WO2011137571A1 - Anticorps rvfab5 neutralisant d'origine humaine contre la glycoprotéine du virus de la rage - Google Patents

Anticorps rvfab5 neutralisant d'origine humaine contre la glycoprotéine du virus de la rage Download PDF

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Publication number
WO2011137571A1
WO2011137571A1 PCT/CN2010/001576 CN2010001576W WO2011137571A1 WO 2011137571 A1 WO2011137571 A1 WO 2011137571A1 CN 2010001576 W CN2010001576 W CN 2010001576W WO 2011137571 A1 WO2011137571 A1 WO 2011137571A1
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antibody
rabies virus
human
gene
rabies
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PCT/CN2010/001576
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English (en)
Chinese (zh)
Inventor
梁米芳
孙丽娜
陈哲
李川
李德新
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中国疾病预防控制中心病毒病预防控制所
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Publication of WO2011137571A1 publication Critical patent/WO2011137571A1/fr

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    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to genetically engineered antibody technology, and more particularly to a human anti-rabies virus glycoprotein neutralizing antibody; the present invention also relates to the use of the antibody for the preparation of a medicament for preventing or treating rabies. Background technique
  • Rabies is a worldwide zoonosis caused by rabies virus, which kills 100% of the disease.
  • WHO World Health Organization
  • PRIG human rabies immune globulin
  • ERI Equine rabies immune globulin Due to the serious side effects of ERIG and the inhibition of antibody responses to certain vaccines, HRIG is expensive, limited in supply and potentially pathogenic. Therefore, it is our goal to prepare a passive immunological preparation with high efficiency, low cost and low side reaction.
  • Human or animal serum immunoglobulins containing specific antibodies have a long history of preventing and treating infectious diseases.
  • the in vitro antiviral neutralizing activity of monoclonal antibodies and the protection of the body against viral challenge in vivo have been proved by many experiments, such as murine anti-hepatitis A virus, hantavirus, measles virus, RSV virus, CMV virus and other neutralizing monoclonal antibodies can be 100% protect animals from viral attack.
  • the use of antigen-immunized animals to obtain polyclonal antiserum pathways has been a classic method of obtaining antibodies, but lacks specificity and homogeneity.
  • McAbs monoclonal antibodies
  • VIG Immunoglobulin Protein
  • the rabies monoclonal antibody CR57 and CR4098 made a monoclonal antibody cocktail that neutralized 26 typical street strains. Protective experiments on animals have shown that the use of monoclonal antibody cocktails for treatment is feasible and superior (Goudsmit J, et al. 2006).
  • Antibody Drug As with the transformation of blood-borne vaccines to genetically engineered vaccines, there is an urgent need to replace genetically-derived VIG with genetically engineered antibodies, such as by chimeric antibody technology.
  • a first object of the present invention is to provide a human anti-rabies virus glycoprotein neutralizing antibody and an active fragment thereof.
  • a second object of the present invention is to provide a gene encoding the above antibody or an active fragment thereof.
  • a third object of the present invention is to provide the use of the above antibody and its active fragment for the preparation of a medicament for the prevention or treatment of rabies or a diagnostic reagent.
  • the invention adopts the phage surface presentation technology to collect a plurality of peripheral blood lymphocytes of vaccine injections with high titer rabies virus antibodies, and constructs a human anti-rabies genetic engineering antibody library by genetic engineering means, and screens to obtain specific anti-drug Rabies virus genetically engineered antibody Fab segment.
  • the obtained Fab segment antibody was named RVFab5.
  • This recombinant antibody is determined by the hypervariable region (CDRs)-specific gene sequences present in the variable regions of the antibody light and heavy chain genes, and is specifically expressed in prokaryotic cells to specifically bind to the function of rabies virus.
  • CDRs hypervariable region
  • They specifically recognize rabies virus particle antigens, and both target rabies virus glycoprotein G, and have obvious immunofluorescence reaction (IFA) and enzyme-linked immunosorbent assay (ELISA) reactions with rabies virus, and have neutralizing activity against rabies virus infection.
  • the RVFab5-specific light chain and heavy chain variable region genes are derived from the specific enrichment screening of the human anti-rabies virus antibody gene pool, which is derived from the peripheral blood lymphocyte gene of the Chinese rabies virus vaccine.
  • the corresponding three CDR region sequence combinations of the light chain and heavy chain variable regions and the framework region sequences between the CDR regions constitute the sequence characteristics of each antibody variable region, and RVFab5 belongs to the antibody light chain family VL1.
  • the function of the antibody protein is determined by the specific nucleotide sequence and its complement in the CDR1, CDR2 and CDR3 of the determinant complementary region of the light chain and heavy chain variable regions of the antibody gene, and the corresponding amino acid sequences of the corresponding CDR regions constitute the antibody.
  • the specific antigen binding region determines the antigen binding characteristics and anti-rabies virus function characteristics of each antibody in the invention.
  • the detailed amino acid sequence of the light chain and heavy chain variable regions of the antibody which determines the function of each neutralizing antibody and its comparison results are shown in Table 1: Table 1
  • the amino acid sequence of the RVFab5 light chain variable region is shown in SEQ ID No. 1, and the amino acid sequence of the heavy chain variable region is shown in SEQ ID No. 2.
  • the gene sequence encoding the light chain variable region of RVFab5 is shown in SEQ ID No. 3, and the gene sequence of the heavy chain variable region is shown in SEQ ID No. 4.
  • amino acid sequence for example, replaces an amino acid having similar properties in a non-hypervariable region, such as replacing Val at position 8 of the heavy chain VH sequence of RVFab5 with Ala.
  • the gene sequence encoding the above Fab fragment antibody can be modified in its coding region without changing the amino acid sequence to obtain a gene encoding the same antibody.
  • Those skilled in the art can artificially engineer the gene according to the preference of the expression of the antibody host to improve the expression efficiency of the antibody.
  • the present invention recombines the light chain variable region and the heavy chain variable region of the above Fab antibody to obtain a single-chain antibody (ScFv) having a smaller molecular weight, which antibody can also specifically recognize a rabies virus surface antigen, and has intracellular The role of immunity.
  • Single-chain antibodies have strong penetrating power and are easy to enter local tissues.
  • the gene encoding the Fab antibody and the ScFv gene can be cloned into an expression vector, and then transformed into a host, and a Fab antibody and a single-chain antibody can be obtained by inducing expression.
  • the light chain coding gene and the heavy Fd fragment gene of the above Fab antibody can be cloned into a total anti-expression vector and introduced into a host cell to obtain a total anti-immunoglobulin expressing anti-rabies virus.
  • the light chain and heavy Fd of the above Fab antibody RVFab5 The segment genes were cloned into the whole antibody expression vector pAC-L-Fc and transfected into insect Sf9 cells, and the secreted expression of the whole antibody was achieved by the baculovirus/insect cell system to obtain the whole antibody RVIgG5.
  • RVIgG5 specifically binds to the aG strain and the CTN strain rabies virus particles, and expresses ERA with the baculovirus/insect cell system.
  • CVS, CTN and aG strains ffl species of rabies virus strain glycoprotein have specific binding.
  • the rabies virus rapid immunofluorescence inhibition assay (RFFIT) was used to identify the whole antibody. The results showed that: RVIgG5 has good neutralizing activity, can reach 689.8 IU/mg, and fully possesses the neutralizing international standard attack strain CVS- The capacity of 11 strains.
  • the present invention successfully obtains a human neutralizing antibody specific for a rabies virus glycoprotein by using a phage antibody library technology; using the human neutralizing anti-rabies virus glycoprotein genetically engineered antibody variable region gene obtained by the above, Fab
  • the antibody gene and the whole antibody gene under the characteristics of each of the above antibody genes can express and produce the antibody in prokaryotic cells, yeast cells, eukaryotic cells and any recombinant system or the modified gene containing the antibody gene based thereon Any other gene that obtains an antibody product that neutralizes rabies virus infection, and is made into a specific antibody drug for clinical use in the prevention and treatment of rabies.
  • Figure 1 is an immunofluorescence analysis of human rabies virus Fab antibody and rabies virus glycoproteins of ERA, CVS, CTN and aG strains;
  • Figure 2 is a SDS-PAGE electropherogram of purified IgG
  • Figure 3 shows an anti-rabies virus human IgG antibody against CVS-11 rabies virus rapid immunofluorescence inhibition assay.
  • the baculovirus expression vector is pAC-L-Fc (PROGEN PR3003, Germany) (Liang, MF, Stefan, D., Li, DX, Queitsch, I., Li, W., and Bautz, EF Baculovirus expression cassette vectors for rapid production Of complete human IgG from phage displayselected antibody fragments. Journal of Immunological Methods. 247: 119-130. Insect cells Sf from the American Cell Culture Center
  • the recombinant plasmid was obtained as: pAc-HA.
  • Recombinant baculovirus was prepared by transfecting the recombinant plasmid into insect cells for protein expression, and the expression was carried out using the BaculoGold co-transfection kit of Pharmogen, USA. The method of operation is as follows: After mixing 5Mg of recombinant plasmid DNA with 0.5Mg of BaculoGold linear DNA, the Sf cells with a growth density of 50% were transfected with the transfection reagent in the kit, and cultured for 4 days after 27 days, the supernatant was collected. Titration and amplification are carried out as a virus of the recombinant virus.
  • the rabies virus aG strain and the CTN strain were harvested respectively to infect BHK-21 cells, and the supernatant was cultured. After formaldehyde inactivation and safety check, the virus particles were purified by centrifugation at 20 °C with a continuous sucrose density gradient of 35000 g at 3 °C (Beckman). SW28).
  • the PCR conditions were: 94 ° C lmin, 54 ° C 1 min, 72 ° C 2 min, 35 cycles.
  • the method of building the library is basically carried out according to the literature (Barbas, C. Fill., Kang, AS, and lamer, RA Assembly of combinatorial antibody libraries on phage surface: the genelll site. Proc. Natl. Acad. Sci. US A.1991; 88 (18): 7978-7982).
  • Enrichment screening of phage antibody library and induction expression of Fab fragment antibody The screening antigen was an inactivated virus particle aG and CTN strain purified by ultracentrifugation. Dilute with 0.1m/L NaHC0 3 (pH8.6) solution, coat the immunotube, and block with 4% skim milk-PBS, 37 °C for 2 h, then add the above phage antibody library, 1 ml per tube, 37 Incubate for 2 h at ° C, and wash repeatedly with 5% Tween-20-TBS for 20 times. Finally, elute with 1 ml of a pH 2. 2 glycine-hydrochloric acid eluate, and neutralize the pH 9.6 Tris solution.
  • the specific enrichment screening method and the induced expression of the Fab segment were basically carried out according to the literature (Barbas, C. Fill., Kang, AS, and lamer, RA Assembly of combinatorial antibody libraries on phage surface: the genelll site. Proc. Natl. Acad. Sci. USA. 1991; 88(18): 7978-7982).
  • the antibody was coated with anti-human Fab antibody (Sigma, 1:2000 dilution) in a solution of 0.1 m/L NaHC0 3 (pH 9.6) on the plate, overnight at 4 ° C; 4% skim milk was blocked , 37°C lh, added Fab antibody, 37°C lh; added enzyme-labeled anti-human Fab secondary antibody (US Sigma, 1:2000 dilution), 37°C lh; color developing solution, 2M H 2 The reaction was terminated by S0 4 , and the absorbance A value was measured by a microplate reader.
  • IFA Indirect immunofluorescence assay: Sf cells were infected with recombinant baculovirus expressing rabies virus glycoprotein, and infected cells were harvested 4 to 5 days later to prepare recombinant rabies virus glycoprotein antigen tablets. The expressed Fab was added, incubated at 37 °C for 30 min, rinsed, added with FITC-labeled anti-Fab antibody (Sigma, USA), incubated at 37 °C for 30 min, washed, air-dried, and observed under a microscope.
  • nucleic acid sequence analysis of human Fab antibody variable region gene Plasmid DNA was prepared using Qiagen Miniprep Kit (QIAGEN, Germany) for nucleic acid sequence analysis.
  • the primers for the light and heavy chains are 5'-AAACTAGCTAGTCGCC AAGGA-3' (as shown in SEQ ID No. 5) and 5'-CCGCGGTGGCGGCCGCAAAT-3' (as shown in SEQ ID No. 6).
  • the sequencing results were compared with the IgG gene sequence in the Internet V-Base gene pool.
  • Transfection and recombinant virus infection and proliferation The BaculoGold co-transfection kit from Pharmogen, USA. The method of operation is as follows: After mixing 5 g of recombinant plasmid DNA with 0.5 g of BaculoGold linear DNA, the Sf cells with a growth density of 50% were transfected with the transfection reagent in the kit, and cultured at 27 ° C for 4 days, collected. The supernatant was titrated and amplified as a virus of the recombinant virus. See the Baculovirus expression vector system manual (BD Biosciences Pharmingen, USA) for specific procedures. 10.
  • RFFIT Human anti-rabies virus antibody rapid immunofluorescence inhibition assay
  • the fluorescent antibody can inhibit the highest dilution factor of ⁇ 50% of the antibody, which is the neutralizing antibody titer of the antibody to be tested. According to the Reed & Muench formula, the ED 5() of each antibody sample and the labeled product was calculated to obtain the titer of each antibody to be tested. 12. Study on the resistance of rabies virus to antibodies in non-hypervariable region
  • RV IgG5 heavy chain variable region amino acid sequence Based on the RV IgG5 heavy chain variable region amino acid sequence, the Val at position 8 of the amino acid sequence shown in SEQ ID No. 2 was replaced with Ala, and the 10th position of the RV IgG5 light chain variable region (shown by SEQ ID No. 1) Replace Ala with Gly.
  • the heavy chain encoding nucleic acid sequence of RV IgG5 (replacement of the codon gtg with gcc at the corresponding position) and the light chain encoding nucleic acid sequence (replacement of the codon gcc with ggg at the corresponding position) were separately synthesized.
  • the light chain gene and the heavy chain Fd fragment were cloned into pAC-L-Fc according to the above methods 8 to 11 and transfected into insect Sf cells, and the secreted expression of the whole antibody was achieved by the baculovirus/insect cell system, and The mutant was subjected to immunological detection. Result
  • the phage antibody library was enriched and screened with purified rabies virus particle CTN strain. After 2 rounds of screening, 2400 clones were randomly picked.
  • the anti-human Fab antibody (sigma company, 1 : 2 000 diluted use), rabies virus particle aG strain antigen coated 96-well plate, added to the test sample supernatant, with enzyme-labeled anti-human Fab secondary antibody (Sigma, 1: 2 000 dilutions used) detection.
  • the results showed that a total of 1833 human Fab-positive clones were obtained, as shown in Table 3. Of the 1833 human-derived Fab-positive clones, 79 clones specifically bind to the rabies virus particle CTN strain, and 34 of the Fab clones were identified as directed against rabies virus glycoproteins.
  • VR variable region VH, heavy chain in VR (heavy chain variable region); VL, light chain in VR
  • the neutralizing antibody level is equal to or higher than 0.5 IU/ml, indicating that the antibody has neutralizing activity, so the 5 human monoclonal antibodies obtained in this study are directed against rabies virus.
  • the neutralizing activity of RVIgG9 was weak, and the other 4 strains had good neutralizing activity, and fully possessed the ability to neutralize the international standard attack strain CVS-11, as shown in Fig. 3.
  • RVIgG5 The light chain gene and heavy chain gene modified based on RVIgG5 were cloned into pAC-L-Fc according to the above methods 8 to 11, and transfected into insect Sf cells, and whole antibody secretion was achieved by baculovirus/insect cell system. Expression of the type, the mutant RVIgG5 was obtained. Immunological detection of the mutant, indirect immunofluorescence experiments showed that RVFab5' can specifically target rabies virus glycoprotein G, and use rapid immunofluorescence inhibition assay to detect antibodies in vitro and international standard attack strain CVS-11 strain. The neutralization reaction showed that the properties were substantially the same as those of RVIgG5. Industrial applicability

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Abstract

La présente invention concerne un anticorps RVFab5 neutralisant d'origine humaine contre la glycoprotéine du virus de la rage. La présente invention concerne également l'emploi de l'anticorps dans la fabrication d'un médicament destiné au traitement prophylactique ou thérapeutique de la rage.
PCT/CN2010/001576 2010-05-06 2010-10-09 Anticorps rvfab5 neutralisant d'origine humaine contre la glycoprotéine du virus de la rage WO2011137571A1 (fr)

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CN101812130B (zh) * 2010-05-06 2012-07-04 中国疾病预防控制中心病毒病预防控制所 人源抗狂犬病毒糖蛋白中和性抗体(RVFab5)
CN103998059B (zh) * 2011-09-30 2016-01-20 赛特瑞恩股份有限公司 用于中和狂犬病病毒的结合分子
CN103505729B (zh) * 2013-05-24 2015-10-28 华北制药集团新药研究开发有限责任公司 一种稳定的狂犬病毒人源抗体组合制剂
CN113185608B (zh) * 2021-05-08 2022-08-09 南昌大学 一种高亲和力抗狂犬病病毒的全人源单克隆抗体及其用途
CN113501873B (zh) * 2021-07-07 2023-05-23 高光 Rbv的蛋白结合分子及其用途

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WO2013174003A1 (fr) * 2012-05-24 2013-11-28 Mountgate Group Limited Compositions et procédés associés à la prévention et au traitement d'une infection rabique
EP2855521A1 (fr) * 2012-05-24 2015-04-08 Mountgate Group Limited Compositions et procédés associés à la prévention et au traitement d'une infection rabique
CN104603149A (zh) * 2012-05-24 2015-05-06 万机集团有限公司(英国) 与预防和治疗狂犬病感染相关的组合物和方法
EP2855521A4 (fr) * 2012-05-24 2016-03-02 Mountgate Group Ltd Compositions et procédés associés à la prévention et au traitement d'une infection rabique
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EP3508497A1 (fr) * 2012-05-24 2019-07-10 Mountgate Group Limited Compositions et procédés associés à la prévention et au traitement d'une infection rabique

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