TW202339767A - Pharmaceutical combination of spirocyclic aryl phosphorus oxide and anti-EGFR antibody - Google Patents
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
Description
本發明要求於2022年1月18日提交中國專利局、申請號為202210052633.1發明名稱為“螺環芳基磷氧化物與抗EGFR抗體的藥物組合”的中國專利申請的優先權，其全部內容藉由引用結合在本發明中。The present invention claims the priority of the Chinese patent application submitted to the China Patent Office on January 18, 2022, with the application number 202210052633.1 and the invention name is "Drug combination of spirocyclic aryl phosphorus oxide and anti-EGFR antibody", the entire content of which is borrowed from incorporated herein by reference.
本發明屬於藥物化學領域，關於治療腫瘤的聯用藥物組合物。具體的，本發明關於螺環芳基磷氧化物與抗體的藥物組合物及其在製備抗腫瘤藥物中的用途。The invention belongs to the field of medicinal chemistry and relates to a combined pharmaceutical composition for treating tumors. Specifically, the present invention relates to the pharmaceutical composition of spirocyclic aryl phosphorus oxide and antibody and its use in the preparation of anti-tumor drugs.
間變性淋巴瘤激酶（ALK）是一種受體酪胺酸激酶（RTK），為胰島素受體（IR）超家族成員。1994年ALK首次以融合蛋白NPM（核磷蛋白）-ALK的形式在60-80%間變性大細胞淋巴瘤（ALCLS）細胞系中被發現，NPM-ALK是由t (2;5）染色體易位造成。儘管ALK在癌症中的生理功能還不清楚，但ALK融合蛋白已經在各種人類癌症中被發現，如乳腺癌、結腸直腸癌、炎性肌纖維母細胞瘤（IMT），彌散性大B細胞淋巴瘤（DLBCL），其中最為顯著的是在非小細胞肺癌（NSCLC）中。因此，與ALK融合蛋白相關的激酶活性被認為對人類癌細胞存活與增殖起著非常重要的作用。Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) and a member of the insulin receptor (IR) superfamily. In 1994, ALK was first discovered in 60-80% of anaplastic large cell lymphoma (ALCLS) cell lines in the form of the fusion protein NPM (nucleophosmin)-ALK. NPM-ALK is caused by the t (2;5) chromosome transgene. bit caused. Although the physiological function of ALK in cancer is unclear, ALK fusion proteins have been found in various human cancers, such as breast cancer, colorectal cancer, inflammatory myofibroblastic tumor (IMT), and diffuse large B-cell lymphoma. (DLBCL), most notably in non-small cell lung cancer (NSCLC). Therefore, the kinase activity associated with ALK fusion proteins is considered to play a very important role in the survival and proliferation of human cancer cells.
ALK基因提供了一種訊號傳導的指令，使受體酪胺酸激酶將訊號從細胞表面傳導到細胞中。這一過程起始於當激酶在細胞表面受到刺激後，然後附著到類似的激酶（二聚）。二聚化後，激酶被一個磷酸基團標記，這一過程稱為磷酸化。磷酸化激活激酶，活化激酶是能夠將磷酸基轉移到細胞內的另一個蛋白，活化持續藉由訊號通路中一系列的蛋白質。而這些訊號通路對於許多細胞過程非常重要，如細胞生長和***（增殖）或成熟（分化）等。The ALK gene provides signaling instructions that enable receptor tyrosine kinase to conduct signals from the cell surface into the cell. This process begins when kinases are stimulated on the cell surface and then attach to similar kinases (dimerization). After dimerization, the kinase is tagged with a phosphate group, a process called phosphorylation. Phosphorylation-activated kinase. Activated kinase is another protein that can transfer a phosphate group to the cell. The activation continues through a series of proteins in the signaling pathway. These signaling pathways are important for many cellular processes, such as cell growth and division (proliferation) or maturation (differentiation).
通常ALK染色體重排，使得ALK的酪胺酸激酶結構域與其它蛋白的5’-端結構域融合，例如棘皮動物微管相關蛋白樣4（EML4）在NSCLC或核磷酸蛋白（NPM）在間變性大細胞淋巴瘤。對所有ALK融合基因其中斷點非常保守，位於外顯子編碼的基因內區的上游激酶域。由於ALK涉及的重排部分不包括跨膜結構域，所形成的融合蛋白從細胞膜重新遷移到細胞質。融合蛋白的5’-端通常含有捲曲螺旋或白胺酸拉鍊結構域，從而使融合蛋白低聚化，並且導致ALK酪胺酸激酶的配體依賴性活化。這一結果反過來又組成性激活下游訊號傳導，如Ras/MAPK，PI3K/AKT，和JAK/STAT等通路。ALK驅動的肺癌在用ALK小分子酪胺酸激酶抑制劑治療後產生回應和消退。這一發現表明了“腫瘤基因的依賴性”，即癌細胞變得依賴於致癌驅動基因，因此對抑制癌基因高度敏感。Often ALK is chromosomally rearranged such that the tyrosine kinase domain of ALK is fused to the 5'-end domain of other proteins, such as echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC or nucleophosphoprotein (NPM) in Metaplastic large cell lymphoma. The breakpoint is very conserved for all ALK fusion genes and is located in the upstream kinase domain of the intragenic region encoded by the exon. Since the rearrangement involved in ALK does not include the transmembrane domain, the resulting fusion protein relocates from the cell membrane to the cytoplasm. The 5’-end of the fusion protein usually contains a coiled-coil or leucine zipper domain, which oligomerizes the fusion protein and leads to ligand-dependent activation of ALK tyrosine kinase. This result, in turn, constitutively activates downstream signaling pathways such as Ras/MAPK, PI3K/AKT, and JAK/STAT pathways. ALK-driven lung cancer responds and regresses after treatment with ALK small-molecule tyrosine kinase inhibitors. This finding demonstrates "oncogene dependence," whereby cancer cells become dependent on oncogenic driver genes and are therefore highly sensitive to the suppression of oncogenes.
克唑替尼（Crizotinib）是第一個被FDA批准的用於治療ALK陽性肺癌的ALK抑制劑。儘管患者對克唑替尼治療最初回應非常有效，但多數患者由於產生耐藥性而在治療的第一年復發。2014年4月，FDA批准了色瑞替尼（Ceritinib）用於治療間變性淋巴瘤激酶（ALK）陽性的轉移性非小細胞肺癌（NSCLC），包括對克唑替尼有效以及耐藥的患者。然而耐藥總是會隨治療時間的延長而產生，從而使藥物失去有效性。Crizotinib is the first ALK inhibitor approved by the FDA for the treatment of ALK-positive lung cancer. Although patients initially respond very effectively to crizotinib treatment, most patients relapse during the first year of treatment due to the development of drug resistance. In April 2014, the FDA approved ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), including patients who are responsive to and resistant to crizotinib. . However, drug resistance always develops with the prolongation of treatment time, causing the drug to lose its effectiveness.
螺環芳基磷氧化物，化學名稱為：（2-（（5-氯-2-（（2-甲氧基-4-（9-甲基-3,9-二氮雜螺[5.5]十一烷-3-基）苯基）胺基）嘧啶-4-基）胺基）苯基）二甲基氧膦，是一種新型ALK/ROS1抑制劑，用於治療ALK/ROS1陽性的非小細胞肺癌。其具有如下結構式（I）： 式（I）。 Spiroaryl phosphorus oxide, chemical name: (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]) Undecyl-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide is a new ALK/ROS1 inhibitor used to treat ALK/ROS1-positive non- Small cell lung cancer. It has the following structural formula (I): Formula (I).
該式（I）化合物藉由抑制ALK激酶的激活，抑制ALK磷酸化，進而阻止下游訊號分子的磷酸化，如ERK、STAT5和AKT。另外，該式（I）化合物藉由抑制ROS1融合激酶的磷酸化抑制ROS1的激活，進而阻止下游訊號分子如ERK或AKT的磷酸化。最終藉由抑制激酶磷酸化抑制ALK或ROS1激酶驅動的腫瘤生長。相關專利文獻包括：專利WO2016/000581公開了作為ALK抑制劑的螺環芳基磷氧化物；專利CN106928275公開了螺環芳基磷氧化物的製備方法及其中間體；專利CN110407877公開了螺環芳基磷氧化物的多晶型。The compound of formula (I) inhibits the phosphorylation of ALK by inhibiting the activation of ALK kinase, thereby preventing the phosphorylation of downstream signaling molecules, such as ERK, STAT5 and AKT. In addition, the compound of formula (I) inhibits the activation of ROS1 by inhibiting the phosphorylation of ROS1 fusion kinase, thereby preventing the phosphorylation of downstream signaling molecules such as ERK or AKT. Ultimately, ALK or ROS1 kinase-driven tumor growth is inhibited by inhibiting kinase phosphorylation. Relevant patent documents include: patent WO2016/000581 discloses spirocyclic aryl phosphorus oxides as ALK inhibitors; patent CN106928275 discloses the preparation method and intermediates of spirocyclic arylphosphorus oxides; patent CN110407877 discloses spirocyclic aryl phosphorus oxides Polymorphic form of phosphorus oxide.
近年來有越來越多證據表明表皮生長因子受體(epithelial growth factorreceptor，EGFR)與許多腫瘤的發生和發展有關。EGFR在正常情況下可説明調節人體內細胞的生長，但其也會刺激癌細胞生長。EGFR存在於癌細胞的表面，當體內出現蛋白質與EGFR相結合時，EGFR會被激活，如表皮生長因子（EGF）或轉化生長因子α（TGF-alpha）。結合改變了EGFR的形態，刺激腫瘤細胞的生長。EGFR表達陽性的腫瘤具有惡性度高、侵襲力強的特點，而且EGFR 表達水準的高低與預後相關。因而同樣成為當前腫瘤分子靶向治療的一個重要靶點。有依據證實HER1/EGFR在實體腫瘤中表達異常，其臨床體現為轉移，生存期縮短，預後差，對化療及激素治療耐受。阻斷HER1/EGFR後能抑制腫瘤的形成，同時改善上述狀況。In recent years, there has been increasing evidence that epidermal growth factor receptor (EGFR) is related to the occurrence and development of many tumors. EGFR regulates the growth of cells in the human body under normal circumstances, but it can also stimulate the growth of cancer cells. EGFR exists on the surface of cancer cells. When proteins in the body bind to EGFR, EGFR is activated, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha). Binding changes the morphology of EGFR, stimulating the growth of tumor cells. Tumors with positive EGFR expression are characterized by high malignancy and strong invasiveness, and the level of EGFR expression is related to prognosis. Therefore, it has also become an important target for current molecular targeted therapy of tumors. There is evidence that HER1/EGFR is abnormally expressed in solid tumors, and its clinical manifestations are metastasis, shortened survival, poor prognosis, and resistance to chemotherapy and hormone therapy. Blocking HER1/EGFR can inhibit tumor formation and improve the above conditions.
目前用於EGFR靶向性治療腫瘤的藥物主要分為兩類：EGFR單株抗體和小分子化合物酪胺酸激酶拮抗劑。EGFR單株抗體是與內源性配體競爭結合EGFR，藉由抑制酪胺酸激酶的激活、促進EGFR內化等作用產生抗腫瘤效應。目前國內外已有3種抗 EGFR單株抗體上市，與其他化療藥相比，這些抗體作用特異性強，副作用小，在臨床上取得了較好的療效。Currently, drugs used for EGFR-targeted treatment of tumors are mainly divided into two categories: EGFR monoclonal antibodies and small molecule compound tyrosine kinase antagonists. EGFR monoclonal antibodies compete with endogenous ligands to bind to EGFR and produce anti-tumor effects by inhibiting the activation of tyrosine kinase and promoting the internalization of EGFR. Currently, three anti-EGFR monoclonal antibodies are on the market at home and abroad. Compared with other chemotherapy drugs, these antibodies have strong specificity and few side effects, and have achieved good clinical efficacy.
EGFR基因的常見突變位點發生在第18、19、20和21號外顯子上，其中19號外顯子的非移碼缺失突變約占45%，21號外顯子的L858R點突變占40-45%，這兩種突變被稱為常見敏感突變，其他的突變被稱為罕見突變。Common mutation sites of the EGFR gene occur in exons 18, 19, 20 and 21, of which non-frameshift deletion mutations in exon 19 account for approximately 45%, and L858R point mutations in exon 21 account for 40-45%. %, these two mutations are called common sensitive mutations, and the other mutations are called rare mutations.
帕尼單抗(panitumumab)是第一個完全人源化單株抗體，其靶向作用於表皮生長因子受體(EGFR)。帕尼單抗可以特異性地與正常和腫瘤細胞的EGFR結合，是一種EGFR配體的競爭性抑制劑。非臨床研究顯示，帕尼單抗與EGFR的結合可以阻止配體誘導受體的自磷酸化和受體相關激酶的活化，抑制細胞生長和誘導其凋亡，降低促炎症細胞因子和血管生長因子的產生及EGFR的內化。Panitumumab is the first fully humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). Panitumumab can specifically bind to EGFR in normal and tumor cells and is a competitive inhibitor of EGFR ligands. Non-clinical studies have shown that the binding of panitumumab to EGFR can prevent ligand-induced receptor autophosphorylation and activation of receptor-related kinases, inhibit cell growth and induce apoptosis, and reduce pro-inflammatory cytokines and vascular growth factors. production and internalization of EGFR.
在腫瘤治療過程中遇到的最大挑戰是由於腫瘤免疫耐受和逃逸，導致藥物療效不好。因此，藉由將小分子抗腫瘤化合物與抗EGFR抗體的聯合使用來治療腫瘤，具有重要的應用價值。The biggest challenge encountered during tumor treatment is poor drug efficacy due to tumor immune tolerance and escape. Therefore, the combined use of small molecule anti-tumor compounds and anti-EGFR antibodies to treat tumors has important application value.
本發明的目的在於提供一種聯用藥物組合物，其包含ALK抑制劑以及抗EGFR抗體。具體的，本發明的藥物組合物，其包含作為ALK抑制劑的式（I）化合物或其藥學上可接受的鹽，以及抗EGFR抗體。 式（I）。 The object of the present invention is to provide a combination pharmaceutical composition comprising an ALK inhibitor and an anti-EGFR antibody. Specifically, the pharmaceutical composition of the present invention contains a compound of formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof, and an anti-EGFR antibody. Formula (I).
在本發明的一些方案中，上述聯用藥物組合物中的抗EGFR抗體是帕尼單抗。In some aspects of the present invention, the anti-EGFR antibody in the above combination pharmaceutical composition is panitumumab.
在本發明的一些方案中，上述聯用藥物組合物是非固定組合。在一些方案中，所述非固定組合中抗EGFR抗體和式（I）化合物或其藥學上可接受的鹽各自呈藥物組合物的形式。在一些方案中，還提供了一種用於治療肺臟腫瘤的聯用藥物組合物的試劑盒，其中含有（a）第一種藥物組合物，其包含抗EGFR抗體；和（b）第二種藥物組合物，其含有式（I）化合物作為活性成分。In some aspects of the present invention, the above-mentioned combined pharmaceutical composition is a non-fixed combination. In some embodiments, the anti-EGFR antibody and the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition. In some aspects, a kit of a combined pharmaceutical composition for treating lung tumors is also provided, which contains (a) a first pharmaceutical composition comprising an anti-EGFR antibody; and (b) a second drug Compositions containing a compound of formula (I) as an active ingredient.
本發明還提供一種聯用藥物組合物在製備治療和/或預防肺癌之藥物的用途，所述聯用藥物組合物包含作為ALK抑制劑的式（I）化合物或其藥學上可接受的鹽，以及抗EGFR抗體。The present invention also provides the use of a combined pharmaceutical composition in preparing a drug for treating and/or preventing lung cancer. The combined pharmaceutical composition contains a compound of formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof, and anti-EGFR antibodies.
在本發明的一些方案中，上述用途中的抗EGFR抗體是帕尼單抗。In some embodiments of the invention, the anti-EGFR antibody for use as described above is panitumumab.
在本發明的一些方案中，上述用途中的帕尼單抗可以選自Vectibix或其生物類似藥。In some aspects of the present invention, panitumumab in the above uses can be selected from Vectibix or its biosimilars.
在本發明的一些方案中，上述用途中的抗EGFR抗體和式（I）化合物或其藥學上可接受的鹽各自呈藥物組合物的形式。In some aspects of the invention, the anti-EGFR antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above uses are each in the form of a pharmaceutical composition.
在本發明的一些方案中，上述用途中所述肺癌為EGFR敏感突變陽性。In some aspects of the present invention, the lung cancer described in the above uses is positive for EGFR sensitive mutations.
在本發明的一些方案中，上述用途中所述肺癌是早中期、局部晚期、晚期轉移性非小細胞肺癌。In some aspects of the present invention, the lung cancer in the above-mentioned uses is early-to-mid stage, locally advanced, or late-stage metastatic non-small cell lung cancer.
在本發明的一些方案中，上述用途中所述肺癌為EGFR敏感突變陽性的早中期、局部晚期、晚期轉移性非小細胞肺癌。In some aspects of the present invention, the lung cancer described in the above-mentioned uses is early-stage, locally advanced, or late-stage metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.
在本發明的一些方案中，上述用途中所述肺癌是未經EGFR抑制劑治療或經EGFR抑制劑治療失敗的非小細胞肺癌。In some aspects of the invention, the lung cancer described in the above uses is non-small cell lung cancer that has not been treated with an EGFR inhibitor or has failed treatment with an EGFR inhibitor.
在本發明的一些方案中，上述用途中所述肺癌是經奧希替尼等不可逆EGFR抑制劑治療失敗的具有EGFR敏感突變陽性、T790M突變和C797S突變的非小細胞肺癌。In some aspects of the present invention, the lung cancer described in the above uses is non-small cell lung cancer with positive EGFR sensitive mutations, T790M mutation and C797S mutation that failed to be treated with irreversible EGFR inhibitors such as osimertinib.
在本發明的一些方案中，上述用途中所述肺癌是具有Del19突變、T790M突變和C797S突變的非小細胞肺癌。In some aspects of the invention, the lung cancer described in the above uses is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.
在本發明的一些方案中，上述用途中所述肺癌是具有L858R突變、T790M突變和C797S突變的非小細胞肺癌。In some aspects of the invention, the lung cancer described in the above uses is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.
在本發明的一些方案中，上述用途中所述非小細胞肺癌是腺癌、鱗癌、腺鱗癌或大細胞癌。In some aspects of the invention, the non-small cell lung cancer in the above uses is adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma or large cell carcinoma.
在本發明的一些方案中，上述用途中所述抗EGFR抗體和式（I）化合物或其藥學上可接受的鹽各自呈藥物組合物的形式，可同時、順序或間隔給藥。In some aspects of the present invention, the anti-EGFR antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above uses are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
本發明還提供一種用於治療患有癌症或腫瘤的主體的方法，其包括向所述主體施用治療有效量的ALK抑制劑和治療有效量的抗EGFR抗體。The invention also provides a method for treating a subject having cancer or a tumor, comprising administering to the subject a therapeutically effective amount of an ALK inhibitor and a therapeutically effective amount of an anti-EGFR antibody.
在本發明的一些方案中，上述治療方法中所述ALK抑制劑是式（I）所示的螺環芳基磷氧化物。In some aspects of the present invention, the ALK inhibitor in the above treatment method is a spiroarylphosphonoxide represented by formula (I).
在本發明的一些方案中，上述治療方法中所述抗EGFR抗體是帕尼單抗。In some aspects of the invention, the anti-EGFR antibody in the above treatment method is panitumumab.
在本發明的一些方案中，上述治療方法中的帕尼單抗可以選自Vectibix或其生物類似藥。In some aspects of the invention, panitumumab in the above treatment method can be selected from Vectibix or its biosimilars.
在本發明的一些方案中，上述治療方法中的抗EGFR抗體和式（I）化合物或其藥學上可接受的鹽各自呈藥物組合物的形式。In some aspects of the invention, the anti-EGFR antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment methods are each in the form of a pharmaceutical composition.
在本發明的一些方案中，上述治療方法中所述肺癌為EGFR敏感突變陽性。In some aspects of the present invention, the lung cancer described in the above treatment method is EGFR sensitive mutation positive.
在本發明的一些方案中，上述治療方法中所述肺癌是早中期、局部晚期、晚期轉移性非小細胞肺癌。In some solutions of the present invention, the lung cancer in the above treatment method is early-to-mid stage, locally advanced, or late-stage metastatic non-small cell lung cancer.
在本發明的一些方案中，上述治療方法中所述肺癌為EGFR敏感突變陽性的早中期、局部晚期、晚期轉移性非小細胞肺癌。In some solutions of the present invention, the lung cancer described in the above treatment method is early-mid, locally advanced, or late-stage metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.
在本發明的一些方案中，上述治療方法中所述肺癌是未經EGFR抑制劑治療或經EGFR抑制劑治療失敗的非小細胞肺癌。In some aspects of the present invention, the lung cancer in the above treatment method is non-small cell lung cancer that has not been treated with an EGFR inhibitor or has failed to be treated with an EGFR inhibitor.
在本發明的一些方案中，上述治療方法中所述肺癌是經奧希替尼等不可逆EGFR抑制劑治療失敗的EGFR敏感突變陽性、T790M突變和C797S突變的非小細胞肺癌。In some solutions of the present invention, the lung cancer described in the above treatment method is non-small cell lung cancer with positive EGFR sensitive mutations, T790M mutations and C797S mutations that have failed treatment with irreversible EGFR inhibitors such as osimertinib.
在本發明的一些方案中，上述治療方法中所述肺癌是具有Del19突變、T790M突變和C797S突變的非小細胞肺癌。In some aspects of the present invention, the lung cancer described in the above treatment method is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.
在本發明的一些方案中，上述治療方法中所述肺癌是具有L858R突變、T790M突變和C797S突變的非小細胞肺癌。In some aspects of the present invention, the lung cancer described in the above treatment method is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.
在本發明的一些方案中，上述治療方法中所述非小細胞肺癌是腺癌、鱗癌、腺鱗癌或大細胞癌。In some aspects of the present invention, the non-small cell lung cancer in the above treatment method is adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma or large cell carcinoma.
在本發明的一些方案中，上述治療方法中所述抗EGFR抗體和式（I）化合物或其藥學上可接受的鹽各自呈藥物組合物的形式，可同時、順序或間隔給藥。In some aspects of the present invention, the anti-EGFR antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment methods are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
本發明還提供了一種式（I）化合物或其藥學上可接受的鹽用於治療肺癌的用途，所述式（I）化合物或其藥學上可接受的鹽與抗EGFR抗體組合使用。The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating lung cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an anti-EGFR antibody.
本發明還提供了一種抗EGFR抗體用於治療肺癌的用途，所述抗EGFR抗體與式（I）化合物或其藥學上可接受的鹽組合使用。The present invention also provides the use of an anti-EGFR antibody for treating lung cancer, which is used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.
在一些方案中，上述用途的抗EGFR抗體選自帕尼單抗。In some embodiments, the anti-EGFR antibody for use as described above is selected from panitumumab.
在本發明的一些方案中，上述用途中的帕尼單抗可以選自Vectibix或其生物類似藥。In some aspects of the present invention, panitumumab in the above uses can be selected from Vectibix or its biosimilars.
本發明還提供一種藥物包，其在獨立的容器中包含單包裝的藥物組合物，其在一個容器中包含含有式（I）化合物或其藥學上可接受的鹽的藥物組合物，在第二個容器中包含含有抗EGFR抗體的藥物組合物。The present invention also provides a pharmaceutical package containing a single package of a pharmaceutical composition in a separate container, which contains a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a second container. Each container contains a pharmaceutical composition containing an anti-EGFR antibody.
式（I）化合物的藥物組合物Pharmaceutical compositions of compounds of formula (I)
式（I）化合物的藥物組合物能配製用於特定給藥途徑，如口服給藥、胃腸外給藥和直腸給藥等。較佳口服，例如片劑。Pharmaceutical compositions of compounds of formula (I) can be formulated for specific administration routes, such as oral administration, parenteral administration, rectal administration, etc. Preferably taken orally, such as tablets.
在本發明的一些實施方案中，所述式（I）化合物的藥物組合物的施用劑量在大約60mg/次~180mg/次；或者施用劑量在大約90mg/次~180mg/次。In some embodiments of the present invention, the dosage of the pharmaceutical composition of the compound of formula (I) is about 60 mg/time to 180 mg/time; or the dosage is about 90 mg/time to 180 mg/time.
在本發明的一些實施方案中，按照每日給藥1次，每次給予所述式（I）化合物的藥物組合物大約60mg ~180mg；或者大約90mg ~180mg。In some embodiments of the present invention, the pharmaceutical composition of the compound of formula (I) is administered once daily, and the pharmaceutical composition of the compound of formula (I) is administered at approximately 60 mg to 180 mg; or approximately 90 mg to 180 mg.
式（I）化合物Compounds of formula (I)
如本發明所用，式（I）化合物是螺環芳基磷氧化物，化學名稱為：（2-（（5-氯-2-（（2-甲氧基-4-（9-甲基-3,9-二氮雜螺[5.5]十一烷-3-基）苯基）胺基）嘧啶-4-基）胺基）苯基）二甲基氧膦，是一種最新開發的高選擇性間變性淋巴瘤激酶（ALK）抑制劑，其具有如下結構式（I）： 式（I）。 As used in the present invention, the compound of formula (I) is a spirocyclic arylphosphorus oxide, and its chemical name is: (2-((5-chloro-2-((2-methoxy-4-(9-methyl- 3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, is a newly developed high choice Anaplastic lymphoma kinase (ALK) inhibitor, which has the following structural formula (I): Formula (I).
帕尼單抗panitumumab
如本發明所用，帕尼單抗，商品名Vectibix，由美國安進公司研發，是第一個完全人源化單株抗體，其靶向作用於表皮生長因子受體（EGFR），2005年底被FDA批准用於治療化療失敗後轉移性結直腸癌。As used in the present invention, panitumumab, trade name Vectibix, was developed by Amgen in the United States. It is the first fully humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). FDA approved for the treatment of metastatic colorectal cancer after failure of chemotherapy.
QL1203（重組抗EGFR全人單株抗體注射液），是帕尼單抗生物類似藥。QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection) is a biosimilar drug of panitumumab.
上述Vectibix和QL1203的序列和結構均參見文獻WO98/50433，它們的胺基酸序列如下：The sequences and structures of the above-mentioned Vectibix and QL1203 can be found in the document WO98/50433. Their amino acid sequences are as follows:
重鏈： QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK（SEQ ID NO：1）。 Heavy chain: Question DKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1).
輕鏈： DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC（SEQ ID NO：2）。 Light chain: DIQMTQSPSSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 2).
定義和說明Definition and description
除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
這裡所採用的術語“藥學上可接受的”，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
術語“藥學上可接受的鹽”是指本發明化合物的鹽，由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時，可以藉由在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物的中性形式接觸的方式獲得鹼加成鹽。當本發明的化合物中含有相對鹼性的官能團時，可以藉由在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物的中性形式接觸的方式獲得酸加成鹽。本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物藉由常規化學方法合成。一般情況下，這樣的鹽的製備方法是：在水或有機溶劑或兩者的混合物中，經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
術語“抗體”是指具有至少一個抗原結合結構域的結合蛋白。本發明的抗體和其片段可以是整個抗體或其任何片段。因此，本發明的抗體和片段包括單株抗體或其片段和抗體變體或其片段，以及免疫綴合物。抗體片段的實例包括Fab片段、Fab '片段、F(ab) '片段、Fv片段、分離的CDR區、單鏈Fv分子(scFv)和本領域已知的其他抗體片段。抗體和其片段還可以包括重組多肽、融合蛋白和雙特異性抗體。本文揭露的抗PD-L1抗體和其片段可以是IgG1、IgG2、IgG3或IgG4同種型。The term "antibody" refers to a binding protein having at least one antigen-binding domain. The antibodies and fragments thereof of the invention may be whole antibodies or any fragments thereof. Thus, the antibodies and fragments of the invention include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgGl, IgG2, IgG3 or IgG4 isotype.
術語“人源化抗體”是指其中抗原結合位點來源於非人物種且可變區框架來源於人免疫球蛋白序列的抗體。人源化抗體在框架區中可包含置換，使得該框架可能不是表達的人免疫球蛋白或種系基因序列的精確複製。The term "humanized antibody" refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.
術語“單株抗體”(“mAb”)是指單分子組合物的抗體分子。單株抗體組合物顯示出對於特定表位元的單一結合特異性和親和力，或就雙特異性單株抗體而言，顯示出對於兩種不同表位的雙重結合特異性。mAb是分離的抗體的一個例子。藉由本領域技術人員已知的雜交瘤技術、重組技術、轉基因技術或其它技術，可以生產mAb。The term "monoclonal antibody" ("mAb") refers to a single molecular composition of antibody molecules. The monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope, or in the case of a bispecific monoclonal antibody, dual binding specificity for two different epitopes. mAb is an example of an isolated antibody. mAbs can be produced by hybridoma technology, recombinant technology, transgenic technology or other technologies known to those skilled in the art.
術語“抗EGFR抗體”是指以充分的親和力和特異性結合EGFR的抗體。所選擇的抗體通常具有針對EGFR的結合親和性，例如，所述抗體可以以1pM-100nM的Kd值結合EGFR。例如，抗體親和性可以藉由基於表面等離子共振的測定法（如PCT公佈WO2005/012359中所述的BIAcore測定法）進行確定；藉由酶聯免疫吸附測定法（ELISA）進行確定；和競爭測定法（如RIA’s）進行確定。在某些實施方案中，本發明的抗EGFR抗體可以在靶向和干擾其中涉及EGFR活性的疾病或病症中用作治療劑。此外，所述抗體可以進行其他生物學活性測試，例如，以評估其作為治療劑的功效。所述測定法在本領域中是已知的，並且取決於靶抗原和所述抗體的目的應用。實例包括HUVEC抑制測定法；腫瘤細胞生長抑制測定法（例如，WO89/06692中所述）；抗體依賴性細胞毒作用（ADCC）和補體介導的細胞毒性（CDC）測定法（例如專利US5,500,362）；和激動劑活性或造血測定法（參見WO95/27062）。The term "anti-EGFR antibody" refers to an antibody that binds EGFR with sufficient affinity and specificity. The antibody selected typically has binding affinity for EGFR, for example, the antibody can bind EGFR with a Kd value of 1 pM to 100 nM. For example, antibody affinity can be determined by surface plasmon resonance-based assays such as the BIAcore assay described in PCT publication WO2005/012359; by enzyme-linked immunosorbent assay (ELISA); and competition assays methods (such as RIA's) to determine. In certain embodiments, the anti-EGFR antibodies of the invention can be used as therapeutic agents in targeting and interfering with diseases or conditions in which EGFR activity is involved. Additionally, the antibodies can be tested for other biological activities, for example, to assess their efficacy as therapeutic agents. The assays are known in the art and depend on the target antigen and intended application of the antibody. Examples include HUVEC inhibition assays; tumor cell growth inhibition assays (eg, as described in WO89/06692); antibody-dependent cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (eg, patent US5, 500,362); and agonist activity or hematopoiesis assays (see WO95/27062).
術語“治療”一般是指獲得需要的藥理和/或生理效應。該效應根據完全或部分地預防疾病或其症狀，可以是預防性的；和/或根據部分或完全穩定或治癒疾病和/或由於疾病產生的副作用，可以是治療性的。本文使用的“治療”涵蓋了對患者疾病的任何治療，包括：(a)預防易感染疾病或症狀但還沒診斷出患病的患者所發生的疾病或症狀；(b)抑制疾病的症狀，即阻止其發展；或(c)緩解疾病的症狀，即，導致疾病或症狀退化。The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptoms in a patient who is susceptible to the disease or symptoms but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., arresting its progression; or (c) alleviating the symptoms of a disease, i.e., causing regression of the disease or symptoms.
如本發明所用，術語“受試者”表示哺乳動物，諸如齧齒動物、貓科動物、犬科動物和靈長類動物。較佳地，本發明的受試者是人。As used herein, the term "subject" refers to mammals, such as rodents, felines, canines, and primates. Preferably, the subject of the present invention is human.
如本發明所用，術語“施用”表示，使用本領域技術人員已知的多種方法和遞送系統中的任一種，向主體物理引入包含治療劑的組合物。抗EGFR抗體的施用途徑包括靜脈內、肌肉內、皮下、腹膜內、脊柱或其它胃腸外施用途徑，例如藉由注射或輸注。本文中使用的“胃腸外施用”是指，通常藉由注射進行的除了腸內和局部施用以外的施用模式，且包括、但不限於，靜脈內、肌肉內、動脈內、鞘內、***內、病灶內、囊內、眶內、心內、真皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛網膜下、脊柱內、硬膜外和胸骨內注射和輸注、以及體內電穿孔。在某些實施方案中，抗EGFR抗體藉由非胃腸外途徑施用，在某些實施方案中，口服施用。其它非胃腸外途徑包括局部、表皮或黏膜施用途徑，例如，鼻內、***、直腸、舌下或局部。還可以執行施用，例如，一次、多次，和/或在一個或多個延長的時間段中。As used herein, the term "administering" means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration for anti-EGFR antibodies include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, lymphatic Intralesional, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions , and in vivo electroporation. In certain embodiments, the anti-EGFR antibody is administered parenterally, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal administration, for example, intranasal, vaginal, rectal, sublingual or topical. Administration may also be performed, eg, once, multiple times, and/or over one or more extended time periods.
術語“主體”包括任何人或非人動物。術語“非人動物”包括、但不限於脊椎動物諸如非人靈長類動物、綿羊、犬，和齧齒類動物諸如小鼠、大鼠和豚鼠。在某些實施方案中，所述主體是人。術語“主體”和“患者”在本文中的某些語境下可互換地使用。The term "subject" includes any human or non-human animal. The term "non-human animals" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably in certain contexts herein.
藥物或治療劑的“治療有效量”或“治療上有效的劑量”是當單獨使用或與另一種治療劑聯合使用時保護主體免於疾病發作或促進疾病消退的藥物的任何量，所述疾病消退藉由疾病症狀的嚴重程度的降低、無疾病症狀階段的頻率和持續時間的增加、或由疾病折磨引起的損傷或失能的預防來證明。使用熟練的從業人員已知的多種方法可以評價治療劑的促進疾病消退的能力，諸如在臨床試驗期間在人主體中，在預測對於人類的效力的動物模型系統中，或藉由在體外測定法中測定所述藥劑的活性。A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes regression of a disease Regression is evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free phases of the disease, or the prevention of impairment or disability caused by the disease. The ability of therapeutic agents to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by in vitro assays to determine the activity of the agent.
藥物的治療有效量包括“預防有效量”，其為當單獨地或與抗腫瘤劑聯合施用給處於發生癌症的風險的主體(例如，具有惡化前病症的主體)或具有癌症復發的風險的主體時，抑制癌症的發生或復發的任何藥物量。在某些實施方案中，預防有效量完全阻止癌症的發生或復發。“抑制”癌症的發生或復發是指減少癌症的發生或復發的可能性，或完全阻止癌症的發生或復發。A therapeutically effective amount of a drug includes a "prophylactically effective amount" which is when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of recurrence of cancer The amount of any drug that inhibits the occurrence or recurrence of cancer. In certain embodiments, the prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.
“復發性”癌症是在對初始治療(例如手術)產生應答後，在初始部位或遠處部位再生的癌症。“局部復發性”癌症是在治療後，在與先前治療的癌症相同的位置出現的癌症。A "recurrent" cancer is a cancer that grows back at the original site or at a distant site after responding to initial treatment, such as surgery. A "locally recurrent" cancer is a cancer that appears after treatment in the same location as a previously treated cancer.
“不能切除的”癌症是無法藉由手術去除的。"Unresectable" cancer cannot be removed by surgery.
“轉移性”癌症是指從身體的一部分(例如肺部)擴散到身體的另一部分的癌症。"Metastatic" cancer is cancer that has spread from one part of the body, such as the lungs, to another part of the body.
術語“固定組合”指活性組分(例如抗EGFR抗體或式（I）化合物)以固定總劑量或劑量比例，或以單一實體、藥物組合物或製劑的形式同時給予受試者。The term "fixed combination" means that the active components (e.g., an anti-EGFR antibody or a compound of formula (I)) are administered simultaneously to a subject in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or preparation.
術語“非固定組合”指兩種以上活性組分作為獨立的實體(例如藥物組合物、製劑)同時、並行或依序且無具體時間限制地給予受試者，其中所述給予受試者的活性成份達到治療有效量水準。非固定組合可列舉的例子是雞尾酒療法，例如給予3種或以上之活性組分。在非固定組合中，所述各個活性組分可以作為完全獨立的藥物組合物進行包裝、銷售或給藥。所述“非固定組合”也包括“固定組合”之間、或“固定組合”與任一或多種活性組分的獨立實體的聯合使用。The term "non-fixed combination" refers to the administration of two or more active components as independent entities (such as pharmaceutical compositions, preparations) to a subject simultaneously, concurrently or sequentially without specific time limits, wherein the administration to the subject The active ingredient reaches a therapeutically effective amount. Examples of non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" between "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.
術語“聯用”或“聯合使用”意指兩種或更多種活性物質可以在混合物中一起、作為單一製劑同時地或作為單一製劑以任何順序依次地施用於受試者。The term "combination" or "combined use" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single preparation, or sequentially in any order as a single preparation.
術語“藥物組合物”是指一種或多種本發明的活性成分(例如抗EGFR抗體或式Ⅰ化合物)或其藥物組合與藥學上可接受的輔料組成的混合物。藥物組合物的目的是有利於對受試者給予本發明的化合物或其藥物組合。The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present invention (such as anti-EGFR antibodies or compounds of formula I) or pharmaceutical combinations thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to a subject of a compound of the invention or a pharmaceutical combination thereof.
術語“協同效應”指兩種或多種成份(例如抗EGFR抗體或式Ⅰ化合物)所產生的效果(例如抑制肺癌生長)大於成份單獨給藥的效果的簡單加成。The term "synergistic effect" refers to the simple additive effect of two or more ingredients (eg, an anti-EGFR antibody or a compound of Formula I) that produces an effect (eg, inhibition of lung cancer growth) that is greater than the effect of the ingredients administered alone.
施用方式Mode of administration
以下內容並非限制本發明的藥物組合的施用方式。The following content does not limit the administration mode of the pharmaceutical combination of the present invention.
本發明的聯用藥物組合物中的組分可以各自分開配製。在一個實施方案中，本發明的聯用藥物組合物中的組分可以配製成適合於單次或多次施用的藥物組合物。The components in the combined pharmaceutical composition of the present invention can be formulated separately. In one embodiment, the components of the combination pharmaceutical composition of the present invention may be formulated into a pharmaceutical composition suitable for single or multiple administration.
本發明的聯用藥物組合物中的組分可以各自單獨施用，或者其中的部分或全部共同施用。本發明的聯用藥物組合物中的組分可以基本上不同時施用，或者其中的部分或全部基本上同時施用。The components in the combination pharmaceutical composition of the present invention may be administered individually, or part or all of them may be administered together. The components of the combination pharmaceutical composition of the present invention may not be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.
本發明的聯用藥物組合物中的組分可以各自獨立地，或者其中的部分或全部共同以適合的各種途徑施用，包括，但不限於，口服或腸胃外(藉由靜脈內、肌內、局部或皮下途徑)。在一些實施方案中，本發明的聯用藥物組合物的組分可以各自獨立地，或者其中的部分或全部共同口服施用或注射施用，例如靜脈注射或腹腔注射。The components in the combination pharmaceutical composition of the present invention can be administered independently, or part or all of them can be administered together by various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, Topical or subcutaneous route). In some embodiments, the components of the combination pharmaceutical composition of the present invention may be administered independently, or part or all of them may be administered orally or by injection, such as intravenously or intraperitoneally.
本發明的聯用藥物組合物中的組分可以各自獨立地，或者其中的部分或全部共同是適合的劑型，包括，但不限於，片劑、含片、丸劑、膠囊劑(例如硬膠囊、軟膠囊、腸溶膠囊、微囊劑)、酏劑、顆粒劑、糖漿劑、注射劑(肌肉內、靜脈內、腹腔內)、顆粒劑、乳劑、懸浮液、溶液、分散劑和用於口服或非口服給藥的緩釋製劑的劑型。The components in the combination pharmaceutical composition of the present invention can be each independently, or some or all of them together can be suitable dosage forms, including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, Soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and preparations for oral or Dosage forms of sustained-release preparations for parenteral administration.
本發明的聯用藥物組合物中的組分可以各自獨立地，或者其中的部分或全部共同含有藥學上可接受的載體和/或賦形劑。The components in the combination pharmaceutical composition of the present invention may be each independently, or some or all of them may jointly contain pharmaceutically acceptable carriers and/or excipients.
本發明的聯用藥物組合物還可以包含另外的治療劑。在一個實施方式中，所述另外的治療劑可以是本領域已知的癌症治療劑，較佳肺癌治療劑。The combination pharmaceutical compositions of the present invention may also contain additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.
在本發明的一些具體方案中，考察了式（I）化合物、抗EGFR抗體單用或聯用對肺臟腫瘤的療效。實驗結果令人驚奇的發現，式（I）化合物與抗EGFR抗體有明顯的協同效應，打破了機體已經建立的對腫瘤細胞的免疫耐受。In some specific embodiments of the present invention, the efficacy of compounds of formula (I) and anti-EGFR antibodies alone or in combination on lung tumors was examined. The experimental results surprisingly found that the compound of formula (I) and the anti-EGFR antibody had a significant synergistic effect, breaking the body's established immune tolerance to tumor cells.
下面藉由實施例對本發明進行詳細描述，但這些實施例僅用於闡明而並不限制本發明任何的範圍。同樣，本發明不限於本文描述的任何具體較佳的實施方案。本領域技術人員應該理解，對本發明技術特徵所作的等同替換，或相應的改進，仍屬於本發明的保護範圍之內。The present invention will be described in detail below through examples, but these examples are only for illustration and do not limit any scope of the present invention. Likewise, the invention is not limited to any specific preferred embodiments described herein. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the technical features of the present invention still fall within the protection scope of the present invention.
表1-1. 縮略語表
實施例一 H1975 EGFR (Del19/T790M/C797S)皮下異種移植腫瘤BALB/c裸小鼠模型上的體內藥效Example 1 In vivo efficacy of H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor in BALB/c nude mouse model
本實驗的目的在於評估小分子式（I）化合物與帕尼單抗聯用在H1975 EGFR (Del19/T790M/C797S)皮下異種移植腫瘤BALB/c裸小鼠模型上的體內藥效。The purpose of this experiment was to evaluate the in vivo efficacy of the small molecule compound of formula (I) in combination with panitumumab in the H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model.
實驗方案Experimental plan
表1-2. 體內藥效實驗動物分組及給藥方案
註： 1.N: 每組小鼠數目。 2.給藥體積：式（I）化合物根據小鼠體重給藥10 μL/g；QL1203及Vectibix固定體積，200 μL/隻。Vehicle為5% 無水乙醇和聚氧乙烯40氫化蓖麻油混合溶液（1:1）+ 95%滅菌注射用水。 3.所有藥物配製頻率：現配現用。 Note: 1.N: Number of mice in each group. 2. Administration volume: The compound of formula (I) is administered at 10 μL/g according to the mouse body weight; the fixed volume of QL1203 and Vectibix is 200 μL/mouse. Vehicle is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection. 3. Frequency of preparation of all medicines: Prepare as they are and use as they are.
帕尼單抗panitumumab
如本實施例所用，帕尼單抗，商品名Vectibix，由美國安進公司研發。As used in this example, panitumumab, trade name Vectibix, was developed by Amgen of the United States.
QL1203（重組抗EGFR全人單株抗體注射液），是Vectibix生物類似藥。QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection) is a Vectibix biosimilar.
所述Vectibix和QL1203的序列和結構參見文獻WO98/50433，它們的胺基酸序列如下：The sequences and structures of Vectibix and QL1203 can be found in document WO98/50433, and their amino acid sequences are as follows:
重鏈： QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK（SEQ ID NO：1）。 Heavy chain: Question DKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1).
輕鏈： DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC（SEQ ID NO：2）。 Light chain: DIQMTQSPSSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 2).
實驗樣品Experimental samples
(1)名稱：式（I）化合物(1) Name: compound of formula (I)
結構式： Structural formula:
提供者：齊魯製藥有限公司Provider: Qilu Pharmaceutical Co., Ltd.
批號：T9001L51NBatch number: T9001L51N
純度： 99.6%Purity: 99.6%
分子量：569.08Molecular weight: 569.08
性狀描述：類白色粉末Character description: Off-white powder
保存條件：常溫避光保存Storage conditions: Store at room temperature and away from light
(2)名稱：QL1203(2) Name: QL1203
提供者：齊魯製藥有限公司Provider: Qilu Pharmaceutical Co., Ltd.
批號：201905001KJBBatch number: 201905001KJB
濃度： 20 mg/mLConcentration: 20 mg/mL
性狀描述：無色透明液體Description: Colorless transparent liquid
保存條件：4ºC避光保存Storage conditions: Store at 4ºC away from light
(3)名稱：Vectibix(3)Name: Vectibix
提供者：齊魯製藥有限公司Provider: Qilu Pharmaceutical Co., Ltd.
批號：1100612Batch number: 1100612
濃度： 20 mg/mLConcentration: 20 mg/mL
性狀描述：無色透明液體Description: colorless transparent liquid
保存條件：4ºC避光保存Storage conditions: Store at 4ºC away from light
實驗方法與步驟Experimental methods and procedures
細胞培養cell culture
細胞系H1975 EGFR (Del19/T790M/C797S)體外培養，培養條件為RPMI1640培養基中加10%胎牛血清，1%雙抗(青黴素/鏈黴素溶液)，10μg/ml殺稻瘟菌素，37℃ 5% CO 2培養。一週兩次常規離心處理傳代。當細胞匯合度為80%-90%，數量到達要求時，收取細胞，計數，接種。 The cell line H1975 EGFR (Del19/T790M/C797S) was cultured in vitro. The culture conditions were RPMI1640 medium plus 10% fetal calf serum, 1% double antibody (penicillin/streptomycin solution), 10μg/ml blasticidin, 37 Cultivation at 5% CO2 . Passaging was performed by routine centrifugation twice a week. When the cell confluence is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
腫瘤細胞接種tumor cell inoculation
將含有5×10 6個H1975 EGFR (Del19/T790M/C797S)細胞的PBS同Matrigel按1：1的比例混合（終體積為100μL)皮下接種於每隻小鼠的右前肢腋窩皮下，在動物腫瘤平均體積達到185 mm 3時開始分組給藥。實驗分組和給藥方案見表1-2。 PBS containing 5×10 6 H1975 EGFR (Del19/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume: 100 μL) and inoculated subcutaneously into the axilla of the right forelimb of each mouse. Group administration began when the average volume reached 185 mm3 . The experimental grouping and dosage regimen are shown in Table 1-2.
受試物的配製Preparation of test substance
表1-3. 受試物配製方法
註：在給藥前需要輕輕將藥物充分混勻。Note: The drug needs to be mixed gently and thoroughly before administration.
實驗動物日常觀察Daily observation of experimental animals
每天監測動物的健康狀況及死亡情況，例行檢查包括觀察腫瘤生長和藥物治療對動物日常行為表現的影響如行為活動，攝食攝水量（僅目測），體重變化（每天測量一次體重），外觀體征或其它不正常情況。基於各組動物數量記錄了組內動物死亡數和副作用。Monitor the health status and death of the animals every day. Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), weight changes (measure body weight once a day), and appearance signs. or other abnormal conditions. The number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
腫瘤測量和實驗指標Tumor Measurements and Experimental Indicators
實驗指標是考察腫瘤生長是否被抑制、延緩或治癒。每週三次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a×b 2，a和b分別表示腫瘤的長徑和短徑。 The experimental indicator is to examine whether tumor growth is inhibited, delayed or cured. Tumor diameter was measured with vernier calipers three times a week. The calculation formula of tumor volume is: V = 0.5a×b 2 , where a and b represent the long and short diameters of the tumor respectively.
化合物的抑瘤療效用TGI(%)或相對腫瘤增殖率T/C(%)評價。TGI(%)，反映腫瘤生長抑制率。TGI(%)的計算：The tumor inhibitory efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI(%):
TGI(%)=[(1-（某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積）)/(溶媒對照組治療結束時平均瘤體積－溶媒對照組開始治療時平均瘤體積)]×100%。TGI(%)=[(1-(average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the beginning of treatment in this treatment group))/(average tumor volume at the end of treatment in the vehicle control group - start of treatment in the vehicle control group) average tumor volume)]×100%.
相對腫瘤增殖率T/C（%）：計算公式如下：Relative tumor proliferation rate T/C (%): The calculation formula is as follows:
T/C % = TRTV / CRTV × 100 %（TRTV：治療組RTV；CRTV：陰性對照組RTV）。T/C % = TRTV / CRTV × 100 % (TRTV: RTV of treatment group; CRTV: RTV of negative control group).
根據腫瘤測量的結果計算出相對腫瘤體積（relative tumor volume，RTV），計算公式為 RTV = Vt / V0，其中V0是分組給藥時（即d0）測量所得平均腫瘤體積，Vt為某一次測量時的平均腫瘤體積，TRTV與CRTV取同一天資料。The relative tumor volume (RTV) is calculated based on the results of tumor measurement. The calculation formula is RTV = Vt / V0, where V0 is the average tumor volume measured at the time of group administration (i.e. d0), and Vt is the measurement at a certain time. The average tumor volume, TRTV and CRTV are taken from the same day.
統計分析Statistical analysis
統計分析，包括每個組的每個時間點的腫瘤體積的平均值和標準誤（SEM）（具體資料見表1-5）。由於各治療組在給藥後21天表現出較好的治療效果因此基於此資料進行統計學分析評估組間差異。兩組間比較用T-test進行分析。用SPSS 17.0進行所有資料分析。p＜ 0.05認為有顯著性差異。Statistical analysis included the mean and standard error (SEM) of tumor volume at each time point in each group (see Table 1-5 for specific information). Since each treatment group showed better therapeutic effects 21 days after administration, statistical analysis was conducted based on this data to evaluate the differences between the groups. Comparisons between two groups were analyzed using T-test. All data analyzes were performed using SPSS 17.0. p<0.05 was considered to be a significant difference.
樣品採集Sample collection
開始給藥後第21天，根據表1-4進行血漿採集，並對所有血漿進行分析。On day 21 after the start of dosing, plasma collection was performed according to Tables 1-4, and all plasma was analyzed.
表1-4. 血漿採集表
註：a. pre-dose為最後一次給藥前。Note: a. pre-dose is before the last dose.
實驗結果Experimental results
死亡率、發病率及體重變化情況Mortality, morbidity and weight changes
實驗動物的體重作為間接測定藥物毒性的參考指標。在實驗過程中，溶媒組、式（I）化合物 25 mg/kg及75 mg/kg組、QL1203 0.1 mg/隻組、Vectibix 0.1 mg/隻組、式（I）化合物25 mg/kg+QL1203 0.1 mg/隻聯合組及式（I）化合物25 mg/kg+Vectibix 0.1 mg/隻聯合組動物體重保持穩定，式（I）化合物75 mg/kg+Vectibix 0.1 mg/隻及式（I）化合物75 mg/kg+QL1203 0.1 mg/隻聯合組給藥後期有個別小鼠體重有所下降。所有小鼠無發病和死亡現象。The body weight of experimental animals is used as a reference index to indirectly determine drug toxicity. During the experiment, the vehicle group, compound of formula (I) 25 mg/kg and 75 mg/kg, QL1203 0.1 mg/piece group, Vectibix 0.1 mg/piece group, compound of formula (I) 25 mg/kg+QL1203 0.1 mg/animal weight in the combination group and compound of formula (I) 25 mg/kg+Vectibix 0.1 mg/animals in the combination group remained stable, compound of formula (I) 75 mg/kg+Vectibix 0.1 mg/animal and compound of formula (I) 75 mg/kg+QL1203 0.1 mg/mouse combination group had some weight loss in the late administration period. There was no morbidity or death in any mice.
腫瘤體積tumor volume
H1975 EGFR (Del19/T790M/C797S)異種移植瘤雌性BALB/c裸小鼠模型給予式（I）化合物各組腫瘤體積變化如表1-5所示。The changes in tumor volume in each group of H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model given the compound of formula (I) are shown in Table 1-5.
表1-5. 各組不同時間點的瘤體積
註： a. 平均值 ± SEM， b. 給藥後天數。 Note: a. Mean ± SEM, b. Number of days after administration.
腫瘤生長曲線tumor growth curve
H1975 EGFR (Del19/T790M/C797S) 異種移植瘤雌性BALB/c裸小鼠模型給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合治療後各組腫瘤生長曲線及相對腫瘤生長曲線如圖1和圖2所示。H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model after administration of compound of formula (I), QL1203, Vectibix, combination of compound of formula (I) and QL1203, and combination of compound of formula (I) and Vectibix The tumor growth curves and relative tumor growth curves of each group are shown in Figures 1 and 2.
抗腫瘤藥效評價指標Anti-tumor efficacy evaluation index
表1-6. 人肺癌細胞系H1975 EGFR (Del19/T790M/C797S) 異種移植瘤模型的抑瘤藥效評價（基於給藥後第21天腫瘤體積計算得出）
註： a. 平均值± SEM； b. 腫瘤生長抑制由T/C和TGI (TGI (%) = [1-(T 21-T 0)/ (V 21-V 0)] ×100) 計算； c. p值根據相對腫瘤體積計算，以Vehicle組為對照，用 T-test進行兩組間分析比較； d. p值根據相對腫瘤體積計算，以式（I）化合物 25 mg/kg組為對照，與式（I）化合物25 mg/kg + QL1203 0.1 mg/隻或式（I）化合物 25 mg/kg + Vectibix 0.1 mg/隻組兩組間用 T-test進行分析比較； e. p值根據相對腫瘤體積計算，以式（I）化合物 75 mg/kg組為對照，與式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻或式（I）化合物 75 mg/kg + Vectibix 0.1 mg/隻組兩組間用 T-test進行兩組間分析比較； f. p值根據相對腫瘤體積計算，以QL1203 0.1 mg/隻組為對照，與式（I）化合物 25 mg/kg + QL1203 0.1 mg/隻或式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻組兩組間用 T-test進行分析比較； g. p值根據相對腫瘤體積計算，以Vectibix 0.1 mg/隻組為對照，與式（I）化合物 25 mg/kg + Vectibix 0.1 mg/隻或式（I）化合物 75 mg/kg + Vectibix 0.1 mg/隻組兩組間用 T-test進行分析比較； h. p值根據相對腫瘤體積計算，以式（I）化合物 25 mg/kg + QL1203 0.1 mg/隻組為對照，與式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻或式（I）化合物 25 mg/kg + Vectibix 0.1 mg/隻組兩組間用 T-test進行分析比較； i. p值根據相對腫瘤體積計算，以式（I）化合物 75 mg/kg + Vectibix 0.1 mg/隻組為對照，與式（I）化合物 25 mg/kg + Vectibix 0.1 mg/隻或式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻組兩組間用 T-test進行分析比較。 Note: a. Mean ± SEM; b. Tumor growth inhibition was calculated by T/C and TGI (TGI (%) = [1-(T 21 -T 0 )/ (V 21 -V 0 )] ×100); c. The p value is calculated based on the relative tumor volume, with the Vehicle group as the control, and T-test is used to analyze and compare the two groups; d. The p value is calculated based on the relative tumor volume, with the 25 mg/kg group of the compound of formula (I) as the control. , T-test was used to analyze and compare the two groups with the compound of formula (I) 25 mg/kg + QL1203 0.1 mg/bird or the compound of formula (I) 25 mg/kg + Vectibix 0.1 mg/bird; e. The p value is based on The relative tumor volume was calculated using the compound of formula (I) 75 mg/kg group as the control, and the compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal or the compound of formula (I) 75 mg/kg + Vectibix 0.1 mg/ T-test was used to analyze and compare the two groups between the two groups; f. The p value was calculated based on the relative tumor volume, with QL1203 0.1 mg/group as the control, and the compound of formula (I) 25 mg/kg + QL1203 0.1 mg /animal or compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal group was analyzed and compared using T-test between the two groups; g. The p value was calculated based on the relative tumor volume, with the Vectibix 0.1 mg/animal group as the control. T-test was used to analyze and compare the two groups with the compound of formula (I) 25 mg/kg + Vectibix 0.1 mg/bird or the compound of formula (I) 75 mg/kg + Vectibix 0.1 mg/bird; h. p value was based on relative Tumor volume was calculated using the compound of formula (I) 25 mg/kg + QL1203 0.1 mg/animal group as the control, and the compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal or the compound of formula (I) 25 mg/kg + Vectibix 0.1 mg/only group was analyzed and compared using T-test ; i. The p value was calculated based on the relative tumor volume, with the compound of formula (I) 75 mg/kg + Vectibix 0.1 mg/only group as the control, and the formula (I) Compound 25 mg/kg + Vectibix 0.1 mg/bird or compound of formula (I) 75 mg/kg + QL1203 0.1 mg/bird group were analyzed and compared using T-test between the two groups.
實驗結果Experimental results
本實驗中，我們評價了受試物式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合在人肺癌細胞系H1975 EGFR (Del19/T790M/C797S) 移植瘤模型中的體內藥效。各組在不同時間點的腫瘤體積如表1-5、表1-6及圖1、圖2所示。In this experiment, we evaluated the test substances compound of formula (I), QL1203, Vectibix, the combination of compound of formula (I) and QL1203, and the combination of compound of formula (I) and Vectibix in the human lung cancer cell line H1975 EGFR (Del19/T790M/C797S ) In vivo drug efficacy in xenograft tumor models. The tumor volumes of each group at different time points are shown in Tables 1-5, 1-6 and Figures 1 and 2.
給藥後21天，溶媒對照組組荷瘤鼠的瘤體積達到1,683 mm 3。與溶媒對照組相比，單藥組的QL1203 0.1 mg/隻、Vectibix 0.1 mg/隻及式（I）化合物 25 mg/kg均未有顯著的抑瘤效果，腫瘤體積分別為1,955 mm 3（T/C=115.36%，TGI=-18.1%，p=0.487）、2,202 mm 3（T/C=130.78%，TGI=-34.6%，p=0.211）和1,639 mm 3（T/C=97.37%，TGI=2.9%，p=0.930）。聯合用藥的式（I）化合物25 mg/kg與QL1203 0.1 mg/隻或式（I）化合物25 mg/kg與Vectibix 0.1 mg/隻對腫瘤生長具有延緩作用，腫瘤體積分別為1,272 mm 3（T/C=75.46%，TGI=27.5%，p=0.127）和1,419 mm 3（T/C=83.86%，TGI=17.7%，p=0.256）。 21 days after administration, the tumor volume of the tumor-bearing mice in the vehicle control group reached 1,683 mm 3 . Compared with the vehicle control group, QL1203 0.1 mg/animal, Vectibix 0.1 mg/animal and compound of formula (I) 25 mg/kg in the single-drug group had no significant anti-tumor effect, and the tumor volumes were 1,955 mm 3 (T /C=115.36%, TGI=-18.1%, p=0.487), 2,202 mm 3 (T/C=130.78%, TGI=-34.6%, p=0.211) and 1,639 mm 3 ( T/C=97.37%, TGI=2.9%, p=0.930). The combination of 25 mg/kg compound of formula (I) and 0.1 mg of QL1203/animal or 25 mg/kg of compound of formula (I) and 0.1 mg of Vectibix/animal had a delaying effect on tumor growth. The tumor volume was 1,272 mm 3 (T /C=75.46%, TGI=27.5%, p=0.127) and 1,419 mm 3 (T/C=83.86%, TGI=17.7%, p=0.256).
聯合給藥組中，式（I）化合物75 mg/kg + QL1203 0.1 mg/隻以及式（I）化合物75 mg/kg + Vectibix 0.1 mg/隻抑瘤作用分別顯著好於QL1203 0.1 mg/隻單用組（p=0.001）、Vectibix 0.1 mg/隻單用組（p=0.004）及式（I）化合物 25 mg/kg + QL1203 0.1 mg/隻（p=2.13E-4）或式（I）化合物25 mg/kg + Vectibix 0.1 mg/隻（p=0.003）低劑量聯合給藥組，也顯著好於式（I）化合物75 mg/kg單用組（p=2.76E-4和p=1.32E-5）。In the combined administration group, the anti-tumor effects of the compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal and the compound of formula (I) 75 mg/kg + Vectibix 0.1 mg/animal were significantly better than those of QL1203 0.1 mg/animal alone. group (p=0.001), Vectibix 0.1 mg/animal alone group (p=0.004), and compound of formula (I) 25 mg/kg + QL1203 0.1 mg/animal (p=2.13E-4) or formula (I) The low-dose combined administration group of compound 25 mg/kg + Vectibix 0.1 mg/animal (p=0.003) was also significantly better than the compound of formula (I) 75 mg/kg alone group (p=2.76E-4 and p=1.32 E-5).
QL1203 0.1 mg/隻與Vectibix 0.1 mg/隻單用組之間，或QL1203 +式（I）化合物與Vectibix +式（I）化合物聯用組之間，抑瘤效果無顯著差異（p＞0.05）。There is no significant difference in the anti-tumor effect between QL1203 0.1 mg/unit and Vectibix 0.1 mg/unit alone, or between QL1203 + compound of formula (I) and Vectibix + compound of formula (I) combined group (p>0.05) .
綜上所述，式（I）化合物 25 mg/kg、QL1203 0.1 mg/隻及Vectibix 0.1 mg/隻單用藥組均無明顯抑瘤效果，25 mg/kg劑量下的式（I）化合物與QL1203或Vectibix聯用則對腫瘤生長具有一定延緩作用；式（I）化合物在75 mg/kg劑量下與QL1203或Vectibix聯用後抑瘤效果顯著增強。這表明式（I）化合物與QL1203或Vectibix的聯用具有協同效應。In summary, the compound of formula (I) 25 mg/kg, QL1203 0.1 mg/animal and Vectibix 0.1 mg/animal alone have no obvious anti-tumor effect. The compound of formula (I) and QL1203 at the dose of 25 mg/kg The combination with QL1203 or Vectibix has a certain delaying effect on tumor growth; the compound of formula (I) has a significantly enhanced tumor inhibitory effect when combined with QL1203 or Vectibix at a dose of 75 mg/kg. This indicates that the combination of compounds of formula (I) with QL1203 or Vectibix has a synergistic effect.
實施例二 Baf3 EGFR (L858R/T790M/C797S)皮下異種移植腫瘤BALB/c裸小鼠模型上的體內藥效Example 2 In vivo efficacy of Baf3 EGFR (L858R/T790M/C797S) subcutaneous xenograft tumor in BALB/c nude mouse model
本實驗的目的在於評估小分子式（I）化合物與帕尼單抗聯用在Baf3 EGFR (L858R/T790M/C797S)皮下異種移植腫瘤BALB/c裸小鼠模型上的體內藥效。The purpose of this experiment was to evaluate the in vivo efficacy of the small molecule compound of formula (I) in combination with panitumumab in the BALB/c nude mouse model of subcutaneous Baf3 EGFR (L858R/T790M/C797S) subcutaneous xenograft tumors.
實驗方案Experimental plan
表2-1. 體內藥效實驗動物分組及給藥方案
註： a.N：每組小鼠數目； b.如果體重下降超過15%時，小鼠將作停藥觀察處理，直至其體重恢復至10%以上再繼續給藥； c.溶媒為5%無水乙醇和聚氧乙烯40氫化蓖麻油混合溶液(1:1)+ 95%滅菌注射用水。 Note: a.N: number of mice in each group; b. If the body weight drops by more than 15%, the mice will be stopped for observation and treatment until their body weight recovers to more than 10% before continuing the drug; c. The solvent is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection.
實驗樣品Experimental samples
式（I）化合物、QL1203、Vectibix的樣品供應同實施例一。The sample supplies of the compound of formula (I), QL1203, and Vectibix are the same as those in Example 1.
實驗方法與步驟Experimental methods and procedures
細胞培養cell culture
細胞系Baf3 EGFR(L858R/T790M/C797S)體外培養，培養條件為RPMI1640培養基中加10%胎牛血清，1%雙抗(青黴素/鏈黴素溶液)，37℃，5% CO 2培養。一週兩次常規離心處理傳代。當細胞匯合度為80%-90%，數量到達要求時，收取細胞，計數，接種。 The cell line Baf3 EGFR (L858R/T790M/C797S) was cultured in vitro. The culture conditions were RPMI1640 medium plus 10% fetal calf serum, 1% double antibody (penicillin/streptomycin solution), 37°C, and 5% CO2 . Passaging was performed by routine centrifugation twice a week. When the cell confluence is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
腫瘤細胞接種tumor cell inoculation
將含有5×10 5個Baf3 EGFR(L858R/T790M/C797S)細胞的PBS同Matrigel按1：1的比例混合(終體積為100μL)皮下接種於每隻小鼠的右前肢腋窩皮下，在細胞接種後第10天，入組動物腫瘤平均體積達到105 mm 3時開始分組給藥。實驗分組和給藥方案見表2-1。 PBS containing 5×10 5 Baf3 EGFR (L858R/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume: 100 μL) and inoculated subcutaneously into the axilla of the right forelimb of each mouse. On the 10th day afterward, when the average tumor volume of the animals in the group reached 105 mm3 , drug administration was started in groups. The experimental grouping and dosage regimen are shown in Table 2-1.
受試物的配製Preparation of test substance
表2-2. 受試物配製方法
註：藥物現配現用，在給藥前需要輕輕將藥物充分混勻。Note: The medicine is ready for use. It needs to be mixed gently and thoroughly before administration.
實驗動物日常觀察Daily observation of experimental animals
每天監測動物的健康狀況及死亡情況，例行檢查包括觀察腫瘤生長和藥物治療對動物日常行為表現的影響如行為活動，攝食攝水量(僅目測)，體重變化(每天測量一次體重)，外觀體征或其它不正常情況。基於各組動物數量記錄了組內動物死亡數和副作用。Monitor the health status and death of the animals every day. Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), weight changes (measure weight once a day), and appearance signs. or other abnormal conditions. The number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
腫瘤測量和實驗指標Tumor Measurements and Experimental Indicators
實驗指標是考察腫瘤生長是否被抑制、延緩或治癒。每週三次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a×b 2，a和b分別表示腫瘤的長徑和短徑。 The experimental indicator is to examine whether tumor growth is inhibited, delayed or cured. Tumor diameter was measured three times a week using vernier calipers. The calculation formula of tumor volume is: V = 0.5a×b 2 , where a and b represent the long and short diameters of the tumor respectively.
化合物的抑瘤療效用TGI(%)或相對腫瘤增殖率T/C(%)評價。TGI(%)，反映腫瘤生長抑制率。TGI(%)的計算：TGI(%)=[1-(某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積)/(溶媒對照組治療結束時平均瘤體積－溶媒對照組開始治療時平均瘤體積)]×100%。The tumor inhibitory efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [1-(Average tumor volume at the end of administration in a certain treatment group - Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the vehicle control group - The average tumor volume in the vehicle control group at the beginning of treatment)] × 100%.
相對腫瘤增殖率T/C(%)：計算公式如下：T/C % = TRTV / CRTV × 100 %(TRTV：治療組RTV；CRTV：陰性對照組RTV)。根據腫瘤測量的結果計算出相對腫瘤體積(relative tumor volume，RTV)，計算公式為 RTV = Vt / V0，其中V0是分組給藥時(即d0)測量所得平均腫瘤體積，Vt為某一次測量時的平均腫瘤體積，TRTV與CRTV取同一天資料。Relative tumor proliferation rate T/C (%): The calculation formula is as follows: T/C % = TRTV / CRTV × 100 % (TRTV: RTV of treatment group; CRTV: RTV of negative control group). The relative tumor volume (RTV) is calculated based on the results of tumor measurement. The calculation formula is RTV = Vt / V0, where V0 is the average tumor volume measured at the time of group administration (i.e. d0), and Vt is the measurement at a certain time. The average tumor volume, TRTV and CRTV are taken from the same day.
統計分析Statistical analysis
統計分析，包括每個組的每個時間點的腫瘤體積的平均值和標準誤(SEM)(具體資料見表2-3)。由於第10天各組小鼠均存活且各治療組表現出較好的治療效果，第14天實驗結束，因此分別基於第10天和第14天的資料進行統計學分析評估組間差異。兩組間比較用 T-test進行分析，用SPSS 17.0進行所有資料分析。 p＜ 0.05認為有顯著性差異。 Statistical analysis included the mean and standard error (SEM) of tumor volume at each time point in each group (see Table 2-3 for specific information). Since all mice in each group survived on the 10th day and each treatment group showed good therapeutic effects, the experiment ended on the 14th day. Therefore, statistical analysis was performed to evaluate the differences between the groups based on the data on the 10th and 14th days. Comparisons between the two groups were analyzed using T-test , and SPSS 17.0 was used for all data analysis. p < 0.05 was considered a significant difference.
實驗結果Experimental results
死亡率、發病率及體重變化情況Mortality, morbidity and weight changes
在此模型中溶媒組、QL1203 0.1 mg/隻組和Vectibix 0.1 mg/隻組動物體重保持穩定，式（I）化合物 75 mg/kg單藥組、式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻聯合組及式（I）化合物 75 mg/kg + Vectibix 0.1 mg/隻聯合組部分動物出現體重下降，但無動物發病或死亡。In this model, the body weight of animals in the vehicle group, QL1203 0.1 mg/animal group and Vectibix 0.1 mg/animal group remained stable. The compound of formula (I) 75 mg/kg single drug group, the compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal combination group and formula (I) compound 75 mg/kg + Vectibix 0.1 mg/animal combination group showed weight loss in some animals, but no animal became ill or died.
腫瘤體積tumor volume
Baf3 EGFR(L858R/T790M/C797S)異種移植瘤雌性BALB/c裸小鼠模型給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合治療後各組腫瘤體積變化如表2-3所示。Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model after administration of compound of formula (I), QL1203, Vectibix, combination of compound of formula (I) and QL1203, and combination of compound of formula (I) and Vectibix The changes in tumor volume in each group are shown in Table 2-3.
表2-3. 各組不同時間點的瘤體積
註：a. 平均值 ± SEM； b. 給藥後天數。Note: a. Mean ± SEM; b. Days after administration.
腫瘤生長曲線tumor growth curve
Baf3 EGFR(L858R/T790M/C797S)異種移植瘤雌性BALB/c裸小鼠模型給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合治療後各組腫瘤生長曲線及相對腫瘤生長曲線如圖3和圖4所示。Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model after administration of compound of formula (I), QL1203, Vectibix, combination of compound of formula (I) and QL1203, and combination of compound of formula (I) and Vectibix The tumor growth curves and relative tumor growth curves of each group are shown in Figures 3 and 4.
抗腫瘤藥效評價指標Anti-tumor efficacy evaluation index
表2-4. Baf3 EGFR(L858R/T790M/C797S)異種移植瘤模型的的抑瘤藥效評價（基於給藥後第10天腫瘤體積計算得出）
註： a. 平均值±SEM； b. 腫瘤生長抑制T/C和TGI的具體計算見統計分析部分； c. p值根據不同組中各小鼠的相對腫瘤體積以溶媒組為對照運用 T-test進行分析； d. p值根據不同組中各小鼠的相對腫瘤體積以式（I）化合物 75 mg/kg組為對照運用 T-test進行分析； e. p值根據不同組中各小鼠的相對腫瘤體積以QL1203 0.1 mg/隻組為對照運用 T-test進行分析； f. p值根據不同組中各小鼠的相對腫瘤體積以式（I）化合物75 mg/kg + Vectibix 0.1 mg/隻組為對照運用 T-test進行分析。 Note: a. Mean ± SEM; b. The specific calculation of tumor growth inhibition T/C and TGI is shown in the statistical analysis section; c. The p value is based on the relative tumor volume of each mouse in different groups, using the vehicle group as the control and using T- test is used for analysis; d. The p value is based on the relative tumor volume of each mouse in different groups, and the compound of formula (I) 75 mg/kg group is used as a control for T-test analysis; e. The p value is based on the relative tumor volume of each mouse in different groups. The relative tumor volume of QL1203 0.1 mg/mouse group was used as the control group for analysis using T-test ; f. The p value was based on the relative tumor volume of each mouse in different groups using formula (I) compound 75 mg/kg + Vectibix 0.1 mg/ Only group was used as a control for analysis using T-test .
表2-5. Baf3 EGFR(L858R/T790M/C797S)異種移植瘤模型的抑瘤藥效評價(基於給藥後第14天腫瘤體積計算得出)
註： a. 平均值±SEM； b. p值根據不同組中各小鼠的相對腫瘤體積以式（I）化合物 75 mg/kg組為對照運用 T-test進行分析； c. p值根據不同組中各小鼠的相對腫瘤體積以QL1203 0.1 mg/隻組為對照運用 T-test進行分析； d. p值根據不同組中各小鼠的相對腫瘤體積以式（I）化合物75 mg/kg + Vectibix 0.1 mg/隻組為對照運用 T-test進行分析； e. 實驗終點，腫瘤體積大於0，小於初始腫瘤體積視為部分消退； f. 實驗終點，腫瘤體積為0視為完全消退。 Note: a. Mean ± SEM; b. The p value is based on the relative tumor volume of each mouse in different groups. The 75 mg/kg group of the compound of formula (I) was used as a control to analyze using T-test ; c. The p value is based on different The relative tumor volume of each mouse in the group was analyzed using T-test with the QL1203 0.1 mg/mouse group as the control; d. The p value was based on the relative tumor volume of each mouse in different groups using the formula (I) compound 75 mg/kg. + Vectibix 0.1 mg/group was used as a control group for analysis using T-test ; e. At the end of the experiment, the tumor volume was greater than 0 and less than the initial tumor volume was considered partial regression; f. At the end of the experiment, the tumor volume was 0, which was considered complete regression.
實驗結果及討論Experimental results and discussion
死亡率、發病率及體重變化情況Mortality, morbidity and weight changes
在此模型中溶媒組、溶媒組、QL1203單藥組、Vectibix 單藥組動物體重保持穩定，式（I）化合物單用組、式（I）化合物 75 mg/kg + QL1203 0.1 mg/隻聯合組及式（I）化合物75 mg/kg + Vectibix 0.1 mg/隻聯合組有部分動物有一定程度的體重下降，但無動物發病或死亡。In this model, the body weight of animals in the vehicle group, vehicle group, QL1203 single drug group, and Vectibix single drug group remained stable, and the compound of formula (I) alone group, the compound of formula (I) 75 mg/kg + QL1203 0.1 mg/animal combined group In the combination group of compound of formula (I) 75 mg/kg + Vectibix 0.1 mg/animal, some animals had a certain degree of weight loss, but no animal became ill or died.
在本實驗中，我們評價了受試藥物式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合在小鼠原B細胞Baf3 EGFR(L858R/T790M/C797S)異種移植瘤模型中的體內藥效。各組在不同時間點的腫瘤體積變化如表2-3、表2-4、表2-5及圖3、圖4所示。In this experiment, we evaluated the effects of the test drugs compound of formula (I), QL1203, Vectibix, the combination of compound of formula (I) and QL1203, and the combination of compound of formula (I) and Vectibix on mouse primary B cells Baf3 EGFR (L858R/T790M /C797S) in vivo efficacy in xenograft tumor models. The changes in tumor volume in each group at different time points are shown in Table 2-3, Table 2-4, Table 2-5 and Figure 3 and Figure 4.
開始給藥後第10天，溶媒對照組荷瘤鼠的瘤體積達到449 mm 3。與溶媒對照組相比，受試藥物式（I）化合物單藥組、QL1203單藥組、Vectibix單藥組及式（I）化合物與QL1203或Vectibix聯合組均具有顯著的抗腫瘤作用，腫瘤體積分別為289 mm 3(T/C=64.26%, TGI=46.55%, p=0.012)、123 mm 3(T/C=27.27%, TGI=95.01%, p=0.015)、98 mm 3(T/C=21.84%, TGI=102.12%, p=0.010)、58 mm 3(T/C=12.86%, TGI=113.86%, p=0.008)和56 mm 3(T/C=12.54%, TGI=114.24%, p=0.008)。QL1203和Vectibix單藥組之間，或式（I）化合物+ QL1203和式（I）化合物+ Vectibix聯用組之間抑瘤效果無顯著差異（ p ＞0.05）。且式（I）化合物與QL1203的聯用組或式（I）化合物與Vectibix的聯用組抑瘤效果顯著好於式（I）化合物、QL1203或Vectibix單用組（ p ＜0.05）。 On the 10th day after the start of administration, the tumor volume of the tumor-bearing mice in the vehicle control group reached 449 mm 3 . Compared with the vehicle control group, the test drug compound formula (I) single drug group, QL1203 single drug group, Vectibix single drug group, and the compound formula (I) combined with QL1203 or Vectibix group all had significant anti-tumor effects, and the tumor volume They were 289 mm 3 (T/C=64.26%, TGI=46.55%, p =0.012), 123 mm 3 (T/C=27.27%, TGI=95.01%, p =0.015), 98 mm 3 (T/ C=21.84%, TGI=102.12%, p =0.010), 58 mm 3 (T/C=12.86%, TGI=113.86%, p =0.008) and 56 mm 3 (T/C=12.54%, TGI=114.24 %, p =0.008). There was no significant difference in the antitumor effect between QL1203 and Vectibix single-drug groups, or between the compound of formula (I) + QL1203 and the compound of formula (I) + Vectibix combination groups ( p ＞ 0.05). Moreover, the anti-tumor effect of the combination of the compound of formula (I) and QL1203 or the combination of the compound of formula (I) and Vectibix was significantly better than that of the compound of formula (I), QL1203 or Vectibix alone ( p ＜ 0.05).
給藥後第14天，實驗終點，式（I）化合物單藥組、QL1203單藥組、Vectibix單藥組、式（I）化合物+ QL1203聯合給藥組及式（I）化合物+ Vectibix聯合給藥組的腫瘤體積分別為483 mm 3，225 mm 3，171 mm 3，51 mm 3和58 mm 3，各組分別有0/8（0%），0/8（0%），2/8（25%），6/8（75%），5/8（62.5%）隻動物腫瘤達到部分消退，分別有0/8（0%），0/8（0%），0/8（0%），1/8（12.5%），2/8（25%）隻動物腫瘤達到完全消退。由此可見，式（I）化合物與QL1203或Vectibix聯用後顯示出比式（I）化合物、QL1203或Vectibix單藥使用具有更好的抑瘤效果。 On the 14th day after administration, experimental endpoint, compound of formula (I) single drug group, QL1203 single drug group, Vectibix single drug group, compound of formula (I) + QL1203 combined administration group and compound of formula (I) + Vectibix combined administration group The tumor volumes of the drug groups were 483 mm 3 , 225 mm 3 , 171 mm 3 , 51 mm 3 and 58 mm 3 respectively, with 0/8 (0%), 0/8 (0%) and 2/8 in each group respectively. (25%), 6/8 (75%), 5/8 (62.5%) animals achieved partial tumor regression, respectively 0/8 (0%), 0/8 (0%), 0/8 (0 %), 1/8 (12.5%), and 2/8 (25%) animals achieved complete tumor regression. It can be seen that the combination of the compound of formula (I) and QL1203 or Vectibix shows better anti-tumor effect than the compound of formula (I), QL1203 or Vectibix alone.
總結論General conclusion
本發明的式（I）化合物與帕尼單抗聯合使用後，抑瘤效果顯著增強，具有明顯的協同效應。After the compound of formula (I) of the present invention is used in combination with panitumumab, the tumor inhibitory effect is significantly enhanced and has an obvious synergistic effect.
以上所述僅為本發明的較佳實施例，並不用以限制本發明，凡在本發明的精神和原則之內，所做的任何修改、等同替換、改進等，均應包含在本發明保護的範圍之內。The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.
無without
此處所說明的附圖用來提供對本發明的進一步理解，構成本發明的一部分，本發明的示意性實施例及其說明用於解釋本發明，並不構成對本發明的不當限定。The drawings described here are used to provide a further understanding of the present invention and constitute a part of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.
圖1為人肺癌細胞系H1975 EGFR (Del19/T790M/C797S) 異種移植瘤模型荷瘤鼠在給予受試藥物式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合後的腫瘤生長曲線；Figure 1 shows the human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model in tumor-bearing mice given the test drugs compound of formula (I), QL1203, Vectibix, compound of formula (I) and QL1203 combination and formula (I ) Tumor growth curve after combination of compound and Vectibix;
圖2為人肺癌細胞系H1975 EGFR (Del19/T790M/C797S)異種移植瘤模型荷瘤鼠在給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合後的相對腫瘤生長曲線；Figure 2 shows the effects of human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model on tumor-bearing mice after administration of compound of formula (I), QL1203, Vectibix, combination of compound of formula (I) and QL1203, and compound of formula (I) and Relative tumor growth curve after Vectibix combination;
圖3為Baf3 EGFR(L858R/T790M/C797S)異種移植瘤模型荷瘤鼠在給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合後的腫瘤生長曲線；Figure 3 shows the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice after administration of compound of formula (I), QL1203, Vectibix, combination of compound of formula (I) and QL1203, and combination of compound of formula (I) and Vectibix. tumor growth curve;
圖4為Baf3 EGFR(L858R/T790M/C797S)異種移植瘤模型荷瘤鼠在給予式（I）化合物、QL1203、Vectibix、式（I）化合物和QL1203聯合及式（I）化合物和Vectibix聯合後的相對腫瘤生長曲線。Figure 4 shows the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice after administration of the compound of formula (I), QL1203, Vectibix, the combination of the compound of formula (I) and QL1203, and the combination of the compound of formula (I) and Vectibix. Relative tumor growth curve.
TW202339767A_112102048_SEQL.xmlTW202339767A_112102048_SEQL.xml
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