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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 May;87(5):497–504. doi: 10.1111/j.1349-7006.1996.tb00251.x

Anti‐ganglioside GM2 Monoclonal Antibody‐dependent Killing of Human Lung Cancer Cells by Lymphocytes and Monocytes

Masaki Hanibuchi 1, Seiji Yano 1, Yasuhiko Nishioka 1, Hiroaki Yanagawa 1, Saburo Sone 1,✉
PMCID: PMC5921121  PMID: 8641987

Abstract

Ganglioside GM2 (GM2) frequently appears on the cell surface of human cancers of neuroendocrine origin. A mouse‐human chimeric monoclonal antibody (mAb), KM966, against GM2 was previously found to promote the lysis of various cancer cells by human blood mononnclear cells (MNC). In this study, we analyzed the effector cells responsible for the chimeric mAb‐dependent cell‐mediated cytotoxicity (ADCC) against small cell lung cancer (SCLC) cells and examined the enhancing effect of various cytokines on the ADCC activity. The ADCC activity was assessed by 4‐h 51Cr release assay. Highly purified lymphocytes (>99%) and monocytes (>90%) were separated by centrifugal elutriation from peripheral blood MNC of the same healthy donor. KM966 induced lysis of SCLC cells mediated by both lymphocytes and monocytes to similar extents, in a dose‐dependent manner. Pretreatment of lymphocytes with various cytokines [interleukin (IL)‐2, IL‐12 and interferon‐γ] and that of monocytes with macrophage‐colony‐stimulating factor significantly augmented the killer activity against SCLC cells in the presence of KM966 mAb. KM966 was also effective for the lysis of non‐small cell lung cancer cells in direct proportion to the GM2 expression levels. These findings suggest that combined treatment of KM966 mAb with cytokines may be therapeutically useful for in vivo killing of lung cancer cells expressing GM2 through the ADCC reaction.

Keywords: Ganglioside GM2, Chimeric antibody, KM966, ADCC

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REFERENCES

  • 1. ) Ries , L. G. , Pollack , E. S. and Young , J. L.Cancer patient survival: surveillance, epidemiology and end results program, 1973–79 . J. Natl Cancer Inst. , 70 , 693 – 707 ( 1983. ). [PubMed] [Google Scholar]
  • 2. ) Paesraans , M. , Sculier , J. P. , Libert , P. , Bureau , G. , Dabouis , G. , Thiriaux , J. , Michel , J. , Van Cutsem , O. , Sergysels , R. , Mommen , P. and Klastersky , J.Prognostic factors for survival in advanced non‐small‐cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients . J. Clin. Oncol. , 13 , 1221 – 1230 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Sufarlan , A. W. and Zainudin , B. M.Combination chemotherapy for small cell lung cancer . Med. J. Malaysia , 48 , 166 – 170 ( 1993. ). [PubMed] [Google Scholar]
  • 4. ) Blackstein , M. E.Advances in chemotherapy for small cell lung cancer . Semin. Oncol. , 21 ( Suppl. 1 ), 38 – 42 ( 1994. ). [PubMed] [Google Scholar]
  • 5. ) Yang , S. C. , Owen‐Schaub , L. , Grimm , E. A. and Roth , J. A.Induction of lymphokine‐activated killer cytotoxicity with interleukin‐2 and tumor necrosis factor‐alpha against primary lung cancer targets . Cancer Immunol. Immunother. , 29 , 193 – 198 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Vangsted , A. J. and Zeuthen , J.Monoclonal antibodies for diagnosis and potential therapy of small cell lung cancer, the ganglioside antigen fucosyl‐GM1 . Acta Oncol. , 32 , 845 – 851 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Lynch , T. J.Immunotoxin therapy of small‐cell lung cancer. N901‐blocked ricin for relapsed small‐cell lung cancer . Chest , 103 ( Suppl. 4 ), 436 – 439 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Lissoni , P. , Meregalli , S. , Fossati , V. , Paolorossi , F. , Barni , S. , Tancini , G. and Frigerio , F.A randomized study of immunotherapy with low‐dose subcutaneous interleukin‐2 plus melatonin vs chemotherapy with cisplatin and etoposide as first‐line therapy for advanced non‐small cell lung cancer . Tumori , 80 , 464 – 467 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Nakamura , K. , Koike , M. , Shitara , K. , Kuwana , Y. , Kiuragi , K. , Igarashi , S. , Hasegawa , M. and Hanai , N.Chimeric anti‐ganglioside GM2 antibody with antitumor activity . Cancer Res. , 54 , 1511 – 1516 ( 1994. ). [PubMed] [Google Scholar]
  • 10. ) Portoukalian , J. , Zwingelstein , G. and Dore , J.Lipid composition of human malignant melanoma tumors at various levels of malignant growth . Eur. J. Biochem. , 94 , 19 – 23 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Yates , A. J. , Thompson , P. K. , Boesel , C. P. , Albrightson , C. and Hart , R. W.Lipid composition of human neural tumors . J. Lipid Res. , 20 , 428 – 436 ( 1979. ). [PubMed] [Google Scholar]
  • 12. ) Pukel , C. S. , Lloyd , K. O. , Travassor , R. , Dippold , W. G. , Oettgen , H. F. and Old , L. J.GD3, a prominent ganglioside of human melanoma . J. Exp. Med. , 155 , 1133 – 1147 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Ravindranath , M. H. , Tsuchida , T. , Morton , D. L. and Irie , R. F.Ganglioside GM3GD3 ratio as an index for the management of melanoma . Cancer , 67 , 3029 – 3035 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Jennemann , R. , Rodden , A. , Bauer , B. L. , Mennel , H. D. and Wiegandt , H.Glycosphingolipids of human gliomas . Cancer Res. , 50 , 7444 – 7449 ( 1990. ). [PubMed] [Google Scholar]
  • 15. ) Cheung , N. V. , Lazarus , H. and Miraldi , F. D.Ganglioside GD2 specific monoclonal antibody 3F8: a phase‐I study in patients with neuroblastoma and malignant melanoma . J. Clin. Oncol. , 5 , 1430 – 1440 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Irie , R. F. , Matsuki , T. and Morton , D. L.Human monoclonal antibody to ganglioside GM2 for melanoma treatment . Lancet , i , 786 – 787 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Vadhan‐Raj , S. , Cordon‐Cardo , C. , Carswell , E. , Mintzer , D. , Dantis , L. , Duteau , C. , Tempelton , M. A. , Oettgen , H. F. , Old , L. J. and Houghton , A. N.Phase‐I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites . J. Clin. Oncol. , 6 , 1636 – 1648 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Saleh , M. N. , Khazaeli , M. B. , Wheeler , R. H. , Dropcho , E. , Lui , T. , Urist , M. , Miller , D. M. , Lawson , S. , Dixton , P. , Russel , C. H. and LoBuglio , A. F.Phase I trial of the murine monoclonal anti‐GD2 antibody 14G2a in metastatic melanoma . Cancer Res. , 52 , 4342 – 4347 ( 1992. ). [PubMed] [Google Scholar]
  • 19. ) Nishioka , Y. , Sone , S. , Heike , Y. , Hamada , H. , Ariyoshi , K. , Tsuruo , T. and Ogura , T.Effector cell analysis of human multidrug‐resistant cell killing by mouse‐human chimeric antibody against P‐glycoprotein . Jpn. J. Cancer Res. , 83 , 644 – 649 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Masucci , G. , Wersall , P. , Ragnhammer , P. and Mellstedt , H.Granulocyte‐monocyte‐colony‐stimulating factor augments the cytotoxic capacity of lymphocytes and monocytes in antibody‐dependent cellular cytotoxicity . Cancer Immunol. Immunother. , 29 , 288 – 292 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Barker , E. , Mueller , B. M. , Handgretinger , R. , Herter , M. , Yu , A. L. and Reisfeld , R. A.Effect of a chimeric antiganglioside GD2 antibody on cell‐mediated lysis of human neuroblastoma cells . Cancer Res. , 41 , 144 – 149 ( 1991. ). [PubMed] [Google Scholar]
  • 22. ) Orlandi , R. , Figini , M. , Tomasetti , A. , Canevari , S. and Colnaghi , M. I.Characterization of a mouse‐human chimeric antibody to a cancer‐associated antigen . Int. J. Cancer , 52 , 588 – 593 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Yonei , T. , Ohnoshi , T. , Hiraki , S. , Ueoka , H. , Kiura , K. , Moritaka , T. , Shibayama , T. , Tabata , M. , Segawa , Y. and Takigawa , N.Antitumor activity of platinum analogs against human lung cancer cell lines and tumor specimens . Acta Med. Okayama , 47 , 233 – 241 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Mirski , S. E. , Gerlach , J. H. and Cole , S. P.Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin . Cancer Res. , 47 , 2594 – 2598 ( 1987. ). [PubMed] [Google Scholar]
  • 25. ) Teraoka , S. , Kyoizumi , S. , Seyama , T. , Yamakido , M. and Akiyama , M.SCID mice model for the in vivo study of human oncotherapy: studies on the growth and metastasis of human lung cancer . Int. J. Oncol. , 5 , 501 – 508 ( 1994. ). [PubMed] [Google Scholar]
  • 26. ) Ohe , Y. , Nakagawa , K. , Fujiwara , Y. , Sasaki , Y. , Minato , K. , Bungo , M. , Niimi , S. , Horichi , N. , Fukuda , M. and Saijo , N.In vitro evaluation of the new anticancer agents KT6149, MX‐2, SM5887, menogaril, and liblomycin using cisplatin‐ or adriamycin‐resistant human cancer cell lines . Cancer Res. , 49 , 4098 – 4102 ( 1989. ). [PubMed] [Google Scholar]
  • 27. ) Hamada , H. , Okochi , E. , Oh‐hara , T. and Tsuruo , T.Purification of the Mr 22,000 calcium‐binding protein (sorcin) associated with multidrug resistance and its detection with monoclonal antibodies . Cancer Res. , 48 , 3173 – 3178 ( 1988. ). [PubMed] [Google Scholar]
  • 28. ) Maeda , K. , Sone , S. , Ohmoto , Y. and Ogura , T.A novel differentiation antigen on human monocytes that is specifically induced by granulocyte‐macrophage colony‐stimulating factor or IL‐3 . J. Immunol. , 146 , 3779 – 3784 ( 1991. ). [PubMed] [Google Scholar]
  • 29. ) Sone , S. , Inamura , N. , Nii , A. and Ogura , T.Heterogeneity of human lymphokine (IL‐2)‐activated killer (LAK) precursors and regulation of their LAK induction by blood raonocytes . Int. J. Cancer , 42 , 428 – 434 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Yano , S. , Sone , S. , Nishioka , Y. , Naito , M. , Tsuruo , T. and Ogura , T.Cyclosporin A enhances susceptibility of multidrug resistant human cancer cells to anti‐P‐glycoprotein antibody‐dependent cytotoxicity of monocytes, but not of lymphocytes . Jpn. J. Cancer Res. , 85 , 194 – 203 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Haku , T. , Sone , S. , Nabioullin , R. and Ogura , T.Human alveolar macrophages augment natural killer cell stimulatory factor (interleukin‐12)‐inducible killer activity from autologous blood lymphocytes . Jpn. J. Cancer Res. , 86 , 81 – 87 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. ) Sone , S. , Orino , E. , Mizuno , K. , Yano , S. , Nishioka , Y. , Haku , T. , Nii , A. and Ogura , T.Production of IL‐1 and its receptor antagonist is regulated differently by IFN‐γ and IL‐4 in human monocytes and alveolar macrophages . Eur. Respir. J. , 7 , 657 – 663 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Miyake , M. , Ito , M. , Hitomi , S. , Ikeda , S. , Taki , T. , Kurata , M. , Hino , A. , Miyake , N. and Kannagi , R.Generation of two murine monoclonal antibodies that can discriminate N‐glycolyl and N‐acetyl neuraminic acid residues of GM2 gangliosides . Cancer Res. , 48 , 6154 – 6160 ( 1988. ). [PubMed] [Google Scholar]
  • 34. ) Tripathi , A. K. , Taplits , M. , Puri , J. and Hoffman , T.Down‐regulation of surface FcRI and decrease in antibody‐dependent cellular cytotoxicity of cultured monocytes. Reversal by monensin or cytochalasin‐D . J. Immunol. , 146 , 1309 – 1315 ( 1991. ). [PubMed] [Google Scholar]
  • 35. ) Young , D. A. , Lowe , L. D. and Clark , S. C.Comparison of the effects of IL‐3, granulocyte‐macrophage colony‐stimulating factor, and macrophage colony‐stimulating factor in supporting monocyte differentiation in culture. Analysis of macrophage antibody‐dependent cellular cytotoxicity . J. Immunol. , 145 , 607 – 615 ( 1990. ). [PubMed] [Google Scholar]
  • 36. ) Ellis , T. M. , McKenzie , R. S. , Simms , P. E. , Helfrich , B. A. and Fisher , R. I.Induction of human lymphokine‐activated killer cells by IFN‐α and IFN‐γ . J. Immunol. , 143 , 4282 – 4286 ( 1989. ). [PubMed] [Google Scholar]
  • 37. ) DeBlaker , H. D. F. , Yamauchi , A. , Yu , C. R. , Horvath , A. J. A. and Bloom , E. T.IL‐12 synergizes with IL‐2 to induce lymphokine‐activated cytotoxicity and perform and granzyme gene expression in fresh human NK cells . Cell Immunol. , 165 , 33 – 43 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Mueller , B. M. , Romerdahl , C. A. , Gillies , S. D. and Reisfeld , R. A.Enhancement of antibody‐dependent cytotoxicity with chimeric anti‐GD2 antibody . J. Immunol. , 144 , 1382 – 1386 ( 1990. ). [PubMed] [Google Scholar]
  • 39. ) Saleh , M. N. , Khazaeli , M. B. , Wheeler , R. H. , Allen , L. , Tilden , A. B. , Grizzle , W. , Reisfeld , R. A. , Yu , A. L. , Gillies , S. D. and LoBuglio , A. F.A phase I trial of the chimeric anti‐GD2 monoclonal antibody ch14.18 in patients with malignant melanoma . Hum. Antibodies Hybridomas , 3 , 19 – 24 ( 1992. ). [PubMed] [Google Scholar]

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