TW202126302A - Use of ezh2 inhibitor in combination with immune checkpoint inhibitor for preparation of medicament for treating tumor diseases - Google Patents
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本公開涉及EZH2抑制劑與免疫檢查點抑制劑、多靶點酪胺酸激酶抑制聯合在製備治療腫瘤的藥物中的用途。 The present disclosure relates to the use of the combination of EZH2 inhibitors, immune checkpoint inhibitors, and multi-target tyrosine kinase inhibition in the preparation of drugs for treating tumors.
蛋白質程序性死亡1(PD-1)是CD28、受體家族的抑制性成員,該家族還包括CD28、CTLA-4、ICOS和BTLA。PD-1在活化的B細胞、T細胞和髓樣細胞上表達。根據加入單株抗體後對提升T細胞增殖的功能性影響發現了家族最初的成員,CD28和ICOS。藉由在凋亡細胞中篩選差異表達發現了PD-1。目前,已有小野公司的Nivolumab及Merck公司的Pembrolizumab成功獲批上市,用於治療不可切除或轉移性黑色素瘤、非小細胞肺癌、晚期腎細胞癌、霍奇金淋巴瘤、復發性或轉移性鱗狀細胞癌等。PD-1有兩個配體,分別為PD-L1和PD-L2。PD-L1主要表達於T細胞、B細胞、巨噬細胞和樹突狀細胞(dendritic cell,DC)上,在活化後細胞上的表達能夠進行上調。PD-L1藉由和PD-1及B7-1的結合抑制免疫系 統,很多腫瘤細胞及腫瘤組織微環境的免疫細胞表達PD-L1。新的研究發現乳腺癌、肺癌、胃癌、腸癌、腎癌、黑素瘤、非小細胞肺癌、結腸癌、膀胱癌、卵巢癌、胰腺癌及肝癌等人類腫瘤組織中檢測到高PD-L1蛋白的表達,且PD-L1的表達水平和患者的臨床及預後緊密相關。 Protein programmed death 1 (PD-1) is an inhibitory member of the CD28, receptor family, which also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed on activated B cells, T cells and myeloid cells. The first members of the family, CD28 and ICOS, were discovered based on the functional effect of the addition of monoclonal antibodies on the promotion of T cell proliferation. PD-1 was discovered by screening for differential expression in apoptotic cells. Currently, Ono’s Nivolumab and Merck’s Pembrolizumab have been successfully approved for the market for the treatment of unresectable or metastatic melanoma, non-small cell lung cancer, advanced renal cell carcinoma, Hodgkin’s lymphoma, recurrent or metastatic disease Squamous cell carcinoma and so on. PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is mainly expressed on T cells, B cells, macrophages and dendritic cells (dendritic cells, DC), and the expression on cells can be up-regulated after activation. PD-L1 inhibits the immune system by binding to PD-1 and B7-1 In general, many tumor cells and immune cells in the tumor tissue microenvironment express PD-L1. New research found high PD-L1 was detected in human tumor tissues such as breast cancer, lung cancer, stomach cancer, bowel cancer, kidney cancer, melanoma, non-small cell lung cancer, colon cancer, bladder cancer, ovarian cancer, pancreatic cancer and liver cancer. The expression of protein and the expression level of PD-L1 are closely related to the clinical and prognosis of patients.
EZH2基因編碼的組蛋白甲基轉移酶是多梳蛋白抑制性複合體2(PRC2)的催化組分。與正常組織相比,EZH2水平在癌組織異常升高,而在癌症晚期或不良預後中,EZH2的表達水平最高。在一些癌症類型中,EZH2表達過剩與EZH2基因的擴增同時發生。大量si/shRNA實驗研究發現在腫瘤細胞系中減少EZH2表達,可抑制腫瘤細胞的增殖,遷移和侵襲或血管生成,並導致細胞凋亡。 The histone methyltransferase encoded by EZH2 gene is the catalytic component of Polycomb inhibitory complex 2 (PRC2). Compared with normal tissues, the level of EZH2 is abnormally increased in cancer tissues, and the expression level of EZH2 is the highest in advanced cancer or poor prognosis. In some cancer types, overexpression of EZH2 occurs simultaneously with amplification of the EZH2 gene. A large number of si/shRNA experimental studies have found that reducing EZH2 expression in tumor cell lines can inhibit tumor cell proliferation, migration and invasion or angiogenesis, and lead to cell apoptosis.
目前已有進入臨床開發階段的EZH2抑制劑,以下簡要列舉,衛材開發的Tazemetostat(EPZ-6438)用於治療非霍奇金B細胞淋巴瘤,目前處於臨床Ⅱ期階段,Constellation公司開發的CPI-1205用於治療B細胞淋巴瘤,目前處於臨床I期階段,葛蘭素史克公司開發的GSK-2816126用於治療彌漫大B細胞淋巴瘤、濾泡性淋巴瘤,目前處於臨床I期階段。 At present, EZH2 inhibitors have entered the clinical development stage. The following is a brief list. Tazemetostat (EPZ-6438) developed by Eisai is used for the treatment of non-Hodgkin B-cell lymphoma. It is currently in phase II clinical phase. CPI developed by Constellation -1205 is used to treat B-cell lymphoma and is currently in clinical phase I. GSK-2816126 developed by GlaxoSmithKline is used to treat diffuse large B-cell lymphoma and follicular lymphoma and is currently in clinical phase I.
WO2017084494A中提供了一種EZH2抑制劑,結構如下所示: WO2017084494A provides an EZH2 inhibitor, the structure is as follows:
Lu Gan等的綜述中提到了EZH2在腫瘤免疫中的新興作用(Biomarker Research,December 2018,6:10)。 The review by Lu Gan et al. mentioned the emerging role of EZH2 in tumor immunity (Biomarker Research, December 2018, 6:10).
酪胺酸激酶抑制劑(TKIs)的抗腫瘤作用機制可能藉由以下途徑實現:抑制腫瘤細胞的損傷修復、使細胞分裂阻滯在G1期、誘導和維持細胞凋亡、抗新生血管形成等。EGFR過度表達常預示病人預後差、轉移快、對化療藥物抗拒、激素耐藥、生存期較短等。FDA已批准多種多靶點TKIs上市,如:索拉非尼(sorafenib)、凡德他尼(vandetanib)和舒尼替尼(Sunitinib)(Sutent,SU-11248)等。WO2007085188公開了一種與Sunitinib類似的化合物,如下式(II)所示,其可能更好地應用於上述腫瘤的治療。該化合物化學名為5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1,2-二氫-吲哚-3-亞基-甲基)-3-甲基-1,5,6,7-四氫-吡咯[3,2-c]吡啶-4-酮,已知其具有抑制參與腫瘤增殖和血管生成,能夠選擇性抑制血管內皮生長因子(VEGF)受體的激酶活性,臨床上可用於腎癌、胃腸間質瘤、結直腸癌和胰腺神經內分泌瘤等多種腫瘤的治療, The anti-tumor mechanism of tyrosine kinase inhibitors (TKIs) may be achieved through the following ways: inhibiting tumor cell damage and repair, blocking cell division in the G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis. Overexpression of EGFR often indicates poor prognosis, rapid metastasis, resistance to chemotherapy drugs, hormone resistance, and shorter survival time. The FDA has approved a variety of multi-target TKIs, such as sorafenib, vandetanib, and sunitinib (Sutent, SU-11248). WO2007085188 discloses a compound similar to Sunitinib, as shown in the following formula (II), which may be better applied to the treatment of the above-mentioned tumors. The chemical name of the compound is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)- 3-Methyl-1,5,6,7-tetrahydro-pyrrole [3,2-c]pyridin-4-one, which is known to inhibit tumor proliferation and angiogenesis, and can selectively inhibit vascular endothelial growth factor The kinase activity of (VEGF) receptors can be used clinically for the treatment of renal cancer, gastrointestinal stromal tumors, colorectal cancer and pancreatic neuroendocrine tumors.
WO2018068691公開了一種抗PD-1抗體和VEGFR抑制劑聯合在製備治療癌症的藥物中的用途。 WO2018068691 discloses the use of a combination of an anti-PD-1 antibody and a VEGFR inhibitor in the preparation of a medicine for the treatment of cancer.
WO2019097369A公開了一種向患者施用EZH2抑制劑和鉑基抗腫瘤劑聯用治療癌症的方法,進一步還可以施用其他抗癌劑,該其他抗癌劑可選自抗PD-1抗體,抗PD-L1抗體和抗CTLA-4的抗體等。 WO2019097369A discloses a method for administering an EZH2 inhibitor and a platinum-based anti-tumor agent to a patient in combination to treat cancer. Further, other anti-cancer agents can be administered, and the other anti-cancer agents can be selected from anti-PD-1 antibodies and anti-PD-L1 Antibodies and anti-CTLA-4 antibodies, etc.
WO2018223030A實施例1公開針對上皮樣肉瘤和腎髓樣癌患者的組織檢測發現EZH2抑制後PD-L1會發生上調,數據表明這些腫瘤被引發由於腫瘤中存在T細胞介導的免疫應答,但是免疫應答可能受到腫瘤中PD-L1表達增加的抑制,這表明這種腫瘤可藉由EZH2抑制和PD-1/PD-L1抑制的組合來治療。實施例2中針對軟組織肉瘤的患者給與他澤司他(tazemetostat)和阿特珠單抗(atezolizumab)的組合治療,但未公開具體藥效信息。 WO2018223030A Example 1 discloses tissue testing for patients with epithelioid sarcoma and renal medullary carcinoma and found that PD-L1 will be up-regulated after EZH2 inhibition. The data indicate that these tumors are triggered due to the presence of T cell-mediated immune responses in the tumors, but the immune response It may be inhibited by the increased expression of PD-L1 in tumors, indicating that this tumor can be treated by a combination of EZH2 inhibition and PD-1/PD-L1 inhibition. In Example 2, patients with soft tissue sarcoma were given a combination therapy of tazemetostat and atezolizumab, but no specific drug efficacy information was disclosed.
WO2017210395A要求保護一種在有需要的受試者中治療癌症的方法,包括向該受試者施用治療有效量的EZH2抑制劑和治療有效量的免疫檢查點抑制劑,該的免疫檢查點抑制劑可選抗PD-L1抗體,實施例公開了他澤司他(tazemetostat)和阿特珠單抗(atezolizumab)聯用針對局部晚期或轉移性尿路上皮癌患者、彌漫性大B細胞淋巴瘤患者及非霍奇金淋巴瘤的治療方案,但是未給出具體的藥效信息。 WO2017210395A claims a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of an immune checkpoint inhibitor, the immune checkpoint inhibitor can The anti-PD-L1 antibody is selected. The examples disclose the combination of tazemetostat and atezolizumab for patients with locally advanced or metastatic urothelial cancer, patients with diffuse large B-cell lymphoma, and The treatment plan for non-Hodgkin's lymphoma, but no specific information on the efficacy is given.
本公開中提供一種EZH2抑制劑與免疫檢查點抑制劑、多靶點酪胺酸激酶抑制劑聯合在製備治療腫瘤的藥物中的用途。 The present disclosure provides a use of an EZH2 inhibitor, an immune checkpoint inhibitor, and a multi-target tyrosine kinase inhibitor in the preparation of a drug for treating tumors.
某些實施方案中,本公開中該的EZH2抑制劑可選自CPI-0209、CPI-1205、GSK126、瓦勒司他(valemetostat)、他澤司他(tazemetostat)、PF-06821497、DS-3201 GSK-2816126、3-去氮腺嘌呤A(3-deazaneplanocin A)、HKMT-I-005、KM-301中的至少一種。 In certain embodiments, the EZH2 inhibitor in the present disclosure may be selected from CPI-0209, CPI-1205, GSK126, valemetostat, tazemetostat, PF-06821497, DS-3201 At least one of GSK-2816126, 3-deazaneplanocin A, HKMT-I-005, and KM-301.
某些實施方案中,本公開中所述EZH2抑制劑為式(I)所示化合物或其可藥用鹽, In certain embodiments, the EZH2 inhibitor described in the present disclosure is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
本公開中式(I)所示化合物可藥用鹽可以是鹽酸鹽、磷酸鹽、磷酸氫鹽、硫酸鹽、硫酸氫鹽、亞硫酸鹽、乙酸鹽、草酸鹽、丙二酸鹽、戊酸鹽、谷胺酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、對甲苯磺酸鹽、甲磺酸鹽、羥乙基磺酸鹽、馬來酸鹽、蘋果酸鹽、酒石酸鹽、苯甲酸鹽、雙羥萘酸鹽、水楊酸鹽、香草酸鹽、扁桃酸鹽、琥珀酸鹽、葡萄糖酸鹽、乳糖酸鹽或月桂基磺酸鹽等。 The pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, pentane Acid salt, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate , Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonate, etc. .
某些實施方案中,本公開中所述的免疫檢查點抑制劑可以為抗PD-1抗體或者其抗原結合片段。 In certain embodiments, the immune checkpoint inhibitor described in the present disclosure may be an anti-PD-1 antibody or an antigen-binding fragment thereof.
某些實施方案中,本公開中所述的抗PD-1抗體或者其抗原結合片段可選信迪利單抗(sintilimab)、西米普利單抗(cemiplimab)、JS-001、納武單抗(nivolumab)、替雷利珠單抗(tislelizumab)、匹博利珠單抗(pembrolizumab)、AK-103、多西林單抗(dostarlimab)、PD1-PIK、GLS-010、杰諾單抗(genolimzumab)、BI-754091、司帕利珠單抗(spartalizumab)、MGA-012、PF-06801591、XmAb-20717、CS-1003、Sym-021、AGEN-2034、MEDI-5752、MGD-013、AK-105、AK-104、BCD-100、PF-06753512、HLX-10、AMP-224、LZM-009中的至少一種。 In certain embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present disclosure can be selected from sintilimab, cemiprimab, JS-001, nivolumab Anti-(nivolumab), tislelizumab, pebrolizumab, AK-103, dostarlimab, PD1-PIK, GLS-010, genolimzumab ), BI-754091, spartalizumab, MGA-012, PF-06801591, XmAb-20717, CS-1003, Sym-021, AGEN-2034, MEDI-5752, MGD-013, AK- At least one of 105, AK-104, BCD-100, PF-06753512, HLX-10, AMP-224, LZM-009.
在某些實施方式中,本公開中所述的PD-1抗體的輕鏈可變區包含分別如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的 LCDR1、LCDR2和LCDR3,該PD-1抗體的重鏈可變區包含分別如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。 In certain embodiments, the light chain variable region of the PD-1 antibody described in the present disclosure comprises the variable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively. LCDR1, LCDR2 and LCDR3, the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively.
其中,前面所述的各CDR序列如下表1所示: Among them, the aforementioned CDR sequences are shown in Table 1 below:
較佳的,該PD-1抗體為人源化抗體或其片段。 Preferably, the PD-1 antibody is a humanized antibody or a fragment thereof.
在可選實施方案中,本公開中述抗PD-1抗體或其抗原結合片段選自由Fab,Fab’-SH,Fv,scFv,和(Fab’)2片段組成的組的抗體片段。 In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
免疫球蛋白可以來源於任何通常已知的同種型,包括但不限於IgA、分泌型IgA、IgG和IgM。IgG亞類也是本領域技術人員眾所周知的,包括但不限於IgG1、IgG2、IgG3和IgG4。“同種型”是指由重鏈恆定區基因編碼的Ab種類或亞類(例如,IgM或IgG1)。在一些可選實施方案中,本公開中所述抗PD-1抗體或其抗原結合片段包含人源IgG1、IgG2、IgG3或IgG4同種型的重鏈恆定區,較佳包含IgG1或IgG4同種型的重鏈恆定區。 Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM. The IgG subclass is also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the Ab class or subclass (for example, IgM or IgG1) encoded by the heavy chain constant region gene. In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably comprising IgG1 or IgG4 isotype. Constant region of the heavy chain.
在另一些可選實施方案中,該抗PD-1抗體或其抗原結合片段包含κ或λ的輕鏈恆定區的輕鏈恆定區。 In other alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.
進一步地,較佳人源化抗體輕鏈可變區序列為如SEQ ID NO:10所示的序列或其變體,該變體較佳在輕鏈可變區有0-10的胺基酸變化,更佳為A43S的胺基酸變化;該人源化抗體重鏈可變區序列為如SEQ ID NO:9所示的序列或其變體,該變體較佳在重鏈可變區有0-10的胺基酸變化,更佳為G44R的胺基酸變化。 Further, the preferred humanized antibody light chain variable region sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has 0-10 amino acid changes in the light chain variable region , More preferably the amino acid change of A43S; the humanized antibody heavy chain variable region sequence is the sequence shown in SEQ ID NO: 9 or a variant thereof, and the variant preferably has a heavy chain variable region The amino acid change of 0-10 is more preferably the amino acid change of G44R.
前述的人源化抗體重、輕鏈的序列如下所示: The sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:
重鏈可變區 Heavy chain variable region
SEQID NO:9 SEQID NO: 9
輕鏈可變區 Light chain variable region
SEQID NO:10 SEQID NO: 10
較佳的,該人源化抗體輕鏈序列為如SEQ ID NO:8所示的序列或其變體;該變體較佳在輕鏈可變區有0-10的胺基酸變化,更佳為A43S的胺基酸變化;該人源化抗體重鏈序列為如SEQ ID NO:7所示的序列或其變體,該變體較佳在重鏈可變區有0-10的胺基酸變化,更佳為G44R的胺基酸變化。 Preferably, the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; this variant preferably has an amino acid change of 0-10 in the light chain variable region, and more Preferably, the amino acid change of A43S; the humanized antibody heavy chain sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has 0-10 amines in the variable region of the heavy chain The base acid change is more preferably the amino acid change of G44R.
在某些實施方式中,該人源化抗體的輕鏈序列為如SEQ ID NO:8所示的序列,重鏈序列為如SEQ ID NO:7所示的序列。 In some embodiments, the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8, and the heavy chain sequence is the sequence shown in SEQ ID NO: 7.
該人源化抗體重、輕鏈的序列如下所示: The sequences of the heavy and light chains of the humanized antibody are as follows:
重鏈 Heavy chain
SEQID NO:7 SEQID NO: 7
輕鏈 Light chain
SEQID NO:8 SEQID NO: 8
在某些實施方式中,該多靶點酪胺酸激酶抑制可選自舒尼替尼(Sunitinib)、帕唑帕尼(Pazopanib)、樂伐替尼(Lenvatinib)、瑞戈菲尼(Regorafenib)、卡博替尼(Cabozantinib)、多韋替尼(Dovitinib)、索拉菲尼(Sorafenib)、凡得他尼(Vandetanib)、克唑替尼(Crizotinib)、安羅替尼(Anlotinib)、普納替尼(Ponatinib)、伊瑪替尼(Imatinib)、ENMD-2076、阿法替尼(Afatinib)、達沙替尼(Dasatinib)、尼達尼布(nintedanib)中的至少一種。 In certain embodiments, the multi-target tyrosine kinase inhibition may be selected from the group consisting of Sunitinib, Pazopanib, Lenvatinib, Regorafenib , Cabozantinib, Dovitinib, Sorafenib, Vandetanib, Crizotinib, Anlotinib, General At least one of Ponatinib, Imatinib, ENMD-2076, Afatinib, Dasatinib, and nintedanib.
在某些實施方案中,該多靶點酪胺酸激酶抑制劑為式(II)所示化合物或其可藥用鹽, In some embodiments, the multi-target tyrosine kinase inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
本公開中,式(II)所示化合物可藥用鹽可以是鹽酸鹽、磷酸鹽、磷酸氫鹽、硫酸鹽、硫酸氫鹽、亞硫酸鹽、乙酸鹽、草酸鹽、丙二酸鹽、戊酸鹽、谷胺酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、對甲苯磺酸鹽、甲磺酸鹽、羥乙基磺酸鹽、馬來酸鹽、蘋果酸鹽、酒石酸鹽、苯甲酸鹽、雙羥萘酸鹽、水楊酸鹽、香草酸鹽、扁桃酸鹽、琥珀酸鹽、葡萄糖酸鹽、乳糖酸鹽或月桂基磺酸鹽等,可選的實施方案中式(II)所示化合物可藥用鹽為蘋果酸鹽。 In the present disclosure, the pharmaceutically acceptable salt of the compound represented by formula (II) may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, and malonate. , Valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate Acid salt, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonic acid Salt, etc. In an alternative embodiment, the pharmaceutically acceptable salt of the compound represented by formula (II) is malate.
在某些實施方案中,該EZH2的給藥劑量選自1-1600mg,例如:10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、 150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg、500mg、510mg、520mg、530mg、540mg、550mg、560mg、570mg、580mg、590mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg、1025mg、1050mg、1075mg、1100mg、1125mg、1150mg、1175mg、1200mg、1225mg、1250mg、1275mg、1300mg、1325mg、1350mg、1375mg、1400mg、1425mg、1450mg、1475mg、1500mg、1525mg、1550mg、1575mg、1600mg,給藥頻次為每天2次,每天1次,每2天1次,每3天一次,每4天一次,每5天一次,每6天一次,每週一次,每2週一次,每3週一次或每4週一次,較佳每天2次或每天1次。 In some embodiments, the dosage of EZH2 is selected from 1 to 1600 mg, for example: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg , 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, the frequency of administration is 2 times a day, once a day, once every 2 days, Once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks, preferably twice a day or once a day.
在某些實施方案中,該EZH2的給藥劑量選自1-800mg,給藥頻次為每天2次,每天1次,每2天1次,每3天一次,每4天一次,每5天一次,每6天一次,每週一次,每2週一次,每3週一次或每4週一次,較佳每天2次或每天1次。 In some embodiments, the dosage of EZH2 is selected from 1-800mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, every 5 days Once, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks, preferably twice a day or once a day.
在某些實施方案中,該EZH2的給藥劑量選自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg,給藥頻次為每天2次,每天1次,每2天1次,每3天一次,每4天一次,每5天一次,每6天 一次,每週一次,每2週一次,每3週一次或每4週一次,較佳每天2次或每天1次。 In some embodiments, the dosage of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, every 6 days Once, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks, preferably twice a day or once a day.
在某些實施方案中,該EZH2的給藥劑量選自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg,給藥頻次為每天2次或每天1次。 In some embodiments, the dosage of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, and the frequency of administration is It is 2 times a day or 1 time a day.
在某些實施方案中,該EZH2的給藥劑量選自150mg、200mg、250mg、300mg、350mg、400mg、450mg,給藥頻次為每天2次,每天1次,每2天1次,每3天一次,每4天一次,每5天一次,每6天一次,每週一次,每2週一次,每3週一次或每4週一次。 In some embodiments, the dosage of EZH2 is selected from 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, every 3 days Once, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks.
在某些實施方案中,該EZH2的給藥劑量選自150mg、200mg、250mg、300mg、350mg、400mg、450mg,給藥頻次為每天2次或每天1次。 In some embodiments, the dosage of EZH2 is selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, and the frequency of administration is twice a day or once a day.
在一些實施方案中,該免疫檢查點抑制劑的給藥劑量可以在以下範圍內:0.1-10.0mg/kg、0.1-5mg/kg、1-5mg/kg、2-5mg/kg,例如,劑量可以是0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、 8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg,給藥頻次為每週一次、每2週一次、每3週一次、每4週一次、1個月一次、每3-6個月或更長一次的給藥頻次施用。 In some embodiments, the administration dose of the immune checkpoint inhibitor may be in the following range: 0.1-10.0 mg/kg, 0.1-5 mg/kg, 1-5 mg/kg, 2-5 mg/kg, for example, the dose It can be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/ kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/ kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/ kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/ kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg, the frequency of administration is once a week, every 2 It is administered at a frequency of once a week, once every 3 weeks, once every 4 weeks, once a month, once every 3-6 months or longer.
在一些實施方案中,該免疫檢查點抑制劑的劑量範圍選自1-1000mg、80-800mg、80-700mg、80-600mg、80-500mg、80-400mg、80-300mg、100-300mg或200-300mg。例如,劑量可以是1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、 525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg,給藥頻次為每週一次、每2週一次、每3週一次、每4週一次、1個月一次、每3-6個月或更長一次的給藥頻次施用。 In some embodiments, the dose range of the immune checkpoint inhibitor is selected from 1-1000 mg, 80-800 mg, 80-700 mg, 80-600 mg, 80-500 mg, 80-400 mg, 80-300 mg, 100-300 mg, or 200 mg. -300mg. For example, the dosage can be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4 mg, 2.6 mg, 2.8 mg, 3.0 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg , 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg , 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg , 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg , 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg , 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, the frequency of administration is once a week, once every 2 weeks, once every 3 weeks, It is administered every 4 weeks, once a month, every 3-6 months or longer.
可選的實施方案中,免疫檢查點抑制劑的劑量為80mg、100mg、160mg、200mg、240mg、300mg、320mg、400mg、500mg、600mg、700mg或800mg,給藥頻次為每週一次、每2週一次、每3週一次、每4週一次、1個月一次、每3-6個月或更長一次的給藥頻次施用。 In an alternative embodiment, the dose of the immune checkpoint inhibitor is 80 mg, 100 mg, 160 mg, 200 mg, 240 mg, 300 mg, 320 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg, and the frequency of administration is once a week, every 2 weeks It is administered once, once every 3 weeks, once every 4 weeks, once a month, once every 3-6 months or longer.
可選的實施方案中,免疫檢查點抑制劑的量為200mg,給藥頻次為每週一次、每2週一次、每3週一次、每4週一次、1個月一次、每3-6個月或更長一次的給藥頻次施用。 In an alternative embodiment, the amount of immune checkpoint inhibitor is 200 mg, and the frequency of administration is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, every 3-6 It is administered frequently every month or more.
可選的實施方案中,該免疫檢查點抑制劑的給藥頻次為每2週一次或每3週一次。 In an alternative embodiment, the frequency of administration of the immune checkpoint inhibitor is once every 2 weeks or once every 3 weeks.
可選的實施方案中,該多靶點酪胺酸激酶抑制劑的劑量選自0.1-1000mg,給藥頻次可以是每天1次、一日二次、每天3次,較佳每天1次。 In an alternative embodiment, the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-1000 mg, and the frequency of administration may be once a day, twice a day, or 3 times a day, preferably once a day.
可選的實施方案中,該多靶點酪胺酸激酶抑制劑的劑量選自0.1-100mg,具體可選0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、 39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg、100mg,給藥頻次可以是每天1次、一日二次、每天3次,較佳每天1次。 In an optional embodiment, the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, the frequency of administration may be once a day, twice a day, 3 times a day, preferably once a day.
可選的實施方案中,該多靶點酪胺酸激酶抑制劑按體重給藥,該劑量選自0.1-10.0mg/kg。 In an alternative embodiment, the multi-target tyrosine kinase inhibitor is administered by body weight, and the dose is selected from 0.1-10.0 mg/kg.
在上述按照體重給藥的方案中,該多靶點酪胺酸激酶抑制劑的劑量可以為0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg,給藥頻次可以是每天1次、一日二次、每天3次,較佳每天1次。 In the above regimen of administration according to body weight, the dose of the multi-target tyrosine kinase inhibitor can be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2 mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2 mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2 mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2 mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg, give The frequency of medication may be once a day, twice a day, or 3 times a day, preferably once a day.
在可選的實施方案中,多靶點酪胺酸激酶抑制劑的劑量選自1-25mg,具體可選15mg、20mg、25mg,給藥頻次可以是每天1次、一日二次、每天3次,較佳每天1次。 In an alternative embodiment, the dose of the multi-target tyrosine kinase inhibitor is selected from 1-25 mg, specifically 15 mg, 20 mg, 25 mg, and the frequency of administration may be once a day, twice a day, or 3 times a day. Times, preferably once a day.
可選的實施方案中,該多靶點酪胺酸激酶抑制劑為(II)所示化合物蘋果酸鹽。 In an alternative embodiment, the multi-target tyrosine kinase inhibitor is the compound shown in (II) malate.
本公開中所述腫瘤是選自上腺皮質癌、肛門癌、肛門直腸癌、肛管癌、闌尾癌、小腦星形細胞瘤、腦星形細胞瘤、基底細胞癌、皮膚癌(非黑色素瘤)、膽道癌、肝外膽管癌、肝內膽管癌、膀胱癌、骨關節癌、骨肉瘤、惡性纖維組織細胞瘤、腦癌、腦腫瘤、腦幹膠質瘤、室管膜瘤、成神經管細胞瘤、視覺通路和下丘腦神經膠質瘤、乳腺癌、支氣管腺瘤、神經系統癌、神經系統淋巴瘤、中樞神經系統癌、中樞神經系統淋巴瘤、宮頸癌、慢性淋巴細胞白血病、慢性粒細胞白血病白血病、慢性骨髓增生性疾病、結腸癌、結直腸癌、皮膚T細胞淋巴瘤、淋巴腫瘤、蕈樣真菌病、Sezary綜合症、子宮內膜癌、食管癌、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、眼癌、眼內黑色素瘤、視網膜母細胞瘤、膽囊癌、胃癌、胃腸道類癌、胃腸道間質瘤(GIST)、生殖細胞腫瘤、卵巢生殖細胞瘤、頭頸癌、肝細胞癌、霍奇金淋巴瘤、胰島細胞瘤、卡波西肉瘤、腎癌、喉癌、急性淋巴細胞白血病、急性髓性白血病、毛細胞白血病、唇和口腔腔癌、肝癌、肺癌、非小細胞肺癌、小細胞肺癌、非霍奇金淋巴瘤、原發性中樞神經系統淋巴瘤、Waldenstroem巨球蛋白血症、黑色素瘤、間皮瘤、轉移性鱗癌、舌癌、多發性內分泌腫瘤綜合症、骨髓增生異常綜合症、多發性骨髓瘤、鼻咽癌、神經母細胞瘤、口咽癌、卵巢癌、卵巢上皮癌、卵巢低惡性潛能 腫瘤、胰腺癌、胰島細胞胰腺癌、鼻竇和鼻腔癌、甲狀旁腺癌、陰莖癌、咽癌、嗜鉻細胞瘤、松果體瘤、垂體瘤、漿細胞腫瘤、胸膜肺母細胞瘤、前列腺癌、直腸癌、腎盂和輸尿管移行細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、尤文家族肉瘤、卡波西肉瘤、滑膜肉瘤、子宮癌、子宮肉瘤、小腸癌、軟組織肉瘤、鱗狀細胞癌、幕上原始神經外胚層腫瘤、睾丸癌、咽喉癌、胸腺瘤、尿道癌、子宮內膜異位症、陰道癌、外陰癌或威爾姆氏腫瘤,較佳結直腸癌或結腸癌。 The tumor described in the present disclosure is selected from the group consisting of adrenal cortical cancer, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, cerebellar astrocytoma, brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma ), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, bone and joint cancer, osteosarcoma, malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, ependymoma, adult Neuroblastoma, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic Myelocytic leukemia, leukemia, chronic myeloproliferative disease, colon cancer, colorectal cancer, skin T-cell lymphoma, lymphoma, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, Extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, head and neck cancer, Hepatocellular carcinoma, Hodgkin’s lymphoma, islet cell tumor, Kaposi’s sarcoma, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non- Small cell lung cancer, small cell lung cancer, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstroem macroglobulinemia, melanoma, mesothelioma, metastatic squamous cell carcinoma, tongue cancer, multiple endocrine tumors Syndrome, myelodysplastic syndrome, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential Tumor, pancreatic cancer, islet cell pancreatic cancer, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal tumor, pituitary tumor, plasma cell tumor, pleuropulmonary blastoma, Prostate cancer, rectal cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Juventus sarcoma, Kaposi sarcoma, synovial sarcoma, uterine cancer, uterine sarcoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma Stomatocell carcinoma, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma, urethral cancer, endometriosis, vaginal cancer, vulvar cancer or Wilm’s tumor, preferably colorectal cancer or colon cancer.
可以將本公開的免疫檢查點抑制劑構成在組成物中,例如,含有抗體和藥學上可接受的載體的藥物組合物。本文中使用的“藥學上可接受的載體”包括生理學上相容的任意的和所有的溶劑、分散介質、包衣劑、抗細菌劑和抗真菌劑、等滲劑和吸收延遲劑等。在一個實施方案中,用於含有抗體的組成物的載體適合靜脈、肌肉、皮下、胃腸外、腹腔、脊柱或表皮施用(例如,藉由注射或輸注),本公開的藥物組合物可以包括一種或多種藥學上可接受的鹽、抗氧化劑、水性和非水性載體,和/或佐劑,諸如防腐劑、潤濕劑、乳化劑和分散劑。 The immune checkpoint inhibitor of the present disclosure can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, spinal or epidermal administration (for example, by injection or infusion), and the pharmaceutical composition of the present disclosure may include a Or a variety of pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents.
在本公開中較佳的實施方案中,該PD-1抗體或其抗原結合片段以注射的方式給藥,例如皮下或靜脈注射或腹腔,注射前需將PD-1抗體或其抗原結合片段配製成可注射的形式。本公開特別佳的實施方案中抗PD-1抗體的可注射形式是注射液或凍乾粉針,其包含PD-1抗體或其抗原結合片段、緩衝劑、穩定劑,任選地還含有表面活性劑。緩衝劑可選自醋酸鹽、檸檬酸鹽、琥珀酸鹽、以及磷酸鹽中的一種或幾種。穩定劑可選自糖或胺基酸,較佳二糖,例如蔗糖、乳糖、海藻糖、麥芽糖。表面活性劑選自聚氧乙烯氫化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯,
較佳該聚氧乙烯山梨醇酐脂肪酸酯為聚山梨酯20、40、60或80,最佳聚山梨酯20。最為佳的PD-1抗體或其抗原結合片段的可注射形式包含PD-1抗體或其抗原結合片段、醋酸鹽緩衝劑、海藻糖和聚山梨酯20。
In a preferred embodiment of the present disclosure, the PD-1 antibody or its antigen-binding fragment is administered by injection, such as subcutaneous or intravenous injection or intraperitoneal injection. The PD-1 antibody or its antigen-binding fragment must be prepared before injection. Made in an injectable form. In a particularly preferred embodiment of the present disclosure, the injectable form of the anti-PD-1 antibody is an injection or a lyophilized powder injection, which contains the PD-1 antibody or its antigen-binding fragment, a buffer, a stabilizer, and optionally a surface Active agent. The buffer can be selected from one or more of acetate, citrate, succinate, and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, and maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester,
Preferably, the polyoxyethylene sorbitan fatty acid ester is
本公開提供一種治療腫瘤的方法,包括給與患者治療有效量的上述EZH2抑制劑、免疫檢查點抑制劑和多靶點酪胺酸激酶抑制劑。 The present disclosure provides a method for treating tumors, which includes administering to a patient a therapeutically effective amount of the above-mentioned EZH2 inhibitor, immune checkpoint inhibitor, and multi-target tyrosine kinase inhibitor.
本公開另一方面提供一種用於治療腫瘤的EZH2抑制劑,該EZH2抑制劑與該免疫檢查點抑制劑、多靶點酪胺酸激酶抑制劑聯合使用。 Another aspect of the present disclosure provides an EZH2 inhibitor for the treatment of tumors, which is used in combination with the immune checkpoint inhibitor and the multi-target tyrosine kinase inhibitor.
本公開另一方面提供一種用於治療腫瘤的免疫檢查點抑制劑,該免疫檢查點抑制劑與EZH2抑制劑、多靶點酪胺酸激酶抑制劑聯合使用。 Another aspect of the present disclosure provides an immune checkpoint inhibitor for the treatment of tumors, which is used in combination with an EZH2 inhibitor and a multi-target tyrosine kinase inhibitor.
本公開另一方面提供一種多靶點酪胺酸激酶抑制劑,該多靶點酪胺酸激酶抑制劑與EZH2抑制劑、免疫檢查點抑制劑聯合使用。 Another aspect of the present disclosure provides a multi-target tyrosine kinase inhibitor, which is used in combination with an EZH2 inhibitor and an immune checkpoint inhibitor.
可選的實施方案中,本公開提供的治療腫瘤的方法,該患者為人類。 In an alternative embodiment, in the method for treating tumors provided in the present disclosure, the patient is a human.
本公開中所述的酪胺酸激酶抑制劑是指能阻斷酪胺酸激酶的藥物,該多靶點酪胺酸激酶抑制劑是指能同時對於至少兩個受體酪胺酸激酶產生抑制的藥物,受體酪胺酸激酶包括但不限於PDGF-R、VEGFR、flt3、EGFR、HER2、FGFR等。 The tyrosine kinase inhibitor described in the present disclosure refers to a drug that can block tyrosine kinase, and the multi-target tyrosine kinase inhibitor means that it can inhibit at least two receptor tyrosine kinases at the same time. Drugs, receptor tyrosine kinases include but are not limited to PDGF-R, VEGFR, flt3, EGFR, HER2, FGFR, etc.
本公開中所述的“聯合”是一種給藥方式,是指在一定時間期限內給予至少一種劑量的免疫檢查點抑制劑、EZH2抑制劑和多靶點酪胺酸激酶抑制劑,其中三種藥物都顯示藥理學作用。該時間期限可以是一個給藥週期內,例如4週內,3週內,2週內,1週內,或24小時以內。可以同時或不分先後順序給予免疫檢查點抑制劑、EZH2抑制劑和多靶點酪胺酸激酶抑制劑。這種期限包括這樣的治療,其中藉由相同給藥途徑或不同 給藥途徑給予免疫檢查點抑制劑、EZH2抑制劑和多靶點酪胺酸激酶抑制劑。 The “combination” described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of immune checkpoint inhibitor, EZH2 inhibitor and multi-target tyrosine kinase inhibitor within a certain period of time, of which three drugs Both show pharmacological effects. The time period can be within a dosing cycle, for example, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. Immune checkpoint inhibitors, EZH2 inhibitors and multi-target tyrosine kinase inhibitors can be administered simultaneously or in no particular order. This period includes treatments in which the same route of administration or different The route of administration is to give immune checkpoint inhibitors, EZH2 inhibitors and multi-target tyrosine kinase inhibitors.
本公開中所述“人源化抗體(humanized antibody)”,也稱為CDR移植抗體(CDR-grafted antibody),是指將小鼠的CDR序列移植到人的抗體可變區框架,即不同類型的人種系抗體構架序列中產生的抗體。可以克服嵌合抗體由於攜帶大量小鼠蛋白成分,從而誘導的強烈的抗體可變抗體反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得),以及在Kabat,E.A.等人,1991 Sequences of Proteins of Immunologioal Interest,第5版中找到。在本公開中一個較佳的實施方案中,該PD-1人源化抗體的CDR序列選自SEQ ID NO:1,2,3,4,5,6。 The "humanized antibody" in the present disclosure, also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types Of human germline antibody framework sequences. It can overcome the strong variable antibody response induced by the chimeric antibody due to the large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, the germline DNA sequences of the human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. Human, 1991 Sequences of Proteins of Immunologioal Interest, found in 5th edition. In a preferred embodiment of the present disclosure, the CDR sequence of the PD-1 humanized antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.
本公開中所述“抗原結合片段”,指具有抗原結合活性的Fab片段,Fab‘片段,F(ab’)2片段,以及與人PD-1結合的Fv片段sFv片段;包含本公開中所述抗體的選自SEQ ID NO:1至SEQ ID NO:6中的一個或多個CDR區。Fv片段含有抗體重鏈可變區和輕鏈可變區,但沒有恆定區,並具有全部抗原結合位點的最小抗體片段。一般地,Fv抗體還包含在VH和VL結構域之間的多肽接頭,且能夠形成抗原結合所需的結構。也可以用不同的連接物將兩個抗體可變區連接成一條多肽鏈,稱為單鏈抗體(single chain antibody)或單鏈Fv(sFv)。本公開中的術語“與PD-1 結合”,指能與人PD-1相互作用。本公開中的術語“抗原結合位點”指抗原上不連續的,由本公開中抗體或抗原結合片段識別的三維空間位點。 The "antigen-binding fragment" in the present disclosure refers to Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments that bind to human PD-1, sFv fragments that have antigen-binding activity; The antibody is selected from one or more CDR regions in SEQ ID NO:1 to SEQ ID NO:6. The Fv fragment contains the variable region of the heavy chain of the antibody and the variable region of the light chain, but does not have the constant region, and has the smallest antibody fragment with all the antigen binding sites. Generally, Fv antibodies also include a polypeptide linker between the VH and VL domains, and can form the structure required for antigen binding. Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, which is called single chain antibody or single chain Fv (sFv). The term "and PD-1" in this disclosure Binding" refers to the ability to interact with human PD-1. The term "antigen-binding site" in the present disclosure refers to a three-dimensional site that is discontinuous on the antigen and recognized by the antibody or antigen-binding fragment in the present disclosure.
圖1為各組小鼠體重變化曲線圖; Figure 1 is a graph showing changes in body weight of mice in each group;
圖2為CT-26小鼠同種移植模型腫瘤體積變化曲線圖。 Figure 2 is a graph of tumor volume change in CT-26 mouse allograft model.
以下結合實施例用於進一步描述本公開,但這些實施例並非限制本公開的範圍。 The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
實施例1、驗證受試藥在結直腸癌細胞系CT-26雌性huPD-1小鼠同種移植模型中的藥效 Example 1. Verification of the efficacy of the test drug in the colorectal cancer cell line CT-26 female huPD-1 mouse allograft model
1、實驗材料 1. Experimental materials
1)實驗動物 1) Experimental animals
小鼠,huPD-1 BALB/c,江蘇集萃藥康生物科技有限公司,6-8週齡,18-20g,48隻加40%冗餘共68隻。 Mice, huPD-1 BALB/c, Jiangsu Jicui Yaokang Biotechnology Co., Ltd., 6-8 weeks old, 18-20g, 48 mice plus 40% redundancy, a total of 68 mice.
2)實驗細胞 2) Experimental cells
CT-26,來自於中科院,結直腸癌細胞,F3代次;所需細胞量8.2X10E7。 CT-26, from the Chinese Academy of Sciences, colorectal cancer cells, F3 generation; the required cell volume is 8.2X10E7.
3)實驗藥物 3) Experimental drugs
EZH2抑制劑:式(I)所示化合物;多靶點酪胺酸激酶抑制劑:式(II)所示化合物蘋果酸鹽;抗PD-1抗體:WO2017054646A公開 的PD-1抗體,重、輕鏈的序列分別如SEQID NO:7、SEQID NO:8所示。 EZH2 inhibitor: compound represented by formula (I); multi-target tyrosine kinase inhibitor: compound represented by formula (II) malate; anti-PD-1 antibody: disclosed in WO2017054646A The heavy and light chain sequences of the PD-1 antibody are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.
2、實驗方法及步驟 2. Experimental methods and procedures
1)CT-26細胞復蘇,體外培養,獲得1X10E8細胞;68隻6-8週齡雌性huPD-1經1週適應性飼養,稱重,後每隻小鼠於雙側肩胛處皮下接種5*10E5個細胞,每隻接種體積為0.1mL。每週1次測量腫瘤體積及體重,選擇兩側腫瘤體積均在60-120mm3之間的小鼠,依據其右側腫瘤體積和體重隨機分為6組,每組8隻。分組後隨即開始給藥。給藥開始日期視為第0天,給藥及分組信息見表2。給藥開始後,小鼠每週3次測量體重及腫瘤體積。
1) CT-26 cells were resuscitated and cultured in vitro to obtain 1X10E8 cells; 68 6-8 week old female huPD-1 were adaptively reared for 1 week, weighed, and each mouse was inoculated subcutaneously at the bilateral scapula for 5* 10E5 cells, each seeding volume is 0.1mL. The tumor volume and body weight were measured once a week , and mice with tumor volumes between 60-120 mm 3 on both sides were selected and randomly divided into 6 groups according to the tumor volume and body weight on the right side, with 8 mice in each group. The administration was started immediately after grouping. The start date of administration is regarded as
2)實驗藥物配置見表3。 2) The experimental drug configuration is shown in Table 3.
3)實驗觀察及數據收集及統計分析 3) Experimental observation, data collection and statistical analysis
接種後,每工作日觀察動物發病及死亡情況。日常觀察包括,腫瘤生長及藥物對實驗動物造成的影響,如活動變化、攝食飲水變化、消瘦情況、毛髮、眼的外觀變化、死亡及其他臨床症狀。接種後至分組前,每週一次測量實驗動物體重。分組後每週3次測量實驗動物體重或根據客戶要求變更測量小鼠體重頻率。接種後至分組前,當腫瘤可見時,每週一次測量實驗動物腫瘤體積,接種分組後,實驗中的動物腫瘤體積每週測量一次。 After inoculation, observe the morbidity and death of animals every working day. Daily observations include tumor growth and the effects of drugs on laboratory animals, such as changes in activity, changes in food and water, weight loss, changes in hair, eye appearance, death, and other clinical symptoms. After inoculation to before grouping, the weight of the experimental animals was measured once a week. After grouping, measure the weight of experimental animals 3 times a week or change the frequency of measuring the weight of mice according to customer requirements. After inoculation to before grouping, when the tumor is visible, the tumor volume of the experimental animal is measured once a week. After the inoculation and grouping, the tumor volume of the experimental animal is measured once a week.
腫瘤體積測量採用雙向測量法,首先利用遊標卡尺測量腫瘤長短徑,再使用公式TV=0.5×a×b2計算腫瘤體積。其中a是腫瘤的長徑,b是腫瘤的短徑。 Tumor volume is measured by a two-way measurement method. First, the length and short diameter of the tumor are measured with a vernier caliper, and then the tumor volume is calculated using the formula TV=0.5×a×b 2. Where a is the long diameter of the tumor and b is the short diameter of the tumor.
實驗終點時,將採用以下分析方法進行數據分析:%△T/C=(mean(T)-mean(T0))/(mean(C)-mean(C0))* 100%;T-給藥組腫瘤體積,T0-給藥組初始腫瘤體積,C-對照組腫瘤體積,C0-對照組初始腫瘤體積。Mean%△Inhibition(TGI%)=((mean(C)-mean(C0))-(mean(T)-mean(T0)))/(mean(C)-mean(C0))* 100%;T-給藥組腫瘤體積,T0-給藥組初始腫瘤體積,C-對照組腫瘤體積,C0-對照組初始腫瘤體積。 At the end of the experiment, the following analysis methods will be used for data analysis: %△T/C=(mean(T)-mean(T0))/(mean(C)-mean(C0))* 100%; T-dosing Group tumor volume, T0-administration group initial tumor volume, C-control group tumor volume, C0-control group initial tumor volume. Mean%△Inhibition(TGI%)=((mean(C)-mean(C0))-(mean(T)-mean(T0)))/(mean(C)-mean(C0))* 100%; T-administration group tumor volume, T0-administration group initial tumor volume, C-control group tumor volume, C0-control group initial tumor volume.
3、實驗結果 3. Experimental results
1)小鼠體重 1) Mouse body weight
各組體重在不同時間點的平均體重如表4所示。 The average weight of each group's body weight at different time points is shown in Table 4.
各組體重變化百分比見表5。 See Table 5 for the percentage of weight change in each group.
各組小鼠體重變化曲線如圖1所示。 The body weight change curve of each group of mice is shown in Figure 1.
2)腫瘤體積數據 2) Tumor volume data
在本實驗中,1、2、3、4組無瘤內給藥,因此左側和右側腫瘤視為同樣處理方式,數據合併進行分析。第4組34,35#小鼠左側腫瘤體積用Prism異常值分析為異常值,在統計中予以排除,各個處理組腫瘤各時間點的體積如表6所示。 In this experiment, there was no intratumoral administration in groups 1, 2, 3, and 4, so the left and right tumors were treated in the same way, and the data were combined for analysis. The volume of the tumor on the left side of the 34 and 35# mice in the fourth group was analyzed by Prism as an abnormal value, which was excluded from the statistics. The tumor volume of each treatment group at each time point is shown in Table 6.
3)腫瘤生長抑制情況 3) Tumor growth inhibition
各組腫瘤生長抑制情況見表7。 See Table 7 for tumor growth inhibition in each group.
4)腫瘤各單藥組與對應聯合用藥組兩兩比較結果見表8。 4) The results of pairwise comparison between each single-drug group of tumors and the corresponding combination-drug group are shown in Table 8.
5)腫瘤生長曲線 5) Tumor growth curve
各組左右側腫瘤生長曲線如圖2所示。第4組34,35#小鼠左側腫瘤體積用Prism異常值分析為異常值,在製圖中予以排除。 The tumor growth curves on the left and right sides of each group are shown in Figure 2. In the fourth group, the left tumor volume of 34 and 35# mice was analyzed as an abnormal value by Prism abnormal value, which was excluded from the chart.
討論: discuss:
EZH2抑制劑(第2組)在p.o.給藥後第14天平均腫瘤體積為1871.8±263.53mm3,與對照組(第1組,第14天腫瘤體積為2020.2±177.82mm3)相比無顯著差異(TGI%=8%,p=0.6439)。 The average tumor volume of EZH2 inhibitor (group 2) on the 14th day after po administration was 1871.8±263.53mm 3 , which was not significant compared with the control group (group 1, the tumor volume on the 14th day was 2020.2±177.82mm 3) Difference (TGI%=8%, p=0.6439).
抗PD-1抗體與多靶點酪胺酸激酶抑制劑聯合給藥組(第3組)在給藥後第14天平均腫瘤體積為918.4±206.16mm3,與對照組相比有顯著性差異(第1組,第14天腫瘤體積為2020.2±177.82mm3,TGI%=57%,p=0.0003)。 The anti-PD-1 antibody and multi-target tyrosine kinase inhibitor combined administration group (group 3) had an average tumor volume of 918.4±206.16mm 3 on the 14th day after administration, which was significantly different from the control group (In group 1, the tumor volume on day 14 was 2020.2±177.82mm 3 , TGI%=57%, p=0.0003).
EZH2抑制劑、抗PD-1抗體與多靶點酪胺酸激酶抑制劑聯合用藥組(第4組)在給藥後第14天平均腫瘤體積為425.5±110.32mm3,與對照組相比有顯著性差異(第1組,第14天腫瘤體積為2020.2±177.82mm3,TGI%=82%,p<0.0001)。與EZH2抑制劑單獨用藥組(第2組,p<0.0001)和抗PD-1抗體&多靶點酪胺酸激酶抑制劑給藥組(第3組)相比,三藥聯合用藥抑瘤作用更顯著(p<0.0001和p=0.0486)。 The EZH2 inhibitor, anti-PD-1 antibody and multi-target tyrosine kinase inhibitor combination group (group 4) had an average tumor volume of 425.5±110.32mm 3 on the 14th day after administration, which was significantly higher than that of the control group. Significant difference (group 1, tumor volume on day 14 is 2020.2±177.82mm 3 , TGI%=82%, p<0.0001). Compared with the EZH2 inhibitor alone group (group 2, p<0.0001) and the anti-PD-1 antibody & multi-target tyrosine kinase inhibitor group (group 3), the three-drug combination has anti-tumor effect More significant (p<0.0001 and p=0.0486).
<110> 江蘇恆瑞醫藥股份有限公司(JIANGSU HENRUI MEDICINE CO.,LTD.) 蘇州盛迪亞生物醫藥有限公司(SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.) <110> JIANGSU HENRUI MEDICINE CO.,LTD. SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.
<120> EZH2抑制劑與免疫檢查點抑制劑、酪胺酸激酶抑制劑聯合在製備治療腫瘤藥物中的用途 <120> Use of combination of EZH2 inhibitor, immune checkpoint inhibitor and tyrosine kinase inhibitor in the preparation of tumor drugs
<160> 10 <160> 10
<170> SIPOSequenceListing 1.0 <170> SIPOSequenceListing 1.0
<210> 1 <210> 1
<211> 5 <211> 5
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 1 <400> 1
<210> 2 <210> 2
<211> 17 <211> 17
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 2 <400> 2
<210> 3 <210> 3
<211> 7 <211> 7
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 3 <400> 3
<210> 4 <210> 4
<211> 11 <211> 11
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 4 <400> 4
<210> 5 <210> 5
<211> 7 <211> 7
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 5 <400> 5
<210> 6 <210> 6
<211> 9 <211> 9
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 6 <400> 6
<210> 7 <210> 7
<211> 443 <211> 443
<212> PRT <212> PRT
<213> 人工序列(Artificial Sequence) <213> Artificial Sequence
<400> 7 <400> 7
<210> 8 <210> 8
<211> 214 <211> 214
<212> PRT <212> PRT
<213> 人工序列(Artificial Sequence) <213> Artificial Sequence
<400> 8 <400> 8
<210> 9 <210> 9
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<212> PRT <212> PRT
<213> 人工序列(Artificial Sequence) <213> Artificial Sequence
<400> 9 <400> 9
<210> 10 <210> 10
<211> 107 <211> 107
<212> PRT <212> PRT
<213> 人工序列(Artificial Sequence) <213> Artificial Sequence
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