呼肠孤病毒科(Reoviridae)、逆转录病毒科(Retroviridae)、菊科病毒科(Sequiviridae)、细纹病毒(Tenuivirus)、披膜病毒科(Togaviridae)、汤姆布斯病毒科(Tombusviridae)、细胞病毒科(Totiviridae)、鼠疫病毒科(Tymoviridae)。在一些实施方案中，病毒感染包括由一种或多种选自下组的病毒感染：腺病毒、鼻病毒、肝炎、免疫缺陷病毒、脊髓灰质炎、麻疹、埃博拉病毒、柯萨奇(Coxsackie)、犀牛病毒(Rhino)、西尼罗病毒(West Nile)、天花、脑炎、黄热病、登革热、流感(包括人、禽和猪)，拉沙(lassa)，淋巴细胞性脉络丛脑膜炎，胡宁(junin)病毒、machuppo、瓜纳里多(guanarito)、汉坦病毒、裂谷热、拉克罗斯(La Crosse)、加州脑炎、克里米亚-刚果(Crimean-Congo)、马尔堡(Marburg)、日本脑炎、科萨努尔森林病(Kyasanur Forest)、委内瑞拉马脑炎、东部马脑炎、西部马脑炎、严重急性呼吸系统综合征(SARS)、副流感病毒、呼吸道合胞体、蓬塔托罗病毒(Punta Toro)、塔卡里贝病毒(Tacaribe)、巴氏病毒(pachindae viruses)、腺病毒、登革热、甲型流感和乙型流感(包括人、禽和猪)、胡宁(junin)、麻疹(measles)、副流感、皮钦德(Pichinde)、皮钦德(puntatoro)、呼吸道合胞体、鼻病毒、裂谷热、严重急性呼吸系统综合症(SARS)、塔卡里贝(Tacaribe)、委内瑞拉马脑炎、西尼罗河和黄热病病毒、蜱传脑炎病毒、日本脑炎病毒、圣路易斯(St.Louis)脑炎病毒、圣路易斯(Murray Valley)病毒、波瓦桑(Powassan)病毒、罗西奥(Rocio)病毒、跳跃病(louping-ill)病毒、班齐(Banzi)病毒、伊利乌斯(Ilheus)病毒、科科贝尔(Kokobera)病毒、库宁(Kunjin)病毒、阿尔富(Alfuy)病毒、牛腹泻病毒和科萨努尔(Kyasanur)森林病。可根据本发明治疗的细菌感染包括但不限于由以下原因引起的感染：葡萄球菌；链球菌包括化脓性链球菌；肠球菌；芽孢杆菌包括炭疽芽孢杆菌和乳酸杆菌；李斯特菌；白喉棒状杆菌；加德纳菌包括阴道加德纳菌；诺卡氏菌；链霉菌；普通嗜热放线菌；螺旋体；弯曲杆菌、假单胞菌，包括绿脓杆菌；军团菌(Legionella)；奈瑟氏球菌，包括淋病奈瑟菌和脑膜炎奈瑟菌；黄杆菌，包括F.meningosepticum和F.odoraturn；布鲁氏菌；博德特氏菌，包括百日咳杆菌和支气管败血杆菌；大肠杆菌，包括大肠杆菌、克雷伯氏菌；肠杆菌属、沙雷氏菌属，包括粘质沙雷氏菌和液化沙雷氏菌；爱德华氏菌属(Edwardsiella)；变形杆菌，包括奇异变形杆菌和普通变形杆菌；链杆菌；立克次体科包括R.fickettsfi，衣原体包括C.psittaci和C.trachornatis；分枝杆菌，包括结核分枝杆菌、胞内分枝杆菌、毛囊分枝杆菌、拉普拉分枝杆菌、鸟分枝杆菌、牛分枝杆菌、非洲分枝杆菌、堪萨斯分枝杆菌、胞内分枝杆菌和麻风分枝杆菌；和诺卡氏菌。可根据本发明治疗的原生动物感染包括但不限于利什曼原虫、kokzidioa和锥虫引起的感染。传染病的完整清单可在疾病控制中心(CDC)的国家传染病中心(NCID)网站上找到(全球资讯网(www)在cdc.gov/nciod/diseases/)，该列表通过引用并入本文。所有所述疾病都是用于使用根据本发明的组合物进行治疗的候选者。
如本文所用，本文所用术语“抗原”或“Ag”是指能够引发T细胞应答的蛋白质、肽、核酸或组织或细胞制剂。
如本文所用，术语“治疗有效量”是指在所需的剂量和时间段内达到预期治疗效果的有效量。因此，术语“治疗有效量”可以意指针对靶细胞的抗体水平或数量，而不会对靶细胞造成显著的负面或不良副作用，(1)延缓或预防目标疾病的发作；(2)减缓或停止目标疾病的一种或多种症状的进展、加重或恶化；(3)改善目标疾病的症状；(4)降低目标疾病的严重程度或发病率；或(5)治愈目标疾病。治疗有效量可在目标疾病发生之前施用，用于预防或预防作用。备选地，或者另外地，可在目标疾病开始后施用治疗有效量，用于治疗作用。
如本文所用，术语“药学上可接受的载体”是指当施用于动物优选人类时不会产生负面、过敏或其他不良反应的赋形剂。它包括任何和所有溶剂、分散介质、涂料、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。对于人体给药，制剂应符合监管机构(如FDAOffice orEMA)要求的无菌性、热原性、一般安全性和纯度标准。
如本文所用，术语“疫苗”意指可施用于人类或动物以诱导免疫应答的组合物；这种免疫反应可导致抗体的产生，或仅激活某些细胞，尤其是抗原呈递细胞、T淋巴细胞和B淋巴细胞。在一些实施方案中，疫苗能够产生免疫应答，从而导致患者体内产生针对疫苗中提供的抗原的中和抗体。疫苗可以是用于预防目的或治疗目的或两者兼而有的组合物。
如本文所用，术语“受试者”指温血动物，优选哺乳动物(包括人类、家畜和农场动物，以及动物园、运动或宠物动物，例如狗、猫、牛、马、羊、猪、山羊、兔子等……)，更优选是人类。在一个实施方案中，受试者可以是“患者”，即温血动物，更优选人类，其/正在等待接受治疗，或正在接受医疗护理，或过曾经/现在/将成为医疗程序的对象，或正在监测疾病的发展。在一个实施方案中，受试者是成年人(例如18岁以上的受试者)。在另一个实施方案中，受试者是儿童(例如18岁以下的受试者)。在一个实施方案中，受试者是男性。在另一个实施方案中，受试者是女性。
本发明的新型IL-15/IL-15受体α(IL-15Rα)融合蛋白：
本发明的第一个目的涉及一种IL-15/IL-15受体α(IL-15Rα)融合蛋白，包括i)一种含有IL15-Rαsushi的多肽，该多肽包含与SEQ.ID NO：1的氨基酸序列具有至少80％同一性的氨基酸序列；ii)具有如SEQ ID NO：2所示氨基酸序列的连接子和；iii)一种IL-15多肽，该多肽包含与SEQ ID NO：3的氨基酸序列具有至少80％同一性的氨基酸序列。
SEQ ID NO:1>IL-15Rαsushi序列
CPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP
SEQ ID NO:2>Flex序列
DTTEPATPTTPVTTPTTTDDLDA
SEQ ID NO:3>IL-15序列
LDNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
根据本发明，含有IL-15-Ralpha sushi的多肽、连接子和IL-15多肽在框架中融合，其中含有IL-15-Ralpha sushi的多肽的C末端融合到连接子的N末端，连接子的C末端融合到IL-15多肽的N末端。
在一些实施方案中，本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白由如SEQ IDNO：4所示的氨基酸序列组成。
SEQ ID NO:4
根据本发明，本发明的IL-15/IL-15受体α融合蛋白通过常规的自动化肽合成方法或通过重组表达产生。本领域技术人员熟知设计和制造蛋白质的一般原则。本发明的IL-15/IL-15受体α融合蛋白可根据常规技术在溶液或固体载体上合成。各种自动合成器可在市场上买到，并可根据Stewart和Young,Tam等人.,1983；Merrifield,1986and Barany andMerrifield,Gross and Meienhofer,1979中描述的已知协议使用。本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白也可通过固相技术合成，该固相技术采用示例性肽合成器，例如来自Applied Biosystems Inc.的433A型。任何给定蛋白质的纯度、通过自动肽合成或通过重组方法生成的肽可使用反相HPLC分析进行测定。每种肽的化学真实性可通过本领域技术人员熟知的任何方法确定。作为自动肽合成的替代方案，可采用重组DNA技术，其中将编码所选蛋白质的核苷酸序列插入表达载体中，转化或转染到适当的宿主细胞中，并在如下文所述适于表达的条件下培养。重组方法尤其适用于生产更长的多肽。多种表达载体/宿主系统可用于包含和表达肽或蛋白质编码序列。这些包括但不限于微生物，例如用重组噬菌体、质粒或粘粒DNA表达载体转化的细菌；用酵母表达载体转化的酵母(Giga-Hama et al.,1999)；感染病毒表达载体的昆虫细胞系统(例如杆状病毒，参阅Ghosh et al.,2002)；用病毒表达载体(例如花椰菜花叶病毒、CaMV、烟草花叶病毒、TMV)转染或用细菌表达载体(例如Ti或pBR322质粒；参见例如Babe等人,2000)转化的植物细胞系统；或者动物细胞系统。本领域技术人员了解用于优化哺乳动物蛋白质表达的各种技术，参阅例如Kaufman,2000；Colosimo等人,2000。用于重组蛋白生产的哺乳动物细胞包括但不限于VERO细胞、HeLa细胞、中国仓鼠卵巢(CHO)细胞系、COS细胞(例如COS-7)、W138、BHK、HepG2、3T3、RIN、MDCK、A549、PC12、K562和293细胞。本领域技术人员已知用于在细菌、酵母和其他无脊椎动物中重组表达肽底物或融合多肽的示例性方案并在下文简要描述了该方案。本领域技术人员也熟知用于表达重组蛋白的哺乳动物宿主系统。宿主细胞株可被选择，使其具有处理所表达蛋白质或产生某些翻译后修饰的特定能力，这些修饰将有助于提供蛋白质活性。多肽的此类修饰包括但不限于乙酰化、羧化、糖基化、磷酸化、脂质化和酰化。翻译后处理，即切割蛋白质的“前”形式，对于正确插入、折叠和/或功能也可能很重要。不同的宿主细胞例如CHO、HeLa、MDCK、293、WI38等，对于此类翻译后活性具有特定的细胞机制和特征性机制，并且可以选择以确保正确修饰和加工引入的外源蛋白质。
在一些实施方案中，预期本发明的IL-15/IL-15受体α融合蛋白被修饰以提高其治疗效果。治疗性化合物的这种修饰可用于降低毒性、增加循环时间或改变生物分布。例如，通过与各种改变生物分布的药物载体结合，可以显著降低潜在重要治疗性化合物的毒性。提高药物活性的一个策略是利用水溶性聚合物。各种水溶性聚合物已被证明可以改变生物分布，改善细胞摄取模式，通过生理屏障改变通透性；并改变身体的清除率。为了实现靶向或缓释效果，已经合成了水溶性聚合物，其含有药物部分作为端基、作为主链的一部分、或作为聚合物链上的侧基。例如，聚乙二醇化是一种成熟且经验证的修饰一系列多肽的方法。这些益处包括：(a)由于聚合物将分子的表观大小增加到肾小球滤过极限以上而避免肾清除，和/或通过避免细胞清除机制而显著改善体内循环半衰期；(b)PEG所连接分子的抗原性和免疫原性降低；(c)改进的药代动力学；(d)增强共轭蛋白的蛋白水解抗性；和(e)提高聚乙二醇化多肽的热稳定性和机械稳定性。
本发明的免疫细胞因子：
本发明的另一个目的涉及与本发明的IL-15/IL-15受体α融合蛋白融合的抗体的重链。
在一些实施方案中，重链通过连接子与IL-15/IL-15受体α融合蛋白融合。在一些实施方案中，连接子包含如SEQ ID NO:5(即FlexV1连接子)中所述的氨基酸序列。在一些实施方案中，连接子由如SEQ ID NO:6所述的氨基酸序列组成。
SEQ ID NO:5>FlexV1连接子
QTPTNTISVTPTNNSTPTNNSNPKPNP
SEQ ID NO:6>连接子
ASQTPTNTISVTPTNNSTPTNNSNPKPNPDIGM
在一些实施方案中，重链来自具有PD-1特异性的抗体。在一些实施方案中，抗PD-1抗体是已知抗体或新抗体。
为了选择新的抗PD-1抗体，本领域已经描述了各种筛选抗体的方法。此类方法可分为体内系统(例如能够在抗原免疫后产生完全人类抗体的转基因小鼠)和体外系统，包括生成抗体DNA编码库、在适当的抗体生产系统中表达DNA文库、通过亲和性选择标准选择与靶标结合表达的候选抗体的克隆以及恢复所选克隆的相应编码序列。这些体外技术被称为展示技术，包括但不限于噬菌体展示、RNA或DNA展示、核糖体展示、酵母或哺乳动物细胞展示。它们在本领域中得到了很好的描述(例如有关综述请参阅Nelson等人,2010NatureReviews Drug discovery,“Development trends for human monoclonal antibodytherapeutics”(Advance Online Publication)和Hoogenboom等人,in Method inMolecular Biology 178:1-37,O’Brien et al.,ed.,Human Press,Totowa,N.J.,2001)。在一个实施方案中，使用用于筛选与PD-1结合的人重组抗体库的噬菌体展示方法分离人重组抗PD-1抗体。VH和VL基因库或相关CDR区域可通过聚合酶链反应(PCR)单独克隆或通过DNA合成器合成，并在噬菌体库中随机重组，然后可筛选抗原结合克隆。此类用于分离人类抗体的噬菌体展示方法在本领域中建立或在下面的示例中描述。参见例如：Ladner等人的U.S.Patent Nos.5,223,409；5,403,484；和5,571,698；Dower等人的U.S.Patent Nos.5,427,908和5,580,717；McCafferty等人的U.S.Patent Nos.5,969,108和6,172,197；和Griffiths等人的U.S.Patent Nos.5,885,793；6,521,404；6,544,731；6,555,313；6,582,915和6,593,081to。
在一些实施方案中，可使用携带部分人类免疫系统而非小鼠系统的转基因或转染色体小鼠来识别针对PD-1的人类抗体。这些转基因和转染色体小鼠包括本文中分别称为HuMAb小鼠和KM小鼠，在本文中统称为“人Ig小鼠”。HuMAb
(Medarex，Inc.)包含编码未重排的人类重链(μ和γ)和κ轻链免疫球蛋白序列的人类免疫球蛋白基因微位点，以及使内源性μ和κ链位点失活的靶向突变(参阅例如Lonberg等人,1994Nature 368(6474):856-859)。在另一个实施方案中，可以使用在转基因和转染色体上携带人类免疫球蛋白序列的小鼠(例如携带人类重链转基因和人类轻链跨染色体的小鼠)来产生人类抗PD-1抗体。此类小鼠，本文中称为“KM小鼠”，详细描述于Ishida等人的PCT出版物WO 02/43478中。
在一些实施方案中，抗体是嵌合抗体，尤其是嵌合小鼠/人抗体。
在一些实施方案中，抗体为人源化抗体。
可基于如上所述制备的小鼠单克隆抗体的序列制备嵌合抗体或人源化抗体。编码重链和轻链免疫球蛋白的DNA可从感兴趣的小鼠杂交瘤中获得，并使用标准分子生物学技术工程改造，以包含非小鼠(例如人类)免疫球蛋白序列。例如，为了产生嵌合抗体，可以使用本领域已知的方法将小鼠可变区连接到人类恒定区(参阅例如Cabilly等人的U.S.Patent No.4,816,567)。为了创建人源化抗体，可以使用本领域已知的方法将小鼠CDR区域插入到人类框架中。参阅例如Winter的U.S.Patent No.5,225,539,和Queen等人的U.S.Patent Nos.5,530,101；5,585,089；5,693,762and 6,180,370。
在一些实施方案中，抗PD-1抗体选自MDX-1106(也称为Nivolumab、MDX-1106-04、ONO-4538、BMS-936558和
)、Merck 3475(也称为Pembrolizumab、MK-3475、
和SCH-900475)和CT-011(也称为Pidilizumab、hBAT和hBAT-1)。在一些实施方案中，PD-1结合拮抗剂为AMP-224(也称为B7-DCIg)。
在一些实施方案中，抗PD-1抗体是如WO2016020856和Fenwick,Craig,等人"Tumorsuppression of novel anti–PD-1antibodies mediated through CD28 costimulatorypathway."Journal of Experimental Medicine(2019):jem-20182359中公开的抗PD1Gepi135c。
在一些实施方案中，本发明的重链包含如SEQ ID NO：7、8或9中所示的VH结构域。
SEQ ID NO:7>派姆单抗(pembrolizumab)的VH结构域
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS
SEQ ID NO:8>纳武利尤单抗(nivolumab)的VH结构域
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS
SEQ ID NO:9>抗PD1 Gepi 135c的VH结构域
QVQLVQSGAEVKKPGASVKMSCKASGYTFTNFYIHWVRQAPGQGLEWIGSIYPNYGDTAYNQKFKDRATLTVDTSTSTAYMELSSLRSEDTAVYYCARGYSYAMDYWGQGTLVTVSS
在一些实施方案中，重链包含IgG4免疫球蛋白的IgG Fc区域。
在一些实施方案中，重链由如SEQ ID NO：10、11或12所示的氨基酸序列组成。
SEQ ID NO:10>派姆单抗(pembrolizumab)重链
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:11>纳武利尤单抗(nivolumab)重链
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:12<抗PD1Gepi 135c重链
QVQLVQSGAEVKKPGASVKMSCKASGYTFTNFYIHWVRQAPGQGLEWIGSIYPNYGDTAYNQKFKDRATLTVDTSTSTAYMELSSLRSEDTAVYYCARGYSYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
在一些实施方案中，与本发明的IL-15/IL-15受体α融合蛋白融合的抗体重链由如SEQ ID NO：13、14或15所示的氨基酸序列组成。
SEQ ID NO:13>C3711或C3721[hKeytruda(抗-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTNTISVTPTNNSTPTNNSNPKPNPDIGMCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPDTTEPATPTTPVTTPTTTDDLDALDNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
SEQ ID NO:14:>[nivolumab(抗-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTNTISVTPTNNSTPTNNSNPKPNPDIGMCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPDTTEPATPTTPVTTPTTTDDLDALDNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
SEQ ID NO:15>C3789[hHC抗-PD1Gepi 135c-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
QVQLVQSGAEVKKPGASVKMSCKASGYTFTNFYIHWVRQAPGQGLEWIGSIYPNYGDTAYNQKFKDRATLTVDTSTSTAYMELSSLRSEDTAVYYCARGYSYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTNTISVTPTNNSTPTNNSNPKPNPDIGMCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPDTTEPATPTTPVTTPTTTDDLDALDNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
本发明的另一个目的涉及一种免疫细胞因子，其包含与本发明的IL-15/IL-15受体α融合蛋白融合的抗体重链。
在一些实施方案中，本发明的免疫细胞因子对PD-1具有特异性。因此，在一些实施方案中，本发明的免疫细胞因子包含如上所述的重链。
在一些实施方案中，本发明的免疫细胞因子包含重链，该重链由如SEQ ID NO：13、14或15所示的氨基酸序列组成的重链。
在一些实施方案中，本发明的免疫细胞因子包含SEQ ID NO：13所示的重链和SEQID NO：16所示的轻链。
在一些实施方案中，本发明的免疫细胞因子包含SEQ ID NO：14所示的重链和SEQID NO：17所示的轻链。
在一些实施方案中，本发明的免疫细胞因子包含SEQ ID NO：15所示的重链和SEQID NO：18所示的轻链。
SEQ ID NO:16>派姆单抗(pembrolizumab)轻链
EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:17>纳武利尤单抗(nivolumab)轻链
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:18:抗-PD1Gepi 135c抗体轻链
DIQMTQSPSSLSASVGDRVTITCSASQGISGDLNWYQQKPGKAVKLLIYHTSSLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQYYSKDLLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
在一些实施方案中，本发明包括SEQ ID NO:15所述的重链和SEQ ID NO:18所述的轻链的免疫细胞因子，其识别位于PDL-1相互作用的相对面上的PD-1表位。因此，根据本实施方案，免疫细胞因子不阻断PD-1与其配体(PD-L1或PD-L2)的结合。相反，免疫细胞因子可以靶向在已经与派姆单抗(pembrolizumab)或纳武利尤单抗(nivolumab)阻断抗PD-1抗体结合的细胞上的PD-1。因此，免疫细胞因子可用于这些商业抗体中的任何一种的联合治疗，而不会与PD-1竞争结合。该免疫细胞因子还具有结合细胞上的PD-1的潜力，这些细胞与可在抗原呈递细胞或肿瘤细胞上表达的PD-L1或PD-L2配体预复合。免疫细胞因子的抗PD-1部分主要通过CD28共刺激受体在T细胞刺激期间恢复AKT通路的信号传导和钙流通发挥作用。
本发明的核酸、载体和宿主细胞：
本发明的另一个目的涉及编码本发明所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白的核酸。
本发明的另一个目的涉及编码与本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白融合的抗体重链的核酸。
在一些实施方案中，该核酸包含如SEQ ID NO：19或20所示的核酸序列。
SEQ ID NO:19>编码C3711或C3721的核酸[hKeytruda(抗-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
ATGGATCCGAAAGGTTCTCTGAGCTGGCGTATTCTGCTGTTCCTAAGCCTGGCGTTCGAACTGTCTTATGGTCAGGTTCAGCTGGTTCAGTCTGGAGTTGAAGTGAAAAAACCGGGCGCGTCTGTTAAAGTTTCTTGCAAAGCGTCTGGTTACACCTTCACCAACTACTACATGTACTGGGTTCGTCAGGCGCCGGGTCAGGGCCTGGAATGGATGGGCGGTATCAACCCGTCTAACGGTGGCACCAACTTCAACGAAAAATTCAAAAACCGTGTTACCCTGACCACCGATAGCAGCACCACCACCGCGTATATGGAACTGAAATCTCTGCAGTTCGACGACACCGCAGTGTACTACTGCGCCCGCCGCGACTACCGTTTCGACATGGGCTTCGACTACTGGGGGCAAGGTACCACAGTTACCGTATCGAGCGCCAGCACGAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCCAGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCCAAGCCCAACCCCGATATCGGGATGTGCCCTCCCCCCATGTCCGTGGAACACGCAGACATCTGGGTCAAGAGCTACAGCTTGTACTCCAGGGAGCGGTACATTTGTAACTCTGGTTTCAAGCGTAAAGCCGGCACGTCCAGCCTGACAGAGTGCGTGTTGAACAAGGCCACGAATGTCGCCCACTGGACAACCCCCAGTCTCAAATGCATTAGAGACCCTGCCCTGGTTCACCAAAGGCCAGCGCCACCCGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAACAGATGATCTGGATGCACTCGACAACTGGGTGAATGTAATAAGTGATTTGAAAAAAATTGAAGATCTTATTCAATCTATGCATATTGATGCTACTTTATATACGGAAAGTGATGTTCACCCCAGTTGCAAAGTAACAGCAATGAAGTGCTTTCTCTTGGAGCTCCAGGTAATTAGCTTAGAATCTGGCGACGCCAGCATCCACGATACAGTTGAGAATCTGATCATTCTCGCAAACAACTCTCTGTCTTCTAACGGCAACGTGACAGAGTCTGGCTGTAAGGAGTGTGAGGAGCTGGAGGAGAAGAACATCAAGGAGTTTCTGCAGTCTTTTGTGCACATCGTGCAGATGTTTATCAACACCTCTTGA
SEQ ID NO:20>编码C3789的核酸[hHC抗-PD1Gepi 135c-LV-hIgG 4H-C-Flex-v1-hIL-15Ra-hIL-15]
ATGGGATGGTCTTGGATTCTGCTGTTTTTGTTGAGCGTGACAGCTGGAGTGCATAGCCAGGTGCAGTTGGTGCAGAGCGGAGCCGAGGTGAAGAAACCTGGAGCCTCCGTGAAGATGAGCTGTAAGGCTAGTGGATACACTTTTACAAACTTTTACATTCATTGGGTGAGGCAGGCCCCCGGCCAGGGGCTGGAGTGGATCGGCAGCATCTACCCCAACTACGGCGATACCGCCTACAACCAGAAGTTCAAGGATAGGGCCACCCTGACAGTGGACACCAGCACTAGCACAGCCTACATGGAGCTGAGCAGCCTGCGGAGCGAGGACACAGCGGTGTACTACTGCGCCAGGGGCTACAGCTACGCTATGGATTACTGGGGGCAGGGGACCCTGGTGACAGTGAGCAGCGCCAGCACGAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCCAGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCCAAGCCCAACCCCGATATCGGGATGTGCCCTCCCCCCATGTCCGTGGAACACGCAGACATCTGGGTCAAGAGCTACAGCTTGTACTCCAGGGAGCGGTACATTTGTAACTCTGGTTTCAAGCGTAAAGCCGGCACGTCCAGCCTGACAGAGTGCGTGTTGAACAAGGCCACGAATGTCGCCCACTGGACAACCCCCAGTCTCAAATGCATTAGAGACCCTGCCCTGGTTCACCAAAGGCCAGCGCCACCCGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAACAGATGATCTGGATGCACTCGACAACTGGGTGAATGTAATAAGTGATTTGAAAAAAATTGAAGATCTTATTCAATCTATGCATATTGATGCTACTTTATATACGGAAAGTGATGTTCACCCCAGTTGCAAAGTAACAGCAATGAAGTGCTTTCTCTTGGAGCTCCAGGTAATTAGCTTAGAATCTGGCGACGCCAGCATCCACGATACAGTTGAGAATCTGATCATTCTCGCAAACAACTCTCTGTCTTCTAACGGCAACGTGACAGAGTCTGGCTGTAAGGAGTGTGAGGAGCTGGAGGAGAAGAACATCAAGGAGTTTCTGCAGTCTTTTGTGCACATCGTGCAGATGTTTATCAACACCTCTTGA
本发明的另一个目的涉及编码本发明免疫细胞因子的核酸。
通常，所述核酸是DNA或RNA分子，其可包括在任何合适的载体中，例如质粒、粘粒、附加体、人工染色体、噬菌体或病毒载体。
因此，本发明的另一个目的涉及包含本发明核酸的载体。
此类载体可包含调控元件，例如启动子、增强子、终止子等，以在向受试者施用时引起或直接表达所述抗体。动物细胞表达载体中使用的启动子和增强子的实例包括SV40的早期启动子和增强子、Moloney小鼠白血病病毒的LTR启动子和增强子、免疫球蛋白H链的启动子和增强子等。只要能插入并表达编码人类抗体C区的基因，就可以使用任何动物细胞表达载体。合适载体的示例包括pAGE107、pAGE103、pHSG274、pKCR、pSG1βd2-4等。质粒的其他实例包括包含复制起点的复制质粒，或整合质粒，例如pUC、pcDNA、pBR等。病毒载体的其他示例包括腺病毒、逆转录病毒、疱疹病毒和AAV载体。此类重组病毒可通过本领域已知的技术产生，例如通过转染包装细胞或通过辅助质粒或病毒的瞬时转染。典型的病毒包装细胞包括PA317细胞、PsiCRIP细胞、GPenv+细胞、293细胞等。例如，可在WO 95/14785、WO 96/22378、US 5882877、US 6013516、US 4861719、US 5278056和WO 94/19478中找到生产此类复制缺陷重组病毒的详细方案。
本发明的另一个目的涉及已被本发明的核酸和/或载体转染、感染或转化的宿主细胞。
本发明的核酸可用于在合适的表达系统中产生本发明的抗体。常见的表达系统包括大肠杆菌宿主细胞和质粒载体、昆虫宿主细胞和杆状病毒载体以及哺乳动物宿主细胞和载体。宿主细胞的其他示例包括但不限于原核细胞(例如细菌)和真核细胞(例如酵母细胞、哺乳动物细胞、昆虫细胞、植物细胞等)。具体的例子包括大肠杆菌、克鲁维酵母菌(Kluyveromyces)或酵母菌。哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)，中国仓鼠卵巢(CHO细胞)包括与DHFR选择标记一起使用的dhfr-CHO细胞(描述于Urlaub and Chasin,1980)、CHOK1 dhfr+细胞系、NSO骨髓瘤细胞、COS细胞和SP2细胞，例如GS CHO细胞系和GSXceedTM基因表达系统(Lonza)或HEK细胞。
本发明还涉及一种生产表达本发明多肽的重组宿主细胞的方法，所述方法包括以下步骤：(i)将上述重组核酸或载体在体外或离体引入感受态的宿主细胞，(ii)体外或离体培养获得的重组宿主细胞；和(iii)任选地，选择表达和/或分泌所述抗体的细胞。这种重组宿主细胞可用于生产本发明的抗体。
因此，本文所公开的宿主细胞特别适合生产本发明的多肽。实际上，当将重组表达引入哺乳动物宿主细胞时，通过将宿主细胞培养一段足以在宿主细胞中表达多肽的时间并任选地将多肽分泌到宿主细胞生长的培养基中来产生多肽。例如，多肽可以使用标准的蛋白质纯化方法从分泌后的培养基中回收和纯化。
本发明的治疗用途：
本发明的另一个目的涉及本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白作为药物的用途。尤其是，所述融合蛋白特别适合于癌症或传染病的治疗。因此，本发明的另一个目的涉及一种治疗有需要的受试者的方法，包括向患者施用治疗有效量的本发明的IL-15/IL-15受体α(IL-15Rα)融合蛋白。
本发明的另一个目的涉及本发明的免疫细胞因子作为药物的用途。因此，本发明的另一个目的涉及一种治疗有需要的受试者的方法，包括向患者施用治疗有效量的本发明的免疫细胞因子。
具体地，根据本发明的抗PD-1免疫细胞因子特别适合于增强需要T细胞的受试者中T细胞的增殖、迁移、持久性和/或活性。具体地，根据本发明的抗PD-1免疫细胞因子特别适合于增强T CD4+细胞的增殖、迁移、持久性和/或活性。具体地，根据本发明的抗PD-1免疫细胞因子特别适合于增强T CD8+细胞的增殖、迁移、持久性和/或活性。具体地，根据本发明的抗PD-1免疫细胞因子特别适合于增强γδT细胞的增殖、迁移、持久性和/或活性。具体地，根据本发明的抗PD-1免疫细胞因子特别适合于增强CAR-T细胞的增殖、迁移、持久性和/或活性。
因此，本发明的另一个目的是提供一种治疗需要的受试者的方法，包括向受试者施用治疗有效量的至少一种抗PD-1免疫细胞因子，其中所述施用增强受试者中T细胞的增殖、迁移、持久性和/或活性。
更具体地，本发明提供了在有需要的受试者中减少T细胞耗竭的方法，包括向受试者施用治疗有效量的至少一种本发明的抗PD-1免疫细胞因子。
在一些实施方案中，本发明的抗PD-1免疫细胞因子特别适合于增强抗原特异性T细胞的增殖、迁移、持久性和/或活性。
在一些实施方案中，抗原是肿瘤相关抗原(TAA)。TAA的例子包括但不限于黑色素瘤相关抗原Ags(与黑色素瘤相关的Melan-A/MART-1、MAGE-1、MAGE-3、TRP-2、黑素体膜糖蛋白gp100、gp75和MUC-1(粘蛋白-1))；可与例如卵巢癌、黑色素瘤或结肠癌等相关的CEA(癌胚抗原)；卵巢癌表达的叶酸受体α；由许多不同肿瘤表达的游离人绒毛膜促性腺激素β(hCGP)亚基，包括但不限于卵巢肿瘤、睾丸肿瘤和骨髓瘤；与乳腺癌相关的HER-2/neu；与小细胞肺癌相关的脑脊髓炎抗原HuD；与神经母细胞瘤相关的酪氨酸羟化酶；与前列腺癌相关的前列腺特异性抗原(PSA)；与卵巢癌相关的CA125；以及可产生肿瘤特异性免疫(归因于独特型特异性体液免疫反应)的B细胞淋巴瘤的独特型决定因素，与胰腺癌、卵巢癌和肺癌相关的间皮素，与卵巢癌、结直肠癌、非小细胞肺癌相关的P53，与睾丸、卵巢癌相关的NY-ESO-1，与乳腺癌、前列腺癌、肺癌相关的EphA2，与结直肠癌相关的EphA3，与肺癌、乳腺癌、胰腺癌、卵巢癌相关的Survivin，宫颈癌相关的HPV E6和与E7，与NSCL癌相关的EGFR。此外，人类T细胞白血病病毒1型的Ags已被证明可诱导针对病毒诱导的人类成人T细胞白血病(ATL)的特异性细胞毒性T细胞反应和抗肿瘤免疫。同样可以使用其他白血病抗原。可用于本发明的肿瘤相关抗原在《肿瘤抗原的类别》(Hassane M.等人Holland-Frei Cancer Medicine(2003).第6版)一书和Gregory T.等人的综述(“Novel cancer antigens forpersonalized immunotherapies:latest evidence and clinical potential”Ther AdvMed Oncol.2016；8(1):4–31)中公开，所有这些都通过引用并入本文。在一些实施方案中，肿瘤相关抗原为黑色素瘤相关抗原。
在一些实施方案中，抗原是传染病抗原。因此，在一些实施方案中，抗原选自从细菌、病毒、寄生虫和真菌抗原中选择的传染病抗原。通常，抗原是至少一种病毒抗原。例如，至少一种病毒抗原包括来自腺病毒、逆转录病毒、小核糖核酸病毒、疱疹病毒、轮状病毒、汉坦病毒、冠状病毒、披膜病毒(togavirus)、黄病毒(flavirvirus)、弹状病毒、副粘病毒、正粘病毒、布尼亚病毒(bunyavirus)、沙粒病毒、呼肠孤病毒、乳头瘤病毒(papilomavirus)、细小病毒、痘病毒、肝炎病毒、轮状病毒或海绵状病毒的肽。在一些实施方案中，所述至少一种病毒抗原包含来自HIV、CMV、甲型肝炎、乙型肝炎和丙型肝炎、流感中的至少一种的肽；麻疹、脊髓灰质炎、天花、风疹、呼吸道合胞体、单纯疱疹、水痘带状疱疹、爱泼斯坦-巴尔病毒(Epstein-Barr)、日本脑炎、狂犬病、流感或感冒病毒。在一些实施方案中，所述病毒抗原选自以抗原结构域中的一种或多种：HIV-1Gag p24、Nef和Gag p17(包括称为GNG的三种抗原的组合，参见下文详细的氨基酸序列)或HVP16 E6和HPV16 E7抗原的组合(HPV 16E6/E7)(也称为HPV，参见下文详细的氨基酸序列)。在一些实施方案中，所述病毒抗原选自以下HIV抗原结构域中的一种或多种：Gag p17(17-35)、Gag p17-p24(253-284)和Nef(116-145)、Pol 325-344(RT 158-188)和Nef(66-97)。在一些实施方案中，所述病毒抗原选自以下5个HIV抗原结构域的组合：Gag p17(17-35)、Gag p17-p24(253-284)和Nef(116-145)、Pol325-344(RT 158-188)和Nef(66-97)。
本发明的另一个目的涉及用于治疗癌症的本发明抗PD-1免疫细胞因子。实际上，本发明的抗PD-1免疫细胞因子特别适用于增强肿瘤浸润性细胞毒性T淋巴细胞的增殖、迁移、持久性和/或活性。
在一些实施方案中，本发明的方法适用于治疗以表达PD-1的细胞毒性T淋巴细胞的高肿瘤浸润为特征的癌症。通常，所述细胞毒性T淋巴细胞的肿瘤浸润是通过本领域的任何常规方法确定的。例如，所述测定包括量化从患者获得的肿瘤样本中表达PD-1的细胞毒性T淋巴细胞的密度。在一些实施方案中，通过免疫组织化学(IHC)确定表达至少一种免疫检查点蛋白的细胞毒性T淋巴细胞密度的数量。例如，通过将组织肿瘤组织样本与特异于所述细胞的细胞表面标记物的结合配体(例如抗体)接触，对细胞毒性T淋巴细胞的密度进行定量。通常，通过将组织肿瘤样品与一组CD8和PD-1特异性结合配体(例如抗体)接触来对细胞毒性T淋巴细胞的密度进行定量。
本发明的另一个目的涉及一种治疗有需要的癌症患者的方法，包括向患者施用治疗有效量的本发明的抗PD-1免疫细胞因子和治疗有效量的CAR-T细胞群。因此，本发明的抗PD-1免疫细胞因子将防止对肿瘤相关抗原具有特异性的CAR-T细胞群的耗尽。
本发明的另一个目的涉及用于治疗传染病的本发明的抗PD-1免疫细胞因子。更具体地说，本发明的抗PD-1免疫细胞因子特别适合于治疗病毒感染。本发明可治疗的病毒感染的实例包括由感染动物、人类和植物的单链或双链RNA和DNA病毒引起的感染，例如逆转录病毒、痘病毒、免疫缺陷病毒(HIV)感染、埃可病毒感染、细小病毒感染、风疹病毒感染、乳头瘤病毒、先天性风疹感染、爱泼斯坦-巴尔病毒感染、腮腺炎、腺病毒、艾滋病AIDS、水痘、巨细胞病毒、登革热、猫白血病、禽瘟疫、甲型肝炎、乙型肝炎、HSV-1、HSV-2、猪霍乱、甲型流感、乙型流感、日本脑炎、麻疹、副流感、狂犬病、呼吸道合胞病毒、轮状病毒、疣和黄热病、腺病毒、疱疹病毒(例如HSV-I、HSV-II、CMV或VZV)、痘病毒(例如正痘病毒，例如天花或牛痘或接触传染性软疣)、小核糖核酸病毒(例如鼻病毒或肠道病毒)、正粘病毒(例如流感病毒)、副粘病毒(例如副流感病毒、腮腺炎病毒、麻疹病毒和呼吸道合胞病毒(RSV))、冠状病毒(例如SARS)、乳多空病毒(例如乳头瘤病毒、如引起生殖器疣、普通疣或足底疣的病毒)、肝炎病毒(例如乙型肝炎病毒)、黄病毒(例如丙型肝炎病毒或登革热病毒)或逆转录病毒(例如慢病毒，如HIV)。
本发明的抗PD-1免疫细胞因子也特别适用于疫苗接种目的。具体而言，所述免疫细胞因子特别适合于增强疫苗组合物诱导的免疫应答。因此，本发明的另一个目的涉及一种用于在需要的受试者中引发和/或增强针对病毒或肿瘤相关抗原的B细胞和/或T细胞应答的方法，包括向所述需要的受试者施用本发明的抗PD-1免疫细胞因子。在一些实施方案中，将本发明的抗PD-1免疫细胞因子与疫苗顺序或伴随地施用。在一些实施方案中，本发明的抗PD-1免疫细胞因子在向受试者注射疫苗组合物之前临时与疫苗组合物混合。
因此，在一些实施方案中，将本发明的抗PD-1免疫细胞因子与至少一种用于疫苗接种目的的抗原组合施用于受试者。通常，所述抗原是病毒抗原。在一些实施方案中，所述病毒抗原选自以下一个或多个抗原结构域：HIV-1 Gag p24、Nef和Gag p17(包括称为GNG的三种抗原的组合，详细信息见下文氨基酸序列)或HVP16 E6和HPV16 E7抗原的组合(HPV 16E6/E7)(也称为HPV，见下文详细的氨基酸序列)。在一些实施方案中，所述病毒抗原选自以下HIV抗原结构域中的一种或多种：Gag p17(17-35)、Gag p17-p24(253-284)和Nef(116-145)、Pol 325-344(RT 158-188)和Nef(66-97)。在一些实施方案中，所述病毒抗原选自以下5个HIV抗原结构域的组合：Gag p17(17-35)、Gag p17-p24(253-284)和Nef(116-145)、Pol 325-344(RT 158-188)和Nef(66-97)。
在一些实施方案中，抗原或多种抗原与DC缀合靶向抗体，尤其是抗CD40抗体结合。因此，在一些实施方案中，将本发明的抗PD-1免疫细胞因子与至少一种抗CD40抗体结合的抗原组合用于疫苗接种目的施用给受试者。通常，所述抗CD40抗体包含与所述抗体的相应重链或轻链或其抗原结合片段融合或缀合或通过共价偶联偶联的一种或多种抗原。如上文所述，所述抗原可直接与抗CD40抗体的多肽链结合，例如在抗CD40抗体的多肽链的C末端，并且任选地通过肽连接物(例如FlexV1)结合。它们也可以通过非共价进行偶联，例如包括在用于与dockerin结构域偶联的cohesin融合蛋白中。
此外，本文公开的疫苗接种方法还可包括施用一种或多种佐剂。佐剂可直接或间接地附着或缀合到一种或多种疫苗组分，例如如上所述的抗原或抗CD40抗体。在一些实施方案中，佐剂可与疫苗组合物分开提供或施用。在一些实施方案中，佐剂是聚ICLC、CpG、LPS、免疫液体(Immunoquid)、PLA、GLA或细胞因子佐剂，例如IFNα。在一些实施方案中，佐剂可以是toll样的受体激动剂(TLR)。可使用的TLR激动剂的实例包括TLR1激动剂、TLR2激动剂、TLR3激动剂、TLR4激动剂、TLR5激动剂、TLR6激动剂、TLR7激动剂、TLR8激动剂或TLR9激动剂。
在一些实施方案中，本发明的疫苗接种方法用于预防健康受试者被所述病毒感染，包括施用与本发明的抗PD-1免疫细胞因子组合的病毒疫苗，例如未被所述病毒感染的健康受试者(预防性治疗)。在一些实施方案中，本发明的疫苗接种方法用于治疗患有病毒感染的患者的方法中，包括向患者施用与本发明的抗PD-1免疫细胞因子组合的病毒疫苗。
本发明的药物组合物：
本发明的另一个目的涉及包含本发明所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白和药学上可接受的载体的药物。
本发明的另一个目的涉及包含本发明的免疫细胞因子(例如抗PD-1免疫细胞因子)和药学上可接受的载体的药物。
可用于这些组合物中的药学上可接受的载体包括但不限于离子交换剂、氧化铝、硬脂酸盐、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质(例如磷酸盐、甘氨酸、山梨酸、山梨酸钾)、饱和植物脂肪酸、水、盐或电解质的部分甘油酯混合物，如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂肪。用于给患者服用时，将被配制成组合物给患者服用。本发明的组合物可经口服、肠胃外、通过吸入喷雾、局部、直肠、鼻、口腔、阴道或通过植入的贮液器施用。本文使用的技术包括皮下、静脉、肌肉、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输液技术。本发明组合物的无菌可注射形式可以是水性或油质悬浮液。这些悬浮液可以根据本领域已知的技术，使用合适的分散剂或润湿剂以及悬浮剂来配制。无菌可注射制剂也可以是无毒的肠胃外可接受的稀释剂或溶剂中无菌可注射溶液或悬浮液，例如1,3-丁二醇中的溶液。可接受的载体和溶剂包括水、林格溶液和等渗氯化钠溶液。此外，无菌不挥发油通常用作溶剂或悬浮培养基。为此，可使用任何温和的不挥发油，包括合成单甘油酯或双甘油酯。脂肪酸，如油酸及其甘油酯衍生物可用于制备注射剂，天然医药上可接受的油，如橄榄油或蓖麻油，尤其是在其聚氧乙烯化版本中。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂，例如羧甲基纤维素或类似的分散剂，它们通常用于制备药学上可接受的剂型，包括乳液和悬浮液。其他常用的表面活性剂，例如吐温Tweens，司盘Spans和其他乳化剂或生物利用度增强剂，通常用于制造药学上可接受的固体、液体或其他剂型，也可用于制剂的目的。本发明的组合物可以任何口服可接受的剂型口服给药，包括但不限于胶囊、片剂、水悬浮液或溶液。就口服片剂而言，通常使用的载体包括乳糖和玉米淀粉。也通常添加润滑剂，如硬脂酸镁。对于胶囊形式的口服给药，有用的稀释剂包括，例如乳糖。当口服需要水悬浮液时，活性成分与乳化剂和悬浮剂结合。如果需要，还可以添加某些甜味剂、调味品或着色剂。或者，本发明的组合物可以以用栓剂的形式用于直肠给药。可通过将制剂与合适的非刺激性赋形剂混合来制备，该赋形剂在室温下为固体，但在直肠温度下为液体，因此将在直肠中融化以释放药物。这些材料包括可可脂、蜂蜡和聚乙二醇。本发明的组合物也可局部施用，尤其是当治疗目标包括通过局部施用容易到达的区域或器官时，包括眼睛、皮肤或下肠道疾病。为这些区域或器官中的每一个容易地准备合适的局部制剂。对于局部应用，所述组合物可配制成合适的软膏剂，该软膏剂含有悬浮或溶解于一种或多种载体中的活性成分。用于局部施用本发明化合物的载体包括但不限于矿物油、液体矿脂、白矿脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者，可将所述组合物配制成含有悬浮或溶解于一种或多种药学上可接受载体中的活性成分的合适乳液或乳膏。合适的载体包括但不限于矿物油、山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷酯蜡、十六硬脂酸酯、2-辛基十二醇、苯甲醇和水。下肠道的局部施用可通过直肠栓剂制剂(见上文)或合适的灌肠制剂实现。也可以使用贴片。本发明的组合物也可通过鼻喷雾剂或吸入施用。此类组合物根据药物制剂领域众所周知的技术制备，并可制备成盐溶液，使用苯甲醇或其他合适的防腐剂、吸收促进剂以提高生物利用度、氟碳化合物和/或其他常规增溶剂或分散剂。例如，本发明的药物组合物中存在的抗体可在100mg(10mL)或500mg(50mL)单用小瓶中以10mg/mL的浓度提供。将产物配置成用于静脉注射的9.0mg/mL氯化钠、7.35mg/mL二水柠檬酸钠、0.7mg/mL聚山梨酯80和无菌注射用水。将pH值调整至6.5。本发明药物组合物中抗体的示例性合适剂量范围可在约1mg/m2至500mg/m2之间。然而，应当理解，这些方案是示例性的，并且考虑到必须在临床试验中确定的药物组合物中的特定抗体的亲和力和耐受性，可以调整最佳方案和制剂。本发明用于注射(例如，肌肉注射)的注射用药物组合物可制备成含有无菌缓冲水(例如，肌肉注射用1ml)，以及在约1ng至约100mg之间，例如，约50ng至约30mg，或更优选约5mg至约25mg的本发明的多肽。
本发明还涉及包含本发明的抗PD-1免疫细胞因子的疫苗组合物。在一些实施方案中，疫苗组合物包含至少一种如上所述的抗原，其可任选地与如上所述的抗CD40抗体结合。在一些实施方案中，本发明的疫苗组合物可进一步包含至少一种佐剂。可能有效的佐剂示例包括但不限于：氢氧化铝、N-乙酰-胞壁酰-L-苏氨酰-D-异谷氨酰胺(thr-MDP)、N-乙酰-去甲-胞壁酰-L-丙氨酰-D-异谷氨酰胺、MTP-PE和RIBI，在2％角鲨烯/吐温80乳液中，包含从细菌中提取的三种组分：单磷酸脂A、海藻糖二聚体和细胞壁骨架(MPL+TDM+CWS)。佐剂的其他例子包括DDA(二甲基十八烷基溴化铵)、弗氏完全和不完全佐剂以及奎拉QuilA。此外，免疫调节物质，例如淋巴因子(例如，IFN-[γ]、IL-2和IL-12)或合成IFN-[γ]诱导剂，例如聚I:C或聚ICLC(希尔顿醇)，可与本文所述的佐剂结合使用。在一些实施例中，佐剂可在聚ICLC、CpG、LPS、免疫液体、PLA、GLA或细胞因子佐剂(例如IFNα)中选择。在一些实施例中，佐剂可以是toll样受体激动剂(TLR)。可使用的TLR激动剂的实例包括TLR1激动剂、TLR2激动剂、TLR3激动剂、TLR4激动剂、TLR5激动剂、TLR6激动剂、TLR7激动剂、TLR8激动剂或TLR9激动剂。疫苗制剂可制成注射剂，或作为液体溶液或悬浮液；也可以制备适于在感染前溶解于或悬浮于液体中的固体形式。该制剂可以被乳化、包裹在脂质体中。活性免疫原性成分通常与药物上可接受且与活性成分相容的载体混合。
根据本发明的疫苗或药物组合物的施用将通过任何常见途径进行，只要靶标组织可通过该途径获得，以便最大限度地将抗原递送至位点以获得最大(或在某些情况下最小)免疫反应。疫苗接种通常采用原位注射、皮内注射、黏膜注射、皮下注射、肌肉注射、腹腔注射或静脉注射。其他递送区域包括：口服、鼻腔、口腔、直肠、阴道或局部。本发明的疫苗优选通过注射例如皮下注射或肌肉注射进行肠外给药。
本发明的疫苗或药物组合物可以与剂型相容的方式施用，并且以预防和/或治疗有效的量施用。给药量取决于待治疗的受试者，包括例如受试者免疫系统合成抗体的能力，以及所需的保护或治疗程度。合适的剂量范围为每次接种几百微克活性成分，范围约为0.1mg至1000mg，例如，范围约为1mg至300mg，或范围约为10mg至50mg。
疫苗通常可以单剂量或多剂量方案给药。多剂量计划是指一个主要的疫苗接种过程可能包括，例如1-10个单独的剂量，然后在后续时间间隔内给予其他剂量以维持和/或增强免疫应答，例如第二剂在1-4个月，如果需要，在数月后再给予后续剂量。每隔1-5年(通常为3年)进行定期增强免疫，以维持所需的保护性免疫力水平。在免疫过程之后，可以对与抗原共培养的外周血淋巴细胞(PBL)进行体外增殖试验，并通过测量从致敏淋巴细胞释放的IFN-[γ]水平。可使用常规标记例如放射性核苷酸、酶、荧光标记等进行测定。这些技术为本领域技术人员所知，可在U.S.Pat.Nos.3,791,932,4,174,384和3,949,064中找到。
疫苗可以以一种或多种“单位剂量”提供。单位剂量的定义是包含预定数量的疫苗，通过计算产生与其给药相关的预期反应，即适当的途径和治疗方案。给药的量以及特定的途径和制剂在临床技术人员的技能范围内。还可以评估待治疗的受试者，尤其是受试者免疫系统的状态和所需的保护。单位剂量的注射不需要单次注射给药，但可以包括在设定的时间段内持续输注。疫苗的接种量可在约0.001至约0.05mg/kg体重之间变化，例如，每个受试者的接种量在0.1至5mg之间。
本发明将通过以下附图和示例进一步说明。然而，这些示例和附图不应以任何方式解释为限制本发明的范围。
附图说明
图1：抗PD-1/IL-15/Rα对功能活性和体内药代动力学特性进行分析的免疫细胞因子设计。免疫细胞因子包括(A)一个旋钮孔双特异性设计，一个臂靶向PD-1，第个传递IL-15和IL-15受体αsushi域(IC:K-in-H)，(B)具有C端dockerin融合蛋白的抗PD-1抗体，通过N端cohesin结构域(IC:Doc/Coh)与IL-15/Rα融合蛋白紧密结合和(C)C端与IL-15和IL-15Rα通过柔性环连接(IC:Fusion)融合的抗PD-1抗体。
图2：与Keytruda相比，抗PD-1/IL-15/Rα免疫细胞因子增强了耗尽的CD8+T细胞增殖的恢复。HIV衍生肽刺激后HIV特异性CD8+T细胞增殖的恢复。多个CFSE实验的结果显示，相对于每项研究中用作阳性对照参考的Keytruda，细胞增殖增强。
图3：与经典阻断(Keytruda)或非阻断(135C H1cL1c)抗PD-1抗体直接融合的IL-15/IL-15Rα免疫细胞因子的比较。HIV衍生肽刺激后HIV特异性CD8+T细胞增殖的恢复。
图4：在Keytruda或抗PD-1/IL-15/Rα免疫细胞因子存在下刺激的细胞中观察到的抗原特异性CD8 T细胞增殖。用HIV抗原肽刺激来自病毒血症HIV供体的PBMCs，在培养物中培养6天，然后用五聚体MHC肽复合物染色细胞。
图5：抗PD-1抗体Keytruda与不同抗PD-1/IL-15/Rα免疫细胞因子相比的药代动力学特征。测量Keytruda样本中总人IgG抗体，并监测带有结合IL-15的人IgG抗体的免疫细胞因子。
图6：实验设计。在PD1、IL-15/IL-15Rα、aPD1+IL-15/IL-15Rα或与IL-15/IL-15Rα融合的αPD1存在与不存在的情况下，用Gag-P24肽池刺激接种后第16周(样本n＝15)的cART患者的PBMCs。刺激44小时后收集细胞并染色，然后通过流式细胞术分析，以描绘CD4+OX40+CD25+Foxp3+CD39+特异性Tregs和CD4+OX40+CD25+Foxp3-CD39-特异性效应器。同时，我们评估了体外刺激6天后CD8+五聚体+HIV-1特异性细胞增殖和细胞因子的产生。
图7：CD4+HIV-1特异性反应。如图2所示，在有无免疫细胞因子存在的情况下，用Gag P24肽池刺激接种后第16周(n＝15)的cART患者的PBMCs。刺激44小时后通过流式细胞术分析细胞，以描绘CD4+OX40+CD25+Foxp3+CD39+特异性Tregs和CD4+OX40+CD25+Foxp3-CD39-特异性效应器。
图8：CD8+特异性反应。Dalia1样本中的PBMCs(n＝5，但仅显示3个)经CFSE标记，并在体外用Gag-P24肽池刺激，并在存在(或不存在)αPD1或PD1_IL-15/IL-15Rα融合物的情况下进行培养。流式细胞术染色显示CD8+五聚体+特异性细胞(A)、增殖(B)和细胞因子产生(C)的门控策略。
图9：体外抗CD40.HIV5pep-DC疫苗的实验设计。使用来自cART患者(Physiophcohort,Hopital Henri-Mondor Créteil)的PBMCs。样品(n＝10)用于CD14+单核细胞的分离(米尔顿依珠Miltenyi beads)、分化、成熟、活化并装载抗CD40.HIV5pep(DC疫苗)，如Dalia1实验中使用的(图1)。已经进行了在44小时内使用Gag-P24肽池刺激的PBMCs或在-PD1_IL-15/IL-15R融合物存在(或不存在)的情况下与抗CD40.HIV5pep共同培养的实验。使用了上述CD4+OX40+CD25+效应器和Tregs的门控策略。
图10：CD4+HIV-1特异性反应。图9(上图)的读出实验中显示了Teff和Tregs特定的细胞频率。在44小时内，用Gag-P24肽池刺激PBMCs，或在-PD1_IL-15/IL-15R融合物存在(或不存在)的情况下与抗CD40.HIV5EP共培养。已应用如图5所示的CD4+OX40+CD25+效应器和Tregs的门控策略。
图11：CD4+和CD8+HIV-1特异性反应。图9(上图)的读出实验显示了效应器CD4+和CD8+T细胞产生的细胞因子。在44小时(OX40测定)结束前6小时，添加了布雷非菌素A(brefeldinA)，阻断细胞内细胞因子分泌。已进行IL-2/TNF/IFNγ染色并通过流式细胞术分析细胞。蓝色柱状图显示，当PBMCs/抗CD40.HIV5pep-DC共培养物中添加-PD1_IL-15/IL-15R融合物时细胞因子产量增加。
图12：在PD-1HuGEMM体内Panc02肿瘤模型中，免疫疗法诱导肿瘤生长抑制。将Panc02肿瘤细胞植入PD-1huGEMM小鼠，在达到100mm3的平均肿瘤体积后，每周用PBS或四种免疫疗法之一治疗两次。分配给每组的10只小鼠每周监测两次肿瘤体积，显示平均体积与治疗天数的对比。
图13：NB01/IL-15/IL-15Rα免疫细胞因子在免疫治疗开始后第7至24天对Panc02肿瘤生长产生显著抑制。通过计算研究开始后第7天至第24天的曲线下面积(AUC)，评估不同疗法的抗肿瘤效果。使用非参数Mann-Whitney检验确定PBS对照组和个体疗法之间的统计差异。使用Graphpad Prism 8.3.0进行分析。
图14：NB01/IL-15/IL-15Rα免疫细胞因子治疗延长植入Panc02的PD-1HuGEMM小鼠的存活时间。通过Kaplan-Meier生存曲线分析，评估Panc02植入小鼠开始治疗后随时间推移的存活率。对数秩检验证实，NB01/IL-15/IL-15Rα免疫细胞因子单一疗法和Keytruda+IL-15/IL-15RαALT-803超级激动剂双重疗法均显著延长小鼠存活时间。相比之下，单独使用Keytruda或Keytruda/IL-15/IL-15Rα免疫细胞因子单一疗法均不能显著延长Panc02植入小鼠的生存期。使用Graphpad Prism 8.3.0进行分析。
实施例1：
在免疫细胞因子的设计中，我们的重点是确定与抗PD-1治疗相比，在增强抗原特异性T细胞增殖方面具有更好效力以及足够长的体内半衰期的治疗剂。第二个考虑因素是这些免疫细胞因子的产量和生物物理稳定性，这将有助于体内试验和临床前分析的一个有希望的候选进展。如图1所示，对三种不同的免疫细胞因子设计进行了评估。新型抗PD-1/IL-15/Rα的免疫增强活性在体外使用慢性感染HIV的献血者的血单个核细胞进行了高度标准化的CFSE增殖试验。来自这些供体的HIV特异性T细胞在长时间内暴露于高水平的抗原中，因此功能衰竭，表达高水平的PD-1免疫检查点抑制剂，并且在存在抗原特异性刺激的情况下增殖反应较差。用HIV衍生肽刺激血液单个核细胞，然后培养六天，导致已经历增殖的CFSE低CD8 T细胞增加。添加经典的PDL-1阻断抗PD-1抗体Keytruda导致相对于单独的肽对照增殖水平增强，因此表明抗PD-1抗体可以恢复CD8+T细胞的衰竭(图2)。与Keytruda对照抗PD-1抗体相比，平行测试的三种不同免疫细胞因子结构使CD8+T细胞增殖水平至少提高2至4倍。重要的是，即使在蛋白质浓度降低100倍的情况下，IC:Doc/Coh和IC:Fusion构建物相对于Keytruda也具有显著的免疫增强效果。与Keytruda相比，在1μg/ml浓度下，IC:K-in-H构建体诱导CD8 T细胞增殖水平增加，但是IC:K-in-H的效力比IC:Doc/Coh和IC:融合构建体低10倍以上。在另一个实验中，使用IC：融合构建体设计结合135C H1cL1c抗PD-1抗体生成了额外的免疫细胞因子，该抗体不阻断PD-1/PDL-1相互作用(Fenwick等人，2019)。在CFSE增殖试验中，发现直接融合到IL-15/IL-15Rα的135c的功能活性与作为Keytruda-IL-15/IL-15Rα融合体的IC:Fusion相当(图3)。有趣的是，对于来自这种病毒血症HIV感染供体的血液单核细胞，0.1μg/ml的两种不同免疫细胞因子诱导CD8 T细胞增殖比5μg/ml的Keytruda高达20倍。
实施例2：
在存在不同免疫细胞因子的情况下，CD8+T细胞增殖水平的增加凸显了其相对于单独抗PD-1治疗的优越功能活性。然而，同样重要的是，CD8+T细胞扩增对刺激中使用的HIV肽抗原具有特异性。通过用五聚体MHC-HIV肽复合物对CFSE低增殖CD8+T细胞进行染色，确定在存在免疫细胞因子的情况下增强的CD8+T细胞增殖的特异性。图4中的流式细胞术结果显示，对于Keytruda、IC:K-in-H、IC:Doc/Coh和IC:Fusion，大多数(60-80％)增殖的CD8+T细胞是MHC五聚体阳性的，并且对刺激中使用的HIV肽抗原具有特异性。相比之下，SEB T细胞超抗原刺激后，只有2％的增殖性CD8+T细胞对MHC-HIV肽复合物染色呈阳性。这些五聚体染色研究证实，在存在抗原刺激的情况下，免疫细胞因子复合物强烈且特异性的诱导CD8+T细胞增殖的。
实施例3：
为了进一步将这些免疫细胞因子定性为治疗剂，在C57BL/6小鼠中进行了药代动力学研究，这些小鼠服用了2mg/kg的不同药物，并在接下来的7天内收集血清样本。在研究过程中，使用Luminex分析法测定Keytruda和三种免疫细胞因子的PK特性，以检测人IgG或结合IL-15的人IgG(图5)。与其他免疫细胞因子相比，IC:K-in-H结构具有更天然的抗体结构，其体内半衰期最接近Keytruda抗体(t1/2～5天)。然而，与给予小鼠注射同等剂量的Keytruda相比，药物暴露量也低1个对数。考虑到IC:K-in-H结构的效力仅为Keytruda的10倍左右，较低的PK可能会否定这种免疫细胞因子提供的任何功能优势。IC:Doc/Coh和IC:Fusion免疫细胞因子的终止半衰期约为1天，与Keytruda相比，从小鼠体内清除的速度更快。然而，相对于IC:Doc/Coh和IC:Fusion与Keytruda相比显著改善的体外功能效应，IL-15在体内的半衰期明显长于报告的<1小时半衰期，并且在第7天这两种免疫细胞因子的药物水平仍然很高(>0.01μg/ml)。与评估的三种免疫细胞因子的不同性质相比，IC:Fusion的总体特征最好：1)在2个对数浓度范围内，与Keytruda相比，功能活性提高了2倍以上，2)MHC-petamer染色显示抗原特异性增强CD8+T细胞增殖，和3)PK曲线，支持每周一次的给药方案。与IC:Doc/Coh相比，IC:Fusion构建体的另一个优点是，它缺乏dockerin和cohesin结构域，这结构域可能会增加免疫原性，并对重复给药的动物的PK曲线有损害。
实施例4：
根据我们之前的研究结果，我们推断治疗性DC疫苗可以与融合到免疫检查点抑制剂的免疫调节细胞因子结合，以增加T细胞反应。为此，我们使用了一种αPD-1单克隆抗体(Keytruda，一种临床分子)，已证明其在癌症领域的效力，以及IL-15/IL-15Rα，一种已知影响效应CD8+T细胞增殖的细胞因子。在存在与不存在PD-1_IL-15/IL-15R融合物、单独的αPD1、单独的IL-15/IL-15α或αPD-1+IL-15/IL-15α(参考实验设计，图6)的情况下，用Gag-P24肽池体外刺激接种后第16周(Dalia1，n＝15)的PBMCs。刺激44小时后，分析CD4+OX40+CD25+HIV-1特异性细胞。
我们证明，与其他条件相比，在存在α-PD-1IL-15/IL-15Rα融合物的情况下，Gag-P24刺激cART HIV-1+接种患者的PBMCs导致HIV-1特异性T细胞应答显著增加。在图7的A组中，我们显示当在Gag P24刺激的PBMCs中加入α-PD-1_IL-15/IL-15Rα融合物时，CD4+OX40+CD25+HIV-1特异性细胞频率显著增加，包括效应细胞和调节细胞(Teff和Tregs)。与单独使用Gag P24刺激细胞相比，添加αPD-1不会增加CD4+特异性细胞的频率，而添加IL-15/IL-15Rα或IL-15/IL-15Rα+αPD-1的效果稍好，但没有达到使用α-PD-1IL-15/IL-15Rα融合获得的效力。在图7的B组中，我们在放大效应器(OX40+CD25+CD39-Foxp3-)时显示了类似的趋势，有趣的是，我们观察到当添加α-PD-1_IL-15/IL-15Rα融合物时，Treg(OX40+CD25+CD39+Foxp3+)显著减少。这些数据表明，αPD-1与IL-15/IL-15Rα融合物是体外增强HIV-1特异性效应CD4+T细胞的好方法。
实施例5：
为了描述CD8+HIV-1特异性细胞，我们使用五聚体染色法(Proimmune，UK)和流式细胞术分析了6名患者(Dalia1，16周)的PBMCs体外增殖，这些患者受到HLA限制性肽池的刺激。在体外增殖6天后，我们用特定肽进行隔夜再刺激，并进行CFSE染色和流式细胞术，以测量CD8+增殖和细胞内细胞因子的产生(IL-2,TNFα,IFN-γ)。结果表明，与单独的αPD1相比，在存在α-PD-1IL-15/IL-15R融合的情况下，刺激PBMCs可显著增加CD8+五聚体+细胞增殖和细胞因子的产生，与仅刺激肽的情况相比，表现出类似的反应(图8)。图表显示了5名患者中有3名获得的结果。
实施例6：
为了证明αPD-1_IL-15/IL-15Rα融合物也可以与另一种基于DC的疫苗(抗CD40.HIV5pep-DC)一起使用，我们进行了体外实验，在与自体PBMCs共培养之前，将抗CD40.HIV5pep构建物装载在成熟和分化的CD14+单核细胞上，如以下实验设计所示(图9和Cobb et al.JIM 2011)。我们使用OX40测试测定通过流式细胞术描绘CD4+特异性T细胞，如图9所示。
值得注意的是，对于使用OX40测定的读出实验，我们进行了两种条件：在第一种条件下，我们在存在或不存在αPD-1_IL-15/IL-15Rα融合物的情况下刺激Gag P24患者的PBMCs，在第二种条件下，我们在存在或不存在αPD-1_IL-15/IL-15Rα融合物的情况下，将PBMCs与抗CD40.HIV5pep-DC共培养。图10所示的结果表明，在这两种情况下添加αPD-1_IL-15/IL-15Rα融合物增强了CD4+HIV-1特异性效应细胞(蓝色直方图)，但当PBMCs与抗CD40.HIV5pep-DC刺激/共培养时，这种增加更为显著。此外，我们观察到CD4+HIV-1特异性Tregs显著减少(直方图，下图)。
最后，我们测量了CD4+和CD8+细胞中的细胞内细胞因子(IL-2/TNFα/IFNγ)(在OX40试验44小时结束前6小时添加布雷菲德菌素A(brefeldin A))。图11显示，在存在αPD-1_IL-15/IL-15Rα融合物的情况下，当PBMCs与抗CD40.HIV5pep_DC共培养时，细胞因子的产生显著增加。
总的来说，这些结果表明：i)与Gag P24刺激的PBMCs相比，DC靶向(PBMC与抗CD40HIV5pep-DC共培养)导致更好的T细胞反应；ii)αPD-1_IL-15/IL-15Rα融合的组合增强了CD8+特异性反应(增殖和细胞因子产生)并降低了CD4+特异性Tregs，这表明αPD-1U IL-15/IL-15Rα融合是一种可以推广到临床很好的工具。
实施例7：抗PD-1/IL-15/IL15Ra免疫细胞因子在体内Panc02小鼠肿瘤模型中的功效
本研究的目的是评估本申请中描述的抗PD-1/IL-15/IL-15Rα免疫细胞因子检测试剂在雌性HuGEMM hPD-1小鼠皮下Panc02小鼠胰腺癌异种移植治疗中的体内治疗效果。Panc02肿瘤细胞的免疫原性较差，对于大多数癌症免疫疗法来说，它是一种具有挑战性的肿瘤模型。
CrownBio通过敲入人类外显子2来替代小鼠PD-1对应物，建立了HuGEMM PD-1模型。这允许对识别人源化PD-1受体的人类治疗性抗体进行体内疗效评估。6-8周龄的小鼠在0.1mL PBS中接种3×106Panc02肿瘤细胞，7天后当平均肿瘤大小达到约100(70-130)mm3时开始研究。根据“匹配分布”方法(StudyDirectorTM软件，版本3.1.399.19)，将所有动物随机分配到五个研究组，每组10只小鼠。该研究的五个研究组包括：1)PBS未经治疗的对照组，2)每周两次5mg/kg的pembrolizumab
抗PD-1治疗，3)pembrolizumab
5mg/kg+0.1mg/kg IL-15/IL-15RαALT-803超级激动剂，均每周给药两次，4)Keytruda与IL-15/IL-15Rα免疫细胞因子(IC)融合，以2mg/kg的剂量每周给药两次；5)NB01b抗PD-1抗体与IL-15/IL-15Rα免疫细胞因子(IC)融合，以2mg/kg的剂量每周给药两次。研究中使用的Keytruda是从洛桑大学医院购买的一批临床抗体。IL-15/IL-15RαALT-803超级激动剂和免疫细胞因子是通过瞬时转染CHO表达或HEK 293T哺乳动物细胞系而独立产生的重组蛋白。这些蛋白质通过信号序列表达，信号序列在转染细胞分泌时被切割。然后使用蛋白A亲和柱从细胞培养基中纯化每种治疗蛋白。在通过针对PBS的透析进行缓冲液交换后，使用来自Charles River的鲎变形细胞裂解物试剂盒(LAL)验证治疗剂，并确定内毒素水平低于1EU/ml。所有治疗药物均作为PBS缓冲液溶液腹腔注射。所有小鼠每周用卡尺在二维上测量两次肿瘤体积，体积用mm3表示，公式为：体积＝(长×宽×宽)/2。在本研究中，选择1500mm3肿瘤体积截止值来建立小鼠生存标准。每个研究组小鼠肿瘤体积的纵向评估显示，在治疗第10天，与未经PBS治疗的对照小鼠相比，所有基于抗PD-1的治疗均显示出肿瘤抑制的迹象(图12)。单独使用Keytruda和Keytruda/IL-15/IL-15RαIC疗法在研究第14天观察到平均体积增加时，仅对肿瘤生长产生短暂抑制。相比之下，Keytruda+ALT-803超级激动剂和NB01/IL-15/IL-15RαIC疗法显示出延长的体内功能活性，仅在研究第21天7天后观察到平均肿瘤体积增加。在这之后，Panc02细胞逃脱了不同免疫疗法的抑制，在所有基于抗PD-1的治疗组中，肿瘤生长似乎以相似的速度进展。
通过比较研究第7天至第24天曲线下的肿瘤体积面积值，评估不同疗法和PBS组之间的肿瘤抑制相对水平(图13)。在此期间，Keytruda+超级激动剂和NB01/IL-15/IL-15RαIC研究组观察到最强的肿瘤抑制作用。与PBS对照小鼠相比，我们观察到Keytruda+超级激动剂(p＝0.0021)和NB01/IL-15/IL-15RαIC(p＝0.0041)治疗组的肿瘤明显抑制，而Keytruda单独治疗(p＝0.018)组的肿瘤体积减少不太明显。
使用Kaplan-Meier生存曲线分析评估不同疗法的抗肿瘤疗效(图14)。与PBS对照组相比，NB01/IL-15/IL-15Rα免疫细胞因子单药治疗组小鼠存活率在统计学上显著增加了14天(对数秩检验；p＝0.029)，比Keytruda+IL15/IL15Rα超级激动剂双药治疗组(对数秩检验；p＝0.049)的12天增加存活率略长。相比之下，Keytruda和Keytruda/IL-15/IL-15Rα免疫细胞因子单一疗法均未显著增加植入免疫原性差的Panc02肿瘤细胞的小鼠的存活时间。
总的来说，这些研究表明，与未经治疗的小鼠相比，NB01b抗PD-1抗体与IL-15和IL-15Rα的免疫细胞因子融合在抑制Panc02肿瘤生长和延长小鼠存活方面具有显著的功能活性。这表明免疫细胞因子的活性与Keytruda+超级激动剂双重疗法的疗效相当。
参考资料：
在本申请中，各种参考文献描述了本发明所属的现有技术。这些参考文献的披露在此通过引用并入本公开。
序列表
<110> INSERM（法国国家健康医学研究院）(INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE))
巴黎公共救济院（APHP）(ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP))
巴黎第十二大学( UNIVERSITÉ PARIS-EST CRÉTEIL VAL DE MARNE)
贝勒研究协会(BAYLOR RESEARCH INSTITUTE)
马布奎斯特公司(MABQUEST)
<120> 用抗PD-1/IL-15免疫细胞因子靶向PD-1的新型免疫疗法
<130> 25881INS
<141> 2022-05-16
<150> 19306499.5
<151> 2019-11-21
<160> 20
<170> SIPOSequenceListing 1.0
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<212> PRT
<213> Homo sapiens
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Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser
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Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys
20 25 30
Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala
35 40 45
Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp
50 55 60
Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro
65 70 75
<210> 2
<211> 23
<212> PRT
<213> Artificial
<220>
<223> Linker
<400> 2
Asp Thr Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr
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Thr Thr Asp Asp Leu Asp Ala
20
<210> 3
<211> 116
<212> PRT
<213> Homo sapiens
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Leu Asp Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
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Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
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Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
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Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
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Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
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Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
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Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
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Ile Asn Thr Ser
115
<210> 4
<211> 214
<212> PRT
<213> Artificial
<220>
<223> IL-15Ra_Flex_IL-15 in HC sequence
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Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser
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Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys
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Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala
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Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp
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Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Asp Thr Thr Glu Pro
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Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr Thr Thr Asp Asp Leu
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Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
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Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro
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<212> PRT
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<212> PRT
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<223> VH domain of nivolumab
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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 Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
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Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
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Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 9
<211> 117
<212> PRT
<213> Artificial
<220>
<223> VH domain of the anti-PD1Gepi 135c
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe
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Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
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Gly Ser Ile Tyr Pro Asn Tyr Gly Asp Thr Ala Tyr Asn Gln Lys Phe
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Lys Asp Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
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Val Thr Val Ser Ser
115
<210> 10
<211> 440
<212> PRT
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<223> heavy chain of pembrolizumab
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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 Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
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Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
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Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
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Ser Leu Ser Leu Ser Leu Gly Lys
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<210> 11
<211> 447
<212> PRT
<213> Artificial
<220>
<223> heavy chain of nivolumab
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Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
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Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
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Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
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Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
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Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
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Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
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Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
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Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
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Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
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Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
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Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
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Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
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Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
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Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 12
<211> 444
<212> PRT
<213> Artificial
<220>
<223> heavy chain of the anti-PD1Gepi 135c
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Tyr Pro Asn Tyr Gly Asp Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
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Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
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Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
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Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 13
<211> 694
<212> PRT
<213> Artificial
<220>
<223> C3711 or C3721
<220>
<223> [hKeytruda(anti-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala
435 440 445
Ser Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser
450 455 460
Thr Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro Asp Ile Gly Met
465 470 475 480
Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser
485 490 495
Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys
500 505 510
Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala
515 520 525
Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp
530 535 540
Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Asp Thr Thr Glu Pro
545 550 555 560
Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr Thr Thr Asp Asp Leu
565 570 575
Asp Ala Leu Asp Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
580 585 590
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
595 600 605
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
610 615 620
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
625 630 635 640
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
645 650 655
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
660 665 670
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
675 680 685
Met Phe Ile Asn Thr Ser
690
<210> 14
<211> 694
<212> PRT
<213> Artificial
<220>
<223> [nivolumab (anti-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala
435 440 445
Ser Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser
450 455 460
Thr Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro Asp Ile Gly Met
465 470 475 480
Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser
485 490 495
Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys
500 505 510
Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala
515 520 525
Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp
530 535 540
Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Asp Thr Thr Glu Pro
545 550 555 560
Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr Thr Thr Asp Asp Leu
565 570 575
Asp Ala Leu Asp Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
580 585 590
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
595 600 605
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
610 615 620
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
625 630 635 640
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
645 650 655
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
660 665 670
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
675 680 685
Met Phe Ile Asn Thr Ser
690
<210> 15
<211> 691
<212> PRT
<213> Artificial
<220>
<223> C3789 [hHC anti?PD1Gepi 135c-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Tyr Pro Asn Tyr Gly Asp Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Gln Thr
435 440 445
Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr Pro Thr
450 455 460
Asn Asn Ser Asn Pro Lys Pro Asn Pro Asp Ile Gly Met Cys Pro Pro
465 470 475 480
Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu
485 490 495
Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala
500 505 510
Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val
515 520 525
Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu
530 535 540
Val His Gln Arg Pro Ala Pro Pro Asp Thr Thr Glu Pro Ala Thr Pro
545 550 555 560
Thr Thr Pro Val Thr Thr Pro Thr Thr Thr Asp Asp Leu Asp Ala Leu
565 570 575
Asp Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
580 585 590
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
595 600 605
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
610 615 620
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
625 630 635 640
Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn
645 650 655
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
660 665 670
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
675 680 685
Asn Thr Ser
690
<210> 16
<211> 218
<212> PRT
<213> Artificial
<220>
<223> light chain of pembrolizumab
<400> 16
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 17
<211> 214
<212> PRT
<213> Artificial
<220>
<223> light chain of nivolumab
<400> 17
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val 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 Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 18
<211> 214
<212> PRT
<213> Artificial
<220>
<223> light chain of the anti-PD1Gepi 135c antibody
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Gly Ile Ser Gly Asp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Tyr Tyr Ser Lys Asp Leu Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 19
<211> 2157
<212> DNA
<213> Artificial
<220>
<223> nucleic acid encoding for C3711 or C3721
<220>
<223> [hKeytruda(anti-PD-1)-HC-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
<400> 19
atggatccga aaggttctct gagctggcgt attctgctgt tcctaagcct ggcgttcgaa 60
ctgtcttatg gtcaggttca gctggttcag tctggagttg aagtgaaaaa accgggcgcg 120
tctgttaaag tttcttgcaa agcgtctggt tacaccttca ccaactacta catgtactgg 180
gttcgtcagg cgccgggtca gggcctggaa tggatgggcg gtatcaaccc gtctaacggt 240
ggcaccaact tcaacgaaaa attcaaaaac cgtgttaccc tgaccaccga tagcagcacc 300
accaccgcgt atatggaact gaaatctctg cagttcgacg acaccgcagt gtactactgc 360
gcccgccgcg actaccgttt cgacatgggc ttcgactact gggggcaagg taccacagtt 420
accgtatcga gcgccagcac gaagggccca tccgtcttcc ccctggcgcc ctgctccagg 480
agcacctccg agagcacagc cgccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 660
ggcacgaaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720
agagttgagt ccaaatatgg tcccccatgc ccaccctgcc cagcacctga gttcgaaggg 780
ggaccatcag tcttcctgtt ccccccaaaa cccaaggaca ctctcatgat ctcccggacc 840
cctgaggtca cgtgcgtggt ggtggacgtg agccaggaag accccgaggt ccagttcaac 900
tggtacgtgg atggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagttc 960
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaacggc 1020
aaggagtaca agtgcaaggt ctccaacaaa ggcctcccgt cctccatcga gaaaaccatc 1080
tccaaagcca aagggcagcc ccgagagcca caggtgtaca ccctgccccc atcccaggag 1140
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 1200
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260
gtgctggact ccgacggctc cttcttcctc tacagcaggc taaccgtgga caagagcagg 1320
tggcaggagg ggaatgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1380
acacagaaga gcctctccct gtctctgggt aaagctagcc agacccccac caacaccatc 1440
agcgtgaccc ccaccaacaa cagcaccccc accaacaaca gcaaccccaa gcccaacccc 1500
gatatcggga tgtgccctcc ccccatgtcc gtggaacacg cagacatctg ggtcaagagc 1560
tacagcttgt actccaggga gcggtacatt tgtaactctg gtttcaagcg taaagccggc 1620
acgtccagcc tgacagagtg cgtgttgaac aaggccacga atgtcgccca ctggacaacc 1680
cccagtctca aatgcattag agaccctgcc ctggttcacc aaaggccagc gccacccgat 1740
acaacagaac ctgcaacacc tacaacacct gtaacaacac cgacaacaac agatgatctg 1800
gatgcactcg acaactgggt gaatgtaata agtgatttga aaaaaattga agatcttatt 1860
caatctatgc atattgatgc tactttatat acggaaagtg atgttcaccc cagttgcaaa 1920
gtaacagcaa tgaagtgctt tctcttggag ctccaggtaa ttagcttaga atctggcgac 1980
gccagcatcc acgatacagt tgagaatctg atcattctcg caaacaactc tctgtcttct 2040
aacggcaacg tgacagagtc tggctgtaag gagtgtgagg agctggagga gaagaacatc 2100
aaggagtttc tgcagtcttt tgtgcacatc gtgcagatgt ttatcaacac ctcttga 2157
<210> 20
<211> 2133
<212> DNA
<213> Artificial
<220>
<223> nucleic acid encoding for C3789 [hHC anti?PD1Gepi
<220>
<223> 135c-LV-hIgG4H-C-Flex-v1-hIL-15Ra-hIL-15]
<400> 20
atgggatggt cttggattct gctgtttttg ttgagcgtga cagctggagt gcatagccag 60
gtgcagttgg tgcagagcgg agccgaggtg aagaaacctg gagcctccgt gaagatgagc 120
tgtaaggcta gtggatacac ttttacaaac ttttacattc attgggtgag gcaggccccc 180
ggccaggggc tggagtggat cggcagcatc taccccaact acggcgatac cgcctacaac 240
cagaagttca aggatagggc caccctgaca gtggacacca gcactagcac agcctacatg 300
gagctgagca gcctgcggag cgaggacaca gcggtgtact actgcgccag gggctacagc 360
tacgctatgg attactgggg gcaggggacc ctggtgacag tgagcagcgc cagcacgaag 420
ggcccatccg tcttccccct ggcgccctgc tccaggagca cctccgagag cacagccgcc 480
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 600
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cgaagaccta cacctgcaac 660
gtagatcaca agcccagcaa caccaaggtg gacaagagag ttgagtccaa atatggtccc 720
ccatgcccac cctgcccagc acctgagttc gaagggggac catcagtctt cctgttcccc 780
ccaaaaccca aggacactct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc aggaagaccc cgaggtccag ttcaactggt acgtggatgg cgtggaggtg 900
cataatgcca agacaaagcc gcgggaggag cagttcaaca gcacgtaccg tgtggtcagc 960
gtcctcaccg tcctgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccgtcctc catcgagaaa accatctcca aagccaaagg gcagccccga 1080
gagccacagg tgtacaccct gcccccatcc caggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1260
ttcctctaca gcaggctaac cgtggacaag agcaggtggc aggaggggaa tgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacac agaagagcct ctccctgtct 1380
ctgggtaaag ctagccagac ccccaccaac accatcagcg tgacccccac caacaacagc 1440
acccccacca acaacagcaa ccccaagccc aaccccgata tcgggatgtg ccctcccccc 1500
atgtccgtgg aacacgcaga catctgggtc aagagctaca gcttgtactc cagggagcgg 1560
tacatttgta actctggttt caagcgtaaa gccggcacgt ccagcctgac agagtgcgtg 1620
ttgaacaagg ccacgaatgt cgcccactgg acaaccccca gtctcaaatg cattagagac 1680
cctgccctgg ttcaccaaag gccagcgcca cccgatacaa cagaacctgc aacacctaca 1740
acacctgtaa caacaccgac aacaacagat gatctggatg cactcgacaa ctgggtgaat 1800
gtaataagtg atttgaaaaa aattgaagat cttattcaat ctatgcatat tgatgctact 1860
ttatatacgg aaagtgatgt tcaccccagt tgcaaagtaa cagcaatgaa gtgctttctc 1920
ttggagctcc aggtaattag cttagaatct ggcgacgcca gcatccacga tacagttgag 1980
aatctgatca ttctcgcaaa caactctctg tcttctaacg gcaacgtgac agagtctggc 2040
tgtaaggagt gtgaggagct ggaggagaag aacatcaagg agtttctgca gtcttttgtg 2100
cacatcgtgc agatgtttat caacacctct tga 2133
Claims (35)
1.一种IL-15/IL-15受体α(IL-15Rα)融合蛋白，包括i)含有IL15-Rαsushi的多肽，该多肽包含与SEQ.ID NO：1的氨基酸序列具有至少80％同一性的氨基酸序列；ii)具有如SEQ IDNO：2所示氨基酸序列的连接子和；iii)IL-15多肽，该多肽包含与SEQ ID NO：3的氨基酸序列具有至少80％同一性的氨基酸序列。
2.根据权利要求1所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白，其由如SEQ ID NO：4所示的氨基酸序列组成。
3.一种抗体的重链，其与权利要求1的IL-15/IL-15受体α融合蛋白融合。
4.根据权利要求3所述的重链，其通过连接子与IL-15/IL-15受体α融合蛋白融合。
5.根据权利要求4所述的重链，其中，所述连接子包含如SEQ ID NO：5所示的氨基酸序列。
6.根据权利要求5所述的重链，其中，所述连接子由如SEQ ID NO：6所示的氨基酸序列组成。
7.根据权利要求3所述的重链，其来自具有PD-1特异性的抗体。
8.根据权利要求7所述的重链，其包含如SEQ ID NO：7、8或9中所示的VH结构域。
9.根据权利要求7所述的重链，其包含IgG4免疫球蛋白的IgG Fc区。
10.根据权利要求7所述的重链，其包含如SEQ ID NO：10、11或12所示的氨基酸序列。
11.根据权利要求7所述的重链，其由如SEQ ID NO：13、14或15所示的氨基酸序列组成。
12.一种免疫细胞因子，其包含与权利要求1所述的IL-15/IL-15受体α融合蛋白融合的抗体的重链。
13.根据权利要求12所述的免疫细胞因子，其对PD-1具有特异性。
14.根据权利要求12所述的免疫细胞因子，其包含由如SEQ ID NO：13、14或15所示的氨基酸序列组成的重链。
15.根据权利要求12所述的免疫细胞因子，其包含SEQ ID NO：13所示的重链和SEQ IDNO：16所示的轻链。
16.根据权利要求12所述的免疫细胞因子，其包含SEQ ID NO：14所示的重链和SEQ IDNO：17所示的轻链。
17.根据权利要求12所述的免疫细胞因子，其包含SEQ ID NO：15所示的重链和SEQ IDNO：18所示的轻链。
18.一种编码权利要求1所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白的核酸。
19.一种编码与权利要求1所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白融合的抗体重链的核酸。
20.根据权利要求19所述的核酸，其包含如SEQ ID NO：19或20所示的核酸序列。
21.一种编码权利要求12所述的免疫细胞因子的核酸。
22.一种包含权利要求18、19或21所述的核酸的载体。
23.一种宿主细胞，所述宿主细胞已被权利要求18、19或21所述的核酸转染、感染或转化。
24.权利要求1所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白用作药物。
25.权利要求12所述的免疫细胞因子用作药物。
26.一种治疗有需要的受试者的方法，包括向所述受试者施用治疗有效量的至少一种权利要求13所述的抗PD-1免疫细胞因子，其中，所述施用能够增强受试者中T细胞的增殖、迁移、持久性和/或活性。
27.一种在有需要的受试者中减少T细胞耗竭的方法，包括向所述受试者施用治疗有效量的如权利要求13所述的抗PD-1免疫细胞因子中的至少一种。
28.一种在有需要的受试者中治疗癌症的方法，包括向受试者施用治疗有效量的如权利要求13所述的抗PD-1免疫细胞因子。
29.一种在有需要的受试者中治疗传染病的方法，包括向受试者施用治疗有效量的如权利要求13所述的抗PD-1免疫细胞因子。
30.根据权利要求29所述的方法，其中，所述传染病是由感染动物、人类和植物的单链或双链RNA和DNA病毒引起的病毒感染，例如逆转录病毒、痘病毒、免疫缺陷病毒(HIV)感染、埃可病毒感染、细小病毒感染、风疹病毒感染、乳头瘤病毒、先天性风疹感染、爱泼斯坦-巴尔病毒感染、腮腺炎、腺病毒、AIDS、水痘、巨细胞病毒、登革热、猫白血病、禽瘟疫、甲型肝炎、乙型肝炎、HSV-1、HSV-2、猪霍乱、甲型流感、乙型流感、日本脑炎、麻疹、副流感、狂犬病、呼吸道合胞病毒、轮状病毒、疣、和黄热病、腺病毒、疱疹病毒(例如HSV-I、HSV-II、CMV或VZV)、痘病毒(例如正痘病毒，例如天花或牛痘或接触传染性软疣)、小核糖核酸病毒(例如鼻病毒或肠道病毒)、正粘病毒(例如流感病毒)、副粘病毒(例如副流感病毒、腮腺炎病毒、麻疹病毒和呼吸道合胞病毒(RSV))、冠状病毒(例如SARS)、乳多空病毒(例如乳头瘤病毒、如引起生殖器疣、普通疣或足底疣的病毒)、肝炎病毒(例如乙型肝炎病毒)、黄病毒(例如丙型肝炎病毒或登革热病毒)或逆转录病毒(例如慢病毒，如HIV)。
31.一种在有需要的受试者中引发和/或增强针对一种或多种抗原的B细胞和/或T细胞反应的方法，包括向所述受试者施用治疗有效量的如权利要求13所述的抗PD-1免疫细胞因子，所述抗PD-1免疫细胞因子与抗原或多种抗原组合。
32.根据权利要求31所述的方法，其中，所述抗原或所述多种抗原缀合至DC靶向抗体，特别是抗CD40抗体。
33.一种药物，包含权利要求1所述的IL-15/IL-15受体α(IL-15Rα)融合蛋白和药学上可接受的载体。
34.一种药物，包含权利要求12所述的免疫细胞因子(例如抗PD-1免疫细胞因子)和药学上可接受的载体。
35.一种疫苗组合物，包含权利要求13所述的抗PD-1免疫细胞因子。
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| PCT/EP2020/082892 WO2021099576A1 (en) | 2019-11-21 | 2020-11-20 | Novel immunotherapies targeting pd-1 with anti-pd-1/il-15 immunocytokines |
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| EP (1) | EP4061835A1 (zh) |
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| US20240148867A1 (en) * | 2022-10-31 | 2024-05-09 | Regeneron Pharmaceuticals, Inc. | Methods of treating cancer with a combination of adoptive cell therapy and a targeted immunocytokine |
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| JP2023502712A (ja) | 2023-01-25 |
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| KR20220131895A (ko) | 2022-09-29 |
| EP4061835A1 (en) | 2022-09-28 |
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