TWI828626B - Therapy in combination with preparation containing hemolytic streptococcus bacterial cell - Google Patents
Therapy in combination with preparation containing hemolytic streptococcus bacterial cell Download PDFInfo
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- TWI828626B TWI828626B TW107122565A TW107122565A TWI828626B TW I828626 B TWI828626 B TW I828626B TW 107122565 A TW107122565 A TW 107122565A TW 107122565 A TW107122565 A TW 107122565A TW I828626 B TWI828626 B TW I828626B
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Images
Abstract
Description
本發明就一態樣而言，係關於一種癌治療方法，其特徵為將免疫檢查點抑制劑及/或CXCR2抑制劑與包含溶血性鏈球菌之菌體的製劑組合投予。 In one aspect, the present invention relates to a cancer treatment method characterized by administering an immune checkpoint inhibitor and/or a CXCR2 inhibitor in combination with a preparation containing bacterial cells of hemolytic streptococci.
在癌細胞或癌之微小環境中，存在妨礙對癌之免疫反應的各種免疫檢查點分子。免疫檢查點抑制劑為解除免疫抑制機構，將對癌之免疫反應活化的新穎治療法，就免疫檢查點抑制劑而言，抗CTLA-4(細胞毒性T淋巴相關抗原-4(cytotoxic T lymphocyte-associated antigen-4))抗體之易普利姆單抗(ipilimumab)或抗PD-1(計畫性細胞死亡-1(programmed cell death-1))抗體之保疾伏(nivolumab)及吉舒達(pembrolizumab)等已得到國內外許可，可使用於癌治療。 In cancer cells or the microenvironment of cancer, there are various immune checkpoint molecules that hinder the immune response to cancer. Immune checkpoint inhibitors are novel treatments that relieve immune suppression mechanisms and activate the immune response to cancer. As for immune checkpoint inhibitors, anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) associated antigen-4)) antibody ipilimumab (ipilimumab) or anti-PD-1 (programmed cell death-1 (programmed cell death-1)) antibody nivolumab and gisuda (pembrolizumab) and others have been licensed domestically and internationally and can be used in cancer treatment.
必醫你舒(Picibanil)(註冊商標)(CAS登錄編號：39325-01-4，別名：OK-432、PC-B-45)為將溶血性鏈球菌化膿性鏈球菌(Streptococcus pyogenes)(A群3型)Su 株於苄基青黴素鉀存在下，以一定條件處理並經凍結乾燥之菌體製劑，在日本已被許可使用為抗惡性腫瘤劑/淋巴管瘤治療劑。 Picibanil (registered trademark) (CAS registration number: 39325-01-4, alias: OK-432, PC-B-45) is a combination of hemolytic Streptococcus pyogenes (A Group 3 type) Su strain prepared under certain conditions and freeze-dried in the presence of benzyl penicillin potassium has been approved for use as an anti-malignant tumor agent/lymphangioma therapeutic agent in Japan.
已知CXCR2(C-X-C配體趨化因子受體2(C-X-C motif chemokine receptor 2)]為趨化因子受體，參與癌之增殖。再者，已報導藉由與抗CXCR2抗體之併用，而增強抗PD-1抗體之抗腫瘤效果(非專利文獻1)。 CXCR2 (C-X-C ligand chemokine receptor 2 (C-X-C motif chemokine receptor 2)] is known to be a chemokine receptor and is involved in the proliferation of cancer. Furthermore, it has been reported that the combined use with anti-CXCR2 antibodies enhances anti- Anti-tumor effect of PD-1 antibodies (Non-Patent Document 1).
[非專利文獻1]Science Translational Medicine 2014；6(237)：237ra67 [Non-patent document 1]Science Translational Medicine 2014;6(237):237ra67
[非專利文獻2]Cancer Cell 2016；29：832-845 [Non-patent document 2] Cancer Cell 2016;29:832-845
本發明之課題為發現一種有效之癌治療法(併用療法)，並以醫藥品形式提供。 The subject of the present invention is to discover an effective cancer treatment method (combination therapy) and provide it in the form of a pharmaceutical.
本發明人等為了解決前述課題而專心檢討之結果，驚奇地發現藉由免疫檢查點抑制劑及/或CXCR2抑制劑，與包含溶血性鏈球菌之菌體的製劑之組合(以下，簡稱為本發明之組合)，可解決前述問題。 As a result of intensive examination by the present inventors in order to solve the above-mentioned problems, the present inventors surprisingly discovered that a combination of an immune checkpoint inhibitor and/or a CXCR2 inhibitor and a preparation containing hemolytic streptococci (hereinafter referred to as the present invention for short) combination of inventions), which can solve the aforementioned problems.
本發明之實施態樣，例如：[1]一種癌治療劑，其特徵為將免疫檢查點抑制劑及/ 或CXCR2抑制劑與溶血性鏈球菌之菌體組合，作為複合劑、或個別製劑被同時或分別投予；[2]如前述[1]記載之癌治療劑，其特徵為將溶血性鏈球菌之菌體與免疫檢查點抑制劑組合，作為複合劑、或個別製劑被同時或分別投予；[3]如前述[1]記載之癌治療劑，其特徵為將溶血性鏈球菌之菌體與CXCR2抑制劑組合，作為複合劑、或個別製劑被同時或分別投予；[4]如前述[1]記載之癌治療劑，其特徵為將免疫檢查點抑制劑及CXCR2抑制劑與溶血性鏈球菌之菌體組合，作為複合劑、或個別製劑被同時或分別投予；[5]一種包含溶血性鏈球菌之菌體的癌治療劑，其特徵為與免疫檢查點抑制劑及/或CXCR2抑制劑組合投予；[6]如前述[5]記載之包含溶血性鏈球菌之菌體的癌治療劑，其特徵為與免疫檢查點抑制劑組合投予；[7]如前述[5]記載之包含溶血性鏈球菌之菌體的癌治療劑，其特徵為與CXCR2抑制劑組合投予；[8]如前述[5]記載之包含溶血性鏈球菌之菌體的癌治療劑，其特徵為與免疫檢查點抑制劑及CXCR2抑制劑組合投予；[9]一種包含免疫檢查點抑制劑之癌治療劑，其特徵為與包含溶血性鏈球菌之菌體的製劑組合投予；[10]如前述[9]記載之包含免疫檢查點抑制劑之癌治療劑，其特徵為進一步與CXCR2抑制劑組合投予； [11]一種包含CXCR2抑制劑之癌治療劑，其特徵為與包含溶血性鏈球菌之菌體的製劑組合投予；[12]如前述[11]記載之包含CXCR2抑制劑之癌治療劑，其特徵為進一步與免疫檢查點抑制劑組合投予；[13]如前述[1]至[12]中任一項記載之癌治療劑，其中，該溶血性鏈球菌之菌體為化膿性鏈球菌(A群3型)Su株經青黴素處理及凍結乾燥之菌體；[14]如前述[13]記載之癌治療劑，其中，該包含化膿性鏈球菌(A群3型)Su株經青黴素處理及凍結乾燥之菌體的製劑為必醫你舒(註冊商標)；[15]如前述[1]、[2]、[4]至[6]、[8]至[10]及[12]中任一項記載之癌治療劑，其中，該免疫檢查點抑制劑為選自CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM3、BTLA、B7H3、B7H4、2B4、CD160、A2aR、KIR、VISTA及TIGIT所構成之群組中的免疫檢查點分子之抑制劑；[16]如前述[1]、[2]、[4]至[6]、[8]至[10]及[12]中任一項記載之癌治療劑，其中，該免疫檢查點抑制劑係抗CTLA-4抗體(例如，易普利姆單抗(YERVOY(註冊商標))、川美利姆單抗(Tremelimumab)、AGEN-1884)、抗PD-1抗體(例如，保疾伏(nivolumab)(Opdivo(註冊商標)、REGN-2810、吉舒達(KEYTRUDA(註冊商標))、PDR-001、BGB-A317、AMP-514(MEDI0680)、BCD-100、IBI-308、JS-001、PF-06801591、TSR-042)、抗PD-L1抗體(例如，阿泰舟利單抗(Atezolizumab(TECENTRIQ(註冊商標))、RG7446、 MPDL3280A)、阿凡路單抗(Avelumab(BAVENCIO(註冊商標))、PF-06834635、MSB0010718C)、德伐路單抗(Durvalumab(MEDI4736))、BMS-936559、CA-170、LY-3300054)、抗PD-L2抗體(例如，rHIgM12B7)、PD-1抑制劑(例如，AUNP-12)、PD-L1融合蛋白質、PD-L2融合蛋白質(例如，AMP-224)、抗Tim-3抗體(例如，MBG453)、抗LAG-3抗體(例如，BMS-986016、LAG525)、或抗KIR抗體(例如，利里路單抗(Lirilumab))；[17]如前述[1]、[2]、[4]至[6]、[8]至[10]及[12]中任一項記載之癌治療劑，其中，該免疫檢查點抑制劑為PD-1路徑抑制劑；[18]如前述[17]記載之癌治療劑，其中，該PD-1路徑抑制劑為抗PD-1抗體；[19]如前述[1]、[3]至[5]、[7]、[8]及[10]至[12]中任一項記載之癌治療劑，其中，該CXCR2抑制劑為AZD-5069、AZD-8309、丹尼里新(Danirixin)、伊路伯里新(Elubrixin)甲苯磺酸鹽、那伐里新(Navarixin)、SB-265610、三唑并嘧啶衍生物、DF-2755A、拉答里新(ladarixin)、PAC-G31P、來帕里新(reparixin)、SX-517、SX-576、SX-682、SB225002、SB332235、NVP CXCR2 20、SB-656933；[20]如前述[1]、[3]至[5]、[7]、[8]及[10]至[12]中任一項記載之癌治療劑，其中，該CXCR2抑制劑為AZD-5069、丹尼里新、那伐里新、來帕里新、SX-682、SB225002、SB-656933； [21]如前述[1]至[12]中任一項記載之癌治療劑，其特徵為被投予至利用免疫檢查點抑制劑所達到之治療效果不充分的癌患者；[22]如前述[1]至[12]中任一項記載之癌治療劑，其特徵為被投予至利用包含溶血性鏈球菌之菌體的製劑所達到之治療效果不充分的癌患者；[23]如前述[1]至[12]中任一項記載之癌治療劑，其特徵為被投予至利用CXCR2抑制劑所達到之治療效果不充分的癌患者；[24]如前述[1]至[23]中任一項記載之癌治療劑，其中，該癌為白血病(例如，急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病、慢性淋巴性白血病)、惡性淋巴瘤(霍奇金淋巴瘤、非霍奇金淋巴瘤(例如，成人T細胞白血病、濾泡性淋巴瘤、瀰漫性大細胞型B細胞性淋巴瘤))、中樞神經系原發惡性淋巴瘤、睪丸原發性淋巴瘤、多發性骨髓瘤、骨髓增生異常症候群、骨髓增殖症候群、頭頸部癌、鼻咽癌、食道癌、胃食道接合部癌、食道腺癌、胃癌、大腸癌、結腸癌、直腸癌、小腸癌、肛門癌(例如，肛管癌)、肝癌(例如，肝細胞癌)、膽囊癌、膽管癌、膽道癌、胰臟癌、甲狀腺癌、副甲狀腺癌、肺癌(例如，非小細胞肺癌(例如，扁平上皮非小細胞肺癌、非扁平上皮非小細胞肺癌)、小細胞肺癌)、乳癌、卵巢癌(例如，漿液性卵巢癌、卵巢透明細胞腺癌)、輸卵管癌、子宮癌(例如，子宮頸癌、子宮體癌、子宮內膜癌)、陰道癌、外陰部癌、陰莖癌、腎臟 癌(例如，腎細胞癌、透明細胞型腎細胞癌)、副腎臟癌、尿路上皮癌(例如，膀胱癌、上部尿路癌、輸尿管癌、腎盂癌及尿道癌)、前列腺癌、睪丸腫瘤(例如，胚細胞腫瘤)、骨/軟組織肉瘤(例如，尤文氏肉瘤、小兒橫紋肌肉瘤及子宮體部平滑肌肉瘤)、皮膚癌(例如，葡萄膜惡性黑色素瘤、惡性黑色素瘤(例如，皮膚、口腔黏膜上皮或眼窩內等之惡性黑色素瘤)、默克爾(Merkel)細胞癌)、神經膠瘤(例如，神經膠母細胞瘤、神經膠肉瘤)、腦腫瘤(例如，膠母細胞瘤)、脊椎腫瘤、卡波西(Kaposi)肉瘤、扁平上皮癌、胸膜間皮瘤、原發性腹膜癌、內分泌系統癌、兒童癌或原因不明癌；[25]一種癌治療方法，其特徵為將有效用量之包含溶血性鏈球菌之菌體的製劑與有效用量之免疫檢查點抑制劑及/或CXCR2抑制劑組合投予至哺乳動物(較佳為人類患者)；[26]一種癌治療方法，其特徵為將有效用量之包含溶血性鏈球菌之菌體的製劑投予至人類患者，其中，該人類患者進一步接受利用免疫檢查點抑制劑及/或CXCR2抑制劑之治療；[27]一種癌治療方法，其特徵為將有效用量之免疫檢查點抑制劑投予至人類患者，其中，該人類患者進一步接受利用包含溶血性鏈球菌之菌體的製劑的治療；[28]一種癌治療方法，其特徵為將有效用量之CXCR2抑制劑投予至人類患者，其中，該人類患者進一步接受利 用包含溶血性鏈球菌之菌體的製劑的治療；[29]一種用於癌治療之醫藥組成物，其包含免疫檢查點抑制劑及/或CXCR2抑制劑與溶血性鏈球菌之菌體；[30]如前述[29]記載之用於癌治療之醫藥組成物，其包含溶血性鏈球菌之菌體及免疫檢查點抑制劑；[31]如前述[29]記載之用於癌治療之醫藥組成物，其包含溶血性鏈球菌之菌體及CXCR2抑制劑；[32]如前述[29]記載之用於癌治療之醫藥組成物，其包含溶血性鏈球菌之菌體、免疫檢查點抑制劑及CXCR2抑制劑；[33]一種免疫檢查點抑制劑及/或CXCR2抑制劑與包含溶血性鏈球菌之菌體的製劑的組合，其係使用於癌治療；[34]如前述[33]記載之組合，其為包含溶血性鏈球菌之菌體的製劑與免疫檢查點抑制劑，該組合係使用於癌治療；[35]如前述[33]記載之組合，其為包含溶血性鏈球菌之菌體的製劑與CXCR2抑制劑，該組合係使用於癌治療；[36]如前述[33]記載之組合，其為包含溶血性鏈球菌之菌體的製劑與免疫檢查點抑制劑及CXCR2抑制劑，該組合係使用於癌治療；[37]一種包含溶血性鏈球菌之菌體的製劑，其係與免疫檢查點抑制劑及/或CXCR2抑制劑組合，並使用於癌治療； [38]如前述[37]記載之包含溶血性鏈球菌之菌體的製劑，其係與免疫檢查點抑制劑組合，並使用於癌治療；[39]如前述[37]記載之包含溶血性鏈球菌之菌體的製劑，其係與CXCR2抑制劑組合，並使用於癌治療；[40]如前述[37]記載之包含溶血性鏈球菌的製劑，其係與免疫檢查點抑制劑及CXCR2抑制劑組合，並使用於癌治療；[41]一種免疫檢查點抑制劑，其係與包含溶血性鏈球菌之菌體的製劑組合，並使用於癌治療；[42]如前述[41]記載之免疫檢查點抑制劑，其進一步與CXCR2抑制劑組合，並使用於癌治療；[43]一種CXCR2抑制劑，其係與包含溶血性鏈球菌之菌體的製劑組合，並使用於癌治療；[44]如前述[43]記載之CXCR2抑制劑，其係進一步與免疫檢查點抑制劑組合，並使用於癌治療；[45]一種免疫檢查點抑制劑及/或CXCR2抑制劑與溶血性鏈球菌之菌體的組合的用途，其係用於癌治療劑的製造，該癌治療劑係作為複合劑、或個別製劑被同時或分別投予；[46]如前述[45]記載之用途，其係免疫檢查點抑制劑與溶血性鏈球菌之菌體的組合；[47]如前述[45]記載之用途，其係CXCR2抑制劑與溶血性鏈球菌之菌體的組合；[48]如前述[45]記載之用途，其係免疫檢查點抑制劑及 CXCR2抑制劑與溶血性鏈球菌之菌體的組合；[49]一種溶血性鏈球菌之菌體之用途，其係用於癌治療劑的製造，該癌治療劑係與免疫檢查點抑制劑及/或CXCR2抑制劑組合投予；[50]如前述[49]記載之用途，其特徵為該癌治療劑係與免疫檢查點抑制劑組合投予；[51]如前述[49]記載之用途，其特徵為該癌治療劑係與CXCR2抑制劑組合投予；[52]如前述[49]記載之用途，其特徵為該癌治療劑係與免疫檢查點抑制劑及CXCR2抑制劑組合投予；[53]一種免疫檢查點抑制劑之用途，其係用於癌治療劑的製造，該癌治療劑係與溶血性鏈球菌之菌體組合投予；[54]如前述[53]記載之用途，其特徵為該癌治療劑係進一步與CXCR2抑制劑組合投予；[55]一種CXCR2抑制劑之用途，其係用於癌治療劑的製造，該癌治療劑係與溶血性鏈球菌之菌體組合投予；[56]如前述[55]記載之用途，其中，該癌治療劑係進一步與免疫檢查點抑制劑組合並投予；[57]如前述[45]至[56]中任一項記載之用途，其中，該溶血性鏈球菌之菌體為化膿性鏈球菌(A群3型)Su株經青黴素處理及凍結乾燥之菌體；[58]如前述[57]記載之用途，其中，包含該化膿性鏈球菌(A群3型)Su株經青黴素處理及凍結乾燥之菌體的製劑 為必醫你舒(註冊商標)；[59]如前述[45]、[46]、[48]至[50]、[52]至[54]及[56]中任一項記載之用途，其中，該免疫檢查點抑制劑係選自CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM3、BTLA、B7H3、B7H4、2B4、CD160、A2aR、KIR、VISTA及TIGIT所構成之群組中之免疫檢查點分子的抑制劑；[60]如前述[45]、[46]、[48]至[50]、[52]至[54]及[56]中任一項記載之用途，其中，該免疫檢查點抑制劑係抗CTLA-4抗體(例如，易普利姆單抗(YERVOY(註冊商標))、川美利姆單抗、AGEN-1884)、抗PD-1抗體(例如，保疾伏(Opdivo(註冊商標))、REGN-2810、吉舒達(KEYTRUDA(註冊商標))、PDR-001、BGB-A317、AMP-514(MEDI0680)、BCD-100、IBI-308、JS-001、PF-06801591、TSR-042)、抗PD-L1抗體(例如，阿泰舟利單抗(TECENTRIQ(註冊商標)、RG7446、MPDL3280A)、阿凡路單抗(BAVENCIO(註冊商標)、PF-06834635、MSB0010718C)、德伐路單抗(MEDI4736)、BMS-936559、CA-170、LY-3300054)、抗PD-L2抗體(例如，rHIgM12B7)、PD-1抑制劑(例如，AUNP-12)、PD-L1融合蛋白質、PD-L2融合蛋白質(例如，AMP-224)、抗Tim-3抗體(例如，MBG453)、抗LAG-3抗體(例如，BMS-986016、LAG525)、或抗KIR抗體(例如，利里路單抗)；[61]如前述[45]、[46]、[48]至[50]、[52]至[54]及[56]中任一項記載之用途，其中，該免疫檢查點抑制劑為PD-1路徑抑制劑； [62]如前述[61]記載之用途，其中，該PD-1路徑抑制劑為抗PD-1抗體；[63]如前述[45]、[47]至[49]、[51]、[52)及[54]至[56]中任一項記載之用途，其中，該CXCR2抑制劑為AZD-5069、AZD-8309、丹尼里新、伊路伯里新甲苯磺酸鹽、那伐里新、SB-265610、三唑并嘧啶衍生物、DF-2755A、拉答里新、PAC-G31P、來帕里新、SX-517、SX-576、SX-682、SB225002、SB332235、NVP CXCR2 20、SB-656933；[64]如前述[45]、[47]至[49]、[51]、[52]及[54]至[56]中任一項記載之用途，其中，該CXCR2抑制劑為AZD-5069、丹尼里新、那伐里新、來帕里新、SX-682、SB225002、SB-656933；[65]如前述[45]至[56]中任一項記載之用途，其特徵為投予至利用免疫檢查點抑制劑所達到之治療效果不充分的癌患者；[66]如前述[45]至[56]中任一項記載之用途，其特徵為投予至利用包含溶血性鏈球菌之菌體的製劑所達到之治療效果不充分的癌患者；[67]如前述[45]至[56]中任一項記載之用途，其特徵為投予至利用CXCR2抑制劑所達到之治療效果不充分的癌患者；及[68]如前述[45]至[67]中任一項記載之用途，其中，該癌為白血病(例如，急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病、慢性淋巴性白血病)、惡性淋巴瘤(霍 奇金淋巴瘤、非霍奇金淋巴瘤(例如，成人T細胞白血病、濾泡性淋巴瘤、瀰漫性大細胞型B細胞性淋巴瘤))、中樞神經系原發惡性淋巴瘤、睪丸原發性淋巴瘤、多發性骨髓瘤、骨髓增生異常症候群、骨髓增殖症候群、頭頸部癌、鼻咽頭癌、食道癌、胃食道接合部癌、食道腺癌、胃癌、大腸癌、結腸癌、直腸癌、小腸癌、肛門癌(例如，肛管癌)、肝癌(例如，肝細胞癌)、膽囊癌、膽管癌、膽道癌、胰臟癌、甲狀腺癌、副甲狀腺癌、肺癌(例如，非小細胞肺癌(例如，扁平上皮非小細胞肺癌、非扁平上皮非小細胞肺癌)、小細胞肺癌)、乳癌、卵巢癌(例如，漿液性卵巢癌、卵巢透明細胞腺癌)、輸卵管癌、子宮癌(例如，子宮頸癌、子宮體癌、子宮內膜癌)、陰道癌、外陰部癌、陰莖癌、腎臟癌(例如，腎細胞癌、透明細胞型腎細胞癌)、副腎臟癌、尿路上皮癌(例如，膀胱癌、上部尿路癌、輸尿管癌、腎盂癌及尿道癌)、前列腺癌、睪丸腫瘤(例如，胚細胞腫瘤)、骨/軟組織肉瘤(例如，尤文氏肉瘤、小兒橫紋肌肉瘤及子宮體部平滑肌肉瘤)、皮膚癌(例如，葡萄膜惡性黑色素瘤、惡性黑色素瘤(例如，皮膚、口腔黏膜上皮或眼窩內等之惡性黑色素瘤)、默克爾細胞癌)、神經膠瘤(例如，神經膠母細胞瘤、神經膠肉瘤)、腦腫瘤(例如，膠母細胞瘤)、脊椎腫瘤、卡波西肉瘤、扁平上皮癌、胸膜間皮瘤、原發性腹膜癌、內分泌系癌、兒童癌或原因不明癌。 An embodiment of the present invention is, for example: [1] A cancer therapeutic agent characterized by combining an immune checkpoint inhibitor and/or a CXCR2 inhibitor with cells of hemolytic streptococci as a composite agent or individual preparations. Administered simultaneously or separately; [2] The cancer therapeutic agent as described in the above [1], characterized by combining the cells of hemolytic streptococci and an immune checkpoint inhibitor, and administering them simultaneously or separately as a composite agent or individual preparations. Administration; [3] The cancer therapeutic agent as described in the above [1], characterized by combining hemolytic streptococcus cells and a CXCR2 inhibitor, and administering them simultaneously or separately as a composite agent or individual preparations; [4 [ 5] A cancer therapeutic agent containing bacteria of hemolytic Streptococcus, characterized by being administered in combination with an immune checkpoint inhibitor and/or a CXCR2 inhibitor; [6] containing hemolytic Streptococcus as described in the aforementioned [5] A cancer therapeutic agent containing bacterial cells characterized by being administered in combination with an immune checkpoint inhibitor; [7] A cancer therapeutic agent containing bacterial cells containing hemolytic streptococci as described in the aforementioned [5], characterized by being administered in combination with a CXCR2 inhibitor [8] The cancer therapeutic agent containing the bacteria of hemolytic streptococci as described in the aforementioned [5], which is characterized in that it is administered in combination with an immune checkpoint inhibitor and a CXCR2 inhibitor; [9] A drug containing A cancer therapeutic agent containing an immune checkpoint inhibitor, which is characterized in that it is administered in combination with a preparation containing bacterial cells of hemolytic streptococcus; [10] The cancer therapeutic agent containing an immune checkpoint inhibitor as described in the aforementioned [9], wherein It is characterized by further administration in combination with a CXCR2 inhibitor; [11] A cancer therapeutic agent containing a CXCR2 inhibitor, characterized by administration in combination with a preparation containing bacterial cells of hemolytic streptococcus; [12] As mentioned above [11] The described cancer therapeutic agent containing a CXCR2 inhibitor is characterized by being further administered in combination with an immune checkpoint inhibitor; [13] The cancer therapeutic agent according to any one of the above [1] to [12], wherein the The cells of hemolytic Streptococcus are the cells of Streptococcus pyogenes (group A type 3) Su strain that have been treated with penicillin and freeze-dried; [14] The cancer therapeutic agent as described in [13] above, which includes pyogenes The preparation of Streptococcus (group A type 3) Su strain treated with penicillin and freeze-dried cells is Biyinisu (registered trademark); [15] as mentioned above [1], [2], [4] to [6] ], the cancer therapeutic agent according to any one of [8] to [10] and [12], wherein the immune checkpoint inhibitor is selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, Inhibitors of immune checkpoint molecules in the group consisting of LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4, CD160, A2aR, KIR, VISTA and TIGIT; [16] as mentioned above [1], [2] , the cancer therapeutic agent according to any one of [4] to [6], [8] to [10] and [12], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody (for example, Ipril YERVOY (registered trademark), Tremelimumab, AGEN-1884), anti-PD-1 antibodies (e.g., nivolumab (Opdivo (registered trademark), REGN-2810 , KEYTRUDA (registered trademark), PDR-001, BGB-A317, AMP-514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591, TSR-042), anti-PD -L1 antibodies (for example, Atezolizumab (TECENTRIQ (registered trademark)), RG7446, MPDL3280A), Avelumab (BAVENCIO (registered trademark)), PF-06834635, MSB0010718C), Durvalumab (MEDI4736), BMS-936559, CA-170, LY-3300054), anti-PD-L2 antibodies (e.g., rHIgM12B7), PD-1 inhibitors (e.g., AUNP-12), PD- L1 fusion protein, PD-L2 fusion protein (e.g., AMP-224), anti-Tim-3 antibody (e.g., MBG453), anti-LAG-3 antibody (e.g., BMS-986016, LAG525), or anti-KIR antibody (e.g., Lirilumab); [17] Cancer treatment as described in any one of the aforementioned [1], [2], [4] to [6], [8] to [10] and [12] The agent, wherein the immune checkpoint inhibitor is a PD-1 pathway inhibitor; [18] The cancer therapeutic agent as described in the aforementioned [17], wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody; [19 ] The cancer therapeutic agent as described in any one of [1], [3] to [5], [7], [8] and [10] to [12], wherein the CXCR2 inhibitor is AZD-5069 , AZD-8309, Danirixin, Elubrixin tosylate, Navarixin, SB-265610, triazolopyrimidine derivatives, DF-2755A, La Ladarixin, PAC-G31P, reparixin, SX-517, SX-576, SX-682, SB225002, SB332235, NVP CXCR2 20, SB-656933; [20] As mentioned above [1 ], [3] to [5], [7], [8] and [10] to [12], any one of the cancer therapeutic agents, wherein the CXCR2 inhibitor is AZD-5069, Danarixin , navarisin, leparisin, SX-682, SB225002, SB-656933; [21] The cancer therapeutic agent according to any one of the above [1] to [12], characterized by being administered to Cancer patients for whom the therapeutic effect achieved by immune checkpoint inhibitors is insufficient; [22] The cancer therapeutic agent according to any one of the above [1] to [12], characterized in that it is administered to utilize a hemolytic agent containing Cancer patients for whom the therapeutic effect achieved by preparations of Streptococcus bacteria is insufficient; [23] The cancer therapeutic agent according to any one of the above [1] to [12], characterized by being administered to CXCR2 inhibitory agents Cancer patients for whom the therapeutic effect achieved by the agent is insufficient; [24] The cancer therapeutic agent according to any one of the above [1] to [23], wherein the cancer is leukemia (for example, acute myeloid leukemia, chronic myeloid leukemia leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large cell B Cellular lymphoma)), primary malignant lymphoma of the central nervous system, primary testicular lymphoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative syndrome, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal cancer Junction cancer, esophageal adenocarcinoma, stomach cancer, large intestine cancer, colon cancer, rectal cancer, small bowel cancer, anal cancer (e.g., anal canal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder cancer, cholangiocarcinoma, biliary tract cancer , pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous epithelial non-small cell lung cancer, non-squamous epithelial non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g. , serous ovarian cancer, ovarian clear cell adenocarcinoma), fallopian tube cancer, uterine cancer (e.g., cervical cancer, uterine corpus cancer, endometrial cancer), vaginal cancer, vulvar cancer, penile cancer, kidney cancer (e.g., Renal cell carcinoma, clear cell renal cell carcinoma), accessory renal cancer, urothelial cancer (e.g., bladder, upper urinary tract, ureter, renal pelvis, and urethra), prostate cancer, testicular tumors (e.g., embryonic cellular tumors), bone/soft tissue sarcomas (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, and leiomyosarcoma of the uterine body), skin cancers (e.g., uveal malignant melanoma, malignant melanoma (e.g., skin, oral mucosal epithelium, or orbital malignant melanoma (including malignant melanoma), Merkel cell carcinoma), gliomas (e.g., glioblastoma, gliosarcoma), brain tumors (e.g., glioblastoma), spinal tumors, Kaposi Kaposi sarcoma, squamous cell carcinoma, pleural mesothelioma, primary peritoneal cancer, endocrine system cancer, childhood cancer or cancer of unknown cause; [25] A cancer treatment method characterized by including an effective dosage of hemolytic A preparation of Streptococcus bacteria and an effective amount of an immune checkpoint inhibitor and/or a CXCR2 inhibitor are administered to a mammal (preferably a human patient) in combination; [26] A cancer treatment method characterized by adding an effective amount of The preparation containing the bacterial cells of hemolytic streptococcus is administered to a human patient, wherein the human patient further receives treatment using an immune checkpoint inhibitor and/or a CXCR2 inhibitor; [27] A cancer treatment method characterized by: Administering an effective amount of an immune checkpoint inhibitor to a human patient, wherein the human patient further receives treatment using a preparation containing bacterial cells of hemolytic streptococci; [28] A cancer treatment method characterized by administering an effective amount of an immune checkpoint inhibitor A CXCR2 inhibitor is administered to a human patient, wherein the human patient further receives treatment using a preparation containing bacteria of hemolytic streptococcus; [29] A pharmaceutical composition for cancer treatment, which contains immune checkpoint inhibition Agents and/or CXCR2 inhibitors and bacterial cells of hemolytic streptococci; [30] The pharmaceutical composition for cancer treatment as described in the aforementioned [29], which contains bacterial cells of hemolytic streptococci and immune checkpoint inhibitors ; [31] The pharmaceutical composition for cancer treatment as described in the aforementioned [29], which contains hemolytic Streptococcus bacteria and a CXCR2 inhibitor; [32] The pharmaceutical composition for cancer treatment as described in the aforementioned [29] A composition comprising a bacterial cell of hemolytic streptococcus, an immune checkpoint inhibitor and a CXCR2 inhibitor; [33] A preparation of an immune checkpoint inhibitor and/or a CXCR2 inhibitor and a bacterial cell containing hemolytic streptococcus The combination is used for cancer treatment; [34] The combination as described in the aforementioned [33], which is a preparation containing hemolytic streptococci bacteria and an immune checkpoint inhibitor, and the combination is used for cancer treatment; [35 ] The combination as described in the aforementioned [33], which is a preparation containing hemolytic streptococcus bacteria and a CXCR2 inhibitor, and this combination is used for cancer treatment; [36] The combination as described in the aforementioned [33], which is a preparation containing A preparation of hemolytic Streptococcus bacteria and an immune checkpoint inhibitor and a CXCR2 inhibitor, the combination of which is used for cancer treatment; [37] A preparation containing hemolytic Streptococcus bacteria, which is combined with an immune checkpoint inhibitor The preparation and/or CXCR2 inhibitor are combined and used for cancer treatment; [38] The preparation containing the bacterial cells of hemolytic streptococci as described in the aforementioned [37] is combined with an immune checkpoint inhibitor and used for cancer treatment. Treatment; [39] The preparation containing hemolytic streptococci as described in the aforementioned [37], which is combined with a CXCR2 inhibitor and used for cancer treatment; [40] The preparation containing hemolytic streptococci as described in the aforementioned [37] A preparation of Streptococcus, which is combined with an immune checkpoint inhibitor and a CXCR2 inhibitor, and is used for cancer treatment; [41] An immune checkpoint inhibitor, which is combined with a preparation of bacteria containing hemolytic Streptococcus, and used for cancer treatment; [42] the immune checkpoint inhibitor as described in the aforementioned [41], which is further combined with a CXCR2 inhibitor, and used for cancer treatment; [43] a CXCR2 inhibitor, which is composed of a hemolytic Preparations of Streptococcus bacteria are combined and used for cancer treatment; [44] The CXCR2 inhibitor as described in the aforementioned [43] is further combined with an immune checkpoint inhibitor and used for cancer treatment; [45] A The use of a combination of immune checkpoint inhibitors and/or CXCR2 inhibitors and hemolytic streptococci bacteria for the production of cancer therapeutic agents that are administered simultaneously or separately as a composite agent or individual preparations Administration; [46] The use as described in the aforementioned [45], which is a combination of immune checkpoint inhibitors and hemolytic streptococci; [47] The use as described in the aforementioned [45], which is a CXCR2 inhibitor The combination with the bacterial cells of hemolytic streptococci; [48] The use as described in the aforementioned [45], which is a combination of an immune checkpoint inhibitor and a CXCR2 inhibitor and the bacterial cells of hemolytic streptococci; [49] A hemolytic streptococcus. The use of bacterial cells of Streptococcus sexus for the manufacture of cancer therapeutic agents that are administered in combination with immune checkpoint inhibitors and/or CXCR2 inhibitors; [50] as described in the aforementioned [49] Use, characterized in that the cancer therapeutic agent is administered in combination with an immune checkpoint inhibitor; [51] The use as described in the aforementioned [49], characterized in that the cancer therapeutic agent is administered in combination with a CXCR2 inhibitor; [52] ] The use as described in the aforementioned [49], characterized in that the cancer therapeutic agent is administered in combination with an immune checkpoint inhibitor and a CXCR2 inhibitor; [53] The use of an immune checkpoint inhibitor, which is used for cancer treatment Production of an agent, the cancer therapeutic agent is administered in combination with the cells of hemolytic streptococcus; [54] The use as described in the aforementioned [53], characterized in that the cancer therapeutic agent is further administered in combination with a CXCR2 inhibitor; [55] Use of a CXCR2 inhibitor for the production of a cancer therapeutic agent administered in combination with hemolytic streptococci; [56] The use as described in the aforementioned [55], wherein , the cancer therapeutic agent is further combined with an immune checkpoint inhibitor and administered; [57] The use as described in any one of the aforementioned [45] to [56], wherein the cells of the hemolytic Streptococcus are suppurative Penicillin-treated and freeze-dried cells of Streptococcus pyogenes (group A type 3) Su strain; [58] Use as described in the aforementioned [57], which includes the Streptococcus pyogenes (group A type 3) Su strain The preparation of penicillin-treated and freeze-dried bacterial cells is Biyi Ni Shu (registered trademark); [59] as mentioned above [45], [46], [48] to [50], [52] to [54] and [ 56], wherein the immune checkpoint inhibitor is selected from CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4 , inhibitors of immune checkpoint molecules in the group consisting of CD160, A2aR, KIR, VISTA and TIGIT; [60] As mentioned above [45], [46], [48] to [50], [52] to The use according to any one of [54] and [56], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody (for example, ipilimumab (YERVOY (registered trademark)), tremenumab monoclonal antibody, AGEN-1884), anti-PD-1 antibody (for example, Opdivo (registered trademark)), REGN-2810, KEYTRUDA (registered trademark), PDR-001, BGB-A317, AMP-514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591, TSR-042), anti-PD-L1 antibodies (e.g., TECENTRIQ (registered trademark), RG7446 , MPDL3280A), afanalumab (BAVENCIO (registered trademark), PF-06834635, MSB0010718C), dervalumab (MEDI4736), BMS-936559, CA-170, LY-3300054), anti-PD-L2 antibody (e.g., rHIgM12B7), PD-1 inhibitors (e.g., AUNP-12), PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti- LAG-3 antibody (for example, BMS-986016, LAG525), or anti-KIR antibody (for example, rilirumab); [61] As mentioned above [45], [46], [48] to [50], [ The use described in any one of 52] to [54] and [56], wherein the immune checkpoint inhibitor is a PD-1 pathway inhibitor; [62] The use described in the aforementioned [61], wherein the PD The -1 pathway inhibitor is an anti-PD-1 antibody; [63] as described in any one of the aforementioned [45], [47] to [49], [51], [52) and [54] to [56] Purpose, wherein the CXCR2 inhibitor is AZD-5069, AZD-8309, Danarisin, Ilubricin Tosylate, Navarisin, SB-265610, triazolopyrimidine derivatives, DF- 2755A, latarisin, PAC-G31P, latarisin, SX-517, SX-576, SX-682, SB225002, SB332235, NVP CXCR2 20, SB-656933; [64] As mentioned above [45], [ The use described in any one of 47] to [49], [51], [52] and [54] to [56], wherein the CXCR2 inhibitor is AZD-5069, Danalisin, or Navarisin , Leparisin, SX-682, SB225002, SB-656933; [65] The use as described in any one of the aforementioned [45] to [56], characterized by administering to the level achieved by using an immune checkpoint inhibitor Cancer patients with insufficient therapeutic effect; [66] The use as described in any one of the above [45] to [56], characterized by administration of a preparation containing hemolytic streptococcus bacteria to achieve treatment Cancer patients with insufficient therapeutic effects; [67] The use as described in any one of the aforementioned [45] to [56], characterized by administration to cancer patients with insufficient therapeutic effects achieved by using CXCR2 inhibitors; and [ 68] The use according to any one of the above [45] to [67], wherein the cancer is leukemia (for example, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoid leukemia, chronic lymphocytic leukemia), malignant Lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (eg, adult T-cell leukemia, follicular lymphoma, diffuse large cell B-cell lymphoma)), primary malignant lymphoma of the central nervous system , testicular primary lymphoma, multiple myeloma, myelodysplastic syndrome, myeloproliferative syndrome, head and neck cancer, nasopharyngeal head cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer , rectal cancer, small bowel cancer, anal cancer (e.g., anal canal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer (e.g., , non-small cell lung cancer (e.g., squamous epithelial non-small cell lung cancer, non-squamous epithelial non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer, ovarian clear cell adenocarcinoma), fallopian tube cancer , uterine cancer (eg, cervical cancer, uterine corpus cancer, endometrial cancer), vaginal cancer, vulvar cancer, penile cancer, kidney cancer (eg, renal cell carcinoma, clear cell renal cell carcinoma), accessory renal cancer , urothelial cancer (eg, bladder, upper urinary tract, ureter, renal pelvis, and urethra), prostate cancer, testicular tumors (eg, blastoma), bone/soft tissue sarcoma (eg, Ewing's sarcoma, Pediatric rhabdomyosarcoma and leiomyosarcoma of the uterine body), skin cancer (for example, uveal malignant melanoma, malignant melanoma (for example, malignant melanoma of the skin, oral mucosal epithelium or eye socket), Merkel cell carcinoma), neurological Gliomas (e.g., glioblastoma, gliosarcoma), brain tumors (e.g., glioblastoma), spinal tumors, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, primary peritoneal cancer, Endocrine cancer, childhood cancer, or cancer of unknown cause.
本發明之組合在癌治療上有用。 The combination of the present invention is useful in cancer treatment.
第1圖係顯示必醫你舒(註冊商標)對抗原呈現細胞之作用。圖中，im表示無必醫你舒(註冊商標)處置群，OK-DC表示處置群，縱軸表示平均螢光強度(MFI)。 Figure 1 shows the effect of Biyi Ni Shu (registered trademark) on antigen-presenting cells. In the figure, im represents the OK-DC treatment group, OK-DC represents the treatment group, and the vertical axis represents the mean fluorescence intensity (MFI).
第2圖係顯示在小鼠大腸癌細胞株CT26皮下擔癌模型中之抗腫瘤作用。第2圖(A)顯示投予時程。第2圖(B)顯示利用必醫你舒(註冊商標)與抗PD-1抗體(a-PD-1)併用所達到的腫瘤體積之變化。圖中，notx表示PBS群，1KE表示必醫你舒(註冊商標)，a-PD-1表示抗PD-1抗體群，1KE+a-PD-1表示必醫你舒(註冊商標)與抗PD-1抗體併用群，縱軸表示腫瘤體積平均值(Tumor volume)。 Figure 2 shows the anti-tumor effect in the subcutaneous tumor-carrying model of mouse colorectal cancer cell line CT26. Figure 2(A) shows the injection schedule. Figure 2 (B) shows the change in tumor volume achieved by the combined use of Bionisu (registered trademark) and anti-PD-1 antibody (a-PD-1). In the figure, notx represents the PBS group, 1KE represents Biyi Ni Shu (registered trademark), a-PD-1 represents the anti-PD-1 antibody group, 1KE+a-PD-1 represents Bi Yi Ni Shu (registered trademark) and anti-PD-1 antibody group. For the PD-1 antibody combination group, the vertical axis represents the average tumor volume (Tumor volume).
第3圖顯示在小鼠大腸癌細胞株MC38皮下擔癌模型中之抗腫瘤作用。圖中，4H2顯示抗PD-1抗體群，併用表示必醫你舒(註冊商標)與抗PD-1抗體併用群，縱軸表示腫瘤體積中央值。 Figure 3 shows the anti-tumor effect in the subcutaneous tumor-carrying model of mouse colorectal cancer cell line MC38. In the figure, 4H2 shows the anti-PD-1 antibody group, and the column "4H2" indicates the group using Biyinisu (registered trademark) and anti-PD-1 antibody together, and the vertical axis indicates the central value of the tumor volume.
第4圖顯示在細胞株CT26-NY-ESO-1皮下擔癌模型中之抗腫瘤作用，該細胞株CT26-NY-ESO-1能使癌抗原NY-ESO-1在小鼠大腸癌細胞株CT26細胞中穩定地表現。第4圖(A)顯示投予時程。第4圖(B)顯示利用必醫你舒(註冊商標)與抗PD-1抗體(4H2)及CXCR2抑制劑SB225002(Selleck公司)併用所達到的腫瘤體積之變化。圖中，Control表示PBS群，0.5KE表示必醫你舒(註冊商標)群，aPD-1表示抗PD-1抗體群，CXCR2抑制劑表示CXCR2 抑制劑群，0.5KE+CXCR2抑制劑表示必醫你舒(註冊商標)與CXCR2抑制劑併用群，0.5KE+aPD-1表示必醫你舒(註冊商標)與抗PD-1抗體併用群，0.5KE+aPD-1+CXCR2抑制劑表示必醫你舒(註冊商標)與抗PD-1抗體及CXCR2抑制劑併用群，縱軸表示腫瘤體積中央值。 Figure 4 shows the anti-tumor effect in the subcutaneous cancer model of the cell line CT26-NY-ESO-1. The cell line CT26-NY-ESO-1 can induce the cancer antigen NY-ESO-1 in the mouse colorectal cancer cell line. Stably expressed in CT26 cells. Figure 4(A) shows the injection schedule. Figure 4(B) shows the changes in tumor volume achieved by the combined use of Bionisu (registered trademark), anti-PD-1 antibody (4H2) and CXCR2 inhibitor SB225002 (Selleck Company). In the figure, Control represents the PBS group, 0.5KE represents the Biyi Nishu (registered trademark) group, aPD-1 represents the anti-PD-1 antibody group, CXCR2 inhibitor represents the CXCR2 inhibitor group, and 0.5KE+CXCR2 inhibitor represents Biyi Nishu (registered trademark) and CXCR2 inhibitors are used together, 0.5KE+aPD-1 means Biyi In the group using Nishu (registered trademark) with anti-PD-1 antibody and CXCR2 inhibitor, the vertical axis represents the central value of tumor volume.
就溶血性鏈球菌之菌體而言，較佳為化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥菌體。就包含化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥菌體之製劑而言，為必醫你舒(註冊商標)。 As for the cells of hemolytic Streptococcus, freeze-dried cells of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin are preferred. For preparations containing freeze-dried cells of Streptococcus pyogenes (Group A type 3) strain treated with penicillin, it is Bioshu (registered trademark).
必醫你舒(註冊商標)(CAS登錄編號：39325-01-4，別名：OK-432、PC-B-45)為將溶血性鏈球菌化膿性鏈球菌(A群3型)Su株於苄基青黴素鉀存在下，以一定條件處理，並經凍結乾燥的菌體製劑(化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥粉末)。必醫你舒(註冊商標)於1975年作為抗惡性腫瘤劑得到醫藥品製造許可，亦可使用為市售品。 Biyi Ni Shu (registered trademark) (CAS registration number: 39325-01-4, alias: OK-432, PC-B-45) is a strain of hemolytic Streptococcus pyogenes (group A type 3) Su. A bacterial preparation prepared under certain conditions and freeze-dried in the presence of potassium benzylpenicillin (freeze-dried powder of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin). Biyinisu (registered trademark) was licensed as an anti-tumor agent in 1975 and is also available as a commercial product.
就用於本發明之組合的包含溶血性鏈球菌之菌體的製劑的投予方法而言，可為全身性或局部性，以經口或非經口之形式投予，然而較佳為非經口之形式。 The administration method of the preparation containing the bacterial cells of hemolytic streptococci used in the combination of the present invention may be systemic or local, orally or parenterally administered, but is preferably non-orally administered. Oral form.
用於本發明之組合的必醫你舒(註冊商標)之投予量，根據年齡、體重、症狀、治療效果、投予方法、處理時間等而異。必醫你舒(註冊商標)之投予量單位，即1KE，表示以乾燥菌體計為0.1mg。投予量之一態樣，通 常成人每人每次以乾燥菌體計，在0.01mg至10mg之範圍，以一日一次至數次(例如，二次、三次)、二日一次、每週二次或每週一次進行非經口投予。當然如前述，由於投予量係根據各種條件而變動，故有以少於上述投予量之量即充分之情形，亦有必須超過該範圍來投予之情形。 The amount of Bilnis(registered trademark) used in the combination of the present invention varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc. The dosage unit of Biyi Ni Shu (registered trademark) is 1KE, which means 0.1mg based on dry bacterial cells. The dose is usually in the range of 0.01 mg to 10 mg per person per adult based on dry bacterial cells, once to several times a day (for example, two or three times), once every two days, or once a week. Parenteral administration is given twice or once weekly. Of course, as mentioned above, since the dosage varies according to various conditions, there are cases where an dosage less than the above-mentioned dosage is sufficient, and there are also cases where it is necessary to administer an amount exceeding this range.
在本發明中，免疫檢查點分子意指藉由傳達抑制性共通信號而發揮免疫抑制功能的分子。就免疫檢查點分子而言，已知有CTLA-4、PD-1、PD-L1(計畫性細胞死亡配體1(programmed cell death-ligand 1))、PD-L2(計畫性細胞死亡配體2)、LAG-3(淋巴細胞活化基因3)、TIM3(T細胞免疫球蛋白及黏蛋白-3)、BTLA(B及T淋巴細胞衰減因子)、B7H3、B7H4、2B4、CD160、A2aR(腺苷A2a受體)、KIR(殺手細胞抑制受體)、VISTA((V-結構域含Ig之T細胞活化抑制因子))、TIGIT(T細胞免疫球蛋白及ITIM結構域)等，然而只要為具有與(參照Nature Reviews Cancer，12，252-264頁，2012年；Cancer Cell，27，450-461頁，2015年)定義一致之作用的分子則無特別限定。 In the present invention, immune checkpoint molecules mean molecules that exert immunosuppressive functions by conveying inhibitory common signals. As for immune checkpoint molecules, CTLA-4, PD-1, PD-L1 (programmed cell death-ligand 1), PD-L2 (programmed cell death Ligand 2), LAG-3 (lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lymphocyte attenuation factor), B7H3, B7H4, 2B4, CD160, A2aR (adenosine A2a receptor), KIR (killer cell inhibitory receptor), VISTA ((V-domain containing Ig-containing T cell activation inhibitory factor)), TIGIT (T cell immunoglobulin and ITIM domain), etc., however There is no particular limitation as long as it is a molecule that has the same effect as defined in (see Nature Reviews Cancer, 12, pp. 252-264, 2012; Cancer Cell, 27, pp. 450-461, 2015).
本發明之組合所用的免疫檢查點抑制劑，為阻礙免疫檢查點分子之功能的物質。就免疫檢查點抑制劑而言，只要是能夠抑制免疫檢查點分子之功能(信號)的物質則無特別限定。 The immune checkpoint inhibitor used in the combination of the present invention is a substance that blocks the function of immune checkpoint molecules. The immune checkpoint inhibitor is not particularly limited as long as it is a substance that can inhibit the function (signal) of immune checkpoint molecules.
就免疫檢查點抑制劑而言，較佳為人類免疫檢查點分子之抑制劑，更佳為針對人類免疫檢查點分子之中和抗體。 For immune checkpoint inhibitors, preferably they are inhibitors of human immune checkpoint molecules, and more preferably, they are neutralizing antibodies against human immune checkpoint molecules.
就免疫檢查點抑制劑而言，可列舉例如：選自CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM3、BTLA、B7H3、B7H4、2B4、CD160、A2aR、KIR、VISTA及TIGIT所構成之群組中的免疫檢查點分子之抑制劑。以下列舉免疫檢查點抑制劑之例，惟免疫檢查點抑制劑並不被此等所限定。 Examples of immune checkpoint inhibitors include CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4, CD160, A2aR, and KIR. Inhibitors of immune checkpoint molecules in the group consisting of , VISTA and TIGIT. Examples of immune checkpoint inhibitors are listed below, but immune checkpoint inhibitors are not limited to these.
就免疫檢查點抑制劑而言，可為例如：抗CTLA-4抗體(例如，易普利姆單抗(YERVOY(註冊商標))、川美利姆單抗、AGEN-1884)、抗PD-1抗體(例如，保疾伏(Opdivo(註冊商標))、REGN-2810、吉舒達(KEYTRUDA(註冊商標))、PDR-001、BGB-A317、AMP-514(MEDI0680)、BCD-100、IBI-308、JS-001、PF-06801591、TSR-042)、抗PD-L1抗體(例如，阿泰舟利單抗(TECENTRIQ(註冊商標)、RG7446、MPDL3280A)、阿凡路單抗(BAVENCIO(註冊商標)、PF-06834635、MSB0010718C)、德伐路單抗(MEDI4736)、BMS-936559、CA-170、LY-3300054)、抗PD-L2抗體(例如，rHIgM12B7)、PD-1抑制劑(例如，AUNP-12)、PD-L1融合蛋白質、PD-L2融合蛋白質(例如，AMP-224)、抗Tim-3抗體(例如，MBG453)、抗LAG-3抗體(例如，BMS-986016、LAG525)、或抗KIR抗體(例如，利里路單抗)。再者，包含上述已知抗體之重鏈及輕鏈互補性決定區域(CDRs)或可變區域(VR)的抗體亦為免疫檢查點抑制劑之一態樣。例如，就抗PD-1抗體之另一態樣而言，可列舉例如包含保疾伏之重鏈及輕鏈互補性決定區域(CDRs)或可變區域(VR) 的抗體。 Immune checkpoint inhibitors include, for example, anti-CTLA-4 antibodies (for example, ipilimumab (YERVOY (registered trademark)), transmelumab, AGEN-1884), anti-PD- 1 Antibodies (for example, Opdivo (registered trademark)), REGN-2810, KEYTRUDA (registered trademark), PDR-001, BGB-A317, AMP-514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591, TSR-042), anti-PD-L1 antibodies (e.g., TECENTRIQ (registered trademark), RG7446, MPDL3280A), avanumab (BAVENCIO (registered trademark), PF-06834635, MSB0010718C), dervalumab (MEDI4736), BMS-936559, CA-170, LY-3300054), anti-PD-L2 antibodies (e.g., rHIgM12B7), PD-1 inhibitors (e.g., AUNP-12), PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG525), or an anti-KIR antibody (e.g., rilirumab). Furthermore, antibodies containing the heavy chain and light chain complementarity determining regions (CDRs) or variable regions (VR) of the above-mentioned known antibodies are also a form of immune checkpoint inhibitors. For example, another aspect of the anti-PD-1 antibody includes, for example, an antibody comprising complementarity-determining regions (CDRs) or variable regions (VR) of the heavy chain and light chain of the antibody.
就包含保疾伏之重鏈及輕鏈互補性決定區域(CDRs)或可變區域(VR)的抗體而言，可列舉例如(1)包含下列(a)至(f)的抗PD-1抗體：(a)由序列編號3之胺基酸序列構成之重鏈可變區域CDR1、(b)由序列編號4之胺基酸序列構成之重鏈可變區域CDR2、(c)由序列編號5之胺基酸序列構成之重鏈可變區域CDR3、(d)由序列編號6之胺基酸序列構成之輕鏈可變區域CDR1、(e)由序列編號7之胺基酸序列構成之輕鏈可變區域CDR2及(f)由序列編號8之胺基酸序列構成之輕鏈可變區域CDR3；或(2)包含由序列編號1之胺基酸序列構成之重鏈可變區域及由序列編號2之胺基酸序列構成之輕鏈可變區域的抗PD-1抗體(較佳為(1)或(2)之單離人類單株IgG4抗體)。 For antibodies containing the heavy chain and light chain complementarity determining regions (CDRs) or variable regions (VR) of PD-1, examples include (1) anti-PD-1 containing the following (a) to (f) Antibody: (a) heavy chain variable region CDR1 composed of the amino acid sequence of SEQ ID NO: 3, (b) heavy chain variable region CDR2 composed of the amino acid sequence of SEQ ID NO: 4, (c) heavy chain variable region CDR2 composed of the amino acid sequence of SEQ ID NO: 4 The heavy chain variable region CDR3 composed of the amino acid sequence of SEQ ID NO: 5, (d) the light chain variable region CDR1 composed of the amino acid sequence of SEQ ID NO: 6, (e) the CDR3 of the light chain variable region composed of the amino acid sequence of SEQ ID NO: 7 The light chain variable region CDR2 and (f) the light chain variable region CDR3 consisting of the amino acid sequence of SEQ ID NO: 8; or (2) the heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 1 and An anti-PD-1 antibody with a light chain variable region composed of the amino acid sequence of SEQ ID NO: 2 (preferably an isolated human monoclonal IgG4 antibody of (1) or (2)).
抗體亦可為功能性抗體斷片，就此等抗體斷片而言，可列舉Fab、Fab’、F(ab’)2、Fv、scFv、dsFv等。 The antibody may also be a functional antibody fragment. Examples of such antibody fragments include Fab, Fab', F(ab')2, Fv, scFv, dsFv, etc.
就本發明之組合所用的免疫檢查點抑制劑而言，較佳為抗CTLA-4抗體、PD-1路徑抑制劑，更佳為PD-1路徑抑制劑。 As for the immune checkpoint inhibitor used in the combination of the present invention, it is preferably an anti-CTLA-4 antibody or a PD-1 pathway inhibitor, and more preferably a PD-1 pathway inhibitor.
PD-1路徑抑制劑為阻礙PD-1/PD-1配體路徑之藥劑。就PD-1路徑抑制劑而言，只要為阻礙PD-1/PD-1配體路徑之藥劑就無特別限定，例如，可為抗PD-1抗體、抗PD-L1抗體、抗PD-L2抗體、PD-1抑制劑、PD-L1融合蛋白質、PD-L2融合蛋白質。 PD-1 pathway inhibitors are agents that block the PD-1/PD-1 ligand pathway. The PD-1 pathway inhibitor is not particularly limited as long as it blocks the PD-1/PD-1 ligand pathway. For example, it can be an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-L2 Antibodies, PD-1 inhibitors, PD-L1 fusion proteins, PD-L2 fusion proteins.
就PD-1路徑抑制劑而言，較佳為抗PD-1抗體、抗PD-L1抗體、抗PD-L2抗體。特佳為抗PD-1抗體。就抗PD-1抗體而言，較佳為包含保疾伏之重鏈及輕鏈互補性決定區域(CDRs)或可變區域(VR)的抗體(包括保疾伏)，更佳為保疾伏。 For PD-1 pathway inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies are preferred. Particularly preferred are anti-PD-1 antibodies. For anti-PD-1 antibodies, preferably antibodies including the heavy chain and light chain complementarity determining regions (CDRs) or variable regions (VR) of PD-1 (including PD-1), more preferably PD-1 Volt.
此等免疫檢查點抑制劑中之任1種或任意複數種抗體、抑制劑或者融合蛋白質，均可與必醫你舒(註冊商標)組合使用。 Any one or any plurality of antibodies, inhibitors or fusion proteins among these immune checkpoint inhibitors can be used in combination with Biyinisu (registered trademark).
用於本發明之組合的免疫檢查點抑制劑之投予量，係根據年齡、體重、症狀、治療效果、投予方法、處理時間等而異，然而可以獲得最佳期望效果之方式進行調整。 The dosage of the immune checkpoint inhibitor used in the combination of the present invention varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is adjusted so as to obtain the best desired effect.
例如，使用抗PD-1抗體時，投予量之一態樣為0.1至20mg/kg體重。再者，使用包含保疾伏之重鏈及輕鏈互補性決定區域(CDRs)或可變區域(VR)之抗體(例如保疾伏)時，投予量之一態樣，為0.3至10mg/kg體重，較佳為2mg/kg或3mg/kg體重。 For example, when using an anti-PD-1 antibody, one aspect of the dosage is 0.1 to 20 mg/kg body weight. Furthermore, when using an antibody containing the heavy chain and light chain complementarity determining regions (CDRs) or variable regions (VR) of prochivo (for example, prochivo), the dosage may range from 0.3 to 10 mg. /kg body weight, preferably 2 mg/kg or 3 mg/kg body weight.
用於本發明之組合的CXCR2抑制劑，係抑制屬於趨化因子受體之一的CXCR2之功能的物質。 The CXCR2 inhibitor used in the combination of the present invention is a substance that inhibits the function of CXCR2, which is one of the chemokine receptors.
就CXCR2抑制劑而言，可列舉：AZD-5069、AZD-8309、丹尼里新、伊路伯里新甲苯磺酸鹽、那伐里新、SB-265610、三唑并嘧啶衍生物、DF-2755A、拉答里新、PAC-G31P、來帕里新、SX-517、SX-576、SX-682、SB225002、SB332235、NVP CXCR2 20、SB-656933等，惟只要是抑制 CXCR2之功能的物質則無特別限定。 As for CXCR2 inhibitors, examples include: AZD-5069, AZD-8309, danisin, ilubrisin tosylate, navarisin, SB-265610, triazolopyrimidine derivatives, DF -2755A, latarisin, PAC-G31P, latarisin, SX-517, SX-576, SX-682, SB225002, SB332235,
就CXCR2抑制劑而言，以AZD-5069、丹尼里新、那伐里新、來帕里新、SX-682、SB225002、SB-656933為較佳。更佳為AZD-5069、丹尼里新、來帕里新、SX-682、SB225002。 As far as CXCR2 inhibitors are concerned, AZD-5069, Danalisin, Navarisin, Leparisin, SX-682, SB225002, and SB-656933 are better. Better ones are AZD-5069, Danilisin, Laparisin, SX-682, and SB225002.
用於本發明之組合的CXCR2抑制劑之投予量，係根據年齡、體重、症狀、治療效果、投予方法、處置時間等而異，惟可以獲得最佳之期望效果之方式進行調整。 The dosage of the CXCR2 inhibitor used in the combination of the present invention varies according to age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but can be adjusted in a manner to obtain the best desired effect.
本發明之組合的毒性為非常低者，可安全地使用為醫藥品。 The combination of the present invention has very low toxicity and can be safely used as pharmaceuticals.
就藉由本發明之組合進行治療的疾患之一態樣而言，可列舉癌。在本發明中，癌意指所有的惡性腫瘤。就癌而言，無特別限定，可列舉例如：白血病(例如，急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病、慢性淋巴性白血病)、惡性淋巴瘤(霍奇金淋巴瘤、非霍奇金淋巴瘤(例如，成人T細胞白血病、濾泡性淋巴瘤、瀰漫性大細胞型B細胞性淋巴瘤))、中樞神經系原發惡性淋巴瘤、睪丸原發性淋巴瘤、多發性骨髓瘤、骨髓增生異常症候群、骨髓增殖症候群、頭頸部癌、鼻咽頭癌、食道癌、胃食道 接合部癌、食道腺癌、胃癌、大腸癌、結腸癌、直腸癌、小腸癌、肛門癌(例如，肛管癌)、肝癌(例如，肝細胞癌)、膽囊癌、膽管癌、膽道癌、胰臟癌、甲狀腺癌、副甲狀腺癌、肺癌(例如，非小細胞肺癌(例如，扁平上皮非小細胞肺癌、非扁平上皮非小細胞肺癌)、小細胞肺癌)、乳癌、卵巢癌(例如，漿液性卵巢癌、卵巢透明細胞腺癌)、輸卵管癌、子宮癌(例如，子宮頸癌、子宮體癌、子宮內膜癌)、陰道癌、外陰部癌、陰莖癌、腎臟癌(例如，腎細胞癌、透明細胞型腎細胞癌)、副腎臟癌、尿路上皮癌(例如，膀胱癌、上部尿路癌、輸尿管癌、腎盂癌及尿道癌)、前列腺癌、睪丸腫瘤(例如，胚細胞腫瘤)、骨/軟組織肉瘤(例如，尤文氏肉瘤、小兒橫紋肌肉瘤及子宮體部平滑肌肉瘤)、皮膚癌(例如，葡萄膜惡性黑色素瘤、惡性黑色素瘤(例如，皮膚、口腔黏膜上皮或眼窩內等之惡性黑色素瘤)、默克爾細胞癌)、神經膠瘤(例如，神經膠母細胞瘤、神經膠肉瘤)、腦腫瘤(例如，膠母細胞瘤)、脊椎腫瘤、卡波西肉瘤、扁平上皮癌、胸膜間皮瘤、原發性腹膜癌、內分泌系癌、兒童癌或原因不明癌。其中，例如，對於以免疫檢查點抑制劑或包含溶血性鏈球菌之菌體的製劑單獨治療之效果不充分的癌患者，可特別期待本發明之組合能將其抗腫瘤效果發揮至最大限度。再者，例如，對於以CXCR2抑制劑單獨治療之效果不充分的癌患者，亦可特別期待本發明之組合能將其抗腫瘤效果發揮至最大限度。又，藉由本發明之組合，亦可將個別藥劑之用量降低來投予，並且可期待副作 用之減輕。 As one aspect of the disease to be treated by the combination of the present invention, cancer is exemplified. In the present invention, cancer means all malignant tumors. The cancer is not particularly limited, and examples thereof include leukemia (for example, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoid leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, Chikin lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large cell B-cell lymphoma)), primary malignant lymphoma of the central nervous system, primary testicular lymphoma, multiple myeloid neoplasia, myelodysplastic syndrome, myeloproliferative syndrome, head and neck cancer, nasopharyngeal head cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, small bowel cancer, anal cancer (e.g. , anal canal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous cell lung cancer) Small cell lung cancer, non-squamous epithelial non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer, ovarian clear cell adenocarcinoma), fallopian tube cancer, uterine cancer (e.g., cervical cancer, uterine cancer) body cancer, endometrial cancer), vaginal cancer, vulva cancer, penile cancer, kidney cancer (eg, renal cell carcinoma, clear cell renal cell carcinoma), accessory renal cancer, urothelial cancer (eg, bladder cancer, Cancers of the upper urinary tract, ureter, renal pelvis, and urethra), prostate cancer, testicular tumors (e.g., blastoma), bone/soft tissue sarcomas (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, and leiomyosarcoma of the body of the uterus), Skin cancer (e.g., uveal malignant melanoma, malignant melanoma (e.g., malignant melanoma of the skin, oral mucosal epithelium, or orbit, etc.), Merkel cell carcinoma), glioma (e.g., glioblastoma, Gliosarcoma), brain tumors (e.g., glioblastoma), spinal tumors, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, primary peritoneal cancer, endocrine cancer, childhood cancer, or cancer of unknown cause. Among them, for example, for cancer patients whose individual treatment effects are insufficient with immune checkpoint inhibitors or preparations containing hemolytic streptococcus bacteria, the combination of the present invention is particularly expected to maximize the anti-tumor effect. Furthermore, for example, for cancer patients whose treatment with CXCR2 inhibitor alone is insufficient, it is particularly expected that the combination of the present invention can maximize the anti-tumor effect. Furthermore, with the combination of the present invention, the dosage of individual pharmaceutical agents can be reduced and the side effects can be expected to be reduced.
針對利用免疫檢查點抑制劑所達到之治療效果不充分的癌患者所用之本發明之組合而言，較佳為免疫檢查點抑制劑與溶血性鏈球菌之菌體的組合，或免疫檢查點抑制劑與溶血性鏈球菌之菌體及CXCR2抑制劑的組合。 For the combination of the present invention for cancer patients whose therapeutic effects are insufficient with immune checkpoint inhibitors, a combination of immune checkpoint inhibitors and hemolytic streptococcus bacteria, or immune checkpoint inhibition is preferred. The combination of the agent with hemolytic streptococci bacteria and CXCR2 inhibitor.
針對利用包含溶血性鏈球菌之菌體的製劑所達到之治療效果不充分的癌患者所用之本發明之組合而言，較佳為溶血性鏈球菌之菌體與免疫檢查點抑制劑及/或CXCR2抑制劑的組合。 For the combination of the present invention for cancer patients whose therapeutic effects are insufficient using preparations containing bacterial cells of hemolytic streptococci, the preferred combination is bacterial cells of hemolytic streptococci and immune checkpoint inhibitors and/or Combinations of CXCR2 inhibitors.
針對利用CXCR2抑制劑所達到之治療效果不充分的癌患者所用之本發明之組合而言，較佳為CXCR2抑制劑與溶血性鏈球菌之菌體的組合，或CXCR2抑制劑與溶血性鏈球菌之菌體及免疫檢查點抑制劑的組合。 For the combination of the present invention for cancer patients in whom the therapeutic effects achieved by CXCR2 inhibitors are insufficient, a combination of a CXCR2 inhibitor and hemolytic streptococci, or a combination of a CXCR2 inhibitor and hemolytic streptococci is preferred. A combination of bacteria and immune checkpoint inhibitors.
本發明中之利用免疫檢查點抑制劑所達到之治療效果不充分的癌患者，意指(1)免疫檢查點抑制劑難以奏效的罹癌患者或(2)在利用免疫檢查點抑制劑之治療中惡化或者治療後再復發之癌患者。 In the present invention, cancer patients for whom the therapeutic effect of immune checkpoint inhibitors is insufficient means (1) cancer patients for whom immune checkpoint inhibitors are difficult to respond or (2) patients who are undergoing treatment with immune checkpoint inhibitors. Cancer patients who have worsened or relapsed after treatment.
就本發明中之免疫檢查點抑制劑難以奏效之癌而言，可列舉例如乳癌、胰臟癌、前列腺癌、大腸癌(例如，微衛星安定性大腸癌)，然而不以此等為限。 Cancers for which immune checkpoint inhibitors in the present invention are difficult to respond include, but are not limited to, breast cancer, pancreatic cancer, prostate cancer, and colorectal cancer (eg, microsatellite stable colorectal cancer).
本發明中之利用包含溶血性鏈球菌之菌體的製劑所達到之治療效果不充分的癌患者，意指(1)包含溶血性鏈球菌之菌體的製劑難以奏效的罹癌患者或(2)在利 用包含溶血性鏈球菌之菌體的製劑之治療中惡化或者治療後再復發之癌患者。 In the present invention, the cancer patients for whom the therapeutic effect of the preparation containing the bacterial cells of hemolytic Streptococcus is insufficient means (1) the cancer patients for whom the preparation containing the bacterial cells of hemolytic Streptococcus is difficult to be effective or (2) ) Cancer patients who have worsened during treatment with a preparation containing hemolytic streptococci or have relapsed after treatment.
本發明中之利用CXCR2抑制劑所達到之治療效果不充分的癌患者，意指(1)CXCR2抑制劑難以奏效之罹癌患者或(2)在利用CXCR2抑制劑之治療中惡化或者治療後再復發的癌患者。 In the present invention, cancer patients for whom the therapeutic effect of CXCR2 inhibitors is insufficient means (1) cancer patients for whom CXCR2 inhibitors are difficult to respond or (2) patients who deteriorate during treatment with CXCR2 inhibitors or relapse after treatment. Patients with recurrent cancer.
本發明之組合，就一態樣而言，亦可適用於轉移性癌之治療或轉移之抑制。 The combination of the present invention, in one aspect, can also be applied to the treatment of metastatic cancer or the inhibition of metastasis.
本發明之組合，就一態樣而言，為抑制復發。 The combination of the present invention, in one aspect, inhibits recurrence.
本發明之組合，就一態樣而言，為使癌性胸水、癌性腹水、或浮腫減少。 The combination of the present invention, in one aspect, reduces cancerous pleural effusion, cancerous ascites, or edema.
在本發明中，治療意指產生下述中之至少1種效果：無惡化生存期間(PFS)延長、整體生存期間(OS)之延長、無病生存(DFS)之延長、疾病進展期間(TTP)之延長、無事件生存(EFS)之延長、無復發生存(RFS)之延長、腫瘤大小之降低、腫瘤成長之抑制(延遲或停止)、腫瘤轉移之抑制(延遲或停止)、復發之抑制(防止或延遲)、及與一個或複數個與癌相關之症狀的緩和。 In the present invention, treatment means producing at least one of the following effects: prolongation of progression-free survival (PFS), prolongation of overall survival (OS), prolongation of disease-free survival (DFS), and prolongation of disease progression (TTP). Prolongation of event-free survival (EFS), prolongation of recurrence-free survival (RFS), reduction of tumor size, inhibition of tumor growth (delay or stop), inhibition of tumor metastasis (delay or stop), inhibition of recurrence ( prevent or delay), and alleviation of one or more cancer-related symptoms.
在本發明中，併用投予包含相同或相異劑型中之化合物的同時投予，或者化合物之分別投予(例如，逐次投予)。在本發明中，「組合投予」表示與併用投予相同之意義，更具體而言，可以在同一製劑中調配有全部成分之複合劑形式進行投予，或者亦可採取以個別製劑之形 式進行投予。以個別製劑之形式投予時，包含同時投予及相隔一段時間投予。再者，相隔一段時間投予，可先投予必醫你舒(註冊商標)，再投予其他藥物，亦可先投予其他藥物，然後投予必醫你舒(註冊商標)。各個投予方法可相同亦可相異。 In the present invention, combined administration includes simultaneous administration of compounds in the same or different dosage forms, or separate administration of the compounds (eg, sequential administration). In the present invention, "combination administration" means the same meaning as combined administration. More specifically, it can be administered in the form of a complex preparation containing all the ingredients in the same preparation, or it can be administered in the form of individual preparations. Make the investment. When administered in the form of individual preparations, it includes simultaneous administration and administration at a certain interval. Furthermore, when administered at intervals of some time, you can administer BiomedNexus (registered trademark) first, and then other drugs, or you can administer other drugs first, and then administer BiomedNexu (registered trademark). Each administration method may be the same or different.
在本發明中，本發明之組合為了(1)治療效果之補全及/或增強，(2)動態/吸收之改善、投予量之減低，及/或(3)副作用之減輕，亦可與其他藥物(例如，周知之抗癌劑)組合投予。 In the present invention, the combination of the present invention can also be used to (1) complement and/or enhance the therapeutic effect, (2) improve dynamics/absorption, reduce the dosage, and/or (3) alleviate side effects. Administered in combination with other drugs (eg, well-known anticancer agents).
以下，顯示實施例具體地說明本發明，惟本發明並不是被此等所限定者。 Hereinafter, the present invention will be explained concretely by showing examples, but the present invention is not limited by these.
必醫你舒(註冊商標)注射用5KE(以下稱為必醫你舒(註冊商標)，化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥粉末)係從中外製藥股份有限公司取得。藉由使用菲科爾(Ficoll)之密度梯度離心法從消化道癌患者之末梢血調製末梢血單核細胞。使用CD14微珠粒(MiltenyiBiotec公司)從末梢血單核細胞分離出CD14陽性單核球。以使分離後之細胞的最終濃度成為20ng/mL之方式使用添加有 IL-4及GM-CSF之X-VIVO15培養基(Lonza Japan股份有限公司)，於37℃、5%CO2培育箱中培養5日，使其分化成樹狀細胞。利用最終濃度10μg/mL之必醫你舒(註冊商標)之凍結乾燥粉末刺激分化後之樹狀細胞48小時。將刺激後之樹狀細胞懸浮於添加有最終濃度為2%之牛胎兒血清之PBS(以下稱為FACS緩衝液)後，添加人類Fc受體結合抑制劑(eBioscience公司)，並於4℃反應10分鐘。然後用FACS緩衝液進行洗淨，添加各種樹狀細胞成熟標記(HLA-DR、CD80、CD40、CD86)及PD-L1之螢光色素標識抗體，並於4℃反應15分鐘。然後，用FACS緩衝液進行洗淨，利用LSRFortessaX-20(Becton Dickinson公司製)解析各種標記之表現。解析係將活細胞中之CD3陰性、CD11c陽性、HLA-DR陽性細胞當作樹狀細胞，藉由平均螢光強度(MFI)進行評估。 BiYiNiShu (registered trademark) 5KE for injection (hereinafter referred to as BiYiNisu (registered trademark), freeze-dried powder of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin) is produced by Chugai Pharmaceutical Co., Ltd. obtained by the company. Peripheral blood mononuclear cells were prepared from peripheral blood of patients with gastrointestinal cancer by using Ficoll density gradient centrifugation. CD14-positive monocytes were isolated from peripheral blood mononuclear cells using CD14 microbeads (Miltenyi Biotec). X-VIVO15 medium (Lonza Japan Co., Ltd.) supplemented with IL-4 and GM-CSF was used so that the final concentration of the separated cells would be 20 ng/mL, and cultured in a 37°C, 5% CO2 incubator for 5 day to differentiate into dendritic cells. Stimulate differentiated dendritic cells with freeze-dried powder of Bionisu (registered trademark) at a final concentration of 10 μg/mL for 48 hours. The stimulated dendritic cells were suspended in PBS (hereinafter referred to as FACS buffer) with a final concentration of 2% bovine fetal serum, and human Fc receptor binding inhibitor (eBioscience) was added and reacted at 4°C. 10 minutes. Then wash with FACS buffer, add various dendritic cell maturation markers (HLA-DR, CD80, CD40, CD86) and PD-L1 fluorochrome-labeled antibodies, and react at 4°C for 15 minutes. Then, it was washed with FACS buffer, and the expression of various markers was analyzed using LSRFortessaX-20 (manufactured by Becton Dickinson). The analysis system treats CD3-negative, CD11c-positive, and HLA-DR-positive cells in living cells as dendritic cells and evaluates them by mean fluorescence intensity (MFI).
將結果示於第1圖。藉由必醫你舒(註冊商標)成熟化之樹狀細胞，係在任一癌患者檢體中，均使樹狀細胞成熟標記及PD-L1之細胞表面表現量上升。從上述結果可確認必醫你舒(註冊商標)促進樹狀細胞之成熟化，同時使抑制性信號分子PD-L1之表現上升，而進行過度的免疫反應的抑制。 The results are shown in Figure 1. The dendritic cells matured by BioNix(registered trademark) increased the cell surface expression of dendritic cell maturation markers and PD-L1 in any cancer patient specimen. From the above results, it can be confirmed that Biyi Ni Shu (registered trademark) promotes the maturation of dendritic cells, increases the expression of the inhibitory signaling molecule PD-L1, and suppresses excessive immune responses.
必醫你舒(註冊商標)注射用5KE(以下稱為必醫你舒(註冊商標)，化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥粉末)係從中外製藥股份有限公司取得。屬於抗小鼠PD-1抗體之4H2係使用依照WO2006/121168之實施例12記載的方法而製作者。將來自BALB/c小鼠之大腸癌細胞株CT26皮下移植至同種同系小鼠(BALB/c，雌，6週齡(Clea Japan公司))之右背部，製作出皮下擔癌小鼠。在腫瘤之長徑顯示為6mm之日，根據腫瘤體積實施分群(將腫瘤移植日當作Day0)，對於CT26皮下擔癌小鼠，設定為PBS群(於Day6、9、12、15進行腫瘤內投予，Day6、12進行腹腔內投予，n=7)、必醫你舒(註冊商標)群(於Day6、9、12、15以1KE/個體進行腫瘤內投予，n=7)、抗PD-1抗體4H2群(於Day6、12以200μg/個體進行腹腔內投予，n=7)、必醫你舒，(註冊商標)及抗PD-1抗體併用群(必醫你舒(註冊商標)係於Day6、9、12、15以1KE/個體進行腫瘤內投予，4H2係於Day6、12以200μg/個體進行腹腔內投予，n=7)。持續地測定腫瘤體積之變化至Day17為止。腫瘤體積係藉由下述式計算出。 BiYiNiShu (registered trademark) 5KE for injection (hereinafter referred to as BiYiNisu (registered trademark), freeze-dried powder of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin) is produced by Chugai Pharmaceutical Co., Ltd. obtained by the company. 4H2, which is an anti-mouse PD-1 antibody, was produced according to the method described in Example 12 of WO2006/121168. The colon cancer cell line CT26 derived from BALB/c mice was subcutaneously transplanted into the right back of a syngeneic mouse (BALB/c, female, 6 weeks old (Clea Japan Co., Ltd.)) to create subcutaneous cancer-bearing mice. On the day when the long diameter of the tumor showed to be 6 mm, the groups were grouped according to the tumor volume (the day of tumor transplantation was regarded as Day 0). For the CT26 subcutaneous tumor-bearing mice, the PBS group was set (intra-tumor examination was performed on
[腫瘤體積(mm3)]=[長徑(mm)]×[短徑(mm)]2×0.5 [Tumor volume (mm 3 )] = [Long diameter (mm)] × [Short diameter (mm)] 2 × 0.5
此外，從動物倫理之觀點而言，腫瘤體積 超過2000mm3之個體進行安樂死處置。 In addition, from the perspective of animal ethics, individuals with tumor volume exceeding 2000 mm 3 should be euthanized.
將結果示於第2圖。Day17之腫瘤體積之平均值，相對於PBS群為1628.6mm3，必醫你舒(註冊商標)投予群為1392.4mm3，抗PD-1抗體投予群為1512.2mm3。另一方面，將必醫你舒(註冊商標)與抗PD-1抗體併用時的腫瘤體積之平均值為786.4mm3，相較於各藥劑之單獨投予，確認到強力之併用效果。 The results are shown in Figure 2. The average tumor volume on
從上述結果，可確認在抗PD-1抗體單劑難以顯示有效性之模型中，藉由將必醫你舒(註冊商標)與抗PD-1抗體併用可增強抗腫瘤效果。 From the above results, it was confirmed that in a model in which a single dose of anti-PD-1 antibody is difficult to show efficacy, the anti-tumor effect can be enhanced by combining Biyinisu (registered trademark) with an anti-PD-1 antibody.
必醫你舒(註冊商標)注射用5KE(以下稱為必醫你舒(註冊商標)，化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥粉末)係從中外製藥股份有限公司取得。屬於抗小鼠PD-1抗體之4H2，係使用依照WO2006/121168之實施例12記載之方法所製作者。InvivoMAb Mouse IgG Isotype Control Clone MOPC-21(以下稱為對照IgG)係從 BioXell公司取得。將來自C57/BL6小鼠之大腸癌細胞株MC38皮下移植至同種同系小鼠(C57/BL6，雌，6週齡(Charles River Japan公司))之右側腹部(將移植日當作Day0)，製作MC38皮下擔癌小鼠。移植7日後，根據腫瘤體積實施分群，對於MC38皮下擔癌小鼠，設定對照(Control)群(將對照IgG於Day7、12、18進行腹腔內投予，n=8)、載劑(Vehicle)群(將對照IgG於Day7、12、18進行腹腔內投予，將生理食鹽水於Day7、11、14、17、19、21、24進行腫瘤內投予，n=8)、必醫你舒群(將對照IgG於Day7、12、18進行腹腔內投予，將必醫你舒(註冊商標)於Day7、11、14、17、19、21、24以1KE/個體之用量進行腫瘤內投予，n=8)、4H2群(將4H2於Day7以20mg/kg，於Day12、18以10mg/kg之用量進行腹腔內投予，將生理食鹽液於Day7、11、14、17、19、21、24進行腫瘤內投予，n=12)、併用群(將4H2於Day7以20mg/kg，於Day12、18以10mg/kg之用量進行腹腔內投予，將必醫你舒(註冊商標)於Day7、11、14、17、19、21、24以1KE/個體之用量進行腫瘤內投予，n=8)。持續地測定腫瘤體積之變化至Day49為止。腫瘤體積係藉由下述式計算出。 BiYiNiShu (registered trademark) 5KE for injection (hereinafter referred to as BiYiNisu (registered trademark), freeze-dried powder of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin) is produced by Chugai Pharmaceutical Co., Ltd. obtained by the company. 4H2, which is an anti-mouse PD-1 antibody, was produced using the method described in Example 12 of WO2006/121168. InvivoMAb Mouse IgG Isotype Control Clone MOPC-21 (hereinafter referred to as control IgG) was obtained from BioXell. The colon cancer cell line MC38 derived from C57/BL6 mice was subcutaneously transplanted into the right abdomen of a syngeneic mouse (C57/BL6, female, 6 weeks old (Charles River Japan Co., Ltd.)) (the transplantation day was regarded as Day 0), and the production MC38 subcutaneous cancer-bearing mice. Seven days after transplantation, groups were divided according to tumor volume. For MC38 subcutaneous tumor-carrying mice, a control group (Control IgG was administered intraperitoneally on
[腫瘤體積(mm3)]=[長徑(mm)]×[短徑(mm)]2×0.5 [Tumor volume (mm 3 )] = [Long diameter (mm)] × [Short diameter (mm)] 2 × 0.5
此外，從動物倫理之觀點而言，腫瘤體積超過1500mm3之個體進行安樂死處置。在成為安樂死處置之對象的個體達到群之半數時，結束該群之評估。 In addition, from the perspective of animal ethics, individuals with tumor volume exceeding 1500 mm 3 should be euthanized. When the number of individuals targeted for euthanasia reaches half of the group, the evaluation of the group ends.
將結果示於第3圖。Day34中之腫瘤體積之中央值，相對於4H2群為480.5mm3，必醫你舒(註冊商標)群為294.7mm3。另一方面，併用群為38.1mm3，相較於各藥劑之單獨投予，確認到強力併用效果。再者，4H2或必醫你舒(註冊商標)之單獨投予，可確認到腫瘤消失之個體分別為4/12例及2/8例，而在4H2與必醫你舒(註冊商標)併用為4/8例。 The results are shown in Figure 3. The median tumor volume in Day34 was 480.5mm 3 in the 4H2 group and 294.7mm 3 in the Biyi Ni Shu (registered trademark) group. On the other hand, the combined group was 38.1 mm 3 , and compared with the individual administration of each agent, a stronger combined effect was confirmed. Furthermore, when 4H2 or BiNexu (registered trademark) was administered alone, the number of individuals with confirmed tumor disappearance was 4/12 cases and 2/8 cases respectively, while in 4H2 when it was administered together with BiNisu (registered trademark) For 4/8 cases.
從上述結果，可確認到即使在抗PD-1抗體單劑或必醫你舒(註冊商標)單劑顯示有效性之模型中，必醫你舒(註冊商標)與抗PD-1抗體之併用可發揮強力的抗腫瘤效果。 From the above results, it was confirmed that even in a model in which a single dose of an anti-PD-1 antibody or a single dose of Bionisu (registered trademark) showed efficacy, the combined use of Bionisu (registered trademark) and an anti-PD-1 antibody Can exert powerful anti-tumor effect.
必醫你舒(註冊商標)注射用5KE(以下稱為必醫你舒(註冊商標)，化膿性鏈球菌(A群3型)Su株經青黴素處理之凍結乾燥粉末)係從中外製藥股份有限公司取得。屬於抗小鼠PD-1抗體之4H2，係使用依照WO2006/121168之實施例12記載之方法所製作者。屬於CXCR2抑制劑之SB225002，係從Selleck公司取得。將來自BALB/c小鼠 之大腸癌細胞株CT26-NY-ESO-1皮下移植至同種同系小鼠(BALB/c，雌，6週齡(Clea Japan公司))之右背部，製成皮下擔癌小鼠。在腫瘤之長徑顯示各個體的平均值為約6mm之日，根據腫瘤體積實施分群(將腫瘤移植日當作Day0)，對於CT26-NY-ESO-1皮下擔癌小鼠，設定PBS群(於Day8、11、14進行腫瘤內投予，Day8、14、22、28進行腹腔內投予，n=7)、必醫你舒(註冊商標)群(於Day8、11、14以0.5KE/個體進行腫瘤內投予，n=7)、抗PD-1抗體群(於Day8、14、22、28以200μg/個體進行腹腔內投予，n=7)、CXCR2抑制劑群(以7mg/Kg，從Day6至Day15進行腹腔內投予，n=6)、必醫你舒(註冊商標)與CXCR2抑制劑併用群(必醫你舒(註冊商標)係於Day8、11、14進行0.5KE/個體腫瘤內投予，CXCR2抑制劑係以7mg/Kg從Day6至Day15進行腹腔內投予，n=7)、必醫你舒(註冊商標)與抗PD-1抗體併用群(必醫你舒(註冊商標)係於Day8、11、14進行0.5KE/個體腫瘤內投予，4H2係於Day8、14、22、28進行200μg/個體腹腔內投予)、必醫你舒(註冊商標)與抗PD-1抗體及CXCR2抑制劑併用群(必醫你舒(註冊商標)係於Day8、11、14進行0.5KE/個體腫瘤內投予，4H2係於Day8、14、22、28進行200μg/個體腹腔內投予，CXCR2抑制劑係以7mg/Kg從Day6至Day15進行腹腔內投予，n=7)。持續地測定腫瘤體積之變化至腫瘤移植後第32日為止。腫瘤體積係藉由下述式計算出。 BiYiNiShu (registered trademark) 5KE for injection (hereinafter referred to as BiYiNisu (registered trademark), freeze-dried powder of Streptococcus pyogenes (group A type 3) Su strain treated with penicillin) is produced by Chugai Pharmaceutical Co., Ltd. obtained by the company. 4H2, which is an anti-mouse PD-1 antibody, was produced using the method described in Example 12 of WO2006/121168. SB225002, a CXCR2 inhibitor, was obtained from Selleck Company. The colon cancer cell line CT26-NY-ESO-1 derived from BALB/c mice was subcutaneously transplanted into the right back of a syngeneic mouse (BALB/c, female, 6 weeks old (Clea Japan Co., Ltd.)) to make a subcutaneous tumor. cancer mice. On the day when the long diameter of the tumor showed that the average of each individual was about 6 mm, the groups were divided according to the tumor volume (the day of tumor transplantation was regarded as Day 0). For the CT26-NY-ESO-1 subcutaneous tumor-bearing mice, the PBS group was set ( Intra-tumor administration was performed on Days 8, 11, and 14, intraperitoneal administration was performed on Days 8, 14, 22, and 28, n=7), Biyi Nishu (registered trademark) group (0.5KE/ Individuals were administered intratumorally, n=7), anti-PD-1 antibody group (intraperitoneally administered at 200 μg/individual on Days 8, 14, 22, and 28, n=7), CXCR2 inhibitor group (administered intraperitoneally at 7 mg/ Kg, administered intraperitoneally from Day 6 to Day 15, n = 6), a group of co-administration of BiNiShu (registered trademark) and CXCR2 inhibitors (BiNiSu (Registered Trademark) was administered on Days 8, 11, and 14 for 0.5KE /Intra-tumor administration to individual, CXCR2 inhibitor was administered intraperitoneally from Day 6 to Day 15 at 7 mg/Kg, n=7), Biyi Ni Shu (registered trademark) and anti-PD-1 antibody combination group (Bi Yi Ni Shu) Shu (registered trademark) is administered intra-tumorally at 0.5 KE/individual on Days 8, 11, and 14, 4H2 is administered intraperitoneally at 200 μg/individual on Days 8, 14, 22, and 28), Biyi Ni Shu (registered trademark) The group used in combination with anti-PD-1 antibodies and CXCR2 inhibitors (Biyi Nishu (registered trademark)) was administered intratumorally at 0.5KE/individual on Days 8, 11, and 14, and 4H2 was administered at 200 μg on Days 8, 14, 22, and 28. /Individual intraperitoneal administration, CXCR2 inhibitor was administered intraperitoneally from Day6 to Day15 at 7 mg/Kg, n=7). The changes in tumor volume were continuously measured until the 32nd day after tumor transplantation. Tumor volume was calculated by the following formula.
[腫瘤體積(mm3)]=[長徑(mm)]×[短徑(mm)]2×0.5 [Tumor volume (mm 3 )] = [Long diameter (mm)] × [Short diameter (mm)] 2 × 0.5
此外，從動物倫理之觀點而言，腫瘤體積超過3000mm3之個體進行安樂死處置。 In addition, from the perspective of animal ethics, individuals with tumor volume exceeding 3000 mm 3 should be euthanized.
將結果示於第4圖。Day32之腫瘤體積的中央值，於對照群為2857.7mm3，於CXCR2抑制劑群為2328.9mm3，於必醫你舒(註冊商標)群為2382.7mm3。另一方面，於必醫你舒(註冊商標)與CXCR2抑制劑併用群為1774.9mm3，相較於各藥劑之單獨投予，確認到強力併用效果。再者，相對於必醫你舒(註冊商標)與抗PD-1抗體併用群之腫瘤體積的中央值為900.5mm3，於必醫你舒(註冊商標)與抗PD-1抗體及CXCR2抑制劑3劑併用群為271.4mm3。從上述結果，確認到必醫你舒(註冊商標)與抗PD-1抗體及CXCR2抑制劑之3劑併用，比必醫你舒(註冊商標)與抗PD-1抗體之2劑併用發揮更強力的抗腫瘤效果。 The results are shown in Figure 4. The median tumor volume on Day32 was 2857.7mm 3 in the control group, 2328.9mm 3 in the CXCR2 inhibitor group, and 2382.7mm 3 in the Biyi Nishu (registered trademark) group. On the other hand, the group of 1774.9 mm 3 of the combined use of Biyinisu (registered trademark) and CXCR2 inhibitor showed a strong combined effect compared to the individual administration of each agent. Furthermore, compared to the median tumor volume of the group using Bionisu (registered trademark) and anti-PD-1 antibody in combination, the median value of tumor volume was 900.5 mm 3 . The group using three agents together is 271.4mm 3 . From the above results, it was confirmed that the combined use of three doses of Bionisu (registered trademark), anti-PD-1 antibody and CXCR2 inhibitor is more effective than the combined use of two doses of Bionisu (registered trademark) and anti-PD-1 antibody. Powerful anti-tumor effect.
藉由上述實施例，PD-1路徑抑制劑及/或CXCR2抑制劑與必醫你舒(註冊商標)之併用，明顯地發揮相乘的抗腫瘤效果，在作為癌治療之組合上有用。 Through the above embodiments, the combined use of PD-1 pathway inhibitors and/or CXCR2 inhibitors and BiNexu (registered trademark) clearly exerts synergistic anti-tumor effects and is useful as a combination for cancer treatment.
本發明之組合，由於發揮強力抗腫瘤效果，故在癌治療上有用。 The combination of the present invention exerts a strong anti-tumor effect and is therefore useful in cancer treatment.
序列編號1：保疾伏_VH Serial number 1: Baojifu_VH
序列編號2：保疾伏_VL Serial number 2: Baojifu_VL
序列編號3：保疾伏_VH CDR1 Serial number 3: Baojifu_VH CDR1
序列編號4：保疾伏_VH CDR2 Serial number 4: Baojifu_VH CDR2
序列編號5：保疾伏_VH CDR3 Serial number 5: Baojifu_VH CDR3
序列編號6：保疾伏_VL CDR1 Serial number 6: Baojifu_VL CDR1
序列編號7：保疾伏_VL CDR2 Serial number 7: Baojifu_VL CDR2
序列編號8：保疾伏_VL CDR3 Serial number 8: Baojifu_VL CDR3
<110> 日商小野藥品工業股份有限公司 <110> Nissho Ono Pharmaceutical Co., Ltd.
<120> 一種治療癌症的方法，包括含有溶血性鏈球菌之菌體的製劑與免疫檢查點抑製劑的組合投予 <120> A method of treating cancer, comprising the combined administration of a preparation containing hemolytic streptococci and an immune checkpoint inhibitor
<130> P180279TW <130> P180279TW
<150> JP 2017-129585 <150> JP 2017-129585
<151> 2017-06-30 <151> 2017-06-30
<160> 8 <160> 8
<210> 1 <210> 1
<211> 113 <211> 113
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 1 
<210> 2 <210> 2
<211> 107 <211> 107
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 2 
<210> 3 <210> 3
<211> 5 <211> 5
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 3 
<210> 4 <210> 4
<211> 17 <211> 17
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 4 
<210> 5 <210> 5
<211> 4 <211> 4
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 5 
<210> 6 <210> 6
<211> 11 <211> 11
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 6 
<210> 7 <210> 7
<211> 7 <211> 7
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 7 
<210> 8 <210> 8
<211> 9 <211> 9
<212> PRT <212> PRT
<213> 智人 <213> Homo sapiens
<400> 8 
本案之圖式皆為實驗數據圖，不足以代表本案發明，故本案無指定代表圖。 The diagrams in this case are all experimental data diagrams and are not sufficient to represent the invention in this case, so there is no designated representative diagram in this case.
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