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Topical antibody delivery systems produce sustained levels in mucosal tissue and blood

Abstract

Immunity at mucosal surfaces, which are ports of entry for many pathogens, is essential in preventing infections. But most current strategies for passive immunization involve injection of antibodies for systemic, not mucosal, protection. We measured mucosal and systemic antibody levels after controlled topical delivery to the vagina. Poly(ethylene-co-vinyl acetate) disks containing 125l-labeled monoclonal IgG or anti-lactate dehydrogenase-C4 antibodies were placed in the vaginas of mice. High antibody levels (0.26–12 μg/ml) were maintained at the mucosal surface for 7 days after disk insertion. Antibody molecules also penetrated into the vaginal epithelium, presumably by diffusing through the extracellular space, and entered the circulation. Biologically active antibodies were detected in the blood. The antibody concentration in the blood was approximately 1% of the concentration in the vagina. Although the permeability of the epithelium to macro-molecules is low, high concentrations were maintained at the luminal surface for an extended period, permitting substantial systemic uptake of antibody.

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References

  1. Ma, J.K.-C. and Lehner, T. 1990. Prevention of colonization of Streptococcus mutans by topical application of monoclonal antibodies in human subjects. Arch. Oral Biol. 36:1158–1228

    Google Scholar 

  2. Tacket, C.O., Losonsky, G., Link, H., Hoang, Y, Guesry, P., Hilpert, H., and Levine, M.M. 1988.Protection by milk immunoglobulin concentrate against oral challenge with enterotoxigenic E. Co//. N. Eng. J. Med. 318:1240–1243

    Article  CAS  Google Scholar 

  3. Whaley, K.J., Zeitlin, L.R., 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. 118:647–649

    Article  Google Scholar 

  4. SherwoodV, J.K., ZeitlinV, 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. Bio/Technology 14:468–471

    Google Scholar 

  5. Castle, RE., Whaley, K.J., Hoen, I.E., Moench, T.R., and Cone, R.A. 1997. Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits. Biol. Reprod. 56:153–159

    Article  CAS  Google Scholar 

  6. 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. Rephd. Immunol. 31:1–18

    Article  Google Scholar 

  7. Saltzman, W.M. 1993. Antibodies for treating and preventing disease: the potential role of polymeric controlled release. Crit Rev. Ther. Drug Carrier Sys. 10:111–142

    CAS  Google Scholar 

  8. Benziger, D. and Edelson, J. 1983. Absorption from the vagina. Drug Metabol. Rev. 14:137–168.

    Article  CAS  Google Scholar 

  9. Okada, H. 1991. Vaginal route of peptide and protein drug delivery, pp. 633-666 in Peptide and protein drug delivery. Lee, V.H. (ed), Marcel Dekker, New York.

    Google Scholar 

  10. Schiff, I., Tulchinsky, D., and Ryan, K. 1977. Vaginal absorption of estrone and 17β-estradiol. Fertil. Steril. 28:1063–1066.

    Article  CAS  Google Scholar 

  11. Apter, D., Cacciatore, B., Stenman, U. Alapiessa, U., and Assendorp, R. 1990. Clinical performance and endocrine profiles of contraceptive vaginal rings releasing 3-keto-desogestrel and ethinytestradiol. Contraception 42:285–295

    Article  CAS  Google Scholar 

  12. Olsson, S. and Odlind, V. 1990. Contraception with vaginal ring releasing 3-keto-desogestrel and ethinylestradiol. Contraception 42:563–572

    CAS  PubMed  Google Scholar 

  13. Schiff, I., Wentworth, B., Koos, B., Ryan, K., and Tulchinsky,D. 1978. Effect of estriol administration on the hypogonadal woman. Fertil. Steril. 30:278–282

    Article  CAS  Google Scholar 

  14. Schiff, I., Tulchinsky, D., Ryan, K., Kadner, S., and Levitz,M.. 1980. Plasma estriol and its conjugates following oral and vaginal administration of estriol to postmenopausal women: Correlations with gonadotropin levels. Am. J. Obstet. Gynecol. 138:1137–1141

    Article  CAS  Google Scholar 

  15. Beck, L., Boots, L., and Stevens, V. 1975. Absorption of antibodies from the baboon vagina. Biol. Reprod. 13:10–16.

    Article  CAS  Google Scholar 

  16. 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  CAS  Google Scholar 

  17. 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  CAS  Google Scholar 

  18. O'Hern, PA, Bambra, C.S., Isahakia, M., and Goldberg, E. 1995. Reversible contraception in female baboons immunized with a synthetic epitope of sperm-specific lactate dehydrogenase. Biol. Reprod. 52:331–339

    Article  CAS  Google Scholar 

  19. Saltzman, W.M. and Langer, R. 1989. Transport rates of proteins in porous polymers with known microgeometry. Biophys. J. 55:163–171

    Article  CAS  Google Scholar 

  20. Sherwood, J.K. Long-term delwery of antibodies using controlled release polymers. (Ph.D. dissertation, The Johns Hopkins University, Baltimore, MD, 1996

    Google Scholar 

  21. Kuo,P.Y-R Enhancing antibody availability at the vaginal mucosa with controlled-release polymers. (Master's thesis, The Johns Hopkins University, Baltimore, MD,1996

    Google Scholar 

  22. Kuo,P.Y.P and Saltzman, W.M. 1996. Novel systems for controlled delivery of macromolecules. Crit. Rev. Euk Gene Expr. 6:59–73.

    Article  CAS  Google Scholar 

  23. Parr,M.B. and Parr, E.L. 1994. Mucosal immunity in the female and male reproductive tracts. 677–689 Handbook of mucosal immunology. Ogra, PL., Mestecky, J., Lamm, M.E., Strober, W, McGhee, J.R., and Bienenstock, J. (eds.), Academic Press, Inc., San Diego

    Google Scholar 

  24. Wira,C.R ., Richardson, J., and Prabhala, R. 1994. Endocrine regulation of mucosal immunity: effect of sex hormones and cytokines on the afferent and efferent arms of the immune system in the female reproductive tract, 705–718 in Handbook of mucosal immunology. Ogra, RL, Mestecky, J., Lamm, M.E., Strober, W., McGhee, J.R., and Bienenstock, J. (eds.), Academic Press, Inc., San Diego.

    Chapter  Google Scholar 

  25. Snell,G.D. 1941. Reproduction. 55–88 in Biology of the laboratory mouse Snell, G.D. (ed.), Blakiston Company, Philadelphia.

  26. Gude,W.D., Cosgrove, G.E., and Hirsch, G.P. 1982. Histological atlas of the laboratory mouse. Plenum Press, New York.

    Book  Google Scholar 

  27. Sherwood,J.K. Controlled release of antibodies and antibody fragments for immunoprotection of the mucus epithelia. (Master's thesis, The Johns Hopkins University, Baltimore, MD, 1993).

    Google Scholar 

  28. Clauss,M.A. and Jain, R.K. 1990. Interstitial transport of rabbit and sheep antibodies in normal and neoplastic tissues. Cancer Res. 50:3487–3492

    CAS  PubMed  Google Scholar 

  29. Baxter,L.T., Zhu, H., Mackensun, D.G., and Jain, R.K. 1994. Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res. 54:1517–1528.

    CAS  PubMed  Google Scholar 

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Correspondence to W. Mark Saltzman.

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Kuo, P., Sherwood, J. & Saltzman, W. Topical antibody delivery systems produce sustained levels in mucosal tissue and blood. Nat Biotechnol 16, 163–167 (1998). https://doi.org/10.1038/nbt0298-163

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