WO2004011633A1 - Anticorps dirige contre la souche de type o du vih, lignee cellulaire d'hybridomes produisant cet anticorps et utilisations correspondantes - Google Patents

Anticorps dirige contre la souche de type o du vih, lignee cellulaire d'hybridomes produisant cet anticorps et utilisations correspondantes Download PDF

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WO2004011633A1
WO2004011633A1 PCT/CN2002/000551 CN0200551W WO2004011633A1 WO 2004011633 A1 WO2004011633 A1 WO 2004011633A1 CN 0200551 W CN0200551 W CN 0200551W WO 2004011633 A1 WO2004011633 A1 WO 2004011633A1
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hiv
cell line
monoclonal antibody
hybridoma cell
epitope
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French (fr)
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Yinghua Chen
Jin Huang
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BEIJING QINGDA YINGHUA BIO-TECH Co Ltd
Tsinghua University
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BEIJING QINGDA YINGHUA BIO-TECH Co Ltd
Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
    • C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
    • 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
    • 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

Definitions

  • the invention relates to an antibody of an HIV type 0 strain, a production cell line and application thereof.
  • HIV-1 is an immunological disease. There is currently no effective drug for complete cure, and no vaccine can prevent it. The high variability of immunodeficiency viruses has been a problem in the design of HIV vaccines and drugs.
  • HIV-1 membrane protein gpl60 precursor protein of membrane protein gP 120 and transmembrane protein gp41
  • Neutralizing antibodies can inhibit mucosal transmission of HIV-1 virus and mother-to-child transmission, and can clear HIV-1 virus from the blood (Nature Medicine 1999, 5: 204 ; Nature Medicine 2000, 6: 200; Nature Medicine 1999, 5: 211);
  • the epitope-specific monoclonal antibody to the primary neutralizing epitope ELDKWA on the transmembrane protein gp41 of human immunodeficiency virus (HIV-1) can inhibit in vitro Multiple HIV-1 strains infect target cells (J. Virology 1993, 67: 6642; AIDS Res. Human Retroviruses 1994, 10: 1651; AIDS 1996, 10: one 587).
  • HIV 1 can escape the neutralization of neutralizing antibodies by limiting mutations in neutralizing epitopes (Immunity 10, 431-438, 1999).
  • ELDKWA is recognized as an important HIV-1 neutralizing epitope. This epitope is highly conserved, but certain restricted mutations at the D or K site can make the virus escape the neutralizing effect of monoclonal antibody.
  • the inventors of the present invention have discovered a new immunological epitope of HIV type 0 strain through research.
  • the epitope includes two adjacent amino acid residues whose nitrogen terminus is aspartic acid and whose carbon terminus is glutamic acid.
  • the amino acid residues connected to the two amino acid residues are usually leucine at the nitrogen terminal and tryptophan at the carbon terminal.
  • the amino acid residue sequence of the immunological epitope is LDEW, Based on this sequence, the amino acid residue linked to the nitrogen terminal is usually glutamic acid and the amino acid residue linked to the carbon terminal is alanine.
  • the amino acid residue sequence of the immunological epitope is ELDEWA.
  • the unique epitope of type 0 strain can be used as a target site for the identification and diagnosis of HIV-1 virus type 0 strain, and can also be used as a target site for therapeutic drugs.
  • Table 1 Characteristic ELDEWA epitopes of HIV-1 virus type 0 strain
  • An object of the present invention is to provide a monoclonal antibody capable of specifically binding to an HIV type 0 strain, the antibody having specificity for an epitope DE, particularly an epitope ELDEWA.
  • the mouse hybridoma cell line 14D9 capable of secreting a monoclonal antibody specifically binding to HIV type 0 strain has been deposited on June 27, 2002 at the General Center for Microbiology (CGMCC) of the China Microbial Species Collection Management Committee and deposited The number is CGMCC Na0753.
  • CGMCC General Center for Microbiology
  • the monoclonal antibody 14D9 produced by the mouse hybridoma cell line 14D9 can specifically recognize the ELDEWA-epitope specific to the transmembrane protein gp41 of HIV-1 virus type 0 strain, and does not recognize the ELDKWA carried by other HIV-1 virus subtypes. ELNKWA- and ELEKWA- epitopes.
  • Figure 1 shows the fusion of a monoclonal antibody of the present invention with a recombinant, soluble gp41 protein with different epitopes Electrophoresis picture after reaction.
  • An epitope polypeptide containing an ELDEWA-epitope specific to the transmembrane protein gp41 of HIV-1 0 strain was artificially synthesized.
  • the epitope polypeptide contains 4 repeated ELDEWA-immunological epitopes, and the amino acid residue sequence is: CELDEWAGELDEWAGELDEWAGELDEWA;
  • Example 2 Specific recognition of the ELDEWA-epitope of HIV-1 virus type 0 antibody by the antibody of the present invention
  • a monoclonal antibody secreted by the hybridoma cell line 14D9 and a recombinant, soluble gp41 fusion protein with different epitopes were subjected to a warm bath reaction The results are shown in Figure 1. From the results, it can be seen that the monoclonal antibody secreted by the hybridoma cell line 14D9 has specific recognition of the ELDEWA-epitope of HIV-1 virus type 0 strain.
  • A molecular weight Protein
  • B the monoclonal antibody of the present invention recognizes rsgp41 (GST-rsgp41 EL DEWA) with an ELDEWA epitope [42KD]
  • C the monoclonal antibody of the present invention does not recognize rsgp41 (GST_rsgp41 ELDKM ) with an ELDKWA epitope
  • D The monoclonal antibody of the present invention does not recognize GST
  • E The monoclonal antibody of the present invention recognizes GST-ELDEWA (26KD) containing an ELDEWA epitope.
  • the monoclonal antibody of the present invention will be widely used in identifying and diagnosing HIV-1 virus type 0 strain and preparing a passive immune drug for H.IV-10 type strain infection.
  • the medicine using the monoclonal antibody of the present invention as an active ingredient is expected to be applied in the treatment of AIDS. Notes on microbial deposits

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • AIDS & HIV (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Description

艾滋病病毒 0型株的一种抗体及其生产细胞系与应用 技术领域
本发明涉及艾滋病病毒 0型株的一个抗体及其生产细胞系与应用。
背景技术
获得性免疫缺陷综合症， 又称艾滋病， 是由人类免疫缺陷病毒 I型
(HIV-1 ) 引起的一种免疫性疾病， 目前尚无彻底治愈的有效药物， 也没有 疫苗可以预防。 免疫缺陷病毒的高变异性一直是 HIV疫苗和药物设计中的难 题。
最近国外抗艾滋病药物临床研究结果证明， 在被动免疫治疗中， 组合 使用针对 HIV- 1 膜蛋白 gpl60 (膜蛋白 gP120及跨膜蛋白 gp41的前体蛋白） 上 的几个特定中和表位的中和抗体 (其中包括 ELDKWA表位特异性的单克隆抗体 2F5) ,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) ; 人免疫缺陷病毒（HIV- 1)跨膜蛋白 gp41 上的主要中和表位 ELDKWA的表位特异性单克隆抗体能够体外抑制多种 HIV— 1 病毒株感染靶细胞 ( J. Virology 1993, 67 : 6642 ; AIDS Res. Human Retroviruses 1994, 10 : 1651； AIDS 1996， 10 :一587 ) 。 研究证明， HIV 1 能够通过中和表位的限制性变异逃脱中和抗体的中和作用 （Immunity 10, 431-438, 1999 ) 。 ELDKWA是公认的重要的 HIV-1中和表位， 该表位的保守 性很强， 但在 D或 K位点的某些限制性变异， 能够使病毒逃脱单抗的中和作 用。
发明公开
本发明的发明人经研究发现了艾滋病病毒 0型株的一个新的免疫学表位， 该表位包括氮末端为天门冬氨酸， 碳末端为谷氨酸的两个相邻氨基酸残基。 与该两个氨基酸残基相连的， 通常氮末端连接的氨基酸残基为亮氨酸， 碳末 端连接的氨基酸残基为色氨酸， 这时该免疫学表位的氨基酸残基序列为 LDEW, 在该序列的基础上， 通常氮端连接的氨基酸残基为谷氨酸， 碳端连接 的氨基酸残基为丙氨酸， 这时该免疫学表位的氨基酸残基序列为 ELDEWA。
发明人通过对 HIV数据库 (http：〃 Mv-web. lanl. gov)的检索发现， 所 有 HIV- 1 病毒 0 型株的跨膜蛋白 gp41 均带有 ELDEWA 表位 （如表 1 所 示） ， 而其它 HIV- 1病毒亚型不带有此表位， 进一步证实 ELDEWA是 HIV- 1 病毒 0型株的特有表位， 可用于 HIV- 1病毒 0型株鉴别和诊断的靶位点， 也 可以作为治疗药物的靶位点。
表 1： HIV-1 病毒 0型株带有特征性的 ELDEWA表位
Figure imgf000004_0001
本发明的目的是提供能与艾滋病病毒 0型株专一结合的单克隆抗体， 该 抗体具有对表位 DE， 特别是表位 ELDEWA的特异性。
能够分泌与艾滋病病毒 0型株专一结合的单克隆抗体的小鼠杂交瘤细胞 系 14D9 , 已于 2002年 06月 27日保藏于中国微生物菌种保藏管理委员会普 通微生物中心 （简称 CGMCC) ， 保藏号为 CGMCC Na0753。
小鼠杂交瘤细胞系 14D9产生的单克隆抗体 14D9能够特异性识别 HIV - 1 病毒 0型株跨膜蛋白 gp41特有的 ELDEWA-表位， 而不识别其它 HIV- 1病毒 亚型所携带 ELDKWA -、 ELNKWA- 和 ELEKWA-表位。
下面结合具体实施例对本发明做进一步说明。
附图说明
图 1为本发明单克隆抗体与带有不同表位的重组、 可溶性 gp41融合蛋白 反应后的电泳图。
实施发明的最佳方式
实施例 1、 鼠类来源的杂交瘤细胞系 14D9的制备过程：
1、 人工合成一条含有 HIV- 1 0型株跨膜蛋白 gp41特有的 ELDEWA-表位的 表位多肽， 该表位多肽含有 4次重复的 ELDEWA-免疫学表位， 其氨基酸残基序 列为： CELDEWAGELDEWAGELDEWAGELDEWA；
2、 禾 |J用 MBS (nrmaleimidobenzoyHH]ydroxy succinimide 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 （两种物质的重量比为， 耦联物： 福 氏佐剂 = 1 : 1 ) 免疫 Balb/c小鼠， 每两周免疫一次。 首次使用完全福氏佐 剂， 以后使用不完全福氏佐剂。 每次免疫抗原剂量为： 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细胞融合技术融 合， 并制备杂交瘤， 从杂交瘤细胞中筛选出能分泌 ELDEWA-表位特异性单克 隆抗体的杂交瘤；
5、 克隆杂交瘤， 获得能分泌 ELDEWA表位特异性单克隆抗体的克隆杂交 瘤细胞系 14D9。
实施例 2、 本发明抗体对 HIV- 1病毒 0型株 ELDEWA-表位的特异性识别 将杂交瘤细胞系 14D9分泌的单克隆抗体与带有不同表位的重组、 可溶性 gp41 融合蛋白进行温浴反应， 结果如图 1所示， 从图中的结果可以看出， 杂交瘤 细胞系 14D9分泌的单克隆抗体对 HIV-1病毒 0型株 ELDEWA-表位具有特异性识 别， 图中， A : 分子量蛋白； B: 本发明单克隆抗体识别带有 ELDEWA表位的 rsgp41 (GST - rsgp41ELDEWA) 〔 42KD〕 ； C : 本发明单克隆抗体不识别带有 ELDKWA表位的 rsgp41 (GST _ rsgp41ELDKM)； D : 本发明单克隆抗体不识别 GST; E: 本发明单克隆抗体识别含有 ELDEWA表位的 GST- ELDEWA (26KD) 。 工业应用
本发明的单克隆抗体在鉴别、 诊断 HIV-1病毒 0型株、 制备用于 H.IV - 1 0型毒株感染被动免疫药物中将得到广泛应用。 以本发明单克隆抗体为活性 成份的药物可望在治疗艾滋病中得到应用。 关于微生物保藏的说明
(细则 13之二）
A. 对说明书第 2 页， 第 8— 10 行所述的微生物的说明。
B. 保藏事项 其他保藏在补充页中 □ 保藏单位名称 中国微生物菌种保藏管理委员会普通微生物中心
CHINA GENERAL MICROBIOLOGICAL CULTURE COLLECTION CENTER
保藏单位地址
(包括邮政编码和国名）
中国北京市海淀区中关村北一条 13号 邮编： 100080
Na 13, North 1 Lane, Zhongguancun Street, HaiDian District, Bei jingl00080, CHINA 保藏日期 2002年 06月 27日 I保藏编号 CGMCCNa0753
C.补充说明（必要时） 本栏内容有补充页 □
D. 本说明是为下列指定国作的（如果说明不是为所有指定国而作的)
E. 补充说明（必要时)
下列说明将随后向国际局提供（写出说明的类别， 例如： "保藏的编号 '
由受理局填写 ' 由国际局填写 ¾本页已经和国际申请一起收入到 □本页已经和国际申请一起收入到 受权官员 受权官员

Claims

权利要求书
1、 鼠类来源的杂交瘤细胞系 14D9， CGMCC Ns0753。
2、 由保藏号为 CGMCC Na0753 的杂交瘤细胞系 14D9 产生的单克隆抗 体。
3、 根据权利要求 2 所述的单克隆抗体， 其特征在于： 所述抗体具有艾 滋病病毒 0型株 DE表位特异性。
4、 根据权利要求 3 所述的单克隆抗体， 其特征在于： 所述抗体具有艾 滋病病毒 0型株 LDEW表位特异性。
5、 根据权利要求 3 所述的单克隆抗体， 其特征在于： 所述抗体具有艾 滋病病毒 0型株 ELDEWA表位特异性。
6、 权利要求 2— 5中任意一项所述的单克隆抗体在鉴别、 诊断 HIV-1病 毒 0型株中的应用。
7、 权利要求 2— 5中任意一项所述的单克隆抗体在制备用于 HIV 1 0型 毒株感染被动免疫药物中的应用。
8、 以权利要求 2— 5中任意一项所述的单克隆抗体为活性成份的药物。
4
PCT/CN2002/000551 2002-07-29 2002-08-09 Anticorps dirige contre la souche de type o du vih, lignee cellulaire d'hybridomes produisant cet anticorps et utilisations correspondantes Ceased WO2004011633A1 (fr)

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CNB021253714A CN1238499C (zh) 2002-07-29 2002-07-29 艾滋病病毒0型株的一种抗体及其生产细胞系与应用

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492560A2 (en) * 1990-12-26 1992-07-01 Joseph P. Cotropia Human monoclonal antibodies directed against the transmembrane glycoprotein (gp41) of HIV-1, and related peptides
WO1999045969A2 (de) * 1998-03-08 1999-09-16 Wolfgang Bergter Radioimmunpharmakon zur behandlung der hiv-1-infektion

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492560A2 (en) * 1990-12-26 1992-07-01 Joseph P. Cotropia Human monoclonal antibodies directed against the transmembrane glycoprotein (gp41) of HIV-1, and related peptides
WO1999045969A2 (de) * 1998-03-08 1999-09-16 Wolfgang Bergter Radioimmunpharmakon zur behandlung der hiv-1-infektion

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AU2002325466A8 (en) 2004-02-16
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AU2002325466A1 (en) 2004-02-16

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