Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Construction and Characterization of an Anti-Hepatitis B Virus preS1 Humanized Antibody that Binds to the Essential Receptor Binding Site

  • Wi, Jimin (Department of Systems Immunology, College of Biomedical Science, Kangwon National University) ;
  • Jeong, Mun Sik (Department of Systems Immunology, College of Biomedical Science, Kangwon National University) ;
  • Hong, Hyo Jeong (Department of Systems Immunology, College of Biomedical Science, Kangwon National University)
  • Received : 2017.03.30
  • Accepted : 2017.04.27
  • Published : 2017.07.28
Download PDF
⟨ Previous Next ⟩

Abstract

Hepatitis B virus (HBV) is a major cause of liver cirrhosis and hepatocellular carcinoma. With recent identification of HBV receptor, inhibition of virus entry has become a promising concept in the development of new antiviral drugs. To date, 10 HBV genotypes (A-J) have been defined. We previously generated two murine anti-preS1 monoclonal antibodies (mAbs), KR359 and KR127, that recognize amino acids (aa) 19-26 and 37-45, respectively, in the receptor binding site (aa 13-58, genotype C). Each mAb exhibited virus neutralizing activity in vitro, and a humanized version of KR127 effectively neutralized HBV infection in chimpanzees. In the present study, we constructed a humanized version (HzKR359-1) of KR359 whose antigen binding activity is 4.4-fold higher than that of KR359, as assessed by competitive ELISA, and produced recombinant preS1 antigens (aa 1-60) of different genotypes to investigate the binding capacities of HzKR359-1 and a humanized version (HzKR127-3.2) of KR127 to the 10 HBV genotypes. The results indicate that HzKR359-1 can bind to five genotypes (A, B, C, H, and J), and HzKR127-3.2 can also bind to five genotypes (A, C, D, G, and I). The combination of these two antibodies can bind to eight genotypes (A-D, G-J), and to genotype C additively. Considering that genotypes A-D are common, whereas genotypes E and F are occasionally represented in small patient population, the combination of these two antibodies might block the entry of most virus genotypes and thus broadly neutralize HBV infection.

Keywords

References

  1. Ganem D, Varmus HE. 1987. The molecular biology of the hepatitis B viruses. Annu. Rev. Biochem. 56: 651-693. https://doi.org/10.1146/annurev.bi.56.070187.003251
  2. Rehermann B, Nascimbeni M. 2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5: 215-229. https://doi.org/10.1038/nri1573
  3. Ott JJ, Stevens GA, Groeger J, Wiersma ST. 2012. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 30: 2212-2219. https://doi.org/10.1016/j.vaccine.2011.12.116
  4. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. 2012. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095-2128. https://doi.org/10.1016/S0140-6736(12)61728-0
  5. McGlynn KA, London WT. 2011. The global epidemiology of hepatocellular carcinoma: present and future. Clin. Liver Dis. 15: 223-243, vii-x. https://doi.org/10.1016/j.cld.2011.03.006
  6. GBD 2013 Mortality and Causes of Death Collaborators (Naghavi M, Wang H, Lozano R, Davis A, Liang X, Zhou M, et al.). 2015. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385: 117-171. https://doi.org/10.1016/S0140-6736(14)61682-2
  7. Kramvis A, Kew M, Francois G. 2005. Hepatitis B virus genotypes. Vaccine 23: 2409-2423. https://doi.org/10.1016/j.vaccine.2004.10.045
  8. Schaefer S. 2007. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J. Gastroenterol. 13: 14-21. https://doi.org/10.3748/wjg.v13.i1.14
  9. Kramvis A, Kew MC. 2007. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol. Res. 37: S9-S19. https://doi.org/10.1111/j.1872-034X.2007.00098.x
  10. Norder H, Courouce AM, Coursaget P, Echevarria JM, Lee SD, Mushahwar IK, et al. 2004. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 47: 289-309. https://doi.org/10.1159/000080872
  11. Kramvis A. 2014. Genotypes and genetic variability of hepatitis B virus. Intervirology 57: 141-150. https://doi.org/10.1159/000360947
  12. Tatematsu K, Tanaka Y, Kurbanov F, Sugauchi F, Mano S, Maeshiro T, et al. 2009. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J. Virol. 83: 10538-10547. https://doi.org/10.1128/JVI.00462-09
  13. Sunbul M. 2014. Hepatitis B virus genotypes: global distribution and clinical importance. World J. Gastroenterol. 20: 5427-5434. https://doi.org/10.3748/wjg.v20.i18.5427
  14. Westland C, Delaney W, Yang H, Chen SS, Marcellin P, Hadziyannis S, et al. 2003. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 125: 107-116. https://doi.org/10.1016/S0016-5085(03)00700-5
  15. Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH. 1984. Large surface proteins of hepatitis B virus containing the pre-S sequence. J. Virol. 52: 396-402.
  16. Stibbe W, Gerlich WH. 1983. Structural relationships between minor and major proteins of hepatitis B surface antigen. J. Virol. 46: 626-628.
  17. Glebe D, Urban S. 2007. Viral and cellular determinants involved in hepadnaviral entry. World J. Gastroenterol. 13: 22-38. https://doi.org/10.3748/wjg.v13.i1.22
  18. Engelke M, Mills K, Seitz S, Simon P, Gripon P, Schnolzer M, et al. 2006. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology 43: 750-760. https://doi.org/10.1002/hep.21112
  19. Xie Y, Zhai J, Deng Q, Tiollais P, Wang Y, Zhao M. 2010. Entry of hepatitis B virus: mechanism and new therapeutic target. Pathol. Biol. (Paris) 58: 301-307. https://doi.org/10.1016/j.patbio.2010.04.001
  20. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1: e00049.
  21. Glebe D, Urban S, Knoop EV, Cag N, Krass P, Grun S, et al. 2005. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology 129: 234-245. https://doi.org/10.1053/j.gastro.2005.03.090
  22. Schulze A, Schieck A, Ni Y, Mier W, Urban S. 2010. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J. Virol. 84: 1989-2000. https://doi.org/10.1128/JVI.01902-09
  23. Ecker DM, Jones SD, Levine HL. 2015. The therapeutic monoclonal antibody market. mAbs 7: 9-14. https://doi.org/10.4161/19420862.2015.989042
  24. Shawler DL, Bartholomew RM, Smith LM, Dillman RO. 1985. Human immune response to multiple injections of murine monoclonal IgG. J. Immunol. 135: 1530-1535.
  25. Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, Duncan JF, et al. 1989. A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86: 10029-10033. https://doi.org/10.1073/pnas.86.24.10029
  26. Riechmann L, Clark M, Waldmann H, Winter G. 1988. Reshaping human antibodies for therapy. Nature 332: 323-327. https://doi.org/10.1038/332323a0
  27. Ryu C J, K im YK, H ur H , Kim HS, O h JM, Kang Y J, et al. 2000. Mouse monoclonal antibodies to hepatitis B virus preS1 produced after immunization with recombinant preS1 peptide. Hybridoma 19: 185-189. https://doi.org/10.1089/02724570050031248
  28. Maeng CY, Ryu CJ, Gripon P, Guguen-Guillouzo C, Hong HJ. 2000. Fine mapping of virus-neutralizing epitopes on hepatitis B virus PreS1. Virology 270: 9-16. https://doi.org/10.1006/viro.2000.0250
  29. Hong HJ, Ryu CJ, Hur H, Kim S, Oh HK, Oh MS, et al. 2004. In vivo neutralization of hepatitis B virus infection by an anti-preS1 humanized antibody in chimpanzees. Virology 318: 134-141. https://doi.org/10.1016/j.virol.2003.09.014
  30. Kim JH, Gripon P, Bouezzedine F, Jeong MS, Chi SW, Ryu SE, et al. 2015. Enhanced humanization and affinity maturation of neutralizing anti-hepatitis B virus preS1 antibody based on antigen-antibody complex structure. FEBS Lett. 589: 193-200. https://doi.org/10.1016/j.febslet.2014.11.046
  31. Backliwal G, Hildinger M, Hasija V, Wurm FM. 2008. Highdensity transfection with HEK-293 cells allows doubling of transient titers and removes need for a priori DNA complex formation with PEI. Biotechnol. Bioeng. 99: 721-727. https://doi.org/10.1002/bit.21596
  32. Cho S, Park I, Kim H, Jeong MS, Lim M, Lee ES, et al. 2016. Generation, characterization and preclinical studies of a human anti-L1CAM monoclonal antibody that cross-reacts with rodent L1CAM. mAbs 8: 414-425. https://doi.org/10.1080/19420862.2015.1125067
  33. Faleye TO, Adewumi OM, Ifeorah IM, Akere A, Bakarey AS, Omoruyi EC, et al. 2015. Detection and circulation of hepatitis B virus immune escape mutants among asymptomatic community dwellers in Ibadan, southwestern Nigeria. Int. J. Infect. Dis. 39: 102-109. https://doi.org/10.1016/j.ijid.2015.08.008
  34. Tran TT, Trinh TN, Abe K. 2008. New complex recombinant genotype of hepatitis B virus identified in Vietnam. J. Virol. 82: 5657-5663. https://doi.org/10.1128/JVI.02556-07
  35. Wei CH, Lee ES, Jeon JY, Heo YS, Kim SJ, Jeon YH, et al. 2011. Structural mechanism of the antigen recognition by the L1 cell adhesion molecule antibody A10-A3. FEBS Lett. 585: 153-158. https://doi.org/10.1016/j.febslet.2010.11.028

Cited by

  1. Generation and Characterization of a Neutralizing Human Monoclonal Antibody to Hepatitis B Virus PreS1 from a Phage-Displayed Human Synthetic Fab Library vol.28, pp.8, 2017, https://doi.org/10.4014/jmb.1803.03056
  2. Hepatitis E Virus Methyltransferase Inhibits Type I Interferon Induction by Targeting RIG-I vol.28, pp.9, 2017, https://doi.org/10.4014/jmb.1808.08058
  3. Hepatitis B Virus Entry into Cells vol.9, pp.6, 2017, https://doi.org/10.3390/cells9061486
  4. Recent Advances in Hepatitis B Treatment vol.14, pp.5, 2017, https://doi.org/10.3390/ph14050417
  5. Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure vol.27, pp.21, 2017, https://doi.org/10.3748/wjg.v27.i21.2727
  6. Epitope-Paratope Interaction of a Neutralizing Human Anti-Hepatitis B Virus PreS1 Antibody That Recognizes the Receptor-Binding Motif vol.9, pp.7, 2017, https://doi.org/10.3390/vaccines9070754