[go: up one dir, main page]

WO2017045595A1 - Application du gmp-amp cyclique (cgamp) en association avec du bévacizumab au traitement de la résistance tumorale - Google Patents

Application du gmp-amp cyclique (cgamp) en association avec du bévacizumab au traitement de la résistance tumorale Download PDF

Info

Publication number
WO2017045595A1
WO2017045595A1 PCT/CN2016/098931 CN2016098931W WO2017045595A1 WO 2017045595 A1 WO2017045595 A1 WO 2017045595A1 CN 2016098931 W CN2016098931 W CN 2016098931W WO 2017045595 A1 WO2017045595 A1 WO 2017045595A1
Authority
WO
WIPO (PCT)
Prior art keywords
bevacizumab
cgamp
tumor
combination
application
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/098931
Other languages
English (en)
Chinese (zh)
Inventor
张跃茹
袁红
谭瀛轩
谭相石
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Liaocheng City Orient Biomedical Technology Co Ltd
Original Assignee
Liaocheng City Orient Biomedical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liaocheng City Orient Biomedical Technology Co Ltd filed Critical Liaocheng City Orient Biomedical Technology Co Ltd
Publication of WO2017045595A1 publication Critical patent/WO2017045595A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to the application of a cyclic dinucleotide (cGAMP) combined with bevacizumab in antitumor and in preparing antitumor drugs.
  • cGAMP cyclic dinucleotide
  • Tumors are currently a major class of diseases that seriously endanger human health. They are characterized by abnormal cell proliferation and differentiation, and are difficult to suppress. According to WHO experts, by 2020, the number of cancers in the global population will reach 20 million, and the death toll will reach 12 million. Therefore, cancer will become the biggest killer of human beings in this century, posing the most serious threat to human survival. . In China, the incidence and mortality rates of lung cancer, colorectal cancer, stomach cancer, liver cancer, etc. are among the highest in all kinds of malignant tumors. According to the National Cancer Registry (2012 China Cancer Registration Annual Report), new tumor cases occur every year. About 3.12 million cases, an average of 8550 people per day, 6 people per minute in the country were diagnosed with cancer.
  • chemotherapeutic drugs are mainly to prevent the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or protein, or directly affect these macromolecules, thereby inhibiting the proliferation and death of tumor cells. Some drugs can also inhibit tumor growth by altering the hormone balance in the body.
  • anti-tumor drugs have been developed into 6 categories: 1 antimetabolites; 2 alkylating agents; 3 cytotoxic antibiotics; 4 plant alkaloids and other natural drugs; 5 anti-tumor hormones; 6 platinum and other anti-tumor drugs .
  • TKI small molecule tyrosine kinase inhibitors
  • other hot-acting mechanisms include immunostimulants, angiogenesis inhibitors, cell cycle inhibitors, immunosuppressants and stimulators, protein kinase inhibitors, and the like.
  • immunomodulators have been used clinically and for tumor therapy.
  • Microbial and viral DNA can induce an endogenous potent immune response by stimulating interferon secretion in infected mammalian cells.
  • the immune response of the endoplasmic reticulum (ER) receptor protein (STING) to cytoplasmic DNA is an essential factor.
  • ER endoplasmic reticulum
  • STING endoplasmic reticulum receptor protein
  • cGAMP cyclized cGMP-AMP dinucleotide synthetase
  • cGAMP is a cytoplasmic DNA sensor that acts as a second messenger to stimulate INF- ⁇ induction by STING, mediates the activation of TBK1 and IRF-3, and then initiates transcription of the INF- ⁇ gene.
  • cGAMP binds to STING, activates the transcription factor IRF3 and produces beta interferon. Through the STING pathway, cGAMP can be used as an immunomodulator to activate the immune system against tumors.
  • VEGF Vascular endothelial growth factor
  • the VEGF protein was successfully purified and identified by scientists from two biotechnology companies in the United States in 1989, and the gene sequence was cloned and determined, demonstrating that VPF and VEGF are the same protein encoded by the same gene.
  • VEGF has six isoforms: VEGF-A, -B, -C, -D, and -E; its molecular weight ranges from 35 to 44 kDa, and each haplotype specifically interacts with three "vascular endothelial growth.”
  • a specific combination of factor receptors (VEGFR-1, -2, and -3) is combined.
  • VEGF is a highly conserved homodimeric glycoprotein.
  • VEGF121, VEGF145, VEGF165, VEGF185 and VEGF206 are produced.
  • VEGF121, VEGF145 and VEGF165 are secreted soluble proteins, which can directly act on vascular endothelial cells to promote vascular endothelial cell proliferation. Increase vascular permeability.
  • Dr. Folkman of Harvard University in the United States proposed the famous Folkman theory that tumor tissue growth must rely on neovascularization to provide sufficient oxygen and nutrients to maintain. It is considered to be the basis for clinical application of VEGF.
  • Bevacizumab (trade name: Avastin) is a VEGF monoclonal antibody that inhibits vascular endothelial growth factor and is used in the treatment of various metastatic cancers. It is a popular drug for cancer treatment in Roche. Avastin’s 2009 sales reached $5.9 billion. Bevacizumab is a drug that blocks angiogenesis. It blocks the blood supply to tumors by inhibiting the action of vascular endothelial growth factor, inhibits the spread of tumors in the body, and enhances the effect of chemotherapy. The drug is approved by the US Drug Administration for the treatment of lung, colon and rectal cancer and is approved for breast cancer treatment in Europe.
  • cGAMP combined with bevacizumab can significantly inhibit the growth of a variety of tumor cells, has obvious anti-tumor effect, and is superior to bevacizumab alone in treating tumors, so cGAMP can be used for preparation of anti-tumor.
  • the drug or combination is used to treat the tumor.
  • the tumor includes, but is not limited to, adenocarcinoma, lung cancer, colon cancer, melanoma, and the like.
  • cGAMP (cyclized-GMP-AMP) was synthesized by cyclized cGMP-AMP dinucleotide synthetase (cGAS) under the activation conditions of DNA binding according to literature methods. The purity is above 98%. (Ping weiLi, et al., Immunity, 2013, 39(6), 1019-1031.)
  • the bevacizumab variable region was fused to the murine IgG2b constant region as a hybrid antibody, which was synthesized by Nanjing Kingsray and cloned into the pTT3 plasmid.
  • the plasmid extraction kit, the Protein A column, the molecular sieve, and the endotoxin-purifying column and the endotoxin assay kit were purchased from General Medical or Nanjing Kingsray.
  • the 293F cells were transiently transfected with bevacizumab and purified by Protein A column, molecular sieve and endotoxin-clearing column. The purity was 90%, the endotoxin was less than 1 EU/ml, the protein was dissolved in PBS, and stored after lyophilization.
  • Example 3 Anti-tumor effect of cGAMP (cyclized-GMP-AMP)
  • the tumor-bearing mouse model was used to examine the inhibitory effect of cGAMP on the growth of subcutaneous xenografts in animals.
  • Solvent normal saline.
  • Preparation method Prepare a solution of the desired concentration with a physiological saline solution before use.
  • Test drug concentration 5 mg/ml, 10 mg/ml, 20 mg/ml. .
  • mice All C57BL/6 mice were given free access to food and water and were housed at the Experimental Animal Center of a military medical university of the People's Liberation Army at room temperature (23 ⁇ 2) °C. Both the feed and the water were autoclaved, and all the experimental feeding processes were SPF grade.
  • CGAMP was injected into the tail vein of mice, and 3 dose groups were set: 5 mg/kg, 10 mg/kg, 20 mg/kg.
  • Positive control bevacizumab at a dose of 10 mg/kg
  • the number of bevacizumab administrations once every 4 days, 4 times.
  • Adenocarcinoma cell line MC38 lung cancer cell line LLC, melanoma cell line B16-F10, colon cancer cell line MC38, purchased from the Chinese Academy of Sciences cell bank or ATCC.
  • adenocarcinoma cell line MC38 Six subcutaneous xenograft models were prepared: adenocarcinoma cell line MC38, lung cancer cell line LLC, melanoma cell line B16-F10, colon cancer cell line MC38, and the effect of cGAMP combined with bevacizumab was observed.
  • Adenocarcinoma cell line MC38, lung cancer cell line LLC, melanoma cell line B16-F10, colon cancer cell line MC38 were cultured and passaged.
  • the cells were collected in the log phase of the cells to prepare a cell suspension at a concentration of (5.0 ⁇ 10 6 )/ml per ml, and the C57BL/6 mouse was injected into the right forelimb with a 0.2 ml cell suspension (the number of cells was 1.0 ⁇ 10 6 cells/cell). ), about 7-10 days, the tumor grows to a diameter of about 3-6 mm, and the tumor is successful.
  • mice Randomly divided into 5 groups, each group of 10 mice:
  • Negative control group Intravenous saline group
  • Bevacizumab administration group (intravenous injection 10mg/kg group)
  • cGAMP low-dose combination group intravenous cGAMP 5mg/kg plus bevacizumab 10mg/kg
  • cGAMP medium dose combination group (intravenous cGAMP 10mg/kg plus bevacizumab 10mg/kg)
  • High-dose cGAMP combination group (intravenous cGAMP 20 mg/kg plus bevacizumab 10 mg/kg).
  • cGAMP was administered once a day for 14 days.
  • Bevacizumab was administered once every 4 days for a total of 4 times.
  • Data were expressed as x ⁇ s, and were processed by SPSS10.0 software.
  • C57BL/6 mice were subcutaneously inoculated with tumor cells to prepare a subcutaneous xenograft model.
  • cGAMP combined with bevacizumab significantly inhibited tumor growth.
  • the tumor weight after 14 days of administration was significantly lower than that of bevacizumab control group (P). ⁇ 0.05, P ⁇ 0.01), indicating that cGAMP combined with bevacizumab Bevacizumab is used alone, so cGAMP can be used in combination with bevacizumab and has a significant anti-tumor effect.
  • the specific results are shown in Tables 1 to 4.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'application de la GMP-AMP cyclique (cGAMP) en association avec du bévacizumab au traitement de la résistance tumorale. Les recherches ont montré que l'association de cGAMP et de bévacizumab pouvait inhiber significativement la croissance de nombreuses cellules tumorales, avait une efficacité démontrée sur la résistance tumorale, et pouvait être utilisée pour la préparation de médicaments antitumoraux. Un modèle de tumeurs transplantables en sous-cutané chez la souris C57BL/6 a montré que l'association de cGAMP et de bévacizumab présentait des effets significatifs d'inhibition sur la lignée cellulaire d'adénocarcinome MC38, sur la lignée cellulaire de cancer du poumon LLC, sur les lignées cellulaires de mélanome B16 et F10, et sur la lignée cellulaire de cancer du côlon MC38, et que ses effets étaient meilleurs que les effets d'une monothérapie. Par conséquent, l'association de cGAMP et de bévacizumab peut être utilisée pour traiter des tumeurs.
PCT/CN2016/098931 2015-09-18 2016-09-13 Application du gmp-amp cyclique (cgamp) en association avec du bévacizumab au traitement de la résistance tumorale Ceased WO2017045595A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510597098.8A CN106540255A (zh) 2015-09-18 2015-09-18 环二核苷酸cGAMP联合贝伐珠单抗在抗肿瘤中的应用
CN201510597098.8 2015-09-18

Publications (1)

Publication Number Publication Date
WO2017045595A1 true WO2017045595A1 (fr) 2017-03-23

Family

ID=58288031

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/098931 Ceased WO2017045595A1 (fr) 2015-09-18 2016-09-13 Application du gmp-amp cyclique (cgamp) en association avec du bévacizumab au traitement de la résistance tumorale

Country Status (2)

Country Link
CN (1) CN106540255A (fr)
WO (1) WO2017045595A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024255214A1 (fr) * 2023-06-16 2024-12-19 桂林医学院 Utilisation d'un sel de sodium de gmp-amp 2,3-cyclique dans la préparation d'un médicament antitumoral

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113546172A (zh) * 2020-04-24 2021-10-26 山东大学齐鲁医院 Vegf抑制剂在制备治疗缺氧相关疾病药物中的应用
CN117144004B (zh) * 2023-07-21 2024-08-30 中山大学附属第六医院 14-3-3σ在结肠癌治疗中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014099824A1 (fr) * 2012-12-19 2014-06-26 Board Of Regents, The University Of Texas System Ciblage pharmaceutique d'une voie de signalisation de dinucléotide cyclique chez un mammifère
CN103908468A (zh) * 2014-04-21 2014-07-09 复旦大学 环二核苷酸cGAMP在制备抗肿瘤药物中的应用
WO2014179760A1 (fr) * 2013-05-03 2014-11-06 The Regents Of The University Of California Induction de dinucléotide cyclique de l'interféron de type i
WO2014189805A1 (fr) * 2013-05-18 2014-11-27 Auro Biotech, Inc. Compositions et procédés d'activation de la signalisation dépendante de « stimulateur de gènes d'interféron »

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SMT202000561T1 (it) * 2011-11-28 2021-01-05 Merck Patent Gmbh Anticorpi anti-pd-l1 e usi relativi
CN103417964A (zh) * 2012-05-17 2013-12-04 江苏先声药物研究有限公司 一种抗vegf抗体的用途
CN104507538B (zh) * 2012-06-08 2018-04-06 艾杜罗生物科技公司 癌症免疫疗法的组合物和方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014099824A1 (fr) * 2012-12-19 2014-06-26 Board Of Regents, The University Of Texas System Ciblage pharmaceutique d'une voie de signalisation de dinucléotide cyclique chez un mammifère
WO2014179760A1 (fr) * 2013-05-03 2014-11-06 The Regents Of The University Of California Induction de dinucléotide cyclique de l'interféron de type i
WO2014189805A1 (fr) * 2013-05-18 2014-11-27 Auro Biotech, Inc. Compositions et procédés d'activation de la signalisation dépendante de « stimulateur de gènes d'interféron »
CN103908468A (zh) * 2014-04-21 2014-07-09 复旦大学 环二核苷酸cGAMP在制备抗肿瘤药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI, WENKAI: "kang4zhong3liu2xue2guan2 shenglcheng2zhi4liao2 de xin1ce4lue4", JOURNAL OF BINZHOU MEDICAL UNIVERSITY, vol. 37, no. 5, 31 October 2014 (2014-10-31), pages 379 - 381 *
QANG, PENG, DANLKANG4 AVASTIN(BEVACIZUMAB) ZAI4 ZHONG3LIU2 ZHI4LIAO2 ZHONGLDE YING4TONG4 YAN2JIUL JIN4ZHAN3, GUO2WAI4 YILXUE2 ZHONTG3LIU2 FENLCE4, vol. 31, 31 December 2004 (2004-12-31), pages 1 - 4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024255214A1 (fr) * 2023-06-16 2024-12-19 桂林医学院 Utilisation d'un sel de sodium de gmp-amp 2,3-cyclique dans la préparation d'un médicament antitumoral

Also Published As

Publication number Publication date
CN106540255A (zh) 2017-03-29

Similar Documents

Publication Publication Date Title
CN103908468B (zh) 环二核苷酸cGAMP在制备抗肿瘤药物中的应用
Wang et al. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development
CN110833546B (zh) 通佐溴胺在治疗胃癌中的用途
WO2017162055A1 (fr) Applications d'une guanosine monophosphate cyclique et d'une adénosine monophosphate cyclique (cgamp) et d'un liposome à action antitumorale
CN106540256A (zh) 环二核苷酸-脂质体偶联单克隆抗体在抗肿瘤中的应用
WO2022052874A1 (fr) Utilisation de chiauranib en combinaison avec un inhibiteur de point de contrôle immunitaire en thérapie antitumorale
US20200377545A1 (en) Novel anti-tumor compound and application thereof in preparing anti-tumor drugs
WO2021027704A1 (fr) Application d'un polypeptide ou d'un dérivé de dernier
CN110064045B (zh) 微肽cip2a-bp在治疗癌症中的应用
WO2017045595A1 (fr) Application du gmp-amp cyclique (cgamp) en association avec du bévacizumab au traitement de la résistance tumorale
CN108498802A (zh) 用于治疗非小细胞肺癌的药物组合物及其制剂
JP2022500054A (ja) 抗腫瘍アレナウイルスおよびアレナウイルス変異体を生産するための方法
CN109674788B (zh) 羧胺三唑与ido1抑制剂组合在抗肿瘤中的用途
CN110215511B (zh) 微肽asrps在治疗癌症中的应用
CN112569358B (zh) 培干扰素和原癌基因产物靶向抑制剂在协同抑制肿瘤中的应用
US20220378879A1 (en) Application of peg interferon and protooncogene product targeting inhibitor in synergistic treatment of renal carcinoma
CN108992463B (zh) 一种治疗肺癌的组合物及药物制剂
CN106692967A (zh) 环二核苷酸cGAMP联合PD1的抗体（Nivolumab）在制备抗肿瘤药物中的应用
Wang et al. Fusion of dual-targeting peptides with MAP30 promotes the apoptosis of MDA-MB-231 breast cancer cells
EP4591868A1 (fr) Médicament pour la prévention et le traitement d'une tumeur et utilisation associée
WO2019037671A1 (fr) Médicament pour son utilisation combinée dans le traitement du cancer
CN118184759A (zh) Atap多肽及其疫苗的制备方法和应用
CN120549940A (zh) 一种具有fgfr3-tacc3融合基因的肿瘤的联合用药物及其应用
CN117653735A (zh) 溶瘤病毒与血管内皮生长因子受体-2抑制剂在制备治疗骨与软组织肿瘤药物中的应用
CN118987016A (zh) 反义寡核苷酸在制备治疗胶质瘤药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16845709

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16845709

Country of ref document: EP

Kind code of ref document: A1