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Published in: Tumor Biology 12/2014

01-12-2014 | Research Article

Immunization with a novel chimeric peptide representing B and T cell epitopes from HER2 extracellular domain (HER2 ECD) for breast cancer

Authors: Manijeh Mahdavi, Mehrnaz Keyhanfar, Abbas Jafarian, Hassan Mohabatkar, Mohammad Rabbani

Published in: Tumor Biology | Issue 12/2014

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Abstract

Because of direct stimulating immune system against disease, vaccination or active immunotherapy is preferable compared to passive immunotherapy. For this purpose, a newly designed chimeric peptide containing epitopes for both B and T cells from HER2 ECD subdomain III was proposed. To evaluate the effects of the active immunization, a discontinuous B cell epitope peptide was selected based on average antigenicity by bioinformatics analysis. The selected peptide was collinearly synthesized as a chimera with a T helper epitope from the protein sequence of measles virus fusion (208-302) using the GPSL linker. Three mice were immunized with the chimeric peptide. Reactive antibodies with HER2 protein in ELISA and immunofluorescence assays with no cross-reactivity were generated. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay indicated that the anti-peptide sera had inhibitory effects on proliferation of SK-BR-3 cells. Hence, the newly designed, discontinuous chimeric peptide representing B and T cell epitopes from subdomain III of HER2-ECD can form the basis for future vaccines design, where these data can be applied for monoclonal antibody production targeting the distinct epitope of HER2 receptor compared to the two broadly used anti-HER2 monoclonal antibodies, Herceptin and pertuzumab.
Literature
1.
go back to reference Correa I, Plunkett T. Update on HER-2 as a target for cancer therapy HER2/neu peptides as tumour vaccines for T cell recognition. Breast Cancer Res. 2001;3:399–403.PubMedPubMedCentral Correa I, Plunkett T. Update on HER-2 as a target for cancer therapy HER2/neu peptides as tumour vaccines for T cell recognition. Breast Cancer Res. 2001;3:399–403.PubMedPubMedCentral
2.
go back to reference Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343–57.PubMed Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343–57.PubMed
3.
go back to reference Jager D, Knuth A. Antibodies and vaccines—hope or illusion? Breast. 2005;14:631–5.PubMed Jager D, Knuth A. Antibodies and vaccines—hope or illusion? Breast. 2005;14:631–5.PubMed
4.
go back to reference Milani A, Sangiolo D, Montemurro F, Aglietta M, et al. Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol. 2013;24(7):1740–8.PubMed Milani A, Sangiolo D, Montemurro F, Aglietta M, et al. Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol. 2013;24(7):1740–8.PubMed
5.
go back to reference Garrett JT, Kaumaya P, Pei D, Dalbey R et al (2007). Peptide based B cell epitope vaccines targeting HER-2/Neu. Dissertation, Ohio State University Garrett JT, Kaumaya P, Pei D, Dalbey R et al (2007). Peptide based B cell epitope vaccines targeting HER-2/Neu. Dissertation, Ohio State University
6.
go back to reference Ladjemi MZ, Jacot W, Pèlegrin A, Navarro-Teulon I. Vaccination anti-HER2: l’avenir du ciblage immunologique de HER2? Review Article. Pathol Biol. 2011;59:173–82.PubMed Ladjemi MZ, Jacot W, Pèlegrin A, Navarro-Teulon I. Vaccination anti-HER2: l’avenir du ciblage immunologique de HER2? Review Article. Pathol Biol. 2011;59:173–82.PubMed
7.
go back to reference Dakappagari NK, Pyles J, Parihar R, Carson WE, et al. Multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumour responses. J Immunol. 2003;170:4242–53.PubMed Dakappagari NK, Pyles J, Parihar R, Carson WE, et al. Multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumour responses. J Immunol. 2003;170:4242–53.PubMed
8.
go back to reference Milich DR. Synthetic T and B cell recognition sites: implications for vaccine development. Adv Immunol. 1989;45:195–282.PubMed Milich DR. Synthetic T and B cell recognition sites: implications for vaccine development. Adv Immunol. 1989;45:195–282.PubMed
9.
go back to reference Gangwara RS, Shil P, Sapkala GN, Khanc SA, et al. Induction of virus-specific neutralizing immune response against West Nile and Japanese encephalitis viruses by chimeric peptides representing T-helper and B-cell epitopes. Vir Res. 2012;163:40–50. Gangwara RS, Shil P, Sapkala GN, Khanc SA, et al. Induction of virus-specific neutralizing immune response against West Nile and Japanese encephalitis viruses by chimeric peptides representing T-helper and B-cell epitopes. Vir Res. 2012;163:40–50.
10.
go back to reference Miyako H, Kametani Y, Katano I, Ito R, et al. Antitumor effect of New HER2 peptide vaccination based on B cell epitope. Anticancer Res. 2011;31:3361–8.PubMed Miyako H, Kametani Y, Katano I, Ito R, et al. Antitumor effect of New HER2 peptide vaccination based on B cell epitope. Anticancer Res. 2011;31:3361–8.PubMed
11.
go back to reference Mahdavi M, Mohabatkar H, Keyhanfar M, Jafarian Dehkordi A, et al. Linear and conformational B cell epitope prediction of HER 2 ECD-subdomain III by in silico methods. Asian Pac J Cancer Prev. 2012;13:3053–9.PubMed Mahdavi M, Mohabatkar H, Keyhanfar M, Jafarian Dehkordi A, et al. Linear and conformational B cell epitope prediction of HER 2 ECD-subdomain III by in silico methods. Asian Pac J Cancer Prev. 2012;13:3053–9.PubMed
12.
go back to reference Mahdavi M, Keyhanfar M, Moreau V, Mohabatkar H, et al. In silico design of discontinuous peptides representative of B and T-cell epitopes from HER2-ECD as potential novel cancer peptide vaccines. Asian Pac J Cancer Prev. 2013;14:5973–81. Mahdavi M, Keyhanfar M, Moreau V, Mohabatkar H, et al. In silico design of discontinuous peptides representative of B and T-cell epitopes from HER2-ECD as potential novel cancer peptide vaccines. Asian Pac J Cancer Prev. 2013;14:5973–81.
13.
go back to reference Jasinska J, Wagner S, Radauer C, Sedivy R, et al. Inhibition of tumour cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of HER-2/Neu. Int J Cancer. 2003;107:976–83.PubMed Jasinska J, Wagner S, Radauer C, Sedivy R, et al. Inhibition of tumour cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of HER-2/Neu. Int J Cancer. 2003;107:976–83.PubMed
14.
go back to reference Zhang AL, Xue H, Ling XG, Gao Y, et al. Anti-HER-2 engineering antibody ChA21 inhibits growth and induces apoptosis of SK-OV-3 cells. J Exp Clin Cancer Res. 2010;29:23–32.PubMedPubMedCentral Zhang AL, Xue H, Ling XG, Gao Y, et al. Anti-HER-2 engineering antibody ChA21 inhibits growth and induces apoptosis of SK-OV-3 cells. J Exp Clin Cancer Res. 2010;29:23–32.PubMedPubMedCentral
15.
go back to reference Kaumaya PTP, Kobs-Conrad S, DiGeorge AM, Stevens V. De novo engineering of protein immunogenic and antigenic determinants. In: Anantharamaiah GM, Basava C, editors. Peptides, design, synthesis & biological activity. Boston: Birkhauser; 1994. p. 133–64. Kaumaya PTP, Kobs-Conrad S, DiGeorge AM, Stevens V. De novo engineering of protein immunogenic and antigenic determinants. In: Anantharamaiah GM, Basava C, editors. Peptides, design, synthesis & biological activity. Boston: Birkhauser; 1994. p. 133–64.
16.
go back to reference Kaumaya PTP. Synthetic peptide vaccines: dream or reality. In: Schneider CH, editor. Peptides in immunology. United Kingdom: Wiley; 1996. p. 117–48. Kaumaya PTP. Synthetic peptide vaccines: dream or reality. In: Schneider CH, editor. Peptides in immunology. United Kingdom: Wiley; 1996. p. 117–48.
17.
go back to reference Partidos CD, Steward MW. Prediction and identification of a T cell epitope in the fusion protein of measles virus immunodominant in mice and humans. J Gen Virol. 1990;71:2099–105.PubMed Partidos CD, Steward MW. Prediction and identification of a T cell epitope in the fusion protein of measles virus immunodominant in mice and humans. J Gen Virol. 1990;71:2099–105.PubMed
18.
go back to reference Maupetit J, Derreumaux P, Tuffery P. PEP-FOLD: an online resource for de novo peptide structure prediction. Nucleic Acids Res. 2009;37:498–503. Maupetit J, Derreumaux P, Tuffery P. PEP-FOLD: an online resource for de novo peptide structure prediction. Nucleic Acids Res. 2009;37:498–503.
19.
go back to reference DeLano WL. The PyMOL molecular graphics system. San Carlos: DeLano Scientific; 2002. DeLano WL. The PyMOL molecular graphics system. San Carlos: DeLano Scientific; 2002.
20.
go back to reference Scott WRP, Hünenberger PH, Tironi IG, Mark AE, et al. The GROMOS biomolecular simulation program package. J Phys Chem A. 1999;103:3596–607. Scott WRP, Hünenberger PH, Tironi IG, Mark AE, et al. The GROMOS biomolecular simulation program package. J Phys Chem A. 1999;103:3596–607.
21.
go back to reference Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1997;18:2714–23.PubMed Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1997;18:2714–23.PubMed
22.
go back to reference Yokoyama WM (1995) Production of monoclonal antibodies. In: Current Protocols in Immunology, John Wiley & Sonc Yokoyama WM (1995) Production of monoclonal antibodies. In: Current Protocols in Immunology, John Wiley & Sonc
23.
go back to reference Tabll A, Khalil SB, El-Shenawy RM, Esmat G, et al. Establishment of hybrid cell lines producing monoclonal antibodies to a synthetic peptide from the E1 region of the hepatitis C virus. J Immunoass Immunochem. 2007;29:91–104. Tabll A, Khalil SB, El-Shenawy RM, Esmat G, et al. Establishment of hybrid cell lines producing monoclonal antibodies to a synthetic peptide from the E1 region of the hepatitis C virus. J Immunoass Immunochem. 2007;29:91–104.
24.
go back to reference Hornbeck P (1991) Enzyme-linked immunosorbent assays. In: Current Protocols in Immunology, John Wiley & Sonc Hornbeck P (1991) Enzyme-linked immunosorbent assays. In: Current Protocols in Immunology, John Wiley & Sonc
25.
go back to reference Larry M, Lantz BJ, Fowlkes IS, Janis VG (2001) Preparation of cells and reagents for flow cytometry. In: Current Protocols in Immunology, Wiley Larry M, Lantz BJ, Fowlkes IS, Janis VG (2001) Preparation of cells and reagents for flow cytometry. In: Current Protocols in Immunology, Wiley
26.
go back to reference Kolaskar AS, Tongaonkar PC. A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBS Lett. 1990;276:172–4.PubMed Kolaskar AS, Tongaonkar PC. A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBS Lett. 1990;276:172–4.PubMed
27.
go back to reference Deulofeut H, Iglesias A, Mikael N, Bing DH, et al. Cellular recognition and HLA restriction of a midsequence HBsAg peptide in hepatitis B vaccinated individuals. Mol Immunol. 1993;30:941–8.PubMed Deulofeut H, Iglesias A, Mikael N, Bing DH, et al. Cellular recognition and HLA restriction of a midsequence HBsAg peptide in hepatitis B vaccinated individuals. Mol Immunol. 1993;30:941–8.PubMed
28.
go back to reference Dakappagari NK, Douglas DB, Triozzi PL, Stevens VC, et al. Prevention of mammary tumours with a chimeric Her-2 B-cell epitope peptide vaccine. Cancer Res. 2000;60:3782–9.PubMed Dakappagari NK, Douglas DB, Triozzi PL, Stevens VC, et al. Prevention of mammary tumours with a chimeric Her-2 B-cell epitope peptide vaccine. Cancer Res. 2000;60:3782–9.PubMed
29.
go back to reference Wang B, Kaumaya PTP, Cohn DE. Immunization with synthetic VEGF peptides in ovarian cancer. Gyn Oncol. 2010;119:564–70. Wang B, Kaumaya PTP, Cohn DE. Immunization with synthetic VEGF peptides in ovarian cancer. Gyn Oncol. 2010;119:564–70.
30.
go back to reference Sundaram R, Lynch MP, Rawale SV, Sun Y, et al. De novo design of peptide immunogens that mimic the coiled coil region of human T-cell leukemia virus type-1 glycoprotein 21 transmembrane subunit for induction of native protein reactive neutralizing antibodies. J Biol Chem. 2004;279:141–51. Sundaram R, Lynch MP, Rawale SV, Sun Y, et al. De novo design of peptide immunogens that mimic the coiled coil region of human T-cell leukemia virus type-1 glycoprotein 21 transmembrane subunit for induction of native protein reactive neutralizing antibodies. J Biol Chem. 2004;279:141–51.
31.
go back to reference Boyer CM, Pusztai L, Wiener JR, Xu FJ, et al. Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185. Int J Cancer. 1999;82:525–31.PubMed Boyer CM, Pusztai L, Wiener JR, Xu FJ, et al. Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185. Int J Cancer. 1999;82:525–31.PubMed
32.
go back to reference Wang JN, Feng JN, Yua M, Xua M, et al. Structural analysis of the epitopes on erbB2 interacted with inhibitory or non-inhibitor monoclonal antibodies. Mol Immunol. 2004;40:963–9.PubMed Wang JN, Feng JN, Yua M, Xua M, et al. Structural analysis of the epitopes on erbB2 interacted with inhibitory or non-inhibitor monoclonal antibodies. Mol Immunol. 2004;40:963–9.PubMed
33.
go back to reference Zhang W, Xiong Y, Zhao M, Zou H, et al. Prediction of conformational B-cell epitopes from 3D structures by random forests with a distance-based feature. BMC Bioinform. 2011;12:341–8. Zhang W, Xiong Y, Zhao M, Zou H, et al. Prediction of conformational B-cell epitopes from 3D structures by random forests with a distance-based feature. BMC Bioinform. 2011;12:341–8.
34.
go back to reference Siyi H, Zhiqiang Z, Liangwei L, Liang C, et al. Epitope mapping and structural analysis of an anti-ErbB2 antibody A21: molecular basis for tumour inhibitory mechanism. Proteins. 2008;70:938–49. Siyi H, Zhiqiang Z, Liangwei L, Liang C, et al. Epitope mapping and structural analysis of an anti-ErbB2 antibody A21: molecular basis for tumour inhibitory mechanism. Proteins. 2008;70:938–49.
35.
go back to reference Haro I, Gomara MJ. Design of synthetic peptidic constructs for the vaccine development against viral infections. Curr Protein Pept Sci. 2004;5:425–33.PubMed Haro I, Gomara MJ. Design of synthetic peptidic constructs for the vaccine development against viral infections. Curr Protein Pept Sci. 2004;5:425–33.PubMed
36.
go back to reference Aguilar RM, Talamantes FJ, Bustamante J, Muñoz J, Treviño LR, et al. Multiple antigen peptide dendrimer elicits antibodies for detecting rat and mouse growth hormone binding proteins. J Pept Sci. 2009;15:78–88.PubMedPubMedCentral Aguilar RM, Talamantes FJ, Bustamante J, Muñoz J, Treviño LR, et al. Multiple antigen peptide dendrimer elicits antibodies for detecting rat and mouse growth hormone binding proteins. J Pept Sci. 2009;15:78–88.PubMedPubMedCentral
37.
go back to reference Jalali A, Sankian M, Tavakkol-Afshari J, Jaafari MR. Induction of tumour-specific immunity by multi-epitope rat HER2/neu-derived peptides encapsulated in LPD Nanoparticles. Nanomed Nanotech Biol Med. 2012;8:692–701. Jalali A, Sankian M, Tavakkol-Afshari J, Jaafari MR. Induction of tumour-specific immunity by multi-epitope rat HER2/neu-derived peptides encapsulated in LPD Nanoparticles. Nanomed Nanotech Biol Med. 2012;8:692–701.
38.
go back to reference Singh R, Rothman AL, Potts J, Guirakhoo F, et al. Sequential immunization with heterologous chimeric flaviviruses induces broad-spectrum cross-reactive CD8+ T cell responses. J Infect Dis. 2010;202:223–33.PubMed Singh R, Rothman AL, Potts J, Guirakhoo F, et al. Sequential immunization with heterologous chimeric flaviviruses induces broad-spectrum cross-reactive CD8+ T cell responses. J Infect Dis. 2010;202:223–33.PubMed
39.
go back to reference Axelsena TV, Holma A, Christiansena G, Birkelund S. Identification of the shortest AB-peptide generating highly specific antibodies against the C-terminal end of amyloid-B42. Vaccine. 2011;29:3260–9. Axelsena TV, Holma A, Christiansena G, Birkelund S. Identification of the shortest AB-peptide generating highly specific antibodies against the C-terminal end of amyloid-B42. Vaccine. 2011;29:3260–9.
40.
go back to reference Ripoll DR. Conformational study of a peptide epitope shows large preferences for beta-turn conformations. Int J Pept Protein Res. 1992;40:575–81.PubMed Ripoll DR. Conformational study of a peptide epitope shows large preferences for beta-turn conformations. Int J Pept Protein Res. 1992;40:575–81.PubMed
41.
go back to reference Dakappagari NK, Lute KD, Rawale S, Steele JT, et al. Conformational HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumour cell binding and antitumour activities. J Biol Chem. 2005;280:54–63.PubMed Dakappagari NK, Lute KD, Rawale S, Steele JT, et al. Conformational HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumour cell binding and antitumour activities. J Biol Chem. 2005;280:54–63.PubMed
42.
go back to reference Chen SW, Van Regenmortel MH, Pellequer JL. Structure-activity relationships in peptide-antibody complexes: implications for epitope prediction and development of synthetic peptide vaccines. Curr Med Chem. 2009;16:953–9.PubMed Chen SW, Van Regenmortel MH, Pellequer JL. Structure-activity relationships in peptide-antibody complexes: implications for epitope prediction and development of synthetic peptide vaccines. Curr Med Chem. 2009;16:953–9.PubMed
43.
go back to reference Yarden Y, Peles E. Biochemical analysis of the ligand for the neu oncogenic receptor. Biochem. 1991;30:3543–50. Yarden Y, Peles E. Biochemical analysis of the ligand for the neu oncogenic receptor. Biochem. 1991;30:3543–50.
44.
go back to reference Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D, et al. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Sci. 1990;249:1552–5. Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D, et al. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Sci. 1990;249:1552–5.
45.
go back to reference Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA. 1991;88:8691–5.PubMedPubMedCentral Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA. 1991;88:8691–5.PubMedPubMedCentral
46.
go back to reference Hurwitz E, Stancovski I, Sela M, Yarden Y. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci U S A. 1995;92:3353–7.PubMedPubMedCentral Hurwitz E, Stancovski I, Sela M, Yarden Y. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci U S A. 1995;92:3353–7.PubMedPubMedCentral
47.
go back to reference Courtenay-Luck NS, Epenetos AA, Moore R, Larche M, Pectasides D, Dhokia B, et al. Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms. Cancer Res. 1986;46(12 Pt 1):6489–93.PubMed Courtenay-Luck NS, Epenetos AA, Moore R, Larche M, Pectasides D, Dhokia B, et al. Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms. Cancer Res. 1986;46(12 Pt 1):6489–93.PubMed
Metadata
Title
Immunization with a novel chimeric peptide representing B and T cell epitopes from HER2 extracellular domain (HER2 ECD) for breast cancer
Authors
Manijeh Mahdavi
Mehrnaz Keyhanfar
Abbas Jafarian
Hassan Mohabatkar
Mohammad Rabbani
Publication date
01-12-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2503-y

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