Journal of Microbiology and Biotechnology

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

DOI QR Code

Development of an Equine Antitoxin by Immunizing the Halla Horse with the Receptor-Binding Domain of Botulinum Neurotoxin Type A1

  • Kim, Na Young (ABION Inc., R&D Center) ;
  • Park, Kyung-eui (ABION Inc., R&D Center) ;
  • Lee, Yong Jin (ABION Inc., R&D Center) ;
  • Kim, Yeong Mun (ABION Inc., R&D Center) ;
  • Hong, Sung Hyun (ABION Inc., R&D Center) ;
  • Son, Won Rak (ABION Inc., R&D Center) ;
  • Hong, Sungyoul (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Lee, Saehyung (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Ahn, Hye Bin (Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University) ;
  • Yang, Jaehyuk (Korea National College of Agriculture and Fisheries) ;
  • Seo, Jong-pil (College of Veterinary Medicine, Jeju National University) ;
  • Lim, Yoon-Kyu (College of Veterinary Medicine, Jeju National University) ;
  • Yu, Chi Ho (Agency for Defense Development) ;
  • Hur, Gyeung Haeng (Agency for Defense Development) ;
  • Jeong, Seong Tae (Agency for Defense Development) ;
  • Lee, Hun Seok (LOGONE Bio Convergence Research Foundation, CRO Center) ;
  • Song, Kyoung (LOGONE Bio Convergence Research Foundation, The Center for Companion Diagnostics) ;
  • Kang, Tae Jin (College of Pharmacy, Sahmyook University) ;
  • Shin, Young Kee (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Choi, Joon-Seok (College of Pharmacy, Daegu Catholic University) ;
  • Choi, Jun Young (ABION Inc., R&D Center)
  • Received : 2019.04.16
  • Accepted : 2019.06.27
  • Published : 2019.07.28
Download PDF
⟨ Previous Next ⟩

Abstract

Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, are the most toxic substances known. However, the number of currently approved medical countermeasures for these toxins is very limited. Therefore, studies on therapeutic antitoxins are essential to prepare for toxin-related emergencies. Currently, more than 10,000 Halla horses, a crossbreed between the native Jeju and Thoroughbred horses, are being raised in Jeju Island of Korea. They can be used for equine antitoxin experiments and production of hyperimmune serum against BoNT/A1. Instead of the inactivated BoNT/A1 toxoid, Halla horse was immunized with the receptor-binding domain present in the C-terminus of heavy chain of BoNT/A1 (BoNT/A1-HCR) expressed in Escherichia coli. The anti-BoNT/A1-HCR antibody titer increased rapidly by week 4, and this level was maintained for several weeks after boosting immunization. Notably, $20{\mu}l$ of the week-24 BoNT/A1-HCR(-immunized) equine serum showed an in vitro neutralizing activity of over 8 international units (IU) of a reference equine antitoxin. Furthermore, $20{\mu}l$ of equine serum and $100{\mu}g$ of purified equine $F(ab^{\prime})_2$ showed 100% neutralization of 10,000 $LD_{50}$ in vivo. The results of this study shall contribute towards optimizing antitoxin production for BoNT/A1, which is essential for emergency preparedness and response.

Keywords

References

  1. Anderson PD. 2012. Bioterrorism: toxins as weapons. J. Pharm. Pract. 25: 121-129. https://doi.org/10.1177/0897190012442351
  2. Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS, Galbraith M, et al. 2001. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg. Infect. Dis. 7: 933-944. https://doi.org/10.3201/eid0706.010604
  3. Shukla HD, Sharma SK. 2005. Clostridium botulinum: a bug with beauty and weapon. Crit. Rev. Microbiol. 31: 11-18. https://doi.org/10.1080/10408410590912952
  4. Tucker JB. 1999. Historical trends related to bioterrorism: an empirical analysis. Emerg. Infect. Dis. 5: 498-504. https://doi.org/10.3201/eid0504.990406
  5. Hedeland M, Moura H, Baverud V, Woolfitt AR, Bondesson U, Barr JR. 2011. Confirmation of botulism in birds and cattle by the mouse bioassay and Endopep-MS. J. Med. Microbiol. 60: 1299-1305. https://doi.org/10.1099/jmm.0.031179-0
  6. Sonnabend O, Sonnabend W, Heinzle R, Sigrist T, Dirnhofer R, Krech U. 1981. Isolation of Clostridium botulinum type G and identification of type G botulinal toxin in humans: report of five sudden unexpected deaths. J. Infect. Dis. 143: 22-27. https://doi.org/10.1093/infdis/143.1.22
  7. Barash JR, Arnon SS. 2014. A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J. Infect. Dis. 209: 183-191. https://doi.org/10.1093/infdis/jit449
  8. Huang W, Foster JA, Rogachefsky AS. 2000. Pharmacology of botulinum toxin. J. Am. Acad. Dermatol. 43: 249-259. https://doi.org/10.1067/mjd.2000.105567
  9. Baldwin MR, Bradshaw M, Johnson EA, Barbieri JT. 2004. The C-terminus of botulinum neurotoxin type A light chain contributes to solubility, catalysis, and stability. Protein Expr. Purif. 37: 187-195. https://doi.org/10.1016/j.pep.2004.05.009
  10. Rossetto O, Deloye F, Poulain B, Pellizzari R, Schiavo G, Montecucco C. 1995. The metallo-proteinase activity of tetanus and botulism neurotoxins. J. Physiol. Paris 89: 43-50. https://doi.org/10.1016/0928-4257(96)80550-X
  11. Park JB, Simpson LL. 2003. Inhalational poisoning by botulinum toxin and inhalation vaccination with its heavy-chain component. Infect. Immun. 71: 1147-1154. https://doi.org/10.1128/IAI.71.3.1147-1154.2003
  12. Arnon SS, Damus K, Chin J. 1981. Infant botulism: epidemiology and relation to sudden infant death syndrome. Epidemiol. Rev. 3: 45-66. https://doi.org/10.1093/oxfordjournals.epirev.a036239
  13. Dhaked RK, Singh MK, Singh P, Gupta P. 2010. Botulinum toxin: bioweapon & magic drug. Indian J. Med. Res. 132: 489-503.
  14. Hauschild AHW. 1993. Epidemiology of human foodborne botulism., pp. 69-104. Clostridium botulinum: Ecology and Control in Foods, Ed. CRC Press,
  15. Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, et al. 1992. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359: 832-835. https://doi.org/10.1038/359832a0
  16. Schiavo G, Malizio C, Trimble WS, Polverino de Laureto P, Milan G, Sugiyama H, et al. 1994. Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond. J. Biol. Chem. 269: 20213-20216. https://doi.org/10.1016/S0021-9258(17)31976-2
  17. Schiavo G, Shone CC, Rossetto O, Alexander FC, Montecucco C. 1993. Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J. Biol. Chem. 268: 11516-11519. https://doi.org/10.1016/S0021-9258(19)50230-7
  18. Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, Jahn R. 1993. Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. EMBO J. 12: 4821-4828. https://doi.org/10.1002/j.1460-2075.1993.tb06171.x
  19. Schiavo G, Santucci A, Dasgupta BR, Mehta PP, Jontes J, Benfenati F, et al. 1993. Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett. 335: 99-103. https://doi.org/10.1016/0014-5793(93)80448-4
  20. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. 2006. Human botulism immune globulin for the treatment of infant botulism. N. Engl. J. Med. 354: 462-471. https://doi.org/10.1056/NEJMoa051926
  21. Hu CC, Yin J, Chau D, Cherwonogrodzky JW, Hu WG. 2014. Active immunity induced by passive IgG post-exposure protection against ricin. Toxins (Basel) 6: 380-393. https://doi.org/10.3390/toxins6010380
  22. Li D, Mattoo P, Keller JE. 2012. New equine antitoxins to botulinum neurotoxins serotypes A and B. Biologicals 40: 240-246. https://doi.org/10.1016/j.biologicals.2012.03.004
  23. Long SS. 2007. Infant botulism and treatment with BIG-IV (BabyBIG). Pediatr. Infect. Dis. J. 26: 261-262. https://doi.org/10.1097/01.inf.0000256442.06231.17
  24. Rosow LK, Strober JB. 2015. Infant botulism: review and clinical update. Pediatr. Neurol. 52: 487-492. https://doi.org/10.1016/j.pediatrneurol.2015.01.006
  25. Diseases ZFDaUSAMRIfI. 2011. Medical Management of Biological Casualties Handbook, pp. 120-121. 7th Ed. United States Department of Defense.
  26. Hill SE, Iqbal R, Cadiz CL, Le J. 2013. Foodborne botulism treated with heptavalent botulism antitoxin. Ann. Pharmacother. 47: e12. https://doi.org/10.1345/aph.1R646
  27. Hatheway CH, Snyder JD, Seals JE, Edell TA, Lewis GE, Jr. 1984. Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E. J. Infect. Dis. 150: 407-412. https://doi.org/10.1093/infdis/150.3.407
  28. Tacket CO, Shandera WX, Mann JM, Hargrett NT, Blake PA. 1984. Equine antitoxin use and other factors that predict outcome in type A foodborne botulism. Am. J. Med. 76: 794-798. https://doi.org/10.1016/0002-9343(84)90988-4
  29. Kim NY, Chang DS, Kim Y, Kim CH, Hur GH, Yang JM, et al. 2015. Enhanced immune response to DNA vaccine encoding Bacillus anthracis PA-D4 protects mice against anthrax spore challenge. PLoS One 10: e0139671. https://doi.org/10.1371/journal.pone.0139671
  30. Seo JH, Park KD, Lee HK, Kong HS. 2016. Genetic diversity of Halla horses using microsatellite markers. J. Anim. Sci. Technol. 58: 40. https://doi.org/10.1186/s40781-016-0120-6
  31. GJ C. 2006. Genetic relationship among the Korean native and alien horses estimated by microsatellite polymorphism. Asian-Australas. J. Anim. Sci. 19: 784-788.
  32. Choi JY, Shin S, Kim NY, Son WS, Kang TJ, Song DH, et al. 2017. A novel staphylococcal enterotoxin B subunit vaccine candidate elicits protective immune response in a mouse model. Toxicon 131: 68-77. https://doi.org/10.1016/j.toxicon.2017.03.012
  33. Pellett S. 2013. Progress in cell based assays for botulinum neurotoxin detection. Curr. Top. Microbiol. Immunol. 364: 257-285.
  34. Ruthel G, Burnett JC, Nuss JE, Wanner LM, Tressler LE, Torres-Melendez E, et al. 2011. Post-intoxication inhibition of botulinum neurotoxin serotype A within neurons by small-molecule, non-peptidic inhibitors. Toxins (Basel) 3: 207-217. https://doi.org/10.3390/toxins3030207
  35. Bowmer EJ. 1963. Preparation and assay of the international standards for clostridium botulinum types a, B, C, D and E antitoxins. Bull. World Health Organ. 29: 701-709.
  36. Yu CH, Song DH, Choi JY, Joe HE, Jeong WH, Hur GH, et al. 2018. A mutated recombinant subunit vaccine protects mice and guinea pigs against botulinum type A intoxication. Hum. Vaccin. Immunother. 14: 329-336. https://doi.org/10.1080/21645515.2017.1405201
  37. Jones RG, Corbel MJ, Sesardic D. 2006. A review of WHO International Standards for botulinum antitoxins. Biologicals 34: 223-226. https://doi.org/10.1016/j.biologicals.2005.11.009
  38. Asokan M, Rudicell RS, Louder M, McKee K, O'Dell S, Stewart-Jones G, et al. 2015. Bispecific antibodies targeting different epitopes on the HIV-1 envelope exhibit broad and potent neutralization. J. Virol. 89: 12501-12512. https://doi.org/10.1128/JVI.02097-15
  39. Figuera-Losada M, LoGrasso PV. 2012. Enzyme kinetics and interaction studies for human JNK1beta1 and substrates activating transcription factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun). J. Biol. Chem. 287: 13291-13302. https://doi.org/10.1074/jbc.M111.323766
  40. Wang C, Zeng X, Zhou Z, Zhao J, Pei G. 2016. beta-arrestin-1 contributes to brown fat function and directly interacts with PPARalpha and PPARgamma. Sci. Rep. 6: 26999. https://doi.org/10.1038/srep26999
  41. Larreche S, Mion G, Mayet A, Verret C, Puidupin M, Benois A, et al. 2011. Antivenin remains effective against African Viperidae bites despite a delayed treatment. Am. J. Emerg. Med. 29: 155-161. https://doi.org/10.1016/j.ajem.2009.08.022
  42. Seong WK JK, Shin KS, Kim HH, Park KS, Oh HB. 1999. Immunological characterization of the venoms from Korean snakes of the genus Agkistrodon for therapeutic antivenin production. Korean J. Vet. Public Health. 23: 21-31.
  43. Control CfD. 2004. Epidemiology and Prevention of Vaccine-Preventable Diseases, pp. 65-73. 8th Ed.
  44. Kodihalli S, Emanuel A, Takla T, Hua Y, Hobbs C, LeClaire R, et al. 2017. Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques. PLoS One 12: e0186892. https://doi.org/10.1371/journal.pone.0186892
  45. Byrne MP, Smith LA. 2000. Development of vaccines for prevention of botulism. Biochimie 82: 955-966. https://doi.org/10.1016/S0300-9084(00)01173-1
  46. Middlebrook JL. 2005. Production of vaccines against leading biowarfare toxins can utilize DNA scientific technology. Adv. Drug. Deliv. Rev. 57: 1415-1423. https://doi.org/10.1016/j.addr.2005.01.016
  47. Smith LA, Rusnak JM. 2007. Botulinum neurotoxin vaccines: past, present, and future. Crit. Rev. Immunol. 27: 303-318. https://doi.org/10.1615/CritRevImmunol.v27.i4.20
  48. Stahl C, Unger L, Mazuet C, Popoff M, Straub R, Frey J. 2009. Immune response of horses to vaccination with the recombinant Hc domain of botulinum neurotoxin types C and D. Vaccine 27: 5661-5666. https://doi.org/10.1016/j.vaccine.2009.07.021
  49. Yu YZ, Zhang SM, Wang WB, Du Y, Zhu HQ, Wang RL, et al. 2010. Development and preclinical evaluation of a new F(ab')(2) antitoxin against botulinum neurotoxin serotype A. Biochimie 92: 1315-1320. https://doi.org/10.1016/j.biochi.2010.06.010
  50. Cheng LW, Onisko B, Johnson EA, Reader JR, Griffey SM, Larson AE, et al. 2008. Effects of purification on the bioavailability of botulinum neurotoxin type A. Toxicology 249: 123-129. https://doi.org/10.1016/j.tox.2008.04.018
  51. Duff JT, Wright GG, Klerer J, Moore DE, Bibler RH. 1957. Studies on immunity to toxins of Clostridium botulinum. I. A simplified procedure for isolation of type A toxin. J. Bacteriol. 73: 42-47. https://doi.org/10.1128/JB.73.1.42-47.1957
  52. Gaur PK, El-Nakib O, Chu FS. 1980. Comparison of antibody production against aflatoxin B1 in goats and rabbits. Appl. Environ. Microbiol. 40: 678-680. https://doi.org/10.1128/AEM.40.3.678-680.1980
  53. HF S. 1994. CHAPTER 20 - Polyclonal Antibody Production, pp. 435-448. The Biology of the Laboratory Rabbit, 2nd Ed. Academic Press,
  54. Hill KK, Smith TJ, Helma CH, Ticknor LO, Foley BT, Svensson RT, et al. 2007. Genetic diversity among Botulinum Neurotoxin-producing clostridial strains. J. Bacteriol. 189: 818-832. https://doi.org/10.1128/JB.01180-06
  55. Kalb SR, Lou J, Garcia-Rodriguez C, Geren IN, Smith TJ, Moura H, et al. 2009. Extraction and inhibition of enzymatic activity of botulinum neurotoxins/A1, /A2, and /A3 by a panel of monoclonal anti-BoNT/A antibodies. PLoS One 4: e5355. https://doi.org/10.1371/journal.pone.0005355
  56. Smith TJ, Lou J, Geren IN, Forsyth CM, Tsai R, Laporte SL, et al. 2005. Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization. Infect. Immun. 73: 5450-5457. https://doi.org/10.1128/IAI.73.9.5450-5457.2005
  57. Henkel JS, Tepp WH, Przedpelski A, Fritz RB, Johnson EA, Barbieri JT. 2011. Subunit vaccine efficacy against Botulinum neurotoxin subtypes. Vaccine 29: 7688-7695. https://doi.org/10.1016/j.vaccine.2011.07.134
  58. Henseleit A, Pohl C, Kaltenbach HM, Hettwer K, Simon K, Uhlig S, et al. 2015. Kinetic analyses of data from a human serum albumin assay using the liSPR system. Biosensors (Basel) 5: 27-36. https://doi.org/10.3390/bios5010027
  59. Nowakowski A, Wang C, Powers DB, Amersdorfer P, Smith TJ, Montgomery VA, et al. 2002. Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc. Natl. Acad. Sci. USA 99: 11346-11350. https://doi.org/10.1073/pnas.172229899
  60. Sikarwar B, Sharma PK, Srivastava A, Agarwal GS, Boopathi M, Singh B, et al. 2014. Surface plasmon resonance characterization of monoclonal and polyclonal antibodies of malaria for biosensor applications. Biosens. Bioelectron. 60: 201-209. https://doi.org/10.1016/j.bios.2014.04.025
  61. Chen C, Wang S, Wang H, Mao X, Zhang T, Ji G, et al. 2012. Potent neutralization of botulinum neurotoxin/B by synergistic action of antibodies recognizing protein and ganglioside receptor binding domain. PLoS One 7: e43845. https://doi.org/10.1371/journal.pone.0043845
  62. Diamant E, Lachmi BE, Keren A, Barnea A, Marcus H, Cohen S, et al. 2014 . Evaluating the synergistic neutralizing effect of anti-botulinum oligoclonal antibody preparations. PLoS One 9: e87089. https://doi.org/10.1371/journal.pone.0087089
  63. Diamant E, Torgeman A, Ozeri E, Zichel R. 2015. Monoclonal antibody combinations that present synergistic neutralizing activity: a platform for next-generation antitoxin drugs. Toxins (Basel) 7: 1854-1881. https://doi.org/10.3390/toxins7061854
  64. Ngundi MM, Meade BD, Little SF, Quinn CP, Corbett CR, Brady RA, et al. 2012. Analysis of defined combinations of monoclonal antibodies in anthrax toxin neutralization assays and their synergistic action. Clin. Vaccine Immunol. 19: 731-739. https://doi.org/10.1128/CVI.05714-11
  65. Black RE, Gunn RA. 1980. Hypersensitivity reactions associated with botulinal antitoxin. Am. J. Med. 69: 567-570. https://doi.org/10.1016/0002-9343(80)90469-6
  66. Greenfield RA, Bronze MS. 2003. Prevention and treatment of bacterial diseases caused by bacterial bioterrorism threat agents. Drug. Discov. Today 8: 881-888. https://doi.org/10.1016/S1359-6446(03)02847-2
  67. Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, et al. 2001. Botulinum toxin as a biological weapon: medical and public health management. JAMA 285: 1059-1070. https://doi.org/10.1001/jama.285.8.1059