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A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes

Abstract

The ability to produce monoclonal antibodies (Mabs) in plants offers the opportunity for the development of an inexpensive method of mucosal immunoprotection against sexually transmitted diseases. To investigate the suitability of plant-expressed Mabs for vaginal preventive applications, we compared a humanized anti–herpes simplex virus 2 (HSV-2) Mab expressed in mammalian cell culture with the same antibody expressed in soybean. We found these Mabs to be similar in their stability in human semen and cervical mucus over 24 h, their ability to diffuse in human cervical mucus, and their efficacy for prevention of vaginal HSV-2 infection in the mouse.

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Figure 1
Figure 2: Fluorocytometry of HSV infected Vero cells stained with different doses of (A) mammalian-expressed Mab, (B) plant-expressed Mab, or (C) both (400 ng of each Mab).
Figure 3: In vitro neutralization of HSV-2.
Figure 4: In vivo protection by topically applied Mab against vaginal transmission of HSV-2.

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References

  1. Eng, T. and Butler, W. 1997. The hidden epidemic. National Academy Press, Washington, D.C.

    Google Scholar 

  2. Cone, R.A. and Whaley, K.J. 1994. Monoclonal antibodies for reproductive health: part I. Preventing sexual transmission of disease and pregnancy with topically applied antibodies. Am. J. Reprod. Immunol. 32: 114–131.

    Article  Google Scholar 

  3. Davidson, G.P., Whyte, P.B., Daniels, E., Franklin, K., Nunan, H., McCloud, P.I. et al. 1989. Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus. Lancet 2: 709– 712.

    Article  Google Scholar 

  4. Tamura, S., Funato, H., Hirabayashi, Y., Suzuki, Y., Nagamine, T., Aizawa, C. et al. 1991. Cross-protection against influenza A virus infection by passively transferred respiratory tract IgA antibodies to different hemagglutinin molecules. Eur. J. Immunol. 21: 1337–1344.

    Article  Google Scholar 

  5. Whaley, K.J., Zeitlin, L., Barratt, R.A., Hoen, T.E., and Cone, R.A. 1994. Passive immunization of the vagina protects mice against vaginal transmission of genital herpes infections. J. Infect. Dis. 169: 647 –649.

    Article  Google Scholar 

  6. Zeitlin, L., Whaley, K.J., Sanna, P.P., Moench, T.R., Bastidas, R., De Logu, A. et al 1996. Topically applied human recombinant monoclonal IgG1 antibody and its Fab and F(ab')2 fragments protect mice from vaginal transmission of HSV-2. Virology 225: 213–215.

    Article  Google Scholar 

  7. Zeitlin, L., Doctoral dissertation, Topical methods for preventing genital herpes infection in the mouse. The Johns Hopkins University, Baltimore, MD, 1996.

  8. Co, M.S. and Queen, C. 1991. Humanized antibodies for therapy. Nature 351: 501– 502.

    Article  Google Scholar 

  9. Burton, D. and Barbas, C. 1994. Human antibodies from combinatorial libraries. Adv. Immunol. 57: 191–280.

    Article  Google Scholar 

  10. Winter, G., Griffiths, A., Hawkins, R., and Hoogenboom, H. 1994. Making antibodies by phage display technology. Annu. Rev. Immunol. 12: 433– 455.

    Article  Google Scholar 

  11. Williamson, R., Burioni, R., Sanna, P., Partridge, L., Barbas, C., and Burton, D. 1993. Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries. Proc. Natl. Acad. Sci. USA 90: 4141–4145.

    Article  Google Scholar 

  12. Hiatt, A., Caffertey, R., and Bowdish, K. 1989. Production of antibodies in transgenic plants. Nature 342: 76– 78.

    Article  Google Scholar 

  13. Ma, J., Hiatt, A., Hein, M., Vine, N., Wang, F., Stabila, P. et al. 1995. Generation and assembly of secretory antibodies in plants. Science 268: 716–719.

    Article  Google Scholar 

  14. Hiatt, A. 1990. Antibodies produced in plants. Nature 344: 469–470.

    Article  Google Scholar 

  15. Wright, A. and Morrison, S. 1997. Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol. 15: 26– 32.

    Article  Google Scholar 

  16. Co, M.S., Deschamps, M., Whitley, R.J., and Queen, C. 1991. Humanized antibodies for antiviral therapy. Proc. Natl. Acad. Sci. USA 88: 2869–2873.

    Article  Google Scholar 

  17. Fleming, D., McQuillian, G., Johnson, R., Nahmias, A., Aral, S., Lee, F. et al. 1997. Herpes simplex virus type 2 in the United States, 1976 to 1994. N. Engl. J. Med. 337: 1105–1111.

    Article  Google Scholar 

  18. Hook, E.W., Cannon, R.O., Nahmias, A.J., Lee, F.F., Campbell, C.H., Glasser, D. et al. 1992. Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. J. Infect. Dis. 165: 251– 255.

    Article  Google Scholar 

  19. Gwanzura, L., McFarland, W., Alexander, D., Burke, R.L., and Katzenstein, D. 1998. Association between human immunodeficiency virus and herpes simplex virus type 2 seropositivity among male factory workers in Zimbabwe. J. Infect. Dis. 177: 481–484.

    Article  Google Scholar 

  20. Saltzman, W.M., Radomsky, M.L., Whaley, K.J., and Cone, R.A. 1994. Antibody diffusion in human cervical mucus. Biophys. J. 66: 508–515.

    Article  Google Scholar 

  21. Cone, R. 1999. Mucus, pp. 43–64 in Handbook of mucosal immunology, 2nd ed. Ogra, P.L., Mestecky, J., Lamm, M.E., Strober, W., McGhee, J.R., Bienenstock, J. (eds.). Academic Press, Washington, D.C. In press.

    Google Scholar 

  22. Whaley, K.J., Barratt, R.A., Zeitlin, L., Hoen, T.E., and Cone, R.A. 1993. Nonoxynol-9 protects mice against vaginal transmission of genital herpes infections. J. Infect. Dis. 168: 1009–1011.

    Article  Google Scholar 

  23. Cai, W., Gu, B., and Person, S. 1988. Role of glycoprotein B of herpes simplex virus type 1 in viral entry and cell fusion. J. Virol. 62: 2596–2604.

    PubMed Central  Google Scholar 

  24. Hiatt, A. and Ma, J.-C. 1992. Monoclonal antibody engineering in plants. FEBS Lett. 307: 71–75.

    Article  Google Scholar 

  25. Fiedler, U. and Conrad, U. 1995. High-level production and long-term storage of engineered antibodies in transgenic tobacco seeds. Bio/Technology 13: 1090– 1093.

    Article  Google Scholar 

  26. Hiatt, A. and Ma, J.-C. 1993. Characterization and applications of antibodies produced in plants. Int. Rev. Immunol. 10: 139–152.

    Article  Google Scholar 

  27. Friberg, J. 1974. Sperm-agglutinating antibodies and immunoglobulins G and A in stored human seminal fluid. Acta Obstet. Gyn. Scand. Suppl. 36: 59–63.

    Article  Google Scholar 

  28. Tjokronegoro, A. and Sirisinha, S. 1974 . Degradation of immunoglobulins by secretions of human reproductive tracts. J. Reprod. Fertil. 38: 221– 224.

    Article  Google Scholar 

  29. Castle, P. 1995. Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbit. (Doctoral dissertation). Johns Hopkins University, Baltimore, MD.

  30. Zeitlin, L., Whaley, K.J., Hegarty, T., Moench, T.R., and Cone, R.A. 1997. Tests of vaginal microbicides in the mouse genital herpes model. Contraception 56: 329–335.

    Article  Google Scholar 

  31. Elias, C. and Heise, L. 1994. Challenges for the development of female-controlled vaginal microbicides. AIDS 8: 1–9.

    Article  Google Scholar 

  32. Stone, A. and Hitchcock, P. 1994. Vaginal microbicides for preventing the sexual transmission of AIDS. AIDS (suppl 1) 8: S285–S293.

    Article  Google Scholar 

  33. Stein, Z. 1990. HIV prevention: the need for methods women can use. Am. J. Public Health 80: 460–462.

    Article  Google Scholar 

  34. Sherwood, J.K., Zeitlin, L., Chen, X., Whaley, K.J., Cone, R.A., and Saltzman, W.M. 1996 . Residence half-life of IgG administered topically to the mouse vagina. Biol. Reprod. 54: 264– 269.

    Article  Google Scholar 

  35. Sherwood, J.K., Zeitlin, L., Whaley, K.J., Cone, R.A., and Saltzman, W.M. 1996. Controlled release of antibodies for long-term topical passive immunoprotection of female mice against genital herpes. Nat. Biotechnol. 14: 468–471.

    Article  Google Scholar 

  36. Radomsky, M.L., Whaley, K.J., Cone, R.A., and Saltzman, W.M. 1992 . Controlled vaginal delivery of antibodies in the mouse. Biol. Reprod. 47: 133–140.

    Article  Google Scholar 

  37. Ma, J.K. and Hein, M.B. 1995. Immunotherapeutic potential of antibodies produced in plants. Trends Biotechnol. 13: 522–527.

    Article  Google Scholar 

  38. Miele, L. 1997. Plants as bioreactors for biopharmaceuticals: regulatory considerations. Trends Biotechnol. 15: 45– 50.

    Article  Google Scholar 

  39. Ma, J. K-C., Hikmat, B.Y., Wycoff, K., Vine, N.D., Chargelegue, D., Yu, L. et al. 1998. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med. 4: 601–606.

    Article  Google Scholar 

  40. Sherman-Gold, R. August 1997. Monoclonal antibodies: the evolution from '80s magic bullets to mature, mainstream applications as clinical therapeutics. Genetic Engineering News. August, p. 4.

  41. Wong, J. 1998. Monoclonals to hit stride in '98. Genetic Engineering News. January, p. 21.

  42. Zeitlin, L., Cone, R.A., and Whaley, K.J. Monoclonal antibodies for preventing mucosal transmission of epidemic infectious diseases. Emerg. Infect. Dis. In press.

  43. Francisco, J.A., Gawlak, S.A., Miller, M., Bathe, J., Russell, D., Chance, D. et al. 1997. Expression and characterization of bryodin 1 and a bryodin 1-based single-chain immunotoxin from tobacco cell culture. Bioconjugate Chem. 8: 708–713.

    Article  Google Scholar 

  44. McCabe, D.E., Swain, W.F., Martinell, B.J., and Christou, P. 1988. Stable transformation of soybean (Glycine max) by particle acceleration. Bio/Technology 6: 923–926.

    Google Scholar 

  45. Wolf, D. 1989. Designing, building, and using a fluorescence recovery after photobleaching instrument. pp 271–306 in Fluorescence microscopy of living cells in culture. Part B. Taylor, D. and Wang, Y. (eds.). Academic Press, San Diego, CA.

    Chapter  Google Scholar 

  46. Barisas, B. and Leuther, M. 1977. Fluorescence photobleaching recovery measurement of protein absolute diffusion constants. Biophys. Chem. 10: 221– 229.

    Article  Google Scholar 

  47. Matthews, D. and Farewell, V. 1985. Using and understanding medical statistics. Karger, Basel, Switzerland.

    Google Scholar 

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Correspondence to Kevin J. Whaley.

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Zeitlin, L., Olmsted, S., Moench, T. et al. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat Biotechnol 16, 1361–1364 (1998). https://doi.org/10.1038/4344

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