Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 Sep;36(5):281–292. doi: 10.1007/BF01741166

Induction of delayed-type hypersensitivity responses by monoclonal anti-idiotypic antibodies to tumor cells expressing carcinoembryonic antigen and tumor-associated glycoprotein-72

K Irvine 1, J Schlom 1,✉
PMCID: PMC11038909  PMID: 7682893

Abstract

The use of anti-idiotypic antibodies as immunogens represents one potential approach to active specific immunotherapy of cancer. Two panels of syngeneic monoclonal anti-idiotypic antibodies were generated. One panel was directed against mAb CC49 and the other to mAb COL-1. mAb CC49 recognizes the pancarcinoma antigen (Ag), tumor-associated glycoprotein-72 (TAG-72), and mAb COL-1 recognizes carcinoembryonic antigen (CEA). Seven anti-idiotypic (AI) antibodies (Ab2) designated AI49-1–7 were generated that recognize the variable region of mAb CC49. These mAb were shown to inhibit the interaction of mAb CC49 (Ab1) with TAG-72 (Ag). Five anti-idiotypic antibodies designated CAI-1–5 were also generated to the anti-CEA mAb, COL-1 (Ab1). These Ab2 were shown to inhibit the interaction between COL-1 (Ab1) and CEA (Ag). Immunization of mice, rats, and rabbits with Ab2 directed against CC49 or COL-1 could not elicit specific Ab3 humoral immune responses, i.e., antibody selectively reactive with their respective target antigens. However, immunization of mice with the CC49 anti-idiotypic antibody (Ab2), designated AI49-3, could induce a delayed-type hypersensitivity response (DTH) specific for tumor cells that express TAG-72. Similarly, immunization of mice with an anti-idiotypic antibody directed against COL-1, designated CAI-1, could induce specific DTH cell-mediated immune responses to murine tumor cells that express human CEA on their surface. These results thus demonstrate that while some anti-idiotype mAb may not be potent immunogens in eliciting Ab3 humoral responses, they are capable of eliciting specific cellular immune responses against human carcinoma-associated antigens. This type of mAb may ultimately be useful in active immunotherapy protocols for human carcinoma.

Key words: Carcinoembryonic antigen, Anti-idiotype antibody, Delayed-type hypersensitivity

Footnotes

Some of the studies described in this paper were in partial fulfillment of requirements for the completion of Dr. Irvine's dissertation at the George Washington University

References

  • 1.Barnd DL, Kerr LA, Metzgar RS, Finn OJ. Human tumor-specific cytotoxic T-cell lines generated from tumor-draining lymph node infiltrate. Transplant Proc. 1988;20:339–339. [PubMed] [Google Scholar]
  • 2.Beatty JD, Williams LE, Yamauchi D, Morton BA, Hill R, Beatty BG, Paxton RJ, Merchant B, Shively JE (1990) Presurgical imaging with indium-labeled anti-carcinoembryonic antigen for colon cancer staging. Cancer Res 50 [Suppl]: 922s [PubMed]
  • 3.Bhattacharya-Chatterjee S, Biddle W, Foon K, Kohler H. Murine monoclonal anti-idiotype antibody as a potential network antigen for human carcinoma embryonic antigen. J Immunol. 1990;145:2758–2758. [PubMed] [Google Scholar]
  • 4.Chen ZJ, Yang H, Yamada M, Kageshita T, Zhen Y, Bae JW, Mittelman A, Ferrone S. In: Cellular immunity and the immunotherapy of cancer. Lotze MT, Finn OJ, editors. New York: Wiley-Liss; 1990. pp. 351–359. [Google Scholar]
  • 5.Colcher D, Horan-Hand P, Nuti M, Schlom J. A spectrum of monoclonal antibodies reactive with human mammary tumor cells. Proc Natl Acad Sci USA. 1981;78:3199–3199. doi: 10.1073/pnas.78.5.3199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Colcher D, Esteban JM, Carrasquillo JA, Sugarbaker P, Reynolds JC, Bryant G, Larson SM, Schlom J. Complementation of intracavitary and intravenously administered mAb B72.3 in patients with carcinoma. Cancer Res. 1987;47:4218–4218. [PubMed] [Google Scholar]
  • 7.Dunn PL, Johnson CA, Styles JM, Pease SS, Dean CJ. Vaccination with syngeneic monoclonal anti-idiotype protects against a tumour challenge. Immunology. 1987;60:181–181. [PMC free article] [PubMed] [Google Scholar]
  • 8.Durrant LG, Denton GWL, Jacobs E, Mee M, Moss R, Austin EB, Baldwin RW, Hardcastle JD, Robins RA. An idiotypic replica of carcinoembryonic antigen inducing cellular and humoral immune responses directed against human colorectal tumours. Int J Cancer. 1992;50:811–811. doi: 10.1002/ijc.2910500525. [DOI] [PubMed] [Google Scholar]
  • 9.Ertl HC, Finberg RW. Sendai virus-specific T cell clones: induction of cytolytic T cells by an anti-idiotypic antibody directed against a helper T-cell clone. Proc Natl Acad Sci USA. 1984;81:2850–2850. doi: 10.1073/pnas.81.9.2850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Esteban JM, Colcher D, Sugarbaker P, Carrasquillo JA, Bryant G, Thor A, Reynolds JC, Larson SM, Schlom J. Quantitative and qualitative aspects of radiolocalization in colon cancer patients of intravenously administered mAb B72.3. Int J Cancer. 1987;39:50–50. doi: 10.1002/ijc.2910390110. [DOI] [PubMed] [Google Scholar]
  • 11.Fox BA, Spiess PF, Kasid A, Puri R, Mule JJ, Weber JS, Rosenberg SA. In vitro and in vivo anti-human properties of a T-cell clone generated from tumor-infiltrating lymphocytes. J Biol Response Mod. 1990;9:499–499. [PubMed] [Google Scholar]
  • 12.Fraker PJ, Speck JC., Jr Protein and cell membrane iodinations with a sparingly soluble chloramid 1,3,4,6-tetrachloro-3a,6a-diphenylglycouril. Biochem Biophys Res Commun. 1978;80:849–849. doi: 10.1016/0006-291x(78)91322-0. [DOI] [PubMed] [Google Scholar]
  • 13.Gaida F-J, Fenger U, Wagener C, Neumaier M. A monoclonal anti-idiotypic antibody bearing the image of an epitope specific to the human carcinoembryonic antigen. Int J Cancer. 1992;51:459–459. doi: 10.1002/ijc.2910510320. [DOI] [PubMed] [Google Scholar]
  • 14.Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122:467–467. doi: 10.1084/jem.122.3.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Goldenberg DM, Goldenberg H, Sharkey RM, Higginbotham-Ford E, Lee RE, Swayne LC, Burger KL, Tsai D, Horowitz J, Hall TC, Pinsky CM, Hansen HJ (1990) Clinical studies of cancer radioimmunodetection with carcinoembryonic antigen monoclonal antibody fragments labeled with123I or99mTc. Cancer Res [Suppl] 50: 909s [PubMed]
  • 16.Grych JM, Capron M, Lambert PH, Dissous C, Torres S, Capron A. An anti-idiotypic vaccine against experimental schistomiasis. Nature. 1985;316:76–76. doi: 10.1038/316074a0. [DOI] [PubMed] [Google Scholar]
  • 17.Herlyn M, Ross AH, Iliopoulos D, Koprowski H. Induction of specific immunity to human colon carcinoma by anti-idiotypic antibodies to monoclonal antibody CO17-1A. Eur J Immunol. 1987;7:1649–1649. doi: 10.1002/eji.1830171120. [DOI] [PubMed] [Google Scholar]
  • 18.Herlyn D, Benden A, Kane M, Somasundaram R, et al. Anti-idiotype cancer vaccines: pre-clinical and clinical studies. In Vivo. 1991;5:615–615. [PubMed] [Google Scholar]
  • 19.Herzenberg LA, Herzenberg LA, Milstein C. Handbook of experimental immunology. London: Blackwell Scientific Publications; 1978. Cell hybrids of myelomas and antibody forming cells and T lymphocytes with T cells; pp. 25.1–25.1. [Google Scholar]
  • 20.Jerne NK. Towards a network theory of the immune system. Annu Rev Immunol. 1974;125:373–373. [PubMed] [Google Scholar]
  • 21.Johnson VG, Schlom J, Paterson AJ, Bennet J, Magnani JL, Colcher D. Analysis of a human tumor-associated glycoprotein (TAG-72) identified by monoclonal antibody B72.3. Cancer Res. 1986;46:850–850. [PubMed] [Google Scholar]
  • 22.Kahn M, Hellstrom I, Estin CD, Hellstrom KE. Monoclonal anti-idiotypic antibodies to the p97 human melanoma antigen. Cancer Res. 1989;49:3157–3157. [PubMed] [Google Scholar]
  • 23.Kohler G, Milstein C. Derivation of specific antibody producing tissue culture and tumor cell lines by cell fusion. Eur J Immunol. 1976;6:511–511. doi: 10.1002/eji.1830060713. [DOI] [PubMed] [Google Scholar]
  • 24.Kohler H, Kieber-Emmons T, Srinivasav S, Kaveri S, Morrow WJW, Muller S, Kang C-Y, Raychaudhuri S. Short analytical review: revised immune network concepts. Clin Immunol Immunopathol. 1989;52:104–104. doi: 10.1016/0090-1229(89)90197-9. [DOI] [PubMed] [Google Scholar]
  • 25.Koprowski H, Herlyn D, Lubeck M, DeFreitas E, Sears HF. Human anti-idiotypic antibodies in cancer patients. Is the modulation of the immune response beneficial to the patient? Proc Natl Acad Sci USA. 1984;81:216–216. doi: 10.1073/pnas.81.1.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kuroki M, Greiner JW, Simpson JF, Primus FJ, Guadagni F, Schlom J. Serologic mapping and biochemical characterization of the carcinoembryonic antigen epitopes using fourteen distinct monoclonal antibodies. Int J Cancer. 1989;44:208–208. doi: 10.1002/ijc.2910440204. [DOI] [PubMed] [Google Scholar]
  • 27.Kuroki M, Fernsten PD, Wunderlich D, Colcher D, Simpson JF, Poole DJ, Schlom J. Serologic mapping of the TAG-72 tumor-associated antigen employing 19 distinct monoclonal antibodies. Cancer Res. 1990;50:4872–4872. [PubMed] [Google Scholar]
  • 28.Kusama M, Kageshita T, Chen ZJ, Ferrone S. Characterization of syngeneic anti-idiotypic monoclonal antibodies to murine anti-human high molecular weight melanoma-associated antigen monoclonal antibodies. J Immunol. 1989;143:3844–3844. [PubMed] [Google Scholar]
  • 29.Lee VK, Harriott TG, Kuchroo VK, Halliday WJ, Hellstrom I, Hellstrom KE. Monoclonal anti-idiotope antibodies related to a murine oncofetal bladder tumor antigen induce specific cell-mediated tumor immunity. Proc Natl Acad Sci USA. 1985;82:6286–6286. doi: 10.1073/pnas.82.18.6286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Losman M, Hansen H, Sharkey R, Goldenberg DM, Monestier M. Human response against NP-4, a mouse antibody to carcinoembryonic antigen: human anti-idiotypic antibodies mimic an epitope on the tumor antigen. Proc Natl Acad Sci USA. 1988;85:1052–1052. doi: 10.1073/pnas.88.8.3421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–265. [PubMed] [Google Scholar]
  • 32.Maguire RT, Schmelter RF, Pacucci VL, Conklin JJ. Immunoscintography of colorectal adenocarcinoma. Results with a site-specifically radiolabeled B72.3 (111In-CYT-103) Antibody Immunoconj Radiopharmacol. 1989;2:257–257. [Google Scholar]
  • 33.Maloney DG, Kaminski MS, Burowski D, Haimovich J, Levy R. Monoclonal anti-idiotypic antibodies against the murine B cell lymphoma 38C13: characterization and use as probes for the biology of the tumor in vivo and in vitro. Hybridoma. 1985;4:191–191. doi: 10.1089/hyb.1985.4.191. [DOI] [PubMed] [Google Scholar]
  • 34.McNamara MK, Ward RE, Kohler H. Monoclonal anti-idiotypic vaccine against streptococcus pneumonial infection. Science. 1984;226:1325–1325. doi: 10.1126/science.6505692. [DOI] [PubMed] [Google Scholar]
  • 35.Mellstedt H, Frodin JE, Biberfield P, Fagerberg J, Giscombe R, Hernandez A, Mascucci G, Li S-L, Steinitz M. Patients treated with a monoclonal antibody (Ab1) to the colorectal carcinoma antigen 17-1A develop a cellular response (DTH) to the “internal image of the antigen” (Ab2) Int J Cancer. 1991;48:344–344. doi: 10.1002/ijc.2910480306. [DOI] [PubMed] [Google Scholar]
  • 36.Mittelman A, Chen ZJ, Kageshita T, Yang H, Yamada M, Baskind P, Goldberg N, Ahmed T, Arlin Z, Ferrone S. Active specific immunotherapy in patients with melanoma. A clinical trial with mouse monoclonal antibodies elicited with syngeneic anti-high-molecular weight-melanoma associated antigen monoclonal antibodies. J Clin Invest. 1990;86:2136–2136. doi: 10.1172/JCI114952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Monestier M, Debbas ME, Goldenberg DM. Syngeneic anti-idiotypic monoclonal antibodies to murine anti-carcinoembryonic antigen monoclonal antibodies. Cancer Res. 1989;49:123–123. [PubMed] [Google Scholar]
  • 38.Muraro R, Wunderlich D, Thor A, Noguchi P, Cunningham R, Schlom J. Definition by monoclonal antibodies of a repertoire of epitopes on carcinoembryonic antigen differentially expressed in human colon carcinomas versus normal adult tissues. Cancer Res. 1985;45:5768–5768. [PubMed] [Google Scholar]
  • 39.Muraro R, Nuti M, Natali PG, Bigotti A, Simpson JF, Primus FJ, Colcher D, Greiner JW, Schlom J. A monoclonal antibody (D612) with selective reactivity for malignant and normal gastrointestinal epithelium. Int J Cancer. 1989;43:598–598. doi: 10.1002/ijc.2910430411. [DOI] [PubMed] [Google Scholar]
  • 40.Nissonoff A, Lamoyi E. Implications of the presence of an internal image of the antigen on an anti-idiotypic antibody. Clin Immunol Immunopathol. 1981;21:397–397. doi: 10.1016/0090-1229(81)90228-2. [DOI] [PubMed] [Google Scholar]
  • 41.Rajewsky K, Takemori T. Genetics, expression and function of idiotype. Annu Rev Immunol. 1983;1:569–569. doi: 10.1146/annurev.iy.01.040183.003033. [DOI] [PubMed] [Google Scholar]
  • 42.Raychaudhuri S, Saeki Y, Fuji H, Kohler H. Tumor specific idiotypic vaccines: I. Generation and characterization of an internal image tumor antigen. J Immunol. 1986;137:1743–1743. [PubMed] [Google Scholar]
  • 43.Reagan KJ, Wunner WH, Wiktor TJ, Koprowski H. Anti-idiotypic antibodies induce neutralizing antibodies to rabies virus glycoprotein. J Virol. 1983;48:660–660. doi: 10.1128/jvi.48.3.660-666.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Robbins PF, Kantor J, Salgaller M, Hand P, Fernsten PD, Schlom J. Transduction and expression of the human carcinoembryonic antigen gene in a murine colon carcinoma cell line. Cancer Res. 1991;51:3657–3657. [PubMed] [Google Scholar]
  • 45.Sharkey RM, Goldenberg DM, Goldenberg H, Lee RE, Ballance C, Pawlyk D, Varga D, Hansen HJ. Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans. Cancer Res. 1990;50:2823–2823. [PubMed] [Google Scholar]
  • 46.Sheer DG, Schlom J, Cooper H. Purification and composition of the human tumor associated glycoprotein (TAG-72) defined by monoclonal antibodies CC49 and B72.3. Cancer Res. 1988;48:6811–6811. [PubMed] [Google Scholar]
  • 47.Snedecor GW, Cochran WG. Statistical methods. 8th edn. Ames, Iowa: Iowa State Press; 1989. pp. 132–132. [Google Scholar]
  • 48.Steward AM, Nixon D, Zamcheck N, Aisenberg A. Carcinoembryonic antigen in breast cancer patients: serum levels and disease progress. Cancer. 1974;33:1246–1246. doi: 10.1002/1097-0142(197405)33:5<1246::aid-cncr2820330509>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  • 49.Thor A, Viglione MJ, Muraro R, Ohuchi N, Schlom J, Gorstein F. Monoclonal antibody B72.3 reactivity with human endometrium: a study of normal and malignant tissues. Int J Gynecol Pathol. 1987;6:235–235. doi: 10.1097/00004347-198709000-00005. [DOI] [PubMed] [Google Scholar]
  • 50.Tom BH, Rutzky LP, Jakstys MM. Human colonic adenocarcinoma cells: I. Establishment and description of a new line. In Vitro. 1976;12:180–180. doi: 10.1007/BF02796440. [DOI] [PubMed] [Google Scholar]
  • 51.Tsujisaki M, Imai K, Tokuchi S, Hanzawa Y, Ishida I, Kitagawa H, Hinoda Y, Yachi A. Induction of antigen-specific immune response with the use of anti-idiotypic monoclonal antibodies to carcinoembryonic antigen antibodies. Cancer Res. 1991;51:2599–2599. [PubMed] [Google Scholar]
  • 52.Viale G, Flamini G, Grassi F, Buffa R. Idiotypic replica of an anti-human tumor-associated antigen monoclonal antibody. Analysis of monoclonal Ab1 and Ab3 fine specificity. J Immunol. 1989;15:4338–4338. [PubMed] [Google Scholar]
  • 53.Vincent RG, Chu TM. Carcinoembryonic antigen in patients with carcinoma of the lung. J Thorac Cardiovasc Surg. 1978;66:320–320. [PubMed] [Google Scholar]
  • 54.Wettendorf M, Iliopoulos D, Tempero M, Kay D, DeFreitas E, Koprowski H, Herlyn D. Idiotypic cascades in cancer patients treated with MoAb CO171A. Proc Natl Acad Sci USA. 1989;86:3787–3787. doi: 10.1073/pnas.86.10.3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Wolf BC, Salem RR, Sears HF, Horst DA, Lavin PT, Herlyn M, Itzkowitz SH, Schlom J, Steele GD. The expression of colorectal carcinoma-associated antigens in the normal colonic mucosa: an immunohistochemical analysis of regional distribution. Am J Pathol. 1989;135:111–111. [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES