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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2000 Aug;91(8):817–824. doi: 10.1111/j.1349-7006.2000.tb01019.x

Antibody‐dependent Cytotoxicity Mediated by Chimeric Monoclonal Antibody Nd2 and Experimental Immunotherapy for Pancreatic Cancer

Tamahiro Nishihara 1, Tetsuji Sawada 1,, Atsushi Yamamoto 1, Yoshito Yamashita 1, Jenny J L Ho 2, Young‐Sik Kim 2, Kosei Hirakawa‐YS Chung 1
PMCID: PMC5926427  PMID: 10965023

Abstract

In a previous study, mouse monoclonal antibody (MoAb) Nd2 (m‐Nd2, mouse IgGl) labeled with 131 I exhibited efficacy in in vivo radioimmunotherapy against pancreatic cancer. In this study we prepared mouse/human chimeric antibody Nd2 (c‐Nd2, human IgG1) for clinical use and examined whether c‐Nd2 induced antibody‐dependent cell‐mediated cytotoxicity (ADCC). Cytotoxicity to pancreatic cancer (PC) cell lines, including Nd2 antigen‐positive (SW1990, RWP‐1, Capan‐1) and Nd2 antigen‐negative (Panc‐1, MiaPaca‐2, Capan‐2) lines, was evaluated by mixed human leukocyte and tumor cell culture (MLTC) at an effector cell to target cell (E/T) ratio of 50 with or without Nd2. Cytotoxicities to SW1990 with no antibody, m‐Nd2 and c‐Nd2 (1 μg/ml) were 26.7%, 38.0% and 55%, respectively; to RWP‐1, 28%, 41% and 70%; to Capan‐1, 26%, 30% and 52%; to Panc‐1, 24%, 28% and 30%; to MiaPaca‐2, 18%, 20% and 27% and to Capan‐2, 29.7%, 35.0% and 40.6%. Cytotoxic capacity during MLTC with c‐Nd2 was significantly higher than during MLTC with m‐Nd2 or with no antibody. These findings indicated that cytotoxicity to Nd2‐positive PC cells during MLTC is induced by ADCC. Intraperitoneal injection of c‐Nd2 inhibited the tumor growth of SW1990 xenografted subcutaneously in nude mice and prolonged the survival of nude mice in which SW1990 tumor was transplanted orthotopically at the tail of the pancreas. These findings suggested that, because of its ability to induce ADCC, c‐Nd2 may be clinically useful for the immunotherapeutic treatment of pancreatic cancer.

Keywords: Pancreatic cancer, Monoclonal antibody, Chimeric Nd2, ADCC, Immunotherapy

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REFERENCES

  • 1. ) Andreas , P. K. , Mill , W. B. , Aikaterini , A. K. , Nathan , H. S. and Ross , L.Establishment and characterization of human pancreatic adenocarcinoma cell line SW‐1990 in tissue culture and nude mouse . Cancer Res. , 43 , 4393 – 4401 ( 1983. ). [PubMed] [Google Scholar]
  • 2. ) Chung , Y.‐S. , Sawada , T. , Kondo , Y. , Hirayama , K. , Inui , A. , Yamashita , Y. , Nakata , B. , Okamura , T. , Ochi , H. , Ho , J. J. L. , Kim , Y. S. and Sowa , M.Radioimmuodetection with 111In‐labeled monoclonal antibody Nd2 in patients with pancreatic cancer . Jpn. J. Cancer Res. , 88 , 427 – 434 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Ho , J. J. L. , Bi , N. , Yan , P. S. , Yuan , M. , Norton , K. A. and Kim , Y. S.Characterization of new pancreatic cancer reactive monoclonal antibodies against purified mucin . Cancer Res. , 51 , 372 – 380 ( 1991. ). [PubMed] [Google Scholar]
  • 4. ) Inui , A. , Chung , Y.‐S. , Sawada , T. , Kondo , Y. , Ho , J. J. L. , Kim , Y.‐S. and Sowa , M.Radioimmunotherapy for pancreatic carcinoma using 131l‐labeled monoclonal antibody Nd2 in xenografted nude mice . Jpn. J. Cancer Res. , 87 , 977 – 984 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Kondo , Y. , Chung , Y.‐S. , Sawada , T. , Inui , A. , Yamashita , Y. , Hirayama , K. , Nakata , B. , Ho , J. J. L. , Kim , Y. S. and Sowa , M.Intratumoral injection of an adriamycin immunoconjugate against human pancreatic cancer xenografts . Jpn. J. Cancer Res. , 86 , 1072 – 1079 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Sawada , T. , Chung , Y. S. , Kondo , Y. , Ho , J. J. L. , Kim , Y. S. and Sowa , M.Radioimmunodetection of human pancreatic cancer using 111‐In‐labeled monoclonal antibody Nd2 . Antibiot. Immunoconjug. Radiopharm. , 4 , 493 – 494 ( 1991. ). [Google Scholar]
  • 7. ) Boulianne , G. L. , Hozumi , N. and Schulman , M. J.Production of functional chimeric mouse/human antibody . Nature , 312 , 643 – 646 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Morrison , S. L. , Johnson , M. J. , Herzenberg , L. , Herzenberg , L. A. and Oi , V. T.Chimeric human antibody molecules: mouse antigen‐binding domains with human constant region domains . Proc. Natl. Acad. Sci. USA , 81 , 6851 – 6855 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Caron , P. C. , Lai , L. T. and Scheinberg , D. A.Interleukin‐2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti‐CD33) in myelogenous leukemia . Clin. Cancer Res. , 1 , 63 – 70 ( 1995. ). [PubMed] [Google Scholar]
  • 10. ) Juweid , M. , Sharkey , R. M. , Markowitz , A. , Behr , T. , Swayne , L. C. , Dunn , R. , Hansen , H. J. , Shevitz , J. , Leung , S. O. , Rubin , A. D. , Herskovic , T. , Hanley , D. and Goldenberg , D. M.Treatment of non‐Hodgkin's lymphoma with radiolabeled murine, chimeric, or humanized LL2, an anti‐CD22 monoclonal antibody . Cancer Res. , 55 ( Suppl. ), 5899s – 5907s ( 1995. ). [PubMed] [Google Scholar]
  • 11. ) Baselga , J. , Norton , L. , Albanel , J. , Kim , Y. M. and Mendelsohn , J.Recombinant humanized anti‐HER2 antibody (herceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts . Cancer Res. , 58 , 2825 – 2831 ( 1998. ). [PubMed] [Google Scholar]
  • 12. ) Liu , A. , Robinson , R. R. , Murray , E. D. , Jr. , Ledbetter , J. A. , Hellstrom , I. and Hellstrom , K. E.Chimeric mousehuman IgGI antibody that can mediate lysis of cancer cells . Proc. Natl. Acad. Sci. USA , 84 , 3439 – 3443 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Liu , A. Y. , Robinson , R. R. , Murray , E. D. , Jr. , Ledbetter , J. A. , Hellstrom , I. and Hellstrom , K. E.Production of a mouse‐human chimeric monoclonal antibody to CD2 with potent Fc‐dependent biologic activity . J. Immunol. , 139 , 3521 – 3526 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Nishimura , Y. , Yokoyama , M. , Araki , K. , Ueda , R. , Kudo , A. and Watanabe , T.Recombinant human mouse chimeric monoclonal antibody specific for common acute lymphocytic leukaemia antigen . Cancer Res. , 47 , 999 – 1005 ( 1987. ). [PubMed] [Google Scholar]
  • 15. ) Shitara , K. , Kuwana , Y. , Nakamura , K. , Tokutake , Y. , Ohta , S. , Miyaji , H. , Hasegawa , M. and Hanai , N.A mouse/human chimeric anti‐(ganglioside GD3) antibody with enhanced antitumor activities . Cancer Immunol. Immunother. , 36 , 373 – 380 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Hirayama , K. , Chung , Y. S. , Sawada , T. , Kim , Y. S. and Sowa , M.Characterization and biodistribution of a mouse/human chimeric antibody directed against pancreatic cancer mucin . Cancer , 75 ( Suppl. ), 1545 – 1553 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Yasukawa , K. , Kaneko , T. , Iba , Y. , Sawada , T. , Chung , Y. S. , Sowa , M. , Ho , J. J. L. and Kim , Y. S.Preparation of mouse‐human chimeric antibody against pancreatic cancerassociated mucin . Int. J. Oncol. , 6 , 1047 – 1051 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Sawada , T. , Nishihara , T. , Yamamoto , A. , Teraoka , H. , Yamashita , Y. , Okamura , T. , Ochi , H. , Ho , J. J. L. , Kim , Y. S. and Hirakawa , K.Preoperative clinical radioimmunodetection of pancreatic cancer by 111In‐labeled chimeric monoclonal antibody Nd2 . Jpn. J. Cancer Res. , 90 , 1179 – 1186 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Yamamoto , A. , Sawada , T. , Yamashita , Y. , Nishihara , T. , Ho , J. J. , Kim , Y. and Chung , K. H.Radioimmunotherapy of orthotopically transplanted pancreatic cancer with 13II‐labeled chimeric monoclonal antibody Nd2 . Oncol. Rep. , 6 , 179 – 184 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Behl , C. , Davis , J. B. , Lesley , R. and Schubert , D.Hydrogen peroxide mediates amyloid β protein toxicity . Cell , 77 , 817 – 827 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Brander , C. , Wyss‐Coray , T. , Murai , D. , Bettens , F. and Pichler , W. J.Carrier‐mediated uptake and presentation of a major histocompatibility complex class I‐restricted peptide . Eur. J. Immunol. , 23 , 3217 – 3223 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Herlyn , D. , Herlyn , M. and Steplewski , Z.Monoclonal antibodies in cell‐mediated cytotoxicity against human melanoma and colorectal carcinoma . Eur. J. Immunol. , 9 , 657 – 661 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Graziano , R. and Fanger , M. W.FcγRI and FcγRII on monocytes and granulocytes are cytotoxic trigger molecules for tumor cells . J. Immunol. , 139 , 3536 – 3540 ( 1987. ). [PubMed] [Google Scholar]
  • 24. ) Lubeck , M. D. , Steplewski , Z. , Baglia , F. , Klein , M. H. , Dorrington , K. J. and Koprowski , H.The interaction of murine IgG subclass proteins with human monocyte Fc receptors . J. Immunol. , 135 , 1299 – 1304 ( 1985. ). [PubMed] [Google Scholar]
  • 25. ) Steplewki , Z. , Lubeck , M. D. and Koprowski , H.Human macrophages armed with murine immunoglobulin G2a antibodies to tumors destroy human cancer cells . Science , 221 , 865 – 867 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Sung , M. W. , Yasumura , S. and Johnson , J. T.Natural killer cells as effectors of antibody‐dependent cytotoxicity with chimeric antibodies reactive with human squamous cell carcinomas of head and neck . Int. J. Cancer , 61 , 864 – 872 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Hanibuchi , M. , Yano , S. , Nishioka , Y. , Yanagawa , H. and Sone , S.Anti‐ganglioside GM2 monoclonal antibodydependent killing of human lung cancer cells by lymphocytes and monocytes . Jpn. J. Cancer Res. , 87 , 497 – 504 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Pullyblank , A. M. , Guillou , P. J. and Monson , J. R.m17–1–, c17–1A‐ and cSF25‐mediated antibody‐dependent cellmediated cytotoxicity in patients with advanced cancer . Br. J. Cancer , 70 , 753 – 758 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Johnson , W. J. , Steplewski , Z. , Matthews , T. J.Hamilton , T. A. , Koprowski , H. and Adams , D. O.Cytolic interaction between murine macrophages, tumor cells and monoclonal antibodies: characterization of lytic condition and requirements for effector activation . J. Immunol. , 136 , 4704 – 4713 ( 1986. ). [PubMed] [Google Scholar]
  • 30. ) Masucci , G. , Lindemalm , C. , Frodin , J. A. , Hagstrom , B. and Mekkstedt , H.Effect of human blood mononuclear cell populations in antibody‐dependent cellular cytotoxicity (ADCC) using two murine (CO17‐IA and Br55–2) and one chimeric (17–1A) monoclonal antibodies against a human colorectal cell line (SW948) . Hybridoma , 7 , 429 – 440 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Ortaldo , J. R. , Woodhouse , C. , Morgan , A. C. , Herberman , R. B. , Cheresh , D. A. and Reisfeld , R.Analysis of effector cells in human antibody‐dependent cellular cytotoxicity with murine monoclonal antibodies . J. Immunol. , 138 , 3566 – 3572 ( 1987. ). [PubMed] [Google Scholar]
  • 32. ) Steplewski , Z. and Sun , L. K.Biological activity of human‐mouse IgG1, IgG2, IgG3 and IgG4 chimeric monoclonal antibodies with antitumor specificity . Proc. Natl. Acad. Sci. USA , 85 , 4852 – 4856 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. ) Hogarth , P. , Hulett , M. and Powell , M. S.Identification of the immunoglobulin binding regions of FcγR II and FcγR . Immunol. Rev. , 125 , 21 – 36 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Grattge , L. , McKenzie , I. F. C. and Hogarth , P. M.Effects of PMA, cytokines and dexamethasone on the expression of cell surface Fc receptors and mRNA in U937 cells . Immunol. Cell Biol. , 70 , 97 – 102 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) van de Winkel , J. G. and Capel , P. J.Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications . Immunol. Today , 14 , 215 – 217 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Ravetch , J. and Kinet , J. P.Fc receptors . Annu. Rev. Immunol. , 9 , 457 – 458 ( 1991. ). [DOI] [PubMed] [Google Scholar]

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