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. 1991 Aug;64(2):281–287. doi: 10.1038/bjc.1991.292

Xenogeneic monoclonal antibodies in the management of cancer: control of their in vivo immunogenicity and induction of specific unresponsiveness using an antibody-drug immunoconjugate.

G B Sivolapenko 1, C Moreno 1, W Smith 1, J Corválan 1, M A Ritter 1, A A Epenetos 1
PMCID: PMC1977510  PMID: 1892756

Abstract

A bispecific mouse monoclonal antibody (mAb) that recognises carcinoembryonic antigen (CEA) with one binding site and vinblastine (VLB) with the other was used, and its in vivo immunosuppressive effect specific for anti-mouse immunoglobulin (Ig) was studied. The antibody was incubated with VLB at a molar ratio (MR) of 1:1, and administered i.v. to rabbits. Control animals received either the MAb alone, or the MAb with VLB covalently linked (MR 1:1), or the parental anti-CEA with equimolar amount of VLB. Seven days later, the rabbit anti-mouse Ig primary response was measured, and found to be almost 55% reduced in the animals that received the VLB 'loaded' MAb. In vivo kinetics and stability experiments revealed that the T1/2 of the MAb was 68 +/- 5 h, whereas free VLB disappeared within minutes. It was concluded that as soon as the drug dissociates from the antibody's binding site, it is rapidly removed. This problem was overcome by subcutaneously implanting osmotic mini-pumps containing VLB. The pumps released the drug at a constant rate for a period greater than 1 week, saturating the antibody's binding site. Under these conditions rabbits developed 80% less anti-mouse Ig antibodies when the bispecific antibody was administered (compared with the parental anti-CEA). The immunosuppression observed was specific for the mouse Ig, under conditions compatible with the full clinical therapeutic potential of the MAb. In conclusion, these experiments show, that it is possible to develop hybrid antibodies that can act as a 'lethal bait' to any specific lymphocyte in vivo, thus preventing undesirable responses against the xenogeneic MAb.

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Selected References

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  1. Abu-Hadid M. M., Bankert R. B., Mayers G. L. Selective elimination of idiotype-binding cells in vivo by a drug-idiotype conjugate demonstrates the functional significance of these cells in immune regulation. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3990–3994. doi: 10.1073/pnas.85.11.3990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abu-hadid M. M., Bankert R. B., Mayers G. L. Antigen-specific drug-targeting used to manipulate an immune response in vivo. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7232–7236. doi: 10.1073/pnas.84.20.7232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brust S., Filipp G., Hofmann U., Kalies I., Peper K., Rajki K., Sterz R. K., Trommer W. E. Antigen-gelonin conjugates. Preparation and application in experimental myasthenia gravis. Biol Chem Hoppe Seyler. 1987 Aug;368(8):991–999. doi: 10.1515/bchm3.1987.368.2.991. [DOI] [PubMed] [Google Scholar]
  4. Byers V. S., Baldwin R. W. Therapeutic strategies with monoclonal antibodies and immunoconjugates. Immunology. 1988 Nov;65(3):329–335. [PMC free article] [PubMed] [Google Scholar]
  5. Corvalan J. R., Smith W. Construction and characterisation of a hybrid-hybrid monoclonal antibody recognising both carcinoembryonic antigen (CEA) and vinca alkaloids. Cancer Immunol Immunother. 1987;24(2):127–132. doi: 10.1007/BF00205589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Corvalan J. R., Smith W., Gore V. A., Brandon D. R., Ryde P. J. Increased therapeutic effect of vinca alkaloids targeted to tumour by a hybrid-hybrid monoclonal antibody. Cancer Immunol Immunother. 1987;24(2):138–143. doi: 10.1007/BF00205591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corvalan J. R., Smith W., Gore V. A., Brandon D. R. Specific in vitro and in vivo drug localisation to tumour cells using a hybrid-hybrid monoclonal antibody recognising both carcinoembryonic antigen (CEA) and vinca alkaloids. Cancer Immunol Immunother. 1987;24(2):133–137. doi: 10.1007/BF00205590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Corvalan J. R., Smith W., Gore V. A. Tumour therapy with Vinca alkaloids targeted by a hybrid-hybrid monoclonal antibody recognising both CEA and Vinca alkaloids. Int J Cancer Suppl. 1988;2:22–25. doi: 10.1002/ijc.2910410708. [DOI] [PubMed] [Google Scholar]
  9. Courtenay-Luck N. S., Epenetos A. A., Moore R., Larche M., Pectasides D., Dhokia B., Ritter M. A. Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms. Cancer Res. 1986 Dec;46(12 Pt 1):6489–6493. [PubMed] [Google Scholar]
  10. Courtenay-Luck N. S., Epenetos A. A., Sivolapenko G. B., Larche M., Barkans J. R., Ritter M. A. Development of anti-idiotypic antibodies against tumour antigens and autoantigens in ovarian cancer patients treated intraperitoneally with mouse monoclonal antibodies. Lancet. 1988 Oct 15;2(8616):894–897. doi: 10.1016/s0140-6736(88)92482-8. [DOI] [PubMed] [Google Scholar]
  11. Crichton R., Solomon J., Barton A. M. The development of an enzyme-linked immunosorbent assay for measuring the potency of vaccines containing Clostridium chauvoei antigens. Biologicals. 1990 Jan;18(1):49–54. doi: 10.1016/1045-1056(90)90070-g. [DOI] [PubMed] [Google Scholar]
  12. Diener E., Diner U. E., Sinha A., Xie S., Vergidis R. Specific immunosuppression by immunotoxins containing daunomycin. Science. 1986 Jan 10;231(4734):148–150. doi: 10.1126/science.3484557. [DOI] [PubMed] [Google Scholar]
  13. Durrant L. G., Robins R. A., Marksman R. A., Garnett M. C., Ogunmuyiwa Y., Baldwin R. W. Abrogation of antibody responses in rats to murine monoclonal antibody 791T/36 by treatment with daunomycin-cis-aconityl-791T/36 conjugates. Cancer Immunol Immunother. 1989;28(1):37–42. doi: 10.1007/BF00205799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Epenetos A. A., Carr D., Johnson P. M., Bodmer W. F., Lavender J. P. Antibody-guided radiolocalisation of tumours in patients with testicular or ovarian cancer using two radioiodinated monoclonal antibodies to placental alkaline phosphatase. Br J Radiol. 1986 Feb;59(698):117–125. doi: 10.1259/0007-1285-59-698-117. [DOI] [PubMed] [Google Scholar]
  15. Epenetos A. A., Munro A. J., Stewart S., Rampling R., Lambert H. E., McKenzie C. G., Soutter P., Rahemtulla A., Hooker G., Sivolapenko G. B. Antibody-guided irradiation of advanced ovarian cancer with intraperitoneally administered radiolabeled monoclonal antibodies. J Clin Oncol. 1987 Dec;5(12):1890–1899. doi: 10.1200/JCO.1987.5.12.1890. [DOI] [PubMed] [Google Scholar]
  16. Goldman-Leikin R. E., Kaplan E. H., Zimmer A. M., Kazikiewicz J., Manzel L. J., Rosen S. T. Long-term persistence of human anti-murine antibody responses following radioimmunodetection and radioimmunotherapy of cutaneous T-cell lymphoma patients using 131I-T101. Exp Hematol. 1988 Nov;16(10):861–864. [PubMed] [Google Scholar]
  17. Kalofonos H. P., Pawlikowska T. R., Hemingway A., Courtenay-Luck N., Dhokia B., Snook D., Sivolapenko G. B., Hooker G. R., McKenzie C. G., Lavender P. J. Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies against epidermal growth factor receptor and placental alkaline phosphatase. J Nucl Med. 1989 Oct;30(10):1636–1645. [PubMed] [Google Scholar]
  18. Karpinski K. F., Hayward S., Tryphonas H. Statistical considerations in the quantitation of serum immunoglobulin levels using the enzyme-linked immunosorbent assay (ELISA). J Immunol Methods. 1987 Nov 5;103(2):189–194. doi: 10.1016/0022-1759(87)90289-4. [DOI] [PubMed] [Google Scholar]
  19. McCardle R. J., Harper P. V., Spar I. L., Bale W. F., Andros G., Jiminez F. Studies with iodine-131-labeled antibody to human fibrinogen for diagnosis and therapy of tumors. J Nucl Med. 1966 Nov;7(11):837–847. [PubMed] [Google Scholar]
  20. Schroff R. W., Foon K. A., Beatty S. M., Oldham R. K., Morgan A. C., Jr Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res. 1985 Feb;45(2):879–885. [PubMed] [Google Scholar]
  21. Sears H. F., Bägli D. J., Herlyn D., DeFreitas E., Suzuki H., Steele G., Koprowski H. Human immune response to monoclonal antibody administration is dose-dependent. Arch Surg. 1987 Dec;122(12):1384–1388. doi: 10.1001/archsurg.1987.01400240030004. [DOI] [PubMed] [Google Scholar]
  22. Sedgwick A. K., Ballow M., Sparks K., Tilton R. C. Rapid quantitative microenzyme-linked immunosorbent assay for tetanus antibodies. J Clin Microbiol. 1983 Jul;18(1):104–109. doi: 10.1128/jcm.18.1.104-109.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shelton D., Fujii Y., Knogge W., Lindstrom J. Specific suppression of the antibody response to acetylcholine receptor in vitro and in vivo by daunomycin-acetylcholine receptor conjugates. Ann N Y Acad Sci. 1988;540:530–532. doi: 10.1111/j.1749-6632.1988.tb27161.x. [DOI] [PubMed] [Google Scholar]
  24. Smith W., Gore V. A., Brandon D. R., Lynch D. N., Cranstone S. A., Corvalan J. R. Suppression of well-established tumour xenografts by a hybrid-hybrid monoclonal antibody and vinblastine. Cancer Immunol Immunother. 1990;31(3):157–163. doi: 10.1007/BF01744730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Spitler L. E., del Rio M., Khentigan A., Wedel N. I., Brophy N. A., Miller L. L., Harkonen W. S., Rosendorf L. L., Lee H. M., Mischak R. P. Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin. Cancer Res. 1987 Mar 15;47(6):1717–1723. [PubMed] [Google Scholar]
  26. Vitetta E. S., Krolick K. A., Miyama-Inaba M., Cushley W., Uhr J. W. Immunotoxins: a new approach to cancer therapy. Science. 1983 Feb 11;219(4585):644–650. doi: 10.1126/science.6218613. [DOI] [PubMed] [Google Scholar]
  27. Zimmer A. M., Rosen S. T., Spies S. M., Goldman-Leikin R., Kazikiewicz J. M., Silverstein E. A., Kaplan E. H. Radioimmunotherapy of patients with cutaneous T-cell lymphoma using an iodine-131-labeled monoclonal antibody: analysis of retreatment following plasmapheresis. J Nucl Med. 1988 Feb;29(2):174–180. [PubMed] [Google Scholar]
  28. de Savigny D., Voller A. The communication of ELISA data from laboratory to clinician. J Immunoassay. 1980;1(1):105–128. doi: 10.1080/01971528008055779. [DOI] [PubMed] [Google Scholar]

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