WO2015165368A1 - Anticorps monoclonal anti-her2 à action de neutralisation, et utilisation de celui-ci - Google Patents

Anticorps monoclonal anti-her2 à action de neutralisation, et utilisation de celui-ci Download PDF

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Publication number
WO2015165368A1
WO2015165368A1 PCT/CN2015/077447 CN2015077447W WO2015165368A1 WO 2015165368 A1 WO2015165368 A1 WO 2015165368A1 CN 2015077447 W CN2015077447 W CN 2015077447W WO 2015165368 A1 WO2015165368 A1 WO 2015165368A1
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her2
amino acid
sequence
acid sequence
monoclonal antibody
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PCT/CN2015/077447
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English (en)
Chinese (zh)
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孙乐
王慕旸
李茂华
李英姿
张翠娟
张小刚
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京天成生物技术(北京)有限公司
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Publication of WO2015165368A1 publication Critical patent/WO2015165368A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • the present invention relates to the field of immunology and antibody preparation techniques, and in particular to anti-HER2 neutralizing active monoclonal antibodies and uses thereof. Background technique
  • Human epidermal growth factor receptor 2 is a member of the epidermal growth factor receptor (ErbB2) family and is a transmembrane receptor-like protein with a relative molecular mass of 185,000 and has tyrosine kinase activity.
  • HER2 is an important breast cancer prognostic factor, HER2-positive (overexpressed or expanded) breast cancer, its clinical characteristics and biological behavior have a special performance, and the treatment pattern is also very different from other types of breast cancer.
  • the drug acting on the HER2 target is currently the most commonly used and most effective drug for the treatment of breast cancer, mainly trastuzumab and pertuzumab.
  • Herceptin the first antibody against the breast cancer marker HER2, in 1997. With annual sales of more than $5 billion, it has become a hotspot for generics. In 2012, Genentech introduced an anti-drug against HER-Domain2, which is better in combination with Herceptin. In March 2013, Genentech also added Herceptin and the drug DM1 conjugate, which is also very effective for patients with advanced cancer. Summary of the invention
  • the present invention provides anti-HER2 neutralizing active monoclonal antibodies and uses thereof.
  • the present invention provides two anti-HER2 neutralizing active monoclonal antibodies, designated clone6B2 and clone4G8, respectively.
  • the anti-HER2 neutralizing active monoclonal antibody clone6B2 i) has the amino acid sequence of the light chain variable region as shown in SEQ ID No. 1, or the sequence is substituted, deleted or added with one or several amino acids to form an equivalent function. Amino acid sequence;
  • amino acid sequence of the heavy chain variable region thereof is set forth in SEQ ID No. 2, or the sequence is substituted, deleted or added with one or several amino acids to form an equivalent functional amino acid sequence Column.
  • the anti-HER2 neutralizing active monoclonal antibody clone4G8, i) has the amino acid sequence of the light chain variable region as set forth in SEQ ID No. 3, or the sequence is substituted, deleted or added with one or several amino acids to form an equivalent function. Amino acid sequence;
  • amino acid sequence of the heavy chain variable region thereof is as shown in SEQ ID No. 4, or the sequence is substituted, deleted or added with one or several amino acids to form an equivalent functional amino acid sequence.
  • the present invention also provides hybridoma cells producing the monoclonal antibodies clone6B2, clone4G8, respectively.
  • the invention also provides a method for preparing anti-HER2 neutralizing active monoclonal antibodies clone6B2 and clone4G8, and synthesizing and synthesizing a polypeptide containing amino acid 266-296 of Domain 2 of HER2 extracellular region with HER2 as a target protein, and coupling with carrier protein KLH as The immunogen was prepared by immunizing mice.
  • the amino acid sequence of the polypeptide is: PALVTY TDTFESMPNPEGRYTFG.
  • the present invention provides the use of the polypeptide sequence of amino acid 266-296 of the HER2 extracellular domain Domain 2 in the preparation of HER2 neutralizing monoclonal antibody, and the use thereof in the preparation of a therapeutic agent for diseases targeting HER2 and
  • the amino acid sequence of the polypeptide is: PALVTYNTDTFESMPNPEGRYTFG, or an amino acid sequence of the same sequence formed by substitution, deletion or addition of one or several amino acids.
  • the present invention also provides the use of the monoclonal antibodies clone6B2 and clone4G8 in the preparation of a therapeutic agent for diseases targeting HER2.
  • the present invention further provides a medicament, a detection reagent, and a kit comprising the monoclonal antibodies clone6B2 and/or clone4G8.
  • the invention provides a human epidermal growth factor receptor 2 (HER2) monoclonal antibody that differs from a Herceptin recognition epitope and a hybridoma cell line that produces the monoclonal antibody.
  • HER2 human epidermal growth factor receptor 2
  • the peptide sequence is conjugated to the KLH carrier protein as an immunogen to immunize the mouse, and hybridoma technology is used to obtain a hybridoma cell strain capable of continuously and stably secreting the anti-HER2 monoclonal antibody by cell fusion, and the monoclonal antibody is secreted to obtain a monoclonal antibody. antibody.
  • the above polypeptide sequence is selected from HER2:
  • the monoclonal antibody obtained by coupling the polypeptide sequence with the carrier protein as the immunogen can specifically recognize the polypeptide sequence of the HER2 protein, and 82 positive clones were screened, and 15 positive clones were obtained by screening, and further screening for neutralization activity was screened. Two positive clones were named, and the two monoclonal antibodies were named clone6B2 and clone4G8, respectively.
  • the clones 6B2 and clone 4G8 have good affinity, and experiments have shown that the affinity of clone 6B2 and clone 4G8 to HER2-positive cells SK-BR-3 cells has an EC50 of 1.3 nM. It can bind to SK2 on the surface of SK-BR-3 cells and effectively inhibit the proliferation of breast cancer cells. It can be an ideal biotargeting antibody.
  • the monoclonal antibody of the present invention recognizes a linear epitope in the extracellular domain Domain 2 of HER2, which is clearer than the site of pertuzumab obtained by immunizing mice with HER2 extracellular domain Domain 2, and Hercetpin
  • the recognition of therapeutic monoclonal antibodies is completely different in HER2 epitopes. It can be combined with Herceptin to enhance the therapeutic effect and has broad prospects in the treatment of breast cancer.
  • Example 1 is a positive clone for screening and recognizing HER2 by indirect ELIS A method in Example 1 of the present invention, wherein 700 clones were screened, 395 positive clones were selected, and 82 positive clones were selected for further screening.
  • Figure 2 is a diagram showing the SDS-PAGE electrophoresis of the monoclonal antibody in Example 2 of the present invention; wherein M is the molecular weight standard of the protein, and 6B2 and 4G8 are the two monoclonal antibodies clone6B2 and clone4G8 respectively obtained in the present invention.
  • FIG 3 subtypes identified in Example 2 two clones embodiment of the invention; wherein, clone6B2 displayed the strongest signal I g G2b, clone4G8 show the strongest signal I g G2b Similarly, according subtype Kam In the kit description, the sub-type of clone6B2 and clone4G8 is IgG2b.
  • Figure 4 is a diagram showing the flow cytometry of two clones combined with SK-BR-3 cells in Example 3 of the present invention; wherein, Figure 4A is a map of clone 6B2 binding to SK-BR-3 cell flow cytometry, and Figure 4B is a clone4G8 Combined with SK-BR-3 cell flow cytometry, it was shown that it can bind to the surface of SK-BR-3 cells.
  • Figure 5 is a graph showing the proliferation curve of two clones binding to SK-BR-3 cells and inhibiting their proliferation in Example 4 of the present invention; wherein, Figure 5A is a proliferation curve in which clone 6B2 binds to SK-BR-3 cells and inhibits proliferation thereof, The inhibition effect was shown to be 40%, and Fig. 5B is a proliferation curve in which clone 4G8 binds to SK-BR-3 cells and inhibits proliferation thereof, showing good neutralizing activity.
  • Example 1 Establishment of a hybridoma cell line producing clone6B2, clone4G8
  • Immunogen Using HER2 as a target protein, select a polypeptide sequence (the polypeptide of amino acid domain 266-296 of HER2 extracellular domain), and the sequence is as follows: PALVTY TDTFESMPNPEGRYTFG
  • the above polypeptides are prepared by chemical synthesis, and the purity requirement is greater than 90%.
  • the polypeptide is coupled to KLH to prepare an immunogen.
  • Culture medium DMEM medium was purchased from Hyclone Co., Ltd., HAT, HT was selected as the medium, and phlegm was purchased from sigma.
  • mice Balb/c mice, 8-12 weeks old, female, SPF animals were cultured.
  • mice collected in a conventional manner were fused with SP2/0 cells at a ratio of 10:1 at 500 g/L of PEG4000.
  • the culture was selected with HAT medium, and 10-15 days after the fusion, the supernatant was subjected to indirect ELISA to screen for hybridoma cell lines secreting anti-HER2 antigen.
  • the resulting positive clones were subcloned using the limiting dilution method.
  • the procedure of the indirect ELISA method was as follows: 200 ⁇ l of HER2 coated plate, immunized mouse serum 1:2000 as a positive control, no cloned growth medium supernatant and normal mouse serum as a negative control, plus 1:2000 HRP per well - Goat anti-mouse IgG ⁇ , and finally determine the 450 nm OD value. If the OD450 value is more than 2 times larger than the negative control, the positive clone can be initially determined. A total of 395 positive clones were obtained, from which 82 better positive clones were selected. (figure 1 )
  • the indirect ELISA method for detecting the purified antibody prepared by the above hybridoma cells has a titer of 0.05-10 ng/ml.
  • the above hybridoma cell line was further cultured and passaged in DMEM medium containing 10% fetal calf serum, and after 10 passages, the hybridoma cell line was still able to grow well and stably pass, and the supernatant of the culture supernatant was still available. Reached 1: 10,000 or more.
  • the above results indicate that the obtained hybridoma cell line can be stably passaged, and can stably and stably secrete monoclonal antibodies against HER2.
  • a part of the hybridoma cells must be preserved, otherwise mutation or chromosome drift may occur during continuous passage to lose the intrinsic property or to lose the antibody-producing property.
  • mutation or chromosome drift may occur during continuous passage to lose the intrinsic property or to lose the antibody-producing property.
  • pollution in the long-term cultivation process, it is inevitable that pollution will not occur and will be destroyed. Therefore, it is necessary to refrigerate a part.
  • the method of preservation is as follows:
  • dimethyl sulfoxide protection solution (dimethyl sulfoxide can damage the filter and is destroyed by high pressure, so it can not be filtered or autoclaved. It is itself a drug, sterile): 10% dimethyl sulfoxide, 20% inactivated fetal bovine serum, 70% RPMI-1640 solution.
  • FCS-16 40 medium penicillin 100 U/ml, streptomycin 10 ( ⁇ g/ml.
  • mice were selected and intraperitoneally inoculated with pristane, 0.5 ml per mouse. After 7-10 days, the 16th generation hybridoma cells were inoculated intraperitoneally, and each mouse was I x l0 6 -2 x l0 6 . After 5 days interval, the abdomen is obviously enlarged, and when the hand is touched, the skin is tense, that is, the ascites can be collected with a 9-gauge needle.
  • the ascites was centrifuged (13,000 r/min for 30 minutes), cell components and other precipitates were removed, and the supernatant was collected. Purification was carried out with Protein G ⁇ Sepharose CL-4B.
  • the upper column was 20 mM PBS buffer, and the column chromatography eluate was: pH 2.7, 20 mM glycine buffer to obtain a monoclonal antibody against HER2.
  • the Ig subtype of the antibody produced by the above hybridoma cells was identified by an indirect ELISA using antibodies against various mouse Ig subtypes, and the results showed that both clone6B2 and clone4G8 were IgG2b (Fig. 3). 3. Variable region sequence determination of clone 6B2 and clone 4G8
  • variable region amino acid sequence of clone6B2 and clone4G8 The amino acid sequence of the light chain variable region of clone 6B2 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 amino acid sequence of the light chain variable region of clone 4G8 is shown in SEQ ID No. 3, and the amino acid sequence of the heavy chain variable region is shown in SEQ ID No. 4.
  • the clone affinity test was performed using the clone6B2 and clone4G8 antibodies to determine the binding EC50 value to HER2-positive SK-BR-3 cells. The results are shown in Table 2.
  • SK-BR-3 cell plating preparation select well-grown SK-BR-3 cells, wash 3 times with sterile PBS, add 0.1% trypsin to digest cells for 1-3 minutes, add 10 5 ml of DMEM medium of % FBS, the cells were harvested after centrifugation, and the cells were counted and adjusted to 1 ⁇ 10 5 /ml, and 200 ⁇ l per well was placed in 96 wells, and cultured overnight. The next day, the cell culture supernatant was removed, washed twice with PBS, and fixed with 95% alcohol for 15 min.
  • the cells were washed twice with sterile water and then blocked with 200 ⁇ l/well of 5% skim milk for 1 h.
  • PBS After washing 3 times, add gradient dilution of Clone 6B2, Clone4G8, incubate for 1 h at 37 °C, wash 3 times with PBS, and add HRP (horseradish peroxidase)-labeled murine secondary antibody (1:2000) for 1 h.
  • the PBS was washed 5 times (the first three times 5 minutes, the last two times lOmin) and the color developing agent was added for 15 minutes to detect the OD 450 .
  • the developer A liquid solution is added with urinary urea lg, 10.3g citric acid, 35.8g Na 2 HP0 4 -12 H 2 0, Tween-20 ⁇ , ⁇ 5 per 10000mL of water; sputum formula is distilled water per lOOmL Tetramethylbenzidine ( ⁇ ) 700 mg (dissolved in 40 mL of DMSO), 10.3 g of citric acid, pH 2.4 were added.
  • EC50 values of clone6B2 and clone4G8 were both up to 1.3 ⁇ , indicating a high affinity.
  • Cell preparation Take SK-BR-3 cells grown in log phase, aspirate the cell supernatant, and wash once with 5-10 ml PBS. Add 211 1 0.1% trypsin 37 ° digestion 51 ⁇ 11, add DMEM containing 10% FBS to terminate digestion, centrifuge at 1400 rpm for 3 min to collect cells. After washing the cells three times with DMEM without fetal bovine serum, the cells were resuspended in PBS, centrifuged at 1400 rpm for 3 min, and 20 ug/ml antibody was added and incubated at 4 ° C for 1 h.
  • the cells were collected by centrifugation at 1400 rpm for 3 min, and the cells were washed three times with PBS, and then incubated with FITC-labeled murine secondary antibody (1:100) for 30 min at 4 ° C, and then centrifuged at 400 rpm for 3 min to collect the cells. After washing three times with PBS, the up-flow cytometer detects the fluorescence information. As shown in Figure 4, clone6B2 and clone4G8 were able to bind to HER2 on SK-BR-3 cells. Example 4 Detection of neutralizing activity of purified antibodies
  • SK-BR-3 cells grown in log phase, aspirate the cell supernatant, and wash once with 5-10 ml PBS. 211 1 0.1% trypsin was added to digest 511 01, and the digestion was terminated by adding DMEM or F-12 containing 10% FBS, and the cells were collected by centrifugation at 1400 rpm for 3 min. The cells were diluted with 8 ml of DMEM containing 10% FBS, and the cells were counted by trypan blue cell counting and used with 10% FBS. DMEM was diluted to 2 x 10 4 /ml. Each well of a 96-well plate was plated with ⁇ , ie, 2000/well, and cultured at 37 °C, 5% C0 2 for 4 hours.
  • clone6B2 and clone4G8 were able to bind to SK-BR-3 cells and inhibit their proliferation, wherein clone6B2 inhibited the proliferation of SK-BR-3 cells by 40%; clone4G8 inhibited the proliferation of SK-BR-3 cells. 30%.
  • Industrial applicability As shown in Figure 5, clone6B2 and clone4G8 were able to bind to SK-BR-3 cells and inhibit their proliferation, wherein clone6B2 inhibited the proliferation of SK-BR-3 cells by 40%; clone4G8 inhibited the proliferation of SK-BR-3 cells. 30%.
  • the present invention provides an anti-HER2 (human epidermal growth factor receptor 2) neutralizing active monoclonal antibody and use thereof.
  • HER2 human epidermal growth factor receptor 2
  • the secretion of multiple hybridoma cells can be obtained by immunizing mice.
  • the monoclonal antibody of the present invention has an affinity for binding to HER2 of 1.3 nM, and binds to HER2 on the surface of tumor cells, thereby effectively inhibiting the proliferation of tumor cells, and is an ideal biotargeting therapeutic antibody.
  • Trp lie Asp Leu Glu Asn Gly Asp Ser Asp Tyr Ala Pro Lys Phe Gin 50 55 60

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Abstract

L'invention concerne un anticorps monoclonal anti-HER2 à action de neutralisation, et son utilisation. L'anticorps est préparé par immunisation d'une souris avec un immunogène obtenu par couplage d'un polypeptide de la région extracellulaire de HER2 (PALVTYNTDTFESMPNPEGRYTFG) et de la protéine porteuse KLH.
PCT/CN2015/077447 2014-04-30 2015-04-24 Anticorps monoclonal anti-her2 à action de neutralisation, et utilisation de celui-ci WO2015165368A1 (fr)

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CN201410183637.9A CN105017425B (zh) 2014-04-30 2014-04-30 抗her2中和活性单克隆抗体及其应用
CN201410183637.9 2014-04-30

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CN108610419B (zh) * 2016-12-09 2020-08-18 泰州迈博太科药业有限公司 一种人源化抗her2单克隆抗体
CN115975035B (zh) * 2022-08-18 2023-08-18 北京诺赛国际医学研究院 干细胞和抗体联合治疗癌症的用途

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US20070060516A1 (en) * 2005-06-15 2007-03-15 The Ohio State University Research Foundation Her-2 peptides
CN102099376A (zh) * 2008-06-13 2011-06-15 阿特拉斯医疗有限公司 针对her2的细胞外结构域2和3的抗体
CN103102414A (zh) * 2013-02-04 2013-05-15 无锡傲锐东源生物科技有限公司 抗her2蛋白单克隆抗体及其用途

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CN1210308C (zh) * 2001-11-16 2005-07-13 上海中信国健药业有限公司 人源化抗her2单克隆抗体及其制法和药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060516A1 (en) * 2005-06-15 2007-03-15 The Ohio State University Research Foundation Her-2 peptides
CN102099376A (zh) * 2008-06-13 2011-06-15 阿特拉斯医疗有限公司 针对her2的细胞外结构域2和3的抗体
CN103102414A (zh) * 2013-02-04 2013-05-15 无锡傲锐东源生物科技有限公司 抗her2蛋白单克隆抗体及其用途

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