Abstract
Immunoconjugate targeting of solid tumors has not been routinely successful because the endothelial cells of blood vessels act as a physical barrier against the transport of macromolecules, such as antibodies. In the present study, we attempted to achieve tumor vascular targeting with an antitumor tissue endothelium‐specific monoclonal antibody (TES‐23). TES‐23, an IgG1 monoclonal antibody raised against rat KMT‐17 fibrosarcoma‐derived endothelial cells, was covalently conjugated with neocarzinostatin (NCS) in a previous study. The TES‐23‐NCS conjugate induced tumor hemorrhagic necrosis, and showed marked anti‐tumor effects against rat KMT‐17 fibrosarcoma. This result prompted us to investigate whether this approach would be applicable to various other types of solid tumors. One hour after injection of 125I‐labeled TES‐23 into BALB/c mice bearing Meth‐A fibrosarcoma and Colon 26 adenocarcinoma, the tumor accumulation of TES‐23 was greater than that of the control IgG. In the present study, we report the anti‐tumor effects of this monoclonal antibody in mice bearing Meth‐A fibrosarcoma. Mice treated with the immunoconjugate showed improved survival with no side effects. This result indicates that common antigens may be found in different kinds of tumor endothelial cells, and that TES‐23 might recognize these antigens.
Keywords: Tumor vascular endothelium, Immunoconjugate, Cancer targeting therapy, Immunoconjugates
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REFERENCES
- 1. ) Dvorak , H. F. , Nagy , J. A. and Dvorak , A. M.Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies . Cancer Cells , 3 , 77 – 85 ( 1991. ). [PubMed] [Google Scholar]
- 2. ) Zlotecki , R. A. , Baxter , L. T. , Boucher , Y. and Jain , R. K.Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation . Microvasc. Res. , 50 , 429 – 443 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Burrows , F. J. , Watanabe , Y. and Thorpe , P. E.A murine model for antibody‐directed targeting of vascular endothelial cells in solid tumors . Cancer Res. , 52 , 5954 – 5962 ( 1992. ). [PubMed] [Google Scholar]
- 4. ) Thorpe , P. E. , Wallace , P. M. , Knowles , P. P. , Relf , M. G. , Brown , A. N. , Watson , G. J. , Knyba , R. E. , Wawrzynczak , E. J. and Blakey , D. C.New coupling agents for the synthesis of immunotoxins containing a hindered disulfide bond with improved stability in vivo . Cancer Res. , 47 , 5924 – 5931 ( 1987. ). [PubMed] [Google Scholar]
- 5. ) Engert , A. , Martin , G. , Pfreundschuh , M. , Amlot , P. , Hsu , S. M. , Diehl , V. and Thorpe , P. E.Antitumor effects of ricin A chain immunotoxins prepared from intact antibodies and Fab' fragments on solid human Hodgkin's disease tumors in mice . Cancer Res. , 50 , 2929 – 2935 ( 1990. ). [PubMed] [Google Scholar]
- 6. ) Shockley , T. R. , Lin , K. , Nagy , J. A. , Tompkins , R. G. , Dvorak , H. F. and Yarmush , M. L.Penetration of tumor tissue by antibodies and other immunoproteins . Ann. NY Acad. Sci. , 618 , 367 – 382 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Folkman , J.The role of angiogenesis in tumor growth . Semin. Cancer Biol. , 3 , 65 – 71 ( 1992. ). [PubMed] [Google Scholar]
- 8. ) Denekamp , J.Vascular attack as a therapeutic strategy for cancer . Cancer Metastasis Rev. , 9 , 267 – 282 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Burrows , F. J. and Thorpe , P. E.Vascular targeting—a new approach to the therapy of solid tumors . Pharmacol. Ther. , 64 , 155 – 174 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Dvorak , H. F. , Nagy , J. A. , Dvorak , J. T. and Dvorak , A. M.Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules . Am. J. Pathol. , 133 , 95 – 109 ( 1988. ). [PMC free article] [PubMed] [Google Scholar]
- 11. ) Yuan , F. , Leunig , M. , Berk , D. A. and Jain , R. K.Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice . Microvasc. Res. , 45 , 269 – 289 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Wu , N. Z. , Klitzman , B. , Dodge , R. and Dewhirst , M. W.Diminished leukocyte‐endothelium interaction in tumor microvessels . Cancer Res. , 52 , 4265 – 4268 ( 1992. ). [PubMed] [Google Scholar]
- 13. ) Nawroth , P. P. , Bank , I. , Handley , D. , Cassimeris , J. , Chess , L. and Stern , D.Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1 . J. Exp. Med. , 163 , 1363 – 1375 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Utoguchi , N. , Dantakean , A. , Makimoto , H. , Wakai , Y. , Tsutsumi , Y. , Nakagawa , S. and Mayumi , T.Isolation and properties of tumor‐derived endothelial cells from rat KMT‐17 fibrosarcoma . Jpn. J. Cancer Res. , 86 , 193 – 201 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. ) Ohizumi , I. , Tsunoda , S. , Taniguchi , K. , Saito , H. , Esaki , K. , Koizumi , K. , Makimoto , H. , Wakai , Y. , Matsui , J. , Tsutsumi , Y. , Nakagawa , S. , Utoguchi , N. , Ohsugi , Y. and Mayumi , T.Monoclonal antibodies recognize antigens expressed on rat tumor vasculature . Int. J. Cancer , 77 , 561 – 566 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Makimoto , H. , Koizumi , K. , Tsunoda , S. , Wakai , Y. , Matsui , J. , Tsutsumi , Y. , Nakagawa , S. , Ohizumi , I. , Taniguchi , K. , Saito , H. , Utoguchi , N. , Ohsugi , Y. and Mayumi , T.Tumor vascular targeting using a tumor‐tissue endothelium‐specific monoclonal antibody as an effective strategy for cancer chemotherapy . Biochem. Biophys. Res. Commun. , 260 , 346 – 350 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Zara , J. J. , Wood , R. D. , Boon , P. , Kim , C. H. , Pomato , N. , Bredehorst , R. and Vogel , C. W.A carbohydrate‐directed heterobifunctional cross‐linking reagent for the synthesis of immunoconjugates . Anal. Biochem. , 194 , 156 – 162 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Richardson , A. P. , Mountford , P. J. , Baird , A. C. , Heyderman , E. , Richardson , T. C. and Coakley , A. J.An improved iodogen method of labelling antibodies with 123I . Nucl. Med. Commun. , 7 , 355 – 362 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Laborda , J. , Douillard , J. Y. , Lizzio , E. F. and Hoffman , T.Comparative pharmacokinetics of a murine monoclonal antibody to a rat colon tumor in rats and nude mice . Cancer Res. , 50 , 873 – 876 ( 1990. ). [PubMed] [Google Scholar]
- 20. ) Shibuya , M. , Yamaguchi , S. , Yamane , A. , Ikeda , T. , Tojo , A. , Matsushime , H. and Sato , M.Nucleotide sequence and expression of a novel human receptor‐type tyrosine kinase gene (flt) closely related to the fms family . Oncogene , 5 , 519 – 524 ( 1990. ). [PubMed] [Google Scholar]
- 21. ) Millauer , B. , Wizigmann , V. S. , Schnurch , H. , Martinez , R. , Moller , N. P. , Risau , W. and Ullrich , A.High affinity VEGF binding and developmental expression suggest Flk‐1 as a major regulator of vasculogenesis and angiogenesis . Cell , 72 , 835 – 846 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Friedlander , M. , Brooks , P. C. , Shaffer , R. W. , Kincaid , C. M. , Varner , J. A. and Cheresh , D. A.Definition of two angiogenic pathways by distinct alpha v integrins . Science , 270 , 1500 – 1502 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Maisonpierre , P. C. , Suri , C. , Jones , P. F. , Bartunkova , S. , Wiegand , S. J. , Radziejewski , C. , Compton , D. , McClain , J. , Aldrich , T. H. , Papadopoulos , N. , Daly , T. J. , Davis , S. , Sato , T. N. and Yancopoulos , G. D.Angiopoietin‐2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis . Science , 277 , 55 – 60 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Clarke , M. S. , Kiff , R. S. , Kumar , S. , Kumar , P. and West , D. C.The identification of proliferation‐related proteins in human endothelial cells as a possible target in tumor therapy . Int. J. Radiat. Biol. , 60 , 17 – 23 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Utoguchi , N. , Mizuguchi , H. , Saeki , K. , Ikeda , K. , Tsutsumi , Y. , Nakagawa , S. and Mayumi , T.Tumor‐conditioned medium increases macromolecular permeability of endothelial cell monolayer . Cancer Lett. , 89 , 7 – 14 ( 1995. ). [DOI] [PubMed] [Google Scholar]