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. 1990 Nov;31(6):349–357. doi: 10.1007/BF01741406

Chimeric B72.3 mouse/human (IgG1) antibody directs the lysis of tumor cells by lymphokine-activated killer cells

F James Primus 1, Tribhuvan K Pendurthi 1, Paula Hutzell 1, Syed Kashmiri 1, Dale C Slavin 1, Robert Callahan 1, Jeffrey Schlom 1
PMCID: PMC11038277  PMID: 2386980

Abstract

Chimeric mouse/human B72.3 (cB72.3) antibodies having a human IgG1 (γ1) or IgG4 (γ4) constant region were compared to the native murine IgG1 B72.3 (nB72.3) monoclonal antibody (mAb) for their ability to participate with human effector cells in antibody-dependent cellular cytotoxicity (ADCC). Because the TAG-72 antigen recognized by B72.3 is poorly expressed on tissuecultured tumor cell lines, the xenografted OVCAR-3 human ovarian carcinoma ascites was used as a cytotoxicity target. The lytic activity of the cB72.3(γ1) mAb with peripheral blood lymphocytes was 1.5- to 50-fold greater than that of the nB72.3 mAb and usually the cB72.3(γ4) mAb. However, lymphocytes from some donors had similar ADCC activity with either the cB72.3(γ1) or cB72.3(γ4) mAb. The cB72.3(γ1) and the murine anti-colon carcinoma CO17-1A mAb had comparable activity in mediating ADCC against the OVCAR-3 tumor. Exposure of lymphoid cells to interleukin-2 (IL-2) (100–500 U/ml) for 24 h to generate lymphokine-activated killer (LAK) cells augmented ADCC mediated by the cB72.3(γ1) mAb 2- to 22-fold. By contrast, LAK cells from most donors expressed weak non-specific cytotoxicity against OVCAR-3 ascites tumor cells. The cB72.3(γ1), and to a lesser extent, the cB72.3(γ4) chimera also participated with monocytes in mediating ADCC, but the antibody-dependent lytic potency of monocytic effectors was much weaker than that of IL-2-activated lymphoid cells. These studies show that the cB72.3(γ1) mAb has appreciable ADCC-mediating properties, suggesting a potential role for its incorporation into treatment strategies utilizing adoptive killer cell and/or lymphokine therapy.

Keywords: Ovarian Carcinoma, Peripheral Blood Lymphocyte, Lymphoid Cell, Lytic Activity, Cellular Cytotoxicity

Footnotes

Offprint requests to: J. Schlom, to whom reprint requests should be sent at 9000 Rockville Pike, Building 10, Room 8B07, Bethesda, MD 20892, USA

References

  • 1.Berinstein N, Levy R. Treatment of a murine B cell lymphoma with monoclonal antibodies and IL-2. J Immunol. 1987;139:971–971. [PubMed] [Google Scholar]
  • 2.Berinstein N, Starnes C, Levy R. Specific enhancement of the therapeutic effect of anti-idiotype antibodies on a murine B cell lymphoma by IL-2. J Immunol. 1988;140:2839–2839. [PubMed] [Google Scholar]
  • 3.Bruggemann M, Williams GT, Bindon CI, Clark MR, Walker MR, Jefferis R, Waldmann H, Neuberger MS. Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med. 1987;166:1351–1351. doi: 10.1084/jem.166.5.1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Burton DR. Immunoglobulin G: functional sites. Mol Immunol. 1985;22:161–161. doi: 10.1016/0161-5890(85)90151-8. [DOI] [PubMed] [Google Scholar]
  • 5.Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Strandjord SE, Coccia PF, Berger NA. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol. 1987;5:1430–1430. doi: 10.1200/JCO.1987.5.9.1430. [DOI] [PubMed] [Google Scholar]
  • 6.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]
  • 7.Eisenthal A, Lafreniere R, Lefor AT, Rosenberg SA. Effect of anti-B16 melanoma monoclonal antibody on established murine B16 melanoma liver metastases. Cancer Res. 1987;47:2771–2771. [PubMed] [Google Scholar]
  • 8.Eisenthal A, Cameron RB, Uppenkamp I, Rosenberg SA. Effect of combined therapy with lymphokine-activated killer cells, interleukin 2 and specific monoclonal antibody on established B16 melanoma lung metastases. Cancer Res. 1988;48:7140–7140. [PubMed] [Google Scholar]
  • 9.Estaban 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]
  • 10.Fischer DG, Hubbard WJ, Koren HS. Tumor cell killing by freshly isolated peripheral blood monocytes. Cell Immunol. 1981;58:426–426. doi: 10.1016/0008-8749(81)90235-5. [DOI] [PubMed] [Google Scholar]
  • 11.Greiner JW, Horan Hand P, Noguchi P, Fisher PB, Pestka S, Schlom J. Enhanced expression of surface tumor-associated antigens on human breast and colon tumor cells after recombinant human leukocyte α-interferon treatment. Cancer Res. 1984;44:3208–3208. [PubMed] [Google Scholar]
  • 12.Greiner JW, Guadagni F, Smalley RV, Goldstein D, Borden EC, Schlom J. Enhanced expression of tumor-associated antigens on human adenocarcinoma ascites cells as a result of intraperitoneal administration of interferon-gamma (IFN-γ) (abstract) Washington, DC: American Association for Cancer Research; 1990. [Google Scholar]
  • 13.Guadagni F, Schlom J, Johnston WW, Szpak CA, Goldstein D, Smallry R, Simpson JF, Borden EC, Pestka S, Greiner JW. Selective interferon-induced enhancement of tumor-associated antigens on a spectrum of freshly isolated human adenocarcinoma cells. J Natl Cancer Inst. 1989;81:502–502. doi: 10.1093/jnci/81.7.502. [DOI] [PubMed] [Google Scholar]
  • 14.Hamilton TC, Young RC, Louie KG, Behrens BC, McKoy WM, Grotzinger KR, Ozols RF. Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res. 1984;44:5286–5286. [PubMed] [Google Scholar]
  • 15.Hellstrom I, Hellstrom KE. Antitumor antibodies for therapy. Nucl Med Biol. 1989;16:613–613. doi: 10.1016/0883-2897(89)90082-2. [DOI] [PubMed] [Google Scholar]
  • 16.Hellstrom I, Garrigues U, Lavie E, Hellstrom KE. Antibodymediated killing of human tumor cells by attached effector cells. Cancer Res. 1988;48:624–624. [PubMed] [Google Scholar]
  • 17.Herlyn DM, Koprowski H. Monoclonal anticolon carcinoma antibodies in complement-dependent cytotoxicity. Int J Cancer. 1981;27:769–769. doi: 10.1002/ijc.2910270607. [DOI] [PubMed] [Google Scholar]
  • 18.Herlyn D, Koprowski H. IgG2 a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci USA. 1982;79:4761–4761. doi: 10.1073/pnas.79.15.4761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci USA. 1979;76:1438–1438. doi: 10.1073/pnas.76.3.1438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Herlyn D, Herlyn M, Steplewski Z, Koprowski H. Monoclonal anti-human tumor antibodies of six isotypes in cytotoxic reactions with human and murine effector cells. Cell Immunol. 1985;92:105–105. doi: 10.1016/0008-8749(85)90068-1. [DOI] [PubMed] [Google Scholar]
  • 21.Honsik CJ, Jung G, Reisfeld RA. Lymphokine-activated killer cells targeted by monoclonal antibodies to the disialogangliosides GD2 and GD3 specifically lyse human tumor cells of neuroectodermal origin. Proc Natl Acad Sci USA. 1986;83:7893–7893. doi: 10.1073/pnas.83.20.7893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Horan Hand P, Colcher D, Salomon D, Ridge J, Noguchi P, Schlom J. Influence of spatial configuration of carcinoma cell populations on the expression of a tumor-associated glycoprotein. Cancer Res. 1985;45:833–833. [PubMed] [Google Scholar]
  • 23.Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed MR, Ottegen HF, Old LJ. Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: A phase I trial patients with malignant melanoma. Proc Natl Acad Sci USA. 1985;82:1242–1242. doi: 10.1073/pnas.82.4.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Hutzell P, Kashmiri S, Colcher D, Primus J, Horan Hand P, Roselli M, Yarranton G, Callahan R, Schlom J (1990) Generation and characterization of a recombinant/chimeric B72.3 (human γ1) (submitted)
  • 25.Johnston WW, Szpak CA, Lottich SC, Thor A, Schlom J. Use of monoclonal antibody (B72.3) as an immunocytochemical adjunct to diagnosis of adenocarcinoma in human effusions. Cancer Res. 1985;45:1894–1894. [PubMed] [Google Scholar]
  • 26.Kawase I, Komuta K, Hara H, Inoue T, Hosoe S, Ikeda T, Shirasaka T, Yokota S, Tanio Y, Masuno T, Kishimoto S. Combined therapy of mice bearing a lymphokine-activated killer-resistant tumor with recombinant interleukin-2 and an antitumor monoclonal antibody capable of inducing antibody-dependent cellular cytotoxicity. Cancer Res. 1988;48:1173–1173. [PubMed] [Google Scholar]
  • 27.Klug TL, Sattler MA, Colcher D, Schlom J. Monoclonal antibody immunoradiometric assay for an antigenic determinant (CA 72) on a novel pancarcinoma antigen (TAG-72) Int J Cancer. 1986;38:661–661. doi: 10.1002/ijc.2910380508. [DOI] [PubMed] [Google Scholar]
  • 28.Lastoria S, D'Amico P, Mansi L, Giordano GG, Rosiello R, Schlom J, Pace E, Panza N, Pacilio G, Salvatorie M. A prospective imaging study of131I-B72.3 monoclonal antibody in patients with epithelial ovarian cancer: preliminary report. Nucl Med Commun. 1988;9:347–347. doi: 10.1097/00006231-198805000-00003. [DOI] [PubMed] [Google Scholar]
  • 29.Liu AY, Robinson RR, Hellstrom KE, Murray ED, Jr, Chang CP, Hellstrom I. Chimeric mouse-human IgG1 antibody that can mediate lysis of cancer cells. Proc Natl Acad Sci USA. 1987;84:3439–3439. doi: 10.1073/pnas.84.10.3439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Liu AY, Robinson RR, Murray ED, Jr, Ledbetter JA, Hellstrom I, Hellstrom KE. Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J Immunol. 1987;139:3521–3521. [PubMed] [Google Scholar]
  • 31.LoBuglio AF, Saleh MN, Lee J, Khazaeli MB, Carrano R, Holden H, Wheeler RH. Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects. J Natl Cancer Inst. 1988;80:932–932. doi: 10.1093/jnci/80.12.932. [DOI] [PubMed] [Google Scholar]
  • 32.LoBuglio AF, Wheeler RH, Trang J, Haynes A, Rogers K, Harvey EB, Sun L, Ghrayeb J, Khazaeli MB. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci USA. 1989;86:4220–4220. doi: 10.1073/pnas.86.11.4220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Masucci G, Lindemalm C, Frodin JE, Hagstrom B, Mellstest H. Effect of human blood mononuclear cell populations in antibody dependent cellular cytotoxicity (ADCC) using two murine (CO17-1A and Br55-2) and one chimeric (17-1A) monoclonal antibodies against a human colorectal carcinoma cell line (SW948) Hybridoma. 1988;7:429–429. doi: 10.1089/hyb.1988.7.429. [DOI] [PubMed] [Google Scholar]
  • 34.Mujoo K, Cheresh DA, Yang HM, Reisfeld RA. Disialoganglioside GD2 on human neuroblastoma cells: target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res. 1987;46:1098–1098. [PubMed] [Google Scholar]
  • 35.Munn DH, Cheung NKV. Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res. 1987;47:6600–6600. [PubMed] [Google Scholar]
  • 36.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 gastro-intestinal epithelium. Int J Cancer. 1989;43:598–598. doi: 10.1002/ijc.2910430411. [DOI] [PubMed] [Google Scholar]
  • 37.Muul LM, Director EP, Hyatt CL, Rosenberg SA. Large scale production of human lymphokine activated killer cells for use in adoptive immunotherapy. J Immunol Methods. 1986;88:265–265. doi: 10.1016/0022-1759(86)90015-3. [DOI] [PubMed] [Google Scholar]
  • 38.Nieroda CA, Mojzisik C, Sardi A, Farrar WB, Hinkle G, Siddiqi MA, Ferrara PJ, James A, Schlom J, Thurston MO, Martin EW., Jr Staging of carcinoma of the breast using a hand-held gamma detecting probe and monoclonal antibody B72.3. Surg Gynecol Obstet. 1989;169:35–35. [PubMed] [Google Scholar]
  • 39.Nishimura Y, Yokoyama M, Araki K, Udea R, Kudo A, Watanabe T. Recombinant human mouse chimeric monoclonal antibody specific for common acute lymphocytic leukemia antigen. Cancer Res. 1987;47:999–999. [PubMed] [Google Scholar]
  • 40.Ortaldo JR, Woodhouse C, Morgan AC, Herberman RB, Cheresh DA, Reisfeld R. Analysis of effector cells in human antibody-dependent cellular cytotoxicity with murine monoclonal antibodies. J Immunol. 1987;138:3566–3566. [PubMed] [Google Scholar]
  • 41.Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature. 1988;332:323–323. doi: 10.1038/332323a0. [DOI] [PubMed] [Google Scholar]
  • 42.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. 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;316:889–889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 43.Scheinberg DA, Houghton AN. Current status of antitumor therapy with monoclonal antibodies. Oncology. 1987;1:31–31. [PubMed] [Google Scholar]
  • 44.Shaw DR, Khazaeli MB, LoBuglio AF. Mouse/human chimeric antibodies to a tumor-associated antigen: biologic activity of the four human IgG subclasses. J Natl Cancer Inst. 1988;80:1553–1553. doi: 10.1093/jnci/80.19.1553. [DOI] [PubMed] [Google Scholar]
  • 45.Sheer DG, Schlom J, Cooper HL. 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]
  • 46.Sosman JA, Kohler PC, Hank J, Moore KH, Bechhofer R, Storer B, Sondel PM. Repetitive weekly cycles of recombinant human interleukin-2: responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst. 1988;80:60–60. doi: 10.1093/jnci/80.1.60. [DOI] [PubMed] [Google Scholar]
  • 47.Steplewski Z, Sun LK, Shearman CW, Ghrayeb J, Daddona P, Koprowski H. Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificity. Proc Natl Acad Sci USA. 1988;85:4852–4852. doi: 10.1073/pnas.85.13.4852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Thor A, Ohuchi N, Szpak CA, Johnston WW, Schlom J. Distribution of oncofetal antigen tumor-associated glycoprotein-72 defined monoclonal antibody B72.3. Cancer Res. 1986;46:3118–3118. [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.Tong AW, Lee JC, Wang RM, Ordonez G, Stone MJ. Augmentation of lymphokine-activated killer cell cytotoxicity by monoclonal antibodies against human small cell lung carcinoma. Cancer Res. 1989;49:4103–4103. [PubMed] [Google Scholar]
  • 51.Welt S, Carswell EA, Vogel CW, Oettgen HF, Old LJ. Immune and nonimmune effector functions of IgG3 mouse monoclonal antibody R24 detecting the disialoganglioside GD3 on surface of melanoma cells. Clin Immunol Immunopathol. 1987;45:214–214. doi: 10.1016/0090-1229(87)90036-5. [DOI] [PubMed] [Google Scholar]
  • 52.Whittle N, Adair J, Lloyd C, Jenkins L, Devine J, Schlom J, Raubitschek A, Colcher D, Bodmer M. Expression in COS cells of a mouse-human chimeric B72.3 antibody. Protein Engineering. 1987;1:499–499. doi: 10.1093/protein/1.6.499. [DOI] [PubMed] [Google Scholar]
  • 53.Wiltrout RH, Taramelli D, Holden HT. Indium-111 assay of macrophage-mediated cytolysis. In: Herscowitz HB, editor. Manual of macrophage methodology: collection, characterization, and function. New York: Dekker; 1981. pp. 531–531. [Google Scholar]

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