Skip to main content

Advertisement

SpringerLink
Log in

Anti-tumor × anti-lymphocyte heteroconjugates augment colon tumor cell lysisin Vitro and prevent tumor growthin Vivo

  • Original Contributions
  • Published:
Diseases of the Colon & Rectum

Abstract

Cross-linking an anti-tumor antibody, specific for tumor cell surface antigens, and an anti-lymphocyte antibody, specific for the T lymphocyte receptor complex (TCR/ CD3), produces a heteroconjugate that can direct T cells to lyse tumor cells. We tested the ability of anti-tumor × anti-lymphocyte (CD3) heteroconjugates to redirect human peripheral blood lymphocytes (PBLs) to lyse human colon cancer cells in cytotoxicity assays and in a murine colon tumor model. We demonstratedin vitro,that cultured human PBLs alone produced low levels of tumor lysis, but PBLs treated with anti-tumor × anti-CD3 heteroconjugates produced significantly greater tumor cell lysis (P<0.0025). Similarly, nude mice injected with LS174T human colon cancer cells and treated with cultured human PBLs and anti-tumor × anti-CD3 heteroconjugates survived significantly longer than saline control mice (P<0.01), or mice treated with PBLs alone (P<0.01), or heteroconjugates alone (P<0.05). F(ab′)2heteroconjugates were equally as effective in prolonging animal survival, but irrelevant heteroconjugates and monoclonal anti-tumor antibodies showed no therapeutic benefit. Anti-tumor × anti-CD3 heteroconjugates may represent an effective approach to tumor-specific cellular immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495–7.

    Article  PubMed  CAS  Google Scholar 

  2. Herlyn D, Koprowski H. IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci U S A 1982;79:4761–5.

    PubMed  CAS  Google Scholar 

  3. Herlyn D, Powe J, Ross AH, Herlyn M, Koprowski H. Inhibition of human tumor growth by IgG2a monoclonal antibodies correlates with antibody density of tumor cells. J Immunol 1985;134:1300–4.

    PubMed  CAS  Google Scholar 

  4. Rodeck U, Herlyn M, Herlyn D, et al. Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects. Cancer Res 1987;47:3692–6.

    PubMed  CAS  Google Scholar 

  5. Badger CC, Anasetti C, Davis J, Bernstein ID. Treatment of malignancy with unmodified antibody. Pathol Immunopathol Res 1987;6:419–34.

    Article  PubMed  CAS  Google Scholar 

  6. Lanier LL, Babcock GF, Raybourne RB, Arnold LW, Warner NL, Haughton G. Mechanism of B cell lymphoma immunotherapy with passive xenogeneic anti-idiotype serum. J Immunol 1980;125:1730–6.

    PubMed  CAS  Google Scholar 

  7. Sears HF, Herlyn D, Steplewski Z, Koprowski H. Phase II clinical trial of a murine monoclonal antibody cytotoxic for gastrointestinal adenocarcinoma. Cancer Res 1985;45:5910–3.

    PubMed  CAS  Google Scholar 

  8. Spitler LE, del Rio M, Khentigan Aet al. Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin. Cancer Res 1987;47:1717–23.

    PubMed  CAS  Google Scholar 

  9. Byers VS, Baldwin RW. Therapeutic strategies with monoclonal antibodies and immunoconjugates. Immunology 1988;65:329–35.

    PubMed  CAS  Google Scholar 

  10. Lenhard RE, Order SE, Spunberg JJ, Asbell SO, Leibel SA. Isotopic immunoglobulin: a new systemic therapy for advanced Hodgkin's disease. J Clin Oncol 1985;3:1296–30.

    PubMed  Google Scholar 

  11. Schulz G, Bumol TF, Reisfeld RA. Monoclonal antibody-directed effector cells selectively lyse human melanoma cellsin vitro andin vivo. Proc Natl Acad Sci U S A 1983;80:5407–11.

    PubMed  CAS  Google Scholar 

  12. Eberlein TJ, Rosenstein M, Rosenberg SA. Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin-2. J Exp Med 1982;156:385–97.

    Article  PubMed  CAS  Google Scholar 

  13. Rosenberg SA, Lotze MT, Muul LMet al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889–97.

    Article  PubMed  CAS  Google Scholar 

  14. Schwab R, Crow MK, Russo C, Weksler ME. Requirements for T cell activation by OKT3 monoclonal antibody: role of modulation of T3 molecules and interleukin 1. J Immunol 1985:135:1714–8.

    PubMed  CAS  Google Scholar 

  15. Van Wauwe JP, DeMey JR, Goossens JG. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol 1980;124:2708–13.

    PubMed  Google Scholar 

  16. Leeuwenberg JFM, Spits H, Tax WJM, Capel PJ. Induction of nonspecific cytotoxicity by monoclonal anti-T3 antibodies. J Immunol 1985;134:3770–5.

    PubMed  CAS  Google Scholar 

  17. Hoffman RW, Bluestone JA, Leo O, Shaw S. Lysis of anti-T3-bearing murine hybridoma cells by human allospecific cytotoxic T cell clones and inhibition of that lysis by anti-T3 and anti-LFA-1 antibodies. J Immunol 1985;135:5–8.

    PubMed  CAS  Google Scholar 

  18. Perez P, Titus JA, Lotze MTet al. Specific lysis of human tumor cells by T cells coated with anti-T3 cross-linked to anti-tumor antibody. J Immunol 1986;137:2069–72.

    PubMed  CAS  Google Scholar 

  19. Jung G, Honsik CJ, Reisfeld RA, Muller-Eberhard HJ. Activation of human peripheral blood mononuclear cells by anti-T3: killing of tumor target cells coated with anti-target-anti-T3 conjugates. Proc Natl Acad Sci U S A 1986;83:4479–83.

    PubMed  CAS  Google Scholar 

  20. Liu MA, Kranz DM, Kurnick JT, Boyle LA, Levy R, Eisen HN. Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 1985;82:8648–52.

    PubMed  CAS  Google Scholar 

  21. Barr IG, Buchegger F, MacDonald HR, Carrel S, von Fliedner V. Retargeting of cytolytic T lymphocytes by heteroaggregated (bispecific) antibodies. Cancer Detect Prev 1988;12:439–50.

    PubMed  CAS  Google Scholar 

  22. Lotze MT, Roberts K, Custer MC, Segal DA, Rosenberg SA. Specific binding and lysis of human melanoma by IL-2 activated cells coated with anti-T3 or anti-Fc receptor cross-linked to antimelanoma antibody: a possible approach to the immunotherapy of human tumors. J Surg Res 1987;42:580–9.

    Article  PubMed  CAS  Google Scholar 

  23. Bjorn MJ, Ring D, Frankel A. Evaluation of monoclonal antibodies for the development of breast cancer immunotoxins. Cancer Res 1985;45:1214–21.

    PubMed  CAS  Google Scholar 

  24. Frankel AE, Ring DB, Tringale F, Hsieh-Ma ST. Tissue distribution of breast cancer-associated antigens defined by monoclonal antibodies. J Biol Response Mod 1985;4:273–86.

    PubMed  CAS  Google Scholar 

  25. Pearson JW, Sivam G, Manger R, Wiltrout RH, Morgan AC Jr, Longo DL. Enhanced therapeutic efficacy of an immunotoxin in combination with chemotherapy against an intraperitoneal human tumor xenograft in athymic nude mice. Cancer Res 1989;49:4990–5.

    PubMed  CAS  Google Scholar 

  26. Kehrl JH, Dukovich M, Whalen G, Katz P, Fauci AS, Greene WC. Novel interleukin-2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells. J Clin Invest 1988;81:200–5.

    Article  PubMed  CAS  Google Scholar 

  27. Parham P. On the fragmentation of monoclonal IgG1, IgG2a, and IgG2b from BALB/c mice. J Immunol 1983;131:2895–902.

    PubMed  CAS  Google Scholar 

  28. Nelson H, McKean DJ, Kerr LA, Donohue JH. 1990. Anti-tumor X anti-CD3 heteroconjugates direct human peripheral blood lymphocytes to lyse colon tumor cells. J Surg Res 1990 (in press).

  29. Karpovsky B, Titus JA, Stephany DA, Segal DM. Production of target-specific effector cells using heterocross-linked aggregates containing anti-target cell and anti-FCγ receptor antibodies. J Exp Med 1984;160:1686–701.

    Article  PubMed  CAS  Google Scholar 

  30. Beck BN, Glimcher LH, Nilson AE, Pierres M, McKean DJ. The structure-function relationship of I-A molecules: correlation of serologic and functional phenotypes of four I-Ak mutant cell lines. J Immunol 1984;133:3176–82.

    PubMed  CAS  Google Scholar 

  31. Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS. Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol 1981:1:51–63.

    Article  PubMed  CAS  Google Scholar 

  32. Steel RG, Torrie JH. Principles and procedures of statistics. New York: McGraw Hill, 1960.

    Google Scholar 

  33. Titus JA, Garrido MA, Hecht TT, Winkler DF, Wunderlich JR, Segal DM. Human T cells targeted with anti-T3 cross-linked to antitumor antibody prevent tumor growth in nude mice. J Immunol 1987;138:4018–22.

    PubMed  CAS  Google Scholar 

  34. Perez P, Hoffman RW, Titus JA, Segal DM. Specific targeting of human peripheral blood T cells by heteroaggregates containing anti-T3 crosslinked to antitarget cell antibodies. J Exp Med 1986;163:166–78.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Surgery and Immunology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

    Heidi Nelson M.D., Patrick S. Ramsey B.S., David J. McKean Ph.D., Roger R. Dozois M.D. & John H. Donohue M.D.

Authors
  1. Heidi Nelson M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick S. Ramsey B.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David J. McKean Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger R. Dozois M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John H. Donohue M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, April 29–May 4, 1990. Dr. Nelson was supported by the Leon Hirsch Traveling Scholarship, awarded by the Research Foundation of The American Society of Colon and Rectal Surgeons. This material was acknowledged with a research award from the New England Society of Colon and Rectal Surgeons. Dr. Donohue is the recipient of a Cancer Development Award from the American Cancer Society.

About this article

Cite this article

Nelson, H., Ramsey, P.S., McKean, D.J. et al. Anti-tumor × anti-lymphocyte heteroconjugates augment colon tumor cell lysisin Vitro and prevent tumor growthin Vivo . Dis Colon Rectum 34, 140–147 (1991). https://doi.org/10.1007/BF02049988

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02049988

Key words

Search

Navigation