Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1992 Jul;83(7):769–774. doi: 10.1111/j.1349-7006.1992.tb01978.x

Efficacy and Specificity of a Monoclonal Antibody‐Drug Conjugate in Chemotherapy by Intratumoral Injection

Kazuya Kitamura 1,✉, Toshio Takahashi 1, Takuya Miyagaki 1, Nobuki Yamaoka 1, Hiroshi Tsurumi 1, Eigo Ohtsuji 1, Michiko Kamiguchi 1, Akinori Noguchi 1, Toshiharu Yamaguchi 1
PMCID: PMC5918930  PMID: 1387634

Abstract

The murine monoclonal antibody (Mab) A7 conjugated to neocarzinostatin (A7‐NCS) was injected intratumorally (IT) into tumor bearing nude mice. Its pharmacokinetics and tumoricidal effects were compared in the high, moderate and low antigen expressing xenograft for SW1116, WiDr and KB tumor‐bearing nude mice, respectively. When injected IT into nude mice, [125I]A7‐NCS was retained in the tumors according to the degree of antigen expression; it was also disseminated into the blood inverse proportion to the antigen expression. Addition of an excess amount of Mab A7 reduced [125I]‐A7‐NCS accumulation in SW1116 xenograft and elevated the [125I]A7‐NCS concentration in the circulation. Complete tumor reduction was found in all 5 mice with SW1116 tumor, and 2 of 5 mice with WiDr tumor. However, only incomplete tumor suppression was observed in mice with the KB tumor. The significant tumor reduction in SW1116 bearing nude mice was attenuated when excess of Mab A7 was simultaneously administered with A7‐NCS‐ These findings indicate that A7‐NCS was localized in the target tumors and exerted its tumoricidal effects depending on the degree of antigen‐antibody interaction when administered IT. Thus, A7‐NCS can be used successfully in vivo for local therapy, auguring new and promising applications for local cancer therapy.

Keywords: Key words, Intratumoral injection, A7‐NCS, Cancer chemotherapy

Full Text

The Full Text of this article is available as a PDF (362.7 KB).

REFERENCES

  • 1. ) Miller , R. A. and Levy , R.Response of cutaneous T cell lymphoma to therapy with hybridoma monoclonal antibody . Lancet , 2 , 226 – 230 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Herlyn , D. and Koprowski , H.IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells . Proc. Natl Acad. Sci. USA , 79 , 4761 – 4765 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Hurwitz , E.Specific and nonspecific macromolecule‐drug conjugates for the improvement of cancer chemotherapy . Biopolymer , 22 , 557 – 567 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Shawler , D. L. , Bartholomew , R. M. , Smith , L. M. , and Dillman , R. O.Human immune response to multiple injection of murine monoclonal IgG . J. Immunol. , 135 , 1530 – 1535 ( 1985. ). [PubMed] [Google Scholar]
  • 5. ) Takahashi , T. , Yamaguchi , T. , Takahashi , T. , Noguchi , A. , Honda , M. and Ohtsuji , E.Missile therapy for colorectal and pancreatic cancer — clinical trial of monoclonal antibody, A7‐NCS, for 73 patients with colorectal and pancreatic cancers , Jpn. J. Cancer Chemother. , 17 , 1111 – 1119 ( 1990. ) ( in Japanese ). [PubMed] [Google Scholar]
  • 6. ) Rowland , G. F. , Simmonds , R. G. , Gore , V. A. , Marsden , C. H. and Smith , W.Drug localization and growth inhibition studies of vindesine‐monoclonal anti‐CEA conjugates in a human tumour xenograft . Cancer Immunol. Immunother. , 21 , 183 – 187 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Pimm , M. V. , Clegg , J. A. , Caten , J. E. , Ballantype , K. D. , Perkins , A. C. , Garnett , M. C. and Baldwin , R. W.Bio‐distribution of methotrexate‐monoclonal antibody conjugates and complexes: experimental and clinical studies . Cancer Treatment Rev. , 14 , 411 – 420 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Pimm , M. V. , Paul , M. A. , Ogumujuma , P. Y. and Baldwin , R. W.Biodistribution and tumour localization of a daunomycin‐monoclonal antibody conjugate in nude mice with human tumour xenografts . Cancer Immunol. Immunother. , 27 , 267 – 271 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Pimm , M. V. , Clegg , J. A. , Garnet , M. C. and Baldwin , R. W.Biodistribution and tumour localization of a methotrexate‐monoclonal‐antibody 791T/36 conjugate in nude mice with human tumour xenografts . Int. J. Cancer , 41 , 886 – 891 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Kitamura , K. , Takahashi , T. , Yamaguchi , T. , Kitai , S. , Amagai , T. and Imanishi , J.Monoclonal antibody A7 tumor localization enhancement by its F(ab')2 fragments to colon carcinoma xenografts in nude mice . Jpn. J. Clin. Oncol , 20 , 139 – 144 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Kitamura , K. , Takahashi , T. , Yamaguchi , T. , Yokota , T. , Noguchi , A. , Amagai , T. and Imanishi , J.Immunochemical characterization of the antigen recognized by the murine monoclonal antibody A7 against human colorectal cancer . Tohoku J. Exp. Med. , 157 , 83 – 92 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Kotanagi , H. , Takahashi , T. , Masuko , T. , Hashimoto , Y. and Koyama , K.A monoclonal antibody against human colon cancers . Tohoku J. Exp. Med. , 148 , 353 – 360 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Ohtsuji , E. , Takahashi , T. , Yamaguchi , T. , Yamaguchi , N. and Imanishi , J.Specific cytotoxic effect of neocarzino‐statin conjugated to monoclonal antibody A7 on human pancreatic carcinoma . Gastroenterol Jpn. , 25 , 244 – 248 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Fukuda , K.Study of targeting chemotherapy against gastrointestinal cancer: preparation of anticancer drug‐monoclonal antibody conjugate and investigation about its biological activities . Akita J. Med. , 12 , 455 – 468 ( 1985. ). [Google Scholar]
  • 15. ) Takahashi , T. , Yamaguchi , T. , Kitamura , K. , Suzuyama , H. , Honda , M. , Yokota , T. , Kotanagi , H. , Takahashi , M. and Hashimoto , Y.Clinical application of monoclonal antibody‐drug conjugates for immunotargeting chemotherapy of colorectal carcinoma . Cancer , 61 , 881 – 888 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Kitamura , K. , Takahashi , T. , Tsurumi , H. , Takashina , T. , Noguchi , A. , Noguchi , A. , Okuzumi , J. and Yamaguchi , T.Pharmacokinetics of the monoclonal antibody A7‐neocarzinostatin conjugate administered to nude mice . Tohoku J. Exp. Med. , 164 , 203 – 211 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Greenwood , F. C. , Hunter , W. M. and Glover , J. S.The preparation of 131I‐labeled human growth hormone of high specific reactivity . Biochem. J. , 89 , 114 – 123 ( 1963. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Yamaoka , K. and Nakayama , T.A nonlinear least‐squares program based on differential equations, MULTI (RUNGE) for microcomputers . J. Pharmacobio-Dyn. , 6 , 595 – 606 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Covell , D. G. , Barbet , J. , Holton , O. D. , Black , C. D. V. , Parker , R. J. and Weinstein , J. N.Pharmacokinetics of monoclonal immunoglobulin G1, F(ab')2 and Fab' in mice . Cancer Res. , 46 , 3969 – 3978 ( 1986. ). [PubMed] [Google Scholar]
  • 20. ) Hillman , G. W. , Runge , W. , Jansen , F. K. and Vallera , D.A. Cytotoxic effect of anti‐Mr 67000 protein immuno‐toxin on human tumors in a nude mouse model . Cancer Res. , 45 , 1328 – 1336 ( 1985. ). [PubMed] [Google Scholar]
  • 21. ) Kanellos , J. , Mckenzie , I. F. C. and Pietersz , G. A.In‐tratumor therapy of solid tumours with ricin‐antibody conjugates . Immunol. Cell Biol , 67 , 89 – 99 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Spitler , L. E. , De Rio , M. , Khentigan , A. , Wedel , N. L. , Brophy , N. A. , Miller , L. L. , Harkonen , W. S. , Rosendorf , L. L. , Lee , H. M. , Mischak , R. P. , Kawahata , R. T. , Stoudemire , J. B. , Fradkin , L. B. , Bautista , E. E. and Scannon , P. J.Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody‐ricin A chain immunotoxin . Cancer Res. , 47 , 1717 – 1723 ( 1987. ). [PubMed] [Google Scholar]
  • 23. ) Weiman , L. M. , Odwyer , J. , Kitson , J. , Cowis , R. L. , Frankel , A. E. , Bauer , R. J. , Konrad , M. S. and Groves , E. S.Phase I evaluation of an anti‐breast carcinoma monoclonal antibody 260F9‐recombinant ricin A chain immunoconjugate . Cancer Res. , 49 , 4062 – 4067 ( 1989. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES