CN116802738A - 为个体化癌症疫苗选择新抗原 - Google Patents
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Abstract
本文公开了用于从受试者的肿瘤选择一种或多种肿瘤特异性新抗原以用于个体化免疫原性组合物的方法。本文还公开了通过施用包含使用本文公开的所述方法选择的肿瘤特异性新抗原的免疫原性组合物来治疗有需要的受试者的癌症的方法。
Description
本申请要求2020年11月6日提交的美国临时申请号63/110,711的权益,所述美国临时申请的全部内容以引用的方式并入本文。
序列表的引用
本申请含有计算机可读形式的序列表。所述计算机可读形式以引用的方式并入本文。所述ASCII拷贝创建于2021年10月28日,命名为146401_091524_SL.txt并且大小为75,598字节。
背景技术
癌症是全球死亡的主要病因,占全部死亡的四分之一。Siegel等人,CA:A CancerJournal for Clinicians,68:7-30(2018)。2018年有1810万新的癌症病例和960万癌症相关死亡。Bray等人,CA:A Cancer Journal for Clinicians,68(6):394-424。有许多现有的癌症护理疗法标准,包括消融技术(例如,外科手术和辐射)和化学技术(例如,化疗剂)。遗憾的是,此类疗法往往伴随着严重的风险、毒副作用和极高成本以及不确定的疗效。
癌症免疫疗法(例如,癌症疫苗)已作为有前景的癌症治疗方式出现。癌症免疫疗法的目标是利用免疫系统来选择性地消灭癌症但不损害正常组织。传统的癌症疫苗通常靶向肿瘤相关抗原。正常组织中通常会存在肿瘤相关抗原,但在癌症中过度表达。然而,由于这些抗原经常存在于正常组织中,因此免疫耐受会阻止免疫激活。与标准护理治疗相比,针对肿瘤相关抗原的若干临床试验未能证明持久有益的效果。Li等人,Ann Oncol.,28(增刊12):xii11–xii17(2017)。
新抗原代表了癌症免疫疗法的有吸引力的靶标。新抗原是具有个体特异性的非自体蛋白质。新抗原来源于肿瘤细胞基因组中的随机体细胞突变并且不在正常细胞的表面上表达。Id.由于新抗原只在肿瘤细胞上表达并且因此不诱导中枢免疫耐受,靶向癌症新抗原的癌症疫苗具有潜在的优点,包括中枢免疫耐受减弱和安全性提高。Id.
癌症的突变形势很复杂并且肿瘤突变对于每个个体受试者来说通常是独特的。通过测序检测到的大多数体细胞突变均不会产生有效的新抗原。只有肿瘤DNA或肿瘤细胞中的一小部分的突变以足够的准确性转录、翻译并处理成肿瘤特异性新抗原以设计出可能有效的疫苗。此外,并不是所有的新抗原均是免疫原性的。事实上,T细胞自发辨识内源性新抗原的比例为约1%至2%。参见Karpanen等人,Front Immunol.,8:1718(2017)。此外,与生产新抗原疫苗相关联的成本和时间是巨大的。
因此,对用于免疫原性组合物的新抗原候选物进行高效而准确地预测、优先排序和选择仍是一项挑战。因此,对表征肿瘤基因组物质以识别新抗原、识别免疫系统靶向哪种新抗原并选择哪种可能适合于有效的免疫原性组合物的新抗原的综合方法的重大需求并未得到满足。
发明内容
本公开涉及一种从受试者的肿瘤选择一种或多种肿瘤特异性新抗原以用于受试者特异性免疫原性组合物的新型方法。本公开还涉及通过施用包含使用用于选择肿瘤特异性新抗原的新型方法选择的肿瘤特异性新抗原的免疫原性组合物来治疗有需要的受试者的癌症的方法,以及配制包含所选择的肿瘤特异性新抗原的免疫原性组合物的方法。所述方法通过从肿瘤获得序列数据来进行。使用所述序列数据获得表示一种或多种肿瘤特异性新抗原的多肽序列的数据。所述序列数据可为核苷酸序列数据、多肽序列数据、外显子组序列数据、转录物组序列数据或全基因组核苷酸序列数据。所述序列数据可为全外显子组序列数据、RNA序列数据、全基因组序列数据或其组合。所述序列数据可为全外显子组序列数据、RNA序列数据和全基因组序列数据的组合。
接着,将所述受试者的多肽序列和MHC分子输入到机器学习平台中。使用所述机器学习平台来识别肿瘤特异性新抗原是否是免疫原性的(例如,所述一种或多种肿瘤特异性新抗原将引发所述受试者的免疫应答)。基于这些预测,所述机器学习平台产生一种或多种肿瘤特异性新抗原将引发受试者的免疫应答的数值概率评分。
所述受试者的所述MCH分子可为MHC I类分子和/或MHC II类分子。编码一种或多种肿瘤特异性新抗原的所述多肽序列可能来自短多肽。短多肽通常呈递在MCH I类分子上。替代地,编码一种或多种肿瘤特异性新抗原的所述多肽序列可能来自长多肽。
所述受试者的所述免疫应答可包括将一种或多种肿瘤特异性新抗原呈递到肿瘤细胞表面、通过肿瘤细胞上的一种或多种MHC分子呈递一种或多种肿瘤特异性新抗原、或能够通过抗原呈递细胞将一种或多种肿瘤特异性新抗原呈递到T细胞。
所述受试者的所述免疫应答可为CD4+介导应答或CD8+介导应答。通常,所述免疫应答是CD4+介导应答或CD8+介导应答。
相对于较低的数值概率评分,肿瘤特异性新抗原具有较高的数值概率评分指示肿瘤特异性新抗原将在受试者体内引发更大的免疫应答。
还将一种或多种肿瘤特异性新抗原在肿瘤中的RNA表达(优选地mRNA表达)量化以进一步识别充分地表达以在受试者体内引发免疫应答的一种或多种肿瘤特异性新抗原。接着,可任选地表征肿瘤克隆以确保肿瘤特异性新抗原代表了整个肿瘤的足够的分数(例如,基因多样性)。在实施方案中,合适的肿瘤特异性新抗原可代表约1%的肿瘤。在其他情况下,合适的肿瘤特异性新抗原可代表约5%的肿瘤。
使用这些参数来计算肿瘤特异性新抗原评分以得到一种或多种肿瘤特异性新抗原评分。使用所述肿瘤特异性新抗原评分来选择适合于配制受试者特异性免疫原性组合物的肿瘤特异性新抗原。相对于较低的肿瘤特异性新抗原评分来说,较高的肿瘤特异性新抗原评分指示新抗原具有更强的免疫原性,并且因此更有可能诱导强烈的免疫应答并引发稳定的治疗效果(即,更有可能适合于免疫原性组合物)。在实施方案中,选择至少约10种肿瘤特异性新抗原来配制受试者特异性免疫原性组合物。在实施方案中,选择至少约20种肿瘤特异性新抗原来配制受试者特异性免疫原性组合物。
本文公开的方法还可包括测量一种或多种肿瘤特异性新抗原诱导正常组织的自身免疫应答的能力。相对于不会诱导自身免疫应答的肿瘤特异性新抗原来说,诱导正常组织的自身免疫应答的肿瘤特异性新抗原将具有更低的肿瘤特异性新抗原评分。将不会选择诱导自身免疫应答的肿瘤特异性新抗原来用于免疫原性组合物。
配制的免疫原性组合物可包含至少约10种肿瘤特异性新抗原或至少约20种肿瘤特异性新抗原。肿瘤特异性新抗原可由短多肽或长多肽编码。免疫原性组合物可包含核苷酸序列、多肽序列、RNA、DNA、细胞、质粒、载体、树突状细胞或合成长肽。免疫原性组合物还可包含佐剂。
本公开还涉及治疗有需要的受试者的癌症的方法,所述方法包括施用个体化免疫原性组合物,所述个体化免疫原性组合物包含使用本文描述的方法选择的一种或多种肿瘤特异性新抗原。本文公开的方法可适于治疗任何数目种癌症。肿瘤可来自黑色素瘤、乳腺癌、卵巢癌、前列腺癌、肾癌、胃癌、结肠癌、睾丸癌、头颈癌、胰腺癌、脑癌、B细胞淋巴瘤、急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病、T细胞淋巴细胞白血病、膀胱癌或肺癌。优选地,所述癌症是黑色素瘤、乳腺癌、肺癌和膀胱癌。
附图说明
图1是绘示用于选择一种或多种肿瘤特异性新抗原的方法的示意图。
图2是绘示对新一代测序数据(输入和输出)进行生物信息分析的示意性流程图。
图3是用于克隆性反卷积的模块的流程图。
具体实施方式
本公开涉及一种以高准确性为强效的个体化癌症免疫原性组合物(例如,受试者特异性免疫原性组合物)选择肿瘤特异性新抗原的新型方法。本公开还涉及通过施用包含使用用于选择肿瘤特异性新抗原的新型方法选择的肿瘤特异性新抗原的免疫原性组合物来治疗有需要的受试者的癌症的方法,以及配制包含所选择的肿瘤特异性新抗原的免疫原性组合物的方法。发明人已开发出如下一种方法:1)对为一个或多个新抗原的多肽序列编码的DNA和/或RNA进行测序;2)确定肿瘤特异性新抗原是否是免疫原性的(例如,新抗原是否可引发受试者的免疫应答);3)确定肿瘤是否表达了足以引发免疫应答的量的新抗原;以及4)任选地确定新抗原是否代表足够分数的肿瘤。当前可用方法依赖于MHC结合亲和力预测来对新抗原进行排名和选择或依赖于新抗原将被MHC分子呈递的概率。这些方法无法预测免疫原性。此外,当前方法不能够以高准确性评估所有这些因素。
所述方法开始于对从肿瘤活检获得的肿瘤特异性新抗原的多肽序列进行测序。接着,使用预测机器学习平台来识别受试者的MHC分子辨识了哪些新抗原。所述平台可确定肿瘤特异性新抗原是否是免疫原性的(例如,肿瘤特异性新抗原将引发受试者的免疫应答)。基于这些预测,机器学习平台产生肿瘤特异性新抗原将引发免疫应答的数值概率评分。还将肿瘤特异性新抗原的RNA表达(优选地,mRNA表达)量化以集中于大量表达以至于它们可能会引发免疫应答的肿瘤特异性新抗原。接着,任选地表征肿瘤克隆以确保肿瘤特异性新抗原代表了整个肿瘤的足够的基因多样性。使用这些参数来产生肿瘤特异性新抗原的肿瘤特异性新抗原评分。使用肿瘤特异性新抗原评分来选择适合于配制个体化疫苗的肿瘤特异性新抗原。相对于较低的肿瘤特异性新抗原评分来说,较高的肿瘤特异性新抗原评分指示新抗原具有更强的免疫原性,并且因此更有可能诱导强烈的免疫应答并引发稳定的治疗效果。
本公开中引用的所有公布和专利以引用的方式整体并入本文。在以引用的方式并入的材料与本说明书矛盾或不一致的程度上,本说明书将取代任何此类材料。本文中对任何参考文献的引用并不是承认此类参考文献是本公开的现有技术。当表达值的范围时,它包括使用在所述范围内的任何特定值的实施方案。此外,对范围内的所陈述值的引用包括该范围内的每个值。所有范围均包括其端点并且是可组合的。当通过使用先行词“约”将值表达为近似值时,应当理解,特定值形成另一个实施方案。对特定数值的引用至少包括该特定值,除非上下文另有明确规定。“或”的使用将意指“和/或”,除非其使用的特定上下文另有规定。
贯穿说明书和权利要求,使用与描述的各方面相关的各种术语。将赋予此类术语在本领域中的一般含义,除非另有指示。其他特殊定义的术语应被解释为与本文中所提供的定义一致。本领域技术人员通常能很好地理解并且普遍使用常规方法来采用本文描述或引用的技术和程序,例如像Sambrook等人的Molecular Cloning:A Laboratory Manual第4版(2012)Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY中所描述的广泛利用的分子克隆方法。在适当情况下,涉及使用可商购的套件和试剂的程序通常根据生产商定义的方案和条件来施行,除非另有指明。
如本文所用,单数形式“一(a/an)”和“所述”包括复数形式,除非上下文另有明确指示。术语“包括”、“诸如”等意图传达包含而非限制,除非另有特别指示。
除非另有指示,否则在一系列元素或范围前面的术语“至少”、“小于”和“约”或类似术语被理解为指代在该系列或范围内的每个元素。本领域技术人员将认识到或能够仅使用常规实验就确定本文描述的发明的特定实施方案的很多等效形式。所附权利要求意图囊括此类等效形式。
术语“癌症”指代受试者体内的细胞群体的特征在于不受控的增殖、永生、转移潜能、快速的生长和增殖速率和/或某些形态特征的生理状况。癌症经常可呈肿瘤或肿块的形式,但可单独存在于受试者体内,或者可作为独立细胞(诸如白血病或淋巴瘤细胞)在血流中循环。术语癌症包括所有类型的癌症和转移瘤,包括恶性血液肿瘤、实体肿瘤、肉瘤、癌以及其他实体和非实体肿瘤。癌症的实例包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤和白血病。此类癌症的更特定的实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤、乳腺癌(例如,三阴性乳腺癌、激素受体阳性乳腺癌)、骨肉瘤、黑色素瘤、结肠癌、结直肠癌、子宫内膜(例如,浆液)或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)以及各种类型的头颈癌。三阴性乳腺癌指代雌激素受体(ER)、孕酮受体(PR)和Her2/neu的基因表达为阴性的乳腺癌。激素受体阳性乳腺癌指代ER或PR中的至少一者为阳性并且Her2/neu(HER2)为阴性的乳腺癌。
如本文所用的术语“新抗原”指代例如经由肿瘤细胞的突变或对肿瘤细胞具有特异性的翻译后修饰而具有至少一处使其不同于对应的亲代抗原的改变的抗原。突变可包括移码、插入缺失、错义或无义取代、剪接位点改变、基因组重排或基因融合或产生新抗原的任何基因组表达改变。突变可包括剪接突变。对肿瘤细胞具有特异性的翻译后修饰可包括异常磷酸化。对肿瘤细胞具有特异性的翻译后修饰还可包括蛋白酶体产生的剪接抗原。参见Lipe等人,Science,354(6310):354:358(2016)。一般来说,点突变占约95%的肿瘤突变并且插入缺失和移码突变占剩余部分。参见Snyder等人,N Engl J Med.,371:2189–2199(2014)。
如本文所用,术语“肿瘤特异性新抗原”是存在于受试者的肿瘤细胞或组织中但不存在于受试者的正常细胞或组织中的新抗原。
如本文所用的术语“新一代测序”或“NGS”指代与传统方法(例如,Sanger测序)相比具有增大的通量的测序技术,它能够一次产生成千上万个序列读段。
如本文所用的术语“神经网络”指代用于分类或回归的机器学习模型,所述机器学习模型由以下项组成:先是多层线性变换,之后是逐元素非线性变换,它们通常经由随机梯度下降和反向传播来训练。
如本文所用的术语“受试者”指代任何动物,诸如任何哺乳动物,包括但不限于人类、非人灵长类动物、啮齿类动物等。在一些实施方案中,所述哺乳动物是小鼠。在一些实施方案中,所述哺乳动物是人类。
如本文所用的术语“肿瘤细胞”指代作为癌细胞或来源于癌细胞的任何细胞。术语“肿瘤细胞”还可指代表现出类似癌症的性质(例如,不受控的繁殖、抵抗抗生长信号、能够转移以及丧失经历程序性细胞死亡的能力)的细胞。
本文提供了对方法和所述方法的实践指南的附加描述。
Ⅰ.用于选择肿瘤特异性新抗原的方法
本文公开了从受试者的肿瘤选择适合于受试者特异性免疫原性组合物的肿瘤特异性新抗原的方法。合适的肿瘤特异性新抗原是可能呈递在肿瘤的细胞表面上、可能是免疫原性的、经预测以足以引发受试者的免疫应答的量表达并且任选地代表整个肿瘤的足够的多样性的肿瘤特异性新抗原。
从受试者的肿瘤选择一种或多种肿瘤特异性新抗原的第一步骤包括从所述肿瘤获得序列数据。使用所述序列数据获得表示一种或多种肿瘤特异性新抗原的多肽序列的数据。通常,表示一种或多种肿瘤特异性新抗原的多肽序列的序列数据是通过对肿瘤样本进行序列分析来确定。
所述序列数据可为外显子组序列数据、转录物组序列数据、全基因组核苷酸序列数据、核苷酸序列数据或多肽序列数据。所述序列数据可为全外显子组序列数据、RNA序列数据、全基因组序列数据或其组合。所述序列数据可为全外显子组序列数据、RNA序列数据和全基因组序列数据的组合。
本文描述的方法中可使用获得序列数据的各种方法。测序方法在本领域中是众所周知的并且包括但不限于基于PCR的方法,包括实时PC、全外显子组测序、深度测序、高通量测序或其组合。在一些实施方案中,根据例如Sambrook等人的Molecular Cloning:ALaboratory Manual第4版(2012)Cold Spring Harbor Laboratory Press,Cold SpringHarbor,NY中所描述的方法执行前述技术和程序。还参见Austell等人的CurrentProtocols in Molecular Biology,编著者Greene Publishing and Wiley-InterscienceNew York(1992)(定期更新)。
测序方法还可包括但不限于高通量测序、单细胞RNA测序、RNA测序、焦磷酸测序、合成法测序、单分子测序、纳米孔测序、半导体测序、合成法测序、连接法测序、杂交法测序、RNA-Sew(Illumina)、数字基因表达(Helicos)、新一代测序、单分子合成法测序(SMSS)(Helicos)、大规模并行测序、克隆单分子阵列(Solexa)、鸟枪法测序、Maxam-Hilbery或Sanger测序、全基因组测序、全外显子组测序、引物步移、使用PacBio、SOLid、Ion Torrent或纳米孔平台的测序和本领域已知的任何其他测序方法。本文采用的获得序列数据的测序方法优选地是高通量测序。高通量测序技术能够并行地对多个核酸分子进行测序,从而使得能够一次对数百万个核酸分子进行测序。参见Churko等人的Circ.Res.112(12):1613-1623(2013)。
在一些情况下,可执行全外显子组测序、RNA测序、全基因组测序或其组合。在一些情况下,可执行全外显子组测序、RNA测序、全基因组测序的组合。
在一些情况下,高通量测序可为新一代测序。存在使用不同测序技术(例如,使用可从Illumina(圣地亚哥,加利福尼亚州)获得的HiSeq或MiSeq仪器)的许多不同的新一代平台。可采用这些平台中的任一者来对本文公开的基因材料进行测序。新一代测序是基于对大量独立读段进行测序,每个读段表示核酸的10至1000个碱基之间的任意个碱基。合成法测序是新一代测序中使用的常见技术。一般来说,测序涉及将引物与模板杂交以形成模板/引物双链体,从而在存在带可检测标记的核苷酸的情况下在准许聚合酶以模板依赖性方式将核苷酸添加到引物的条件下使所述双链体与聚合酶接触。接着使用来自可检测标记的信号识别掺入的碱基,并依序重复所述步骤以确定模板中的核苷酸的线性次序。示例性可检测标记包括放射性标记、荧光标记、酶标记等。已知许多技术用于检测序列,诸如利用循环端测序的Illumina NextSeq平台。
一旦获得表示一种或多种肿瘤特异性新抗原的多肽序列的序列数据,就将所述序列数据连同受试者的MHC分子一起输入到机器学习平台中。所述机器学习平台产生数值概率评分,所述数值概率评分预测一种或多种肿瘤特异性新抗原是否是免疫原性的(例如,将引发受试者的免疫应答)。
MHC分子将肽转运并呈递在细胞表面上。所述MHC分子被分类为MHC I类分子和II类分子。MHC I类存在于身体的几乎所有细胞的表面上,包括大多数肿瘤细胞。MHC I类的蛋白质装载有通常来自于内源性蛋白质或细胞内存在的病原体的抗原,然后呈递到细胞毒性T淋巴细胞(即,CD8+)。MHC I类分子可包括HLA-A、HLA-B或HLA-C。MHC II类分子仅存在于树突状细胞、B淋巴细胞、巨噬细胞及其他抗原呈递细胞上。所述MHC II类分子主要将从外部抗原来源(即细胞之外)处理的肽呈递到辅助性T(Th)细胞(即,CD4+)。MHC II类分子可包括HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA及HLA-DRB1。在一些时候,MHC II类分子还可在癌细胞上表达。
可将MHC I类分子和/或MHC II类分子输入到机器学习平台中。通常,将MHC I类分子或MHC II类分子输入到机器学习平台中。在一些实施方案中,将MHC I类分子输入到机器学习平台中。在其他实施方案中,将MHC II类分子输入到机器学习平台中。
MHC I类分子结合到短肽。MHC I类分子可适应通常为约8个氨基酸至约10个氨基酸长度的肽。在实施方案中,编码一种或多种肿瘤特异性新抗原的序列数据是长度为约8个氨基酸至约10个氨基酸的短肽。MHC II类分子结合到长度更长的肽。MHC II类可适应通常为约13个氨基酸的长度至约25个氨基酸的长度的肽。在实施方案中,编码一种或多种肿瘤特异性新抗原的序列数据是长度为约13至25个氨基酸的长肽。
编码一种或多种肿瘤特异性新抗原的序列数据可为约5个氨基酸的长度、约6个氨基酸的长度、约7个氨基酸的长度、约8个氨基酸的长度、约9个氨基酸的长度、约10个氨基酸的长度、约11个氨基酸的长度、约12个氨基酸的长度、约13个氨基酸的长度、约14个氨基酸的长度、约15个氨基酸的长度、约16个氨基酸的长度、约17个氨基酸的长度、约18个氨基酸的长度、约19个氨基酸的长度、约20个氨基酸的长度、约21个氨基酸的长度、约22个氨基酸的长度、约23个氨基酸的长度、约24个氨基酸的长度、约25个氨基酸的长度、约26个氨基酸的长度、约27个氨基酸的长度、约28个氨基酸的长度、约29个氨基酸的长度或约30个氨基酸的长度。
机器学习平台预测一种或多种肿瘤特异性新抗原是免疫原性(例如,将引发免疫应答)的可能性。
免疫原性肿瘤特异性新抗原不在正常组织中表达。它们可由抗原呈递细胞呈递到CD4+和CD8+T细胞以产生免疫应答。在实施方案中,由一种或多种肿瘤特异性新抗原引发的受试者的免疫应答包括将一种或多种肿瘤特异性新抗原呈递到肿瘤细胞表面。更具体来说,由一种或多种肿瘤特异性新抗原引发的受试者的免疫应答包括通过肿瘤细胞上的一个或多个MHC分子呈递一种或多种肿瘤特异性新抗原。可预期的是,由一种或多种肿瘤特异性新抗原引发的免疫应答是T细胞介导应答。由一种或多种肿瘤特异性新抗原引发的受试者的免疫应答可涉及能够通过抗原呈递细胞(诸如树突状细胞)将一种或多种肿瘤特异性新抗原呈递到T细胞。优选地,所述一种或多种肿瘤特异性新抗原能够激活CD8+T细胞和/或CD4+T细胞。
在实施方案中,机器学习平台可预测一种或多种肿瘤特异性新抗原将激活CD8+T细胞的可能性。在实施方案中,机器学习平台可预测一种或多种肿瘤特异性新抗原将激活CD4+T细胞的可能性。在一些情况下,机器学习平台可预测一种或多种肿瘤特异性新抗原可引发的抗体滴度。在其他情况下,机器学习平台可预测一种或多种肿瘤特异性新抗原进行CD8+激活的频率。
机器学习平台可包括根据训练数据训练的模型。所述训练数据可从一系列不同的受试者获得。训练数据可包括来源于健康受试者以及患有癌症的受试者的数据。训练数据可包括可用于产生指示一种或多种肿瘤特异性新抗原是否将引发受试者的免疫应答的概率评分的各种数据。示例性训练数据可包括表示来源于正常组织和/或细胞的核苷酸或多肽序列的数据、表示来源于肿瘤组织的核苷酸或多肽序列的数据、表示来自正常组织和肿瘤组织的MHC多肽组序列的数据、肽MHC结合亲和力测量结果或其组合。所述参考数据还可包括质谱数据、DNA测序数据、RNA测序数据、来自健康受试者和患有癌症的受试者的临床数据、细胞因子谱数据、T细胞毒性测定数据、肽MHC单体或多聚体数据以及单等位基因细胞系的蛋白质组数据,所述单等位基因细胞系被工程化为表达预定MHC等位基因,随后暴露于合成蛋白质、正常人类细胞系和肿瘤人类细胞系、新鲜和冷冻的初始样本以及T细胞测定。
机器学习平台可为监督学习平台、无监督学习平台或半监督学习平台。机器学习平台可使用基于序列的方法来产生一种或多种肿瘤特异性新抗原可引发免疫应答(例如,将诱导高或低抗体应答或CD8+应答)的数值概率。基于序列的预测可包括监督机器学习模块,所述监督机器学习模块包括人工神经网络(例如,深度人工神经网络或其他形式)、支持向量机、K最近邻、逻辑多网络约束回归(LogMiNeR)、回归树、随机森林、adaboost、XGBoost或隐马尔可夫模型。这些平台需要包括已知的MHC结合肽的训练数据集。
已采用许多预测程序来预测肿瘤特异性新抗原是否可呈递在MHC分子上并引发免疫应答。示例性预测程序包括例如HLAminer(Warren等人,Genome Med.,4:95(2012);HLAtype predicted by orienting the assembly of shotgun sequence data andcomparing it with the reference allele sequence database)、VariantEffectPredictor Tool(McLaren等人,Genome Biol.,17:122(2016))、NetMHCpan(Andreatta等人,Bioinformatics.,32:511–517(2016);sequence comparison method based onartificial neural network,and predict the affinit y of peptide-MHC-I typemolecular)、UCSC browser(Kent等人,Genome Res.,12:996–1006(2002))、CloudNeopipeline(Bais等人,Bioinformatics,33:3110–2(2017))、OptiType(Szolek等人,Bioinfor matics,30:3310–316(2014))、ATHLATES(Liu C等人,Nucleic Ac ids Res.41:e142(2013))、pVAC-Seq(Hundal等人,Genome Med.8:11(2016))、MuPeXI(Bjerregaard等人,Cancer Immunol Immunot her.,66:1123–30(2017))、Strelka(Saunders等人,Bioinformatics.28:1811–7(2012))、Strelka2(Kim等人,Nat Methods.2018;15:591–4.)、VarScan2(Koboldt等人,Genome Res.,22:568–76(2012))、Somati cseq(Fang L等人,Genome Biol.,16:197(2015))、SMMPMBEC(Kim等人,BMC Bioinformatics.,10:394(2009))、NeoPredPipe(Sche nck RO,BMC Bioinformatics.,20:264(2019))、Weka(Witten等人,Data mining:practical machine-learning tools and techniques.第4版,Elsevier,ISBN:97801280435578(eBook)(2017))或Orange(Demsar等人,Orange:DataMining Toolbox in Python.,J.Mach Learn Re s.,14:2349-2353(2013))。可采用任何已知的预测程序作为机器学习平台来产生指示新抗原是否将引发免疫应答的数值概率评分。
根据所采用的机器学习平台,可应用附加的过滤器来对肿瘤特异性新抗原候选物进行优先排序,包括:消除假定(Riken)蛋白质;使用抗原处理算法来消除不可能通过组成性蛋白酶体或免疫蛋白酶体以蛋白水解方式产生的表位以及在新抗原具有比对应的野生型序列更高的预测结合亲和力的情况下对所述新抗原进行优先排序。
所述数值概率评分可为0与1之间的数字。在实施方案中,所述数值概率评分可为数字0、0.0001、0.0002、0.0003、0.0004、0.0005、0.0006、0.0007、0.0008、0.0009、0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.20、0.30、0.40、0.50、0.60、0.70、0.80、0.90或1。相对于较低的数值概率评分来说,具有较高的数值概率评分的肿瘤特异性新抗原指示肿瘤特异性新抗原将在受试者体内引发更大的免疫应答,并且因此有可能是适合于免疫原性组合物的候选物。举例来说,数值概率评分为1的肿瘤特异性新抗原可能会在受试者体内引发比数值概率评分为0.05的肿瘤特异性新抗原更大的免疫应答。类似地,数值概率评分为0.5的肿瘤特异性新抗原可能会在受试者体内引发比数值概率评分为0.1的肿瘤特异性新抗原更大的免疫应答。
相对于较低的数值概率评分来说,优选较高的数值概率评分。优选地,肿瘤特异性新抗原具有至少0.8、0.81、0.82、0.83、0.84、0.85、0.86、0.87、0.88、0.89、0.9、0.95、0.96、0.97、0.98、0.99或1的数值概率评分指示可能会在受试者体内引发免疫应答。
虽然较高的数值概率评分是优选的,但较低的数值概率评分仍可能指示肿瘤特异性新抗原能够引发足够的免疫应答,使得所述肿瘤特异性新抗原有可能是合适的候选物。
在各情况下,本文描述的机器学习平台还可预测一种或多种肿瘤特异性新抗原将由肿瘤细胞上的MHC分子呈递的可能性。机器学习平台可预测一种或多种肿瘤特异性新抗原将由MHC I类分子或MHC II类分子呈递的可能性。
用于选择一种或多种肿瘤特异性新抗原的方法还可包括以下步骤:经由计算机模拟测量一种或多种肿瘤特异性新抗原结合到受试者体内MHC分子的亲和力。肿瘤特异性新抗原与MHC分子的结合亲和力小于约1000nM指示一种或多种肿瘤特异性新抗原可适合于免疫原性组合物。肿瘤特异性新抗原与MHC分子的结合亲和力小于约500nM、小于约400nM、小于约300nM、小于约200nM、小于约100nM、小于约50nM可指示一种或多种肿瘤特异性新抗原可适合于免疫原性组合物。一种或多种肿瘤特异性新抗原结合到受试者体内MHC分子的亲和力可预测肿瘤特异性新抗原的免疫原性。替代地,中位数亲和力可为预测肿瘤特异性新抗原的免疫原性的有效方式。可使用表位预测算法(诸如NetMHCpan、ANN、SMM和SMMPMBEC)计算中位数亲和力。
一种或多种肿瘤特异性新抗原的RNA表达也被量化。将一种或多种肿瘤特异性新抗原的RNA表达量化以识别将引发受试者的免疫应答的一种或多种新抗原。存在用于测量RNA表达的各种方法。已知的可测量RNA表达的技术包括RNA-seq和原位杂交(例如,FISH)、Northern印迹法、DNA微阵列、叠瓦式阵列和定量聚合酶链反应(qPCR)。可使用本领域已知的其他技术来将RNA表达量化。RNA可为信使RNA(mRNA)、短干扰RNA(siRNA)、微RNA(miRNA)、环状RNA(circRNA)、转移RNA(tRNA)、核糖体RNA(rRNA)、小核仁RNA(snRNA)、Piwi相互作用RNA(piRNA)、长非编码RNA(长ncRNA)、次基因组RNA(sgRNA)、来自整合病毒或非整合病毒的RNA或任何其他RNA。优选地,测量mRNA表达。
本文公开的方法可任选地包括对肿瘤克隆进行测序。对肿瘤克隆进行测序以识别代表足够分数的肿瘤的一种或多种肿瘤特异性新抗原。可例如使用本文公开的测序技术并且使用本领域技术人员已知的其他已知测序技术来对肿瘤克隆进行测序。
在实施方案中,肿瘤特异性新抗原在整个肿瘤中具有至少约1%、至少约2%、至少约3%、至少约4%、至少约5%、至少约6%、至少约7%、至少约8%、至少约9%、至少约10%、至少约15%、至少约20%、至少约25%或至少约30%的肿瘤克隆分数指示肿瘤特异性新抗原代表了足够分数的肿瘤。肿瘤的足够分数指示肿瘤特异性新抗原提供了整个肿瘤的足够的基因多样性。
所述方法还可包括测量一种或多种肿瘤特异性新抗原诱导正常组织的自身免疫应答的能力。可预期的是,具有与正常抗原类似的序列的肿瘤特异性新抗原可诱导正常组织的自身免疫应答。举例来说,至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%类似于正常抗原的肿瘤特异性新抗原可诱导自身免疫应答。经预测会诱导自身免疫应答的肿瘤特异性新抗原不会被优先考虑用于免疫原性组合物。通常不会选择经预测会诱导自身免疫应答的肿瘤特异性新抗原来用于免疫原性组合物。所述方法还可包括测量一种或多种肿瘤特异性新抗原激起免疫耐受的能力。经预测会激起免疫耐受的肿瘤特异性新抗原不会被优先考虑用于免疫原性组合物。经预测会激起免疫耐受的肿瘤特异性新抗原不会被优先考虑用于免疫原性组合物。
基于通过获得一种或多种肿瘤特异性新抗原将引发受试者的免疫应答的数值概率评分和一种或多种肿瘤特异性新抗原的RNA表达水平来产生的数据而计算肿瘤特异性评分。除了用于计算肿瘤特异性评分的以上计算之外,可任选地包括整个肿瘤的肿瘤克隆分数。具有高的数值概率评分(例如,肿瘤特异性新抗原是免疫原性的)并具有高水平的RNA表达的肿瘤特异性新抗原将被优先考虑。相比之下,经预测会诱导自身免疫应答的肿瘤特异性抗原相对于不会诱导免疫应答的肿瘤特异性新抗原来说将具有更低的肿瘤特异性新抗原评分并且不会被选择来包含在免疫原性组合物中。具有高的数值概率评分(例如,肿瘤特异性新抗原是免疫原性的)、具有高的RNA表达水平并提供整个肿瘤的足够的肿瘤克隆分数的肿瘤特异性新抗原将被优先考虑。
与具有高的数值概率评分、高的RNA表达水平并任选地提供整个肿瘤的足够的肿瘤克隆分数的肿瘤特异性新抗原相比,具有高的数值概率评分(例如,肿瘤特异性新抗原是免疫原性的)并任选地提供整个肿瘤的足够的肿瘤克隆分数但具有低的RNA表达水平的肿瘤特异性新抗原将具有更低的肿瘤特异性评分。在此实例中,具有较低的肿瘤特异性评分的肿瘤特异性新抗原不会优先于具有较高的肿瘤特异性评分的肿瘤特异性新抗原。与具有高的数值概率评分、高的RNA表达水平并提供整个肿瘤的足够的肿瘤克隆分数的肿瘤特异性新抗原相比,具有高的数值概率评分(例如,肿瘤特异性新抗原是免疫原性的)并具有足以引发免疫应答的RNA表达水平但不提供整个肿瘤的足够的肿瘤克隆分数的肿瘤特异性新抗原将具有更低的肿瘤特异性评分。与具有高的数值概率评分、高的RNA表达水平并提供整个肿瘤的足够的肿瘤分数的肿瘤特异性新抗原相比,具有足以引发免疫应答的RNA表达水平、提供整个肿瘤的足够的肿瘤分数但具有低的数值概率评分的肿瘤特异性新抗原将具有更低的肿瘤特异性评分。
最后,基于肿瘤特异性评分而选择一种或多种肿瘤特异性新抗原来用于配制受试者特异性免疫原性组合物。在实施方案中,选择至少约1、至少约2、至少约3、至少约4、至少约5、至少约6、至少约7、至少约8、至少约9、至少约10、至少约11、至少约12、至少约13、至少约14、至少约15、至少约16、至少约17、至少约18、至少约19、至少约20、至少约25、至少约30、至少约35、至少约40、至少约50种或更多种肿瘤特异性新抗原来用于免疫原性组合物。通常,选择至少约10种肿瘤特异性新抗原。在其他情况下,选择至少约20种肿瘤特异性新抗原。
Ⅱ.治疗方法
本公开还涉及治疗有需要的受试者的癌症的方法,所述方法包括施用个体化免疫原性组合物,所述个体化免疫原性组合物包含使用本文描述的方法选择的一种或多种肿瘤特异性新抗原。
癌症可为任何实体肿瘤或任何血液肿瘤。本文公开的方法优选地适合于实体肿瘤。肿瘤可为原发性肿瘤(例如,位于肿瘤首次出现的最初部位处的肿瘤)。实体肿瘤可包括但不限于乳腺癌肿瘤、卵巢癌肿瘤、前列腺癌肿瘤、肺癌肿瘤、肾癌肿瘤、胃癌肿瘤、睾丸癌肿瘤、头颈癌肿瘤、胰腺癌肿瘤、脑癌肿瘤和黑色素瘤肿瘤。血液肿瘤可包括但不限于来自淋巴瘤(例如,B细胞淋巴瘤)和白血病(例如,急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病和T细胞淋巴细胞白血病)的肿瘤。
本文公开的方法可用于任何合适的癌性肿瘤,包括恶性血液肿瘤、实体肿瘤、肉瘤、癌以及其他实体和非实体肿瘤。说明性的合适的癌症包括例如急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、肾上腺皮质癌、肛门癌、阑尾癌、星形细胞瘤、基底细胞癌、脑肿瘤、胆管癌、膀胱癌、骨癌、乳腺癌、支气管肿瘤、原发灶不明癌、心脏肿瘤、宫颈癌、脊索瘤、结肠癌、结直肠癌症、颅咽管瘤、导管癌、胚胎瘤、子宫内膜癌、室管膜瘤、食管癌、嗅神经母细胞瘤、纤维组织细胞瘤、尤因肉瘤、眼癌、生殖细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤、妊娠滋养细胞疾病、胶质瘤、头颈癌、肝细胞癌、组织细胞增多症、霍奇金淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波西肉瘤、肾癌、朗格汉斯细胞组织细胞增生症、喉癌、唇癌和口腔癌、肝癌、小叶原位癌、肺癌、巨球蛋白血症、恶性纤维组织细胞瘤、黑色素瘤、梅克尔细胞癌、间皮瘤、隐匿原发的转移性鳞状颈癌、牵涉NUT基因的中线道癌、口癌、多发性内分泌瘤病综合征、多发性骨髓瘤、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性肿瘤、鼻腔和鼻旁窦癌、鼻咽癌、成神经细胞瘤、非小细胞肺癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、乳头瘤病、副神经节瘤、甲状旁腺癌、阴茎癌、咽喉癌、嗜铬细胞瘤、垂体瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂和输尿管癌、视网膜母细胞瘤、横纹肌样肿瘤、唾液腺癌、塞扎里综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、骨髓瘤、胃癌、T细胞淋巴瘤、畸胎瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、尿道癌、子宫癌、阴道癌、外阴癌和肾母细胞瘤。优选地,癌症是黑色素瘤、乳腺癌、卵巢癌、前列腺癌、肾癌、胃癌、结肠癌、睾丸癌、头颈癌、胰腺癌、脑癌、B细胞淋巴瘤、急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病、T细胞淋巴细胞白血病、膀胱癌或肺癌。特别关注黑色素瘤。还特别关注乳腺癌、肺癌和膀胱癌。
免疫原性组合物刺激受试者的免疫系统,尤其是特异性CD8+T细胞或CD4+T细胞的应答。由CD8+细胞和辅助性T CD4+细胞产生的干扰素γ调节PD-L1的表达。当受到T细胞攻击时,肿瘤细胞中的PD-L1表达上调。因此,肿瘤疫苗可诱导特异性T细胞的产生并且同时上调PD-L1的表达,这可限制疫原性组合物的疗效。此外,虽然激活了免疫系统,但T细胞表面报道基因CTLA-4的表达对应地增加,其与抗原呈递细胞上的配体B7–1/B7–2结合并且发挥免疫抑制效果。因此,在一些情况下,还可对受试者施用抗免疫抑制或免疫刺激物,诸如检查点抑制剂。检查点抑制剂可包括但不限于抗CTL4-A抗体、抗PD-1抗体和抗PD-L1抗体。这些检查点抑制剂结合到T细胞的免疫检查点蛋白以消除肿瘤细胞对T细胞功能的抑制。抗体对CTLA-4或PD-L1的阻断可增强患者体内对癌细胞的免疫应答。已经显示,CTLA-4在遵循疫苗接种方案时是有效的。
可对已被诊断出癌症、已患有癌症、患有复发性癌症(即,复发症)或有患癌风险的受试者施用包含一种或多种肿瘤特异性新抗原的免疫原性组合物。可向对其他形式的癌症治疗(例如,化疗、免疫疗法或辐射)具有抗性的受试者施用包含一种或多种肿瘤特异性新抗原的免疫原性组合物。可在其他标准的癌症护理疗法(例如,化疗、免疫疗法或辐射)之前对受试者施用包含一种或多种肿瘤特异性新抗原的免疫原性组合物。可与其他标准的癌症护理疗法(例如,化疗、免疫疗法或辐射)同时地、在其他标准的癌症护理疗法之后或与其他标准的癌症护理疗法组合地对受试者施用包含一种或多种肿瘤特异性新抗原的免疫原性组合物。
受试者可为人类、狗、猫、马或需要肿瘤特异性应答的任何动物。
以足以引发对肿瘤特异性新抗原的免疫应答并消灭或至少部分地遏制症状和/或并发症的量对受试者施用免疫原性组合物。在实施方案中,免疫原性组合物可提供长效免疫应答。可通过对受试者施用加强剂量的免疫原性组合物来建立长效免疫应答。可通过对受试者施用加强剂量来延长对免疫原性组合物的免疫应答。在实施方案中,可施用至少一个、至少两个、至少三个或更多个加强剂量以减轻癌症。第一加强剂量可将免疫应答增加至少50%、至少100%、至少200%、至少300%、至少400%、至少500%或至少1000%。第二加强剂量可将免疫应答增加至少50%、至少100%、至少200%、至少300%、至少400%、至少500%或至少1000%。第三加强剂量可将免疫应答增加至少50%、至少100%、至少200%、至少300%、至少400%、至少500%或至少1000%。
足以引发免疫应答的量被定义为“治疗有效剂量”。有效用于这种用途的量将取决于例如组合物、施用方式、正在治疗的疾病的阶段和严重性、患者的体重和一般健康状况以及处方医生的判断。应牢记,通常可在严重疾病状态下(即威胁生命或可能威胁生命的情况,尤其是当癌症已转移时)采用免疫原性组合物。在此类情况下,鉴于外来物质最少化以及新抗原的相对无毒性质,治疗医生可能并且可能感到需要施用明显超量的这些免疫原性组合物。
可对受试者单独施用或与其他治疗剂组合地施用包含一种或多种肿瘤特异性新抗原的免疫原性组合物。治疗剂可为例如化疗剂、辐射或免疫疗法。可针对特定癌症施用任何合适的治疗处理。示例性化疗剂包括但不限于:阿地白介素、六甲蜜胺、氨磷汀、天冬酰胺酶、博来霉素、卡培他滨、卡铂、卡莫司汀、克拉屈滨、西沙必利、顺铂、环磷酰胺、阿糖胞苷、达卡巴嗪(DTIC)、更生霉素、多西他赛、阿霉素、屈大麻酚、α促红细胞生成素、依托泊苷、非格司亭、氟达拉滨、氟尿嘧啶、吉西他滨、格拉司琼、羟基脲、伊达比星、异环磷酰胺、干扰素α、伊立替康、兰索拉唑、左旋咪唑、亚叶酸、甲地孕酮、美司钠、甲氨蝶呤、胃复安、丝裂霉素、米托坦、米托蒽醌、奥美拉唑、昂丹司琼、紫杉醇毛果芸香碱、丙氯拉嗪、利妥昔单抗、它莫西芬、他克唑、盐酸拓扑替康、曲妥珠单抗、长春花碱、长春新碱和酒石酸长春瑞滨。可对受试者施用小分子或靶向疗法(例如,激酶抑制剂)。还可对受试者施用抗CTLA抗体或抗PD-1抗体或抗PD-L1抗体。抗体对CTLA-4或PD-L1的阻断可增强患者体内对癌细胞的免疫应答。
Ⅲ.免疫原性组合物
本发明还涉及包含使用本文描述的方法选择的一种或多种肿瘤特异性抗原的个体化(即,受试者特异性)免疫原性组合物(例如,癌症疫苗)。此类免疫原性组合物可根据本领域中的标准程序来配制。所述免疫原性组合物能够提高特异性免疫应答。
免疫原性组合物可被配制成使得肿瘤特异性新抗原的选择和数目根据受试者的特定癌症进行调整。举例来说,肿瘤特异性新抗原的选择可取决于特定癌症类型、癌症状态、受试者的免疫状态和受试者的MHC类型。
免疫原性组合物可包含至少1、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、31、32、33、34、35、37、37、38、39、40、41、42、43、44、45、46、47、48、49、50种或更多种肿瘤特异性新抗原。免疫原性组合物可含有约10至20种肿瘤特异性新抗原、约10至30种肿瘤特异性新抗原,约10至40种肿瘤特异性新抗原、约10至50种肿瘤特异性新抗原、约10至60种肿瘤特异性新抗原、约10至70种肿瘤特异性新抗原、约10至80种肿瘤特异性新抗原、约10至90种肿瘤特异性新抗原或约10至100种肿瘤特异性新抗原。优选地,免疫原性组合物包含至少约10种肿瘤特异性新抗原。还优选的是包含至少约20种肿瘤特异性新抗原的免疫原性组合物。
免疫原性组合物还可包含天然抗原或合成抗原。所述天然抗原或合成抗原可增加免疫应答。示例性天然抗原或合成抗原包括但不限于泛DR表位(PADRE)和破伤风毒素抗原。
免疫原性组合物可呈任何形式,例如合成长肽、RNA、DNA、细胞、树突状细胞、核苷酸序列、多肽序列、质粒或载体。
肿瘤特异性新抗原还可包含在基于病毒载体的疫苗平台中,诸如牛痘、鸡痘、自我复制α病毒(alphavim)、马拉巴病毒(marabavirus)、腺病毒(参见例如Tatsis等人,Molecular Therapy,10:616-629(2004))或慢病毒,包括但不限于第二代、第三代或混合的第二代/第三代慢病毒和被设计成靶向特定细胞类型或受体的任一代重组慢病毒(参见例如Hu等人,Immunol Rev.,239(1):45-61(2011);Sakma等人,Biochem J.,443(3):603-18(2012))。根据对上述基于病毒载体的疫苗平台的封装能力,这种方法可递送编码一种或多种肿瘤特异性新抗原肽的一种或多种核苷酸序列。序列可由非突变序列侧接,可被接头分开或可在前面具有靶向亚细胞区室的一个或多个序列(参见例如Gros等人,Nat Med.,22(4):433-8(2016);Stronen等人,Science.,352(6291):1337-1341(2016);Lu等人,ClinCancer Res.,20(13):3401-3410(2014))。在被引入宿主之后,被感染的细胞表达一种或多种肿瘤特异性新抗原,并且由此引发宿主对一种或多种肿瘤特异性新抗原的免疫(例如,CD8+或CD4+)应答。例如美国专利号4,722,848中描述了可用于免疫方案的牛痘载体和方法。另一种载体是BCG(卡介苗)。Stover等人(Nature 351:456-460(1991))中描述了BCG载体。还可使用可用于治疗性施用或免疫接种新抗原的各种各样的其他疫苗载体,根据本文的描述,这对于本领域技术人员来说将是显而易见的。
根据特定受试者的个人需求,免疫原性组合物可含有个体化组分。
本文描述的免疫原性组合物还可包含佐剂。佐剂是混合到免疫原性组合物中会增加或者另外增强和/或加强对肿瘤特异性新抗原的免疫应答,但当它单独施用时不会产生对肿瘤特异性新抗原的免疫应答的任何物质。佐剂优选地产生对新抗原的免疫应答,而不会产生过敏反应或其他不良反应。本文中预期,可在施用免疫原性组合物之前、与之一起、同时地或之后施用免疫原性组合物。
佐剂可通过几种机制来增强免疫应答,包括例如淋巴细胞募集、刺激B和/或T细胞以及刺激巨噬细胞。当本发明的免疫原性组合物包含佐剂或与一种或多种佐剂一起施用时,可使用的佐剂包括但不限于矿物盐佐剂或矿物盐凝胶佐剂、粒状佐剂、微粒型佐剂、黏膜佐剂和免疫刺激佐剂。佐剂的实例包括但不限于铝盐(alum)(诸如氢氧化铝、磷酸铝和硫酸铝)、3脱-O-酰化单磷酰脂质A(MPL)(参见GB 2220211)、MF59(Novartis)、AS03(GlaxoSmithKline)、AS04(Glaxo SmithKline)、聚山梨酯80(Tween 80;ICL Americas,Inc.)、咪唑并吡啶化合物(参见作为国际公布号WO2007/109812公布的国际申请号PCT/US2007/064857)、咪唑并喹喔啉化合物(参见作为国际公布号WO2007/109813公布的国际申请号PCT/US2007/064858)以及皂苷,诸如QS21(参见Kensil等人,Vaccine Design:The Subunitand Adjuvant Approach(编著者Powell&Newman,Plenum Press,NY,1995);美国专利号5,057,540)。在一些实施方案中,佐剂是弗氏佐剂(完全或不完全)。其他佐剂是任选地与免疫刺激剂(诸如单磷酰脂质A)组合的水包油乳液(诸如角鲨烯或花生油)(参见Stoute等人,N.Engl.J.Med.336,86-91(1997))。
还报道了CpG免疫刺激性寡核苷酸在疫苗环境中增强
佐剂的效果。还可使用其他TLR结合分子(诸如RNA结合TLR 7、TLR 8和/或TLR 9)。
有用佐剂的其他实例包括但不限于化学修饰的CpG(例如,CpR、Idera)、聚(I:C)(例如polyi:CI2U)、聚ICLC、非CpG细菌DNA或RNA以及免疫活性小分子和抗体,诸如环磷酰胺、舒尼米布(sunitmib)、贝伐珠单抗、西乐葆(赛来昔布)、NCX-4016、西地那非、他达拉非、伐地那非、索拉非尼、XL-999、CP-547632、帕唑帕尼(pazopamb)、ZD2171、AZD2171、伊匹单抗、替西木单抗和SC58175,它们可在治疗上和/或作为佐剂起作用。在实施方案中,聚ICLC是优选的佐剂。
免疫原性组合物可单独或连同药学上可接受的载体一起包含本文描述的一种或多种肿瘤特异性新抗原。可使用一种或多种肿瘤特异性新抗原的悬浮液或分散液,尤其是等渗水相悬浮液、分散液或两亲溶剂(ampgipgilic solvent)。免疫原性组合物可为无菌的和/或可包含赋形剂(例如,防腐剂、稳定剂、润湿剂和/或乳化剂、增溶剂、调节渗透压的盐和/或缓冲液),并且以原本已知的方式制备,例如通过常规的分散和悬浮工艺来制备。在某些实施方案中,此类分散液或悬浮液可包含黏度调节剂。悬浮液或分散液保持在大约2℃至8℃的温度,或优先地为了长时间储存可冷冻,然后在使用前不久解冻。为了注射,疫苗或免疫原性制剂可配制在水相溶液中,优选地配制在生理上相容的缓冲液中,诸如汉克斯溶液、林格氏溶液或生理盐水缓冲液。所述溶液可含有配方剂,诸如悬浮剂、稳定剂和/或分散剂。
在某些实施方案中,本文描述的组合物另外包括防腐剂,例如汞衍生物硫柳汞。在特定实施方案中,本文描述的药用组合物包含0.001%至0.01%的硫柳汞。在其他实施方案中,本文描述的药用组合物不包含防腐剂。
赋形剂可独立于佐剂存在。赋形剂的功能可为例如增大免疫原性组合物的分子量、提高活性或免疫原性、赋予稳定性、提高生物活性或延长血清半衰期。赋形剂还可用于辅助将一种或多种肿瘤特异性新抗原呈递到T细胞(例如,CD4+或CD8+T细胞)。赋形剂可为载体蛋白质,诸如但不限于钥孔虫戚血蓝蛋白、血清蛋白诸如运铁蛋白、牛血清白蛋白、人类血清白蛋白、甲状腺球蛋白或卵清蛋白、免疫球蛋白或激素,诸如胰岛素或棕榈酸。对于人类的免疫来说,载体通常是人类可接受并且安全的生理上可接受的载体。替代地,所述载体可为葡聚糖,例如琼脂糖。
细胞毒性T细胞辨识结合到MHC分子的肽形式的抗原,而非完整的外源抗原本身。MHC分子本身位于抗原呈递细胞的细胞表面处。因此,如果存在肽抗原、MHC分子和抗原呈递细胞(APC)的三聚体复合体,则可激活细胞毒性T细胞。如果不仅使用一种或多种肿瘤特异性抗原激活细胞毒性T细胞,而且如果添加具有相应MHC分子的附加APC,则可增强免疫应答。因此,在一些实施方案中,免疫原性组合物另外含有至少一种APC。
免疫原性组合物可包含可接受的载体(例如,水相载体)。可使用各种水相载体,例如水、缓冲水、0.9%盐水、0.3%甘氨酸、透明质酸等。可通过常规的众所周知的灭菌技术对这些组合物进行灭菌,或可进行无菌过滤。所得的水相溶液可原样封装使用或冻干,冻干制剂在施用之前与无菌溶液组合。组合物可视需要含有在药学上可接受的辅助物质以接近生理条件,诸如pH调节和缓冲剂、张力调节剂、润湿剂等,例如乙酸钠、乳酸钠、氯化钠、氯化钾、氯化钙、山梨醇酐月桂酸酯、油酸三乙醇胺等。
还可经由脂质体施用新抗原,所述脂质体使新抗原靶向特定细胞组织,诸如淋巴组织。脂质体还可用于延长半衰期。脂质体包括乳液、泡沫、胶束、不溶性单层、液晶、磷脂分散液、片状层等。待递送的新抗原作为脂质体的一部分单独地掺入或与结合到(例如)淋巴样细胞当中普遍存在的受体的分子(诸如结合到CD45抗原的单克隆抗体)一起,或者与其他治疗或免疫原性组合物一起掺入在这些制剂中。因此,可将填充有所需新抗原的脂质体引导到淋巴样细胞的位点,其中脂质体接着递送所选择的免疫原性组合物。脂质体可由标准的囊泡形成脂质形成,所述囊泡形成脂质通常包括中性和带负电的磷脂以及固醇,诸如胆固醇。通常通过考虑例如脂质体大小、血流中脂质体的酸不稳定性和稳定性来指导脂质的选择。各种方法均可用于制备脂质体,如在例如Szoka等人An.Rev.Biophys.Bioeng.9;467(1980),美国专利号4,235,871、4,501,728、4,501,728、4,837,028和5,019,369中所描述。
为了靶向免疫细胞,待掺入到脂质体中的配体可包括例如对所需免疫系统细胞的细胞表面决定簇具有特异性的抗体或其片段。可以一定剂量静脉地、局部地、局部性地等施用脂质体悬浮液,所述剂量尤其根据施用方式、所递送的肽和正在治疗的疾病的阶段而变化。
作为靶向免疫细胞的替代方法,可将免疫原性组合物的组分(诸如抗原(即,肿瘤特异性新抗原)、配体或佐剂(例如,TLR))掺入到聚(乳酸-羟基乙酸共聚物)微球中。聚(乳酸-羟基乙酸共聚物)微球可作为内体递送装置包埋免疫原性组合物的组分。
为了达到治疗或免疫目的,还可对患者施用编码本文描述的肿瘤特异性新抗原的核酸。可便利地使用许多方法来将核酸递送给患者。举例来说,核酸可作为“裸DNA”被直接递送。例如Wolff等人Science247:1465-1468(1990)以及美国专利号5,580,859和5,589,466中描述了这种方法。还可使用例如美国专利号5,204,253中所描述的弹道递送施用核酸。可施用仅由DNA构成的颗粒。替代地,DNA可附着到颗粒,诸如金颗粒。用于递送核酸序列的方法可包括病毒载体、mRNA载体和DNA载体,同时进行或不进行电穿孔。还可将核酸与阳离子化合物(诸如阳离子脂质)复合来进行递送。
可通过(包括但不限于)口腔、皮内、瘤内、肌内、腹膜内、静脉、局部、皮下、经皮、鼻内和吸入途径,并经由划痕(例如使用分叉针划破皮肤表层)来将本文提供的免疫原性组合物施用于受试者。可在肿瘤部位处施用免疫原性组合物以诱导对肿瘤的局部免疫应答。
一种或多种肿瘤特异性新抗原的剂量可取决于组合物的类型并且取决于受试者的年龄、体重、体表面积、个体条件、个体药物代谢动力学数据和施用模式。
本文还公开了一种生产免疫原性组合物的方法,所述免疫原性组合物包含通过执行本文公开的方法的步骤选择的一种或多种肿瘤特异性新抗原。可使用本领域已知的方法生产如本文所描述的免疫原性组合物。举例来说,本文公开的一种产生肿瘤特异性新抗原或载体(例如,包含编码一种或多种肿瘤特异性新抗原的至少一种序列的载体)的方法可包括在适合于表达新抗原或载体的条件下培养宿主细胞,其中宿主细胞包含编码新抗原或载体的至少一种多核苷酸;以及将新抗原或载体纯化。标准的纯化方法包括层析技术、电泳、免疫、沉淀、透析、过滤、浓缩和聚焦层析技术。
宿主细胞可包括中国仓鼠卵巢(CHO)细胞、NS0细胞、酵母或HEK293细胞。可用一种或多种多核苷酸来转化宿主细胞,所述一种或多种多核苷酸包含编码本文公开的一种或多种肿瘤特异性新抗原或载体的至少一种核酸序列。在某些实施方案中,分离的多核苷酸可为cDNA。
Ⅳ.样本
本文公开的方法包括选择来源于肿瘤的一种或多种肿瘤特异性新抗原。选择一种或多种肿瘤特异性新抗原的方法包括获得来源于肿瘤的序列数据。这种序列数据可来源于受试者的肿瘤样本。所述肿瘤样本可从肿瘤活检获得。
所述肿瘤样本可从人类受试者或非人类受试者获得。优选地,所述肿瘤样本从人类获得。所述肿瘤样本可从包含癌性肿瘤的各种生物源获得。肿瘤可来自肿瘤部位或来自血液中的循环肿瘤细胞。示例性样本可包括但不限于体液、组织活检、血液样本、血清血浆、粪便、皮肤样本等。样本源可为实体组织样本,诸如肿瘤组织活检。组织活检样本可为来自例如肺、前列腺、结肠、皮肤、乳腺组织或淋巴结的活检。样本还可为例如骨髓样本,包括骨髓抽出物和骨髓活检。样本还可为液体活检,例如循环肿瘤细胞、无细胞循环肿瘤DNA或外泌体。血液样本可为全血、部分纯化的血液、或全血或部分纯化的血液的一部分,诸如外周血单核细胞(PBMC)。
本文描述的肿瘤样本可直接从受试者获得、来源于受试者、或来源于从受试者获得的样本,诸如来源于生物流体或组织样本的培养细胞。肿瘤活检可为新鲜样本。新鲜样本可在从受试者移除之后用任何已知的固定剂(例如,福尔马林、岑克尔固定剂或B-5固定剂)固定。肿瘤活检还可为存档样本,诸如直接从受试者获得的细胞或来源于从受试者获得的细胞的细胞的冷冻样本、冷藏样本。优选地,从受试者获得的肿瘤样本是新鲜肿瘤活检。
可通过任何手段(包括但不限于肿瘤活检、针抽吸、刮削、手术切除、手术切开、静脉穿刺或本领域已知的其他手段)从受试者获得肿瘤样本。肿瘤活检是一种获得肿瘤的优选方法。可从任何癌症部位(例如,原发性肿瘤或继发性肿瘤)获得肿瘤活检。来自原发性肿瘤的肿瘤活检通常是优选的。本领域技术人员将认识到用于获得肿瘤样本的其他合适的技术。
可在单次程序中从受试者获得肿瘤样本。可在一段时间内反复地从受试者获得肿瘤样本。举例来说,可一天一次、一周一次、每月、每半年或每年获得肿瘤样本。在一段时间内获得许多样本可用于识别并选择新的肿瘤特异性新抗原。可从同一处肿瘤或不同的肿瘤获得肿瘤样本。
肿瘤样本可从原发性肿瘤、一个或多个转移瘤和/或个别肿瘤生长部位(例如,来自不同骨骼部分(诸如髋、骨或椎骨)的骨髓)获得。肿瘤样本可从同一部位或不同的部位获得。
等效形式
本领域技术人员将容易显而易见的是,本文描述的发明方法的其他合适的修改和改动是明显的,并且可在不脱离本公开或实施方案的范围的情况下使用合适的等效形式做出所述修改和改动。尽管现在已详细描述了某些组合物和方法,但通过参考以下实施例将更清楚地理解所述组合物和方法,介绍以下实施例仅是为了说明而不意图加以限制。
实施例
以下是本发明的方法和组合物的实施例。应当理解,考虑到本文提供的一般描述,可实践各种其他实施方案。
实施例1.新抗原肽选择
这个实施例描述用于选择根据从患者的肿瘤组织和正常组织产生的新一代测序数据识别的新抗原免疫原性肽的各个程序步骤。
1.1.样本制备以及WES、WGS和RNA-Seq数据的产生
在知情同意的情况下从研究参与者收集肿瘤活检或手术外植体,并以冰镇的组织培养基的形式运输到临床试验CLIA实验室。在该处,对样本进行登记并分配特定的唯一样本标识。接下来,对组织称重、分份并放置在五(5)倍于其体积的RNAlater稳定溶液(ThermoFisher,CatNo AM7020)中。接着,使样本在4℃下过夜,从RNAlater溶液移除,并放置在具有1mL STEMCELL CroyStor10(CatNo 07952)的冷冻小瓶中,并且在-80℃下转移到CoolCell(Corning,CatNo 432000)中。
将在随附研究方案下从参与者收集在ACD管中的外周血运输到试样处理与研究细胞库,在该处根据SOP使用Ficoll进行PBMC处理。可在肿瘤活检之前进行PBMC处理以允许将PBMC和肿瘤活检组织同时运送给测序提供商。
表1.样本
注意:
1通过组织消化和组织破坏产生单细胞悬浮液
2用3mm的打孔工具进行两遍处理
3用14号针总共进行10遍处理
所有试样(肿瘤活检和PBMC)由CLIA实验室在干冰上连夜送往测序提供商。
使用AllPrep DNA/RNA/miRNA通用试剂盒(QIAGEN)从同一组织或细胞试样中同时分离出DNA、RNA和miRNA。
使用合适的方法(例如,Qubit,BioAnalyzer)评定DNA/RNA样本的质量和数量并记录以下量度:
DNA:浓度(ng/μL)、总量(ng)、体积(μL)
RNA:浓度(ng/μL)、总量(ng)、体积(μL)、纯度(RIN)
表2.来自工程试运样本的基因组DNA和总RNA产率
将含有超过200ng基因组DNA的DNA样本等分,其中200ng用于WES,并且将剩余的DNA运送给另一个测序提供商以进行WGS。
执行NGS。下表3中示出了文库制备和测序策略的概述。
表3.在PNV-21生产中执行的新一代测序的细节
使用来自成对的肿瘤/正常样本的WES数据来识别患者及其肿瘤的种系和体细胞变体。
在商业测序供应商处使用Agilent SureSelect All Exon v6诱饵试剂盒执行WES,并且产生文库并在Illumina NovaSeq6000仪器上进行测序。使用100bp PE策略、75X平均覆盖率和3800万读段的目标对来自PBMC样本的DNA进行WES。使用100bp PE策略、125X平均覆盖率和6300万读段的目标对来自组织样本的DNA进行WES。
使用RNA测序数据来识别对具有足够高表达的RNA转录物进行编码的新抗原,并且独立地确认来自WES的体细胞变体。
使用Illumina Stranded mRNA测序方法,使用50bp PE策略和一亿读段的目标来对RNA进行测序。
使用Illumina TruSeq Stranded mRNA方法创建测序文库,所述方法优先通过利用聚腺苷酸化尾选择信使RNA。
使用WGS数据来执行CNV调用并识别肿瘤样本的亚克隆。
在商业CLIA验证实验室中根据如上文所详述制备的肿瘤和正常基因组DNA来执行WGS。在Illumina S4流动池(FC)上对来自同一个体的两个汇集的文库进行测序,其中读段长度为2x101。传递Q30>80%且错误率<3%的在FC上产生的数据以进行解复用。
从测序供应商传送FASTQ格式的NGS数据以供进一步的生物信息分析。
在经官方认可的临床免疫遗传学实验室处利用分子测定执行HLA分型。
1.2.NGS数据的生物信息分析
使用Illumina DRAGEN Bio-IT平台(v3.8.5)对NGS读段与hg19参考基因组进行映射和比对。图2中描述了关于输入和输出文件的细节,以及用于映射和比对的处理步骤的自动执行。
所有NGS分析是使用hg19人类参考基因组组装(初始UCSC参考组装,基于初始GRCh37版本,md5检验和a244d8a32473650b25c6e8e1654387d6,从Sentieon参考包下载)执行。从UCSC下载已知的ENSEMBL基因与hg19染色体坐标(GTF文件)之间的映射。此文件用于量化RNA基因表达。DRAGEN Bio-IT平台用于产生进行映射、比对和变体调用所需的一系列哈希表文件。将产生的哈希表文件和hg19 ENSEMBLE GTF文件上传到S3数据存储贮体。
DNA序列映射和比对步骤采用NGS FASTQ文件作为输入,并独立于正常样本和肿瘤样本(如果提供的话)而将读段与所提供的参考基因组哈希表进行比对。正常映射/比对包括产生种系变体调用,其在模块A3中用于体细胞CNV调用(称为B等位基因文件)。
表.4NGS FASTQ输入
除了映射/比对算法之外,此模块利用用于质量控制的DRAGEN的报告功能(包括映射统计和修整报告)。
对于肿瘤样本映射/比对,表5中概括了命令行。
表.5用于肿瘤样本映射/比对的命令行
使用启用了量化和基因融合检测的DRAGEN Bio-IT平台(v3.8.5)RNA模块对RNASeq FASTQ文件与UCSC hg19人类参考基因组进行比对。GENCODE hg19/GRCg37.p13 GTF文件用于将基因和基因转录物(Ensembl基因和转录物ID)映射到基因组区域。
表6.用于RNA序列比对和RNA量化的命令行
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单独使用与UCSC hg19人类参考基因组比对的正常(PBMC)WES和WGS.BAM文件以产生种系变体调用的列表(.VCF文件),从而指示研究参与者的基因组与参考基因组的差异。检测到的变体是单碱基或多碱基突变、插入和缺失。不处理结构变体。下文描述了用DRAGENBio-IT平台(v3.8.5)导出种系变体调用并产生未过滤和已过滤的种系.VCF文件的详细命令行自变量。
使用所得的种系.VCF文件来确保候选疫苗肽不表示研究参与者的种系序列(自体肽),并且还作为输入B等位基因频率文件用于CNV调用。
使用DRAGEN Bio-IT平台从WES和WGS比对的.BAM文件识别作为肿瘤样本与正常研究参与者样本之间的差异而出现的体细胞变体。在第一步骤中,对肿瘤.BAM文件与正常.BAM文件进行比较以识别肿瘤特异性(体细胞)DNA突变,所述突变以.VCF文件输出,一个未经过滤,并且一个经过过滤以得到高置信度变体。在第二步骤中且仅针对WGS,产生CNV调用并以.VCF文件输出。此步骤的输入是肿瘤.BAM文件和正常.BAM文件以及用作B等位基因频率输入的硬过滤的种系变体调用文件。
表8中描述了用于执行体细胞变体和CNV调用的附加细节和命令行界面选项。
表7.DNA体细胞变体调用的自动化工作流程
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将体细胞.VCF文件(硬过滤)用于下游的疫苗肽选择模块。
DRAGEN中的CNV调用需要B等位基因.VCF文件。CNV调用之前是种系调用和来自模块A1的正常/肿瘤.BAM文件。
表8.模块A4 DNA体细胞CNV调用
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为了分析重叠群间的映射/比对效果,模块A-QC1采用以.BAM文件作为输入的mosdepth分析程序。对于WES,另外提供将分析限制于限定的基因组区域的.BED文件。从Agilent网站下载Agilent Sure Select All Exon v6捕获诱饵集的hg19 bed文件并存储在S3中以由处理管道自动下载。
表9.模块A-QC1比对覆盖率分析
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mosdepth汇总文件是由制表符分隔的文本文件,其指示.BAM文件中存在的所有重叠群(染色体列)的平均覆盖率(平均值列)。如果提供了.BED文件,则后缀“_region”标示.BED限制重叠群的度量。示出了mosdepth汇总文件的缩略列表(例如,表10)。
表10.Mosdepth汇总文件
染色体 | 长度 | 碱基 | 平均值 | 最小 | 最大 |
chrM | 16571 | 385781 | 23.28 | 7 | 91 |
chrM_region | 0 | 0 | 0.00 | 0 | 0 |
chr1 | 249250621 | 974106896 | 3.91 | 0 | 4709 |
chr1_region | 6066056 | 716175291 | 118.06 | 0 | 4709 |
chr2 | 243199373 | 680541943 | 2.80 | 0 | 3488 |
chr2_region | 4449345 | 484022026 | 108.79 | 0 | 1162 |
chr3 | 198022430 | 529198467 | 2.67 | 0 | 2197 |
chr3_region | 3462072 | 381197919 | 110.11 | 0 | 2197 |
为了进行分析和质量控制,使用肿瘤和正常mosdepth汇总文件来产生规范报告。
下表11至表15中示出了来自映射比对的示例结果。
表11.每个重叠群的WES正常(PBMC)样本和总比对覆盖率
表12.每个重叠群的WES肿瘤样本和总比对覆盖率
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表13.每个重叠群的WGS正常(PBMC)样本和总比对覆盖率
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表14.每个重叠群的WGS肿瘤样本和总比对覆盖率
表15.每个重叠群的RNA seq肿瘤样本和总比对覆盖率
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表16至表19中示出了变体调用过程的结果。
表16.WES正常(PMC)种系变体的数目
区域 | 量度 | AAAAA | BBBBB | CCCCC | DDDDD | EEEEE | FFFFF | GGGGG |
全部 | ||||||||
插入缺失数 | 30,973 | 25,934 | 32,148 | 50,833 | 29,681 | 47,556 | 51,418 | |
记录数 | 209,535 | 180,749 | 219,602 | 307,090 | 204,141 | 294,761 | 307,494 | |
SNP数 | 178,629 | 154,862 | 187,522 | 256,349 | 174,505 | 247,278 | 256,162 | |
CDS | ||||||||
插入缺失数 | 1,105 | 1,061 | 1,104 | 1,120 | 1,055 | 1,110 | 1,066 | |
记录数 | 33,753 | 33,422 | 33,595 | 33,764 | 33,364 | 33,733 | 33,402 | |
SNP数 | 32,653 | 32,366 | 32,494 | 32,646 | 32,310 | 32,628 | 32,342 |
表17.WES肿瘤/正常体细胞变体的数目
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表18.WGS正常种系变体的数目
区域 | 量度 | DDDDD | FFFFF | GGGGG |
全部 | ||||
插入缺失数 | 931,451 | 934,986 | 939,511 | |
记录数 | 4,693,517 | 4,705,612 | 4,727,192 | |
SNP数 | 3,767,056 | 3,775,609 | 3,792,797 | |
CDS | ||||
插入缺失数 | 1,190 | 1,149 | 1,119 | |
记录数 | 34,546 | 34,431 | 34,649 | |
SNP数 | 33,359 | 33,287 | 33,536 |
表19.WGS肿瘤/正常体细胞变体的数目
区域 | 量度 | DDDDD | FFFFF | GGGGG |
全部 | ||||
插入缺失数 | 3,186 | 7,884 | 928 | |
记录数 | 29,927 | 182,205 | 5,103 | |
SNP数 | 26,741 | 174,321 | 4,175 | |
CDS | ||||
插入缺失数 | 3 | 16 | 2 | |
记录数 | 366 | 1,570 | 54 | |
SNP数 | 363 | 1,554 | 52 |
工作流程的后续模块处理由模块A从肿瘤-正常WGS样本调用的肿瘤体细胞变体和拷贝数变体,并且将每个体细胞变体的归属概率输出到一组N个肿瘤特异性亚克隆中,其中N是模块输出的参数。所述模块还输出每个突变的细胞患病率的估计。此模块还执行变体到亚克隆的大量反卷积。在模块A中从DRAGEN产生WGS文件并且在此模块中加以处理,以从体细胞变体的细胞患病率估计亚克隆性。图3示出了用于克隆性反卷积的模块的工作流程图。
1.3.根据NGS数据进行肽选择
通过个体化肽预测管道(p4vax)内的肽预测和机器学习算法选择待生产的疫苗肽。本文简要描述了这种软件解决方案的所有组件。
肽预测工作流程引入了映射/比对、RNA基因表达、种系变体、体细胞变体和CNV调用程序输出文件以及HLA单体分型的结果以:
1.识别对表达的RNA具有编码效果的变体
2.跨越非同义变体选择推定的MHC I类和II类结合肽
3.确认RNA测序读段中变体的存在
4.估计MHC I类和II类处理、呈递和免疫原性
5.通过用种系变体调用校正hg19参考来确认突变仅存在于肿瘤DNA中而不存在于种系(正常)DNA中
6.过滤可能有毒性的肽或者内肽酶或外肽酶代谢产物
7.根据MHC I类和II类处理、呈递和免疫原性对肽进行排名
8.将肽靶向的肿瘤细胞的预期百分比最大化
具体来说,针对肽选择,使用基于WES和WES的体细胞变体调用的结果。
使用肿瘤亚克隆反卷积算法,工作流程处理由模块A从肿瘤-正常WGS样本调用的肿瘤体细胞变体和拷贝数变体并且另外将每个体细胞变体的归属概率输出到一组N个肿瘤特异性突变/细胞患病率组群中。步骤8中使用来自此步骤的结果。
肽预测管道的输出是按MHC I类和II类结合/呈递评分、免疫原性以及肿瘤细胞患病率组群的组合排名的潜在疫苗肽的详尽列表。
从潜在肽合成候选物的这个排名列表中,选择列表中排名最高的一组多达80个的肽。在手动验证了体细胞变体的存在之后,将由验证的体细胞变体产生的肽序列传达给肽生产商以进行合成。
对工作示例样本DDDDD、FFFFF和GGGGG执行肽选择(表20至表22)并且进一步选择20个肽作为池配制的候选物。
表20.工程试运样本DDDDD的肽选择
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表21.工程试运样本FFFFF的肽选择
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表22.工程试运样本GGGGG的肽选择
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1.4.肽生产
疫苗肽生产和池配制由肽生产商执行肽合成、质量控制、肽和肽池的溶解和混合来进行。
通过固相肽合成制备肽,使用RP-HPLC柱纯化,并分析质量(身份、纯度、肽含量、乙酸盐/TFA含量、残留有机溶剂)。
表23至表25中示出了肽合成的结果。
表23.样本DDDDD_2020的肽合成工程试运批次
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表24.样本FFFFF的肽合成工程试运批次
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表25.样本GGGGG的肽合成工程试运批次
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接着将如通过质量控制标准(外观、身份、肽含量、肽纯度、乙酸盐含量、TFA含量、残留有机溶剂)所确定成功生产的肽引入到池优化算法中。
简要来说,此算法将所选择的肽分配到4个池,从而优化分配,使得每个池含有具有高MHC I类和II类评分的肽。在最初排除含有多于两个半胱氨酸的序列以避免池配制期间的多聚化之后,优化算法识别出大约14种长疫苗肽与6种短肽的最佳组合,以组合成单独的疫苗肽池。如果最初的肽预测或生产产生少于14种长疫苗肽,则长肽与短肽的比率可能会改变,以适应四个池各自具有五种肽的目标。类似地,如果疫苗肽池由少于三(3)种长肽组成(外推到CD4参与的机会低),则选择池肽中的一个肽作为PADRE。
接着将提议的池组合物传达给肽生产商,并执行疫苗肽池配制:
选择并汇集成组的肽。制备多达四(4)个池,每个池中具有不超过(NMT)五(5)种肽。将每种肽溶解于5.538%(v/v)DMSO中,然后溶解于0.9%NaCl溶液中,每种肽的浓度为0.4158mg/mL。对于该组池,接受明显溶解的肽。在成功汇集组内的所有肽之后,通过0.2μm尼龙过滤器过滤所述池。将肽装在无菌管中运送,并标有池名、批号、组分、生产数据、数量/浓度和储存条件。
1.5.肽疫苗的配制
为了配制个体化疫苗,使用以下程序将肽池与作为佐剂的聚ICLC混合:
从冰箱中对每个池分别取出一个肽小瓶。对肽池中的每一者执行以下步骤。
在室温下将肽池解冻20至30分钟。肽溶液含有DMSO并且可需要轻微加热(手动加热)和/或搅动才能完全解冻。预期物质是透明的无色溶液。如果形成沉淀物,则可使用旋涡混合器混合溶液以解决沉淀物。
解冻时,为步骤4-9准备并标记注射器(参见表26)。(A)每个池两(2)个混合注射器,标记为“M1-2[A-D]”(标示池):(i)注射器1:10mL(或适当大小)和(ii)注射器2:1mL(或适当大小);以及(B)每个池一(1)个施用注射器,标记为“施用注射器[A-D]”(标示池)。
表26.用于制备和施用的注射器的列表。
所需的附加材料(每个肽池)
1(一)个保护型母头对母头鲁尔适配器
1(一)个3”抽吸针,用于将肽池转移到混合注射器M1中
1(一)个无菌低蛋白结合注射器过滤器,无热原。孔大小0.22μm。(例如,PallDMSO-Safe Aerodisc注射器过滤器,#4433,或Millex-GV 0.22μm PVDF,33mm,γ灭菌.Millipore,#SLGVM33RS)
3(三)个适当规格的无菌皮下注射针
1(一)个用于IM注射的Spiros封闭系统药物转移装置(CSTD)[ICU医疗,#SH2000SC-10]
无菌过滤每个小瓶的内容物:使用连接到0.22μm无菌过滤器的具有卢尔锁的10mL注射器(混合注射器1,M1),在组件上滑动3”抽吸针,并从小瓶取出2mL肽池。
制备聚ICLC溶液。使用1mL注射器(混合注射器2,M2)和适当大小的针,在无菌条件下抽吸0.760mL的聚ICLC。聚ICLC是白色乳白色溶液。下游步骤可产生可接受的乳白色产物。
从混合注射器1(M1)和混合注射器2(M2)移除针,并从混合注射器1(M1)移除无菌过滤器。
经由母头对母头鲁尔锁保护连接器将聚ICLC混合注射器2(M2)与肽池混合注射器1(M1)连接
将聚ICLC混合注射器2(M2)转移到混合注射器1(M1)中并在两个注射器之间充分混合。产物中可形成气泡。轻敲注射器可有助于收集气泡。所得的混合物是个体化疫苗。
序列表
<110> 亚马逊科技公司
<120> 为个体化癌症疫苗选择新抗原
<130> 146401.091524
<140>
<141>
<150> 63/110,711
<151> 2020-11-06
<160> 297
<170> PatentIn version 3.5
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<213> 智人
<400> 54
Val Gly Ser Glu Ile Ala Gly Gly Ala Gly Leu Gly Trp Val Leu Pro
1 5 10 15
Phe Thr Ala Gly Gly Phe
20
<210> 55
<211> 19
<212> PRT
<213> 智人
<400> 55
Gly Phe Arg Arg Val Leu Cys Val Gly Thr Leu Arg Leu His Glu Leu
1 5 10 15
Ile Lys Leu
<210> 56
<211> 18
<212> PRT
<213> 智人
<400> 56
Ser Ala Ile Gln Val Leu Glu Ser Ser Ser Leu Ser Leu Thr Asp Ser
1 5 10 15
Leu Asn
<210> 57
<211> 16
<212> PRT
<213> 智人
<400> 57
Leu Pro Leu Leu Leu Phe Ser Arg Ala Pro Thr Val Asp Pro Pro Arg
1 5 10 15
<210> 58
<211> 15
<212> PRT
<213> 智人
<400> 58
Leu Pro Leu Leu Leu Phe Ser Arg Ala Pro Thr Val Asp Pro Pro
1 5 10 15
<210> 59
<211> 21
<212> PRT
<213> 智人
<400> 59
Ala Lys Cys Thr Gly Asp Phe Ser Pro Ser Leu Glu Lys Leu Val Lys
1 5 10 15
Ser Gly Asn Pro Leu
20
<210> 60
<211> 22
<212> PRT
<213> 智人
<400> 60
Gly Glu Ser Asn Ser Leu Thr Ser Ser Val Leu Tyr Pro Thr Ala Ser
1 5 10 15
Leu Val Ser Gln Asn Glu
20
<210> 61
<211> 18
<212> PRT
<213> 智人
<400> 61
Gly Ala Lys Gly Glu Val Glu Ala Asp Gly Ile Pro Gly Phe Pro Gly
1 5 10 15
Leu Pro
<210> 62
<211> 21
<212> PRT
<213> 智人
<400> 62
Pro Val Asp Asn Ser Ser Ala Lys Ile Val Leu Lys Ile Ser Tyr Ala
1 5 10 15
Ser Lys Val Lys Glu
20
<210> 63
<211> 22
<212> PRT
<213> 智人
<400> 63
Val Val Val Ser Ser Leu Leu Leu Gln Glu Glu Glu Leu Leu Ala Gly
1 5 10 15
Gly Lys Pro Gly Ala Asp
20
<210> 64
<211> 21
<212> PRT
<213> 智人
<400> 64
Ala Arg Lys Cys Leu Ala Lys Gln Ala Glu Asp Ala Ala Arg Glu Lys
1 5 10 15
Ser Cys Lys Arg Gly
20
<210> 65
<211> 22
<212> PRT
<213> 智人
<400> 65
Arg Asn Leu Tyr Ile Ser Gly Phe Ser Leu Cys Phe Trp Leu Val Leu
1 5 10 15
Arg Arg Leu Val Thr Leu
20
<210> 66
<211> 21
<212> PRT
<213> 智人
<400> 66
Lys Gln Lys Tyr Leu Thr Val Ile Ser Asn Arg Arg Trp Leu Leu Glu
1 5 10 15
Pro Ile Pro Arg Lys
20
<210> 67
<211> 21
<212> PRT
<213> 智人
<400> 67
Arg Phe Ser Ala Pro Leu Phe Leu Ser His Ser His Phe Leu Asn Ala
1 5 10 15
Asp Pro Val Leu Ala
20
<210> 68
<211> 22
<212> PRT
<213> 智人
<400> 68
Trp Asp His Asn Ala Gln Leu Val Val Met Ile Leu Asp Gly Gln Asn
1 5 10 15
Met Ala Glu Asp Glu Phe
20
<210> 69
<211> 22
<212> PRT
<213> 智人
<400> 69
Ala Ile Trp Asp Gly Tyr Leu Gln Gln Ala Gly Pro Phe Phe Ile Tyr
1 5 10 15
Phe Leu Met Leu Ile Ile
20
<210> 70
<211> 18
<212> PRT
<213> 智人
<400> 70
Ala Ser His Leu Glu Glu Tyr Asn Glu Arg Leu Glu Leu Ile Leu Lys
1 5 10 15
Trp Ile
<210> 71
<211> 21
<212> PRT
<213> 智人
<400> 71
Lys Arg Glu Leu Val Asn Ser Ala Ser Met Lys Gln Ala Leu Ile Ala
1 5 10 15
Ser Ala Arg Arg Leu
20
<210> 72
<211> 16
<212> PRT
<213> 智人
<400> 72
Pro Leu Asp Pro Gly Gly Tyr Phe Ile Ile Met Asp Gln Lys Arg Phe
1 5 10 15
<210> 73
<211> 22
<212> PRT
<213> 智人
<400> 73
Leu Gln Glu Ala Leu Thr Ser Arg Lys Ala Ile Pro Lys Lys Ala Gln
1 5 10 15
Glu Lys Glu Arg His Leu
20
<210> 74
<211> 22
<212> PRT
<213> 智人
<400> 74
Leu Asn Arg Met Asn Gly Val Met Phe Ser Gly Asn Ser Pro Ser Tyr
1 5 10 15
Thr Glu Arg Ser Asn Ile
20
<210> 75
<211> 19
<212> PRT
<213> 智人
<400> 75
Gln Arg Leu Ala Leu Trp Glu Gly Pro Phe Lys Ala His Thr Lys Gly
1 5 10 15
Ser His Gln
<210> 76
<211> 21
<212> PRT
<213> 智人
<400> 76
Arg Glu Tyr Phe Gly Glu Lys Thr Asp Leu Lys Glu Lys Ile Asp Ile
1 5 10 15
Gly Leu Pro Pro Pro
20
<210> 77
<211> 22
<212> PRT
<213> 智人
<400> 77
Pro Ala Leu Glu Glu Glu Glu Ala Pro Gln Ala Leu Ser Leu Leu Ser
1 5 10 15
Leu Pro Pro Lys Lys Arg
20
<210> 78
<211> 20
<212> PRT
<213> 智人
<400> 78
Leu Ser Asn Arg Cys Gln Val Phe Asp Cys Phe Gln Asp Thr Val Ser
1 5 10 15
Gln His Val Val
20
<210> 79
<211> 19
<212> PRT
<213> 智人
<400> 79
Asp Cys Tyr Arg Val Asp Ile Asp Gln Glu Ala Asp Met Gln Lys Glu
1 5 10 15
Ser Lys Glu
<210> 80
<211> 21
<212> PRT
<213> 智人
<400> 80
Arg Arg Arg Gly Gly Cys Glu Lys Leu Arg Ala Glu Pro Gln Ala Val
1 5 10 15
Leu Ala Ser Gly Ser
20
<210> 81
<211> 17
<212> PRT
<213> 智人
<400> 81
His Phe Tyr Lys Val Ile Gly Val Phe Ile Arg Ala Glu Asp Gly Leu
1 5 10 15
Cys
<210> 82
<211> 20
<212> PRT
<213> 智人
<400> 82
Ala Leu Thr Leu Val Phe Asp Asp Val Gln Gly Tyr Asp Leu Met Gly
1 5 10 15
Ser Val Thr Leu
20
<210> 83
<211> 22
<212> PRT
<213> 智人
<400> 83
Met Ile Leu Ala Ser Pro Arg Tyr Val Asp Gln Val Thr Glu Phe Leu
1 5 10 15
Gln Gln Lys Leu Lys Gln
20
<210> 84
<211> 22
<212> PRT
<213> 智人
<400> 84
Asn Ser Thr Gln Asp Asn Asn Tyr Gly Cys Val Ser Leu Leu Glu Asp
1 5 10 15
Ser Glu Thr Arg Lys Asn
20
<210> 85
<211> 22
<212> PRT
<213> 智人
<400> 85
Glu Glu Glu Glu Arg Lys Arg Arg Pro Pro Ser Leu Glu Pro Ser Thr
1 5 10 15
Lys Val Ser Glu Glu Ala
20
<210> 86
<211> 22
<212> PRT
<213> 智人
<400> 86
Ala Gly Gly Gly Pro Pro Pro Ala Pro Pro Leu Ser Ala Ala Gln Gly
1 5 10 15
Pro Gly Gly Gly Gly Ala
20
<210> 87
<211> 22
<212> PRT
<213> 智人
<400> 87
Lys Leu Asn Asp Ala Asp Pro Asp Asp Lys Phe Tyr Cys Leu Arg Leu
1 5 10 15
Phe Arg His Phe Tyr His
20
<210> 88
<211> 22
<212> PRT
<213> 智人
<400> 88
Val Gln Gln Lys Leu Glu Gln Leu Asn Gln Tyr Ser Asp Phe Asn Asn
1 5 10 15
Tyr Leu Ile Phe Val Leu
20
<210> 89
<211> 20
<212> PRT
<213> 智人
<400> 89
Thr Thr Val Glu Thr Leu Glu Lys Glu Asn Ser Trp Tyr Cys Pro Ser
1 5 10 15
Cys Lys Gln His
20
<210> 90
<211> 15
<212> PRT
<213> 智人
<400> 90
Val Asp Gly Asp Trp Val Leu His Leu Pro Glu Ala Leu Ser Ala
1 5 10 15
<210> 91
<211> 18
<212> PRT
<213> 智人
<400> 91
Arg Phe Arg Arg Leu Arg Gln Glu Arg Glu Phe Leu Gly Leu Trp Gly
1 5 10 15
Pro Glu
<210> 92
<211> 10
<212> PRT
<213> 智人
<400> 92
Met Glu Thr Ala Leu Val Thr Leu Ile Leu
1 5 10
<210> 93
<211> 9
<212> PRT
<213> 智人
<400> 93
Ser Val Leu Tyr Pro Thr Ala Ser Leu
1 5
<210> 94
<211> 10
<212> PRT
<213> 智人
<400> 94
Ala Leu Val Thr Leu Ile Leu Leu Gln Ile
1 5 10
<210> 95
<211> 11
<212> PRT
<213> 智人
<400> 95
Glu Ala Asp Gly Ile Pro Gly Phe Pro Gly Leu
1 5 10
<210> 96
<211> 11
<212> PRT
<213> 智人
<400> 96
Gly Glu Val Glu Ala Asp Gly Ile Pro Gly Phe
1 5 10
<210> 97
<211> 10
<212> PRT
<213> 智人
<400> 97
Arg Leu Trp Thr Ser Glu Asn Lys Ser Lys
1 5 10
<210> 98
<211> 19
<212> PRT
<213> 智人
<400> 98
His Glu His Trp Arg Phe Val Leu Gln His Leu Val Phe Leu Ala Ala
1 5 10 15
Phe Val Val
<210> 99
<211> 22
<212> PRT
<213> 智人
<400> 99
Gln Ser Pro Ala Arg Ala Arg Glu Glu Glu Asn His Ser Phe Leu Pro
1 5 10 15
Leu Val His Asn Ile Ile
20
<210> 100
<211> 17
<212> PRT
<213> 智人
<400> 100
Glu Asp Glu Glu Glu Glu Asn Ile Glu Leu Lys Val Thr Lys Pro Val
1 5 10 15
Gln
<210> 101
<211> 21
<212> PRT
<213> 智人
<400> 101
Pro Glu Leu Met Pro Phe Arg Leu Thr Cys Gln Phe Ile Asn Leu Met
1 5 10 15
Leu Pro Met Lys Glu
20
<210> 102
<211> 22
<212> PRT
<213> 智人
<400> 102
Glu Glu Trp Gln Gln Leu Asp Pro Glu Gln Asn Ile Thr Tyr Arg Asp
1 5 10 15
Val Met Leu Glu Asn Tyr
20
<210> 103
<211> 20
<212> PRT
<213> 智人
<400> 103
Asp Phe Lys Gly Arg Phe Lys Ala Arg Pro Lys Leu Glu Glu Leu Leu
1 5 10 15
Ala Lys Leu Lys
20
<210> 104
<211> 22
<212> PRT
<213> 智人
<400> 104
Ala Ser Ser Gln Ser Met Pro Trp Leu Val Asp Leu Val Gln Ser Ser
1 5 10 15
Glu Gly Ser Leu Asp Val
20
<210> 105
<211> 21
<212> PRT
<213> 智人
<400> 105
Arg Phe Phe Pro Pro Lys Ser Asn Lys Ala Cys His Tyr His Ser Tyr
1 5 10 15
Asn Gly Trp Asn Arg
20
<210> 106
<211> 21
<212> PRT
<213> 智人
<400> 106
Met Tyr Leu Ala Gly Tyr His Cys Arg Asn Cys Asn Val Arg Glu Ala
1 5 10 15
Leu Gln Ala Trp Ala
20
<210> 107
<211> 15
<212> PRT
<213> 智人
<400> 107
Leu Val Phe Cys Leu Leu Pro Ser Lys Asp Val Gln Phe Leu Ser
1 5 10 15
<210> 108
<211> 19
<212> PRT
<213> 智人
<400> 108
Arg Arg Arg Gln Cys Asp Leu Val Gly Val Glu Thr Cys Lys Ser Leu
1 5 10 15
Glu Ser Gln
<210> 109
<211> 21
<212> PRT
<213> 智人
<400> 109
Phe Leu Arg Ala Leu Lys Glu Asn Lys Asp Gln Lys Glu Gln Ala Ala
1 5 10 15
Lys Ala Glu Arg Arg
20
<210> 110
<211> 9
<212> PRT
<213> 智人
<400> 110
Phe Val Leu Gln His Leu Val Phe Leu
1 5
<210> 111
<211> 9
<212> PRT
<213> 智人
<400> 111
Arg Glu Glu Glu Asn His Ser Phe Leu
1 5
<210> 112
<211> 11
<212> PRT
<213> 智人
<400> 112
Arg Glu Glu Glu Asn His Ser Phe Leu Pro Leu
1 5 10
<210> 113
<211> 9
<212> PRT
<213> 智人
<400> 113
Val Leu Gln His Leu Val Phe Leu Ala
1 5
<210> 114
<211> 9
<212> PRT
<213> 智人
<400> 114
Glu Glu Asn His Ser Phe Leu Pro Leu
1 5
<210> 115
<211> 9
<212> PRT
<213> 智人
<400> 115
Ser Met Pro Trp Leu Val Asp Leu Val
1 5
<210> 116
<211> 10
<212> PRT
<213> 智人
<400> 116
Arg Ala Arg Glu Glu Glu Asn His Ser Phe
1 5 10
<210> 117
<211> 9
<212> PRT
<213> 智人
<400> 117
Lys Ala Arg Pro Lys Leu Glu Glu Leu
1 5
<210> 118
<211> 10
<212> PRT
<213> 智人
<400> 118
Phe Val Leu Gln His Leu Val Phe Leu Ala
1 5 10
<210> 119
<211> 9
<212> PRT
<213> 智人
<400> 119
Arg Leu Thr Cys Gln Phe Ile Asn Leu
1 5
<210> 120
<211> 10
<212> PRT
<213> 智人
<400> 120
Gln Leu Asp Pro Glu Gln Asn Ile Thr Tyr
1 5 10
<210> 121
<211> 11
<212> PRT
<213> 智人
<400> 121
Asn Ile Glu Leu Lys Val Thr Lys Pro Val Gln
1 5 10
<210> 122
<211> 8
<212> PRT
<213> 智人
<400> 122
Arg Glu Glu Glu Asn His Ser Phe
1 5
<210> 123
<211> 10
<212> PRT
<213> 智人
<400> 123
Glu Glu Glu Asn His Ser Phe Leu Pro Leu
1 5 10
<210> 124
<211> 10
<212> PRT
<213> 智人
<400> 124
Asn Ile Glu Leu Lys Val Thr Lys Pro Val
1 5 10
<210> 125
<211> 8
<212> PRT
<213> 智人
<400> 125
Phe Val Leu Gln His Leu Val Phe
1 5
<210> 126
<211> 11
<212> PRT
<213> 智人
<400> 126
Asp Glu Glu Glu Glu Asn Ile Glu Leu Lys Val
1 5 10
<210> 127
<211> 10
<212> PRT
<213> 智人
<400> 127
Glu Glu Glu Glu Asn Ile Glu Leu Lys Val
1 5 10
<210> 128
<211> 11
<212> PRT
<213> 智人
<400> 128
Arg Ala Arg Glu Glu Glu Asn His Ser Phe Leu
1 5 10
<210> 129
<211> 10
<212> PRT
<213> 智人
<400> 129
Val Leu Gln His Leu Val Phe Leu Ala Ala
1 5 10
<210> 130
<211> 11
<212> PRT
<213> 智人
<400> 130
Glu Glu Glu Glu Asn Ile Glu Leu Lys Val Thr
1 5 10
<210> 131
<211> 10
<212> PRT
<213> 智人
<400> 131
Gln Ser Met Pro Trp Leu Val Asp Leu Val
1 5 10
<210> 132
<211> 9
<212> PRT
<213> 智人
<400> 132
Leu Thr Cys Gln Phe Ile Asn Leu Met
1 5
<210> 133
<211> 11
<212> PRT
<213> 智人
<400> 133
Glu Glu Glu Asn Ile Glu Leu Lys Val Thr Lys
1 5 10
<210> 134
<211> 8
<212> PRT
<213> 智人
<400> 134
Val Leu Gln His Leu Val Phe Leu
1 5
<210> 135
<211> 10
<212> PRT
<213> 智人
<400> 135
Leu Leu Pro Ser Lys Asp Val Gln Phe Leu
1 5 10
<210> 136
<211> 11
<212> PRT
<213> 智人
<400> 136
Glu Asp Glu Glu Glu Glu Asn Ile Glu Leu Lys
1 5 10
<210> 137
<211> 11
<212> PRT
<213> 智人
<400> 137
Gln Leu Asp Pro Glu Gln Asn Ile Thr Tyr Arg
1 5 10
<210> 138
<211> 9
<212> PRT
<213> 智人
<400> 138
Ala Leu Lys Glu Asn Lys Asp Gln Lys
1 5
<210> 139
<211> 8
<212> PRT
<213> 智人
<400> 139
Lys Leu Glu Glu Leu Leu Ala Lys
1 5
<210> 140
<211> 11
<212> PRT
<213> 智人
<400> 140
Ala Arg Glu Glu Glu Asn His Ser Phe Leu Pro
1 5 10
<210> 141
<211> 8
<212> PRT
<213> 智人
<400> 141
Lys Ser Asn Lys Ala Cys His Tyr
1 5
<210> 142
<211> 8
<212> PRT
<213> 智人
<400> 142
Pro Ser Lys Asp Val Gln Phe Leu
1 5
<210> 143
<211> 9
<212> PRT
<213> 智人
<400> 143
Glu Glu Glu Glu Asn Ile Glu Leu Lys
1 5
<210> 144
<211> 13
<212> PRT
<213> 智人
<400> 144
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 145
<211> 13
<212> PRT
<213> 智人
<400> 145
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 146
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 146
Pro Ala Ser Ser Gln Ala Gly Thr Val Thr Leu Tyr Gly Pro Thr Ser
1 5 10 15
Ser Val Ala Leu Gly Phe Thr Ser Leu
20 25
<210> 147
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 147
Glu Asp Asp Asp Glu Ser Ala Gly Glu Asn Pro Leu Glu Glu Glu Glu
1 5 10 15
Glu Gln Pro Ala Pro
20
<210> 148
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 148
Met Ser Lys Pro Lys Trp Pro Leu Glu Asp Glu Ile Ser Lys Pro Glu
1 5 10 15
Val Pro
<210> 149
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 149
Asn Gln Pro Lys Ile Gly Gly Pro Leu Gly Thr Gly Ala Phe Glu Ala
1 5 10 15
Pro Gly Phe Asn Thr Thr Thr Ala Thr Leu Gly Phe
20 25
<210> 150
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 150
Phe Gly Ala Leu His Glu Asp Ala Asn Lys Val Ile Lys Pro Thr Ser
1 5 10 15
Ser Asn Thr Ala
20
<210> 151
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 151
Lys Asn Pro Gln Met Gly Asp Pro Gly Ser Leu Gln Pro Lys Ser Ala
1 5 10 15
Glu Thr Met Asn Asn Ile Asp Arg Leu Arg Met Glu
20 25
<210> 152
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 152
Leu Gln Met Leu Cys Pro Gln Glu Ala Pro Gln Ile Leu Ser Arg Leu
1 5 10 15
Glu Ala Val Arg
20
<210> 153
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 153
Tyr Val Met Val Val Met Ser Asp Ser Ser Ile Pro Ser Ala Ala Thr
1 5 10 15
Leu Ile Asn Ile Arg Asn Ala
20
<210> 154
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 154
Ser Ser Cys Met Gly Gly Met Asn Gln Arg Pro Ile Leu Thr Ile Ile
1 5 10 15
Thr Leu Glu Asp
20
<210> 155
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 155
Tyr Arg Ala Pro Glu Ile Ile Leu Gly Leu Leu Phe Cys Glu Ala Ile
1 5 10 15
<210> 156
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 156
Asp Pro Arg Leu Val Ile Phe Ser Gly Cys Ala Thr Arg Leu Phe Glu
1 5 10 15
Ala
<210> 157
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 157
Ala Arg Pro Glu Ala Gln Ser Arg Ser Ser Pro Thr Leu Glu Ser
1 5 10 15
<210> 158
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 158
Asp Gly Ala Asp Thr Ser Val Phe Ser Asn Asn Val Val Phe Val Thr
1 5 10 15
<210> 159
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 159
Gly Gln Arg Arg Asp Arg Leu Leu Thr Val Gln Ala Leu Ser Gly Leu
1 5 10 15
<210> 160
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 160
Trp Leu Pro Glu Leu Pro Ser Leu Pro Ser Asn Gly Asp Pro Pro Ala
1 5 10 15
Ile Cys Glu
<210> 161
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 161
Leu Leu Gly Thr Val Asp Lys His Ser Val Lys Val Thr Asn Cys Phe
1 5 10 15
Ser Val Pro His Asn
20
<210> 162
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 162
Lys Asp Lys Ile Trp Leu Arg Arg Thr Lys Pro Ser Lys His Gln Tyr
1 5 10 15
Gln Ile Cys Leu Ala Ile Asp Asp Ser Ser Ser Met
20 25
<210> 163
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 163
Gln Glu Leu Ser Pro Glu Lys Leu Lys Ser Trp Gly Gly Ser Leu Leu
1 5 10 15
Gly Pro Trp Leu Ser Ser Gly Leu Lys Pro Leu Lys
20 25
<210> 164
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 164
Glu Ser Ala Asp Leu Pro Pro Lys Gly Phe Gln Ala Ser Tyr Gly Lys
1 5 10 15
Asp Glu
<210> 165
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 165
Thr Tyr Pro Glu Ala Asp Ser Phe Pro Ser Trp Ala Ala Ala His Arg
1 5 10 15
Lys Gly Ser Ser
20
<210> 166
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 166
Arg Asp Ala Phe Glu Ser Leu Phe Gln Ser Phe Glu Thr Trp His Arg
1 5 10 15
Gly Asp Ala Leu Ser Arg Leu Asp
20
<210> 167
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 167
Ala Pro Pro Thr Arg Leu Ala Pro Pro Gln Arg Pro Pro Pro Pro Ser
1 5 10 15
<210> 168
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 168
Met Trp Ser Ser Ile Asn Cys Ile Ile Cys Ala Cys Val Lys Gly Arg
1 5 10 15
<210> 169
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 169
Arg Arg Trp Arg Lys Leu Tyr Arg Ala Asn Ser His Leu Phe Gln Ala
1 5 10 15
Lys Arg Phe Asn
20
<210> 170
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 170
Ala Val Val Ser Tyr Val Val Ala Asp Met Lys Glu Met Leu Pro Arg
1 5 10 15
Ser
<210> 171
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 171
Leu Asn Gly Ser Glu Pro Thr Gly Ala Tyr Ser Ile Lys Gly Phe Phe
1 5 10 15
Ala Asp Tyr Glu Ile Pro Asn
20
<210> 172
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 172
Gly Gln Leu Phe Pro Tyr Arg Ala Arg Ile Glu Ile Lys Asn Lys Phe
1 5 10 15
<210> 173
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 173
Gln Phe Asp Gln Leu Tyr Arg Thr Lys Pro Gly Met Thr Met Ser Cys
1 5 10 15
<210> 174
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 174
Pro Arg Thr Glu Ser Ser Asp Val Ala Asp Gln Leu Trp Ala Gln
1 5 10 15
<210> 175
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 175
Arg Asp Ile Leu Glu Leu Gly Gly Pro Glu Glu Asp Ala Ala Ser Gly
1 5 10 15
Thr Ile Ser Lys Lys Asp
20
<210> 176
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 176
Ser Gln Ala Gly Thr Val Thr Leu
1 5
<210> 177
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 177
Gln Ser Arg Ser Ser Pro Thr Leu
1 5
<210> 178
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 178
Lys Val Thr Asn Cys Phe Ser Val
1 5
<210> 179
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 179
Thr Trp His Arg Gly Asp Ala Leu
1 5
<210> 180
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 180
Ser Ser Gln Ala Gly Thr Val Thr Leu
1 5
<210> 181
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 181
Ala Gln Ser Arg Ser Ser Pro Thr Leu
1 5
<210> 182
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 182
Arg Arg Ala Cys Gly Ala Arg Thr Leu
1 5
<210> 183
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 183
Ala Ser Ser Gln Ala Gly Thr Val Thr Leu
1 5 10
<210> 184
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 184
Arg Ala Pro Glu Ile Ile Leu Gly Leu Leu
1 5 10
<210> 185
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 185
Glu Ala Gln Ser Arg Ser Ser Pro Thr Leu
1 5 10
<210> 186
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 186
Asn Thr Ser Ala Leu Pro Leu Val Ser Leu
1 5 10
<210> 187
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 187
Asp Ser Ser Ile Pro Ser Ala Ala Thr Leu
1 5 10
<210> 188
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 188
Ser Ala Gly Glu Asn Pro Leu Glu Glu Glu Glu
1 5 10
<210> 189
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 189
Asn Ser Pro Ser Thr Pro Thr Glu Gln Arg Ile
1 5 10
<210> 190
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 190
Phe Glu Ala Pro Gly Phe Asn Thr Thr Thr Ala
1 5 10
<210> 191
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 191
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 192
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 192
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 193
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 193
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 194
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 194
Leu Phe Met Leu Thr Phe Ser Thr Ser Pro Gly Leu Glu Ser Pro Val
1 5 10 15
Glu Ser Phe Ile Ala Phe Leu Leu Ile
20 25
<210> 195
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 195
Pro Val Val Asn Gly Glu Ser Asn Ser Leu Thr Ser Ser Val Leu Tyr
1 5 10 15
Pro Thr Ala Ser Leu Val Ser Gln Asn
20 25
<210> 196
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 196
Ser Ala Arg Lys Cys Leu Ala Lys Gln Ala Glu Asp Ala Ala Arg Glu
1 5 10 15
Lys Ser Cys Lys
20
<210> 197
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 197
Thr Asn Ser Ala Ile Gln Val Leu Glu Ser Ser Ser Leu Ser Leu Thr
1 5 10 15
Asp Ser Leu Asn Gly Asn Ser
20
<210> 198
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 198
Pro Thr Leu Pro Gln Pro Ala Ser His Phe Ser Pro Pro Pro Pro Pro
1 5 10 15
Pro Pro Leu Pro Pro
20
<210> 199
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 199
Phe Ile Asn Pro Ile Phe Glu Phe Ser Gln Ala Met Arg Arg Leu Gly
1 5 10 15
Leu Asp Asp Ala
20
<210> 200
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 200
Ser Thr Val Gln Lys Arg Glu Leu Val Asn Ser Ala Ser Met Lys Gln
1 5 10 15
Ala Leu Ile Ala Ser Ala Arg Arg Leu Pro
20 25
<210> 201
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 201
Glu Asp Thr Gly Gln Asp Met Leu Ala Leu Phe Leu Arg Thr Asn Arg
1 5 10 15
Gln Ala Ala Lys
20
<210> 202
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 202
Tyr Gly Arg Thr Val Val Pro Phe Leu Val Pro Gly Thr Ser Gln Leu
1 5 10 15
Gly Gln
<210> 203
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 203
Tyr Ile His Thr Ser Val Ser Gln Asp Phe Ser Gln Ser Val Pro Gly
1 5 10 15
Thr Thr Ser Ser Pro Leu
20
<210> 204
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 204
Val Val Val Ser Ser Leu Leu Leu Gln Glu Glu Glu Leu Leu Ala Gly
1 5 10 15
Gly Lys Pro Gly Ala Asp Gly
20
<210> 205
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 205
Leu Ser Asn Gln Gln Pro Gly Leu Met Val Ser Phe Ser Leu Arg Leu
1 5 10 15
Phe Pro Leu Phe Val
20
<210> 206
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 206
Pro Val Asp Asn Ser Ser Ala Lys Ile Val Leu Lys Ile Ser Tyr Ala
1 5 10 15
Ser Lys Val Lys Glu
20
<210> 207
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 207
Gln Ile Met Leu Arg Ser Gly Val Asp Leu Ser Val Thr Asp Lys Arg
1 5 10 15
Glu Trp Arg Pro
20
<210> 208
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 208
Arg Asn Gln His Gln Arg Leu Leu Lys Asn Met Gly Ala His Leu Val
1 5 10 15
Val Leu Asp Leu Leu Gln Ile Pro Tyr Glu
20 25
<210> 209
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 209
Gln Pro Ala Ser Ala Ala Lys Cys Thr Gly Asp Phe Ser Pro Ser Leu
1 5 10 15
Glu Lys Leu Val Lys Ser Gly Asn Pro Leu Gln Pro Val Ser
20 25 30
<210> 210
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 210
Thr Pro Ser Ala Pro Glu Gly Tyr Asp Leu Lys Ile Gly Leu Phe Leu
1 5 10 15
Ala Pro Arg Arg Gly Ser Leu Pro Asp
20 25
<210> 211
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 211
Met Ile Leu Ala Ser Pro Arg Tyr Val Asp Gln Val Thr Glu Phe Leu
1 5 10 15
Gln Gln Lys Leu Lys
20
<210> 212
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 212
Val Gly Arg Ala Trp Asp Ala Ile Thr Asp His Leu Val Gly Leu Cys
1 5 10 15
Ile Ser Lys Ser Pro
20
<210> 213
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 213
Phe Leu Ser Pro Gly Gln Leu Leu Gln Glu Pro Arg Thr Ser Leu Leu
1 5 10 15
Ile Ile Asn Asn Thr
20
<210> 214
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 214
Arg Ser Thr Thr Lys Ser Pro Gly Pro Ser Arg His Ser Lys Ser Pro
1 5 10 15
Ala Ser Thr Ser Ser Val Asn
20
<210> 215
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 215
Lys Leu Glu Ser Thr Val Gly Ser Pro Lys Lys Pro Leu Ser Asp Leu
1 5 10 15
Gly Lys Leu Ser
20
<210> 216
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 216
Gly Arg Pro Arg Met Met Gly Thr Gly Leu Ser Pro Tyr Pro Glu His
1 5 10 15
Leu Thr Ser Pro Leu Ser Pro Ala Gln
20 25
<210> 217
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 217
Pro Leu Asn Pro Pro Ala Ser Thr Ala Phe Ser Gln Glu Pro His Ser
1 5 10 15
Gly Ser Pro Ala
20
<210> 218
<211> 27
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 218
Ala Ala Phe Val Thr Pro Asp Gln Lys Tyr Ser Met Asp Asn Thr Leu
1 5 10 15
His Thr Pro Thr Pro Phe Lys Asn Ala Leu Glu
20 25
<210> 219
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 219
Arg Asn Leu Tyr Ile Ser Gly Phe Ser Leu Cys Phe Trp Leu Val Leu
1 5 10 15
Arg Arg Leu Val Thr
20
<210> 220
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 220
Asn Ala Gln Leu Val Val Met Ile Leu Asp Gly Gln Asn Met Ala Glu
1 5 10 15
Asp Glu Phe
<210> 221
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 221
Arg Val Leu Cys Val Gly Thr Leu Arg Leu His Glu Leu Ile Lys Leu
1 5 10 15
Thr Ala
<210> 222
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 222
His Lys Asp Ala Val Thr Cys Val Asn Phe Ser Ser Ser Gly His Leu
1 5 10 15
Leu Ala Ser Gly Ser Arg
20
<210> 223
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 223
Leu Gly Asn Leu Ala Gln Phe Trp Glu Cys Cys Leu Ser Ser Ser Gly
1 5 10 15
Asp Ala Asp Gly Glu Ser Phe
20
<210> 224
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 224
His Ile Ala Gly Thr Ser Gly Phe Ser Leu Ser Phe His Ser Thr Val
1 5 10 15
Ile Asn
<210> 225
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 225
Leu Pro Thr Ile Lys Tyr Leu Thr Leu Arg Leu Gln Asp Tyr Leu Ser
1 5 10 15
Leu Ser His Leu Val Val Tyr Val Pro Ser
20 25
<210> 226
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 226
Arg Leu Val His Ser Gly Ser Gly Cys Arg Ser Pro Phe Leu Gly Ser
1 5 10 15
Asp Leu Thr Phe Ala Thr Arg Thr Gly Ser Arg Gln
20 25
<210> 227
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 227
Pro Pro Lys Ser Pro Gly Pro His Ser Glu Lys Glu Asp Glu Ala Glu
1 5 10 15
Pro Ser Thr Val Pro Gly
20
<210> 228
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 228
Pro Phe Leu His Thr Val Ser Lys Thr Arg Leu Phe Glu Tyr Leu Arg
1 5 10 15
Leu Thr Ser Leu
20
<210> 229
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 229
Thr Gly Gln Asp Met Leu Ala Leu
1 5
<210> 230
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 230
Tyr Lys Thr Asp Leu His Ser Leu
1 5
<210> 231
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 231
Leu Ala Gln Phe Trp Glu Cys Cys Leu
1 5
<210> 232
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 232
Ser Leu Leu Leu Gln Glu Glu Glu Leu
1 5
<210> 233
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 233
Cys Thr Gly Asp Phe Ser Pro Ser Leu
1 5
<210> 234
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 234
Ala Gln Phe Trp Glu Cys Cys Leu
1 5
<210> 235
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 235
Leu Leu Leu Gln Glu Glu Glu Leu
1 5
<210> 236
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 236
Thr Gly Asp Phe Ser Pro Ser Leu
1 5
<210> 237
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 237
Gln Val Leu Glu Ser Ser Ser Leu
1 5
<210> 238
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 238
Asn Ser Leu Thr Ser Ser Val Leu
1 5
<210> 239
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 239
Asn Ser Ser Ala Lys Ile Val Leu
1 5
<210> 240
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 240
Asn Ser Ala Ser Met Lys Gln Ala Leu
1 5
<210> 241
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 241
Ala Ile Gln Val Leu Glu Ser Ser Ser Leu
1 5 10
<210> 242
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 242
Leu Gly Ile Gly Gly Leu Gln Asp Leu
1 5
<210> 243
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 243
Leu Ser Pro Tyr Pro Glu His Leu
1 5
<210> 244
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 244
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 245
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 245
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 246
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 246
Ser Pro Arg Val Ala Pro Gly Ser Ala Pro Pro Trp Pro Ala Leu Arg
1 5 10 15
Ser Leu Leu His
20
<210> 247
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 247
Val Leu Gly Thr Ser Ala Pro Gly Ser Ser Arg Leu Ala Ala Val Asp
1 5 10 15
Leu Gly Gly
<210> 248
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 248
Ala Arg Pro Pro Gly Gly Ser Gly Pro Leu Arg Val Leu Ile Pro Asp
1 5 10 15
Leu Gln Leu
<210> 249
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 249
Pro Ser Ala Pro Gln Gln Glu Gly Val Ala Ser Lys Glu Lys Glu Glu
1 5 10 15
Val
<210> 250
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 250
Thr Ser Gln Ala Tyr Asn Ala Leu Thr Leu Val Val Thr Ser Cys Lys
1 5 10 15
Asn Phe Lys Val Arg Ile
20
<210> 251
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 251
Gly Glu Asn Ser Val Ser Ser Ser Pro Ser Ala Ser Ser Thr Ala Ala
1 5 10 15
Leu Asn Thr Ala Ala Ala
20
<210> 252
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 252
Phe Glu Thr Thr Thr Gly Phe Asp Pro His Ser Gly Thr Pro Leu Ser
1 5 10 15
Asp His Glu Ala Leu
20
<210> 253
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 253
Phe Gln Ser Leu Cys Gln Ala Pro Pro Leu Leu Lys Asp Lys Val Leu
1 5 10 15
Thr Ala Leu Glu
20
<210> 254
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 254
Val Val Pro Gly Asn Val Thr Leu Ser Val Val Gly Ser Thr Ser Val
1 5 10 15
Pro Leu Ser Ser
20
<210> 255
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 255
Arg Pro Gly Glu Asp Pro Ser Leu His Gly Ile Val Lys Glu Gln Leu
1 5 10 15
<210> 256
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 256
Ser Pro Ala Glu Ser Cys Asp Leu Leu Gly Ala Ile Gln Thr Cys Ile
1 5 10 15
Arg Lys Ser Leu Gly
20
<210> 257
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 257
Met Lys Met Ala Ser Phe Leu Ala Phe Leu Leu Leu Asn Phe His Val
1 5 10 15
Cys Leu Leu Leu Leu Gln Leu Leu Met
20 25
<210> 258
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 258
Ser Glu Asn Gln Gln Pro Gly Ala Pro Asn Thr Pro Thr His Pro Ala
1 5 10 15
Pro Pro Gly Leu His
20
<210> 259
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 259
His Leu Ile Asn Tyr Gln Asp Asp Ala Glu Leu Ala Thr His Ala Leu
1 5 10 15
Pro Glu Leu Thr Lys Leu Leu Asn Asp Glu Asp Pro Val
20 25
<210> 260
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 260
Leu Ile Val Glu Asn Val His Phe Gln Ala His Lys Ala Leu Leu Ala
1 5 10 15
Ala
<210> 261
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 261
Ser Thr Ala Pro Ala Glu Ala Thr Leu Pro Lys Pro Gly Glu Ala Glu
1 5 10 15
Ala Pro
<210> 262
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 262
Pro Tyr Ser Gly Leu Gly Gly Val Gly Asp Pro Tyr Ala Pro Leu Met
1 5 10 15
Val Leu Met Cys Arg Val Cys Leu Glu Asp
20 25
<210> 263
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 263
Asp Phe Tyr Leu Arg Gly Ala Val Ala Leu Ser Val Arg Pro Ile Ser
1 5 10 15
<210> 264
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 264
Thr Asp Val Asp Pro Gln Ser Ala Val Met Gln Glu Glu Ile Phe
1 5 10 15
<210> 265
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 265
Asn Ser Leu Gln Asn Gln Ala Leu Gln Thr Leu Gln Glu Arg Leu His
1 5 10 15
Glu Ala Asp Ala Thr
20
<210> 266
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 266
Gly Ala Glu Asp Ser Ile Asp Ser Pro Ser Ala Cys Pro Leu Ser Thr
1 5 10 15
Gly Cys Pro Ala Leu
20
<210> 267
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 267
Arg Phe Ile Gly Pro Leu Pro Arg Glu Gly Ser Val Gly Ser Thr Ser
1 5 10 15
Asp Tyr Val Ser Gln Ser
20
<210> 268
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 268
Ile Gln Ser Ile Tyr Gly Gly Leu Pro Lys Val Pro Ala Lys Pro Lys
1 5 10 15
Glu Pro Thr Ile Pro His
20
<210> 269
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 269
Phe Trp Gly Ile Leu Gly Phe Pro Ala Leu Tyr Thr His Leu Pro Ala
1 5 10 15
Phe Leu Glu Trp Thr Leu Cys Leu Leu Ser
20 25
<210> 270
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 270
Val Asp Leu Lys Phe Pro Ala Ser Val Pro Thr Gly Ala Gln Asp Leu
1 5 10 15
Ile Ser Lys Leu
20
<210> 271
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 271
Leu Ala Pro Gly Gln Pro Phe Leu Ser Ser Gln Gly Ser Leu Cys Ile
1 5 10 15
<210> 272
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 272
Arg Val Gly Asp Leu Ser Pro Lys Gln Lys Glu Ala Leu Ala Lys Pro
1 5 10 15
Glu Ala
<210> 273
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 273
Leu Ala Val Arg Trp Phe Phe Ala His Ser Ser Asp Ser Gln Glu Ala
1 5 10 15
Leu Met Val
<210> 274
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 274
Tyr Ser Gly Ile Gln Glu Ser Ser Ser Ala Ser Pro Leu Ser Ile Lys
1 5 10 15
Lys Cys Pro Ile
20
<210> 275
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 275
Leu Ile Lys Pro Pro Ala His Thr Ser Ala Ile Leu Thr Val Leu Arg
1 5 10 15
<210> 276
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 276
Met Ser Tyr Glu Leu Lys Cys Ala Gln Glu Leu Ser Gln Lys Gln Asp
1 5 10 15
Gly
<210> 277
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 277
Gln Val His Gln Cys Ser Val Leu Leu Val Ala Thr Gly Leu Ser Val
1 5 10 15
Pro
<210> 278
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 278
Arg Ser Leu Thr Leu Glu Pro Asp Pro Ile Val Val Pro Gly Asn Val
1 5 10 15
Thr Leu Ser Val Val Gly
20
<210> 279
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 279
Leu Asp Arg Gln His Val Gln His Gln Leu Leu Val Ile Leu Lys Glu
1 5 10 15
Leu Arg Lys
<210> 280
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 280
Thr Val Asp Met Leu Gln Cys Leu Arg Phe Pro Gly Leu Ala Leu Pro
1 5 10 15
His Thr Arg Ala Pro Ser Pro Leu Gly
20 25
<210> 281
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 281
Ser Ala Pro Gly Ser Ser Arg Leu Ala Ala Val
1 5 10
<210> 282
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 282
Val Ala Leu Ser Val Arg Pro Ile
1 5
<210> 283
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 283
Ser Ala Val Met Gln Glu Glu Ile
1 5
<210> 284
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 284
Ala Ala Ile Gln Glu Lys Lys Glu Ile
1 5
<210> 285
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 285
Val Ser Pro Asp Ile Phe Met Gln Ser His Leu
1 5 10
<210> 286
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 286
Gln Ala Tyr Asn Ala Leu Thr Leu
1 5
<210> 287
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 287
Arg Val Leu Ile Pro Asp Leu Gln Leu
1 5
<210> 288
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 288
Ala Pro Gly Ser Ser Arg Leu Ala
1 5
<210> 289
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 289
Ser Thr Ala Pro Ala Glu Ala Thr Leu
1 5
<210> 290
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 290
Gly Ala Leu Pro Val Ala Ser Pro Ala Ser Leu
1 5 10
<210> 291
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 291
Ser Ala Pro Gly Ser Ser Arg Leu Ala Ala
1 5 10
<210> 292
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 292
Thr Ser Ala Pro Gly Ser Ser Arg Leu Ala Ala
1 5 10
<210> 293
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 293
Ser Leu Cys Gln Ala Pro Pro Leu
1 5
<210> 294
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 294
Met Ser Tyr Glu Leu Lys Cys Ala Gln Glu Leu
1 5 10
<210> 295
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 295
Leu Ala Pro Gly Gln Pro Phe Leu
1 5
<210> 296
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 296
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
<210> 297
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列描述:
合成肽
<400> 297
Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala
1 5 10
Claims (47)
1.一种从受试者的肿瘤选择一种或多种肿瘤特异性新抗原以用于受试者特异性免疫原性组合物的方法,所述方法包括:
a)从所述肿瘤获得序列数据,其中所述序列数据用于获得表示一种或多种肿瘤特异性新抗原的多肽序列的数据;
b)将所述受试者的所述多肽序列和MHC分子输入到机器学习平台中以产生所述一种或多种肿瘤特异性新抗原将引发所述受试者的免疫应答的数值概率评分;
c)将所述一种或多种肿瘤特异性新抗原在肿瘤中的RNA表达量化,以识别表达所述一种或多种肿瘤特异性新抗原的足以引发所述受试者的免疫应答的量的一种或多种肿瘤特异性新抗原;
d)基于步骤b)和步骤c)而计算所述一种或多种肿瘤特异性新抗原的肿瘤特异性新抗原评分;以及
e)基于所述肿瘤特异性评分而选择一种或多种肿瘤特异性新抗原以用于配制受试者特异性免疫原性组合物。
2.一种用于治疗有需要的受试者的癌症的方法,所述方法包括:
a)从肿瘤获得序列数据,其中所述序列数据用于获得一种或多种肿瘤特异性新抗原的多肽序列;
b)将所述受试者的所述多肽序列和MHC分子输入到机器学习平台中以产生所述一种或多种肿瘤特异性新抗原将引发所述受试者的免疫应答的数值概率评分;
c)将所述一种或多种肿瘤特异性新抗原在肿瘤中的RNA表达量化,以识别表达所述一种或多种肿瘤特异性新抗原的足以引发所述受试者的免疫应答的量的一种或多种肿瘤特异性新抗原;
d)基于步骤b)和步骤c)而计算所述一种或多种肿瘤特异性新抗原的肿瘤特异性新抗原评分;
e)基于所述肿瘤特异性评分而选择一种或多种肿瘤特异性新抗原以为所述受试者配制受试者特异性免疫原性组合物;
f)形成包含一种或多种肿瘤特异性新抗原的受试者特异性免疫原性组合物;以及
g)对所述受试者施用所述免疫原性组合物。
3.如权利要求1或2中任一项所述的方法,所述方法还包括在步骤d)之前,对所述肿瘤的肿瘤克隆进行测序以识别代表足够分数的所述肿瘤的一种或多种肿瘤特异性新抗原。
4.如权利要求3所述的方法,其中所述肿瘤特异性新抗原评分是基于步骤b)、步骤c)和对所述肿瘤克隆进行测序而计算。
5.如权利要求1或2中任一项所述的方法,其中步骤b的编码一种或多种肿瘤特异性新抗原的所述多肽序列是来自短多肽。
6.如权利要求5所述的方法,其中所述短多肽由MHC I类分子呈递。
7.如权利要求1或2中任一项所述的方法,其中步骤b的编码一种或多种肿瘤特异性新抗原的所述多肽序列是来自长多肽。
8.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答包括将所述一种或多种肿瘤特异性新抗原呈递到肿瘤细胞表面。
9.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答包括由肿瘤细胞上的一种或多种MHC分子呈递所述一种或多种肿瘤特异性新抗原。
10.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答是CD4+介导应答。
11.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答是CD8+介导应答。
12.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答是CD4+介导应答或CD8+介导应答。
13.如前述权利要求中任一项所述的方法,其中所述受试者的所述免疫应答包括能够通过抗原呈递细胞将一种或多种肿瘤特异性新抗原呈递到T细胞。
14.如前述权利要求中任一项所述的方法,其中相对于较低的数值概率评分来说,肿瘤特异性新抗原具有较高的数值概率评分指示所述肿瘤特异性新抗原将在所述受试者体内引发较大的免疫应答。
15.如前述权利要求中任一项所述的方法,其中所述MHC分子是MHC I类分子和/或MHCII类分子。
16.如前述权利要求中任一项所述的方法,其中所述RNA表达是mRNA表达。
17.如权利要求3-16中任一项所述的方法,其中所述一种或多种肿瘤特异性新抗原代表至少约1%的所述肿瘤。
18.如权利要求3-16中任一项所述的方法,其中所述一种或多种肿瘤特异性新抗原代表至少约5%的所述肿瘤。
19.如前述权利要求中任一项所述的方法,其中所述序列数据是核苷酸序列数据。
20.如前述权利要求中任一项所述的方法,其中所述序列数据是多肽序列数据。
21.如前述权利要求中任一项所述的方法,其中所述序列数据是外显子组、转录物组或全基因组核苷酸序列数据。
22.如前述权利要求中任一项所述的方法,其中选择至少约10种肿瘤特异性新抗原来配制所述受试者特异性免疫原性组合物。
23.如前述权利要求中任一项所述的方法,其中选择至少约20种肿瘤特异性新抗原来配制所述受试者特异性免疫原性组合物。
24.如权利要求2-21中任一项所述的方法,其中所述免疫原性组合物包含至少约10种肿瘤特异性新抗原。
25.如权利要求2-21中任一项所述的方法,其中所述免疫原性组合物包含至少约20种肿瘤特异性新抗原。
26.如权利要求2-21中任一项所述的方法,其中所述免疫原性组合物包含由短多肽编码的一种或多种肿瘤特异性新抗原。
27.如权利要求2-21中任一项所述的方法,其中所述免疫原性组合物包含由长多肽编码的一种或多种肿瘤特异性新抗原。
28.一种治疗患有肿瘤的受试者的方法,所述方法包括执行如权利要求1所述的步骤,并且还包括配制包含肿瘤特异性新抗原中的所述选择的一种或多种的免疫原性组合物以及对所述受试者施用所述免疫原性组合物。
29.如前述权利要求中任一项所述的方法,所述方法还包括测量所述一种或多种肿瘤特异性新抗原诱导正常组织的自身免疫应答的能力。
30.如权利要求29所述的方法,其中不选择诱导正常组织的自身免疫应答的所述一种或多种肿瘤特异性新抗原来用于所述免疫原性组合物。
31.如权利要求29或30所述的方法,其中相对于不会诱导自身免疫应答的肿瘤特异性新抗原来说,诱导正常组织的自身免疫应答的所述一种或多种肿瘤特异性新抗原具有更低的肿瘤特异性新抗原评分。
32.如前述权利要求中任一项所述的方法,其中所述肿瘤是来自黑色素瘤、乳腺癌、卵巢癌、前列腺癌、肾癌、胃癌、结肠癌、睾丸癌、头颈癌、胰腺癌、脑癌、B细胞淋巴瘤、急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病、T细胞淋巴细胞白血病、膀胱癌或肺癌。
33.如权利要求32所述的方法,其中所述肿瘤是选自由黑色素瘤、乳腺癌、肺癌和膀胱癌组成的组的癌症。
34.如权利要求32或33中任一项所述的方法,其中所述肿瘤是黑色素瘤。
35.如权利要求32或33中任一项所述的方法,其中所述肿瘤是乳腺癌肿瘤。
36.如权利要求32或33中任一项所述的方法,其中所述肿瘤是肺癌肿瘤。
37.如权利要求2-31中任一项所述的方法,其中所述癌症是黑色素瘤、乳腺癌、卵巢癌、前列腺癌、肾癌、胃癌、结肠癌、睾丸癌、头颈癌、胰腺癌、脑癌、B细胞淋巴瘤、急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病、T细胞淋巴细胞白血病、膀胱癌或肺癌。
38.如权利要求37所述的方法,其中所述癌症选自由黑色素瘤、乳腺癌、肺癌和膀胱癌组成的组。
39.如权利要求37或38中任一项所述的方法,其中所述癌症是黑色素瘤。
40.如权利要求37或38中任一项所述的方法,其中所述癌症是乳腺癌。
41.如权利要求37或38中任一项所述的方法,其中所述癌症是肺癌。
42.一种生产免疫原性组合物的方法,所述方法包括执行如权利要求1所述的步骤,并且还包括配制包含所述选择的一种或多种肿瘤特异性新抗原的免疫原性组合物。
43.一种免疫原性组合物,所述免疫原性组合物包含通过执行如权利要求1、3-27和29-41中任一项所述的方法选择的一种或多种肿瘤特异性新抗原。
44.如前述权利要求中任一项所述的免疫原性组合物,其中所述免疫原性组合物包含核苷酸序列、多肽序列、RNA、DNA、细胞、质粒、载体、树突状细胞或合成长肽。
45.如前述权利要求中任一项所述的免疫原性组合物,所述免疫原性组合物还包含佐剂。
46.如权利要求1-41中任一项所述的方法,其中所述序列数据是全外显子组序列数据、RNA序列数据、全基因组序列数据或其组合。
47.如权利要求1-41中任一项所述的方法,其中所述序列数据是全外显子组序列数据、RNA序列数据和全基因组序列数据的组合。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063110711P | 2020-11-06 | 2020-11-06 | |
US63/110,711 | 2020-11-06 | ||
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US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4722848A (en) | 1982-12-08 | 1988-02-02 | Health Research, Incorporated | Method for immunizing animals with synthetically modified vaccinia virus |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
US5204253A (en) | 1990-05-29 | 1993-04-20 | E. I. Du Pont De Nemours And Company | Method and apparatus for introducing biological substances into living cells |
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