CN115867303A - 用于治疗癌症的药物组合物 - Google Patents
用于治疗癌症的药物组合物 Download PDFInfo
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- CN115867303A CN115867303A CN202180049519.7A CN202180049519A CN115867303A CN 115867303 A CN115867303 A CN 115867303A CN 202180049519 A CN202180049519 A CN 202180049519A CN 115867303 A CN115867303 A CN 115867303A
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Abstract
本公开包括用于治疗HLA‑A*02:07、HLA‑A*03:01、HLA‑B*15:01或HLA‑B*27:05‑阳性受试者中的癌症的药物组合物,所述药物组合物包含WT1‑衍生的癌抗原肽或含有所述WT1‑衍生的癌抗原肽的肽缀合物等。
Description
技术领域
本申请要求日本专利申请号2020-083905的优先权,其全文以引用的方式并入本文。
本公开属于癌症免疫疗法领域,并具体涉及由WT1蛋白衍生的癌抗原肽的用途。
背景
WT1是癌症抗原蛋白,其在白血病和各种实体肿瘤中高度表达,并且特别是在癌症-疫苗靶抗原中受到关注。细胞免疫,特别是细胞毒性T细胞(也被称为细胞毒性T淋巴细胞,下文称为CTL),通过活体在肿瘤细胞清除中发挥重要作用。通过前体T细胞识别由与MHCI类抗原复合的来自肿瘤抗原蛋白的肽(即肿瘤抗原肽),经过它们的分化和增殖,从前体T细胞衍生得到攻击癌细胞的CTL。例如,作为WT1-衍生的癌抗原肽,WT1126-134肽(RMFPNAPYL,SEQ ID NO: 2)、WT1235-243肽(CMTWNQMNL,SEQ ID NO: 3)、WT110-18肽(ALLPAVPSL,SEQ IDNO: 4)、WT1187-195肽(SLGEQQYSV,SEQ ID NO: 5)、WT1302-310肽(RVPGVAPTL,SEQ ID NO: 6)和WT137-45肽(VLDFAPPGA,SEQ ID NO: 7)是已知的。
例如,WT1126-134肽是癌抗原肽,其能够诱导HLA-A*02:01-限制性肽特异性CTL。由于对WT1126-134肽特异性的CTL显示针对HLA-A*02:01-阳性WT1表达的癌细胞的细胞毒性,含有WT1126-134肽的癌症疫苗在HLA-A*02:01-阳性病人中已经进行临床试验。
发明内容
技术问题
本公开的一个目的是扩大WT1-衍生的癌抗原肽或含有所述肽的肽缀合物的适用受试者范围。
问题解决方案
通过使用接受癌症肽疫苗的癌症患者的外周血,本发明人发现WT1-衍生的癌抗原肽的HLA I类限制,所述癌抗原肽无法通过与HLA I类的结合预测或使用施用所述癌症肽疫苗前的癌症患者的外周血来源的T细胞的测定来鉴定,并基于该发现完成本发明。
在一个实施方案中,本公开提供了用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的药物组合物,其包含:
(a) 由7-30个氨基酸残基组成的MHC I类-限制性肽或其药学上可接受的盐,其中所述MHC I类-限制性肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;或
(b)由式(1)表示的化合物或其药学上可接受的盐:
其中Xa和Ya各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xa和Ya中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽A是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽A的N-末端氨基酸的氨基基团结合式(1)中的Ya,并且所述癌抗原肽A的C-末端氨基酸的羰基基团结合式(1)中的羟基基团,
R1是氢原子,
由式(2)表示的基团:
其中Xb和Yb各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xb和Yb中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽B是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽B的N-末端氨基酸的氨基基团结合式(2)中的Yb,并且所述癌抗原肽B的C-末端氨基酸的羰基基团结合式(2)中的羟基基团,和
式(2)中的硫原子经由二硫键结合式(1)中的硫原子,
或癌抗原肽C,其中所述癌抗原肽C是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC I类-限制性肽或由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHCII类-限制性肽,并且所述癌抗原肽C的半胱氨酸残基的硫原子经由二硫键结合式(1)中的硫原子,并且任选由1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端,
前提是当R1是氢原子时,所述癌抗原肽A是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是由式(2)表示的基团时,所述癌抗原肽A和/或癌抗原肽B是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQID NO: 7),或包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是所述癌抗原肽C时,所述癌抗原肽A和/或癌抗原肽C是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ IDNO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ IDNO: 7),或包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是由式(2)表示的基团并且所述癌抗原肽B包括一个半胱氨酸残基时,所述癌抗原肽B的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽;和
当R1是所述癌抗原肽C,并且由包括一个半胱氨酸残基的1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N末端时,结合所述癌抗原肽C的N末端的肽的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
发明作用
本发明使得使用WT1-衍生的癌抗原肽,诸如WT1126-134肽或含有用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者的癌症的肽的肽缀合物成为可能,并且扩大WT1-衍生的癌抗原肽或含有所述肽的肽缀合物的适用受试者范围。
附图简述
图1显示了使用来源于HLA-A*03:01-阳性患者的外周血单核细胞(PBMC)的四聚物测定结果。分析来源于4个患者的PBMC的HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者的PBMC在医学药剂施用前制备,并且在有式(5)的化合物的存在下培养。
图2显示了使用来源于HLA-B*15:01-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用前制备,并且在有式(5)的化合物的存在下培养。
图3显示了使用来源于HLA-A*03:01-阳性患者的PBMC的四聚物测定结果。分析来源于4个患者的PBMC的HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者的PBMC在医学药剂施用后制备,并且在有式(5)的化合物的存在下培养。
图4显示了使用来源于HLA-B*15:01-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用后制备,并且在有式(5)的化合物的存在下培养。
图5显示了使用HLA四聚体-阳性T细胞的ELISPOT测定结果。含有WT1126-134/HLA-A*03:01四聚体-阳性CD8-阳性T细胞的PBMC用WT1126-134肽标记的HLA-A*03:01-表达的K562细胞("K562-A3 + Pep")或没有所述肽标记的HLA-A*03:01-表达的K562细胞("K562-A3")来刺激。显示了4个患者的结果。
图6显示了使用HLA四聚体-阳性T细胞的ELISPOT测定结果。含有WT1126-134/HLA-B*15:01四聚体-阳性CD8-阳性T细胞的PBMC用WT1126-134肽标记的HLA-B*15:01-表达的K562细胞("K562-B15 + Pep")或没有所述肽标记的HLA-B*15:01-表达的K562细胞("K562-B15")来刺激。显示了一个患者的结果。
图7显示了使用来源于HLA-A*02:07-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用前制备,并且在有式(5)的化合物的存在下培养。
图8显示了使用来源于HLA-A*02:07-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用后制备,并且在有式(5)的化合物的存在下培养。
图9显示了使用HLA四聚体-阳性T细胞的ELISPOT测定结果。含有WT1126-134/HLA-A*02:07四聚体-阳性CD8-阳性T细胞的PBMC用WT1126-134肽标记的HLA-A*02:07表达的K562细胞("K562-A2.7 + Pep")或没有所述肽标记的HLA-A*02:07表达的K562细胞("K562-A2.7")来刺激。显示了一个患者的结果。
图10显示了使用来源于HLA-A*03:01-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用后制备,并且在有SEQ ID NO: 13的肽的存在下培养。
图11显示了使用来源于HLA-B*15:01-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用后制备,并且在有SEQ ID NO: 13的肽的存在下培养。
图12显示了使用来源于HLA-A*02:07-阳性患者的PBMC的四聚物测定结果。分析患者来源的PBMC的HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞,所述患者来源的PBMC在医学药剂施用后制备,并且在有SEQ ID NO: 13的肽的存在下培养。
实施方案描述
如本文所用的“氨基酸残基”是指构成肽或蛋白质分子的氨基酸中的单一氨基酸单元。“氨基酸残基”可以是天然或非天然的α-氨基酸残基、β-氨基酸残基、γ-氨基酸残基或δ-氨基酸残基;更具体地,天然的α-氨基酸残基、鸟氨酸残基、高丝氨酸残基、高半胱氨酸残基、β-丙氨酸、γ-氨基丁酸或δ-氨基戊酸。当“氨基酸残基”是光学活性的,它包括L-型和D-型,并且优选L-型。
本文所使用的“氨基酸残基”的缩写表示如下:
Ala或A:丙氨酸残基
Arg或R:精氨酸残基
Asn或N:天冬酰胺残基
Asp或D:天冬氨酸残基
Cys或C:半胱氨酸残基
Gln或Q:谷氨酰胺残基
Glu或E:谷氨酸残基
Gly或G:甘氨酸残基
His或H:组氨酸残基
Ile或I:异亮氨酸残基
Leu或L:亮氨酸残基
Lys或K:赖氨酸残基
Met或M:甲硫氨酸残基
Phe或F:苯丙氨酸残基
Pro或P:脯氨酸残基
Ser或S:丝氨酸残基
Thr或T:苏氨酸残基
Trp或W:色氨酸残基
Tyr或Y:酪氨酸残基
Val或V:缬氨酸残基
Abu:2-氨基丁酸残基(也被称为α-氨基丁酸残基)
Orn:鸟氨酸残基
Cit:瓜氨酸残基。
本文描述了“肽”的氨基酸序列,因此根据通常的描述方法,N-末端氨基酸残基位于左侧,且C-末端氨基酸残基位于右侧。除非另有说明,在“肽”中,N-末端氨基酸残基的氨基基团结合氢原子(成为游离氨基),且C-末端氨基酸残基的羰基基团结合羟基。二价肽基团是指通过N-末端氨基和通过C-末端羰基基团结合其它化学部分的肽基团。例如,在与由式(1)表示的化合物的部分结构对应的肽中,式(4)或式(5)的化合物,除非另有说明,N-末端氨基酸残基的氨基基团结合氢原子,且C-末端氨基酸残基的羰基基团结合羟基。
本公开涉及
(a) 由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述MHC I类-限制性肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO:3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;或其药学上可接受的盐(在本文中也被称为(a)的肽);或
(b) 由式(1)表示的化合物:
或其药学上可接受的盐的用途。
“癌抗原肽A”是指由7-30个氨基酸残基组成的MHC I类-限制性肽。在式(1)中,所述癌抗原肽A的N-末端氨基酸的氨基基团结合式(1)中的Ya,并且所述癌抗原肽A的C-末端氨基酸的羰基基团结合式(1)中的羟基基团。
"Xa"和"Ya"各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团。在Xa和Ya中的氨基酸残基数量的总和是0-4的整数。例如,当在Xa和Ya中的氨基酸残基数量的总和是整数0时,Xa和Ya均是单键。当在Xa和Ya中的氨基酸残基数量的总和是整数4时,每个Xa和Ya可以是由两个氨基酸残基组成的二价肽基团;Xa可以是由三个氨基酸残基组成的二价肽基团,且Ya可以是由一个氨基酸残基组成的二价肽基团;或Xa可以是由四个氨基酸残基组成的二价肽基团,且Ya可以是单键。
在Xa和Ya中的氨基酸残基数量的总和优选是0至2,更优选0至1,并且最优选0。也就是说,最优选,Xa和Ya均是单键。
当在Xa和Ya中的氨基酸残基数量的总和是整数2时,Xa可以是由两个氨基酸残基组成的二价肽基团,且Ya可以是单键;Xa和Ya可以是独立由一个氨基酸残基组成的二价肽基团;或Xa可以是单键,且Ya可以是由两个氨基酸残基组成的二价肽基团。
当在Xa和Ya中的氨基酸残基数量的总和是整数1时,Xa可以是由一个氨基酸残基组成的二价肽基团,且Ya可以是单键;或Xa可以是单键,且Ya可以是由一个氨基酸残基组成的二价肽基团。在优选的实施方案中,Xa是单键,且Ya是丙氨酸、亮氨酸或甲硫氨酸的残基;或Xa是丙氨酸、亮氨酸或甲硫氨酸的残基,且Ya是单键。
在式(1)中,"R1"是氢原子,基团由式(2)表示:
或癌抗原肽C。优选,"R1"是由式(2)表示的基团或癌抗原肽C,且更优选癌抗原肽C。
当R1是氢原子时,由式(1)表示的化合物是由式(1-1)表示的化合物(即,肽):
其中Xa、Ya和癌抗原肽A具有如上述式(1)所定义的相同含义,且Cys代表半胱氨酸残基。
“癌抗原肽B”是由7-30个氨基酸残基组成的MHC I类-限制性肽。在式(2)中,所述癌抗原肽B的N-末端氨基酸的氨基基团结合式(2) (或式(1-2))中的Yb,并且该C-末端氨基酸的羰基基团结合式(2)中的羟基基团。
"Xb"和"Yb"各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团。在Xb和Yb中的氨基酸残基数量的总和是0-4的整数。例如,当在Xb和Yb中的氨基酸残基数量的总和是整数0时,Xb和Yb均是单键。当在Xb和Yb中的氨基酸残基数量的总和是整数4时,每个Xb和Yb可以是由两个氨基酸残基组成的二价肽基团;Xb可以是由三个氨基酸残基组成的二价肽基团,且Yb可以是由一个氨基酸残基组成的二价肽基团;或Xb可以是由四个氨基酸残基组成的二价肽基团,且Yb可以是单键。
在Xb和Yb中的氨基酸残基数量的总和优选是整数0至2,更优选整数0至1,或最优选0。也就是说,最优选,Xb和Yb均是单键。
当在Xb和Yb中的氨基酸残基数量的总和是整数2时,Xb可以是由两个氨基酸残基组成的二价肽基团,且Yb可以是单键;每个Xb和Yb可以是独立由一个氨基酸残基组成的二价肽基团;或Xb可以是单键,且Yb可以是由两个氨基酸残基组成的二价肽基团。
当在Xb和Yb中的氨基酸残基数量的总和是整数1时,Xb可以是由一个氨基酸残基组成的二价肽基团,且Yb可以是单键;或Xb可以是单键,且Yb可以是由一个氨基酸残基组成的二价肽基团。在优选的实施方案中,Xb是单键,且Yb是丙氨酸、亮氨酸或甲硫氨酸的残基;或Xb是丙氨酸、亮氨酸或甲硫氨酸的残基,且Yb是单键。
当R1是由式(2)表示的化合物时,由式(1)表示的化合物是由式(1-2)表示的化合物:
其中Xa、Ya和癌抗原肽A具有如上述式(1)所定义的相同含义,且Xb、Yb和癌抗原肽B具有如上述式(2)所定义的相同含义。
“癌抗原肽C”是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC I类-限制性肽,或由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。当R1是癌抗原肽C时,所述癌抗原肽C的半胱氨酸残基的硫原子经由二硫键结合式(1)中的硫原子。对于所述癌抗原肽C的N-末端,由1-4个氨基酸残基(即,一个氨基酸残基或由2至4个氨基酸残基组成的肽)组成的肽结合。
癌抗原肽C在它的氨基酸序列中包括至少一个半胱氨酸残基。半胱氨酸残基的数量优选是1至3个,更优选1至2个,最优选1个。
在一个实施方案中,由1-4个氨基酸残基组成并结合癌抗原肽C的N-末端的肽由1-4个氨基酸残基组成,所述氨基酸残基独立选自丙氨酸残基、精氨酸残基、天冬酰胺残基、半胱氨酸残基、谷氨酰胺残基、谷氨酸残基、组氨酸残基、异亮氨酸残基、亮氨酸残基、赖氨酸残基、甲硫氨酸残基、苯丙氨酸残基、脯氨酸残基、丝氨酸残基、苏氨酸残基、色氨酸残基、酪氨酸残基和缬氨酸残基。在进一步实施方案中,由1-4个氨基酸残基组成的肽由1-4个氨基酸残基组成,所述氨基酸残基独立选自精氨酸残基,谷氨酰胺残基,谷氨酸残基,组氨酸残基,赖氨酸残基,苯丙氨酸残基和酪氨酸残基。
在一个实施方案中,由1-4个氨基酸残基组成并结合癌抗原肽C的N-末端的肽包括一个半胱氨酸残基。在进一步实施方案中,由CA组成的二肽结合癌抗原肽C的N-末端。
在一个实施方案中,选自精氨酸残基,谷氨酰胺残基,谷氨酸残基,组氨酸残基,赖氨酸残基,苯丙氨酸残基和酪氨酸残基的一个氨基酸残基结合癌抗原肽C的N-末端。
在一个实施方案中,由式(1)表示的化合物不是同源二聚体而是异源二聚体。与同源二聚体相反,其是指相同肽单体的二聚产物,异源二聚体是指两个不同肽单体的二聚产物。
当R1是由式(2)表示的化合物,且所述癌抗原肽B包括一个半胱氨酸残基时,所述癌抗原肽B的半胱氨酸残基的硫原子可经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
当R1是所述癌抗原肽C,且由包括一个半胱氨酸残基的1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端时,结合所述癌抗原肽C的N-末端的肽的半胱氨酸残基的硫原子可以经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数;和癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
“癌抗原肽D”是由7-30个氨基酸残基组成的MHC II类-限制性肽。在式(3)中,所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团。
“癌抗原肽E”是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
"Xd"和"Yd"各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团。在Xd和Yd中的氨基酸残基数量的总和是0-4的整数。例如,当在Xd和Yd中的氨基酸残基数量的总和是整数0时,Xd和Yd均是单键。当在Xd和Yd中的氨基酸残基数量的总和是整数4时,每个Xd和Yd可以是由两个氨基酸残基组成的二价肽基团;Xd可以是由三个氨基酸残基组成的二价肽基团,且Yd可以是由一个氨基酸残基组成的二价肽基团;或Xd可以是由四个氨基酸残基组成的二价肽基团,且Yd可以是单键。
在Xd和Yd中的氨基酸残基数量的总和优选是整数0至2,更优选整数0至1,或最优选0。也就是说,最优选,Xd和Yd均是单键。
当在Xd和Yd中的氨基酸残基数量的总和是整数2时,Xd可以是由两个氨基酸残基组成的二价肽基团,且Yd可以是单键;每个Xd和Yd可以是独立由一个氨基酸残基组成的二价肽基团;或Xd可以是单键,且Yd可以是由两个氨基酸残基组成的二价肽基团。
当在Xd和Yd中的氨基酸残基数量的总和是整数1时,Xd可以是由一个氨基酸残基组成的二价肽基团,且Yd可以是单键;或Xd可以是单键,且Yd可以是由一个氨基酸残基组成的二价肽基团。在优选的实施方案中,Xd是单键,且Yd是丙氨酸、亮氨酸或甲硫氨酸的残基;或Xd是丙氨酸、亮氨酸或甲硫氨酸的残基,且Yd是单键。
在本文中“MHC I类-限制性肽”和“MHC II类-限制性肽”可以是由在SEQ ID NO: 1的人WT1的氨基酸序列中连续的氨基酸残基组成的肽,或其改变的肽(在本文中也被称为"WT1肽")。
术语“MHC I类-限制”是指肽的结合主要组织相容性复合体(MHC) I类分子和诱导CTL的能力。在本文中术语“MHC I类-限制性肽”是指肽在体外和/或在体内能够结合MHC I类分子和诱导细胞毒性T细胞(CTL)的能力(也就是说,具有诱导CTL的能力的肽)。术语“MHCI类-限制性肽”也被称为“杀伤肽”。
人类中的MHC被称为人类白细胞型抗原(HLA)。对应于MHC I类分子的HLA分子被分类为亚型,诸如HLA-A、B、Cw、F和G。MHC I类限制的优选实例包括HLA-A、HLA-B和HLA-Cw限制。
对于每种HLA亚型,等位基因多态性是已知的。等位基因多态性的实例包括HLA-A1、HLA-A2、HLA-A24、HLA-A3、HLA-A11、HLA-A33、HLA-B7、HLA-B15、HLA-B27、HLA-B40、HLA-B44、HLA-Cw1、HLA-Cw3、HLA-Cw4、HLA-Cw6以及HLA-A*01:01、HLA-A*02:01、HLA-A*02:06、HLA-A*02:07、HLA-A*24:02、HLA-A*03:01、HLA-A*11:01、HLA-A*33:01、HLA-A*33:03、HLA-B*15:01、HLA-B*27:05、HLA-B*40:01、HLA-B*40:02、HLA-B*40:03、HLA-B*40:06、HLA-B*44:03、HLA-Cw*01:01、HLA-Cw*03:01、HLA-Cw*04:0、HLA-Cw*06:02。
“MHC I类-限制的WT1肽”可由任何类型的任何数量的氨基酸的序列组成。然而,越长的肽链越容易可以通过蛋白酶以降解。此外,太小的肽可能不能成功在MHC I类分子的肽-结合沟中捕获。“MHC I类-限制性肽”通常由7-30、优选7至15、8至12、8至11,或8或9个氨基酸残基组成。在一个实施方案中,所述MHC I类-限制性肽由9至30、优选9至15、9至12、9至11、9至10,或9个氨基酸残基组成。
术语“MHC I类-限制的WT1肽”包括提供“MHC I类-限制的表位”的肽,所述肽经过诸如在体外或在体内用蛋白酶体和/或蛋白酶降解,和/或由ERAP1剪切(也被称为修剪)至适当的肽长度等方法。术语“MHC I类-限制的表位”是指对应于与MHC I类分子复合的实际肽且存在的肽。也就是说,术语“MHC I类-限制的WT1肽”包括这样的肽,所述肽是指经过在体外或在体内降解或修剪的方法产生能够结合MHC I类分子的肽 (也就是说,在诸如体外或体内降解或修剪的方法之后,结合MHC I类分子的肽)。
“MHC I类-限制的表位”可以通过用蛋白酶体和/或蛋白酶降解来源于“MHC I类-限制性肽”,随后由ERAP1修剪(剪切),其中所述“MHC I类-限制的表位”的C-末端氨基酸残基和N-末端氨基酸残基可以分别通过蛋白酶体/蛋白酶和ERAP1的处理确定。因此,所述“MHC I类-限制的表位”可以是由7-30个氨基酸残基组成的肽,其中0至23个氨基酸残基通过它的C-末端羰基附于由7至12个残基组成的“MHC I类-限制的表位”。
“MHC I类-限制的表位”通常由7至12个氨基酸残基组成,并且优选9个氨基酸残基。在一个实施方案中,“MHC I类-限制性肽”是包含“MHC I类-限制的表位”和附于它的C-末端的氨基酸残基的肽。在进一步实施方案中,所述“MHC I类-限制的WT1肽”是由8至30个氨基酸残基组成的肽,其中1至23个氨基酸残基通过它的C-末端羰基附于“MHC I类-限制的表位”。
如本文所用,包含给定氨基酸序列的肽是指具有给定氨基酸序列的肽,如通常所理解,其可任选地具有附于所述给定序列的N-末端和/或C-末端的氨基酸的氨基酸残基的额外序列。“MHC I类-限制性肽”可具有优选附于它的C-末端的氨基酸残基的额外序列。
如本文所用,术语“改变的肽”是指由氨基酸序列组成的肽,所述氨基酸序列在原始肽的氨基酸序列中具有一个或几个改变的氨基酸残基。在改变的肽中,从原始肽的氨基酸序列缺失、取代和/或添加(或插入)一个或几个的氨基酸残基,例如1至9个氨基酸残基,优选1至5个氨基酸残基,1-4或1至3个氨基酸残基,更优选1至2个氨基酸残基,或最优选一个氨基酸残基。为了改变肽,氨基酸取代可以在具有任何类型氨基酸的原始序列的氨基酸残基的任何位置进行。优选保守的氨基酸取代。例如,可以用Asp取代Glu;Tyr取代Phe;Ile取代Leu;Ser取代Ala;或Arg取代His。氨基酸添加或缺失可以优选在肽的N-或C-末端进行。然而,氨基酸添加或缺失可在内部进行。氨基酸取代或添加可以用二十种遗传编码的氨基酸或甚至任何非天然氨基酸进行。
如本文所用,由改变的氨基酸序列组成的杀伤肽也被称为“改变的杀伤肽”。当由九个氨基酸残基的氨基酸序列组成的杀伤肽通过氨基酸取代改变时,所述取代可以是位置1 (N-末端)、位置2、位置3或位置9。当改变的杀伤肽具有添加的氨基酸残基时,添加的氨基酸的数量优选为1或2,或更优选为一。氨基酸添加优选在N-末端或C-末端进行。当杀伤肽是通过氨基酸缺失改变时,缺失的氨基酸数量优选为一。
可以与HLA抗原的多态性序列复合的肽具有特定模式的氨基酸序列(也就是说,结合基序)用于结合所述HLA抗原的多态性序列。氨基酸取代可以在组成此类结合基序的任何氨基酸残基上进行。例如,已知由8至11个氨基酸残基组成的HLA-A24-结合肽具有在位置2的Tyr、Phe、Met或Trp,和在C-末端的Phe、Leu、Ile、Trp或Met(J. Immunol., 152, p3913,1994; J. Immunol., 155, p4307, 1994; Immunogenetics, 41, p178, 1995)。因此,例如,已知由九个氨基酸残基组成的肽可以通过氨基酸取代,以具有在位置2的Leu或Met,和/或在位置9(C-末端)的Val或Leu,以给出可作为改变的杀伤肽的改变肽。
所述“MHC I类-限制性肽”的实例包括包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3),
ALLPAVPSL (SEQ ID NO: 4),
SLGEQQYSV (SEQ ID NO: 5),
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7),
或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸残基改变的氨基酸序列且具有诱导CTL能力的肽。进一步优选,由选自SEQ ID NO: 2至7的氨基酸序列组成的肽,或由在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸残基改变的氨基酸序列组成且具有诱导CTL能力的肽。
所述改变的杀伤肽的实例包括以下肽:
RMFPNAPYL (SEQ ID NO: 2)的改变的杀伤肽,诸如
RYFPNAPYL (SEQ ID NO: 8) (参见,WO03/106682);
FMFPNAPYL (SEQ ID NO: 9)、
RLFPNAPYL (SEQ ID NO: 10)、
RMMPNAPYL (SEQ ID NO: 11)、
RMFPNAPYV (SEQ ID NO: 12),或
YMFPNAPYL (SEQ ID NO: 13) (参见,WO2009/072610);
CMTWNQMNL (SEQ ID NO: 3)的改变的杀伤肽,诸如
CYTWNQMNL (SEQ ID NO: 14) (参见WO02/79253);
Xaa-Met-Thr-Trp-Asn-Gln-Met-Asn-Leu (SEQ ID NO: 15) (其中Xaa是Ser或Ala) 或
Xaa-Tyr-Thr-Trp-Asn-Gln-Met-Asn-Leu (SEQ ID NO: 16) (其中Xaa是Ser、Ala、Abu、Arg、Lys、Orn、Cit、Leu、Phe或Asn) (参见,WO2004/026897);
ALLPAVPSL (SEQ ID NO: 4)的改变的杀伤肽,诸如AYLPAVPSL (SEQ ID NO: 17)(参见,WO2003/106682);
SLGEQQYSV (SEQ ID NO: 5)的改变的杀伤肽,诸如
FLGEQQYSV (SEQ ID NO: 18)、
SMGEQQYSV (SEQ ID NO: 19)或
SLMEQQYSV (SEQ ID NO: 20) (参见,WO2009/072610);或
RVPGVAPTL (SEQ ID NO: 6)的改变的杀伤肽,诸如RYPGVAPTL (SEQ ID NO: 21)(参见,WO2003/106682)。
在一个实施方案中,改变的杀伤肽是改变的肽,其中1-4个氨基酸残基附于杀伤肽的N-末端。在一个实施方案中,添加的氨基酸独立选自丙氨酸残基、精氨酸残基、天冬酰胺残基、半胱氨酸残基、谷氨酰胺残基、谷氨酸残基、组氨酸残基、异亮氨酸残基、亮氨酸残基、赖氨酸残基、甲硫氨酸残基、苯丙氨酸残基、脯氨酸残基、丝氨酸残基、苏氨酸残基、色氨酸残基、酪氨酸残基和缬氨酸残基,优选选自精氨酸残基、谷氨酰胺残基、谷氨酸残基、组氨酸残基,赖氨酸残基、苯丙氨酸残基和酪氨酸残基。优选添加1至3个氨基酸残基,进一步优选1至2个氨基酸残基,并且最优选1个氨基酸残基。
所述改变的杀伤肽的实例包括由10至12个氨基酸组成的肽,其包含SEQ ID NO: 3或SEQ ID NO: 14的氨基酸序列和附于所述序列的N-末端半胱氨酸的氨基的1至3个氨基酸残基。
在一个实施方案中,改变的杀伤肽是包含或由选自以下的氨基酸序列组成的肽:
RCMTWNQMNL (SEQ ID NO: 22)、
RCYTWNQMNL (SEQ ID NO: 23)、
QCMTWNQMNL (SEQ ID NO: 24)、
QCYTWNQMNL (SEQ ID NO: 25)、
ECMTWNQMNL (SEQ ID NO: 26)、
ECYTWNQMNL (SEQ ID NO: 27)、
HCMTWNQMNL (SEQ ID NO: 28)、
HCYTWNQMNL (SEQ ID NO: 29)、
KCMTWNQMNL (SEQ ID NO: 30)、
KCYTWNQMNL (SEQ ID NO: 31)、
FCMTWNQMNL (SEQ ID NO: 32)、
FCYTWNQMNL (SEQ ID NO: 33)、
YCMTWNQMNL (SEQ ID NO: 34),和
YCYTWNQMNL (SEQ ID NO: 35)。
在一个实施方案中,“MHC I类-限制性肽”是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7)
或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
在进一步实施方案中,“MHC I类-限制性肽”是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2)、
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7)
或由在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列组成且具有诱导CTL能力的肽。
在进一步实施方案中,“MHC I类-限制性肽”是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2)、
CMTWNQMNL (SEQ ID NO: 3)和
VLDFAPPGA (SEQ ID NO: 7),或
包含在选自SEQ ID NO: 2、3和7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
在进一步实施方案中,“MHC I类-限制性肽”是由选自以下氨基酸序列组成的肽:
RMFPNAPYL (SEQ ID NO: 2)、
CMTWNQMNL (SEQ ID NO: 3)和
VLDFAPPGA (SEQ ID NO: 7),或
由在选自SEQ ID NO: 2、3和7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列组成且具有诱导CTL能力的肽。
在进一步实施方案中,“MHC I类-限制性肽”是包含或由选自以下的氨基酸序列组成的肽:
RMFPNAPYL (SEQ ID NO: 2)、
RYFPNAPYL (SEQ ID NO: 8)、
YMFPNAPYL (SEQ ID NO: 13)、
CMTWNQMNL (SEQ ID NO: 3)、
CYTWNQMNL (SEQ ID NO: 14),和
VLDFAPPGA (SEQ ID NO: 7)。
在进一步实施方案中,“MHC I类-限制性肽”是包含或由选自以下的氨基酸序列组成的肽:RMFPNAPYL (SEQ ID NO: 2)、RYFPNAPYL (SEQ ID NO: 8)或YMFPNAPYL (SEQ IDNO: 13)。
在进一步实施方案中,“MHC I类-限制性肽”是包含或由选自以下的氨基酸序列组成的肽:RMFPNAPYL (SEQ ID NO: 2)、VLDFAPPGA (SEQ ID NO: 7)或YMFPNAPYL (SEQ IDNO: 13)。
在进一步实施方案中,“MHC I类-限制性肽”是包含或由选自以下的氨基酸序列组成的肽:RMFPNAPYL (SEQ ID NO: 2)。
在进一步实施方案中,“MHC I类-限制性肽”是由选自以下的氨基酸序列组成的肽:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41),和
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)。
在进一步实施方案中,“MHC I类-限制性肽”是由选自以下的氨基酸序列组成的肽:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)和
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)。
术语“MHC II类-限制”指肽结合主要组织相容性复合体(MHC) II类分子以诱导辅助T细胞的能力。所述“MHC II类-限制性肽”是指肽在体外和/或在体内能够结合MHC II类分子和诱导辅助T细胞的能力(也就是说,具有诱导辅助T细胞的能力的肽)。在本文中所述“MHC II类-限制性肽”也被称为“辅助肽”。
对应于MHC II类-分子的HLA分子被分类为亚型,诸如HLA-DR、DQ和DP。“MHC II类-限制”的优选实例包括HLA-DR限制、HLA-DQ限制或HLA-DP限制。
对于每种HLA亚型,等位基因多态性是已知的。等位基因多态性的实例包括DRB1*0101、DRB1*0405、DRB1*0802、DRB1*0803、DRB1*0901、DRB1*1201、DRB1*1403、DRB1*1501、DRB1*1502、DPB1*0201、DPB1*0202、DPB1*0402、DPB1*0501、DPB1*0901、DQB1*0301、DQB1*0302、DQB1*0401、DQB1*0501、DQB1*0601、DQB1*0602和DRB5*0102。优选,提到的DRB1*0101、DRB1*0405、DRB1*1502、DPB1*0201、DPB1*0202或DQB1*0601。
所述“MHC II 类-限制性肽”可由任何类型的任何数量的氨基酸的序列组成。然而,越长的肽链越容易可以通过蛋白酶以降解。此外,太小的肽可能不能成功在MHC II类分子的肽-结合沟中捕获。所述“MHC II 类-限制性肽”通常由9至30个氨基酸残基、优选10至25个氨基酸残基、更优选12至24个氨基酸残基、或再更优选15至22个氨基酸残基组成。
所述“MHC II类-限制性肽”包括此类肽,所述肽用蛋白酶体和/或蛋白酶降解,和/或用ERAP1剪切或修剪至适当的肽长度,以提供“MHC II类-限制的表位”。术语“MHC II类-限制的表位”是指对应于与MHC II类分子复合的实际肽且存在的肽。也就是说,术语“MHCII类-限制性肽”包括这样的肽,所述肽经过诸如在体外或在体内降解或修剪的方法产生能够结合MHC II类分子的肽 (也就是说,在诸如体外或体内降解或修剪的方法之后,结合MHCII类分子的肽)。
如本文所用,在本文中由改变的氨基酸序列组成的辅助肽也被称为“改变的辅助肽”。当包括HLA-DRB1*0405结合基序的由九个氨基酸残基的氨基酸序列组成的辅助肽由氨基酸取代改变时,所述取代优选在位置1、位置4、位置6和/或位置9进行。更优选,包括HLA-DRB1*0405结合基序的由九个氨基酸残基的序列组成的辅助肽由氨基酸取代改变,以具有选自以下的氨基酸残基:
在位置1的苯丙氨酸、色氨酸、缬氨酸、异亮氨酸、亮氨酸或甲硫氨酸;
在位置4的缬氨酸、异亮氨酸、甲硫氨酸、天冬氨酸和谷氨酸;
在位置6的天冬酰胺、丝氨酸、苏氨酸、谷氨酰胺、赖氨酸和天冬氨酸;和
在位置9的天冬氨酸,谷氨酸和谷氨酰胺。
所述“MHC II类-限制性肽”的实例包括包含选自以下氨基酸序列的肽:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48),或
包含在选自SEQ ID NO: 36至48的氨基酸序列中具有一个或几个氨基酸残基改变的氨基酸序列且具有诱导辅助T细胞能力的肽。进一步优选,所述“MHC II类-限制性肽”的实例包括由在选自SEQ ID NO: 36至48的氨基酸序列组成的肽,和由在选自SEQ ID NO: 36至48的氨基酸序列中具有一个或几个氨基酸残基改变的氨基酸序列且具有诱导辅助T细胞能力的肽。
在一个实施方案中,R1代表癌抗原肽C,并且所述癌抗原肽C是由选自以下氨基酸序列的氨基酸序列组成的肽:
CMTWNQMNL (SEQ ID NO: 3)、
CYTWNQMNL (SEQ ID NO: 14)、
RCMTWNQMNL (SEQ ID NO: 22)、
RCYTWNQMNL (SEQ ID NO: 23)、
QCMTWNQMNL (SEQ ID NO: 24)、
QCYTWNQMNL (SEQ ID NO: 25)、
ECMTWNQMNL (SEQ ID NO: 26)、
ECYTWNQMNL (SEQ ID NO: 27)、
HCMTWNQMNL (SEQ ID NO: 28)、
HCYTWNQMNL (SEQ ID NO: 29)、
KCMTWNQMNL (SEQ ID NO: 30)、
KCYTWNQMNL (SEQ ID NO: 31)、
FCMTWNQMNL (SEQ ID NO: 32)、
FCYTWNQMNL (SEQ ID NO: 33)、
YCMTWNQMNL (SEQ ID NO: 34),和
YCYTWNQMNL (SEQ ID NO: 35)。
由式(1)表示的化合物的实例包括式(6)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(7)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(8)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(9)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(10)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(11)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(12)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(13)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(14)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(15)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(16)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(17)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;
式(18)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;和
式(19)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
进一步,由式(1)表示的化合物可以是包含或由选自以下氨基酸序列组成的肽:
CRMFPNAPYL (SEQ ID NO: 49)、
CCMTWNQMNL (SEQ ID NO: 50)、
CCYTWNQMNL (SEQ ID NO: 51)、
CALLPAVPSL (SEQ ID NO: 52)、
CSLGEQQYSV (SEQ ID NO: 53)、
CRVPGVAPTL (SEQ ID NO: 54)和
CVLDFAPPGA (SEQ ID NO: 55)。
肽可以在它序列中具有氨基酸残基的修饰。修饰可以通过常规方法进行,例如通过在氨基酸残基官能团上酯化、烷基化、卤化、磷酸化、磺化或酰胺化。肽的氨基酸修饰也可以是肽的N-末端和/或C-末端的任意各种部分的添加。肽可以通过以下方式来修饰,所述方式有调节肽溶解度的此类部分的添加、稳定肽来抵抗例如蛋白水解降解、将肽引导至特定的组织或器官,或提高通过抗原呈递细胞对肽的捕获。
在肽中,它的N-末端氨基酸的氨基或它的C-末端氨基酸的羧基可以被修饰。例如,所述氨基可以通过添加选自以下的一至三个基团来修饰:C1-6-烷基、苯基、环烷基、或酰基,诸如C1-6-烷酰基、苯基-C1-6-烷酰基、C5-7-环烷基-羰基、C1-6-烷基磺酰、苯磺酰基、C2-6-烷氧基-羰基、苯基-烷氧羰基、C5-7-环烷氧基-羰基或苯氧羰基。所述C-末端的羧基可以被修饰,例如通过转化为酯,诸如C1-6-烷基酯、苯基-C0-6-烷基酯、或C5-7-环烷基酯,或转化为酰胺,诸如单-或双-C1-6-烷基酰胺、单-或双-苯基-C0-6-烷基酰胺、或双-取代酰胺,其中所述双取代基与氮原子共同形成,它们附于5-至7-元氮杂环烷衍生物。
在肽中,氨基酸残基之间的键可以是肽键或其它类型的键,诸如碳-碳键、碳-氮键、或碳-硫键。如本文所描述的肽可以包含一个或多个D-氨基酸残基。
关于肽的修饰的以上说明仅仅是解释性的,并且其各种变化对本领域技术人员来说可设想的。此类修饰的肽可由本领域普通技术人员来制备、测试或使用。
肽诱导CTL或辅助T细胞的能力通过常规方法来证明。例如,CTL的诱导可以通过由HLA四聚体方法或限制稀释法(Nat. Med.: 4, 321-327 (1998))计数CTL(Int. J.Cancer: 100, 565-570 (2002))来证实。由HLA-A24-限制性肽诱导的CTL也可以通过如WO02/47474或Int. J. Cancer: 100, 565-570 (2002)中所描述的使用HLA-A24小鼠模型来证实。例如,辅助T细胞的诱导可以通过如Cancer Immunol. Immunother. 51: 271 (2002)或本文实施例部分所描述的方法来证实。
如本文所描述的肽或化合物,或用于其合成的中间肽可以使用用于肽合成的常规方法来合成,所述方法例如如在以下所述的那些:Peptide Synthesis, Interscience,New York, 1966; The Proteins, Vol 2, Academic Press Inc., New York, 1976;peptide synthesis, Maruzen Co., LTD., 1975; Basics and Experiment of PeptideSynthesis, Maruzen Co., LTD., 1985; or Development of Pharmaceutical Productsubsequent vol. 14, Peptide Synthesis, Hirokawa Shoten, 1991。此类技术的实例包括通过Fmoc方法或Boc方法的固相合成,或通过液相中的Boc-氨基酸或Z-氨基酸的相继缩合的液相合成(其中Fmoc是9-芴基甲氧基羰基基团,Boc是叔丁氧基羰基基团,Z是苄基氧基羰基基团)。所述肽可以通过根据常规已知方法使用核苷酸序列编码的肽的遗传技术来获得,所述常规已知方法例如如Molecular Cloning, T. Maniatis et al., CSHLaboratory (1983), DNA Cloning, DM. Glover, IRL PRESS (1985)中所描述。
由式(1)表示的化合物可以从两种不同的MHC I类-限制性肽,或从MHC I类-限制性肽和MHC II类-限制性肽来制备,例如,通过二硫键连接来连接所述肽(WO 2014/157692)。
在由式(1)表示的化合物合成期间,中间化合物的官能团,诸如氨基、羧基或巯基,可以用适当的保护基团来保护,或如所需要的通过常规方法来脱保护。对于此类保护基团的信息,或保护或脱保护的方法,可参考"Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.; 1990)"。作为巯基的保护基,乙酰氨基甲基或三苯甲基基团可以是有用的。
当由式(1)表示的化合物包括二硫键,连接在所述化合物的两种不同的包含半胱氨酸的肽组分之间,或在所述化合物的包含半胱氨酸的肽组分和半胱氨酸残基之间形成。此类二硫键可以通过如以下所述的方法形成,例如所述方法如Peptide Synthesis,Interscience, New York, 1966; The Proteins, Vol. 2, Academic Press Inc., NewYork, 1976; peptide synthesis, Maruzen Co., LTD., 1975; Basics and Experimentof peptide synthesis, Maruzen Co., LTD., 1985; 或Development ofPharmaceutical Product sequential vol. 14, Peptide Synthesis, HirokawaShoten, 1991中所述。
具体地,为了从具有一个半胱氨酸残基的肽制备具有二硫键(二硫化物化合物)的化合物,所述肽可以经过用于在半胱氨酸残基的包括巯基的官能团上除去任何保护基团的脱保护反应,并且之后在氧化条件下,在惰性溶剂中处理,用于形成二硫键。二硫化物化合物也可以从两种不同的具有巯基的中间体通过在氧化条件下,在适当的溶剂中处理它们来制备。用于二硫键形成的氧化条件在肽合成领域是已知的。例如,已知的碘氧化方法、在碱性条件下的空气氧化方法,或在碱性或酸性条件下通过氧化剂的氧化可用于形成二硫键。作为氧化剂,碘、二甲亚砜(DMSO)或铁氰化钾可以被使用。作为用于反应的溶剂,水、乙酸、甲醇、氯仿、DMF,或DMSO,或其混合物可以被使用。此类氧化条件经常产生以对称和不对称二硫化物化合物的混合物为形式的产物。期望的不对称二硫化物化合物可以通过适当的色谱方法或重结晶来回收或纯化。具有活性巯基的中间体,例如结合Npys基(3-硝基-2-吡啶亚磺酰基基团)的巯基,可以被使用。为了在中间体的给定巯基上形成二硫键,在与另一中间体连接之前,所述基团可以通过2,2'-二硫代双(5-硝基吡啶)活化(TetrahedronLetters. Vol. 37. No. 9, pp. 1347-1350)。
以上所描述的方法可用于从具有一个以上半胱氨酸的肽来制备二硫化物化合物。然而,在那种情况下,可以形成在不同半胱氨酸残基之间具有二硫键的不同二硫化物化合物的混合物。为了选择性制备由在单体特定位置之间的二硫键二聚化的产物,不同的保护基团可以组合使用用于所述半胱氨酸残基的官能团的保护。保护基团的此类组合的实例包括MeBzl (甲基苄基)和Acm (乙酰氨基甲基);Trt (三苯甲基)和Acm;Npys (3-硝基-2-吡啶基硫基)和Acm;以及S-Bu-t (S-叔丁基)和Acm的组合。例如,当用MeBzl和Acm的组合保护的肽被用于选择性二硫键形成时,在第一步,除了某些半胱氨酸残基,除去氨基酸残基的官能团上的所有MeBzl保护基团和Acm保护基团。然后,在空气氧化条件下处理在溶液中的所述肽单体,二硫键可以在所述单体的选择性脱保护的半胱氨酸残基之间形成。然后,经过除去剩余的Acm保护基团和在氧化条件下用碘处理,进一步的二硫键可以在新脱保护的半胱氨酸残基上形成。
合成的肽、化合物或中间体可以通过本领域或肽化学领域已知的任何纯化方法来纯化。此类纯化技术的实例包括各种类型的色谱(例如硅胶柱色谱、离子交换柱色谱、凝胶过滤或反相色谱)和来自溶剂的重结晶,所述溶剂例如醇溶剂诸如甲醇、乙醇或2-丙醇;醚溶剂诸如乙醚;酯溶剂诸如乙酸乙酯;芳烃溶剂诸如苯或甲苯;酮溶剂诸如丙酮;烃溶剂诸如己烷;非质子溶剂诸如二甲基甲酰胺或乙腈;水;或其混合物。对于进一步有用的纯化方法,可以参考例如Jikken Kagaku Kouza (The Chemical Society of Japan ed.,Maruzen) vol. 1。二硫化物化合物的纯化方法也在Peptide Synthesis, Interscience,New York, 1966; The Proteins, Vol. 2, Academic Press Inc., New York, 1976;peptide synthesis, Maruzen Co., LTD., 1975; Basics and Experiment of peptidesynthesis, Maruzen Co., LTD., 1985; 或Development of Pharmaceutical Productsequential vol. 14, Peptide Synthesis, Hirokawa Shoten, 1991中描述。通过HPLC的纯化是优选的。
由式(1)表示的化合物可具有一个或多个不对称中心。此类化合物可以从具有对应的不对称中心的起始物质(氨基酸)来制备。此外,可以通过在它的合成方法中的包含光学拆分步骤来获得高光学纯度的由式(1)表示的化合物。例如,根据用于光学拆分的非对映异构体方法,由式(1)表示的化合物或中间体产物可以用在惰性溶剂(例如醇溶剂诸如甲醇、乙醇或2-丙醇,醚溶剂诸如乙醚,酯溶剂诸如乙酸乙酯,烃溶剂诸如甲苯,非质子溶剂诸如乙腈,或其混合物)中的光学活性酸处理(例如单羧酸诸如扁桃酸、N-苄基氧基丙氨酸或乳酸,二羧酸诸如酒石酸、邻二异亚丙基酒石酸或苹果酸或磺酸诸如樟脑磺酸或溴樟脑磺酸),以形成盐。为了光学拆分由式(1)表示的化合物或具有诸如羧基的酸性官能团的中间体产物,它的盐可以与光学活性胺(例如,有机胺诸如α-苯乙胺、激肽、奎尼丁、辛可尼定、辛可宁或士的宁)形成。
盐可以在一定温度形成,所述温度在室温高至使用的溶剂的沸点的范围。为了获得高光学纯度形式的产物,期望在一段时间段内升温至所述溶剂的沸点附近。使形成的盐结晶,并且之后过滤,为了提高得率,可选冷却。用于盐形成的光学活性的酸或胺可以以相对于光学拆分的化合物的量的约0.5至约2.0当量、优选约1当量的量使用。结晶产物可以通过从惰性溶剂(例如醇溶剂诸如甲醇、乙醇或2-丙醇,醚溶剂诸如乙醚,酯溶剂诸如乙酸乙酯,烃溶剂诸如甲苯,非质子溶剂诸如乙腈,或其混合物)中重结晶来任选进一步纯化。可以任选用酸或碱处理将以盐形式回收的产物转化为游离的碱或酸。
如本文所用的术语“药学上可接受的盐”包括酸加成盐和碱加成盐。所述酸加成盐可以是无机酸盐诸如盐酸盐、氢溴酸盐、硫酸盐、氢碘酸盐、硝酸盐或磷酸盐,或有机酸盐诸如柠檬酸盐、草酸盐、乙酸盐、甲酸盐、丙酸盐、苯甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。碱加成盐可以是与无机碱的盐诸如钠盐、钾盐、钙盐、镁盐或铵盐,与有机碱的盐诸如三乙基铵盐、三乙醇铵盐、吡啶鎓盐或二异丙基铵盐。“药学上可接受的盐”也包括具有碱性或酸性氨基酸诸如精氨酸、天冬氨酸和谷氨酸的盐。如本文所用的术语“肽”或“化合物”包括药学上可接受的盐的形式的肽或化合物,除非上下文另有要求。
本公开进一步包括水合物和溶剂化物,诸如如本文所描述的,(a)的肽的乙醇溶剂化物或由式(1)表示的化合物或所述肽或其药学上可接受的盐。本公开也包括任何立体异构体,诸如非对映异构体或对映异构体,和如本文所描述的化合物或肽的任何晶体形式。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐可用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。因此,在一个实施方案中,本公开提供包含(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的药物组合物,用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。
HLA-A*02:07-阳性受试者、HLA-A*03:01-阳性受试者、HLA-B*15:01-阳性受试者和HLA-B*27:05-阳性受试者是指具有HLA单倍型的受试者,所述HLA单倍型:分别为HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05。HLA等位基因(HLA类型)由通常使用的HLA分型(具体而言,基因分型)来指定。所述“受试者”的实例包括人类和非人类动物,诸如非人灵长类、羊、犬、猫、马和牛。人类受试者是优选的。
如本文所用,所述治疗癌症包括完全或部分抑制癌症发展,并且至少部分降低癌症的一种或多种症状。所述治疗癌症也包括诱导缓解、维持缓解和抑制复发。
在一个实施方案中,所述药物组合物是癌症疫苗。在另一个实施方案中,所述药物组合物是用于在癌症细胞免疫疗法中诱导CTL的组合物。
在一个实施方案中,所述癌症是指其中表达WT1的癌症或具有升高的WT1基因表达水平的癌症。
在一个实施方案中,所述癌症是指血液癌症或实体癌症。在进一步实施方案中,所述癌症是指选自以下的癌症:慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病和慢性成淋巴细胞性白血病、骨髓增生异常综合征、多发性骨髓瘤、恶性淋巴瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、宫颈癌、卵巢癌、脑肿瘤、胶质瘤、中枢神经系统原发性恶性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞淋巴瘤、淋巴细胞淋巴瘤、T细胞淋巴瘤、骨癌、胰腺癌、头和颈部癌、皮肤或眼内恶性黑色素瘤、直肠癌、肛门癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、儿童实体肿瘤、肾癌或输尿管癌、肾盂癌、中枢神经系统肿瘤、肿瘤血管生成、脊髓肿瘤、脑干神经胶质瘤、脑垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、环境诱导的癌症,包括石棉诱导的癌症,以及这些癌症的组合。在进一步实施方案中,所述癌症选自慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性成淋巴细胞性白血病和慢性成淋巴细胞性白血病、骨髓增生异常综合征、多发性骨髓瘤、恶性淋巴瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、宫颈癌、卵巢癌、脑肿瘤和神经胶质瘤。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,或包含相同物质的药物组合物可以与至少一种不同的癌抗原肽,具体而言,MHC I类-限制性肽或MHC II类-限制性肽、其缀合物或其药学上可接受的盐组合使用。不同的癌抗原肽或缀合物的实例包括如以下出版物所描述的肽或其衍生物,或其缀合物:WO2000/006602、WO2002/079253、WO2003/106682、WO2004/026897、WO2004/063903、WO2007/063903、WO2010/123065、WO2014/157692、WO2005/053618、WO2007/047764、WO2007/120673、WO2005/045027、WO2010/037395、WO2000/018795、WO2002/028414、WO2003/037060和WO2004/100870。
在一个实施方案中,(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,或包含相同物质的药物组合物可以与MHC II类-限制性肽组合使用。在一个实施方案中,所述MHC II类-限制性肽包括或由通过WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)表示的氨基酸序列组成。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,或包含相同物质的药物组合物可以与至少一种不同的药物(在本文中也被称为共施用药物)组合使用。
所述共施用药物可以是“免疫调节剂”。如本文所用,术语“免疫调节剂”是指通过与参与共刺激信号的传递且存在于抗原-呈递细胞和/或T细胞上的分子相互作用,而控制通过抗原-呈递细胞活化T细胞期间的共刺激信号的传递的任何试剂,以及直接或间接控制参与建立免疫系统中的免疫耐受(免疫抑制)的分子功能的任何试剂。由于癌抗原肽对增加肿瘤中的肿瘤反应性CTL是有效的,它有潜力用作与免疫调节剂共同施用的药物,用于减少免疫调节剂的必需剂量或减少由免疫调节剂造成的不良事件。因此,本公开提供了经过使用与免疫调节剂组合的癌抗原肽,具有提高疗效和安全性的疗法。
“免疫调节剂”可以是抗体、核酸、蛋白质、肽,或小化合物形式的试剂,但不限于此。作为“免疫调节剂”的“抗体”包括抗体片段。抗体片段的实例包括抗体(VH和VL)、F(ab')2、Fab'、Fab、Fv、Fd、sdFv和scFV的重链和轻链可变区。作为“免疫调节剂”的“蛋白”是指除了抗体以外的任何蛋白。所述“免疫调节剂”的实例包括免疫检查点抑制剂、共刺激分子激动剂、免疫活化剂和低分子抑制剂。
“免疫检查点抑制剂”抑制由癌细胞或抗原呈递细胞诱导的免疫抑制作用。免疫检查点抑制剂的实例包括,但不限于,针对选自以下的分子的试剂:(1) CTLA-4 (例如,伊匹单抗和曲美木单抗(tremelimumab)); (2) PD-1 (例如,纳武单抗、派姆单抗、AMP-224、AMP-514 (MEDI0680)和pidilizumab (CT-011)); (3) LAG-3 (例如,IMP-321和BMS-986016); (4) BTLA; (5) KIR (例如,IPH2101); (6) TIM-3; (7) PD-L1 (例如,durvalumab (MEDI4736), MPDL3280A, BMS-936559和avelumab (MSB0010718C)); (8)PD-L2; (9) B7-H3 (例如,MGA-271); (10) B7-H4; (11) HVEM; (12) GAL9; (13)CD160; (14) VISTA; (15) BTNL2; (16) TIGIT; (17) PVR; (18) BTN1A1; (19)BTN2A2; (20) BTN3A2 (Nat Rev Drug Discov. 2013; 12: 130-146; Nikkei MedicalCancer Review 2014; 9; Nat Rev Immunol. 2014; 14: 559-69);和(21) CSF1-R。
“共刺激分子激动剂”通过经由T细胞和/或抗原呈递细胞上的共刺激分子传递辅助信号来增强T细胞,并且减弱癌细胞或抗原呈递细胞的免疫抑制作用。共刺激分子激动剂的实例包括,但不限于,针对选自以下的分子的试剂:(1) 4-1BB;(2) 4-1BB-L;(3) OX40(4) OX40-L;(5) GITR;(6) CD28;(7) CD40;(8) CD40-L;(9) ICOS;(10) ICOS-L;(11)LIGHT;和(12) CD27。
“免疫活化剂”通过直接或间接活化免疫细胞诸如T细胞和树突细胞,有效地刺激淋巴结中的CTL。免疫活化剂的实例包括,但不限于,Toll-样受体(TLR)激动剂、干扰素基因的刺激剂(STING)激动剂、细胞因子和针对热休克蛋白(HSP)的试剂。
“Toll-样受体(TLR)激动剂”的实例包括,但不限于,TLR1/2激动剂、TLR2激动剂、TLR3激动剂(例如聚I:C)、TLR4激动剂(例如S型脂多糖、紫杉醇、脂质A和单磷酰脂质A)、TLR5激动剂(例如鞭毛蛋白)、TLR6/2激动剂(例如MALP-2)、TLR7激动剂 (例如gardiquimod、咪喹莫特、洛索立宾)、TLR7/8激动剂(例如瑞喹莫德(R848))、TLR7/9激动剂、TLR8激动剂(例如,motolimod (VTX-2337))、TLR9激动剂(例如CpG-ODN)和TLR11激动剂(例如前纤维蛋白(profilin))。
“细胞因子”的实例包括,但不限于,IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、干扰素(INF)-α、INF-β、INF-γ、SCF、GM-CSF、G-CSF、M-CSF、促红细胞生成素、促血小板生成素、巨噬细胞炎性蛋白(MIP)和单核细胞趋化蛋白(MCP)。
“热休克蛋白(HSP)”的实例包括,但不限于,HSP70、HSP90、HSP90α、HSP90β、HSP105、HSP72和HSP40。针对热休克蛋白的试剂包括HSP抑制剂。例如,HSP90抑制剂的实例包括,但不限于,塔尼霉素(17-AAG)、luminespib (AUY-922、NVP-AUY922)、阿螺旋霉素(17-DMAG)盐酸盐、ganetespib (STA-9090)、BIIB021、onalespib (AT13387)、格尔德霉素、NVP-BEP800、SNX-2112 (PF-04928473)、PF-4929113 (SNX-5422)、KW-2478、XL888、VER155008、VER-50589、CH5138303、VER-49009、NMS-E973、PU-H71、HSP990 (NVP-HSP990)和KNK437。
“低分子抑制剂”的实例包括,但不限于,组蛋白脱乙酰酶抑制剂、组蛋白脱甲基酶抑制剂、组蛋白乙酰转移酶抑制剂、组蛋白甲基转移酶抑制剂、DNA甲基转移酶抑制剂、蒽环类抗生素、铂制剂、MAPK抑制剂、β-联蛋白抑制剂、STAT3抑制剂、NF-kB抑制剂、JAK抑制剂、mTOR抑制剂、IDO抑制剂、COX-2抑制剂、CXCR4抑制剂和精氨酸酶抑制剂。
“组蛋白脱乙酰酶抑制剂”的实例包括,但不限于,伏立诺他(SAHA、MK0683)、恩替诺特(MS-275)、帕比司他(LBH589)、曲古抑菌素A (TSA)、mocetinostat (MGCD0103)、BG45、BRD73954、贝利司他 (PXD101)、罗米地辛(FK228、缩酚酸肽)、4SC-202、HPOB、LMK-235、CAY10603、他喹莫德、TMP269、nexturastat A、罗西司他(ACY-1215)、RGFP966、RG2833(RGFP109)、scriptaid、pacinostat (SB939)、CUDC-101、M344、PCI-34051、达西司特(LAQ824)、tubastatin A盐酸盐、abexinostat (PCI-24781)、CUDC-907、AR-42、苯基丁酸钠、resminostat、tubacin、quisinostat (JNJ-26481585)二盐酸盐、MC1568、givinostat(ITF2357)、droxinostat、西达本胺(C S055、HBI-8000)、CHR-2485、CHR-3996、DAC-060、FRM-0334 (EVP-0334)、MGCD-290、CXD- 101 (AZD-9468)、CG200745、精氨酸丁酸酯、萝卜硫素、SHP-141、CUDC-907、YM753 (OBP-801)、丙戊酸钠、apicidin和CI994 (tacedinaline)。
“组蛋白脱甲基酶抑制剂”的实例包括,但不限于,GSK J4 HCl、OG-L002、JIB-04、IOX1、SP2509、ORY-1001 (RG-6016)、GSK J1、ML324和GSK-LSD1 2HCl。
“组蛋白乙酰转移酶抑制剂”的实例包括但不限于C646、MG149、remodelin和漆树酸。
“组蛋白甲基转移酶抑制剂”的实例包括,但不限于,pinometostat (EPZ5676)、EPZ005678、GSK343、BIX01294、tazemetostat (EPZ6438)、3-脱氮腺苷类似物A ((DZNeP)HCl、UNC1999、MM-102、SGC0946、恩他卡朋、EPZ015666、UNC0379、EI1、MI-2(menin-MLL抑制剂)、MI-3(menin-MLL抑制剂)、PFI-2、GSK126、EPZ04777、BRD4770、GSK-2816126和UNC0631。
“DNA甲基转移酶抑制剂”的实例包括,但不限于,地西他滨、氮杂环丁烷、RG108、硫鸟嘌呤、zebularine、SGI-110、CC-486、SGI-1027、罗米鲁曲和普鲁卡因酰胺盐酸盐。
“蒽环类抗生素”被间插在DNA链之间以抑制DNA松弛。蒽环类抗生素的实例包括,但不限于,多柔比星、多柔比星脂质体、道诺霉素、吡柔比星、表柔比星、伊达比星、阿柔比星、氨柔比星、芦荟素和米托蒽醌。
“铂制剂”的实例包括,但不限于,顺铂、卡铂、miboplatin、奈达铂、赛特铂(JM-126)、奥沙利铂(ELOXATIN)、四硝酸三铂及其DDS制剂。
“MAPK抑制剂”的实例包括,但不限于,SB203580、达马莫德(BIRB796)、SB202190(FHPI)、LY2228820、VX-702、SB239063、培美替尼(ARRY-614)、PH-797804、VX-745和TAK-715。
“β-联蛋白抑制剂”的实例包括,但不限于,XAV-939、ICG-001、IWR-1-endo、Wnt-C59 (C59)、LGK-974、KY02111、IWP-2、IWP-L6、WIKI4和FH535。
“STAT3抑制剂”的实例包括,但不限于,S3I-201、Stattic、氯硝柳胺、硝呋齐特、napabucasin (BBI608)、隐丹参酮、HO-3867、WHI-P154、FLLL32、STA-21、WP1066和SH-4-54。
“NF-κB抑制剂”的实例包括,但不限于,QNZ (EVP4593)、4-氨基水杨酸钠、JSH-23、咖啡酸苯乙酯、水杨酸钠、穿心莲内酯和SC75741。
“JAK抑制剂”的实例包括,但不限于,鲁索替尼(INCB018424)、托法替尼 (CP-690550)柠檬酸盐、AZD1480、fedratinib (SAR302503、TG101348)、AT9283、酪氨酸磷酸化抑制剂B42(AG-490)、momelotinib (CYT387)、托法替尼(CP-690550、tasocitinib)、WP1066、TG101209、gandotinib (LY2784544)、NVP-BSK805 2HCl、巴瑞克替尼(LY3009104、INCB02850)、AZ960、CEP-33779、pacritinib (SB1518)、WHI-P154、XL019、S-鲁索替尼(INCB018424)、ZM39923 HCl、decernotinib (VX-509)、cerdulatinib (PRT062070、PRT2070)、filgotinib (GLPG0634)、FLLL32、培非替尼(ASP015K、JNJ-54781532)、GLPG0634类似物、Go6976和姜黄醇。
“mTOR抑制剂”的实例包括,但不限于,西罗莫司(雷帕霉素)、deforolimus(AP23573、MK-8669)、依维莫司(RAD-001)、替西罗莫司(CCI-779、NSC683864)、佐他莫司(ABT-578)、biolimus A9 (umirolimus)、AZD8055、KU-0063794、voxtalisib (XL765、SAR245409)、MHY1485、dactolisib (BEZ235、NVP-BEZ235)、PI-103和torkinib (PP242)。
“IDO抑制剂”的实例包括,但不限于,NLG919、INCB024360类似物、indoximod(NLG-8189)和epacadostat (INCB024360)。
“COX-2抑制剂”的实例包括,但不限于,伐地考昔、罗非考昔、卡洛芬、塞来昔布、罗美昔布、托芬那酸、尼美舒利、尼氟酸、阿那达林、氯诺昔康、甲氯芬那酸钠、氨芬酸钠、双氯芬酸钠、酮洛芬、酮咯酸、萘普生钠、吲哚美辛、布洛芬、阿司匹林、甲芬那酸、溴芬酸钠、奥沙普秦、扎托布洛芬和奈帕芬胺。
“CXCR4抑制剂”的实例包括,但不限于,WZ811、普乐沙福(AMD3100)和普乐沙福8HCl (AMD3100 8HCl)。
共施用药物可以是一种或多种选自以下的药物:“激素治疗剂”、“免疫治疗剂”、“生物药物”、“细胞生长因子”、“细胞生长因子抑制剂”、“细胞生长因子受体抑制剂”、“放射治疗剂”、“辅助剂”和“化学治疗剂”。例如,从以上药物组选择的一至五种药物、一至三种药物,或一种药物可与(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,或包含相同物质的药物组合物组合使用。
“激素治疗剂”的实例包括肾上腺皮质激素药剂(例如甾体抗炎剂、雌激素制剂、孕酮制剂和雄激素制剂)、抗雌激素药剂、雌激素控制药剂、雌激素合成抑制剂、抗雄激素药剂、雄激素控制药剂、雄激素合成抑制剂、LH-RH激动剂制剂、LH-RH拮抗剂制剂、芳香酶抑制剂、类固醇内酯酶抑制剂、避孕丸、类维生素A和延缓类维生素A的代谢的药剂。
“激素治疗剂”的实例包括磷雌酚、己烯雌酚、fluoxymesterol、氯烯雌醚、甲基睾酮、醋酸甲羟孕酮、醋酸甲地孕酮、醋酸氯地孕酮、醋酸环丙孕酮、达那唑、烯丙雌醇、孕三烯酮、美帕曲星、雷洛昔芬、奥美昔芬、左美洛昔芬、柠檬酸他莫昔芬、柠檬酸托瑞米芬、碘氧昔芬、避孕药丸、美雄烷、睾丸内酯、氨鲁米特、醋酸戈舍瑞林、布舍瑞林、抑那通、亮丙瑞林、屈洛昔芬、表雄甾醇、乙炔雌二醇磺酸盐、雌莫司汀、盐酸法倔唑、阿那曲唑、terorazole、酮康唑、来曲唑、依西美坦、伏罗唑、福美司坦、氟他胺、比卡鲁胺、尼鲁米特、恩杂鲁胺、米非司酮、非那雄胺、地塞米松、泼尼松龙、倍他米松、曲安西龙、阿比特龙、利罗唑、贝沙罗汀和DN101。
“免疫治疗剂”的实例包括毕西巴尼、云芝孢内多糖、西索非兰、香菇多糖、乌苯美司、干扰素(IFN)-α、干扰素(IFN)-β、干扰素(IFN)-γ、白介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、促红细胞生成素、淋巴毒素、BCG疫苗、短小棒状杆菌、左旋咪唑、多糖K、丙考达唑、抗-CTLA4抗体、抗PD-1抗体和TLR激动剂(例如TLR7激动剂、TLR8激动剂、TLR9激动剂)。
“生物药物”的实例包括,但不限于,白介素-2(阿地白介素)、干扰素-α、干扰素-β、干扰素-γ、促红细胞生成素(EPO)、粒细胞集落刺激因子(非格司亭)、粒细胞-巨噬细胞集落刺激因子(沙格司亭)、IL13-PE38QQR、卡介苗、左旋咪唑、奥曲肽、CPG7909、Provenge、GVAX、Myvax、Favld、来那度胺、曲妥珠单抗、利妥昔单抗、吉妥珠单抗奥唑米星、阿仑单抗、内皮抑素、替坦异贝莫单抗、托西莫单抗、西妥昔单抗、zanolimumab、奥法木单抗、HGS-ETR1、帕妥珠单抗、M200、SGN-30、马妥珠单抗、adecatumumab、地诺单抗、zalutumumab、MDX-060、尼妥珠单抗、MORAb-003、Vitaxin、MDX-101、MDX-010、DPC4抗体、NF-1抗体、NF-2抗体、Rb抗体、p53抗体、WT1抗体、BRCA1抗体、BRCA2抗体、神经节苷脂(GM2)、前列腺特异性抗原(PSA)、α-胎蛋白(AFP)、癌胚抗原(CEA)、黑色素瘤相关抗原(MART-1、gap100、MAGE 1,3酪氨酸)、乳头状瘤病毒E6和E7片段及其DDS制剂。
关于“细胞生长因子”、“细胞生长因子抑制剂”和“细胞生长因子受体抑制剂”,细胞生长因子可以是促进细胞增殖的任何药剂。例如,细胞生长因子可以是具有不超过20,000的分子量的肽,并且可以与受体结合,并且以低浓度起作用。
“细胞生长因子”的实例包括,但不限于,表皮生长因子(EGF)、胰岛素样生长因子(IGF(例如胰岛素、IGF-1和IGF-2))、转化生长因子(TGF(例如TGF-α和TGF-β))、神经生长因子(NGF)、脑源性神经营养因子(BDNF)、血管内皮生长因子(VEGF)、集落刺激因子(CSF(例如粒细胞集落刺激(G-CSF))、粒细胞-巨噬细胞集落刺激因子(GM-CSF))、血小板衍生生长因子(PDGF)、促红细胞生成素(EPO)、成纤维细胞生长因子(FGF(例如酸性FGF、碱性FGF、角质形成细胞生长因子(KGK)和FGF-10))、肝细胞生长因子(HGF)、调蛋白和血管生成素。术语“细胞生长因子”与术语“生长因子”同义。
“细胞生长因子抑制剂”的实例包括,但不限于,表皮生长因子抑制剂(EGF抑制剂)、胰岛素样生长因子抑制剂(IGF抑制剂)、神经生长因子抑制剂(NGF抑制剂)、脑源性神经营养因子(BDNF抑制剂)、血管内皮细胞生长因子抑制剂(VEGF抑制剂)、集落刺激因子抑制剂(CSF抑制剂)、血小板衍生生长因子抑制剂(PDGF抑制剂)、促红细胞生成素抑制剂(EPO抑制剂)、成纤维细胞生长因子抑制剂(FGF抑制剂)、肝细胞生长因子抑制剂(HGF抑制剂)、调蛋白抑制剂和促血管生成素抑制剂。术语“细胞生长因子抑制剂”与术语“生长因子抑制剂”同义。
“细胞生长因子受体抑制剂”的实例包括,但不限于,表皮生长因子受体抑制剂(EGFR抑制剂)、胰岛素样生长因子受体抑制剂(IGFR抑制剂)、神经生长因子受体抑制剂(NGFR抑制剂)、脑源性神经营养因子受体抑制剂(BDNFR抑制剂)、血管内皮细胞生长因子受体抑制剂(VEGFR抑制剂)、集落刺激因子受体抑制剂(CSFR抑制剂)、血小板衍生生长因子受体抑制剂(PDGFR抑制剂)、促红细胞生成素受体抑制剂(EPOR抑制剂)、成纤维细胞生长因子受体抑制剂(FGFR抑制剂)、肝细胞生长因子受体抑制剂(HGFR抑制剂)、调蛋白受体抑制剂和血管生成素受体抑制剂。术语“细胞生长因子受体抑制剂”与术语“生长因子受体抑制剂”同义。
“放射治疗剂”的实例包括,但不限于,放射性材料和放射增敏剂。
“辅助剂”是与抗癌剂共同使用的试剂,用于抑制由抗癌剂引起的副作用或呕吐。“辅助剂”的实例包括,但不限于,阿瑞匹坦、昂丹司琼、劳拉西泮、地塞米松、苯海拉明、雷尼替丁、西咪替丁、雷尼替丁、法莫替丁、西咪替丁、普罗克瑞、依泊汀α、非格司亭、奥普瑞白介素、亚叶酸和粒细胞-巨噬细胞集落刺激因子(GM-CSF)。
“化学治疗剂”的实例包括,但不限于,烷化剂、铂制剂、抗代谢物、拓扑异构酶抑制剂、DNA嵌入剂、抗有丝分裂剂、抗肿瘤抗生素、植物来源的抗癌剂、表观基因组药物、免疫调节药物、分子靶向药物、血管生成抑制剂和其它化学治疗剂。下面列出一些典型的化学治疗剂的实例。
“烷化剂”的实例包括,但不限于,氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替派、卡波醌、英丙舒凡甲苯磺酸盐、白消安、盐酸尼莫司汀、二溴甘露醇、美法仑、达卡巴嗪、丙卡巴肼、雷莫司汀、雌莫司汀磷酸钠、曲他胺、卡莫司汀、洛莫司汀、链脲霉素、哌泊溴烷、依托格鲁、六甲蜜胺、氨莫司汀、二溴螺氯铵、福莫司汀、泼尼莫司汀、苯达莫司汀、乌拉莫司汀、司莫司汀、嘌嘧替派、ribomustin、替莫唑胺、曲奥舒凡、曲洛磷胺、净司他丁斯酯、阿多来新、半胱胺亚硝脲、比折来新、二氯甲基二乙胺、尿嘧啶氮芥、链脲霉素、曲贝替定、becaterin、双氯乙基甲胺、甘露舒凡、三亚胺醌、丙卡巴肼、canfosfamide、亚硝基脲类及其DDS制剂。
“铂制剂”的实例包括,但不限于,顺铂、卡铂、miboplatin、奈达铂、赛特铂、奥沙利铂、四硝酸三铂及其DDS制剂。
“抗代谢物”的实例包括,但不限于,抗叶酸剂、嘧啶代谢抑制剂、嘌呤代谢抑制剂、核糖核苷酸还原酶抑制剂和核苷酸类似物。
“抗代谢物”的实例包括,但不限于,巯基嘌呤、6-巯基嘌呤核苷、硫代肌苷、甲氨蝶呤、培美曲塞、eoshitabin、依诺他滨、阿糖胞苷、阿糖胞苷十八烷基磷酸酯、盐酸安西他滨、5-FU药剂(诸如氟尿嘧啶、Carzonal、Bennan、Lunachol、Lunapon、替加氟、替加氟-尿嘧啶、替加氟-吉美嘧啶-氧嗪酸钾(TS-1)、UFT、去氧氟尿苷、卡莫氟、gallocitabine、乙嘧替氟和卡培他滨)、氨喋呤、奈拉滨、亚叶酸钙、Tabloid、丁卡因、亚叶酸钙、左亚叶酸钙、克拉屈滨、乙嘧替氟、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛、碘苷、米托胍腙、噻唑呋林、氨莫司汀、苯达莫司汀、氟尿苷、亚叶酸、羟基脲、硫鸟嘌呤、天冬酰胺酶、硼替佐米、雷替曲塞、氯法拉滨、依诺他滨、sapacitabine、氮杂胞苷、磺胺嘧啶、磺胺甲噁唑、甲氧苄氨嘧啶、Liproxstatin-1、D4476、黄腐酚、Epacadostat (INCB024360)、Vidofludimus、P7C3、GMX1778 (CHS828)、NCT-501、SW033291、Ro61-8048及其DDS制剂。
“拓扑异构酶抑制剂”的实例包括,但不限于,阿霉素、道诺霉素、表柔比星、伊达比星、蒽二酮、米托蒽醌、丝裂霉素C、博来霉素、更生霉素、plicatomycin、依立替康、喜树碱、鲁比替康、贝洛替康、依托泊苷、替尼泊苷、安吖啶及其DDS制剂。
“DNA嵌入剂”的实例包括,但不限于,原黄素、阿霉素(亚德里亚霉素)、道诺霉素、放线菌素D、沙利度胺及其DDS制剂。
“抗有丝分裂剂”的实例包括,但不限于,紫杉醇、紫杉醇衍生物(例如DHA紫杉醇、聚谷氨酸紫杉醇、nab-紫杉醇、胶束紫杉醇、7α-葡糖基氧基乙酰基紫杉醇和BMS-275183)、多西他赛、长春瑞滨、长春新碱、长春花碱、长春地辛、长春利定、依托泊苷、替尼泊苷、伊沙匹隆、拉洛他赛、奥塔他赛、替他塞尔、ispinesib、秋水仙碱、长春氟宁及其DDS制剂。
“抗肿瘤抗生素”的实例包括,但不限于,放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、光神霉素A、盐酸博来霉素、硫酸博来霉素、硫酸培洛霉素、盐酸道诺霉素、盐酸阿霉素、盐酸阿柔比星、盐酸吡柔比星、盐酸表柔比星、盐酸氨柔比星、新制癌菌素、净司他丁斯酯、光神霉素、肉瘤霉素、嗜癌菌素、米托坦、盐酸佐柔比星、盐酸米托蒽醌、盐酸伊达比星、脂质体多柔比星及其DDS制剂。
“植物来源的抗癌剂”的实例包括,但不限于,依立替康、nogitecan、依托泊苷、磷酸依托泊苷、艾日布林、索布佐生、硫酸长春碱、硫酸长春新碱、硫酸长春地辛、替尼泊苷、紫杉醇、紫杉醇注射液、多西他赛、DJ-927、长春瑞滨、拓扑替康及其DDS制剂。
“表观基因组药物”的实例包括,但不限于,DNA甲基化抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂、DNA甲基转移酶(DNMT)抑制剂、组蛋白脱乙酰酶活化剂、组蛋白脱甲基酶抑制剂和甲基化核苷酸。
“表观基因组药物”的具体实例包括,但不限于,伏立诺他、贝林司他、mocetinostat (MGCD0103)、恩替司他(SNDX-275)、罗米地辛、氮胞苷、地西他滨、GSK2879552 2Hl、SGC707、ORY-1001 (RG-6016)、PFI-4、SirReal2、GSK2801、CPI-360、GSK503、AMI-1、CPI-169及其DDS制剂。
“免疫调节药物”的实例包括,但不限于,沙利度胺、来那度胺、泊马度胺及其DDS制剂。
“分子靶向药物”可以是小的化合物或抗体。“分子靶向治疗剂”的实例包括,但不限于,激酶抑制剂、蛋白酶体抑制剂、单克隆抗体、mTOR抑制剂、TNF抑制剂和T-细胞抑制剂。
“激酶抑制剂”的实例包括,但不限于,酪氨酸激酶抑制剂、丝氨酸/苏氨酸激酶抑制剂、Raf激酶抑制剂、细胞周期蛋白依赖性激酶(CDK)抑制剂和促分裂原活化蛋白激酶(MEK)抑制剂。
“激酶抑制剂”的具体实例包括,但不限于,伊马替尼、吉非替尼、埃罗替尼、阿法替尼、达沙替尼、波舒替尼、凡德他尼、舒尼替尼、阿西替尼、帕唑帕尼、乐伐替尼、拉帕替尼、尼达尼布、尼罗替尼、克里唑替尼、色瑞替尼、艾乐替尼、鲁索替尼、托法替尼、依鲁替尼、索拉非尼、维罗菲尼、达拉菲尼、帕博西尼、曲美替尼、瑞戈非尼、cedivanib、来他替尼、班德替尼、瓦他拉尼、塞来西布、tivantinib、卡奈替尼、培利替尼、tesevatinib、赛地替尼、莫特塞尼、米哚妥林、福替尼、卡博替尼、司美替尼、来那替尼、volasertib、塞卡替尼、enzastaurin、坦度替尼、semaxanib、alvocidib、ICR-62、AEE788、PD0325901、PD153035、TK787、amcasertib (BBI503)、E6201、E7050及其DDS其制剂。
“蛋白酶体抑制剂”的实例包括,但不限于,硼替佐米、卡非佐米及其DDS制剂。
“单克隆抗体”的实例包括,但不限于,抗CD22抗体、抗CD20抗体、抗CD25抗体、抗CD30抗体、抗CD33抗体、抗CD5抗体、抗CD52抗体、抗表皮生长因子受体抗体(EGFR抗体)、抗血管内皮细胞生长因子抗体(VEGF抗体)、抗TNF-α抗体、抗IL-1受体抗体、抗IL-2受体抗体、抗IL-5受体抗体、抗IL-6受体抗体、抗HER2抗体、抗IgE抗体、抗IgG抗体、抗RS病毒抗体、抗CCR4抗体、抗细胞毒性T淋巴细胞相关抗原4(CTLA-4、CD152)抗体、抗PD-1抗体、抗核因子κB配体(RANKL)的受体激活剂的抗体、抗c-Met抗体和抗CXCR4抗体。
“单克隆抗体”的具体实例包括,但不限于,替坦异贝莫单抗、利妥昔单抗、西妥昔单抗、英夫利昔单抗、巴利昔单抗、brentuximab vedotin、托珠单抗、曲妥珠单抗、贝伐单抗、奥马珠单抗、美泊利单抗、吉妥珠单抗、奥佐米星、帕利珠单抗、兰尼单抗、赛妥珠单抗、ocrelizumab、莫库珠单抗、依库珠单抗、帕妥珠单抗、阿仑单抗、伊珠单抗、帕尼单抗、奥法木单抗、戈利木单抗、阿达木单抗、雷莫芦单抗、纳武单抗、阿那白滞素、德尼单抗、伊匹单抗、派姆单抗、马妥珠单抗、farletuzumab、MORAb-004、MORA-b009及其DDS制剂。
“mTOR抑制剂”的实例包括,但不限于,依维莫司(RAD001)、雷帕霉素(西罗莫司)、AZD8055、坦西莫司(CCI-779、NSC683864)、KU-0063794、voxtalisib (XL-765、SAR245409)、MHY1485、dactolisib (BEZ235)、PI-103、torkinib (PP242)、地磷莫司(deforolimus、MK-8669)、INK-128 (MLN0128)、Torin1、omipalisib (GSK2126458、GSK458)、OSI-027、PF-04691502、apitolisib (GDC-0980、RG7422)、GSK1059615、gedatolisib (PF-05212384、PKI-587)、WYE-132、PP121、WYE-354、AZD2014、Torin2、WYE-687、CH5132799、WAY-600、ETP-46464、GDC-0349、XL388、佐他莫司(ABT-578)、他克莫司(FK506)、BGT226 (NVP-BGT226)、Palomid 529 (P529)、大黄酸及其DDS制剂。
“TNF抑制剂”的实例包括,但不限于,依那西普、来那度胺(CC-5013)、泊马度胺、沙利度胺、necrostatin-1和QNZ (EVP4593)。
“T-细胞抑制剂”的实例包括,但不限于,阿巴西普。
“血管生成抑制剂”的实例包括,但不限于,CM101、IFN-α、IL-12、血小板因子-4、苏拉明、塞马尼、血小板反应蛋白、VEGFR拮抗剂、血管生成抑制类固醇和肝素的组合、软骨来源的血管生成抑制剂、基质金属蛋白酶抑制剂、巴马司他、马立马司他、血管生成抑制因子、内皮抑制素、2-甲氧基雌二醇、tecogalan、血小板反应蛋白、αVβ3抑制剂、利诺胺、ADH-1、E7820及其DDS其制剂。
“其它化学治疗剂”的实例包括,但不限于,非那雄胺、索布佐生、obatoclax、乙丙昔罗、替吡法尼和洛那法尼。
当如本文所描述的(a)的肽或由式(1)表示的化合物或其药学上可接受的盐与不同癌抗原肽或其药学上可接受的盐和/或共施用药物组合使用时,这些活性试剂可以配制成单独的组合物,或合并在单一的组合物中。在一个实施方案中,(a)的肽或由式(1)表示的化合物或其药学上可接受的盐与不同癌抗原肽合并在单一的组合物中。在另一个实施方案中,(a)的肽或由式(1)表示的化合物或其药学上可接受的盐与不同癌抗原肽配制成单独的组合物。组合物可以包含一种或多种类型的(a)的肽或由式(1)表示的化合物或其药学上可接受的盐和/或一种或多种不同癌抗原肽。包含任何活性试剂的组合物可以与所述组合物和其它活性试剂组合使用的剂量和施用的说明共同提供。包含任何活性试剂的没种组合物可以合并到单一试剂盒中。此类试剂盒可以进一步包含所述组合物组合使用的剂量和施用的说明,或可以被包装。在一种以上活性试剂的组合施用中,所述试剂可以以相同施用计划表或不同施用计划表施用。
本公开的组合物可包含除(a)的肽或由式(1)表示的化合物或其药学上可接受的盐之外的药学上可接受的载体。此外,本公开的组合物可进一步包含或与适当的佐剂组合施用,用于通过所述组合物增强CTL和/或辅助T细胞的诱导。
“药学上可接受的载体”是指对暴露于使用的一定量或浓度的载体下的细胞或哺乳动物无毒性的载体。在一些实施方案中,pH缓冲水溶液可以用作药学上可接受的载体。“药学上可接受的载体”的实例包括缓冲剂(诸如磷酸盐、柠檬酸盐、乳酸盐、酒石酸盐、三氟乙酸盐和其它有机酸);抗氧化剂(诸如抗坏血酸);低分子量多肽(少于约10个残基);蛋白质(诸如血清白蛋白、明胶或免疫球蛋白);亲水聚合物(诸如聚乙烯吡咯烷酮);氨基酸(诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸、甲硫氨酸或赖氨酸);单糖、二糖和其它碳水化合物(诸如葡萄糖、甘露糖或糊精);螯合剂(诸如EDTA);糖醇(诸如甘露醇、海藻糖或山梨糖醇);稳定剂(诸如二亚乙基三胺五乙酸);成盐抗衡离子(诸如钠);增溶剂(诸如聚山梨酸酯80®),和/或非离子表面活性剂(诸如TWEEN®、聚乙二醇(PEG)和PLURONICS®)。缓慢代谢的大分子物质,诸如蛋白质、多肽、脂质体、多糖、聚丙交酯、聚乙醇酸、聚合氨基酸、氨基酸共聚物和灭活病毒颗粒也可用作药学上可接受的载体。为了施用,如本文所描述的由式(1)表示的化合物或肽可以以脂质体制剂配制,附于具有微米级直径的珠,或与脂质载体相关联。
所述佐剂可以是Clin. Microbiol. Rev., 7:277-289, 1994中描述的任何试剂。具体地,所述佐剂可以是微生物-衍生试剂,GM-CSF,细胞因子诸如白介素-2、白介素-7或白介素-12,植物-衍生试剂,海洋生物-衍生试剂,矿物凝胶诸如氢氧化铝,溶血卵磷脂,表面活性剂诸如普朗尼克多元醇,聚阴离子,肽或油乳剂(乳剂制剂)。微生物-衍生试剂的实例包括脂质A、作为脂质A的衍生物的单磷酰脂质A、死细菌(例如分枝杆菌细菌诸如BCG细菌)、细菌衍生蛋白、多核苷酸、弗氏不完全佐剂、弗氏完全佐剂、细胞壁骨架组分(例如BCG-CWS)、海藻糖二霉菌酸酯(TDM)。
所述佐剂也可以是沉淀佐剂或油佐剂。沉降性佐剂可以是吸附肽的无机物质的悬浮液。所述沉降性佐剂的实例包括氢氧化钠、氢氧化铝(Alum)、磷酸钙、磷酸铝、明矾、Pepesu和羧基乙烯基聚合物。油佐剂可以是通过形成包封在矿物油膜中的包含肽的水溶液相的胶束,能够乳化肽的油乳化剂。所述油佐剂的实例包括,但不限于,液体石蜡、羊毛脂、弗氏佐剂(弗氏完全佐剂和弗氏不完全佐剂)、Montanide和W/O乳剂(参见WO2006/078059)。
本公开的组合物可以作为用于口服施用或肠胃外施用的剂型提供。用于肠胃外施用的剂型的实例包括可注射制剂、外用制剂、栓剂、可吸入制剂或经鼻制剂。在优选的实施方案中,本公开的组合物是作为可注射制剂提供。
可注射制剂可以是溶液、悬浮液或乳液的形式,其包含一种或多种溶解、分散或乳化于注射用液体中的活性剂,或者可以作为包含在使用时溶解或分散于注射用液体中的活性剂的固体制剂提供。可注射制剂可以额外包含稳定剂、增溶助剂(诸如谷氨酸、天冬氨酸或聚山梨醇酯80®)、分散剂、乳化剂、止痛剂、缓冲剂、防腐剂或其它适当的添加剂。为了为可注射制剂提供无菌制剂,其可以在其生产的最后步骤中进行灭菌,或者在其整个生产过程中进行无菌生产。用于注射的制剂可以以无菌固体制剂提供,例如冻干制剂,所述冻干制剂可在使用前在注射用的无菌水中或其它适当无菌液体中重构。
外用制剂可以是软膏、凝胶、乳膏、膏药、贴剂、擦剂、喷雾剂、吸入剂、气溶胶、滴眼剂或鼻腔滴剂的形式,其可以根据常规已知的制备方法制备,并且可以包含一种或多种活性剂。
软膏可以根据常规已知的制备方法制备,例如软膏可以通过在软膏基质中将一种或多种活性剂通过研磨或熔化来合并而制备。为了制备软膏,可使用任何常规使用的软膏基质,其可以包含高级脂肪酸或脂肪酸酯(诸如己二酸、肉豆蔻酸、棕榈酸、硬脂酸或油酸或其酯),蜡(诸如蜂蜡、鲸蜡或地蜡),表面活性剂(诸如聚氧乙烯烷基醚磷酸酯),高级醇(诸如鲸蜡醇、硬脂醇或鲸蜡硬脂醇),硅油(诸如二甲基聚硅氧烷),烃类(诸如亲水矿脂、白矿脂、纯化羊毛脂或液体石蜡),二醇(诸如乙二醇、二甘醇、丙二醇、聚乙二醇或聚乙二醇),植物油(诸如蓖麻油、橄榄油、芝麻油或松节油),动物油(诸如貂油、蛋黄油、角鲨烷或角鲨烯),水,吸收增强剂,皮肤保护剂或其组合。软膏可以额外包含润湿剂、防腐剂、稳定剂、抗氧化剂、香料或其它适当的添加剂。
凝胶形式的药物组合物可以根据常规已知的制备方法制备,例如凝胶可以通过在凝胶基质中将一种或多种活性剂通过熔化来合并而制备。为了制备凝胶,可以使用任何常规使用的药物凝胶基质,其可以包含低级醇(诸如乙醇或异丙醇),胶凝剂(诸如羧甲基纤维素、羟乙基纤维素、羟丙基纤维素或乙基纤维素),中和剂(诸如三乙醇胺或二异丙醇胺),表面活性剂(诸如聚氧乙烯甘醇单硬脂酸酯),树胶,水,吸收增强剂,皮肤保护剂或其组合。凝胶可以额外包含防腐剂、抗氧化剂、香料或任何其它适当的添加剂。
乳膏形式的药物组合物可以根据常规已知的制备方法制备,例如乳膏可以通过在药物乳膏基质中将一种或多种活性剂通过熔化或乳化来合并而制备。为了制备乳膏,可以使用任何常规使用的药物乳膏基质,其可以包含高级脂肪酸酯、低级醇、烃、多元醇(诸如丙二醇或1,3-丁二醇)、高级醇(诸如2-己基癸醇或十六醇)、乳化剂(诸如聚氧乙烯烷基醚或脂肪酸酯)、水、吸收增强剂、皮肤保护剂或其组合。乳膏可以额外包含防腐剂、抗氧化剂、香料或其它适当的添加剂。
膏药形式的药物组合物可以根据常规已知的制备方法制备,例如膏药可以通过在膏药基质中将一种或多种活性剂通过熔化来合并并将混合物施加至支持物上来制备。为了制备膏药,可以使用任何常规使用的药物膏药基质,其可以包含增稠剂(诸如聚丙烯酸、聚乙烯吡咯烷酮、阿拉伯树胶、淀粉、明胶或甲基纤维素),湿润剂(诸如尿素、甘油或丙二醇),填充剂(诸如高岭土、氧化锌、滑石、钙或镁),水,增溶助剂,增粘剂,皮肤保护剂或其组合。膏药可以额外包含防腐剂、抗氧化剂、香料或任何其它适当的添加剂。
贴剂形式的药物组合物可以根据常规已知的制备方法制备,贴剂可以通过在贴剂基质中将一种或多种活性剂通过熔化来合并并将混合物施加至支持物上来制备。为了制备贴剂,可以使用任何常规使用的药物贴剂基质,其可以包含聚合物、油或脂肪、高级脂肪酸、增粘剂、皮肤保护剂或其组合。贴剂可以额外包含防腐剂、抗氧化剂、香料或其它适当的添加剂。
擦剂形式的药物组合物可以根据常规已知的制备方法制备,例如擦剂可以通过将一种或多种活性剂溶解、分散或乳化于媒介物中来制备,所述媒介物可以包含水、醇(诸如乙醇或聚乙二醇)、高级脂肪酸、甘油、皂、乳化剂、分散剂或其组合。擦剂可以额外包含防腐剂、抗氧化剂、香料或其它适当的添加剂。
喷雾剂或吸入剂形式的药物组合物可以在媒介物中包含活性剂和任选稳定剂诸如亚硫酸氢钠,或张度剂或缓冲剂,诸如氯化钠、柠檬酸钠或柠檬酸。
用于吸入的剂型的药物组合物可以是气溶胶、可吸入粉末或可吸入液体的形式,或者可以作为在使用前溶解或分散于水或任何其他适当的媒介物中以形成可吸入制剂的液体浓缩物提供。用于吸入的制剂可以根据常规已知的制备方法制备。可吸入液体可以任选地包含防腐剂(诸如苯扎氯铵或对羟基苯甲酸酯)、着色剂、缓冲剂(诸如磷酸钠或乙酸钠)、张度剂(诸如氯化钠或浓甘油)、增稠剂(诸如羧基乙烯基聚合物)、吸收增强剂或其它适当的添加剂。可吸入粉末可以任选地包含润滑剂(诸如硬脂酸或其盐)、粘合剂(诸如淀粉或糊精)、填充剂(诸如乳糖或纤维素)、着色剂、防腐剂(诸如苯扎氯铵或对羟基苯甲酸酯)、吸收增强剂或其它适当的添加剂。为了施用可吸入液体,通常使用喷雾装置(诸如喷雾器或雾化器)。可吸入粉末通常从粉末吸入装置分配。
喷雾剂形式的药物组合物可以在媒介物中包含活性剂和任选稳定剂(诸如亚硫酸氢钠),或张度剂或缓冲剂(诸如氯化钠、柠檬酸钠或柠檬酸)。喷雾剂可以根据例如US 2,868,691或US 3,095,355中所述的制备方法制备。
其它肠胃外剂型包括直肠栓剂或阴道栓剂。
在一个实施方案中,包含(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的组合物包含选自以下的一种或多种药学上可接受的载体:海藻糖、甘露醇、甲硫氨酸、柠檬酸、乳酸、酒石酸、乙酸、三氟乙酸和pH调节剂。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,和如果有,共施用药物可以通过适当的方法向受试者施用,所述方法根据待治疗的疾病、受试者的状况、施用的靶部位,或其它因素。例如,肠胃外施用,优选通过注射或输注的静脉内、肌内、皮内、腹膜内或皮下施用,可以是有用的。如本文所描述的肽或化合物或其药学上可接受的盐可以用于淋巴细胞疗法或DC (树突细胞)疗法中。
剂量频率或剂量间隔可以根据待治疗的疾病、受试者的状况、施用途径或其它因素来适当选择。通常重复施用,优选每隔几天或几个月。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐,和如果有,共施用药物可以分别根据待治疗的疾病、受试者的状况、施用途径或其它因素,以适当的量向受试者施用。所述肽或化合物或其药学上可接受的盐可以通常以每次0.0001 mg至1000 mg,优选0.001 mg至1000 mg,更优选0.1 mg至10 mg的量施用。共施用药物可以以在该药物已知临床剂量的基础上适当选择的量施用。例如,作为共施用药物的免疫调节剂可以通常以每kg体重0.0001 mg至1000 mg,优选每kg体重0.001 mg至1000 mg,更优选每kg体重0.1 mg至10mg的量施用。
当一种以上活性药剂合并在单一组合物中时,它们可以根据待治疗的疾病、受试者的状况、施用途径或其它因素以适当选择的量比例来合并。例如,用于治疗人类受试者,共施用药物诸如免疫调节剂可以以相对于本文所描述的肽和/或化合物的0.01至100份重量的量来使用。
如本文所用的术语“有效量”是指完全或部分抑制癌症的进展或至少部分缓解癌症的一种或多种症状,或能够提供诱导缓解、维持缓解和/或抑制复发的活性试剂的量。试剂的有效量根据受试者的年龄或性别、待用试剂治疗的病况的类型或严重程度、用试剂治疗的期望的结果,或其它因素来确定。特定受试者的有效量可以通过本领域技术人员任何已知的方法来确定。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐可以与非药物疗法,或甚至选自以下的一种以上非药物疗法组合施用,所述非药物疗法例如手术、放射疗法、基因疗法、过热、冷冻疗法或激光燃烧疗法。例如,(a)的肽或由式(1)表示的化合物或其药学上可接受的盐可以在非药物疗法诸如手术之前或之后施用,或在两种或三种非药物疗法的组合之前或之后施用。
(a)的肽或由式(1)表示的化合物或其药学上可接受的盐可以与非药物疗法可以进一步与试剂组合使用,以减少不利的副作用,如果有,诸如止吐剂、睡眠诱导剂或抗惊厥药。
在另一个实施方案中,本公开涉及通过HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05呈递(a)的肽的抗原-呈递细胞(例如树突细胞、B-淋巴细胞或巨噬细胞)。CTL可以在HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中通过使用此类抗原-呈递细胞诱导。通过HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05呈递(a)的肽的抗原-呈递细胞可以通过在(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的存在下,培养HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性未成熟抗原-呈递细胞来获得。
在另一个实施方案中,本公开提供诱导抗原呈递细胞的方法,其包含在(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的存在下,培养HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性未成熟抗原-呈递细胞。在本文中术语“未成熟抗原-呈递细胞”是指可以成熟为抗原呈递细胞(例如树突细胞、B-淋巴细胞或巨噬细胞)的细胞。由于未成熟抗原-呈递细胞含在例如PBMC中,PBMC可以在所述肽或化合物或其药学上可接受的盐的存在下培养。
在另一个实施方案中,本公开提供治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的方法,其包含向对应的HLA亚型阳性的受试者施用通过HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05呈递(a)的肽的抗原-呈递细胞。所述抗原呈递细胞可以根据待治疗的疾病、受试者的状况、施用的靶部位或其它因素,通过适当选择的任何方法施用。所述抗原呈递细胞可以静脉内、皮内、皮下、肌内或鼻内施用,或通过其它施用途径。
在另一个实施方案中,本公开涉及通过(a)的肽或由式(1)表示的化合物或其药学上可接受的盐诱导的CTL。所述CTL可以损害HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者的癌细胞。
在另一个实施方案中,本公开涉及诱导CTL的方法,其包含在(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的存在下,培养HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者的PBMC。当PBMC在所述肽或化合物或其药学上可接受的盐的存在下培养,在PBMC中从前体细胞诱导肽-特异性CTL。通过所述方法获得的肽-特异性CTL可以向HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者施用,以治疗所述受试者的癌症。
在另一个实施方案中,本公开涉及治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的方法,其包括向受试者施用(a)的肽特异性的CTL。所述肽特异性的CTL可以根据待治疗的疾病、受试者的状况、施用的靶部位或其它因素,通过适当选择的方法施用。所述CTL可以静脉内、皮内、皮下、肌内、鼻内或口服施用,或通过其它施用途径。
在另一个实施方案中,本公开涉及将包含在(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的试剂盒作为组分。在一个实施方案中,所述试剂盒用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。在另一个实施方案中,所述试剂盒在本文所描述的诱导抗原-呈递细胞的方法或诱导CTL的方法中使用。所述试剂盒可以含有,除了所述肽或由化合物或其药学上可接受的盐以外,从受试者提取样本(例如外周血单个核细胞)的方法、佐剂或反应容器。说明小册子通常附于所述试剂盒。
在一个实施方案中,本公开提供治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的方法,其包含向HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者施用(a)的肽或由式(1)表示的化合物或其药学上可接受的盐。
在一个实施方案中,本公开提供(a)的肽或由式(1)表示的化合物或其药学上可接受的盐治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的用途。
在一个实施方案中,本公开提供(a)的肽或由式(1)表示的化合物或其药学上可接受的盐用于制造药物的用途,所述药物用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。
在另一个实施方案中,本公开提供包含(a)的肽或由式(1)表示的化合物或其药学上可接受的盐的药物组合物,用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的良性肿瘤。该实施方案可以根据以上关于癌症治疗的描述进行。
“良性肿瘤”是无病理恶性发现的肿瘤,并且被理解为与恶性肿瘤不同。据说良性肿瘤不表现出转移或浸润倾向。诊断为良性肿瘤并不一定意味着良好的临床预后。例如,在脑干发生的低-等级脑膜瘤是良性肿瘤,但它难以治疗,并且它在临床上是恶性的,因为它压迫脑干,并显示出不良的预后,并因此通常需要治疗或预防。
良性肿瘤包括,但不限于,家族性腺瘤息肉病、非遗传性结直肠腺瘤、导管内乳头状粘液瘤、脑膜瘤、神经鞘瘤、器官的上皮性腺瘤、乳头状瘤、非上皮性肌瘤、脂肪瘤、软骨瘤和血管瘤。
在一个实施方案中,良性肿瘤是家族性腺瘤息肉病。家族性腺瘤息肉病是遗传性疾病,以肿瘤抑制基因APC(腺瘤息肉环)的突变和在肠道内形成的大量腺瘤为特征。术语“家族性腺瘤息肉病”、“家族性息肉环”、“家族性腺瘤息肉环”和 "FAP" 可以交换使用。家族性腺瘤息肉病也包括与在除肠道以外组织中的肿瘤相吻合的疾病,诸如加德纳氏综合征。
在进一步实施方案中,本公开提供治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的良性肿瘤的方法,其包含向HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者施用(a)的肽或由式(1)表示的化合物或其药学上可接受的盐;(a)的肽或由式(1)表示的化合物或其药学上可接受的盐用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的良性肿瘤的用途;和(a)的肽或由式(1)表示的化合物或其药学上可接受的盐用于制备药物的用途,所述药物用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。
本发明的实施例将在以下更具体地描述。
[1] 用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的药物组合物,其包括:
(a) 由7-30个氨基酸残基组成的MHC I类-限制性肽或其药学上可接受的盐,其中所述MHC I类-限制性肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6),和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;或
(b) 由式(1)表示的化合物或其药学上可接受的盐:
其中Xa和Ya各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xa和Ya中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽A是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽A的N-末端氨基酸的氨基基团结合式(1)中的Ya,并且所述癌抗原肽A的C-末端氨基酸的羰基基团结合式(1)中的羟基基团,
R1是氢原子,
由式(2)表示的基团:
其中Xb和Yb各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xb和Yb中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽B是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽B的N-末端氨基酸的氨基基团结合式(2)中的Yb,并且所述癌抗原肽B的C-末端氨基酸的羰基基团结合式(2)中的羟基基团,和
式(2)中的硫原子经由二硫键结合式(1)中的硫原子,
或癌抗原肽C,其中所述癌抗原肽C是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC I类-限制性肽或由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHCII类-限制性肽,并且所述癌抗原肽C的半胱氨酸残基的硫原子经由二硫键结合式(1)中的硫原子,并且任选由1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端,
前提是当R1是氢原子时,所述癌抗原肽A是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是由式(2)表示的基团时,所述癌抗原肽A和/或癌抗原肽B是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQID NO: 7),或包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是所述癌抗原肽C时,所述癌抗原肽A和/或癌抗原肽C是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ IDNO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ IDNO: 7),或包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽;
当R1是由式(2)表示的基团并且所述癌抗原肽B包括一个半胱氨酸残基时,所述癌抗原肽B的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽;和
当R1是所述癌抗原肽C,并且由包括一个半胱氨酸残基的1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N末端时,结合所述癌抗原肽C的N末端的肽的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
[2] 根据项目[1]的药物组合物,其中所述受试者是HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性的受试者。
[3] 根据项目[1]的药物组合物,其中所述受试者是HLA-A*02:07-阳性的受试者。
[4] 根据项目[1]的药物组合物,其中所述受试者是HLA-A*03:01-阳性的受试者。
[5] 根据项目[1]的药物组合物,其中所述受试者是HLA-B*15:01-阳性的受试者。
[6] 根据项目[1]的药物组合物,其中所述受试者是HLA-B*27:05-阳性的受试者。
[7] 根据项目[1]至[6]中任一项的药物组合物,其包含(a)的肽或其药学上可接受的盐。
[8] 根据项目[7]的药物组合物,其中(a)的肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)和VLDFAPPGA (SEQ ID NO: 7),或包含在选自SEQ ID NO: 2 、3和7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
[9] 根据项目[7]或[8]的药物组合物,其中(a)的肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、RYFPNAPYL (SEQ ID NO: 8)、YMFPNAPYL (SEQ ID NO:13)、CMTWNQMNL (SEQ ID NO: 3)、CYTWNQMNL (SEQ ID NO: 14)和VLDFAPPGA (SEQ ID NO:7)。
[10] 根据项目[7]至[9]中任一项的药物组合物,其中(a)的肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、RYFPNAPYL (SEQ ID NO: 8)或YMFPNAPYL(SEQ ID NO: 13)。
[11] 根据项目[7]至[10]中任一项的药物组合物,其中(a)的肽是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)。
[12] 根据项目[1]至[6]中任一项的药物组合物,其包含(b)的由式(1)表示的化合物或其药学上可接受的盐。
[13] 根据项目[12]的药物组合物,其中Xa是由两个氨基酸残基组成的二价肽基团,且Ya是单键;Xa和Ya每个是独立由一个氨基酸残基组成的二价肽基团;Xa是单键,且Ya是由两个氨基酸残基组成的二价肽基团;Xa是由一个氨基酸残基组成的二价肽基团,且Ya是单键;Xa是单键,且Ya是由一个氨基酸残基组成的二价肽基团;或Xa和Ya是单键。
[14] 根据项目[12]或[13]的药物组合物,其中Xa是单键,且Ya是单键、丙氨酸残基、亮氨酸残基或甲硫氨酸残基。
[15] 根据项目[12]至[14]中任一项的药物组合物,其中Xa是单键或由一个氨基酸残基组成的二价肽基团,且Ya是单键。
[16] 根据项目[12]至[15]中任一项的药物组合物,其中Xa和Ya是单键。
[17] 根据项目[12]至[16]中任一项的药物组合物,其中所述癌抗原肽A是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7),或
包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
[18] 根据项目[12]至[17]中任一项的药物组合物,其中所述癌抗原肽A是包含或由选自以下氨基酸序列的肽组成:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7)。
[19] 根据项目[18]的药物组合物,其中所述癌抗原肽A是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)。
[20] 根据项目[18]的药物组合物,其中所述癌抗原肽A是由选自以下氨基酸序列的肽组成:RMFPNAPYL (SEQ ID NO: 2)。
[21] 根据项目[12]至[20]中任一项的药物组合物,其中R1是氢原子。
[22] 根据项目[21]的药物组合物,其中由式(1)表示的化合物是包含或由选自以下氨基酸序列的肽组成:
CRMFPNAPYL (SEQ ID NO: 49)、
CCMTWNQMNL (SEQ ID NO: 50)、
CCYTWNQMNL (SEQ ID NO: 51)、
CALLPAVPSL (SEQ ID NO: 52)、
CSLGEQQYSV (SEQ ID NO: 53)、
CRVPGVAPTL (SEQ ID NO: 54),和
CVLDFAPPGA (SEQ ID NO: 55)。
[23] 根据项目[12]至[20]中任一项的药物组合物,其中R1是由式(2)表示的基团。
[24] 根据项目[23]的药物组合物,其中Xb是由两个氨基酸残基组成的二价肽基团,且Yb是单键;Xb和Yb每个是独立由一个氨基酸残基组成的二价肽基团;Xb是单键,且Yb是由两个氨基酸残基组成的二价肽基团;Xb是由一个氨基酸残基组成的二价肽基团,且Yb是单键;和Xb是单键,且Yb是由一个氨基酸残基组成的二价肽基团;或Xb和Yb是单键。
[25] 根据项目[23]或[24]的药物组合物,其中Xb是单键,且Yb是单键、丙氨酸残基、亮氨酸残基或甲硫氨酸残基。
[26] 根据项目[23]至[25]中任一项的药物组合物,其中Xb是单键或由一个氨基酸残基组成的二价肽基团,且Yb是单键。
[27] 根据项目[23]至[26]中任一项的药物组合物,其中Xb和Yb是单键。
[28] 根据项目[23]至[27]中任一项的药物组合物,其中所述癌抗原肽B是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7),或
包含在选自SEQ ID NO: 2 至7的氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
[29] 根据项目[23]至[28]中任一项的药物组合物,其中所述癌抗原肽B是包含或由选自以下氨基酸序列的肽组成:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7)。
[30] 根据项目[29]的药物组合物,其中所述癌抗原肽B是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)。
[31] 根据项目[29]的药物组合物,其中所述癌抗原肽B是由选自以下氨基酸序列的肽组成:RMFPNAPYL (SEQ ID NO: 2)。
[32] 根据项目[23]至[28]中任一项的药物组合物,其中由式(1)表示的化合物是
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[33] 根据项目[12]至[20]中任一项的药物组合物,其中R1是所述癌抗原肽C。
[34] 根据项目[33]的药物组合物,其中所述癌抗原肽C是MHC I类-限制性肽。
[35] 根据项目[34]的药物组合物,其中所述癌抗原肽C是包含CMTWNQMNL (SEQID NO: 3)氨基酸序列的肽,或包含在CMTWNQMNL (SEQ ID NO: 3)氨基酸序列中具有一个或几个氨基酸的缺失、取代和/或添加的氨基酸序列且具有诱导CTL能力的肽。
[36] 根据项目[34]至[35]中任一项的药物组合物,其中所述癌抗原肽C是包含或由选自以下氨基酸序列的肽组成:
CMTWNQMNL (SEQ ID NO: 3)和
CYTWNQMNL (SEQ ID NO: 14)。
[37] 根据项目[34]至[36]中任一项的药物组合物,其中所述癌抗原肽C是包含或由选自以下氨基酸序列的肽组成:CMTWNQMNL (SEQ ID NO: 3)。
[38] 根据项目[34]至[36]中任一项的药物组合物,其中所述癌抗原肽C是包含或由选自以下氨基酸序列的肽组成:CYTWNQMNL (SEQ ID NO: 14)。
[39] 根据项目[33]至[38]中任一项的药物组合物,其中由式(1)表示的化合物是
式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;或
式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[40] 根据项目[39]的药物组合物,其中由式(1)表示的化合物是
式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[41] 根据任一项目[33]至[38]的药物组合物,其中由1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端。
[42] 根据项目[41]的药物组合物,其中由式(1)表示的化合物是
式(7)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(8)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(9)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(10)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(11)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;或
式(12)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[43] 根据项目[33]的药物组合物,其中所述癌抗原肽C是MHC II类-限制性肽。
[44] 根据项目[43]的药物组合物,其中所述癌抗原肽C是包含或由选自以下氨基酸序列的肽组成:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48)。
[45] 根据项目[44]的药物组合物,其中由式(1)表示的化合物是
式(13)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(14)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(15)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起,
式(16)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[46] 根据任一项目[23]至[30]的药物组合物,其中R1是由式(2)表示的化合物,所述癌抗原肽B包括一个半胱氨酸残基,所述癌抗原肽B的半胱氨酸残基的硫原子经由二硫键结合式(3)中的硫原子,或所述癌抗原肽E的半胱氨酸残基的硫原子。
[47] 根据任一项目[33]至[38]的药物组合物,其中R1是所述癌抗原肽C,由包括一个半胱氨酸残基的1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端,并且结合所述癌抗原肽C的N-末端的肽的半胱氨酸残基的硫原子经由二硫键结合式(3)中的硫原子,或所述癌抗原肽E的半胱氨酸残基的硫原子。
[48] 根据项目[47]的药物组合物,其中由包括一个半胱氨酸残基的1-4个氨基酸残基组成并结合所述癌抗原肽C的N-末端的肽是由CA组成的二肽。
[49] 根据任一项目[46]至[48]的药物组合物,其中Xd是由两个氨基酸残基组成的二价肽基团,且Yd是单键;Xd和Yd每个是独立由一个氨基酸残基组成的二价肽基团;Xd是单键,且Yd是由两个氨基酸残基组成的二价肽基团;Xd是由一个氨基酸残基组成的二价肽基团,且Yd是单键;Xd是单键,且Yd是由一个氨基酸残基组成的二价肽基团;或Xd和Yd是单键。
[50] 根据任一项目[46]或[49]的药物组合物,其中Xd是单键,且Yd是单键、丙氨酸残基、亮氨酸残基或甲硫氨酸残基。
[51] 根据任一项目[46]至[50]的药物组合物,其中Xd是单键或由一个氨基酸残基组成的二价肽基团,且Yd是单键。
[52] 根据任一项目[46]至[51]的药物组合物,其中Xd和Yd是单键。
[53] 根据任一项目[46]至[52]的药物组合物,其中所述癌抗原肽D是包含或由选自以下氨基酸序列的肽组成:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48)。
[54] 根据任一项目[46]至[52]的药物组合物,其中
所述癌抗原肽E是包含或由选自以下氨基酸序列的肽组成:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48)。
[55] 根据项目[46]的药物组合物,其中由式(1)表示的化合物是
式(17)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[56] 根据项目[47]的药物组合物,其中由式(1)表示的化合物是
式(18)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[57] 根据项目[47]的药物组合物,其中由式(1)表示的化合物是
式(19)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[58] 根据任一项目[1]至[57]的药物组合物,其中所述药物组合物进一步包含或与MHC II类-限制性肽组合使用。
[59] 根据项目[58]的药物组合物,其中所述MHC II类-限制性肽包含或由选自以下氨基酸序列的肽组成:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48),
或其药学上可接受的盐。
[60] 根据项目[59]的药物组合物,其中所述MHC II类-限制性肽包含选自以下氨基酸序列的肽:WAPVLDFAPPGASAYGSL (SEQ ID NO: 36),或其药学上可接受的盐。
[61] 根据项目[59]的药物组合物,其中所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
[62] 根据项目[58]至[61]中任一项的药物组合物,其中由式(1)表示的化合物是式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;和
所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
[63] 根据任一项目[58]至[61]的药物组合物,其中
由式(1)表示的化合物是式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起;和
所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
[64] 根据项目[1]至[63]中任一项的药物组合物,其中所述癌症是指其中表达WT1的癌症或具有升高的WT1表达水平的癌症。
[65] 根据项目[1]至[64]中任一项的药物组合物,所述癌症是血液癌症或实体癌症。
[66] 根据项目[1]至[65]中任一项的药物组合物,其中所述癌症选自慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病和慢性成淋巴细胞性白血病,骨髓增生异常综合征、多发性骨髓瘤、恶性淋巴瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、宫颈癌、卵巢癌、脑肿瘤、胶质瘤、中枢神经系统原发性恶性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞淋巴瘤、淋巴细胞淋巴瘤、T细胞淋巴瘤、骨癌、胰腺癌、头和颈部癌、皮肤或眼内恶性黑色素瘤、直肠癌、肛门癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、儿童实体瘤、肾癌或输尿管癌、肾盂癌、中枢神经系统肿瘤、肿瘤血管生成、脊髓肿瘤、脑干神经胶质瘤、脑垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、环境诱导的癌症,包括石棉诱导的癌症,以及任何这些癌症的组合。
[67] 根据项目[66]的药物组合物,其中所述癌症选自慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性成淋巴细胞性白血病和慢性成淋巴细胞性白血病,骨髓增生异常综合征、多发性骨髓瘤、恶性淋巴瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、宫颈癌、卵巢癌、脑肿瘤和神经胶质瘤。
[68] 根据项目[1]至[67]中任一项的药物组合物,其中所述药物组合物用作癌症疫苗。
[69] 根据项目[1]至[67]中任一项的药物组合物,其中所述药物组合物是用作用于在癌症细胞免疫疗法中诱导CTL的组合物。
[70] 用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的方法,其包含向HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者施用根据项目[1]的(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐。
[71] 根据项目[70]的方法,其中所述受试者是HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性的受试者。
[72] 根据项目[70]的方法,其中所述受试者是HLA-A*02:07-阳性的受试者。
[73] 根据项目[70]的方法,其中所述受试者是HLA-A*03:01-阳性的受试者。
[74] 根据项目[70]的方法,其中所述受试者是HLA-B*15:01-阳性的受试者。
[75] 根据项目[70]的方法,其中所述受试者是HLA-B*27:05-阳性的受试者。
[76] 根据项目[70]至[75]中任一项的方法,其包括向所述受试者施用(b)的由式(1)表示的化合物或其药学上可接受的盐。
[77] 根据项目[70]至[76]中任一项的方法,其中由式(1)表示的化合物是式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[78] 根据任一项目[70]至[76]的方法,其中由式(1)表示的化合物是式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[79] 根据项目[70]至[78]中任一项的方法,其进一步包含MHC II类-限制性肽。
[80] 根据项目[79]的方法,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单一组合物中。
[81] 根据项目[79]的方法,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单独的组合物中。
[82] 根据项目[79]至[81]中任一项的方法,其中所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
[83] 根据项目[1]的(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的用途。
[84] 根据项目[83]的肽或化合物或其药学上可接受的盐,其中所述受试者是HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性的受试者。
[85] 根据项目[83]的肽或化合物或其药学上可接受的盐,其中所述受试者是HLA-A*02:07-阳性的受试者。
[86] 根据项目[83]的肽或化合物或其药学上可接受的盐,其中所述受试者是HLA-A*03:01-阳性的受试者。
[87] 根据项目[83]的肽或化合物或其药学上可接受的盐,其中所述受试者是HLA-B*15:01-阳性的受试者。
[88] 根据项目[83]的肽或化合物或其药学上可接受的盐,其中所述受试者是HLA-B*27:05-阳性的受试者。
[89] 根据项目[83]至[88]中任一项的肽或化合物或其药学上可接受的盐,其中所述肽或化合物或其药学上可接受的盐是(b)的由式(1)表示的化合物或其药学上可接受的盐。
[90] 根据项目[83]至[89]中任一项的肽或化合物或其药学上可接受的盐,其中由式(1)表示的化合物是式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[91] 根据任一项目[83]至[89]的肽或化合物或其药学上可接受的盐,其中由式(1)表示的化合物是式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[92] 根据项目[83]至[91]中任一项的肽或化合物或其药学上可接受的盐,其中所述肽或化合物或其药学上可接受的盐与MHC II类-限制性肽组合使用。
[93] 根据项目[92]的肽或化合物或其药学上可接受的盐,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单一组合物中。
[94] 根据项目[92]的肽或化合物或其药学上可接受的盐,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单独的组合物中。
[95] 根据项目[92]至[94]中任一项的肽或化合物或其药学上可接受的盐,其中所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
[96] 根据项目[1]的(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐用于制备药物的用途,所述药物用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症。
[97] 根据项目[96]的用途,其中所述受试者是HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性的受试者。
[98] 根据项目[96]的用途,其中所述受试者是HLA-A*02:07-阳性的受试者。
[99] 根据项目[96]的用途,其中所述受试者是HLA-A*03:01-阳性的受试者。
[100] 根据项目[96]的用途,其中所述受试者是HLA-B*15:01-阳性的受试者。
[101] 根据项目[96]的用途,其中所述受试者是HLA-B*27:05-阳性的受试者。
[102] 根据项目[96]至[101]中任一项的用途,其中所述用途是(b)的由式(1)表示的化合物或其药学上可接受的盐的用途。
[103] 根据项目[96]至[102]中任一项的用途,其中由式(1)表示的化合物是式(4)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[104] 根据项目[96]至[102]中任一项的用途,其中由式(1)表示的化合物是式(5)的化合物:
其中在所述式中显示的C-C是指所述C残基由二硫键连接在一起。
[105] 根据项目[96]至[104]中任一项的用途,其中所述药剂进一步包含MHC II类-限制性肽,或与MHC II类-限制性肽组合使用。
[106] 根据项目[105]的用途,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单一组合物中。
[107] 根据项目[105]的用途,其中(a)的肽或其药学上可接受的盐,或(b)的由式(1)表示的化合物或其药学上可接受的盐和所述MHC II类-限制性肽含在单独的组合物中。
[108] 根据项目[105]至[107]中任一项的用途,其中所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
本发明将通过以下实施例来描述,其不应被解释为在任何意义上限制了本发明。
实施例
作为癌抗原肽特异性的CTL通过所述肽刺激和增殖的方法的第一步,必须使所述肽与HLA I类分子稳定结合。每种HLA I类(亚型)分子需要结合基序的肽,并且形成稳定的三维结构,从而与抗原肽的预确定位置存在的氨基酸残基相互作用。已经开发出多种算法用于预测基于基序的肽和HLA I类分子之间的结合活性;例如,NetMHC4.0、SYFPEITHI或BIMAS是已知的。这些算法的使用使简单列出基于靶蛋白的氨基酸序列信息的HLA I类-限制的T细胞表位候选者成为可能。为了确定通过此类算法获得的表位候选者是否对癌症免疫疗法的发展实际有用,T细胞对每个表位候选者的反应性通过使用患者的外周血单核细胞来测试。
WT1126-134 (RMFPNAPYL (SEQ ID NO: 2))是WT1-衍生的癌抗原肽,并且被报道在HLA-A*02:01阳性癌症患者中具有高临床作用(Blood. 2009; 113: 6541-8)。实际上,通过NetMHC4.0计算的WT1126-134对HLA-A*02:01的结合亲和性是7.14 nM,并且WT1126-134被预测为作为对HLA-A*02:01具有强结合亲和性的肽(表1)。
HLA-A*02:01是在欧洲和美洲很常见到的HLA I类亚型之一。HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05在欧洲和美洲相对常见,虽然这些频率低于HLA-A*02:01 (Hum Immunol. 2001; 62: 1009-30.)。通过NetMHC4.0 计算的WT1126-134对HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05的结合亲和性分别是28,729.70 nM、1,755.02 nM、245.03 nM和2,060.74 nM (表1)。如所述,WT1126-134对HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05的亲和性比WT1126-134对HLA-A*02:01的亲和性低约4,023.8倍、245.8倍、34.3倍和288.6倍。
通过NetMHC4.0 计算的由YMFPNAPYL (SEQ ID NO: 13)表示的WT1126-134改变的肽对HLA-A*02:01、HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05的结合亲和性分别是2.73 nM、19,806.32 nM、8,341.40 nM、190.54 nM和6,182.73 nM (表2)。如所述,改变的肽对HLA-A*02:07、HLA-A*03:01、HLA-B*15:01和HLA-B*27:05的结合亲和性比改变的肽对HLA-A*02:01的的亲和性低约7,255.1倍、3,055.5倍、69.8倍和2,264.7倍。
根据这些结果,由YMFPNAPYL (SEQ ID NO: 13)表示的WT1126-134及其改变的肽不太可能用于在HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症免疫治疗。
表1
HLA I类 | 序列 | 亲和性(nM) |
HLA-A*02:01 | RMFPNAPYL (SEQ ID NO: 2) | 7.14 |
HLA-A*02:07 | RMFPNAPYL (SEQ ID NO: 2) | 28,729.70 |
HLA-A*03:01 | RMFPNAPYL (SEQ ID NO: 2) | 1,755.02 |
HLA-B*15:01 | RMFPNAPYL (SEQ ID NO: 2) | 245.03 |
HLA-B*27:05 | RMFPNAPYL (SEQ ID NO: 2) | 2,060.74 |
表2
HLA I类 | 序列 | 亲和性(nM) |
HLA-A*02:01 | YMFPNAPYL (SEQ ID NO: 13) | 2.73 |
HLA-A*02:07 | YMFPNAPYL (SEQ ID NO: 13) | 19,806.32 |
HLA-A*03:01 | YMFPNAPYL (SEQ ID NO: 13) | 8,341.40 |
HLA-B*15:01 | YMFPNAPYL (SEQ ID NO: 13) | 190.54 |
HLA-B*27:05 | YMFPNAPYL (SEQ ID NO: 13) | 6,182.73 |
接下来,分析癌症患者外周血来源的T细胞对WT1126-134的反应性。本文使用的PBMC由在临床试验(ClinicalTrials.gov 识别码: NCT03149003和NCT02436252)登记的癌症患者提供的外周血来制备。具体地,在登记的癌症患者中,选择HLA-A*03:01-阳性患者(4个患者)、HLA-B*15:01-阳性患者(1个患者),和HLA-A*02:07-阳性患者(1个患者),所述患者的血液可以在施用所述临床试验的药剂之前和之后收集。所述药剂是含有由以下式(5)表示的化合物的三氟醋酸盐的癌抗原肽:
和由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)表示的氨基酸序列组成的肽的醋酸盐。
PBMC在施用药剂之前和之后制备,冷冻,在37℃温育中解冻,并之后在AIM-V培养基中悬浮。活细胞以1.8至2.2X106 个细胞/mL (体积: 200μL/孔)的密度(浓度)接种于96-孔U-底微板的单孔。此时,添加人IL-2 (100 U/mL)和式(5)的化合物或SEQ ID NO: 13的肽(40μg/mL)。之后,在37℃,5% CO2恒温箱中开始培养。开始培养后的三天,从单孔中取出上清液(100μL),添加含有人IL-2 (100 U/mL)和式(5)的化合物或SEQ ID NO: 13 (40μg/mL)的肽的AIM-V培养基(100μL)。开始培养后的七天,回收PBMC,并且部分PBMC用WT1126-134/HLA-A*03:01四聚体、WT1126-134/HLA-B*15:01四聚体或WT1126-134/HLA-A*02:07 四聚体和抗-人CD8抗体染色。通过MACSQuant分析仪检测在CD8阳性T细胞中的四聚体-阳性细胞。当四聚体-阳性T细胞的比率是0.1%或更多时,确定结果为阳性。
施用药剂前的HLA-A*03:01-阳性患者提供的PBMC在和式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*03:01四聚体染色。没有在来自所述患者的任何PBMC样本中检测到HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图1中,横轴代表用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-A*03:01四聚体染色。相似地,当施用药剂前的HLA-B*15:01-阳性患者提供的PBMC在式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-B*15:01四聚体染色时,没有检测到HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图2中,横轴表示用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-B*15:01四聚体染色。相似地,当施用药剂前的HLA-A*02:07-阳性患者提供的PBMC在式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*02:07四聚体染色时,没有检测到HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞。在图7中,横轴表示用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-A*02:07四聚体染色。如所述,在使用来源于癌症病人外周血样本的T细胞的测定中,WT1126-134没有被证实是对HLA-A*03:01、HLA-B*15:01或HLA-A*02:07-阳性患者的癌症免疫治疗有用的抗原肽。
如上所述,从对HLA结合的预测和使用施用药剂前的癌症患者的外周血样本的测定来看,难以开发WT1126-134作为用于治疗HLA-A*03:01-阳性患者、HLA-B*15:01-阳性患者或HLA-A*02:07-阳性患者的癌症的试剂。
然而,在使用施用药剂后的癌症患者的外周血样本的测定中,获得了不同的结果。当根据以上方法施用药剂后的HLA-A*03:01-阳性患者的PBMC在式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*03:01四聚体染色时,令人惊讶的是,检测到HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图3中,横轴代表用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-A*03:01四聚体染色。相似地,当施用药剂后的HLA-B*15:01-阳性患者的PBMC在式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-B*15:01四聚体染色时,检测到HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图4中,横轴表示用FITC-标记的抗-CD8 抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-B*15:01四聚体染色。相似地,当施用药剂后的HLA-A*02:07-阳性患者的PBMC在式(5)的化合物的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*02:07四聚体染色时,检测到HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞。在图8中,横轴表示用FITC-标记的抗-CD8 抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-A*02:07四聚体染色。
进一步,通过培养增殖的HLA-A*03:01、HLA-B*15:01或HLA-A*02:07-限制的WT1126-134 特异性T细胞由IFNγ ELISPOT测定来分析,以确定它们是否对呈递WT1126-134的癌细胞有反应。为了更具体地描述,含有WT1126-134 特异性T细胞的PBMC用WT1126-134肽标记的HLA-A*03:01、HLA-B*15:01或HLA-A*02:07表达的K562细胞(被称作"K562-A3 + Pep"、"K562-B15 + Pep"或"K562-A2.7 + Pep")或没有WT1126-134肽标记的、HLA-B*15:01或HLA-A*02:07表达的K562细胞(被称作"K562-A3"、"K562-B15"或"K562-A2.7")来刺激。细胞在37℃,5% CO2恒温箱中孵育约18小时后,通过ImmunoSpot S5 Versa对单孔拍照。
当培养的含有HLA-A*03:01-限制的WT1126-134特异性CD8-阳性T细胞的PBMC用K562-A3或K562-A3 + Pep刺激时,细胞对K562-A3 + Pep的反应大于对K562-A3的反应(图5)。从这样的结果来看,发现HLA-A*03:01-限制的WT1126-134特异性T细胞识别呈递WT1126-134的HLA-A*03:01阳性癌细胞并且对呈递WT1126-134的HLA-A*03:01阳性癌细胞有反应。相似地,当培养的含有HLA-B*15:01-限制的WT1126-134特异性CD8-阳性T细胞的PBMC用K562-B15或K562-B15 + Pep刺激时,细胞对K562-B15 + Pep的反应大于对K562-B15的反应(图6)。从这样的结果来看,发现HLA-B*15:01-限制的WT1126-134特异性T细胞识别呈递WT1126-134的HLA-B*15:01阳性癌细胞/对呈递WT1126-134的HLA-B*15:01阳性癌细胞有反应。相似地,当培养的含有HLA-A*02:07-限制的WT1126-134特异性CD8-阳性T细胞的PBMC用K562-A2.7或K562-A2.7+ Pep刺激时,细胞对K562-A2.7 + Pep的反应大于对K562-A2.7的反应(图9)。从这样的结果来看,发现HLA-A*02:07-限制的WT1126-134 特异性T细胞识别呈递WT1126-134的HLA-A*02:07阳性癌细胞/对呈递WT1126-134的HLA-A*02:07阳性癌细胞有反应。
如上所述,通过使用来源于接受药剂的癌症患者的PBMC样本,证明了WT1126-134不仅在HLA-A*02:01-阳性患者中,还在HLA-A*03:01、HLA-B*15:01或HLA-A*02:07-阳性患者中可以是治疗癌症的试剂。
此外,当施用药剂后的HLA-A*03:01-阳性患者的PBMC在SEQ ID NO: 13的肽的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*03:01四聚体染色时,检测到HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图10中,横轴代表用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-A*03:01四聚体染色。相似地,当施用药剂后的HLA-B*15:01-阳性患者的PBMC在SEQ ID NO: 13的肽的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-B*15:01四聚体染色时,检测到HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞。在图11中,横轴表示用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/HLA-B*15:01四聚体染色。相似地,当施用药剂后的HLA-A*02:07-阳性患者的PBMC在SEQ ID NO: 13的肽的存在下培养,并且用抗-CD8抗体和WT1126-134/HLA-A*02:07四聚体染色时,检测到HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T细胞。在图12中,横轴表示用FITC-标记的抗-CD8抗体染色,并且竖轴表示用PE-标记的WT1126-134/ HLA-A*02:07四聚体染色。
从这些结果来看,证明了WT1126-134的改变的杀伤肽使HLA-A*03:01-限制的WT1126-134-特异性CD8-阳性T细胞、HLA-B*15:01-限制的WT1126-134-特异性CD8-阳性T细胞和HLA-A*02:07-限制的WT1126-134-特异性CD8-阳性T 细胞活化和增殖。与WT1126-134相似,WT1126-134的改变的杀伤肽被证明不仅在HLA-A*02:01-阳性患者中,还在HLA-A*03:01、HLA-B*15:01或HLA-A*02:07-阳性患者中是有用的治疗癌症的试剂。
序列表
<110> Sumitomo Dainippon Pharma Co., Ltd.
International Institute of Cancer Immunology, Inc.
<120> 用于治疗癌症的药物组合物
<130> 676088
<150> JP 2020-083905
<151> 2020-05-12
<160> 55
<170> PatentIn version 3.5
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<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 44
Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His
1 5 10 15
Ser Arg Lys His
20
<210> 45
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 45
Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His
1 5 10 15
Ser Arg Lys His Thr Gly
20
<210> 46
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 46
Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg
1 5 10 15
Lys
<210> 47
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 47
Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg
1 5 10 15
Lys His
<210> 48
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 48
Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg
1 5 10 15
Lys His Thr Gly
20
<210> 49
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 49
Cys Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5 10
<210> 50
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 50
Cys Cys Met Thr Trp Asn Gln Met Asn Leu
1 5 10
<210> 51
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 51
Cys Cys Tyr Thr Trp Asn Gln Met Asn Leu
1 5 10
<210> 52
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 52
Cys Ala Leu Leu Pro Ala Val Pro Ser Leu
1 5 10
<210> 53
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 53
Cys Ser Leu Gly Glu Gln Gln Tyr Ser Val
1 5 10
<210> 54
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 54
Cys Arg Val Pro Gly Val Ala Pro Thr Leu
1 5 10
<210> 55
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 55
Cys Val Leu Asp Phe Ala Pro Pro Gly Ala
1 5 10
Claims (24)
1.用于治疗HLA-A*02:07、HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性受试者中的癌症的药物组合物,其包含:
(a) 由7-30个氨基酸残基组成的MHC I类-限制性肽或其药学上可接受的盐,其中所述MHC I类-限制性肽是包含选自以下的氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或者是包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对选自SEQ ID NO: 2-7的氨基酸序列的一个或几个氨基酸的缺失、取代和/或添加;或
(b) 由式(1)表示的化合物或其药学上可接受的盐:
其中Xa和Ya各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xa和Ya中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽A是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽A的N-末端氨基酸的氨基基团结合式(1)中的Ya,并且所述癌抗原肽A的C-末端氨基酸的羰基基团结合式(1)中的羟基基团,
R1是氢原子,
由式(2)表示的基团:
其中Xb和Yb各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xb和Yb中的氨基酸残基数量的总和是0-4的整数;
癌抗原肽B是由7-30个氨基酸残基组成的MHC I类-限制性肽,其中所述癌抗原肽B的N-末端氨基酸的氨基基团结合式(2)中的Yb,并且所述癌抗原肽B的C-末端氨基酸的羰基基团结合式(2)中的羟基基团,并且
式(2)中的硫原子经由二硫键结合式(1)中的硫原子,
或癌抗原肽C,其中所述癌抗原肽C是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC I类-限制性肽或由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽,并且所述癌抗原肽C的半胱氨酸残基的硫原子经由二硫键结合式(1)中的硫原子,并且任选地,由1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N-末端,
前提是当R1是氢原子时,所述癌抗原肽A是包含选自以下氨基酸序列的肽:RMFPNAPYL(SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV(SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或者是包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对选自SEQ ID NO: 2-7的氨基酸序列中的一个或几个氨基酸的缺失、取代和/或添加;
当R1是由式(2)表示的基团时,所述癌抗原肽A和/或癌抗原肽B是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ IDNO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ IDNO: 7),或者是包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对选自SEQ ID NO: 2-7的氨基酸序列中的一个或几个氨基酸的缺失、取代和/或添加;
当R1是癌抗原肽C时,所述癌抗原肽A和/或癌抗原肽C是包含选自以下氨基酸序列的肽:RMFPNAPYL (SEQ ID NO: 2)、CMTWNQMNL (SEQ ID NO: 3)、ALLPAVPSL (SEQ ID NO: 4)、SLGEQQYSV (SEQ ID NO: 5)、RVPGVAPTL (SEQ ID NO: 6)和VLDFAPPGA (SEQ ID NO: 7),或者是包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对选自SEQID NO: 2-7的氨基酸序列中的一个或几个氨基酸的缺失、取代和/或添加;
当R1是由式(2)表示的基团并且所述癌抗原肽B包含一个半胱氨酸残基时,所述癌抗原肽B的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽;和
当R1是癌抗原肽C,并且由包括一个半胱氨酸残基的1-4个氨基酸残基组成的肽结合所述癌抗原肽C的N末端时,结合所述癌抗原肽C的N末端的所述肽的半胱氨酸残基的硫原子任选地经由二硫键结合式(3)中的硫原子:
其中Xd和Yd各自独立地表示单键或由1-4个氨基酸残基组成的二价肽基团,前提是Xd和Yd中的氨基酸残基数量的总和是0-4的整数,和
癌抗原肽D是由7-30个氨基酸残基组成的MHC II类-限制性肽,其中所述癌抗原肽D的N-末端氨基酸的氨基基团结合式(3)中的Yd,并且所述癌抗原肽D的C-末端氨基酸的羰基基团结合式(3)中的羟基基团,
或癌抗原肽E的半胱氨酸残基的硫原子,其中所述癌抗原肽E是由包括一个半胱氨酸残基的7-30个氨基酸残基组成的MHC II类-限制性肽。
2.根据权利要求1的药物组合物,其中所述受试者是HLA-A*03:01、HLA-B*15:01或HLA-B*27:05-阳性的受试者。
3.根据权利要求1的药物组合物,其中所述受试者是HLA-A*02:07-阳性的受试者。
4.根据权利要求1的药物组合物,其中所述受试者是HLA-A*03:01-阳性的受试者。
5.根据权利要求1的药物组合物,其中所述受试者是HLA-B*15:01-阳性的受试者。
6.根据权利要求1的药物组合物,其中所述受试者是HLA-B*27:05-阳性的受试者。
7.根据权利要求1-6中任一项的药物组合物,其包含(b)的由式(1)表示的化合物或其药学上可接受的盐。
8.根据权利要求7的药物组合物,其中所述癌抗原肽A是包含选自以下氨基酸序列的肽:
RMFPNAPYL (SEQ ID NO: 2),
CMTWNQMNL (SEQ ID NO: 3)、
ALLPAVPSL (SEQ ID NO: 4)、
SLGEQQYSV (SEQ ID NO: 5)、
RVPGVAPTL (SEQ ID NO: 6),和
VLDFAPPGA (SEQ ID NO: 7),或
包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对选自SEQID NO: 2-7的氨基酸序列中的一个或几个氨基酸的缺失、取代和/或添加。
9.根据权利要求8的药物组合物,其中所述癌抗原肽A是由RMFPNAPYL (SEQ ID NO: 2)的氨基酸序列组成的肽。
10.根据权利要求7-9中任一项的药物组合物,其中R1是癌抗原肽C。
11.根据权利要求10的药物组合物,其中所述癌抗原肽C是MHC I类-限制性肽。
12.根据权利要求11的药物组合物,其中所述癌抗原肽C是包含CMTWNQMNL (SEQ IDNO: 3)的氨基酸序列的肽,或者是包含如下的氨基酸序列且具有诱导CTL的能力的肽,所述氨基酸序列具有对SEQ ID NO: 3的氨基酸序列中的一个或几个氨基酸的缺失、取代和/或添加。
13.根据权利要求12的药物组合物,其中所述癌抗原肽C是包含选自以下氨基酸序列的肽或由选自以下氨基酸序列组成的肽:
CMTWNQMNL (SEQ ID NO: 3),和
CYTWNQMNL (SEQ ID NO: 14)。
16.根据权利要求1-15中任一项的药物组合物,其中所述药物组合物进一步包含MHCII类-限制性肽,或与MHC II类-限制性肽组合使用。
17.根据权利要求16的药物组合物,其中所述MHC II类-限制性肽是包含选自以下氨基酸序列的肽,或由选自以下氨基酸序列组成的肽:
WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)、
CWAPVLDFAPPGASAYGSL (SEQ ID NO: 37)、
WAPVLDFAPPGASAYGSLC (SEQ ID NO: 38)、
SGQARMFPNAPYLPSC (SEQ ID NO: 39)、
SGQAYMFPNAPYLPSC (SEQ ID NO: 40)、
SGQARMFPNAPYLPSCLES (SEQ ID NO: 41)、
SGQAYMFPNAPYLPSCLES (SEQ ID NO: 42)、
PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 43)、
PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 44)、
PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 45)、
CNKRYFKLSHLQMHSRK (SEQ ID NO: 46)、
CNKRYFKLSHLQMHSRKH (SEQ ID NO: 47),和
CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 48),或
其药学上可接受的盐。
18.根据权利要求17的药物组合物,其中所述MHC II类-限制性肽是由WAPVLDFAPPGASAYGSL (SEQ ID NO: 36)的氨基酸序列组成的肽,或其药学上可接受的盐。
21.根据权利要求1-20中任一项的药物组合物,其中所述癌症是指其中表达WT1的癌症或具有升高的WT1表达水平的癌症。
22.根据权利要求1-21中任一项的药物组合物,其中所述癌症选自慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病和慢性成淋巴细胞性白血病,骨髓增生异常综合征、多发性骨髓瘤、恶性淋巴瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、宫颈癌、卵巢癌、脑肿瘤、神经胶质瘤、中枢神经系统原发性恶性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞淋巴瘤、淋巴细胞淋巴瘤、T细胞淋巴瘤、骨癌、胰腺癌、头颈癌、皮肤或眶内恶性黑色素瘤、直肠癌、肛门癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、儿童实体瘤、肾癌或输尿管癌、肾盂癌、中枢神经系统肿瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、环境诱导的癌症,包括石棉诱导的癌症,以及这些癌症的任意组合。
23.根据权利要求1-22中任一项的药物组合物,其中所述药物组合物用作癌症疫苗。
24.根据权利要求1-23中任一项的药物组合物,其中所述药物组合物用作用于诱导癌症细胞免疫疗法中CTL的组合物。
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US20230183316A1 (en) | 2023-06-15 |
KR20230009426A (ko) | 2023-01-17 |
MX2022014249A (es) | 2023-02-22 |
JP7209986B2 (ja) | 2023-01-23 |
WO2021230247A1 (ja) | 2021-11-18 |
JP2022180513A (ja) | 2022-12-06 |
JP7153287B2 (ja) | 2022-10-14 |
JPWO2021230247A1 (zh) | 2021-11-18 |
TW202200188A (zh) | 2022-01-01 |
EP4151227A1 (en) | 2023-03-22 |
AU2021272616A1 (en) | 2022-12-15 |
JP2023036884A (ja) | 2023-03-14 |
JP7248261B2 (ja) | 2023-03-29 |
CA3182959A1 (en) | 2021-11-18 |
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