Breast Cancer Research and Treatment

, Volume 36, Issue 2, pp 237–251

Antibody-directed targeting of the vasculature of solid tumors

  • Philip E. Thorpe
  • Francis J. Burrows
Article

Summary

An attractive strategy for the therapy of carcinomas and other solid tumors would be to target cytotoxic agents or host immune effectors to the endothelial cells of the tumor vasculature rather than to the tumor cells themselves. The key advantage of this approach is that the endothelial cells are freely accessible through the blood whereas the tumor cells are, for the most part, inaccessible. Also, endothelial cells are similar in different tumors, making it feasible to develop a single reagent for treating numerous types of cancer. In this chapter, we review progress in this “vascular targeting” approach, from the validation of the concept in a mouse model to the characterization of the TEC-11 antibody against endoglin, an endothelial cell proliferation marker that is upregulated on endothelial cells in miscellaneous human solid tumors. In addition, we review other tumor endothelial cell markers that are candidates for vascular targeting in man.

Key words

endothelial cells monoclonal antibodies solid tumors TEC-11 antibody therapy vascular targeting 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Shockley TR, Lin K, Nagy JA, Tompkins RG, Dvorak HF, Yarmush ML: Penetration of tumor tissue by antibodies and other immunoproteins. Ann NY Acad Sci 617:367–382, 1991.Google Scholar
  2. 2.
    Byers VS, Baldwin RW: Therapeutic strategies with monoclonal antibodies and immunoconjugates. Immunol 65:329–335, 1988.Google Scholar
  3. 3.
    Vaickus L, Foon KA: Overview of monoclonal antibodies in the diagnosis and therapy of cancer. Cancer Invest 9:195–209, 1991.Google Scholar
  4. 4.
    Lowder JN, Meeker TC, Campbell M, Garcia CF, Gralow J, Miller RA, Warnke R, Levy R: Studies on B lymphoid tumors treated with monoclonal anti-idiotype antibodies: Correlation with clinical responses. Blood 69:199–210, 1987.Google Scholar
  5. 5.
    Vitetta ES, Stone M, Amlot P, Fay J, May R, Till M, Newman J, Clark P, Collins R, Cunningham D, Ghetie V, Uhr JW, Thorpe PE: A Phase I immunotoxin trial in patients with B cell lymphoma. Cancer Res 15:4052–4058, 1991.Google Scholar
  6. 6.
    Burrows FJ, Watanabe Y, Thorpe PE: A murine model for antibody-directed targeting of vascular endothelial cells in solid tumors. Cancer Res 52:5954–5962, 1992.Google Scholar
  7. 7.
    Dvorak HF, Nagy JA, Dvorak AM: Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3:77–85, 1991.Google Scholar
  8. 8.
    Baxter LT, Jain RK: Transport of fluid and macromolecules in tumors. Micro Res 41:5–23, 1991.Google Scholar
  9. 9.
    Sands H: Radioimmunoconjugates: an overview of problems and promises. Antibody Immunoconjugates and Radiopharm 1:213–226, 1988.Google Scholar
  10. 10.
    Epenetos AA, Snook D, Durbin H, Johnson PM, Taylor-Papadimitriou J: Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res 46:3183–3191, 1986.Google Scholar
  11. 11.
    Jain RK: Transport of molecules in the tumor interstitium. Cancer Res 47:3039–3051, 1987.Google Scholar
  12. 12.
    Jain RK, Baxter LT: Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res 48:7022–7032, 1988.Google Scholar
  13. 13.
    Jain RK: Transport of molecules across tumor vasculature. Cancer Metastasis Rev 6:559–594, 1987.Google Scholar
  14. 14.
    Juweid M, Neumann R, Paik C, Perez-Bacete MJ, Sato J, van Osdol W, Weinstein JN: Micropharmacology of monoclonal antibodies in solid tumors; direct experimental evidence for a binding site barrier. Cancer Res 52:5144–5153, 1992.Google Scholar
  15. 15.
    Denekamp J: Vasculature as a target for tumour therapy. Prog Appl Microcirc 4:28–38, 1984.Google Scholar
  16. 16.
    Denekamp J: Endothelial cell attack as a novel approach to cancer therapy. Cancer Top 6:6–8, 1986.Google Scholar
  17. 17.
    Jaffe EA: Biology of Endothelial Cells. Martinus Nijhoff, Boston, 1984.Google Scholar
  18. 18.
    Burrows FJ, Thorpe PE: Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci USA 90:8996–9000, 1993.Google Scholar
  19. 19.
    Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW, Letarte M, Vitetta ES, Thorpe PE: Endoglin is an endothelial cell proliferation marker that is upregulated in tumor vasculature. Clin Cancer Res, submitted.Google Scholar
  20. 20.
    Gougos A, Letarte M: Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265:8361–8364, 1990.Google Scholar
  21. 21.
    Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M: Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 267:19027–19030, 1992.Google Scholar
  22. 22.
    Gougos A, Letarte M: Identification of a human endothelial cell antigen with monoclonal antibody 44G4 produced against a pre-B leukemic cell line. J Immunol 141:1925–1933, 1988.Google Scholar
  23. 23.
    Gougos A, St.Jacques S, Greaves A, O'Connell PJ, d'Apice AJF, Buhring HJ, Bernabeu C, Vanmourik JA, Letarte M: Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells and syncytiotrophoblasts. Int Immunol 4:83–92, 1992.Google Scholar
  24. 24.
    O'Connell PJ, McKenzie A, Fisicaro N, Rockman SP, Pearse MJ, d'Apice AJF: Endoglin: a 180-kD endothelial cell and macrophage restricted differentiation molecule. Clin Exp Immunol 90:154–159, 1992.Google Scholar
  25. 25.
    Buhring HJ, Muller CA, Letarte M, Gongos A, Saalmuller A, van Agthoven AJ, Busch FW: Endoglin is expressed on a subpopulation of immature erythroid cells or normal bone marrow. Leukemia 5:841–847, 1991.Google Scholar
  26. 26.
    Westphal JR, Willems HW, Schalkwijk CJ, Ruiter DJ, deWaal RM: A new 180-kDa dermal endothelial cell activation antigen:in vitro andin situ characteristics. J Invest Dermatol 100:27–34, 1993.Google Scholar
  27. 27.
    Darzynkiewicz Z, Traganos F, Sharpless T, Melamed MR: Lymphocyte stimulation: a rapid multiparameter analysis. Proc Natl Acad Sci USA 73:2881–2884, 1976.Google Scholar
  28. 28.
    Hobson B, Denekamp J: Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer 49:405–413, 1984.Google Scholar
  29. 29.
    Thorpe PE, Wallace PM, Knowles PP, Relf MG, Brown ANF, Watson GJ, Blakey DC, Newell DR: Improved anti-tumor effects of immunotoxins prepared with deglycosylated ricin A chain and hindered disulfide linkages. Cancer Res 48:6396–6403, 1988.Google Scholar
  30. 30.
    Engert A, Brown A, Thorpe P: Resistance of myeloid leukaemia cell lines to ricin A-chain immunotoxins. Leuk Res 15:1079–1086, 1991.Google Scholar
  31. 31.
    Press OW, Martin PJ, Thorpe PE, Vitetta ES: Ricin A-chain containing immunotoxins directed against different epitopes on the CD2 molecule differ in their ability to kill normal and malignant T cells. J Immunol 141:4410–4417, 1988.Google Scholar
  32. 32.
    Hagemeier HH, Vollmer E, Goerdt S, Schulze-Osthoff K, Sorg C: A monoclonal antibody reacting with endothelial cells of budding vessels in tumours and inflammatory tissues and non-reactive with normal adult tissues. Int J Cancer 38:481–488, 1986.Google Scholar
  33. 33.
    Rettig WJ, Garinchesa P, Healey JH, Su SL, Jaffe EA, Old LJ: Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci USA 89:10832–10836, 1992.Google Scholar
  34. 34.
    Wang JM, Kumar S, Pye D, van Agthoven AJ, Krupinski J, Hunter RD: A monoclonal antibody detected heterogeneity in vascular endothelium of tumours and normal tissues. Int J Cancer 54:363–370, 1993.Google Scholar
  35. 35.
    Carnemolla B, Balza E, Siri A, Zardi L, Nicotra MR, Bigotti A, Natali PG: A tumor-associated fibronectin isoform generated by alternative splicing of messenger RNA precursors. J Cell Biol 108:1139–1148, 1989.Google Scholar
  36. 36.
    Bruland OS, Fodstad O, Stenwig AE, Pihl A: Expression and characteristics of a novel human osteosarcoma-associated cell surface antigen. Cancer Res 48:5302–5309, 1988.Google Scholar
  37. 37.
    Senger DR, Vandewater L, Brown LF, Nagy JA, Yeo K-T, Yeo T-K, Berse B, Jackman RW, Dvorak AM, Dvorak HF: Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer & Metastasis Reviews 12:303–324, 1993.Google Scholar
  38. 38.
    Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Vandewater L, Senger DR: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors — concentration in tumor blood vessels. J Exp Med 174:1275–1278, 1991.Google Scholar
  39. 39.
    Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845, 1992.Google Scholar
  40. 40.
    Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848, 1992.Google Scholar
  41. 41.
    Schlingemann RO, Rietveld FJ, de Waal RM, Bradley NJ, Skene AI, Davies AJ, Greaves MF, Denekamp J, Ruiter DJ: Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma. Lab Invest 62:690–696, 1990.Google Scholar
  42. 42.
    Fina L, Molgaard HV, Robertson D, Bradley NJ, Monaghan P, Delia D, Sutherland DR, Baker MA, Greaves MF: Expression of the CD34 gene in vascular endothelial cells. Blood 75:2417–2426, 1990.Google Scholar
  43. 43.
    Schlingemann RO, Dingjan GM, Emeis JJ, Block J, Warnaar SO, Ruiter DJ: Monoclonal antibody PAL-E specific for endothelium. Lab Invest 52:71–76, 1985.Google Scholar
  44. 44.
    Plate KH, Breier G, Farrell CL, Risau W: Plateletderived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest 67:529–534, 1992.Google Scholar
  45. 45.
    Franklin WA, Christison WH, Colley M, Montag AG, Stephens JK, Hart CE:In situ distribution of the alpha-subunit of platelet-derived growth factor receptor in nonneoplastic tissue and in soft tissue tumors. Cancer Res 50:6344–6348, 1990.Google Scholar
  46. 46.
    Jakeman LB, Winer J, Bennett GL, Altar A, Ferrara N: Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89:244–253, 1992.Google Scholar
  47. 47.
    Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G: Tumor angiogenesis — a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875–1887, 1992.Google Scholar
  48. 48.
    Horak ER, Leek R, Klenk N, Lejeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL: Angiogenesis, assessed by platelet endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120–1124, 1992.Google Scholar
  49. 49.
    Chodak GW, Haudenschild C, Gittes RF, Folkman J: Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder. Ann Surg 192:762–771, 1980.Google Scholar
  50. 50.
    Sillman F, Boyce J, Fruchter R: The significance of atypical vessels and neovascularization in cervical neoplasia. Am J Obstet Gynecol 139:154–159, 1981.Google Scholar
  51. 51.
    Burrows FJ, Thorpe PE: Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci USA 90:8996–9000, 1994.Google Scholar
  52. 52.
    Burrows FJ, Thorpe PE: Targeting the vasculature of solid tumors. J Controlled Release 28:195–202, 1994.Google Scholar
  53. 53.
    Thorpe PE, Ross WC: The preparation and cytotoxic properties of antibody-toxin conjugates. Immunol Rev 62:119–158, 1982.Google Scholar
  54. 54.
    Mulligan RC: The basic science of gene therapy. Science 260:926–932, 1993.Google Scholar
  55. 55.
    Nabel EG, Plantz G, Nabel GJ: Site-specific gene expressionin vivo by direct gene transfer into the arterial wall. Science 249:1285–1288, 1990.Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Philip E. Thorpe
    • 1
  • Francis J. Burrows
    • 1
  1. 1.Harold C. Simmons Comprehensive Cancer CenterUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations