TW202200188A - 用以處置癌症之醫藥組合物 - Google Patents
用以處置癌症之醫藥組合物 Download PDFInfo
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Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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Abstract
本發明包括用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之含有源自WT1之癌抗原肽或包含其之肽複合物之醫藥組合物等。
Description
本申請案針對日本專利申請第2020-083905號主張優先權,此處以參照之形式將其全文併入本說明書中。
本發明屬於癌免疫療法領域,尤其關於源自WT(威爾姆氏腫瘤,Wilms' Tumor)1蛋白之癌抗原肽之用途。
WT1為於白血病或各種實體癌中高表現,癌症疫苗之靶抗原之中備受關注之癌抗原蛋白。細胞性免疫、尤其細胞毒殺性T細胞(亦稱為細胞毒殺性T淋巴細胞。以下記為CTL)對於生物體內癌細胞之排除發揮重要作用。CTL係前體T細胞於識別由源自癌抗原蛋白之肽(即癌抗原肽)與MHC-I類分子(MHC Class I)形成之複合體後分化增殖而生成者,攻擊癌細胞。作為源自WT1之癌抗原肽,已知WT1126-134
肽(RMFPNAPYL、序列編號2)、WT1235-243
肽(CMTWNQMNL、序列編號3)、WT110-18
肽(ALLPAVPSL、序列編號4)、WT1187-195
肽(SLGEQQYSV、序列編號5)、WT1302-310
肽(RVPGVAPTL、序列編號6)及WT137-45
肽(VLDFAPPGA、序列編號7)等。
例如,WT1126-134
肽為可誘導HLA-A*
02:01限制性肽特異性CTL之癌抗原肽。該WT1126-134
肽特異性CTL對HLA-A*
02:01陽性之WT1表現癌細胞顯示殺細胞作用,因此,關於包含WT1126-134
肽之癌症疫苗之以HLA-A*
02:01陽性患者為對象之臨床試驗得以推進。
[發明所欲解決之問題]
本發明之目的在於擴大源自WT1之癌抗原肽或包含其之肽複合物之適用對象。
[解決問題之技術手段]
本發明者等人藉由使用已投予癌症肽疫苗之癌症患者之末梢血,發現了利用與HLA-I類分子(HLA Class I)之結合預測及使用源自藥劑投予前之癌症患者末梢血之T細胞之試驗無法鑑定之關於源自WT1之癌抗原肽之HLA-I類分子限制性,從而完成本發明。
於一形態中,本發明提供一種醫藥組合物,其用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症,包含以下之(a)或(b):
(a)包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽,即,含有7~30個殘基之胺基酸之MHC-I類分子限制性肽或其藥學上容許之鹽;或
(b)式(1)所表示之化合物或其藥學上容許之鹽,
[化1]
[式中,Xa
及Ya
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xa
之胺基酸殘基數與Ya
之胺基酸殘基數之和為0~4之整數;
癌抗原肽A表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽A之N末端胺基酸之胺基與式(1)中之Ya
鍵結,癌抗原肽A之C末端胺基酸之羰基與式(1)中之羥基鍵結;
R1
表示氫原子、式(2)所表示之基、或癌抗原肽C,
[化2]
(式中,Xb
及Yb
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xb
之胺基酸殘基數與Yb
之胺基酸殘基數之和為0~4之整數,癌抗原肽B表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽B之N末端胺基酸之胺基與式(2)中之Yb
鍵結,癌抗原肽B之C末端胺基酸之羰基與式(2)中之羥基鍵結,式(2)中之硫原子與式(1)中之硫原子經由雙硫鍵鍵結),
癌抗原肽C表示含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-I類分子限制性肽或含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子(MHC Class II)限制性肽,癌抗原肽C之半胱胺酸殘基之硫原子與式(1)中之硫原子經由雙硫鍵鍵結,於癌抗原肽C之N末端可結合有含有1~4個殘基之胺基酸之肽;
於R1
為氫原子之情形時,癌抗原肽A為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為式(2)所表示之基之情形時,癌抗原肽A及/或癌抗原肽B為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為癌抗原肽C之情形時,癌抗原肽A及/或癌抗原肽C為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為式(2)所表示之基、且癌抗原肽B包含1個半胱胺酸殘基之情形時,癌抗原肽B之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化3]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結);
於R1
為癌抗原肽C、且於癌抗原肽C之N末端結合有含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽之情形時,結合於癌抗原肽C之N末端之肽之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化4]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結)]。
[發明之效果]
根據本發明,可使用WT1126-134
肽等源自WT1之癌抗原肽或包含其之肽複合物來處置HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象之癌,擴大了該等肽或複合物之適用對象。
於本說明書中,所謂「胺基酸殘基」,意指於肽或蛋白質分子上相當於構成肽或蛋白質之胺基酸之一單位的部分。作為「胺基酸殘基」,可例舉:天然或非天然之α-胺基酸殘基、β-胺基酸殘基、γ-胺基酸殘基或δ-胺基酸殘基。具體而言,可例舉:天然之α-胺基酸殘基、鳥胺酸殘基、高絲胺酸殘基、高半胱胺酸殘基、β-丙胺酸殘基、γ-胺基丁酸或δ-胺基戊酸等。於「胺基酸殘基」可能存在光學活性體之情形時,可為L體、D體之任意者,較佳為L體。
於本說明書中,以縮寫符號表示「胺基酸殘基」之情形時,記為以下之縮寫符號。
Ala或A:丙胺酸殘基
Arg或R:精胺酸殘基
Asn或N:天冬醯胺殘基
Asp或D:天冬胺酸殘基
Cys或C:半胱胺酸殘基
Gln或Q:穀醯胺殘基
Glu或E:穀胺酸殘基
Gly或G:甘胺酸殘基
His或H:組胺酸殘基
Ile或I:異白胺酸殘基
Leu或L:白胺酸殘基
Lys或K:離胺酸殘基
Met或M:甲硫胺酸殘基
Phe或F:苯基丙胺酸殘基
Pro或P:脯胺酸殘基
Ser或S:絲胺酸殘基
Thr或T:蘇胺酸殘基
Trp或W:色胺酸殘基
Tyr或Y:酪胺酸殘基
Val或V:纈胺酸殘基
Abu:2-胺基丁酸殘基(亦稱為α-胺基丁酸殘基)
Orn:鳥胺酸殘基
Cit:瓜胺酸殘基
於本說明書中,「肽」之胺基酸序列依據常規方法,以N末端胺基酸之胺基酸殘基位於左側、C末端胺基酸之胺基酸殘基位於右側之方式記載。又,於「肽」中,只要無特別說明,N末端胺基酸之胺基酸殘基之胺基與氫原子鍵結,C末端胺基酸之胺基酸殘基之羰基與羥基鍵結。所謂肽之二價基,意指經由N末端胺基酸之胺基酸殘基之胺基及C末端胺基酸之胺基酸殘基之羰基而鍵結之基。式(1)所表示之化合物中,例如式(4)或(5)之化合物中,相當於其部分結構之肽亦只要無特別說明,則N末端胺基酸之胺基酸殘基之胺基與氫原子鍵結,C末端胺基酸之胺基酸殘基之羰基與羥基鍵結。
本發明關於
(a)包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽,即,含有7~30個殘基之胺基酸之MHC-I類分子限制性肽(於本說明書中亦記為上述(a)之肽)或其藥學上容許之鹽;或
(b)式(1):
[化5]
所表示之化合物或其藥學上容許之鹽
之用途。
「癌抗原肽A」為含有7~30個殘基之胺基酸之MHC-I類分子限制性肽。式(1)中,癌抗原肽A之N末端胺基酸之胺基與式(1)中之Ya
鍵結,癌抗原肽A之C末端胺基酸之羰基與式(1)中之羥基鍵結。
「Xa
」及「Ya
」獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基。Xa
之胺基酸殘基數與Ya
之胺基酸殘基數之和為0~4之整數。例如,所謂該和為整數0,意指Xa
及Ya
為單鍵。又,作為該和為整數4之情形,例如可例舉:Xa
及Ya
獨立地為含有2個殘基之胺基酸之肽之二價基之情形;Xa
為含有3個殘基之胺基酸之肽之二價基、且Ya
為含有1個殘基之胺基酸之肽之二價基之情形;Xa
為含有4個殘基之胺基酸之肽之二價基、且Ya
為單鍵之情形等。
作為該和之整數,可較佳地例舉0~2,可更佳地例舉0~1,可最佳地例舉0。即,作為Xa
及Ya
,最佳為均為單鍵之情形。
作為該和為整數2之情形,可例舉:Xa
為含有2個殘基之胺基酸之肽之二價基、且Ya
為單鍵之情形;Xa
及Ya
獨立地為含有1個殘基之胺基酸之肽之二價基之情形;或Xa
為單鍵、且Ya
為含有2個殘基之胺基酸之肽之二價基之情形。
作為該和為整數1之情形,可例舉:Xa
為含有1個殘基之胺基酸之肽之二價基、且Ya
為單鍵之情形;或Xa
為單鍵、且Ya
為含有1個殘基之胺基酸之肽之二價基之情形。其中,可較佳地例舉:Xa
為單鍵、且Ya
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基之情形;或Xa
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基、且Ya
為單鍵之情形。
「癌抗原肽B」為含有7~30個殘基之胺基酸之MHC-I類分子限制性肽。式(2)中,癌抗原肽B之N末端胺基酸之胺基與式(2)中之Yb
(或式(1-2)中之Yb
)鍵結,C末端胺基酸之羰基與式(2)中之羥基鍵結。
「Xb
」及「Yb
」獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基。Xb
之胺基酸殘基數與Yb
之胺基酸殘基數之和為0~4之整數。例如,所謂該和為整數0,意指Xb
及Yb
為單鍵。又,作為該和為整數4之情形,例如可例舉:Xb
及Yb
獨立地為含有2個殘基之胺基酸之肽之二價基之情形;Xb
為含有3個殘基之胺基酸之肽之二價基、且Yb
為含有1個殘基之胺基酸之肽之二價基之情形;Xb
為含有4個殘基之胺基酸之肽之二價基、且Yb
為單鍵之情形等。
作為該和之整數,可較佳地例舉0~2,可更佳地例舉0~1,可最佳地例舉0。即,作為Xb
及Yb
,最佳為均為單鍵之情形。
作為該和為整數2之情形,可例舉:Xb
為含有2個殘基之胺基酸之肽之二價基、且Yb
為單鍵之情形;Xb
及Yb
獨立地為含有1個殘基之胺基酸之肽之二價基之情形;或Xb
為單鍵、且Yb
為含有2個殘基之胺基酸之肽之二價基之情形。
作為該和為整數1之情形,可例舉:Xb
為含有1個殘基之胺基酸之肽之二價基、且Yb
為單鍵之情形;或Xb
為單鍵、且Yb
為含有1個殘基之胺基酸之肽之二價基之情形。其中,可較佳地例舉:Xb
為單鍵、且Yb
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基之情形;或Xb
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基、且Yb
為單鍵之情形。
於R1
為式(2)所表示之基之情形時,式(1)所表示之化合物為式(1-2):
[化8]
(式中,Xa
、Ya
及癌抗原肽A與上述式(1)中之各者同義,Xb
、Yb
及癌抗原肽B與上述式(2)中之各者同義)所表示之化合物。
「癌抗原肽C」為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-I類分子限制性肽、或含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽。於R1
為癌抗原肽C之情形時,癌抗原肽C之半胱胺酸殘基之硫原子與式(1)中之硫原子經由雙硫鍵鍵結。於癌抗原肽C之N末端可結合有含有1~4個殘基之胺基酸之肽(即,含有1個殘基之胺基酸或2~4個殘基之胺基酸之肽)。
癌抗原肽C只要於該肽之胺基酸序列中包含至少1個半胱胺酸殘基即可,作為所包含之半胱胺酸殘基數,較佳為1~3,更佳為1~2,最佳為1。
於一實施形態中,結合於癌抗原肽C之N末端之含有1~4個殘基之胺基酸之肽含有自丙胺酸殘基、精胺酸殘基、天冬醯胺殘基、半胱胺酸殘基、穀醯胺殘基、穀胺酸殘基、組胺酸殘基、異白胺酸殘基、白胺酸殘基、離胺酸殘基、甲硫胺酸殘基、苯基丙胺酸殘基、脯胺酸殘基、絲胺酸殘基、蘇胺酸殘基、色胺酸殘基、酪胺酸殘基及纈胺酸殘基中獨立選擇之1~4個殘基之胺基酸。於另一實施形態中,上述含有1~4個殘基之胺基酸之肽含有自精胺酸殘基、穀醯胺殘基、穀胺酸殘基、組胺酸殘基、離胺酸殘基、苯基丙胺酸殘基及酪胺酸殘基中獨立選擇之1~4個殘基之胺基酸。
於一實施形態中,結合於癌抗原肽C之N末端之含有1~4個殘基之胺基酸之肽包含1個半胱胺酸殘基。於另一實施形態中,於癌抗原肽C之N末端結合有含有CA之二肽。
於一實施形態中,於癌抗原肽C之N末端結合有選自精胺酸殘基、穀醯胺殘基、穀胺酸殘基、組胺酸殘基、離胺酸殘基、苯基丙胺酸殘基及酪胺酸殘基中之1個殘基之胺基酸。
於一實施形態中,式(1)所表示之化合物為異源二聚物,而非同源二聚物。同源二聚物意指由相同之肽單體二聚物化而成之二聚物,異源二聚物意指由不同之肽單體二聚物化而成之二聚物。
於R1
為式(2)所表示之基、且癌抗原肽B包含1個半胱胺酸殘基之情形時,癌抗原肽B之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化9]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結)。
於R1
為癌抗原肽C、且於癌抗原肽C之N末端結合有含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽之情形時,結合於癌抗原肽C之N末端之肽之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化10]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結)。
「癌抗原肽D」為含有7~30個殘基之胺基酸之MHC-II類分子限制性肽。式(3)中,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結。
「癌抗原肽E」為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽。
「Xd
」及「Yd
」獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基。Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數。例如,所謂該和為整數0,意指Xd
及Yd
為單鍵。又,作為該和為整數4之情形,例如可例舉:Xd
及Yd
獨立地為含有2個殘基之胺基酸之肽之二價基之情形;Xd
為含有3個殘基之胺基酸之肽之二價基、且Yd
為含有1個殘基之胺基酸之肽之二價基之情形;Xd
為含有4個殘基之胺基酸之肽之二價基、且Yd
為單鍵之情形等。
作為該和之整數,可較佳地例舉0~2,可更佳地例舉0~1,可最佳地例舉0。即,作為Xd
及Yd
,最佳為均為單鍵之情形。
作為該和為整數2之情形,可例舉:Xd
為含有2個殘基之胺基酸之肽之二價基、且Yd
為單鍵之情形;Xd
及Yd
獨立地為含有1個殘基之胺基酸之肽之二價基之情形;或Xd
為單鍵、且Yd
為含有2個殘基之胺基酸之肽之二價基之情形。
作為該和為整數1之情形,可例舉:Xd
為含有1個殘基之胺基酸之肽之二價基、且Yd
為單鍵之情形;或Xd
為單鍵、且Yd
為含有1個殘基之胺基酸之肽之二價基之情形。其中,可較佳地例舉:Xd
為單鍵、且Yd
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基之情形;或Xd
為丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基、且Yd
為單鍵之情形。
於本說明書中,「MHC-I類分子限制性肽」及「MHC-II類分子限制性肽」可為含有序列編號1記載之人WT1之胺基酸序列中之連續之胺基酸的肽或其改型肽(於本說明書中亦稱為「WT1肽」)。
所謂「MHC-I類分子限制性」,意指與作為主要組織相容性抗原(Major Histocompatibility Complex,MHC)之I類分子的MHC-I類分子結合而誘導CTL之特性。於本說明書中,所謂「MHC-I類分子限制性肽」,意指具有於體外及/或體內與MHC-I類分子結合而誘導細胞毒殺性T細胞(CTL)之能力的肽(即,具有CTL誘導活性之肽)。有時亦將「MHC-I類分子限制性肽」稱為「殺傷性肽」。
人體中之MHC稱為人白血球型抗原(HLA)。相當於MHC-I類分子之HLA分為HLA-A、B、Cw、F及G等亞型。作為「MHC-I類分子限制性」,可較佳地例舉:HLA-A限制性、HLA-B限制性或HLA-Cw限制性。
關於HLA之各亞型,已知多型(對偶基因)。作為多型,例如可例舉: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,進而可例舉: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類分子限制性肽」之胺基酸序列及長度並無特別限定,肽若過長則易受到蛋白質分解酶之作用,若過短則無法良好地結合於肽容納溝。MHC-I類分子限制性肽之胺基酸殘基數通常為7~30個殘基,較佳為7~15個殘基、8~12個殘基、8~11個殘基、或8~9個殘基。於一實施形態中,MHC-I類分子限制性肽之胺基酸殘基數為9~30個殘基,較佳為9~15個殘基、9~12個殘基、9~11個殘基、9~10個殘基、或9個殘基。
「MHC-I類分子限制性肽」包括藉由在體外或體內被蛋白體及/或蛋白酶分解、及/或被ERAP1切斷(亦稱為修整)成最佳之殘基數等而生成「MHC-I類分子限制性表位」之肽。於本說明書中,所謂「MHC-I類分子限制性表位」,意指與MHC-I類分子結合而以複合體之形式呈現的如此之肽。即,「MHC-I類分子限制性肽」包括藉由體外或體內之分解及/或修整等而生成與MHC-I類分子結合之肽(即,經過體外或體內之分解及/或修整等後與MHC-I類分子結合)者。
作為MHC-I類分子限制性表位之生成過程之一例,可想到如下生成過程:首先,被蛋白體及/或蛋白酶分解,結果生成「MHC-I類分子限制性表位」之C末端胺基酸,其次,被ERAP1修整(切斷),結果生成「MHC-I類分子限制性表位」之N末端胺基酸。因此,作為「MHC-I類分子限制性肽」,較佳為於含有7~12個殘基之胺基酸之「MHC-I類分子限制性表位」之C末端胺基酸之羰基上附加0~23個殘基之胺基酸而成之含有7~30個殘基之胺基酸之肽。
「MHC-I類分子限制性表位」含有通常為7~12個殘基、較佳為9個殘基之胺基酸。於一實施形態中,「MHC-I類分子限制性肽」係於「MHC-I類分子限制性表位」之C末端側附加胺基酸而成者。於另一實施形態中,「MHC-I類分子限制性肽」係於「MHC-I類分子限制性表位」之C末端胺基酸之羰基上附加1~23個殘基之胺基酸而成之含有8~30個殘基之胺基酸之肽。
於本說明書中,所謂包含特定胺基酸序列之肽,一般而言,指可於該胺基酸序列之N末端胺基酸及/或C末端胺基酸上附加另外之胺基酸之肽。於對「MHC-I類分子限制性肽」附加胺基酸之情形時,較佳為附加於C末端側。
於本說明書中,所謂「改型肽」,意指含有原本之肽之胺基酸序列中之1個或數個胺基酸殘基經改型之胺基酸序列的肽。改型肽含有原本之肽之胺基酸序列中缺失、置換及/或附加(於本說明書中亦包括插入之含義)了1個或數個、例如1~9個、較佳為1~5個、1~4個、1~3個、進而較佳為1~2個、更佳為1個胺基酸之胺基酸序列。缺失、置換或附加之胺基酸之個數較佳為1~5、1~4、1~3,進而較佳為1~2,更佳為1。改型肽中之胺基酸之置換可於任意位置、於與任意種類之胺基酸之間進行。較佳為保守性胺基酸置換。例如,可將Glu殘基置換成Asp殘基、Phe殘基置換成Tyr殘基、Leu殘基置換成Ile殘基、Ala殘基置換成Ser殘基、His殘基置換成Arg殘基。胺基酸之附加或缺失較佳為於肽之N末端或C末端進行,亦可於序列內部進行。置換或附加之胺基酸亦可為除基因編碼之20種胺基酸以外之非天然胺基酸。
於本說明書中,含有經改型之胺基酸序列之殺傷性肽亦特別稱為「改型殺傷性肽」。改型殺傷性肽中,作為被置換胺基酸之位置,於含有9個殘基之胺基酸之肽之情形時,可例舉:第1位(N末端)、第2位、第3位及第9位。附加之胺基酸之個數較佳為1或2,更佳為1。作為較佳之附加位置,可例舉:N末端或C末端。缺失之胺基酸之個數較佳為1。
已知HLA之亞型之各多型存在可與HLA抗原結合之肽之胺基酸序列之規則性(結合模體)。作為一例,認為於構成結合模體之胺基酸中進行胺基酸之置換。例如,作為HLA-A24之結合模體,已知於含有8~11個殘基之胺基酸之肽中,第2位之胺基酸為Tyr、Phe、Met或Trp,C末端之胺基酸為Phe、Leu、Ile、Trp或Met(J. Immunol., 152, p3913, 1994;J. Immunol., 155, p4307, 1994;Immunogenetics, 41, p178, 1995)。因此,例如於含有9個殘基之胺基酸之肽之情形時,可用Tyr、Phe、Met及Trp置換第2位之胺基酸,及/或可用Phe、Leu、Ile、Trp或Met置換第9位(C末端)之胺基酸,經過該置換之肽較佳地用作改型殺傷性肽。同樣地,作為HLA-A0201之結合模體,已知於含有8~11個殘基之胺基酸之肽中,第2位之胺基酸為Leu或Met,C末端之胺基酸為Val或Leu,因此,例如於含有9個殘基之胺基酸之肽之情形時,可用Leu或Met置換第2位之胺基酸,及/或可用Val或Leu置換第9位(C末端)之胺基酸,經過該置換之肽較佳地用作改型殺傷性肽。
作為「MHC-I類分子限制性肽」,例如可例舉:包含選自以下之胺基酸序列:
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中有1個或數個胺基酸殘基經改型之胺基酸序列、且具有CTL誘導活性之肽。可進而較佳地例舉:由選自序列編號2~7中之任一胺基酸序列構成之肽、或者由上述任一胺基酸序列中有1個或數個胺基酸殘基經改型之胺基酸序列構成、且具有CTL誘導活性之肽。
作為改型殺傷性肽,可例舉如下之肽。
作為RMFPNAPYL(序列編號2)之改型殺傷性肽的
RYFPNAPYL(序列編號8)(參照國際公開03/106682號)、
FMFPNAPYL(序列編號9)、
RLFPNAPYL(序列編號10)、
RMMPNAPYL(序列編號11)、
RMFPNAPYV(序列編號12)或
YMFPNAPYL(序列編號13)(參照國際公開第2009/072610號);
作為CMTWNQMNL(序列編號3)之改型殺傷性肽的
CYTWNQMNL(序列編號14)(參照國際公開02/79253號)、
Xaa-Met-Thr-Trp-Asn-Gln-Met-Asn-Leu(序列編號15)(本序列中,Xaa表示Ser或Ala)或
Xaa-Tyr-Thr-Trp-Asn-Gln-Met-Asn-Leu(序列編號16)(本序列中,Xaa表示Ser、Ala、Abu、Arg、Lys、Orn、Cit、Leu、Phe或Asn)(參照國際公開2004/026897號);
作為ALLPAVPSL(序列編號4)之改型殺傷性肽的
AYLPAVPSL(序列編號17)(參照國際公開2003/106682號);
作為SLGEQQYSV(序列編號5)之改型殺傷性肽的
FLGEQQYSV(序列編號18)、
SMGEQQYSV(序列編號19)或
SLMEQQYSV(序列編號20)(參照國際公開2009/072610號);或者
作為RVPGVAPTL(序列編號6)之改型殺傷性肽的
RYPGVAPTL(序列編號21)(參照國際公開2003/106682號)。
於一實施形態中,改型殺傷性肽為於N末端附加1~4個殘基之胺基酸之改型肽。於一實施形態中,附加之胺基酸自丙胺酸殘基、精胺酸殘基、天冬醯胺殘基、半胱胺酸殘基、穀醯胺殘基、穀胺酸殘基、組胺酸殘基、異白胺酸殘基、白胺酸殘基、離胺酸殘基、甲硫胺酸殘基、苯基丙胺酸殘基、脯胺酸殘基、絲胺酸殘基、蘇胺酸殘基、色胺酸殘基、酪胺酸殘基及纈胺酸殘基中,較佳為自精胺酸殘基、穀醯胺殘基、穀胺酸殘基、組胺酸殘基、離胺酸殘基、苯基丙胺酸殘基及酪胺酸殘基中獨立地選擇。附加之胺基酸較佳為1~3個殘基,進而較佳為1~2個殘基,最佳為1個殘基。
作為改型殺傷性肽,例如可例舉:包含序列編號3或序列編號14之胺基酸序列、且於上述序列之N末端半胱胺酸殘基之胺基上附加1~3個胺基酸殘基而成之含有10~12個殘基之胺基酸之肽。
於一實施形態中,改型殺傷性肽為包含選自
RCMTWNQMNL(序列編號22)、
RCYTWNQMNL(序列編號23)
QCMTWNQMNL(序列編號24)、
QCYTWNQMNL(序列編號25)、
ECMTWNQMNL(序列編號26)、
ECYTWNQMNL(序列編號27)、
HCMTWNQMNL(序列編號28)、
HCYTWNQMNL(序列編號29)、
KCMTWNQMNL(序列編號30)、
KCYTWNQMNL(序列編號31)、
FCMTWNQMNL(序列編號32)、
FCYTWNQMNL(序列編號33)、
YCMTWNQMNL(序列編號34)及
YCYTWNQMNL(序列編號35)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
於一實施形態中,「MHC-I類分子限制性肽」為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為由選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列構成之肽、或者由選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列構成、且具有CTL誘導活性之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者包含選自序列編號2、3及7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為由選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列構成之肽、或者由選自序列編號2、3及7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列構成、且具有CTL誘導活性之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為包含選自
RMFPNAPYL(序列編號2)、
RYFPNAPYL(序列編號8)、
YMFPNAPYL(序列編號13)、
CMTWNQMNL(序列編號3)、
CYTWNQMNL(序列編號14)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為包含RMFPNAPYL(序列編號2)、RYFPNAPYL(序列編號8)、或YMFPNAPYL(序列編號13)之胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為包含RMFPNAPYL(序列編號2)、VLDFAPPGA(序列編號7)、或YMFPNAPYL(序列編號13)之胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為包含RMFPNAPYL(序列編號2)之胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為由選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)及
SGQAYMFPNAPYLPSCLES(序列編號42)
中之任一胺基酸序列構成之肽。
於另一實施形態中,「MHC-I類分子限制性肽」為由選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)及
WAPVLDFAPPGASAYGSLC(序列編號38)
中之任一胺基酸序列構成之肽。
所謂「MHC-II類分子限制性」,意指與MHC-II類分子結合而誘導輔助性T細胞之特性。所謂「MHC-II類分子限制性肽」,意指具有於體外及/或體內與MHC-II類分子結合而誘導輔助性T細胞之能力的肽(即,具有輔助性T細胞誘導活性之肽)。於本說明書中,有時亦將「MHC-II類分子限制性肽」稱為「輔助性肽」。
相當於MHC-II類分子之HLA分為HLA-DR、DQ及DP等亞型。作為「MHC-II類分子限制性」,可較佳地例舉:HLA-DR限制性、HLA-DQ限制性或HLA-DP限制性。
關於HLA之各亞型,已知多型(對偶基因)。作為多型,例如可例舉: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、或DRB5*
0102,可較佳地例舉:DRB1*
0101、DRB1*
0405、DRB1*
1502、DPB1*
0201、DPB1*
0202、或DQB1*
0601。
「MHC-II類分子限制性肽」之胺基酸序列及長度並無特別限定,肽若過長則易受到蛋白質分解酶之作用,若過短則無法良好地結合於肽容納溝。「MHC-II類分子限制性肽」之胺基酸殘基數通常為9~30,較佳為10~25,更佳為12~24,進而較佳為15~22。
「MHC-II類分子限制性肽」包括藉由在體外或體內被蛋白體及/或蛋白酶分解、及/或被ERAP1切斷(亦稱為修整)成最佳之殘基數等而生成「MHC-II類分子限制性表位」之肽。於本說明書中,所謂「MHC-II類分子限制性表位」,意指與MHC-II類分子結合而以複合體之形式呈現的如此之肽。即,「MHC-II類分子限制性肽」包括藉由體外或體內之分解及/或修整等而生成與MHC-II類分子結合之肽(即,經過體外或體內之分解及/或修整等後與MHC-II類分子結合)者。
於本說明書中,含有經改型之胺基酸序列之輔助性肽亦特別稱為「改型輔助性肽」。於改型輔助性肽中,關於被置換胺基酸之位置,例如於具有針對HLA-DRB1*
0405之結合模體結構之含有9個殘基之胺基酸之肽之情形時,較佳為第1位、第4位、第6位及/或第9位之胺基酸殘基之置換。於具有上述結合模體結構之含有9個殘基之胺基酸之肽之情形時,可進而較佳地例示含有第1位、第4位、第6位及/或第9位之胺基酸殘基被置換成選自如下者中之任一胺基酸殘基之胺基酸序列的肽,
第1位:苯基丙胺酸、色胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、
第4位:纈胺酸、異白胺酸、甲硫胺酸、天冬胺酸、穀胺酸、
第6位:天冬醯胺、絲胺酸、蘇胺酸、穀醯胺、離胺酸、天冬胺酸、
第9位:天冬胺酸、穀胺酸、穀醯胺。
作為「MHC-II類分子限制性肽」,可例舉:包含選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)、
SGQAYMFPNAPYLPSCLES(序列編號42)、
PGCNKRYFKLSHLQMHSRK(序列編號43)、
PGCNKRYFKLSHLQMHSRKH(序列編號44)、
PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、
CNKRYFKLSHLQMHSRK(序列編號46)、
CNKRYFKLSHLQMHSRKH(序列編號47)、及
CNKRYFKLSHLQMHSRKHTG(序列編號48)
中之任一胺基酸序列之肽、或者包含序列編號36~48之任一胺基酸序列中有1個或數個胺基酸殘基經改型之胺基酸序列、且具有輔助性T細胞誘導活性之肽。可進而較佳地例舉:由選自序列編號36~48中之任一胺基酸序列構成之肽、或者由選自序列編號36~48中之任一胺基酸序列中有1個或數個胺基酸殘基經改型之胺基酸序列構成、且具有輔助性T細胞誘導活性之肽。
於一實施形態中,R1
表示癌抗原肽C,癌抗原肽C為由選自以下之胺基酸序列:
CMTWNQMNL(序列編號3)、
CYTWNQMNL(序列編號14)、
RCMTWNQMNL(序列編號22)、
RCYTWNQMNL(序列編號23)
QCMTWNQMNL(序列編號24)、
QCYTWNQMNL(序列編號25)、
ECMTWNQMNL(序列編號26)、
ECYTWNQMNL(序列編號27)、
HCMTWNQMNL(序列編號28)、
HCYTWNQMNL(序列編號29)、
KCMTWNQMNL(序列編號30)、
KCYTWNQMNL(序列編號31)、
FCMTWNQMNL(序列編號32)、
FCYTWNQMNL(序列編號33)、
YCMTWNQMNL(序列編號34)及
YCYTWNQMNL(序列編號35)
中之任一胺基酸序列構成之肽。
作為式(1)所表示之化合物,可例舉:
式(6):
[化11]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(4):
[化12]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(5):
[化13]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(7):
[化14]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(8):
[化15]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(9):
[化16]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(10):
[化17]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(11):
[化18]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(12):
[化19]
(式中,C與C之間的鍵表示雙硫鍵)
式(13):
[化20]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(14):
[化21]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(15):
[化22]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(16):
[化23]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(17):
[化24]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(18):
[化25]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;及
式(19):
[化26]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
式(1)所表示之化合物進而可為包含選自
CRMFPNAPYL(序列編號49)、
CCMTWNQMNL(序列編號50)、
CCYTWNQMNL(序列編號51)、
CALLPAVPSL(序列編號52)、
CSLGEQQYSV(序列編號53)
CRVPGVAPTL(序列編號54)及
CVLDFAPPGA(序列編號55)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
肽之胺基酸序列中之胺基酸殘基可經修飾。胺基酸殘基可藉由公知方法進行修飾。例如,可對構成肽之胺基酸殘基之側鏈中之官能基實施酯化、烷基化、鹵化、磷酸化、磺化、醯胺化等。又,可使肽之N末端及/或C末端結合各種物質。與肽結合之物質可為調節肽之溶解性者,亦可為提高肽之耐蛋白酶作用等穩定性者,或可為例如將肽特異性地遞送至特定之組織、器官者,又或可為具有增強抗原呈現細胞之攝取效率之作用等者。
肽可為其N末端胺基酸之胺基、或C末端胺基酸之羧基經修飾者。作為N末端胺基酸之胺基之修飾基,例如可例舉:1~3個之碳數1至6之烷基、苯基、環烷基、醯基,作為醯基之具體例,可例舉:碳數1至6之烷醯基、經苯基取代之碳數1至6之烷醯基、經碳數5至7之環烷基取代之羰基、碳數1至6之烷基磺醯基、苯基磺醯基、碳數2至6之烷氧基羰基、經苯基取代之烷氧基羰基、經碳數5至7之環烷氧基取代之羰基、苯氧基羰基等。作為C末端胺基酸之羧基經修飾之肽,例如可例舉酯體及醯胺體,作為酯體之具體例,可例舉:碳數1至6之烷基酯、經苯基取代之碳數0至6之烷基酯、碳數5至7之環烷基酯等,作為醯胺體之具體例,可例舉:經1個或2個碳數1至6之烷基取代之醯胺、經1個或2個經苯基取代之碳數0至6之烷基取代之醯胺、包含醯胺基之氮原子而形成5至7員環之氮雜環烷烴之醯胺等。
肽可藉由碳-碳鍵、碳-氮鍵、碳-硫鍵等肽鍵以外之鍵來鍵結胺基酸殘基。進而,肽可包含1個或其以上之D-體胺基酸。
上述肽修飾為例示,業者可容易地設想其變化,進行製造、驗證效果後採用。
肽具有CTL誘導活性或輔助性T細胞誘導活性可由業者適當確認。例如,CTL誘導活性可藉由利用HLA四聚物法(Int. J. Cancer: 100, 565-570(2002))或有限稀釋法(Nat. Med.: 4, 321-327(1998))測定CTL之數量來確認。或者,例如於HLA-A24限制性之CTL誘導活性之情形時,可藉由使用國際公開第02/47474號及Int. J. Cancer: 100, 565-570(2002)中記述之HLA-A24模型小鼠等來驗證。輔助性T細胞誘導活性可藉由例如Cancer Immunol. Immunother. 51: 271(2002)中記載之方法等方法、或本說明書之實施例中記載之方法等來驗證。
本說明書中記載之肽及化合物以及相當於該等之中間物之肽可依據通常採用之肽合成方法製造。例如於Peptide Synthesis, Interscience, New York, 1966;The Proteins, Vol 2, Academic Press Inc., New York, 1976;肽合成, 丸善股份有限公司, 1975;肽合成之基礎與實驗, 丸善股份有限公司, 1985;醫藥品之開發 續 第14卷・肽合成, 廣川書店, 1991等中有記載。例如可例舉:採用Fmoc法或Boc法使用固相合成機製造之方法、或者使Boc-胺基酸或Z-胺基酸藉由液相合成法依次縮合而製造之方法(Fmoc表示9-茀基甲氧基羰基、Boc表示第三丁氧基羰基、Z表示苄氧基羰基)。又,肽亦可基於編碼該肽之核苷酸序列資訊,採用基因工程方法來製造。該基因工程方法為業者周知,可依據Molecular Cloning, T. Maniatis et al., CSH Laboratory(1983)、DNA Cloning, DM. Glover, IRL PRESS(1985)等記載來進行。
式(1)所表示之化合物例如可藉由使2個MHC-I類分子限制性肽、或MHC-I類分子限制性肽與MHC-II類分子限制性肽經由雙硫鍵結合而合成(參照國際公開第2014/157692號)。
對於用以製造式(1)所表示之化合物之中間物中之胺基、羧基、巰基等官能基,可視需要採用保護、去保護之技術,利用適宜之保護基加以保護,或進行去保護。作為適宜之保護基、保護方法及去保護方法,Protective Groups in Organic Synthesis 2nd Edition(John Wiley & Sons, Inc.; 1990)等中有詳細記載。例如,作為巰基之保護基,可例舉:乙醯胺甲基或三苯甲基等。
於式(1)所表示之化合物具有雙硫鍵之情形時,可依據通常採用之肽化學方法,於包含半胱胺酸殘基之不同之2個肽之間、或包含半胱胺酸殘基之肽與半胱胺酸之間形成該雙硫鍵。作為雙硫鍵之形成方法,可例舉上述文獻(Peptide Synthesis, Interscience, New York, 1966;The Proteins, Vol 2, Academic Press Inc., New York, 1976;肽合成, 丸善股份有限公司, 1975;肽合成之基礎與實驗, 丸善股份有限公司, 1985;醫藥品之開發 續 第14卷・肽合成, 廣川書店, 1991)等中記載之方法。
具體而言,於肽所含之半胱胺酸殘基為1個之情形時,將包括半胱胺酸側鏈上之巰基之保護基在內之全部之保護基去除後,於惰性溶劑中進行氧化,藉此可製造具有雙硫鍵之化合物(二硫醚化合物)。又,可藉由將具有巰基之2個中間物於適宜之溶劑中混合、氧化而製造。作為該氧化之方法,適當選擇通常之肽合成中形成雙硫鍵之公知方法即可。例如可例舉:於碘氧化、鹼性條件下進行空氣氧化反應之方法、或者於鹼性或酸性條件下添加氧化劑形成雙硫鍵之方法等。此處,作為氧化劑,可例舉:碘、二甲基亞碸(DMSO)、鐵氰化鉀等。作為溶劑,可使用水、乙酸、甲醇、氯仿、DMF或DMSO等、或者該等之混合液。藉由氧化反應,經常獲得對稱與非對稱性之二硫醚化合物之混合物。目標之非對稱性二硫醚化合物可藉由各種層析法或再結晶等進行純化而獲得。或可使用具有與Npys基(3-硝基-2-吡啶次磺醯基)鍵結之巰基等活化巰基之中間物。預先藉由將一個中間物與例如2,2'-二硫雙(5-硝基吡啶)進行混合而使巰基活化後,添加另一中間物,藉此可形成選擇性之雙硫鍵(Tetrahedron Letters. Vol. 37. No. 9, pp. 1347-1350)。
於肽所含之半胱胺酸殘基為2個以上之情形時亦可採用與上述相同之方法。於該情形時獲得雙硫鍵樣式不同之異構物。藉由將半胱胺酸側鏈之保護基設為特定組合,可獲得於目標之半胱胺酸殘基間形成雙硫鍵之二聚物。作為上述保護基之組合,可例舉:MeBzl(甲基苄基)基與Acm(乙醯胺甲基)基、Trt(三苯甲基)基與Acm基、Npys(3-硝基-2-吡啶基硫基)基與Acm基、S-Bu-t(S-第三丁基)基與Acm基等。例如,於MeBzl基與Acm基之組合之情形時,可例舉如下等方法:首先,將MeBzl基與半胱胺酸側鏈以外之其他保護基去除後,使包含肽單體之溶液進行空氣氧化反應而於去保護之半胱胺酸殘基間形成雙硫鍵,繼而,進行利用碘之去保護及氧化,於經Acm基保護之半胱胺酸殘基間形成雙硫鍵。
所獲得之肽、化合物及中間物可依據業者公知之方法或通常採用之肽化學方法進行純化。例如可藉由各種層析法(例如矽膠管柱層析法、離子交換管柱層析法、凝膠過濾、或逆相層析法)、或再結晶等進行純化。例如,作為再結晶溶劑,可使用甲醇、乙醇、或2-丙醇等醇系溶劑、二乙醚等醚系溶劑、乙酸乙酯等酯系溶劑、苯或甲苯等芳香族烴系溶劑、丙酮等酮系溶劑、己烷等烴系溶劑、二甲基甲醯胺或乙腈等非質子系溶劑、水、或該等之混合溶劑等。作為其他純化方法,可採用實驗化學講座(日本化學會編,丸善)1卷等中記載之方法等。二硫醚化合物之純化方法於上述文獻(Peptide Synthesis, Interscience, New York, 1966;The Proteins, Vol 2, Academic Press Inc., New York, 1976;肽合成, 丸善股份有限公司, 1975;肽合成之基礎與實驗, 丸善股份有限公司, 1985;醫藥品之開發 續 第14卷・肽合成, 廣川書店, 1991)等中有記載。其中,較佳為HPLC。
於式(1)所表示之化合物中存在1個以上之不對稱點之情形時,可依據通常之方法,藉由使用具有該不對稱點之原料(胺基酸)而製造。又,為了提高化合物之光學純度,可於製造步驟之合適階段進行光學拆分等。作為光學拆分法,例如可藉由如下非鏡像異構物法進行,即,使式(1)所表示之化合物或其中間物與光學活性之酸(例如,苦杏仁酸、N-苄氧基丙胺酸或乳酸等單羧酸、酒石酸、鄰二異亞丙基酒石酸或蘋果酸等二羧酸、或者樟腦磺酸或溴樟腦磺酸等磺酸),於惰性溶劑中(例如甲醇、乙醇或2-丙醇等醇系溶劑、二乙醚等醚系溶劑、乙酸乙酯等酯系溶劑、甲苯等烴系溶劑、或乙腈等非質子系溶劑、及該等之混合溶劑)形成鹽。於式(1)所表示之化合物或中間物具有羧基等酸性官能基之情形時,亦可藉由與光學活性之胺(例如α-苯乙基胺、奎寧、奎尼丁、辛可尼丁、辛可寧、番木鼈鹼等有機胺)形成鹽而進行光學拆分。
作為形成鹽時之溫度,於室溫至溶劑之沸點之間的範圍選擇。為了提高光學純度,較理想為暫且將溫度升至溶劑之沸點附近。於濾取所析出之鹽時,可視需要進行冷卻以提高產率。光學活性之酸或胺之使用量相對於基質,宜為約0.5~約2.0當量之範圍,較佳為約1當量之範圍。視需要亦可使結晶於惰性溶劑中(例如甲醇、乙醇、2-丙醇等醇系溶劑、二乙醚等醚系溶劑、乙酸乙酯等酯系溶劑、甲苯等烴系溶劑、乙腈等非質子系溶劑、及該等之混合溶劑)再結晶而獲得高純度之光學活性之鹽。又,亦可視需要藉由通常之方法利用酸或鹼對經光學拆分之鹽進行處理而獲得游離體。
作為本說明書中之「藥學上容許之鹽」,可例舉酸加成鹽及鹼加成鹽。例如,作為酸加成鹽,可例舉:鹽酸鹽、氫溴酸鹽、硫酸鹽、氫碘酸鹽、硝酸鹽、磷酸鹽等無機酸鹽、檸檬酸鹽、草酸鹽、乙酸鹽、甲酸鹽、丙酸鹽、苯甲酸鹽、三氟乙酸鹽、順丁烯二酸鹽、酒石酸鹽、甲磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等有機酸鹽,作為鹼加成鹽,可例舉:鈉鹽、鉀鹽、鈣鹽、鎂鹽、銨鹽等無機鹼鹽、三乙基銨鹽、三乙醇銨鹽、吡啶鎓鹽、二異丙基銨鹽等有機鹼鹽等,進而可例舉精胺酸、天冬胺酸、穀胺酸等鹼性或酸性胺基酸之胺基酸鹽。於本說明書中,只要上下文意無矛盾,術語「肽」或「化合物」包含其藥學上容許之鹽。
本說明書中記載之上述(a)之肽、式(1)所表示之化合物或其藥學上容許之鹽的水合物及乙醇溶劑合物等溶劑合物亦包含於本發明中。進而,本發明亦包含本說明書中記載之化合物或肽之非鏡像異構物、鏡像異構物等可能存在之全部之立體異構物、及所有形態之晶形。
上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽可用於處置HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中之癌症。因此,於一形態中,本發明提供一種醫藥組合物,其包含上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽,用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症。
所謂HLA-A*
02:07陽性對象、HLA-A*
03:01陽性對象、HLA-B*
15:01陽性對象、或HLA-B*
27:05陽性對象,分別指具有包含HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05之HLA單純型之對象。HLA對偶基因(HLA型別)藉由通常採用之HLA分型(尤其是基因型分型)之方法來特定。「對象」包括人、及非人靈長類、羊、狗、貓、馬、牛等非人動物,較佳為人。
於本說明書中,癌症之處置包括完全或部分抑制癌症之進展、或者至少部分緩解癌症之一種以上之症狀。又,癌症之處置包括誘導緩解、維持緩解、及抑制復發。
於一實施形態中,醫藥組合物為癌症疫苗。於另一實施形態中,醫藥組合物為癌症之細胞性免疫療法中之CTL誘導用組合物。
於一實施形態中,癌症為WT1表現之癌症、或伴有WT1基因表現水平上升之癌症。
於一實施形態中,癌症為血液性癌或實體癌。於另一實施形態中,癌症選自包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴細胞性白血病、急性淋巴母細胞性白血病、慢性淋巴細胞性白血病之慢性或急性白血病、骨髓化生不良症候群、多發性骨髓瘤、惡性淋巴瘤、胃癌、大腸癌、肺癌、乳癌、生殖細胞癌、肝癌、皮膚癌、膀胱癌、前列腺癌、子宮癌、宮頸癌(cervical cancer)、卵巢癌、腦瘤、神經膠質瘤、中樞神經系統原發惡性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T細胞淋巴瘤、淋巴細胞性淋巴瘤、T細胞淋巴瘤、骨癌、胰臟癌、頭頸癌、皮膚或眼窩內惡性黑色素瘤、直腸癌、肛門癌、睾丸癌、輸卵管癌、子宮內膜癌、子宮頸部上皮細胞癌(carcinoma of the cervix)、陰道癌、外陰癌、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、兒童實體癌、腎癌或尿道癌、腎盂癌、中樞神經系統腫瘤、腫瘤新血管生成、脊椎腫瘤、腦幹膠質瘤、垂體腺瘤、卡波西肉瘤、鱗狀上皮癌、鱗狀細胞癌、包括由石綿誘發之癌症在內之環境誘發癌症、及上述癌症之組合。於另一實施形態中,癌症選自包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴細胞性白血病之慢性或急性白血病、骨髓化生不良症候群、多發性骨髓瘤、惡性淋巴瘤、胃癌、大腸癌、肺癌、乳癌、生殖細胞癌、肝癌、皮膚癌、膀胱癌、前列腺癌、子宮癌、宮頸癌、卵巢癌、腦瘤、及神經膠質瘤。
上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、或包含其之醫藥組合物亦可與1種以上之其他癌抗原肽、例如MHC-I類分子限制性肽、MHC-II類分子限制性肽或其複合體、或其藥學上容許之鹽併用。作為其他癌抗原肽,可例舉以下之文獻中記載之肽或該等之衍生物、或該等之複合體:參照國際公開第2000/006602號、同第2002/079253、同第2003/106682號、同第2004/026897號、同第2004/063903號、同第2007/063903號、同第2010/123065號、同第2014/157692號、同第2005/053618號、同第2007/047764號、同第2007/120673號、同第2005/045027號、同第2010037395號、同第2000/018795號、同第2002/028414號、同第2003/037060號及同第2004/100870號。
於一實施形態中,上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、或包含其之醫藥組合物與MHC-II類分子限制性肽併用。於一實施形態中,MHC-II類分子限制性肽為包含WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
又,上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、或包含其之醫藥組合物可與1種以上之其他藥物(於本說明書中亦稱為併用藥物)組合使用。
併用藥物可為「免疫調節劑」。於本說明書中,所謂「免疫調節劑」,指藉由與抗原呈現細胞上及/或T細胞上之於由抗原呈現細胞引起之T細胞活化中參與輔助刺激訊號傳遞之分子進行相互作用而控制輔助刺激訊號之傳遞、或者對免疫機制中之直接或間接參與成立免疫耐受(免疫抑制)之分子之功能進行控制之各者。癌抗原肽為增加腫瘤內之腫瘤反應性CTL之藥劑,因此,藉由與免疫調節劑併用,或可降低免疫調節劑之投予量,減少不良事件。即,藉由併用癌抗原肽與免疫調節劑,可提供兼備更佳效果與更高安全性之治療法。
「免疫調節劑」可為選自抗體、核酸、蛋白質、肽及低分子化合物中之藥劑,但並不限定於該等。關於「免疫調節劑」之記載中,術語「抗體」亦包括抗體片段。作為抗體片段,可例示抗體之重鏈及輕鏈可變區(VH及VL)、F(ab')2、Fab'、Fab、Fv、Fd、sdFv、scFV等。關於「免疫調節劑」之記載中,蛋白質意指除抗體以外之所有蛋白質。「免疫調節劑」包括例如免疫檢查點抑制劑、共刺激分子促效劑、免疫活化劑、及低分子抑制劑。
「免疫檢查點抑制劑」抑制癌細胞或抗原呈現細胞之免疫抑制作用。作為免疫檢查點抑制劑,並無特別限定,可例舉針對選自由以下者所組成之群中之分子之藥劑:(1)CTLA(Cytotoxic T lymphocyte associate protein,細胞毒性T淋巴細胞相關蛋白)-4(伊匹單抗、曲美木單抗等);(2)PD-1(納武單抗、帕博利珠單抗、AMP(Adenosine monophosphate,一磷酸腺苷)-224、AMP-514(MEDI0680)、匹地利珠單抗(CT-011)等);(3)LAG(Lymphocyte Activation Gene,淋巴細胞活化基因)-3(IMP-321、BMS-986016等);(4)BTLA(B- and T-lymphocyte Associated Protein,B與T淋巴細胞衰減蛋白);(5)KIR(killer cell immunoglobulin-like receptor,殺傷細胞免疫球蛋白樣受體)(IPH2101等);(6)TIM(T-cell immunoglobulin and mucin-domain containing molecule,T細胞免疫球蛋白及黏蛋白結構域分子)-3;(7)PD-L1(度伐利尤單抗(MEDI4736)、MPDL3280A、BMS-936559、阿維魯單抗(MSB0010718C)等);(8)PD-L2;(9)B7-H3(MGA-271等);(10)B7-H4;(11)HVEM(Herpesvirus entry mediator,疱疹病毒進入介體);(12)GAL(Galectin,半乳糖凝集素)9;(13)CD160;(14)VISTA(V-domain Ig suppressor of T-cell activation,T細胞活化V結構域Ig抑制劑);(15)BTNL(Butyrophilin-like protein,嗜乳脂蛋白樣蛋白)2;(16)TIGIT(T cell Ig and ITIM domain,T細胞免疫球蛋白與ITIM結構域);(17)PVR(Poliovirus Receptor,脊髓灰質炎病毒受體);(18)BTN(Butyrophilin,嗜乳脂蛋白)1A1;(19)BTN2A2;(20)BTN3A2(Nat Rev Drug Discov. 2013; 12: 130-146;Nikkei Medical Cancer Review 2014; 9;Nat Rev Immunol. 2014; 14: 559-69);及(21)CSF1-R(Colony-stimulating factor 1 receptor,巨噬細胞集落刺激因子1受體)。
「共刺激分子促效劑」經由T細胞上或抗原呈現細胞上之共刺激分子傳遞輔助訊號,藉此使T細胞活化,減弱癌細胞或抗原呈現細胞之免疫抑制作用。作為共刺激分子促效劑,並無特別限定,可例舉針對選自以下者中之分子之藥劑:(1)4-1BB;(2)4-1BB-L;(3)OX40;(4)OX40-L;(5)GITR(glucocorticoid-induced tumor necrosis factor receptor,糖皮質激素誘導之腫瘤壞死因子受體);(6)CD28;(7)CD40;(8)CD40-L;(9)ICOS(Inducible T Cell Costimulator,可誘導之T細胞共刺激分子);(10)ICOS-L;(11)LIGHT;及(12)CD27。
「免疫活性化劑」藉由直接或間接使T細胞或樹狀細胞等免疫細胞活化而效率良好地刺激淋巴結中之CTL。作為免疫活化劑,並無特別限定,可例舉:類Toll受體(TLR)促效劑、干擾素基因刺激因子(STING)促效劑、針對細胞激素或熱休克蛋白(HSP)之藥劑。
作為「類Toll受體(TLR)促效劑」,並無特別限定,例如可例舉:TLR1/2促效劑、TLR2促效劑、TLR3促效劑(PolyI:C等)、TLR4促效劑(S型脂多糖、紫杉醇、脂質A、單磷醯脂質A等)、TLR5促效劑(鞭毛蛋白等)、TLR6/2促效劑(MALP-2等)、TLR7促效劑(加地喹莫特、咪喹莫特、洛索立賓等)、TLR7/8促效劑(雷西莫特(R848)等)、TLR7/9促效劑、TLR8促效劑(莫托莫特(VTX-2337)等)、TLR9促效劑(CpG-ODN等)、TLR11促效劑(羥丙茶鹼)等。
作為「細胞激素」,並無特別限定,例如可例舉: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、干擾素(INF)-α、INF-β、INF-γ、SCF、GM-CSF、G-CSF、M-CSF、紅血球生成素、血小板生成素、MIP(macrophage inflammatory protein,巨噬細胞炎性蛋白)及MCP(monocyte chemoattractant protein,單核細胞趨化蛋白)等。
作為「熱休克蛋白(HSP)」,並無特別限定,可例舉:HSP70、HSP90、HSP90α、HSP90β、HSP105、HSP72、HSP40等。針對HSP之藥劑包括HSP抑制劑。例如,作為HSP90抑制劑,並無特別限定,可例舉:坦螺旋黴素(17-AAG)、蘆米司匹(AUY-922、NVP-AUY922)、阿螺旋黴素(17-DMAG)鹽酸鹽、加特司匹(STA-9090)、BIIB021、奧那司匹(AT13387)、格爾德黴素、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)或KNK437等。
作為「低分子抑制劑」,並無特別限定,例如可例舉:組織蛋白去乙醯化抑制劑、組織蛋白去甲基化抑制劑、組織蛋白乙醯化酶抑制劑、組織蛋白甲基化酶抑制劑、DNA甲基轉移酶抑制劑、蒽環系抗生素、鉑製劑、MAPK抑制劑、β-連環蛋白抑制劑、STAT3抑制劑、NF-kB抑制劑、JAK抑制劑、mTOR抑制劑、IDO抑制劑、COX-2抑制劑CXCR4抑制劑及精胺酸酶抑制劑等。
作為「組織蛋白去乙醯化抑制劑」,並無特別限定,例如可例舉:伏立諾他(SAHA、MK0683)、恩替司他(MS-275)、帕比司他(LBH589)、曲古黴素A(TSA)、莫西司他(MGCD0103)、BG45、BRD73954、貝利司他(PXD101)、羅米地辛(FK228、環肽(desipeptide))、4SC-202、HPOB、LMK-235、CAY10603、他喹莫德、TMP269、Nexturastat A、羅昔洛司他(Rocilinostat)(ACY-1215)、RGFP966、RG2833(RGFP109)、Scriptaid、Tubastatin A、普諾司他(Pracinostat)(SB939)、CUDC-101、M344、PCI-34051、達諾司他(LAQ824)、Tubastatin A鹽酸鹽、艾貝司他(PCI-24781)、CUDC-907、AR-42、苯基丁酸鈉、瑞米司他、Tubacin、奎諾司他(JNJ-26481585)二鹽酸鹽、MC1568、吉維司他(Givinostat)(ITF2357)、卓西司他(Droxinostat)、西達本胺(Chidamide)(C S055、HBI-8000)、CHR-2485、CHR-3996、DAC-060、FRM-0334(EVP-0334)、MGCD-290、CXD-101(AZD-9468)、CG200745、精胺酸丁酸鹽、蘿蔔硫素、SHP-141、CUDC-907、YM753(OBP-801)、丙戊酸鈉、阿匹替丁及CI994(泰克地那林(Tacedinaline))等。
作為「組織蛋白去甲基化抑制劑」,並無特別限定,例如可例舉:GSK J4 HCl、OG-L002、JIB-04、IOX1、SP2509、ORY-1001(RG-6016)、GSK J1、ML324、GSK-LSD1 2HCl等。
作為「組織蛋白乙醯化酶抑制劑」,並無特別限定,例如可例舉:C646、MG149、Remodelin、及腰果酸(Anacardic Acid)等。
作為「組織蛋白甲基化酶抑制劑」,並無特別限定,例如可例舉:吡美司他(Pinometostat)(EPZ5676)、EPZ005678、GSK343、BIX01294、他澤司他(Tazemetostat)(EPZ6438)、3-去氮腺嘌呤A(3-deazaneplanocin A)(DZNeP)HCl、UNC1999、MM-102、SGC0946、恩他卡朋、EPZ015666、UNC0379、EI1、MI-2(Menin(多發性內分泌腺瘤1型基因編碼蛋白)-MLL(mixed lineage leukemia,混合譜系白血病)抑制劑)、MI-3(Menin-MLL抑制劑)、PFI-2、GSK126、EPZ04777、BRD4770、GSK-2816126及UNC0631等。
作為「DNA甲基轉移酶抑制劑」,並無特別限定,例如可例舉:地西他濱、阿紮替丁、RG108、硫鳥嘌呤、澤布拉林、SGI-110、CC-486、SGI-1027、羅米魯曲及普魯卡因胺鹽酸鹽等。
「蒽環系抗生素」藉由插入DNA鏈間而抑制DNA分裂。作為蒽環系抗生素,並無特別限定,例如可例舉:多柔比星、脂質多柔比星、柔紅黴素、吡柔比星、表柔比星、伊達比星、阿柔比星、氨柔比星、蘆薈素或米托蒽醌等。
作為「鉑製劑」,並無特別限定,例如可例舉:順鉑、卡鉑、米鉑、奈達鉑、沙鉑(JM-126)、奧沙利鉑(ELOXATIN)、四硝酸三鉑或該等之DDS製劑等。
作為「MAPK抑制劑」,並無特別限定,例如可例舉:SB203580、達馬莫德(BIRB796)、SB202190(FHPI)、LY2228820、VX-702、SB239063、培美替尼(Pexmetinib)(ARRY-614)、PH-797804、VX-745或TAK-715等。
作為「β-連環蛋白抑制劑」,並無特別限定,例如可例舉:XAV-939、ICG-001、IWR-1-endo、Wnt-C59(C59)、LGK-974、KY02111、IWP-2、IWP-L6、WIKI4或FH535等。
作為「STAT3抑制劑」,並無特別限定,例如可例舉:S3I-201、Stattic、氯硝柳胺、硝呋酚醯肼、Napabucasin(BBI608)、隱丹參酮、HO-3867、WHI-P154、FLLL32、STA-21、WP1066或SH-4-54等。
作為「NF-kB抑制劑」,並無特別限定,例如可例舉:QNZ(EVP4593)、4-胺基水楊酸鈉、JSH-23、咖啡酸苯乙酯、水楊酸鈉、穿心蓮內酯或SC75741等。
作為「JAK抑制劑」,並無特別限定,例如可例舉:魯索替尼(INCB018424)、托法替尼(CP-690550)檸檬酸鹽、AZD1480、菲卓替尼(SAR302503、TG101348)、AT9283、酪胺酸磷酸化抑制劑(Tyrphostin)B42(AG-490)、莫美羅替尼(CYT387)、托法替尼(CP-690550、Tasocitinib)、WP1066、TG101209、甘多替尼(LY2784544)、NVP-BSK805 2HCl、巴瑞克替尼(LY3009104、INCB02850)、AZ960、CEP-33779、帕瑞替尼(SB1518)、WHI-P154、XL019、S-魯索替尼(INCB018424)、ZM39923 HCl、得克替尼(VX-509)、賽度替尼(Cerdulatinib)(PRT062070、PRT2070)、非洛替尼(GLPG0634)、FLLL32、佩非西替尼(ASP015K、JNJ-54781532)、GLPG0634模擬(analogue)、Go6976或莪術醇(Curcumol)等。
作為「mTOR抑制劑」,並無特別限定,例如可例舉:西羅莫司(雷帕黴素)、地磷莫司(AP23573、MK-8669)、依維莫司(RAD-001)、替西羅莫司(CCI-779、NSC683864)、咗他莫司(ABT-578)、及Biolimus A9(烏米莫司)、AZD8055、KU-0063794、沃塔昔布(Voxtalisib)(XL765、SAR245409)、MHY1485、達托里昔布(BEZ235、NVP-BEZ235)或PI-103、拓克尼布(Torkinib)(PP242)等。
作為「IDO抑制劑」,並無特別限定,例如可例舉:NLG919、INCB024360類似物、吲哚莫德(NLG-8189)及艾卡哚司他(Epacadostat)(INCB024360)等。
作為「COX2抑制劑」,並無特別限定,例如可例舉:伐地昔布、羅非昔布、卡洛芬、塞來昔布、羅美昔布、托芬那酸、尼美舒利、尼氟滅酸、Asaraldehyde、氯諾昔康、甲氯芬那酸鈉、氨芬酸鈉水合物、雙氯芬酸鈉、酮洛芬、酮咯酸、萘普生鈉、吲哚美辛、布洛芬、阿司匹林、甲芬那酸、溴芬酸鈉、奧沙普秦、紮托布洛芬及奈帕芬胺等。
作為「CXCR4抑制劑」,並無特別限定,例如可例舉:WZ811、普樂沙福(Plerixafor)(AMD3100)及普樂沙福8HCl(AMD3100 8HCl)等。
併用藥物可為選自由「激素療法劑」、「免疫療法劑」、「生物學製劑」、「細胞增殖因子」、「細胞增殖因子抑制劑」、「細胞增殖因子受體抑制劑」、「放射線療法劑」、「輔助劑」或「化學療法劑」所組成之群中之1種或複數種藥物。例如上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、或包含其之醫藥組合物可與選自上述群中之1~5種、1~3種或1種藥物併用。
作為「激素療法劑」,可例舉:腎上腺皮質激素系藥劑(例如類固醇系抗炎症藥、雌激素製劑、黃體酮製劑、雄激素製劑等)、抗雌激素劑、雌激素調整劑、雌激素合成抑制劑、抗雄激素劑、雄激素調整劑、雄激素合成抑制劑、LH-RH促效製劑、LH-RH拮抗製劑、芳香酶抑制劑、類固醇內酯酶抑制劑、丸劑製劑、或視黃醇及延緩視黃醇之代謝之藥劑等。
作為「激素療法劑」,例如可例舉:磷雌酚、己烯雌酚、Fluoxymesterol、氯烯雌醚、甲基睪固酮、乙酸甲羥黃體酮、乙酸甲地孕酮、乙酸氯地孕酮、乙酸環丙孕酮、達那唑、烯丙雌醇、孕三烯酮、美帕曲星、雷洛昔芬、奧美昔芬、左美洛昔芬、檸檬酸他莫昔芬、檸檬酸托瑞米芬、艾多昔芬、丸劑製劑、美雄烷、睾內酯、氨魯米特、乙酸戈舍瑞林、布舍瑞林、亮丙瑞林、柳培林、屈洛昔芬、環硫雄醇、磺酸乙炔雌二醇酯、雌莫司汀、鹽酸法倔唑、阿那曲唑、四唑、酮康唑、來曲唑、依西美坦、伏羅唑、福美司坦、氟他胺、比卡魯胺、尼魯米特、恩雜魯胺、美服培酮、非那雄胺、地塞米松、潑尼松龍、倍他米松、去炎松、阿比特龍、利阿唑、蓓薩羅丁或DN101等。
作為「免疫療法劑」,例如可例舉:必醫你舒(Picibanil)、雲芝多糖、裂褶菌多糖、香菇多醣、烏苯美司、干擾素(IFN)-α、干擾素(IFN)-β、干擾素(IFN)-γ、介白素、巨噬細胞集落刺激因子、粒細胞集落刺激因子、紅血球生成素、淋巴毒素、BCG疫苗、短棒狀桿菌、左美素、多糖K、丙考達唑、抗CTLA4抗體、抗PD-1抗體或TLR促效劑(例如TLR7促效劑、TLR8促效劑、TLR9促效劑)等。
作為「生物學製劑」,並無特別限定,例如可例舉:介白素-2(阿地白介素(Aldesleukin))、干擾素-α、干擾素-β、干擾素-γ、紅血球生成素(EPO)、粒細胞集落刺激因子(非格司亭)、粒細胞-巨噬細胞集落刺激因子(沙格司亭)、IL13-PE38QQR、卡介苗、左美素、奧曲肽、CPG7909、普列威(Provenge)、GVAX、Myvax、Favld、來那度胺、曲妥珠單抗、利妥昔單抗、吉妥珠單抗、阿侖單抗、內皮抑素、替伊莫單抗、托西莫單抗、西妥昔單抗、紮諾莫單抗、奧法木單抗、HGS-ETR1、帕妥珠單抗、M200、SGN-30、馬妥珠單抗、阿德木單抗、地舒單抗、紮魯木單抗、MDX-060、尼妥珠單抗、MORAb-003、Vitaxin、MDX-101、MDX-010、DPC4抗體、NF-1抗體、NF-2抗體、Rb抗體、p53抗體、WT1抗體、BRCA1抗體、BRCA2抗體、神經節苷脂(GM2)、前列腺特異性抗原(PSA)、α-胎蛋白(AFP)、癌胚抗原(CEA)、黑色素瘤相關抗原(MART-1、gap100、MAGE-1、MAGE-3、酪胺酸)、乳頭狀瘤病毒E6及E7片段、或該等之DDS製劑等。
上述「細胞增殖因子」、「細胞增殖因子抑制劑」及「細胞增殖因子受體抑制劑」中之細胞增殖因子只要為促進細胞增殖之物質,則可為任意者,例如可例舉藉由與受體之結合而於低濃度下發揮作用之作為分子量20,000以下之肽的因子。
作為「細胞增殖因子」,並無特別限定,例如可例舉:上皮生長因子(Epidermal Growth Factor:EGF)、類胰島素生長因子(Insulin-Like Growth Factor:IGF(例如,胰島素、IGF-1、IGF-2等))、轉化生長因子(Transforming Growth Factor:TGF(例如,TGF-α、TGF-β))、神經生長因子(Nerve Growth Factor:NGF)、腦源性神經營養因子(Brain-derived Neurotrophic Factor:BDNF)、血管內皮細胞增殖因子(Vesicular Endothelial Growth Factor:VEGF)、集落刺激因子(Colony Stimulating Factor:CSF(例如,粒細胞集落刺激因子(Granulocyte-Colony Stimulating Factor:G-CSF))、粒細胞-巨噬細胞集落刺激因子(Granulocyte-Macrophage-Colony Stimulating Factor:GM-CSF))、血小板衍生生長因子(Platelet-Derived Growth Factor:PDGF)、紅血球生成素(Erythropoietin:EPO)、成纖維細胞增殖因子(Fibroblast Growth Factor:FGF(例如,酸性FGF、鹼性FGF、KGK(Keratinocyte Growth Factor,角質細胞生長因子)、FGF-10等))、肝細胞增殖因子(Hepatocyte Growth Factor:HGF)、調蛋白或血管生成素等。再者,細胞增殖因子與生長因子同義。
作為「細胞增殖因子抑制劑」,並無特別限定,例如可例舉:上皮生長因子抑制劑(EGF抑制劑)、類胰島素生長因子抑制劑(IGF抑制劑)、神經生長因子抑制劑(NGF抑制劑)、腦源性神經營養因子抑制劑(BDNF抑制劑)、血管內皮細胞增殖因子抑制劑(VEGF抑制劑)、集落刺激因子抑制劑(CSF抑制劑)、血小板衍生生長因子抑制劑(PDGF抑制劑)、紅血球生成素抑制劑(EPO抑制劑)、成纖維細胞增殖因子抑制劑(FGF抑制劑)、肝細胞增殖因子抑制劑(HGF抑制劑)、調蛋白抑制劑、或血管生成素抑制劑等。再者,細胞增殖因子抑制劑與生長因子抑制劑同義。
作為「細胞增殖因子受體抑制劑」,並無特別限定,例如可例舉:上皮生長因子受體抑制劑(EGFR抑制劑)、類胰島素生長因子受體抑制劑(IGFR抑制劑)、神經生長因子受體抑制劑(NGFR抑制劑)、腦源性神經營養因子受體抑制劑(BDNFR抑制劑)、血管內皮細胞增殖因子受體抑制劑(VEGFR抑制劑)、集落刺激因子受體抑制劑(CSFR抑制劑)、血小板衍生生長因子受體抑制劑(PDGFR抑制劑)、紅血球生成素受體抑制劑(EPOR抑制劑)、成纖維細胞增殖因子受體抑制劑(FGFR抑制劑)、肝細胞增殖因子受體抑制劑(HGFR抑制劑)、調蛋白受體抑制劑、或血管生成素受體抑制劑等。再者,細胞增殖因子受體抑制劑與生長因子受體抑制劑同義。
作為「放射線療法劑」,並無特別限定,例如可例舉:放射性物質及放射性增感劑等。
「輔助劑」用於抑制抗癌劑之副作用或止吐,並無特別限定,例如可例舉:阿瑞吡坦、昂丹司瓊、勞拉西泮、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、Procrit(重組人類紅細胞生成素α)、阿法依泊汀、非格司亭、奧普瑞白介素、亞葉酸及粒細胞-巨噬細胞集落刺激因子(GM-CSF)等。
作為「化學療法劑」,並無特別限定,例如可使用烷基化劑、鉑製劑、代謝拮抗劑、拓樸異構酶抑制劑、DNA嵌入劑、抗有絲分裂劑、抗癌性抗生素、源自植物之抗癌劑、表觀基因組藥、免疫調整藥、分子靶向治療藥、新血管形成抑制劑及其他化學療法劑等。以下記載代表例。
作為「烷基化劑」,並無特別限定,例如可例舉:氮芥、鹽酸氮芥-N-氧化物、氯芥苯丁酸、環磷醯胺、異環磷醯胺、噻替派、卡波醌、甲磺丙胺、白消安、鹽酸尼莫司汀、二溴甘露醇、美法侖、達卡巴仁、甲基苄肼、雷莫司汀、雌莫司汀磷酸鈉、三伸乙基三聚氰胺、卡莫司汀、洛莫司汀、鏈脲佐菌素、哌泊溴烷、伊托格魯、六甲蜜胺、氨莫司汀、鹽酸二溴螺銨、福莫司汀、潑尼莫司汀、苯達莫司汀、烏拉莫司汀、司莫司汀、嘌嘧替派、鹽酸苯達莫司汀、替莫唑胺、蘇消安、氰乙環磷醯胺、淨司他丁斯酯、阿多來新、希莫司汀、比折來新、Mechlorethamine、尿嘧啶氮芥、曲貝替定、Chlormethine、甘露舒凡、三亞胺醌、丙卡巴肼、Canfosfamide、亞硝基脲及該等之DDS製劑等。
作為「鉑製劑」,並無特別限定,例如可例舉:順鉑、卡鉑、米鉑、奈達鉑、沙鉑、奧沙利鉑、四硝酸三鉑及該等之DDS製劑等。
作為「代謝拮抗劑」,並無特別限定,例如可例舉:葉酸代謝拮抗藥、嘧啶代謝抑制劑、嘌呤代謝抑制劑、核糖核苷酸還原酶抑制劑、及核苷酸類似物。
作為「代謝拮抗劑」,並無特別限定,例如可例舉:巰嘌呤、6-巰基嘌呤核苷、硫代肌苷、甲胺喋呤、培美曲塞、Eocitabine、依諾他濱、阿糖胞苷、阿糖胞苷十八烷基磷酸鹽、鹽酸安西他濱、5-FU系藥劑(例如,氟尿嘧啶、Carzonal、Bennan、
Lunachol、
Lunapon、替加氟、替加氟・尿嘧啶、替加氟・吉莫斯特・奧替拉西鉀(TS-1)、UFT、去氧氟尿苷、卡莫氟、加洛他濱、乙嘧替氟、卡培他濱等)、胺基喋呤、奈拉濱、亞葉酸鈣(Leucovorin calcium)、Tabloid、布縮宮素、亞葉酸鈣(Calcium folinate)、亞葉酸鈣(Calcium Levofolinate)、克拉屈濱、乙嘧替氟、氟達拉濱、吉西他濱、羥基脲(hydroxycarbamide)、噴司他丁、吡曲克辛、碘苷、米托胍腙、噻唑呋啉、氨莫司汀、苯達莫司汀、氟尿苷、亞葉酸、羥基脲(hydroxyurea)、硫鳥嘌呤、門冬醯胺酶、硼替佐米、雷替曲塞、氯法拉濱、依諾他濱、沙帕他濱、阿紮胞苷、磺胺嘧啶、磺胺甲㗁唑、三甲氧苄胺嘧啶、Liproxstatin-1、D4476、黃腐醇(Xanthohumol)、艾卡哚司他(Epacadostat)(INCB024360)、維多氟地莫司(Vidofludimus)、P7C3、GMX1778(CHS828)、NCT-501、SW033291、Ro61-8048及該等之DDS製劑等。
作為「拓樸異構酶抑制劑」,並無特別限定,例如可例舉:多柔比星、柔紅黴素、表柔比星、伊達比星、蒽二酮、米托蒽醌、絲裂黴素C、博來黴素、放線菌素、普卡黴素(Plicatomycin)、伊立替康、喜樹鹼、魯比替康、貝洛替康、依託泊苷、替尼泊苷、托泊替康、安吖啶及該等之DDS製劑等。
作為「DNA嵌入劑」,並無特別限定,例如可例舉:普羅黃素(Proflavine)、多柔比星(阿德力黴素)、柔紅黴素、放線菌素、沙利竇邁及該等之DDS製劑等。
作為「抗有絲分裂劑」,並無特別限定,例如可例舉:紫杉醇、紫杉醇衍生物(例如,DHA紫杉醇、聚穀胺酸鹽化紫杉醇、納布紫杉醇、紫杉醇膠束、7α-葡糖氧基乙醯基紫杉醇、BMS-275183等)、歐洲紫杉醇、Vinorlebine、長春新鹼、長春花鹼、長春地辛、長春利定、依託泊苷、替尼泊苷、伊沙匹隆、拉洛他賽、奧他賽、替司他賽、伊斯平斯、秋水仙鹼、長春氟寧及該等之DDS製劑等。
作為「抗癌性抗生素」,並無特別限定,例如可例舉:放射菌素D、放射菌素C、絲裂黴素C、色黴素A3、光輝黴素A、鹽酸博來黴素、硫酸博來黴素、硫酸培洛黴素、鹽酸柔紅黴素、鹽酸多柔比星、鹽酸阿克拉黴素、鹽酸吡柔比星、鹽酸表柔比星、鹽酸氨柔比星、新抑癌素、淨司他丁斯酯、光輝黴素、沙克黴素、嗜癌菌素、密妥坦、鹽酸佐柔比星、鹽酸米托蒽醌、鹽酸伊達比星、脂質多柔比星及該等之DDS製劑等。
作為「源自植物之抗癌劑」,並無特別限定,例如可例舉:伊立替康、拓樸替康、依託泊苷、磷酸依託泊苷、埃立布林、索布佐生、硫酸長春花鹼、硫酸長春新鹼、硫酸長春地辛、替尼泊苷、紫杉醇、紫杉醇注射劑、歐洲紫杉醇、DJ-927、長春瑞賓、托泊替康及該等之DDS製劑等。
作為「表觀基因組藥」,並無特別限定,例如可例舉:DNA甲基化抑制劑、組織蛋白去乙醯化酶(HDAC)抑制劑、DNA甲基轉移酶(DNMT)抑制劑、組織蛋白去乙醯化酶活化劑、組織蛋白去甲基化酶抑制劑及甲基化核苷酸等。
作為「表觀基因組藥」,並無特別限定,例如可例舉:伏立諾他、貝利司他、莫西替司他(MGCD0103)、恩替司他(SNDX-275)、羅米地辛、阿紮胞苷、地西他濱、GSK2879552 2Hl、SGC707、ORY-1001(RG-6016)、PFI-4、SirReal2、GSK2801、CPI-360、GSK503、AMI-1、CPI-169及該等之DDS製劑等。
作為「免疫調整藥」,並無特別限定,例如可例舉:沙利竇邁、來那度胺、泊馬度胺及該等之DDS製劑等。
「分子靶向治療藥」可為低分子化合物,亦可為抗體。作為「分子靶向治療藥」,並無特別限定,例如可例舉:激酶抑制劑、蛋白酶體抑制劑、單株抗體、mTOR抑制劑、TNF抑制劑、及T細胞抑制劑等。
作為「激酶抑制劑」,並無特別限定,例如可例舉:酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、Raf激酶抑制劑、CDK(週期蛋白依賴性激酶)抑制劑、及MEK(促分裂因子活化蛋白質激酶)抑制劑等。
具體而言,作為「激酶抑制劑」,並無特別限定,例如可例舉:伊馬替尼、吉非替尼、埃羅替尼、阿法替尼、達沙替尼、博舒替尼、凡德他尼、舒尼替尼、阿西替尼、帕唑帕尼、樂伐替尼、拉帕替尼、尼達尼布、尼洛替尼、克唑替尼、色瑞替尼、艾樂替尼、魯索替尼、托法替尼、伊魯替尼、索拉非尼、維莫非尼、達拉非尼、帕博西尼、曲美替尼、瑞戈非尼、西地尼布(Cedivanib)、來他替尼、凡德他尼、瓦他拉尼、塞利西利、替萬替尼、卡奈替尼、培利替尼、特塞瓦替尼、西地尼布、莫特塞尼、米哚妥林、福瑞替尼、卡博替尼、司美替尼、來那替尼、伏拉色替、塞卡替尼、恩雜妥林、坦度替尼、司馬沙尼、阿夫西地、ICR-62、AEE788、PD0325901、PD153035、TK787、amcasertib(BBI503)、E6201、E7050及該等之DDS製劑等。
作為「蛋白酶體抑制劑」,並無特別限定,例如可例舉:硼替佐米、卡非佐米及該等之DDS製劑等。
作為「單株抗體」,並無特別限定,例如可例舉:抗CD22抗體、抗CD20抗體、抗CD25抗體、抗CD30抗體、抗CD33抗體、抗CD5抗體、抗CD52抗體、抗上皮生長因子受體抗體(EGFR抗體)、抗血管內皮細胞增殖因子抗體(VEGF抗體)、抗TNF-α抗體、抗IL-1受體抗體、抗IL-2受體抗體、抗IL-5受體抗體、抗IL-6受體抗體、抗HER2抗體、抗IgE抗體、抗IgG抗體、抗RS病毒抗體、抗CCR4抗體、抗CTLA-4(細胞毒殺性T淋巴細胞相關抗原4、CD152)抗體、抗PD-1抗體、抗RANKL(receptor activator of nuclear factor κB ligand,核因子κ-B配體受體活化劑)抗體、抗c-Met抗體、抗CXCR4抗體等。
具體而言,作為「單株抗體」,並無特別限定,例如可例舉:替伊莫單抗、利妥昔單抗、西妥昔單抗、英夫利昔單抗、巴利昔單抗、本妥昔單抗、托珠單抗、曲妥珠單抗、貝伐單抗、奧馬珠單抗、美泊利單抗、吉妥珠單抗、帕利珠單抗、蘭尼單抗、賽妥珠單抗、奧瑞珠單抗、莫加珠單抗、依庫珠單抗、帕妥珠單抗、阿侖單抗、伊珠單抗、帕尼單抗、奧法木單抗、戈利木單抗、阿達木單抗、雷莫盧單抗、納武單抗、阿那白滯素、地舒單抗、伊匹單抗、帕博利珠單抗、馬妥珠單抗、法雷珠單抗、MORAb-004、MORA-b009及該等之DDS製劑等。
作為「mTOR抑制劑」,並無特別限定,例如可例舉:依維莫司(RAD001)、雷帕黴素(西羅莫司)、AZD8055、替西羅莫司(CCI-779、NSC683864)、KU-0063794、沃塔里昔布(Voxtalisib)(XL-765、SAR245409)、MHY1485、達托里昔布(BEZ235)、PI-103、托基尼布(Torkinib)(PP242)、瑞達福莫司(地磷莫司、MK-8669)、INK-128(MLN0128)、Torin 1、奧米帕西(GSK2126458、GSK458)、OSI-027、PF-04691502、Apitolisib(GDC-0980、RG7422)、GSK1059615、Gedatolisib(PF-05212384、PKI-587)、WYE-132、PP121、WYE-354、AZD2014、Torin 2、WYE-687、CH5132799、WAY-600、ETP-46464、GDC-0349、XL388、咗他莫司(ABT-578)、他克莫司(FK506)、BGT226(NVP-BGT226)、Palomid 529(P529)、大黃酸及該等之DDS製劑等。
作為「TNF抑制劑」,並無特別限定,例如可例舉:依那西普、來那度胺(CC-5013)、泊馬度胺、沙利竇邁、Necrostatin-1或QNZ(EVP4593)等。
作為「T細胞抑制劑」,並無特別限定,例如可例舉:阿巴西普等。
作為「新血管形成抑制劑」,並無特別限定,例如可例舉:CM101、IFN-α、IL-12、血小板因子-4、蘇拉明、司馬沙尼、血小板反應素、VEGFR拮抗劑、肝素聯合類固醇抑制新血管形成、源自軟骨之新血管形成抑制因子、基質金屬蛋白酶抑制劑、巴馬司他、馬立馬司他、血管生長抑素、內皮生長抑素、2-甲氧基雌二醇、替可加蘭、血小板反應素、αVβ3抑制劑、利諾安、ADH-1、E7820及該等之DDS製劑等。
作為「其他化學療法劑」,並無特別限定,例如可例舉:非那雄胺、索布佐生、奧巴拉克、乙丙昔羅、替吡法尼、洛那法尼等。
於將上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽與其他癌抗原肽或其藥學上容許之鹽及/或併用藥物併用之情形時,各有效成分可包含於同一組合物中,亦可包含於不同組合物中。於一實施形態中,上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽與其他癌抗原肽或其藥學上容許之鹽包含於同一組合物中。於另一實施形態中,上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽與其他癌抗原肽或其藥學上容許之鹽包含於不同組合物中。組合物可包含1種以上之上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、及/或1種以上之其他癌抗原肽。於提供包含各有效成分之組合物時可一併提供記載有與其他有效成分併用時之用法、劑量等之說明書等。或可將包含各有效成分之組合物加以組合而以套組之形式提供。提供套組時可一併提供記載有併用時之用法、劑量等之說明書、包裝容器等。於併用複數種有效成分之情形時,該等可按同一投予排程進行投予,亦可按不同投予排程進行投予。
本發明之組合物除包含上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽以外,亦可包含藥學上容許之載體。又,本發明之組合物為了增強CTL及/或輔助性T細胞之誘導效率,亦可包含適宜之佐劑、或可與適宜之佐劑一併投予。
「藥學上容許之載體」於所用之劑量及濃度下對於暴露於該載體中之細胞或哺乳動物無毒性。藥學上容許之載體通常為pH緩衝水溶液。藥學上容許之載體之例包括以下:緩衝劑(例如磷酸、檸檬酸、乳酸、酒石酸、三氟乙酸及其他有機酸);抗氧化劑(包括抗壞血酸);低分子量多肽(約未達10個殘基);蛋白質(例如血清白蛋白、明膠或免疫球蛋白);親水性聚合物(例如聚乙烯吡咯啶酮);胺基酸(例如甘胺酸、穀醯胺、天冬醯胺、精胺酸、甲硫胺酸或離胺酸);單糖類、二糖類及其他碳水化合物(例如葡萄糖、甘露糖或糊精);螯合劑(例如EDTA);糖醇(例如甘露醇、海藻糖或山梨糖醇);穩定劑(例如二伸乙基三胺五乙酸);成鹽抗衡離子(例如鈉);溶解輔助劑(例如Polysorbate 80(註冊商標))及/或非離子性界面活性劑(例如TWEEN(註冊商標)、聚乙二醇(PEG)及PLURONICS(註冊商標))。又,藥學上容許之載體亦可為例如蛋白質、多肽、脂質體、多糖、聚乳糖、聚乙醇酸、聚合胺基酸、胺基酸共聚物、及滅活病毒粒子等大型之代謝緩慢之巨大分子。又,亦可將本說明書中記載之式(1)所表示之化合物或肽製成脂質體製劑、與直徑數μm之珠粒結合而形成之粒子徑之製劑、結合有脂質之製劑等進行投予。
作為佐劑,可應用文獻(Clin. Microbiol. Rev., 7 : 277-289, 1994)中記載者等,具體而言,可例舉:源自菌體之成分、GM-CSF、介白素-2、介白素-7或介白素-12等細胞激素、源自植物之成分、源自海洋生物之成分、氫氧化鋁之類的礦物凝膠、溶血卵磷脂、普朗尼克多元醇之類的界面活性劑、聚陰離子、肽、或油乳懸浮液(乳液製劑)等。作為源自菌體之成分,可例舉:脂質A(lipid A)、作為其衍生物之單磷醯脂質A(monophosphory llipid A)、菌體(可例舉BCG菌等分枝桿菌屬(Mycobacterium)細菌)之死菌、源自細菌之蛋白質、聚核苷酸、弗氏不完全佐劑(Freund's Incomplete Adjuvant)、弗氏完全佐劑(Freund's Complete Adjuvant)、細胞壁骨架成分(例如可例舉BCG-CWS等)、海藻糖二黴菌酸酯(TDM)等。
又,作為佐劑,可例舉:沈澱性佐劑與油性佐劑。沈澱性佐劑表示供肽吸附之無機物之懸浮劑。作為沈澱性佐劑,具體而言,可例舉:氫氧化鈉、氫氧化鋁(Alum)、磷酸鈣、磷酸鋁、明礬、PEPES、羧基乙烯基聚合物等。油性佐劑表示利用礦物油包覆包含肽之水溶液而製成微胞(micelle)並進行乳化之油乳劑。作為油性佐劑,具體而言,可例舉:液態石蠟、羊毛脂、弗氏佐劑(弗氏完全佐劑、弗氏不完全佐劑)、Montanide、W/O乳液(參照WO2006/078059)等,但並不限定於此。
本發明之組合物可為經口投予用或非經口投予用之製劑,例如作為用於非經口投予之注射劑、外用劑、栓劑、吸入劑、經鼻劑等使用。於較佳之實施形態中,本發明之組合物作為注射劑使用。
作為注射劑,包括溶液、懸浮液、乳濁液、及用時溶解或懸浮於溶劑而使用之固態注射劑。注射劑係使一種或其以上之有效成分溶解、懸浮或乳化於溶劑而使用。作為溶劑,例如使用注射用蒸餾水、生理鹽水、植物油、丙二醇、聚乙二醇、乙醇之類的醇類等及該等之組合。該注射劑亦可進而包含穩定劑、溶解輔助劑(穀胺酸、天冬胺酸、Polysorbate 80(註冊商標)等)、懸浮化劑、乳化劑、鎮痛劑、緩衝劑、保存劑等。將該等於最後步驟中進行滅菌或藉由無菌操作法製造。又,亦可製造無菌之固體製劑、例如冷凍乾燥品,於其使用前溶解於無菌化或無菌之注射用蒸餾水或其他溶劑而使用。
外用劑之劑形例如包括軟膏劑、凝膠劑、霜劑、敷劑、貼劑、搽劑、噴霧劑、吸入劑、氣霧劑、氣溶膠劑、滴眼劑、及滴鼻劑等。該等包含一種或其以上之有效成分,依據公知方法或通常使用之配方製造。
軟膏劑依據公知或通常使用之配方製造。例如使一種或其以上之有效成分研合或溶融於基劑而製備。軟膏基劑可自公知或通常使用者中選擇。例如可使用選自高級脂肪酸或高級脂肪酸酯(己二酸、肉豆蔻酸、棕櫚酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕櫚酸酯、硬脂酸酯、油酸酯等)、蠟類(蜂蠟、鯨蠟、地蠟等)、界面活性劑(聚氧乙烯烷基醚磷酸酯等)、高級醇(鯨蠟醇、硬脂醇、鯨蠟硬脂醇等)、矽油(二甲基聚矽氧烷等)、烴類(親水凡士林、白凡士林、純化羊毛脂、液態石蠟等)、二醇類(乙二醇、二乙二醇、丙二醇、聚乙二醇(polyethylene glycol)、聚乙二醇(macrogol)等)、植物油(蓖麻油、橄欖油、芝麻油、松節油等)、動物油(貂油、蛋黃油、角鯊烷、角鯊烯等)、水、吸收促進劑、防斑疹劑中之單獨一種或將2種以上混合使用。亦可進而包含保濕劑、保存劑、穩定劑、抗氧化劑、著香劑等。
凝膠劑依據公知或通常使用之配方製造。例如使一種或其以上之有效成分溶融於基劑而製備。凝膠基劑可自公知或通常使用者中選擇。例如可使用選自低級醇(乙醇、異丙醇等)、凝膠化劑(羧甲基纖維素、羥乙基纖維素、羥丙基纖維素、乙基纖維素等)、中和劑(三乙醇胺、二異丙醇胺等)、界面活性劑(單硬脂酸聚乙二醇酯等)、橡膠類、水、吸收促進劑、防斑疹劑中之單獨一種或將2種以上混合使用。亦可進而包含保存劑、抗氧化劑、著香劑等。
霜劑依據公知或通常使用之配方製造。例如使一種或其以上之有效成分溶融或乳化於基劑而製備。霜劑基劑可自公知或通常使用者中選擇。例如可使用選自高級脂肪酸酯、低級醇、烴類、多元醇(丙二醇、1,3-丁二醇等)、高級醇(2-己基癸醇、鯨蠟醇等)、乳化劑(聚氧乙烯烷基醚類、脂肪酸酯類等)、水、吸收促進劑、防斑疹劑中之單獨一種或將2種以上混合使用。亦可進而包含保存劑、抗氧化劑、著香劑等。
敷劑依據公知或通常使用之配方製造。例如使一種或其以上之有效成分溶融於基劑製成混練物後展延塗佈於支持體上而製造。敷劑基劑可自公知或通常使用者中選擇。例如可使用選自增黏劑(聚丙烯酸、聚乙烯吡咯啶酮、阿拉伯膠、澱粉、明膠、甲基纖維素等)、濕潤劑(脲、甘油、丙二醇等)、填充劑(高嶺土、氧化鋅、滑石、鈣、鎂等)、水、溶解輔助劑、黏著賦予劑、防斑疹劑中之單獨一種或將2種以上混合使用。亦可進而包含保存劑、抗氧化劑、著香劑等。
貼劑依據公知或通常使用之配方製造。例如使一種或其以上之有效成分溶融於基劑後展延塗佈於支持體上而製造。貼劑用基劑可自公知或通常使用者中選擇。例如可使用選自高分子基劑、油脂、高級脂肪酸、黏著賦予劑、防斑疹劑中之單獨一種或將2種以上混合使用。亦可進而包含保存劑、抗氧化劑、著香劑等。
搽劑依據公知或通常使用之配方製造。例如使一種或其以上之活性物質溶解、懸浮或乳化於選自水、醇(乙醇、聚乙二醇等)、高級脂肪酸、甘油、皂、乳化劑、懸浮化劑等中之單獨一種或2種以上者而製備。亦可進而包含保存劑、抗氧化劑、著香劑等。
噴霧劑、吸入劑及氣霧劑除含有一般使用之稀釋劑以外,亦可含有亞硫酸氫鈉之類的穩定劑及如賦予等張性之緩衝劑例如氯化鈉、檸檬酸鈉或檸檬酸之類的等張劑。
作為吸入劑,包括氣溶膠劑、吸入用粉末劑或吸入用液劑,該吸入用液劑亦可為於用時溶解或懸浮於水或其他適宜之介質而使用之形態。該等吸入劑可依據公知方法製造。例如於吸入用液劑之情形時,視需要適當選擇防腐劑(苯紮氯銨、對羥苯甲酸酯等)、著色劑、緩衝化劑(磷酸鈉、乙酸鈉等)、等張化劑(氯化鈉、濃甘油等)、增黏劑(羧基乙烯基聚合物等)、吸收促進劑等進行製備。於吸入用粉末劑之情形時,視需要適當選擇潤滑劑(硬脂酸及其鹽等)、結合劑(澱粉、糊精等)、賦形劑(乳糖、纖維素等)、著色劑、防腐劑(苯紮氯銨、對羥苯甲酸酯等)、吸收促進劑等進行製備。投予吸入用液劑時,通常使用噴霧器(霧化器、噴霧器),投予吸入用粉末劑時,通常使用粉末藥劑用吸入投予器。
氣霧劑除含有一般使用之稀釋劑以外,亦可含有亞硫酸氫鈉之類的穩定劑及如賦予等張性之緩衝劑例如氯化鈉、檸檬酸鈉或檸檬酸之類的等張劑。氣霧劑之製造方法例如於美國專利第2,868,691號說明書及美國專利第3,095,355號說明書中有詳細記載。
作為用於非經口投予之其他組合物,包括用於直腸內投予之栓劑及用於陰道內投予之子宮帽等。
於一實施形態中,包含上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之組合物含有選自由海藻糖、甘露醇、甲硫胺酸、檸檬酸、乳酸、酒石酸、乙酸、三氟乙酸及pH調整劑所組成之群中之1種以上之藥學上容許之載體。
上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽、以及併用藥物之投予方法可根據對象疾病、對象之狀態、靶向部位等條件而適當選擇。投予方法例如為經由注射或輸液之非經口投予,較佳為靜脈內、肌肉內、皮膚內或皮下投予。本說明書中記載之肽、化合物或其藥學上容許之鹽可用於淋巴細胞療法或DC(樹狀細胞)療法。
投予次數及投予間隔可根據對象疾病、對象之狀態、投予路徑等條件而適當選擇。投予通常為複數次,較佳為數日或數月進行一次投予。
上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之投予量、及併用藥物之投予量分別可根據對象疾病、對象之狀態、投予路徑等條件而適當選擇。例如,上述肽或者化合物或其藥學上容許之鹽之每次之投予量通常為0.0001 mg~1000 mg、較佳為0.001 mg~1000 mg、更佳為0.1 mg~10 mg。併用藥物之投予量可以臨床上採用之劑量為基準而適當選擇。例如於免疫調節劑之情形時,其相對於每1 kg體重之投予量通常為0.0001 mg~1000 mg、較佳為0.001 mg~1000 mg、更佳為0.1 mg~10 mg。
於有效成分包含於單一組合物中之情形時,其調配比可根據對象疾病、對象之狀態、投予路徑等而適當選擇。例如於投予對象為人之情形時,相對於本說明書中記載之肽及/或化合物1重量份,可使用免疫調節劑等併用藥物0.01~100重量份。
於本說明書中,所謂「有效量」,指能夠完全或部分抑制癌症之進展、或者至少能夠部分緩解癌症之一種以上之症狀的有效成分之量,或指能夠誘導或維持癌症之緩解、及/或能夠抑制復發的有效成分之量。有效量根據對象之年齡及性別、受處置之狀態、狀態之嚴重程度、以及期望結果等來確定。針對特定對象之有效量可藉由業者所知之方法來確定。
上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽亦可與非藥劑療法進行組合。作為非藥劑療法,例如可例舉:手術、放射線療法、基因治療、溫熱療法、冷凍療法、雷射灼燒療法等,可將組合採用該等之兩種以上。例如,可於手術等非藥劑療法之前或之後、或者組合採用兩種或三種非藥劑療法之治療前或治療後,使用上述肽或者化合物或其藥學上容許之鹽。
為了抑制副作用,上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽亦可進而與止吐劑、誘導睡眠劑、抗痙攣藥等藥劑組合使用。
於另一形態中,本發明關於一種經由HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05呈現上述(a)之肽之抗原呈現細胞(例如,樹狀細胞、B-淋巴細胞、巨噬細胞等)。藉由使用該抗原呈現細胞,可於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中誘導CTL。經由HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05呈現上述(a)之肽之抗原呈現細胞可藉由在上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之存在下,培養HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性之未成熟之抗原呈現細胞而獲得。
於另一形態中,本發明關於一種抗原呈現細胞之誘導方法,其包括:於上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之存在下,培養HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性之未成熟之抗原呈現細胞。於本說明書中之「未成熟之抗原呈現細胞」指成熟後可成為抗原呈現細胞(例如,樹狀細胞、B-淋巴細胞、巨噬細胞等)之細胞。未成熟之抗原呈現細胞例如包含於PBMC等中,因此,可將該細胞於上述肽或者化合物或其藥學上容許之鹽存在下進行培養。
於另一形態中,本發明關於一種於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之方法,其包括:將經由HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05呈現上述(a)之肽之抗原呈現細胞向對應之HLA亞型為陽性之對象進行投予。抗原呈現細胞之投予方法可根據疾病之種類、對象之狀態、靶向部位等條件而適當選擇。作為投予方法,例如可例舉:靜脈內投予、皮內投予、皮下投予、肌肉內投予、經鼻投予等,但並不限於該等。
於另一形態中,本發明關於一種藉由上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽誘導之CTL。該CTL可於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中殺傷癌細胞。
於另一形態中,本發明關於一種CTL之誘導方法,其包括:於上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之存在下,培養HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象之PBMC。藉由在上述肽或者化合物或其藥學上容許之鹽之存在下培養PBMC,而自PBMC中之前驅細胞誘導針對上述肽之特異性CTL。藉由對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象投予所獲得之肽特異性CTL,可處置癌症。
於另一形態中,本發明關於一種於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之方法,其包括:向對象投予針對上述(a)之肽之特異性CTL。肽特異性CTL之投予方法可根據疾病之種類、對象之狀態、靶向部位等條件而適當選擇。作為投予方法,例如可例舉:靜脈內投予、皮內投予、皮下投予、肌肉內投予、經鼻投予、經口投予等,但並不限於該等。
於另一形態中,本發明關於一種包含上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽作為構成成分之套組。於一實施形態中,套組用於處置HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中之癌症。於另一實施形態中,套組用於上述抗原呈現細胞誘導方法或CTL誘導方法。套組除包含上述肽或者化合物或其藥學上容許之鹽以外,亦可包含例如對象試樣(例如末梢血單核細胞)之取得手段、佐劑、反應容器等。一般而言,套組附帶操作說明書。
於一形態中,本發明提供一種用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之方法,其包括:對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象投予上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽。
於一形態中,本發明提供一種上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽,其用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症。
於一形態中,本發明提供一種上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之用途,其用於製造用以於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之醫藥。
於另一形態中,本發明提供一種醫藥組合物,其包含上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽,用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置良性腫瘤。本形態可依據上述關於癌症之處置之記載來實施。
「良性腫瘤」係不具有病理學上惡性表現之腫瘤,有別於惡性腫瘤或癌。良性腫瘤通常不表現出轉移或浸潤傾向。診斷為良性腫瘤並不意味著臨床上之預後一定良好。例如發生於腦幹部之低異型度腦膜瘤屬於良性腫瘤,但治療困難,且壓迫腦幹而預後不良,因此於臨床上為惡性,可謂必須加以治療或予防。
作為良性腫瘤,可例舉:家族性大腸腺瘤症、非遺傳性之大腸腺瘤、胰腺導管內乳頭狀黏液性瘤、腦膜瘤、神經鞘瘤、各內臟之上皮性腺瘤、乳頭狀瘤、非上皮性肌瘤、脂肪瘤、軟骨瘤、血管瘤等。
於一實施形態中,良性腫瘤為家族性大腸腺瘤症。家族性大腸腺瘤症係特徵在於癌抑制基因APC(adenoma polyposis coli,結腸腺瘤性息肉)發生變異,於腸道內形成多個腺瘤之遺傳性疾病。「家族性大腸腺瘤症」、「家族性大腸息肉」、「家族性腺瘤性息肉」及「FAP」之術語可互換使用。於本說明書中,家族性大腸腺瘤症亦包括Gardner症候群等在腸道以外之組織併發腫瘤之疾病。
於另一形態中,本發明提供一種用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置良性腫瘤之方法,其包括:對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象投予上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽;一種上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽,其用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置良性腫瘤;及一種上述(a)之肽或者式(1)所表示之化合物或其藥學上容許之鹽之用途,其用於製造用以於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置良性腫瘤之醫藥。
以下記載本發明之例示之實施形態。
[1]
一種醫藥組合物,其用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症,包含以下之(a)或(b):
(a)包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽,即,含有7~30個殘基之胺基酸之MHC-I類分子限制性肽或其藥學上容許之鹽;或
(b)式(1)所表示之化合物或其藥學上容許之鹽,
[化27]
[式中,Xa
及Ya
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xa
之胺基酸殘基數與Ya
之胺基酸殘基數之和為0~4之整數;
癌抗原肽A表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽A之N末端胺基酸之胺基與式(1)中之Ya
鍵結,癌抗原肽A之C末端胺基酸之羰基與式(1)中之羥基鍵結;
R1
表示氫原子、式(2)所表示之基、或癌抗原肽C,
[化28]
(式中,Xb
及Yb
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xb
之胺基酸殘基數與Yb
之胺基酸殘基數之和為0~4之整數,癌抗原肽B表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽B之N末端胺基酸之胺基與式(2)中之Yb
鍵結,癌抗原肽B之C末端胺基酸之羰基與式(2)中之羥基鍵結,式(2)中之硫原子與式(1)中之硫原子經由雙硫鍵鍵結),
癌抗原肽C表示含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-I類分子限制性肽或含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽C之半胱胺酸殘基之硫原子與式(1)中之硫原子經由雙硫鍵鍵結,於癌抗原肽C之N末端可結合有含有1~4個殘基之胺基酸之肽;
於R1
為氫原子之情形時,癌抗原肽A為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為式(2)所表示之基之情形時,癌抗原肽A及/或癌抗原肽B為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為癌抗原肽C之情形時,癌抗原肽A及/或癌抗原肽C為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽;
於R1
為式(2)所表示之基、且癌抗原肽B包含1個半胱胺酸殘基之情形時,癌抗原肽B之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化29]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結);
於R1
為癌抗原肽C、且於癌抗原肽C之N末端結合有含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽之情形時,結合於癌抗原肽C之N末端之肽之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結,
[化30]
(式中,Xd
及Yd
獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd
之胺基酸殘基數與Yd
之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd
鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結)]。
[2]
如上述1記載之醫藥組合物,其中上述對象為HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象。
[3]
如上述1記載之醫藥組合物,其中上述對象為HLA-A*
02:07陽性對象。
[4]
如上述1記載之醫藥組合物,其中上述對象為HLA-A*
03:01陽性對象。
[5]
如上述1記載之醫藥組合物,其中上述對象為HLA-B*
15:01陽性對象。
[6]
如上述1記載之醫藥組合物,其中上述對象為HLA-B*
27:05陽性對象。
[7]
如上述1至6中任一項記載之醫藥組合物,其包含上述(a)之肽或其藥學上容許之鹽。
[8]
如上述7記載之醫藥組合物,其中上述(a)之肽為由選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)及VLDFAPPGA(序列編號7)中之任一胺基酸序列構成之肽、或者由選自序列編號2、3及7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列構成、且具有CTL誘導活性之肽。
[9]
如上述7或8記載之醫藥組合物,其中上述(a)之肽為由選自RMFPNAPYL(序列編號2)、RYFPNAPYL(序列編號8)、YMFPNAPYL(序列編號13)、CMTWNQMNL(序列編號3)、CYTWNQMNL(序列編號14)及VLDFAPPGA(序列編號7)中之任一胺基酸序列構成之肽。
[10]
如上述7至9中任一項記載之醫藥組合物,其中上述(a)之肽為由RMFPNAPYL(序列編號2)、RYFPNAPYL(序列編號8)、或YMFPNAPYL(序列編號13)之胺基酸序列構成之肽。
[11]
如上述7至10中任一項記載之醫藥組合物,其中上述(a)之肽為由RMFPNAPYL(序列編號2)之胺基酸序列構成之肽。
[12]
如上述1至6中任一項記載之醫藥組合物,其包含上述(b)之式(1)所表示之化合物或其藥學上容許之鹽。
[13]
如上述12記載之醫藥組合物,其中Xa
為含有2個殘基之胺基酸之肽之二價基、且Ya
為單鍵;或者Xa
及Ya
獨立地為含有1個殘基之胺基酸之肽之二價基;或者Xa
為單鍵、且Ya
為含有2個殘基之胺基酸之肽之二價基;或者Xa
為含有1個殘基之胺基酸之肽之二價基、且Ya
為單鍵;或者Xa
為單鍵、且Ya
為含有1個殘基之胺基酸之肽之二價基;或者Xa
及Ya
為單鍵。
[14]
如上述12或13記載之醫藥組合物,其中Xa
為單鍵,Ya
為單鍵、丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基。
[15]
如上述12至14中任一項記載之醫藥組合物,其中Xa
為單鍵或含有1個殘基之胺基酸之肽之二價基,Ya
為單鍵。
[16]
如上述12至15中任一項記載之醫藥組合物,其中Xa
及Ya
為單鍵。
[17]
如上述12至16中任一項記載之醫藥組合物,其中癌抗原肽A為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
[18]
如上述12至17中任一項記載之醫藥組合物,其中癌抗原肽A為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[19]
如上述18記載之醫藥組合物,其中癌抗原肽A為包含RMFPNAPYL(序列編號2)之胺基酸序列之肽。
[20]
如上述18記載之醫藥組合物,其中癌抗原肽A為由RMFPNAPYL(序列編號2)之胺基酸序列構成之肽。
[21]
如上述12至20中任一項記載之醫藥組合物,其中R1
為氫原子。
[22]
如上述21記載之醫藥組合物,其中式(1)所表示之化合物為包含選自
CRMFPNAPYL(序列編號49)、
CCMTWNQMNL(序列編號50)、
CCYTWNQMNL(序列編號51)、
CALLPAVPSL(序列編號52)、
CSLGEQQYSV(序列編號53)、
CRVPGVAPTL(序列編號54)及
CVLDFAPPGA(序列編號55)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[23]
如上述12至20中任一項記載之醫藥組合物,其中R1
為式(2)所表示之基。
[24]
如上述23記載之醫藥組合物,其中Xb
為含有2個殘基之胺基酸之肽之二價基、且Yb
為單鍵;或者Xb
及Yb
獨立地為含有1個殘基之胺基酸之肽之二價基;或者Xb
為單鍵、且Yb
為含有2個殘基之胺基酸之肽之二價基;或者Xb
為含有1個殘基之胺基酸之肽之二價基、且Yb
為單鍵;或者Xb
為單鍵、且Yb
為含有1個殘基之胺基酸之肽之二價基;或者Xb
及Yb
為單鍵。
[25]
如上述23或24記載之醫藥組合物,其中Xb
為單鍵,Yb
為單鍵、丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基。
[26]
如上述23至25中任一項記載之醫藥組合物,其中Xb
為單鍵或含有1個殘基之胺基酸之肽之二價基,Yb
為單鍵。
[27]
如上述23至26中任一項記載之醫藥組合物,其中Xb
及Yb
為單鍵。
[28]
如上述23至27中任一項記載之醫藥組合物,其中癌抗原肽B為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
[29]
如上述23至28中任一項記載之醫藥組合物,其中癌抗原肽B為包含選自
RMFPNAPYL(序列編號2)、
CMTWNQMNL(序列編號3)、
ALLPAVPSL(序列編號4)、
SLGEQQYSV(序列編號5)、
RVPGVAPTL(序列編號6)及
VLDFAPPGA(序列編號7)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[30]
如上述29記載之醫藥組合物,其中癌抗原肽B為包含RMFPNAPYL(序列編號2)之胺基酸序列之肽。
[31]
如上述29記載之醫藥組合物,其中癌抗原肽B為由RMFPNAPYL(序列編號2)之胺基酸序列構成之肽。
[32]
如上述23至29中任一項記載之醫藥組合物,其中式(1)所表示之化合物為
式(6):
[化31]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[33]
如上述12至20中任一項記載之醫藥組合物,其中R1
為癌抗原肽C。
[34]
如上述33記載之醫藥組合物,其中癌抗原肽C為MHC-I類分子限制性肽。
[35]
如上述34記載之醫藥組合物,其中癌抗原肽C為包含
CMTWNQMNL(序列編號3)
之胺基酸序列之肽、或者包含序列編號3之胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
[36]
如上述34或35記載之醫藥組合物,其中癌抗原肽C為包含選自
CMTWNQMNL(序列編號3)及
CYTWNQMNL(序列編號14)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[37]
如上述34至36中任一項記載之醫藥組合物,其中癌抗原肽C為由CMTWNQMNL(序列編號3)之胺基酸序列構成之肽。
[38]
如上述34至36中任一項記載之醫藥組合物,其中癌抗原肽C為由CYTWNQMNL(序列編號14)之胺基酸序列構成之肽。
[39]
如上述33至38中任一項記載之醫藥組合物,其中式(1)所表示之化合物為
式(4):
[化32]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物、或
式(5):
[化33]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[40]
如上述39記載之醫藥組合物,其中式(1)所表示之化合物為
式(5):
[化34]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[41]
如上述33至38中任一項記載之醫藥組合物,其中於癌抗原肽C之N末端結合有含有1~4個殘基之胺基酸之肽。
[42]
如上述41記載之醫藥組合物,其中式(1)所表示之化合物為
式(7):
[化35]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(8):
[化36]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(9):
[化37]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(10):
[化38]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(11):
[化39]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;或
式(12):
[化40]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[43]
如上述33記載之醫藥組合物,其中癌抗原肽C為MHC-II類分子限制性肽。
[44]
如上述43記載之醫藥組合物,其中癌抗原肽C為包含選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)、
SGQAYMFPNAPYLPSCLES(序列編號42)、
PGCNKRYFKLSHLQMHSRK(序列編號43)、
PGCNKRYFKLSHLQMHSRKH(序列編號44)、
PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、
CNKRYFKLSHLQMHSRK(序列編號46)、
CNKRYFKLSHLQMHSRKH(序列編號47)及
CNKRYFKLSHLQMHSRKHTG(序列編號48)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[45]
如上述44記載之醫藥組合物,其中式(1)所表示之化合物為
式(13):
[化41]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(14):
[化42]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;
式(15):
[化43]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物;或
式(16):
[化44]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[46]
如上述23至30中任一項記載之醫藥組合物,其中R1
為式(2)所表示之基,癌抗原肽B包含1個半胱胺酸殘基,癌抗原肽B之半胱胺酸殘基之硫原子與式(3)中之硫原子、或與癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結。
[47]
如上述33至38中任一項記載之醫藥組合物,其中R1
為癌抗原肽C,於癌抗原肽C之N末端結合有含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽,結合於癌抗原肽C之N末端之肽之半胱胺酸殘基之硫原子與式(3)中之硫原子、或與癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結。
[48]
如上述47記載之醫藥組合物,其中結合於癌抗原肽C之N末端之含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽為含有CA之二肽。
[49]
如上述46至48中任一項記載之醫藥組合物,其中Xd
為含有2個殘基之胺基酸之肽之二價基、且Yd
為單鍵;或者Xd
及Yd
獨立地為含有1個殘基之胺基酸之肽之二價基;或者Xd
為單鍵、且Yd
為含有2個殘基之胺基酸之肽之二價基;或者Xd
為含有1個殘基之胺基酸之肽之二價基、且Yd
為單鍵;或者Xd
為單鍵、且Yd
為含有1個殘基之胺基酸之肽之二價基;或者Xd
及Yd
為單鍵。
[50]
如上述46至49中任一項記載之醫藥組合物,其中Xd
為單鍵,Yd
為單鍵、丙胺酸殘基、白胺酸殘基或甲硫胺酸殘基。
[51]
如上述46至50中任一項記載之醫藥組合物,其中Xd
為單鍵或含有1個殘基之胺基酸之肽之二價基,Yd
為單鍵。
[52]
如上述46至51中任一項記載之醫藥組合物,其中Xd
及Yd
為單鍵。
[53]
如上述46至52中任一項記載之醫藥組合物,其中癌抗原肽D為包含選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)、
SGQAYMFPNAPYLPSCLES(序列編號42)、
PGCNKRYFKLSHLQMHSRK(序列編號43)、
PGCNKRYFKLSHLQMHSRKH(序列編號44)、
PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、
CNKRYFKLSHLQMHSRK(序列編號46)、
CNKRYFKLSHLQMHSRKH(序列編號47)及
CNKRYFKLSHLQMHSRKHTG(序列編號48)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[54]
如上述46至52中任一項記載之醫藥組合物,其中癌抗原肽E為包含選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)、
SGQAYMFPNAPYLPSCLES(序列編號42)、
PGCNKRYFKLSHLQMHSRK(序列編號43)、
PGCNKRYFKLSHLQMHSRKH(序列編號44)、
PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、
CNKRYFKLSHLQMHSRK(序列編號46)、
CNKRYFKLSHLQMHSRKH(序列編號47)及
CNKRYFKLSHLQMHSRKHTG(序列編號48)
中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
[55]
如上述46記載之醫藥組合物,其中式(1)所表示之化合物為
式(17):
[化45]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[56]
如上述47記載之醫藥組合物,其中式(1)所表示之化合物為
式(18):
[化46]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[57]
如上述47記載之醫藥組合物,其中式(1)所表示之化合物為
式(19):
[化47]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[58]
如上述1至57中任一項記載之醫藥組合物,其進而包含MHC-II類分子限制性肽、或與MHC-II類分子限制性肽併用。
[59]
如上述58記載之醫藥組合物,其中MHC-II類分子限制性肽為包含選自
WAPVLDFAPPGASAYGSL(序列編號36)、
CWAPVLDFAPPGASAYGSL(序列編號37)、
WAPVLDFAPPGASAYGSLC(序列編號38)、
SGQARMFPNAPYLPSC(序列編號39)、
SGQAYMFPNAPYLPSC(序列編號40)、
SGQARMFPNAPYLPSCLES(序列編號41)、
SGQAYMFPNAPYLPSCLES(序列編號42)、
PGCNKRYFKLSHLQMHSRK(序列編號43)、
PGCNKRYFKLSHLQMHSRKH(序列編號44)、
PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、
CNKRYFKLSHLQMHSRK(序列編號46)、
CNKRYFKLSHLQMHSRKH(序列編號47)及
CNKRYFKLSHLQMHSRKHTG(序列編號48)
中之任一胺基酸序列之肽、或由上述胺基酸序列構成之肽或者該等肽於藥學上容許之鹽。
[60]
如上述59記載之醫藥組合物,其中MHC-II類分子限制性肽為包含WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列之肽或其藥學上容許之鹽。
[61]
如上述59記載之醫藥組合物,其中MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
[62]
如上述58至61中任一項記載之醫藥組合物,其中式(1)所表示之化合物為
式(4):
[化48]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物,
MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
[63]
如上述58至61中任一項記載之醫藥組合物,其中式(1)所表示之化合物為
式(5):
[化49]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物,
MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
[64]
如上述1至63中任一項記載之醫藥組合物,其中癌症為WT1表現之癌症或伴有WT1表現水平上升之癌症。
[65]
如上述1至64中任一項記載之醫藥組合物,其中癌症為血液性癌或實體癌。
[66]
如上述1至65中任一項記載之醫藥組合物,其中癌症選自包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴細胞性白血病、急性淋巴母細胞性白血病、慢性淋巴細胞性白血病之慢性或急性白血病、骨髓化生不良症候群、多發性骨髓瘤、惡性淋巴瘤、胃癌、大腸癌、肺癌、乳癌、生殖細胞癌、肝癌、皮膚癌、膀胱癌、前列腺癌、子宮癌、宮頸癌(cervical cancer)、卵巢癌、腦瘤、神經膠質瘤、中樞神經系統原發惡性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T細胞淋巴瘤、淋巴細胞性淋巴瘤、T細胞淋巴瘤、骨癌、胰臟癌、頭頸癌、皮膚或眼窩內惡性黑色素瘤、直腸癌、肛門癌、睾丸癌、輸卵管癌、子宮內膜癌、子宮頸部上皮細胞癌(carcinoma of the cervix)、陰道癌、外陰癌、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、兒童實體癌、腎癌或尿道癌、腎盂癌、中樞神經系統腫瘤、腫瘤新血管生成、脊椎腫瘤、腦幹膠質瘤、垂體腺瘤、卡波西肉瘤、鱗狀上皮癌、鱗狀細胞癌、包括由石綿誘發之癌症在內之環境誘發癌症、及上述癌症之組合。
[67]
如上述66記載之醫藥組合物,其中癌症選自包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴細胞性白血病之慢性或急性白血病、骨髓化生不良症候群、多發性骨髓瘤、惡性淋巴瘤、胃癌、大腸癌、肺癌、乳癌、生殖細胞癌、肝癌、皮膚癌、膀胱癌、前列腺癌、子宮癌、宮頸癌、卵巢癌、腦瘤、及神經膠質瘤。
[68]
如上述1至67中任一項記載之醫藥組合物,其用作癌症疫苗。
[69]
如上述1至67中任一項記載之醫藥組合物,其用作癌症之細胞性免疫療法中之CTL誘導劑。
[70]
一種用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之方法,其包括:對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象投予如上述[1]記載之上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽。
[71]
如上述70記載之方法,其中上述對象為HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象。
[72]
如上述70記載之方法,其中上述對象為HLA-A*
02:07陽性對象。
[73]
如上述70記載之方法,其中上述對象為HLA-A*
03:01陽性對象。
[74]
如上述70記載之方法,其中上述對象為HLA-B*
15:01陽性對象。
[75]
如上述70記載之方法,其中上述對象為HLA-B*
27:05陽性對象。
[76]
如上述70至75中任一項記載之方法,其包括向對象投予上述(b)之式(1)所表示之化合物或其藥學上容許之鹽。
[77]
如上述70至76中任一項記載之方法,其中式(1)所表示之化合物為
式(4):
[化50]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[78]
如上述70至76中任一項記載之方法,其中式(1)所表示之化合物為
式(5):
[化51]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[79]
如上述70至78中任一項記載之方法,其進而包括投予MHC-II類分子限制性肽。
[80]
如上述79記載之方法,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於同一組合物中。
[81]
如上述79記載之方法,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於不同組合物中。
[82]
如上述79至81中任一項記載之方法,其中MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
[83]
如上述[1]記載之上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽,其用於在HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症。
[84]
如上述83記載之肽、化合物或該等於藥學上容許之鹽,其中上述對象為HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象。
[85]
如上述83記載之肽、化合物或該等於藥學上容許之鹽,其中上述對象為HLA-A*
02:07陽性對象。
[86]
如上述83記載之肽、化合物或該等於藥學上容許之鹽,其中上述對象為HLA-A*
03:01陽性對象。
[87]
如上述83記載之肽、化合物或該等於藥學上容許之鹽,其中上述對象為HLA-B*
15:01陽性對象。
[88]
如上述83記載之肽、化合物或該等於藥學上容許之鹽,其中上述對象為HLA-B*
27:05陽性對象。
[89]
如上述83至88中任一項記載之肽、化合物或其藥學上容許之鹽,其為上述(b)之式(1)所表示之化合物或其藥學上容許之鹽。
[90]
如上述83至89中任一項記載之肽、化合物或其藥學上容許之鹽,其中式(1)所表示之化合物為
式(4):
[化52]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[91]
如上述83至89中任一項記載之肽、化合物或其藥學上容許之鹽,其中式(1)所表示之化合物為
式(5):
[化53]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[92]
如上述83至91中任一項記載之肽、化合物或其藥學上容許之鹽,其與MHC-II類分子限制性肽併用。
[93]
如上述92記載之肽、化合物或其藥學上容許之鹽,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於同一組合物中。
[94]
如上述92記載之肽、化合物或其藥學上容許之鹽,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於不同組合物中。
[95]
如上述92至94中任一項記載之肽、化合物或其藥學上容許之鹽,其中MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
[96]
一種如上述[1]記載之上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽之用途,其用於製造用以於HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象中處置癌症之醫藥。
[97]
如上述96記載之用途,其中上述對象為HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象。
[98]
如上述96記載之用途,其中上述對象為HLA-A*
02:07陽性對象。
[99]
如上述96記載之用途,其中上述對象為HLA-A*
03:01陽性對象。
[100]
如上述96記載之用途,其中上述對象為HLA-B*
15:01陽性對象。
[101]
如上述96記載之用途,其中上述對象為HLA-B*
27:05陽性對象。
[102]
如上述96至101中任一項記載之用途,其為上述(b)之式(1)所表示之化合物或其藥學上容許之鹽之用途。
[103]
如上述96至102中任一項記載之用途,其中式(1)所表示之化合物為
式(4):
[化54]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[104]
如上述96至102中任一項記載之用途,其中式(1)所表示之化合物為
式(5):
[化55]
(式中,C與C之間的鍵表示雙硫鍵)
之化合物。
[105]
如上述96至104中任一項記載之用途,其中醫藥進而包含MHC-II類分子限制性肽、或與MHC-II類分子限制性肽併用。
[106]
如上述105記載之用途,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於同一組合物中。
[107]
如上述105記載之用途,其中上述(a)之肽或其藥學上容許之鹽、或者上述(b)之式(1)所表示之化合物或其藥學上容許之鹽與MHC-II類分子限制性肽包含於不同組合物中。
[108]
如上述105至107中任一項記載之用途,其中MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
藉由以下之實施例來進一步說明本發明,但本發明於任何含義上均不限定於本實施例。
[實施例]
作為針對癌抗原肽之特異性CTL受到肽之刺激而擴增之機制之第一步,需使該肽穩定地結合於HLA-I類分子。HLA-I類分子之各亞型具有肽結合模體,位於抗原肽之特定部位之胺基酸殘基與HLA-I類分子相互作用,藉此形成穩定之立體結構。開發有基於此種模體而能夠預測肽與HLA-I類分子之結合活性之複數種演算法,例如已知NetMHC4.0、SYFPEITHI、BIMAS等。藉由利用該等演算法,根據目標蛋白質之胺基酸序列資訊,可簡易地列出HLA-I類分子限制性之T細胞表位候補清單。為了判斷藉由此種演算法得出之成為候補之表位實際是否可用於開發癌免疫療法,利用癌症患者末梢血單核細胞來試驗T細胞對候補表位之反應性。
WT1126-134
(RMFPNAPYL(序列編號2))為源自WT1之癌抗原肽,報告有於HLA-A*
02:01陽性癌症患者中之較高之臨床效果(Blood. 2009; 113 : 6541-8.)。若實際利用NetMHC4.0計算WT1126-134
之HLA-A*
02:01結合親和力,顯示為7.14nM,預測為HLA-A*
02:01強結合性肽(表1)。
HLA-A*
02:01為於歐美被高頻度識別之HLA-I類分子之亞型之一。HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、及HLA-B*
27:05雖然頻度低於HLA-A*
02:01,但於歐美仍被相對高頻度識別(Hum Immunol. 2001; 62 : 1009-30.)。利用NetMHC4.0計算WT1126-134
對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、及HLA-B*
27:05之結合親和力,分別為28,729.70nM、1,755.02nM、245.03nM、及2,060.74nM(表1)。如此,WT1126-134
對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、及HLA-B*
27:05之親和力比對HLA-A*
02:01之親和力,分別低約4,023.8倍、約245.8倍、約34.3倍、及約288.6倍。
利用NetMHC4.0計算作為WT1126-134
之改型肽的YMFPNAPYL(序列編號13)對HLA-A*
02:01、HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、及HLA-B*
27:05之結合親和力,結果分別為2.73nM、19,806.32nM、8,341.40nM、190.54nM、及6,182.73nM(表2)。如此,上述改型肽對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、及HLA-B*
27:05之親和力比對HLA-A*
02:01之親和力,分別低約7,255.1倍、約3,055.5倍、約69.8倍、及約2,264.7倍。
如上所述,判斷WT1126-134
及作為其改型肽之YMFPNAPYL(序列編號13)可用於針對HLA-A*
02:07、HLA-A*
03:01、HLA-B*
15:01、或HLA-B*
27:05陽性對象之癌免疫療法之可能性極低。
[表1]
[表2]
HLA-I類分子 | 序列 | 親和力(nM) |
HLA-A*02:01 | RMFPNAPYL(序列編號2) | 7.14 |
HLA-A*02:07 | RMFPNAPYL(序列編號2) | 28,729.70 |
I1LA-A*03:01 | RMFPNAPYL(序列編號2) | 1,755.02 |
HLA-B*15:01 | RMFPNAPYL(序列編號2) | 245.03 |
HLA-B*27:05 | RMFPNAPYL(序列編號2) | 2,060.74 |
HLA-I類分子 | 序列 | 親和力(nM) |
HLA-A*02:01 | YMFPNAPYL(序列編號13) | 2.73 |
HLA-A*02:07 | YMFPNAPYL(序列編號13) | 19,806.32 |
HLA-A*03:01 | YMFPNAPYL(序列編號13) | 8,341.40 |
HLA-B*15:01 | YMFPNAPYL(序列編號13) | 190.54 |
HLA-B*27:05 | YMFPNAPL(序列編號13) | 6,182.73 |
其次,解析源自癌症患者末梢血之T細胞對WT1126-134
之反應性。此處,利用由臨床試驗(ClinicalTrials. gov Identifier : NCT03149003及NCT02436252)上註冊之癌症患者提供之末梢血製備之PBMC。具體而言,利用上述癌症患者中之於該臨床試驗中之藥劑之投予前及投予後可採血之HLA-A*
03:01陽性之患者(4名)及HLA-B*
15:01陽性之患者(1名)及HLA-A*
02:07陽性之患者(1名)之PBMC。上述藥劑為包含
下述式(5):
[化56]
之化合物之三氟乙酸鹽、及
由WAPVLDFAPPGASAYGSL(序列編號36)
之胺基酸序列構成之肽之乙酸鹽
之癌症肽疫苗。
將上述藥劑投予前或投予後製備之冷凍PBMC於37℃之溫浴槽中融解後,懸浮於AIM-V培養基。於96孔U底微量盤之各孔以1.8-2.2×106
細胞/mL之濃度接種活細胞(容量:200 μL/孔)。此時,以100 U/mL添加人IL-2、及以40 μg/mL添加式(5)之化合物或序列編號13之肽。其後,於37℃、5%CO2
培養箱內開始培養。培養開始3天後,自各孔去除100 μL上清液後,添加包含100 U/mL之人IL-2、及40 μg/mL之式(5)之化合物或序列編號13之肽的100 μL之AIM-V培養基。於培養開始第7天,回收PBMC,將一部分利用WT1126-134
/HLA-A*
03:01四聚物、WT1126-134
/HLA-B*
15:01四聚物或WT1126-134
/HLA-A*
02:07四聚物與抗人CD8抗體進行染色,藉由MACSQuant Analyzer檢測CD8陽性T細胞中之四聚物陽性細胞。將四聚物陽性T細胞之比率為0.1%以上設為陽性。
將上述藥劑投予前之HLA-A*
03:01陽性患者所提供之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
03:01四聚物進行染色,但於源自各患者之PBMC中均未檢測到HLA-A*
03:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
03:01四聚物染色(圖1)。同樣地,將上述藥劑投予前之HLA-B*
15:01陽性患者所提供之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-B*
15:01四聚物進行染色,但未檢測到HLA-B*
15:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-B*
15:01四聚物染色(圖2)。同樣地,將上述藥劑投予前之HLA-A*
02:07陽性患者所提供之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
02:07四聚物進行染色,但未檢測到HLA-A*
02:07限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
02:07四聚物染色(圖7)。如此,於使用源自癌症患者末梢血之T細胞之試驗中,未確認到WT1126-134
作為用於HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07陽性患者之癌免疫療法之抗原肽之有用性。
如上所述,根據HLA結合預測及使用藥劑投予前之癌症患者末梢血之試驗,認為難以想像開發WT1126-134
作為用於處置HLA-A*
03:01陽性患者、HLA-B*
15:01陽性患者或HLA-A*
02:07陽性患者之癌症之藥劑。
然而,於使用上述藥劑投予後之癌症患者末梢血之試驗中獲得不同結果。藉由上述方法,將HLA-A*
03:01陽性患者之上述藥劑投予後之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
03:01四聚物進行染色,結果驚奇地檢測到HLA-A*
03:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
03:01四聚物染色(圖3)。同樣地,將HLA-B*
15:01陽性患者之上述藥劑投予後之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-B*
15:01四聚物進行染色,結果檢測到HLA-B*
15:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-B*
15:01四聚物染色(圖4)。同樣地,將HLA-A*
02:07陽性患者之上述藥劑投予後之PBMC於式(5)之化合物之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
02:07四聚物進行染色,結果檢測到HLA-A*
02:07限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
02:07四聚物染色(圖8)。
進而,藉由IFNγ ELISPOT分析來解析經過培養擴增之對HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07有限制性之WT1126-134
特異性T細胞是否與呈現WT1126-134
之癌細胞反應。具體而言,利用經WT1126-134
肽脈衝之HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07表現K562細胞(記為「K562-A3+Pep」、「K562-B15+Pep」或「K562-A2.7+Pep」)、或未經上述肽脈衝之HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07表現K562細胞(記為「K562-A3」、「K562-B15」或「K562-A2.7」)刺激包含WT1126-134
特異性T細胞之PBMC。於37℃、5%CO2
培養箱內反應約18小時後,使用ImmunoSpot S5 Versa對各孔進行拍攝。
利用K562-A3或K562-A3+Pep刺激培養包含HLA-A*
03:01限制性WT1126-134
特異性CD8陽性T細胞之PBMC,結果相較於K562-A3,對K562-A3+Pep顯示反應(圖5)。據此判明,HLA-A*
03:01限制性之WT1126-134
特異性T細胞識別呈現WT1126-134
之HLA-A*
03:01陽性癌細胞並與之反應。同樣地,利用K562-B15或K562-B15+Pep刺激培養包含HLA-B*
15:01限制性WT1126-134
特異性CD8陽性T細胞之PBMC,結果相較於K562-B15,對K562-B15+Pep顯示反應(圖6)。據此判明,HLA-B*
15:01限制性之WT1126-134
特異性T細胞識別呈現WT1126-134
之HLA-B*
15:01陽性癌細胞並與之反應。同樣地,利用K562-A2.7或K562-A2.7+Pep刺激培養包含HLA-A*
02:07限制性WT1126-134
特異性CD8陽性T細胞之PBMC,結果相較於K562-A2.7,對K562-A2.7+Pep顯示反應(圖9)。據此判明,HLA-A*
02:07限制性之WT1126-134
特異性T細胞識別呈現WT1126-134
之HLA-A*
02:07陽性癌細胞並與之反應。
如上所述,藉由利用源自投予上述藥劑後之癌症患者之PBMC,表明WT1126-134
可成為不僅用於處置HLA-A*
02:01陽性患者之癌症、且用於處置HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07陽性患者之癌症之藥劑。
又,藉由上述方法,將HLA-A*
03:01陽性患者之上述藥劑投予後之PBMC於序列編號13之肽之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
03:01四聚物進行染色,於該情形時亦檢測到HLA-A*
03:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體之染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
03:01四聚物之染色(圖10)。同樣地,將HLA-B*
15:01陽性患者之上述藥劑投予後之PBMC於序列編號13之肽之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-B*
15:01四聚物進行染色,於該情形時亦檢測到HLA-B*
15:01限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體之染色,縱軸表示利用PE標記WT1126-134
/HLA-B*
15:01四聚物之染色(圖11)。同樣地,將HLA-A*
02:07陽性患者之上述藥劑投予後之PBMC於序列編號13之肽之存在下進行培養後,利用抗CD8抗體及WT1126-134
/HLA-A*
02:07四聚物進行染色,於該情形時亦檢測到HLA-A*
02:07限制性之WT1126-134
特異性CD8陽性T細胞。橫軸表示利用FITC標記抗CD8抗體之染色,縱軸表示利用PE標記WT1126-134
/HLA-A*
02:07四聚物之染色(圖12)。
根據該等之結果,判明WT1126-134
之改型殺傷性肽使HLA-A*
03:01限制性之WT1126-134
特異性CD8陽性T細胞、HLA-B*
15:01限制性之WT1126-134
特異性CD8陽性T細胞及HLA-A*
02:07限制性之WT1126-134
特異性CD8陽性T細胞活化、增殖。表明WT1126-134
之改型殺傷性肽與WT1126-134
同樣地,可成為不僅用於處置HLA-A*
02:01陽性患者之癌症、且用於處置HLA-A*
03:01、HLA-B*
15:01或HLA-A*
02:07陽性患者之癌症之藥劑。
圖1係表示利用源自HLA-A*
03:01陽性患者之末梢血單核細胞(PBMC)之四聚物試驗之結果。對藥劑投予前製備之於存在式(5)之化合物之條件下培養之源自4名患者之PBMC中之HLA-A*
03:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖2係表示利用源自HLA-B*
15:01陽性患者之PBMC之四聚物試驗之結果。對藥劑投予前製備之於存在式(5)之化合物之條件下培養之源自患者之PBMC中之HLA-B*
15:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖3係表示利用源自HLA-A*
03:01陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在式(5)之化合物之條件下培養之源自4名患者之PBMC中之HLA-A*
03:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖4係表示利用源自HLA-B*
15:01陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在式(5)之化合物之條件下培養之源自患者之PBMC中之HLA-B*
15:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖5係表示利用HLA四聚物陽性T細胞之ELISPOT(Enzyme-linked Immunospot Assay,酶聯免疫斑點分析)試驗之結果。利用經WT1126-134
肽脈衝之HLA-A*
03:01表現K562細胞(「K562-A3+Pep」)、或未經上述肽脈衝之HLA-A*
03:01表現K562細胞(「K562-A3」)刺激包含WT1126-134
/HLA-A*
03:01四聚物陽性CD8陽性T細胞之PBMC。顯示4名之結果。
圖6係表示利用HLA四聚物陽性T細胞之ELISPOT試驗之結果。利用經WT1126-134
肽脈衝之HLA-B*
15:01表現K562細胞(「K562-B15+Pep」)、或未經上述肽脈衝之HLA-B*
15:01表現K562細胞(「K562-B15」)刺激包含WT1126-134
/HLA-B*
15:01四聚物陽性CD8陽性T細胞之PBMC。顯示1名之結果。
圖7係表示利用源自HLA-A*
02:07陽性患者之PBMC之四聚物試驗之結果。對藥劑投予前製備之於存在式(5)之化合物之條件下培養之源自患者之PBMC中之HLA-A*
02:07限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖8係表示利用源自HLA-A*
02:07陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在式(5)之化合物之條件下培養之源自患者之PBMC中之HLA-A*
02:07限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖9係表示利用HLA四聚物陽性T細胞之ELISPOT試驗之結果。利用經WT1126-134
肽脈衝之HLA-A*
02:07表現K562細胞(「K562-A2.7+Pep」)、或未經上述肽脈衝之HLA-A*
02:07表現K562細胞(「K562-A2.7」)刺激包含WT1126-134
/HLA-A*
02:07四聚物陽性CD8陽性T細胞之PBMC。顯示1名之結果。
圖10係表示利用源自HLA-A*
03:01陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在序列編號13之肽之條件下培養之源自患者之PBMC中之HLA-A*
03:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖11係表示利用源自HLA-B*
15:01陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在序列編號13之肽之條件下培養之源自患者之PBMC中之HLA-B*
15:01限制性WT1126-134
特異性CD8陽性T細胞進行解析。
圖12係表示利用源自HLA-A*
02:07陽性患者之PBMC之四聚物試驗之結果。對藥劑投予後製備之於存在序列編號13之肽之條件下培養之源自患者之PBMC中之HLA-A*
02:07限制性WT1126-134
特異性CD8陽性T細胞進行解析。
Claims (24)
- 一種醫藥組合物,其用於在HLA-A*02:07、HLA-A*03:01、HLA-B*15:01、或HLA-B*27:05陽性對象中處置癌症,包含以下之(a)或(b): (a)包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽,即,含有7~30個殘基之胺基酸之MHC-I類分子限制性肽或其藥學上容許之鹽;或 (b)式(1)所表示之化合物或其藥學上容許之鹽, [化1] [式中,Xa 及Ya 獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xa 之胺基酸殘基數與Ya 之胺基酸殘基數之和為0~4之整數; 癌抗原肽A表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽A之N末端胺基酸之胺基與式(1)中之Ya 鍵結,癌抗原肽A之C末端胺基酸之羰基與式(1)中之羥基鍵結; R1 表示氫原子、式(2)所表示之基、或癌抗原肽C, [化2] (式中,Xb 及Yb 獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xb 之胺基酸殘基數與Yb 之胺基酸殘基數之和為0~4之整數,癌抗原肽B表示含有7~30個殘基之胺基酸之MHC-I類分子限制性肽,癌抗原肽B之N末端胺基酸之胺基與式(2)中之Yb 鍵結,癌抗原肽B之C末端胺基酸之羰基與式(2)中之羥基鍵結,式(2)中之硫原子與式(1)中之硫原子經由雙硫鍵鍵結), 癌抗原肽C表示含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-I類分子限制性肽或含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽C之半胱胺酸殘基之硫原子與式(1)中之硫原子經由雙硫鍵鍵結,於癌抗原肽C之N末端可結合有含有1~4個殘基之胺基酸之肽; 於R1 為氫原子之情形時,癌抗原肽A為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽; 於R1 為式(2)所表示之基之情形時,癌抗原肽A及/或癌抗原肽B為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽; 於R1 為癌抗原肽C之情形時,癌抗原肽A及/或癌抗原肽C為包含選自RMFPNAPYL(序列編號2)、CMTWNQMNL(序列編號3)、ALLPAVPSL(序列編號4)、SLGEQQYSV(序列編號5)、RVPGVAPTL(序列編號6)及VLDFAPPGA(序列編號7)中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽; 於R1 為式(2)所表示之基、且癌抗原肽B包含1個半胱胺酸殘基之情形時,癌抗原肽B之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結, [化3] (式中,Xd 及Yd 獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd 之胺基酸殘基數與Yd 之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd 鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結); 於R1 為癌抗原肽C、且於癌抗原肽C之N末端結合有含有包含1個半胱胺酸殘基之1~4個殘基之胺基酸之肽之情形時,結合於癌抗原肽C之N末端之肽之半胱胺酸殘基之硫原子可與式(3)中之硫原子、或與作為含有包含1個半胱胺酸殘基之7~30個殘基之胺基酸之MHC-II類分子限制性肽的癌抗原肽E之半胱胺酸殘基之硫原子經由雙硫鍵鍵結, [化4] (式中,Xd 及Yd 獨立地表示單鍵或含有1~4個殘基之胺基酸之肽之二價基,Xd 之胺基酸殘基數與Yd 之胺基酸殘基數之和為0~4之整數,癌抗原肽D表示含有7~30個殘基之胺基酸之MHC-II類分子限制性肽,癌抗原肽D之N末端胺基酸之胺基與式(3)中之Yd 鍵結,癌抗原肽D之C末端胺基酸之羰基與式(3)中之羥基鍵結)]。
- 如請求項1之醫藥組合物,其中上述對象為HLA-A* 03:01、HLA-B* 15:01、或HLA-B* 27:05陽性對象。
- 如請求項1之醫藥組合物,其中上述對象為HLA-A* 02:07陽性對象。
- 如請求項1之醫藥組合物,其中上述對象為HLA-A* 03:01陽性對象。
- 如請求項1之醫藥組合物,其中上述對象為HLA-B* 15:01陽性對象。
- 如請求項1之醫藥組合物,其中上述對象為HLA-B* 27:05陽性對象。
- 如請求項1至6中任一項之醫藥組合物,其包含上述(b)之式(1)所表示之化合物或其藥學上容許之鹽。
- 如請求項7之醫藥組合物,其中癌抗原肽A為包含選自 RMFPNAPYL(序列編號2)、 CMTWNQMNL(序列編號3)、 ALLPAVPSL(序列編號4)、 SLGEQQYSV(序列編號5)、 RVPGVAPTL(序列編號6)及 VLDFAPPGA(序列編號7) 中之任一胺基酸序列之肽、或者包含選自序列編號2~7中之任一胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
- 如請求項8之醫藥組合物,其中癌抗原肽A為由RMFPNAPYL(序列編號2)之胺基酸序列構成之肽。
- 如請求項7至9中任一項之醫藥組合物,其中R1 為癌抗原肽C。
- 如請求項10之醫藥組合物,其中癌抗原肽C為MHC-I類分子限制性肽。
- 如請求項11之醫藥組合物,其中癌抗原肽C為包含 CMTWNQMNL(序列編號3) 之胺基酸序列之肽、或者包含序列編號3之胺基酸序列中缺失、置換及/或附加了1個或數個胺基酸之胺基酸序列、且具有CTL誘導活性之肽。
- 如請求項12之醫藥組合物,其中癌抗原肽C為包含選自 CMTWNQMNL(序列編號3)及 CYTWNQMNL(序列編號14) 中之任一胺基酸序列之肽、或者由上述胺基酸序列構成之肽。
- 如請求項1至15中任一項之醫藥組合物,其進而包含MHC-II類分子限制性肽、或與MHC-II類分子限制性肽併用。
- 如請求項16之醫藥組合物,其中MHC-II類分子限制性肽為包含選自 WAPVLDFAPPGASAYGSL(序列編號36)、 CWAPVLDFAPPGASAYGSL(序列編號37)、 WAPVLDFAPPGASAYGSLC(序列編號38)、 SGQARMFPNAPYLPSC(序列編號39)、 SGQAYMFPNAPYLPSC(序列編號40)、 SGQARMFPNAPYLPSCLES(序列編號41)、 SGQAYMFPNAPYLPSCLES(序列編號42)、 PGCNKRYFKLSHLQMHSRK(序列編號43)、 PGCNKRYFKLSHLQMHSRKH(序列編號44)、 PGCNKRYFKLSHLQMHSRKHTG(序列編號45)、 CNKRYFKLSHLQMHSRK(序列編號46)、 CNKRYFKLSHLQMHSRKH(序列編號47)及 CNKRYFKLSHLQMHSRKHTG(序列編號48) 中之任一胺基酸序列之肽、或由上述胺基酸序列構成之肽或者該等肽於藥學上容許之鹽。
- 如請求項17之醫藥組合物,其中MHC-II類分子限制性肽為由WAPVLDFAPPGASAYGSL(序列編號36)之胺基酸序列構成之肽或其藥學上容許之鹽。
- 如請求項1至20中任一項之醫藥組合物,其中癌症為WT1表現之癌症或伴有WT1表現水平上升之癌症。
- 如請求項1至21中任一項之醫藥組合物,其中癌症選自包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴細胞性白血病、急性淋巴母細胞性白血病、慢性淋巴細胞性白血病之慢性或急性白血病,骨髓化生不良症候群、多發性骨髓瘤、惡性淋巴瘤、胃癌、大腸癌、肺癌、乳癌、生殖細胞癌、肝癌、皮膚癌、膀胱癌、前列腺癌、子宮癌、宮頸癌(cervical cancer)、卵巢癌、腦瘤、神經膠質瘤、中樞神經系統原發惡性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T細胞淋巴瘤、淋巴細胞性淋巴瘤、T細胞淋巴瘤、骨癌、胰臟癌、頭頸癌、皮膚或眼窩內惡性黑色素瘤、直腸癌、肛門癌、睾丸癌、輸卵管癌、子宮內膜癌、子宮頸部上皮細胞癌(carcinoma of the cervix)、陰道癌、外陰癌、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、兒童實體癌、腎癌或尿道癌、腎盂癌、中樞神經系統腫瘤、腫瘤新血管生成、脊椎腫瘤、腦幹膠質瘤、垂體腺瘤、卡波西肉瘤、鱗狀上皮癌、鱗狀細胞癌、包括由石綿誘發之癌症在內之環境誘發癌症、及上述癌症之組合。
- 如請求項1至22中任一項之醫藥組合物,其用作癌症疫苗。
- 如請求項1至23中任一項之醫藥組合物,其用作癌症之細胞性免疫療法中之CTL誘導劑。
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AU4932199A (en) | 1998-07-31 | 2000-02-21 | Haruo Sugiyama | Cancer antigens based on tumor suppressor gene wt1 product |
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MXPA01003344A (es) | 1998-09-30 | 2004-04-21 | Corixa Corp | Composiciones y metodos para inmunoterapia especifica de wt1. |
US20030235557A1 (en) | 1998-09-30 | 2003-12-25 | Corixa Corporation | Compositions and methods for WT1 specific immunotherapy |
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US20040097703A1 (en) | 2001-03-22 | 2004-05-20 | Haruo Sugiyama | Wt1 modified peptide |
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WO2003106682A1 (ja) | 2002-06-12 | 2003-12-24 | 中外製薬株式会社 | Hla−a24拘束性癌抗原ペプチド |
DE60329201D1 (de) | 2002-09-20 | 2009-10-22 | Chugai Pharmaceutical Co Ltd | Substituierte wt1-peptide |
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