Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

In Vivo Kinetics and Biodistribution of a HIV-1 DNA Vaccine after Administration in Mice

  • Kim, Byong-Moon (Research Laboratories, Dong-A Pharm. Co., Ltd.) ;
  • Lee, Dong-Sop (Research Laboratories, Dong-A Pharm. Co., Ltd.) ;
  • Choi, Jae-Hoon (Research Laboratories, Dong-A Pharm. Co., Ltd.) ;
  • Kim, Chae-Young (Research Laboratories, Dong-A Pharm. Co., Ltd.) ;
  • Son, Mi-Won (Research Laboratories, Dong-A Pharm. Co., Ltd.) ;
  • Suh, You-Suk (National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Baek, Kwan-Hyuck (National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Park, Ki-Seok (National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Sung, Young-Chul (National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Kim, Won-Bae (Research Laboratories, Dong-A Pharm. Co., Ltd.)
  • Published : 2003.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

In this study we have investigated the pharmacokinetics and tissue distribution of GX-12, a multiple plasmid DNA vaccine for the treatment of HIV-1 infection. Plasmid DNA was rapidly degraded in blood with a half-life of 1.34 min and was no longer detectable at 90 min after intravenous injection in mice. After intramuscular injection, plasmid DNA concentration in the injection site rapidly declined to less than 1 ％ of the initial concentration by 90 min post-injection. However, sub-picogram levels (per mg tissue) were occasionally detected for several days after injection. The relative proportions of the individual plasm ids of GX-12 remained relatively constant at the injection site until 90 min post-injection. The concentration of plasmid DNA in tissues other than the injection site peaked at 90 min post-injection and decreased to undetectable levels at 8 h post-injection. The rapid in vivo degradation of GX-12 and absence of persistence in non-target tissues suggest that the risk of potential gene-related toxicities by GX-12 administration, such as expression in non-target tissues, insertional mutagenesis and germline transmission, is minimal.

Keywords

References

  1. Choi, S. M. Kang, K. K. Lee, D. S., Choi, J. H., Y. S., Kim, C. Y., Kim, B. M., and Kim, W. B., Gene expression of GX-12, a new naked DNA vaccine for HIV infection, in reproductive organs. J. Toxicol. Pub. Health, 19, 13-19 (2003)
  2. Finzi, D., Blankson, J., Siliciano, J. D., Margolick, J. B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T. C., Chaisson, R. E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., and Siliciano, R. F., Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med., 5, 512-517 (1999) https://doi.org/10.1038/8394
  3. Fomsgaard, A., HIV-1 DNA vaccines. Immunol. Lett., 65, 127-131 (1999) https://doi.org/10.1016/S0165-2478(98)00135-7
  4. Food and Drug Administration, Center of Biologics Evaluation and Research, Office of Vaccine Research and Review, Points to consider on plasmid DNA vaccines for preventive infectious disease indications. Docket No. 96N-0400 (1996)
  5. Gottlieb, M. S., AIDS - past and future. N. Engl. J. Med., 344, 1788-1791 (2001)
  6. Ha, S. J., Chang, J., Song, M. K., Suh, Y. S., Jin, H. T., Lee, C. H., Nam, G. H., Choi, G., Choi, K. Y., Lee, S. H., Kim, W. B., and Sung, Y.C., Engineering N-glycosylation mutations in IL-12 enhances sustained cytotoxic T lymphocyte responses for DNA immunization. Nat. Biotechnol., 20, 381-386 (2002) https://doi.org/10.1038/nbt0402-381
  7. Hunsmann, G., HIV/AIDS vaccine - evaluations in humans and macaques. Presented at the 43th Meeting of the Korean Society for Immunology, Seoul, Korea, 29-30 November (2001)
  8. Kang, K. K., Choi, S. M., Choi, J. H. Lee, D. S. Kim, C. Y., Ahn, B. O., Kim, B. M., and Kim, W. B., Safety evaluation of GX-12, a new HIV therapeutic vaccine: investigation of integration into the host genome and expression in the reproductive organs. Intervirology, in press, 2003
  9. Kawabata, K., Takakura, Y., and Hashida, M., The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharm. Res., 12, 825-830 (1995) https://doi.org/10.1023/A:1016248701505
  10. Lee, A. H., Suh, Y. S., and Sung, Y. C., DNA inoculations with HIV-1 recombinant genomes that express cytokine genes enhance HIV-1 specific immune responses. Vaccine, 17, 473-479 (1999) https://doi.org/10.1016/S0264-410X(98)00221-7
  11. Lew, D., Parker, S. E., Latimer, T., Abai, A. M., Kuwahara-Rundell, A., Doh, S. G., Yang, Z. Y., Laface, D., Gromkowski, S. H., Nabel, G. J., Manthorpe, M., and Norman, J., Cancer gene therapy using plasmid DNA: pharmacokinetic study of DNA following injection in mice. Hum. Gene Ther., 6, 553-564 (1995) https://doi.org/10.1089/hum.1995.6.5-553
  12. Little, S. J., Holte, S., Routy, J. P., Daar, E. S., Markowitz, M., Collier, A. C., Koup, R. A., Mellors, J. W., Connick, E., Conway, B., Kilby, M., Wang, L., Whitcomb, J. M., Hellmann, N. S., and Richman, D. D., Antiretroviral-drug resistance among patients recently infected with HIV. N. Engl. J. Med., 347, 385-394 (2002) https://doi.org/10.1056/NEJMoa013552
  13. Manam, S., Ledwith, B. J., Barnum, A. B., Troilo, P. J., Pauley, C. J., Harper, L. B., Griffiths, T. G. 2nd, Niu, Z., Denisova, L., Follmer, T. T., Pacchione, S. J., Wang, Z., Beare, C. M., Bagdon, W. J., and Nichols, W. W., Plasmid DNA vaccines: tissue distribution and effects of DNA sequence, adjuvants and delivery method on integration into host DNA. Intervirology, 43, 273-281 (2000) https://doi.org/10.1159/000053994
  14. Manthorpe, M., Cornefert-Jensen, F., Hartikka, J., Felgner, J., Rundell, A., Margalith, M., and Dwarki, V., Gene therapy by intramuscular injection of plasmid DNA: studies on firefly luciferase gene expression in mice. Hum. Gene Ther., 4, 419-431 (1993) https://doi.org/10.1089/hum.1993.4.4-419
  15. Palella, F. J. Jr., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Ashman, D. J. and Holmberg, S. D., Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med., 338, 853-860 (1998) https://doi.org/10.1056/NEJM199803263381301
  16. Parker, S. E., Borellini, F., Wenk, M. L., Hobart, P., Hoffman, S. L., Hedstrom, R., Le, T., and Norman, J. A., Plasmid DNA malaria vaccine: tissue distribution and safety studies in mice and rabbits. Hum. Gene Ther., 10, 741-758 (1999) https://doi.org/10.1089/10430349950018508
  17. UNAIDS, WHO, AIDS epidemic update: December 2001. Geneva: Joint United Nations Programme on HIV/AIDS (UNAIDS) (2001)
  18. Winegar, R. A., Monforte, J. A., Suing, K. D., O'Loughlin, K. G., Rudd, C. J., and Macgregor, J. T., Determination of tissue distribution of an intramuscular plasmid vaccine using PCR and in situ DNA hybridization. Hum. Gene Ther., 7, 2185-2194 (1996) https://doi.org/10.1089/hum.1996.7.17-2185
  19. World Health Organization, WHO guidelines for assuring the quality of DNA vaccines. WHO Technical Report Series, No. 878 (1998)
  20. Yeni, P. G., Hammer, S. M., Carpenter, C. C., Cooper, D. A., Fischl, M. A., Gatell, J. M., Gazzard, B. G., Hirsch, M. S., Jacobsen, D. M., Katzenstein, D. A., Montaner, J. S., Richman, D. D., Saag, M. S., Schechter, M., Schooley, R. T., Thompson, M. A., Vella, S., and Volberding, P. A., Antiretroviral treatment for adult HIV infection in 2002. JAMA, 288, 222-235 (2002) https://doi.org/10.1001/jama.288.2.222