Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Apr 1;88(7):2663–2667. doi: 10.1073/pnas.88.7.2663

Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival.

P S Brown Jr 1, G L Parenteau 1, F M Dirbas 1, R J Garsia 1, C K Goldman 1, M A Bukowski 1, R P Junghans 1, C Queen 1, J Hakimi 1, W R Benjamin 1, et al.
PMCID: PMC51298  PMID: 2011577

Abstract

High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

Full text

PDF
2663

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cantarovich D., Le Mauff B., Hourmant M., Peyronnet P., Jacques Y., Boeffard F., Hirn M., Soulillou J. P. Prophylactic use of a monoclonal antibody (33B3.1) directed against interleukin 2 receptor following human renal transplantation. Am J Kidney Dis. 1988 Feb;11(2):101–106. doi: 10.1016/s0272-6386(88)80189-6. [DOI] [PubMed] [Google Scholar]
  2. Cooper M. M., Robbins R. C., Goldman C. K., Mirzadeh S., Brechbiel M. W., Stone C. D., Gansow O. A., Clark R. E., Waldmann T. A. Use of yttrium-90-labeled anti-Tac antibody in primate xenograft transplantation. Transplantation. 1990 Nov;50(5):760–765. doi: 10.1097/00007890-199011000-00005. [DOI] [PubMed] [Google Scholar]
  3. Depper J. M., Leonard W. J., Robb R. J., Waldmann T. A., Greene W. C. Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J Immunol. 1983 Aug;131(2):690–696. [PubMed] [Google Scholar]
  4. Hakimi J., Seals C., Anderson L. E., Podlaski F. J., Lin P., Danho W., Jenson J. C., Perkins A., Donadio P. E., Familletti P. C. Biochemical and functional analysis of soluble human interleukin-2 receptor produced in rodent cells. Solid-phase reconstitution of a receptor-ligand binding reaction. J Biol Chem. 1987 Dec 25;262(36):17336–17341. [PubMed] [Google Scholar]
  5. Hale G., Dyer M. J., Clark M. R., Phillips J. M., Marcus R., Riechmann L., Winter G., Waldmann H. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancet. 1988 Dec 17;2(8625):1394–1399. doi: 10.1016/s0140-6736(88)90588-0. [DOI] [PubMed] [Google Scholar]
  6. Junghans R. P., Waldmann T. A., Landolfi N. F., Avdalovic N. M., Schneider W. P., Queen C. Anti-Tac-H, a humanized antibody to the interleukin 2 receptor with new features for immunotherapy in malignant and immune disorders. Cancer Res. 1990 Mar 1;50(5):1495–1502. [PubMed] [Google Scholar]
  7. Kirkman R. L., Barrett L. V., Gaulton G. N., Kelley V. E., Ythier A., Strom T. B. Administration of an anti-interleukin 2 receptor monoclonal antibody prolongs cardiac allograft survival in mice. J Exp Med. 1985 Jul 1;162(1):358–362. doi: 10.1084/jem.162.1.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. LoBuglio A. F., Wheeler R. H., Trang J., Haynes A., Rogers K., Harvey E. B., Sun L., Ghrayeb J., Khazaeli M. B. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4220–4224. doi: 10.1073/pnas.86.11.4220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. MCFARLANE A. S. Labelling of plasma proteins with radioactive iodine. Biochem J. 1956 Jan;62(1):135–143. doi: 10.1042/bj0620135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Michler R. E., McManus R. P., Smith C. R., Sadeghi A. N., Rose E. A. Technique for primate heterotopic cardiac xenotransplantation. J Med Primatol. 1985;14(6):357–362. [PubMed] [Google Scholar]
  11. Morell A., Terry W. D., Waldmann T. A. Metabolic properties of IgG subclasses in man. J Clin Invest. 1970 Apr;49(4):673–680. doi: 10.1172/JCI106279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Queen C., Schneider W. P., Selick H. E., Payne P. W., Landolfi N. F., Duncan J. F., Avdalovic N. M., Levitt M., Junghans R. P., Waldmann T. A. A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10029–10033. doi: 10.1073/pnas.86.24.10029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Reed M. H., Shapiro M. E., Strom T. B., Milford E. L., Carpenter C. B., Letvin N. L., Waldmann T. A., Kirkman R. L. Prolongation of primate renal allografts with anti-Tac monoclonal antibody. Curr Surg. 1988 Jan-Feb;45(1):28–30. [PubMed] [Google Scholar]
  14. Rubin L. A., Kurman C. C., Biddison W. E., Goldman N. D., Nelson D. L. A monoclonal antibody 7G7/B6, binds to an epitope on the human interleukin-2 (IL-2) receptor that is distinct from that recognized by IL-2 or anti-Tac. Hybridoma. 1985 Summer;4(2):91–102. doi: 10.1089/hyb.1985.4.91. [DOI] [PubMed] [Google Scholar]
  15. Soulillou J. P., Peyronnet P., Le Mauff B., Hourmant M., Olive D., Mawas C., Delaage M., Hirn M., Jacques Y. Prevention of rejection of kidney transplants by monoclonal antibody directed against interleukin 2. Lancet. 1987 Jun 13;1(8546):1339–1342. doi: 10.1016/s0140-6736(87)90648-9. [DOI] [PubMed] [Google Scholar]
  16. Uchiyama T., Broder S., Waldmann T. A. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol. 1981 Apr;126(4):1393–1397. [PubMed] [Google Scholar]
  17. Waldmann T. A., Goldman C. K., Bongiovanni K. F., Sharrow S. O., Davey M. P., Cease K. B., Greenberg S. J., Longo D. L. Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2. Blood. 1988 Nov;72(5):1805–1816. [PubMed] [Google Scholar]
  18. Waldmann T. A., Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110. doi: 10.1159/000385919. [DOI] [PubMed] [Google Scholar]
  19. Waldmann T. A. The multi-subunit interleukin-2 receptor. Annu Rev Biochem. 1989;58:875–911. doi: 10.1146/annurev.bi.58.070189.004303. [DOI] [PubMed] [Google Scholar]
  20. Waldmann T. A. The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. Science. 1986 May 9;232(4751):727–732. doi: 10.1126/science.3008337. [DOI] [PubMed] [Google Scholar]
  21. Yasmeen D., Ellerson J. R., Dorrington K. J., Painter R. H. The structure and function of immunoglobulin domains. IV. The distribution of some effector functions among the Cgamma2 and Cgamma3 homology regions of human immunoglobulin G1. J Immunol. 1976 Feb;116(2):518–526. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES