WO2002026259A1 - Medicament pour le traitement du sida et son procede de preparation - Google Patents

Medicament pour le traitement du sida et son procede de preparation Download PDF

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WO2002026259A1
WO2002026259A1 PCT/CN2001/001191 CN0101191W WO0226259A1 WO 2002026259 A1 WO2002026259 A1 WO 2002026259A1 CN 0101191 W CN0101191 W CN 0101191W WO 0226259 A1 WO0226259 A1 WO 0226259A1
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epitope
gpgrafy
variant
treating aids
preparing
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PCT/CN2001/001191
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English (en)
French (fr)
Inventor
Yinghua Chen
Haijun Tian
Yi Xiao
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Tsinghua University
Chinatex Industry Development Corp.
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Priority to AU2002212074A priority Critical patent/AU2002212074A1/en
Publication of WO2002026259A1 publication Critical patent/WO2002026259A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to a medicine for treating AIDS prepared by bioengineering technology and a preparation method thereof, in particular to a medicine for treating AIDS prepared using a monoclonal antibody against HIV membrane protein and a preparation method thereof.
  • HIV-1 human immunodeficiency virus
  • the object of the present invention is to provide an effective medicine for treating AIDS, which medicine can deal with the mutation of the HIV virus.
  • Another object of the present invention is to provide a method for preparing the above medicament for treating AIDS.
  • the present invention adopts the following design scheme:
  • a medicine for treating AIDS which basically includes at least one monoclonal antibody, and the antigen of the antibody is a neutralization table on the human immunodeficiency virus membrane protein gp 120.
  • GPGRAFY epitope and its variant epitope are also included in the present invention.
  • the variant epitope is GPGQTFY or GPGQAWY.
  • the medicine for treating AIDS of the present invention preferably consists of the following components:
  • GPGRAFY epipe-specific monoclonal antibody
  • GPGQTFY epipe-specific monoclonal antibody
  • GPGQAWY epiderma-specific monoclonal antibody
  • a method for preparing the medicine for treating AIDS basically includes the following steps:
  • the neutralizing epitope is selected from the GPGRAFY epitope or / and its variant epitope or at least one repeating GPGRAFY epitope or / and its variant epitope;
  • the at least one artificially synthesized polypeptide preferably contains at least one repeated GPGRAFY epitope or a variant epitope of the human immunodeficiency virus membrane protein gpl20.
  • the variant epitope of the GPGRAFY epitope is GPGQTFY or GPGQAWY.
  • Example 1 A medicine for treating AIDS, which is made of an antibody against the neutralizing epitope GPGRAFY on HIV-1 gpl20 as a main active ingredient, is produced by the following steps:
  • GPGRAFY epitope polypeptide C— (GPGRAFY) 4 containing 4 repeats of the GPGRAFY neutralizing epitope on the human immunodeficiency virus membrane protein gpl20;
  • MBS m-maleimidobeozoyl-N-hydros succianamide ester
  • the dosage of the drug in actual application is determined according to the patient's condition.
  • the antibodies of GPGQTFY and GPGQAWY are the main active ingredients for the treatment of AIDS. They are produced by the following steps:
  • Three antibodies against the neutralizing epitope GPGRAFY and its variant epitopes GPGQTFY and GPGQAWY on HIV-1 gpl20 are obtained from the cloned products, and the above antibodies are made into drugs for treating AIDS. Among them, various The amount of antibody added is adjusted by the occurrence probability of various epitopes obtained by statistical processing of the applicable population.
  • the mutation of HIV can be obviously resisted, the load of HIV can be reduced, the progress of the disease can be delayed, and finally the purpose of cure is achieved.
  • the medicine for treating AIDS of the present invention is a medicine containing multiple antibodies against the GPGRAFY epitope on human immunodeficiency virus membrane protein gpl20 and its variant epitopes (such as GPGQTFY, GPGQAWY). Even in the case of HIV mutation, injection People with the drug will also have antibodies in the body to kill the mutated virus.
  • the medicament of the invention is not only non-toxic, but also can reduce the cost of AIDS treatment while improving the effect of AIDS immunotherapy.
  • the invention adopts a method of artificially synthesizing epitope polypeptide to induce and prepare a predetermined monoclonal antibody specific for an epitope, which overcomes the need to immunize with a natural protein or a recombinant protein, and then performs a large number of screening and identification to obtain the predetermined epitope specificity.
  • Sexual monoclonal antibodies perform many complex tasks.
  • the corresponding type of medicine can be produced quickly according to the mutation of the HIV virus, without the need for long-term tests, and the production cost can be reduced.
  • This technology will have a significant impact on the world's preventive medicine research and will bring huge economic and social benefits.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • AIDS & HIV (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

一种治疗艾滋病的药物及其制备方法 技术领域
本发明涉及用生物工程技术制备的治疗艾滋病的药物及其制备方法， 特 别是涉及用艾滋病病毒膜蛋白的单克隆抗体制备的治疗艾滋病的药物及其制 备方法。
背景技术
艾滋病又称获得性免疫缺陷综合征， 是由人免疫缺陷病毒 （HIV— 1 ) 引起的一种免疫性疾病。 由于其传播迅速、 病死率极高， 且目前尚无特效治 疗方法， 更无疫苗可以预防。
现有的用于临床的抗艾滋病药物仅能推迟发病期和延长病人的生命， 并且价格昂贵， 毒性大。 最近国外抗艾滋病药物临床研究结果证明， 针对 HIV-1 膜蛋白 gpl20上的几个特定中和表位的中和抗体 (单克隆抗体)在被动 免疫治疗中的组合使用能抑制 HIV— 1病毒的粘膜传染以及母婴传播， 并能 清除血液中的 HIV—1病毒 (Nature Medicine 1999, 5: 204; Nature Medicine 2000, 6:200; Nature Medicine 1999, 5: 211)； HIV-1 gpl20上的主要中和表位 GPGRAFY以及识别该表位的抗体能够体外抑制 HIV— 1感染靶细胞， 并能预 防 HIV—1感染黑猩猩 (Nature 1990, 345:622; Science 1992, 256:1687; Nature 1992, 355:728-730; J. Biol. Chem. 1995, 271:8236)。
发明公开
本发明的目的是提供一种有效的治疗艾滋病的药物， 该药物可对付艾滋 病病毒的变异。
本发明的另一个目的是提供一种制备上述治疗艾滋病的药物的方法。 为实现上述目的， 本发明釆取以下设计方案： 一种治疗艾滋病的药， 它 基本上包括至少一种单克隆抗体， 所述抗体的抗原是人免疫缺陷病毒膜蛋白 gp 120上的中和表位 GPGRAFY表位及其变异表位。
所述变异表位为 GPGQTFY或 GPGQAWY。
本发明治疗艾滋病的药物优选由以下组分组成：
GPGRAFY—表位特异性的单克隆抗体
GPGQTFY—表位特异性的单克隆抗体
GPGQAWY—表位特异性的单克隆抗体
一种制备上述治疗艾滋病的药物的方法， 基本上包括以下步骤：
( 1 )、 人工合成至少一条分别含有人免疫缺陷病毒膜蛋白 gpl20上的中 和表位的表位多肽， 所述中和表位选自 GPGRAFY表位或 /和它的变异表位或 者至少一次重复的 GPGRAFY表位或 /和它的变异表位；
(2)、 将上述多肽分别耦联到载体蛋白或载体多肽上形成耦联物；
(3 )、 用上述耦联物分别配以可接受的佐剂免疫动物；
(4)、 采用常规的细胞融合技术分别制备杂交瘤；
(5 )、 将自上述不同杂交瘤细胞系 （克隆） 产物中得到的抗体纯化， 混 合制成治疗艾滋病的药物。
其中， 所述人工合成的至少一条多肽， 优选为分别含有人免疫缺陷病毒 膜蛋白 gpl20上的至少一次重复的 GPGRAFY表位或它的变异表位。 所述 GPGRAFY表位的变异表位为 GPGQTFY或 GPGQAWY。
下面结合非限制性具体实施例对本发明作进一步说明。
实施发明的最佳方式
实施例 1 : 由抗 HIV— 1 gpl20上的中和表位 GPGRAFY的抗体为主要活 性成分制成的治疗艾滋病的药物， 由以下步骤生产：
( 1 )、 人工合成一条含有人免疫缺陷病毒膜蛋白 gpl20上的 4次重复的 GPGRAFY中和表位的表位多肽 C— (GPGRAFY) 4；
(2)、 利用 MBS(m-maleimidobeozoyl- N- hydros succiriimide ester)将上述表位 多肽与载体蛋白 BSA耦联；；
(3 )、 将上述耦联物与福氏佐剂混合 （两种物质的重量份数比为， 耦联 物： 福氏佐剂 = 1 : 1 ) 免疫 Balb/c小鼠。 第一次用完全福氏佐剂， 以后每两 周免疫一次， 用不完全福氏佐剂， 每次免疫的抗原剂量为： 含 10微克表位多 肽的耦联物 /次 /只， 共免疫 3次；
(4)、 将免疫后的小鼠脾细胞与小鼠骨髓瘤细胞采用常规的细胞融合技 术融合， 并制备杂交瘤；
(5 )、 从上述杂交瘤细胞中筛选出能产生预先定义的表位特异性的单克 隆抗体的克隆， 将提纯的抗体制成治疗艾滋病的药物。
该药物在实际应用中的使用剂量根据患者的病情来确定。
实施例 2 : 由抗 HIV— 1 gpl20上的中和表位 GPGRAFY及其变异表位
GPGQTFY 、 GPGQAWY的抗体为主要活性成分制成的治疗艾滋病的药物， 由以下步骤生产：
( 1 )、 人工合成 4条分别含有人免疫缺陷病毒膜蛋白 gpl20上的中和表位 GPGRAFY及其变异表位 GPGQTFY 、 GPGQAWY的表位多肽：
CGPGRAFYGPGRAFYGPGRAFYGPGRAFY CGPGQTFYGPGQTFYGPGQTFYGPGQTFY
CGPGQAWYGPGQAWYGPGQAWYGPGQAWY
(2)、 利用戊二醛或 MBS将上述多肽分别耦联到载体蛋白牛血清白蛋 白上形成耦联物；
(3 )、 将上述耦联物与福氏佐剂混合 （两种物质的体积比为， 耦联物： 福氏佐剂 = 1 : 1 ) 免疫 Balb/c小鼠。 第一次用完全福氏佐剂， 以后每两周免 疫一次， 用不完全福氏佐剂。 每次免疫的抗原剂量为： 含 10微克表位多肽的 耦联物 /次 /只， 共免疫 3次；
(4)、 将免疫后的小鼠脾细胞与小鼠骨髓瘤细胞系釆用常规的细胞融合 技术融合， 并制备杂交瘤；
(5 )、 从上述杂交瘤细胞中筛选出能产生预先定义的表位特异性的单克 隆抗体的克隆。
( 6 )、 自上述克隆产物中分别得到抗 HIV— 1 gpl20上的中和表位 GPGRAFY及其变异表位 GPGQTFY、 GPGQAWY的 3种抗体， 将上述抗体 制成治疗艾滋病的药物， 其中， 各种抗体的加入量由适用人群的统计学处理 得出的各种表位的出现概率进行调整。
使用本发明的药物， 可以明显抵抗艾滋病病毒的变异， 降低艾滋病病毒 的载量， 延缓疾病的进行， 最后达到治愈的目的。
工业应用
研究表明， 针对 HIV— 1病毒膜蛋白上中和表位的抗体在艾滋病治疗中 能降低病毒的载量， 延缓疾病的进行。 本发明治疗艾滋病的药物是含有抗人 免疫缺陷病毒膜蛋白 gpl20上的 GPGRAFY表位及其变异表位 （如 GPGQTFY, GPGQAWY) 的多种抗体的药物， 即使在艾滋病病毒产生变异 的情况下， 注射了该药物的人体内也会有相应的抗体来杀灭变异的病毒。
本发明的药物不但无毒性， 而且在提高艾滋病的免疫治疗效果的同时， 还可降低艾滋病治疗成本。
本发明采用人工合成表位多肽的方法来诱导、 制备预先确定的表位特异 性的单克隆抗体， 克服了需要利用天然蛋白或重组蛋白免疫， 然后大量筛选 和鉴定才能得到预先确定的表位特异性的单克隆抗体的诸多复杂工作。
根据本发明， 可以按照艾滋病病毒的变异情况， 很快生产出其相应类型 的药物， 不需进行长时间的试验， 降低生产成本。 该技术将对世界预防医学 研究产生重大影响， 并将带来巨大的经济效益和社会效益。

Claims

权利要求书
1、 一种治疗艾滋病的药物， 它基本上包括至少一种单克隆抗体， 所述 抗体的抗原是人免疫缺陷病毒膜蛋白 gpl20上的中和表位 GPGRAFY表位及 其变异表位。
2、 根据权利要求 1所述的一种治疗艾滋病的药物， 其特征在于： 所述变 异表位为 GPGQTFY或 GPGQAWY。
3、 根据权利要求 1或 2所述的一种治疗艾滋病的药物， 其特征在于： 它 是由以下组分组成的： GPGRAFY—表位特异性的单克隆抗体
GPGQTFY—表位特异性的单克隆抗体
GPGQAWY—表位特异性的单克隆抗体
4、 一种制备权利要求 1一 3所述的治疗艾滋病的药物的方法， 基本上包 括以下步骤：
( 1 )、 人工合成至少一条分别含有人免疫缺陷病毒膜蛋白 gpl20上的中 和表位的表位多肽， 所述中和表位选自 GPGRAFY表位或 /和它的变异表位或 者至少一次重复的 GPGRAFY表位或 /和它的变异表位；
( 2 )、 将上述多肽分别耦联到载体蛋白或载体多肽上形成耦联物；
(3 )、 用上述耦联物分别配以可接受的佐剂免疫动物；
(4)、 采用常规的细胞融合技术分别制备杂交瘤；
(5)、 将自上述不同杂交瘤细胞系产物中得到的抗体纯化， 混合制成治 疗艾滋病的药物。
5、 根据权利要求 4所述的制备治疗艾滋病的药物的方法， 其特征在于： 所述人工合成的至少一条多肽， 分别含有人免疫缺陷病毒膜蛋白 gpl20上的 至少一次重复的 GPGRAFY表位或它的变异表位。
6、 根据权利要求 4或 5所述的制备治疗艾滋病的药物的方法， 其特征在 于： 所述 GPGRAFY表位的变异表位为 GPGQTFY或 GPGQAWY。
PCT/CN2001/001191 2000-08-18 2001-07-20 Medicament pour le traitement du sida et son procede de preparation WO2002026259A1 (fr)

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CN00123486.2 2000-08-18
CN00123486A CN1339319A (zh) 2000-08-18 2000-08-18 一种治疗艾滋病的药物及其制备方法

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EP2492279A1 (en) * 2011-02-25 2012-08-29 Laboratorios Del. Dr. Esteve, S.A. Rapid immunogen selection method using lentiviral display

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Publication number Priority date Publication date Assignee Title
GB2223226A (en) * 1988-09-30 1990-04-04 Olympus Optical Co A monoclonal antibody against HIV peptide
WO1993004090A1 (en) * 1991-08-22 1993-03-04 Nissin Shokuhin Kabushiki Kaisha Hiv immunotherapeutics
US5266478A (en) * 1987-05-29 1993-11-30 Tanox Biosystems, Inc. Antibodies which target a neutralization site within the second variable region of human immunodeficiency virus type 1 gp120
US5618922A (en) * 1994-07-25 1997-04-08 Nissin Shokuhin Kabushiki Kaisha NM03 antibody materials and methods
WO1998015658A1 (en) * 1996-10-10 1998-04-16 Probe International Compositions and methods for treating viral infections
US5911989A (en) * 1995-04-19 1999-06-15 Polynum Scientific Immunbiologische Forschung Gmbh HIV-vaccines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266478A (en) * 1987-05-29 1993-11-30 Tanox Biosystems, Inc. Antibodies which target a neutralization site within the second variable region of human immunodeficiency virus type 1 gp120
GB2223226A (en) * 1988-09-30 1990-04-04 Olympus Optical Co A monoclonal antibody against HIV peptide
WO1993004090A1 (en) * 1991-08-22 1993-03-04 Nissin Shokuhin Kabushiki Kaisha Hiv immunotherapeutics
US5618922A (en) * 1994-07-25 1997-04-08 Nissin Shokuhin Kabushiki Kaisha NM03 antibody materials and methods
US5911989A (en) * 1995-04-19 1999-06-15 Polynum Scientific Immunbiologische Forschung Gmbh HIV-vaccines
WO1998015658A1 (en) * 1996-10-10 1998-04-16 Probe International Compositions and methods for treating viral infections

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