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Monoclonal antibody therapy of cancer

Abstract

The most significant recent advances in the application of monoclonal antibodies (mAbs) to oncology have been the introduction and approval of bevacizumab (Avastin), an anti–vascular endothelial growth factor antibody, and of cetuximab (Erbitux), an anti–epidermal growth factor antibody. In combination with standard chemotherapy regimens, bevacizumab significantly prolongs the survival of patients with metastatic cancers of the colorectum, breast and lung. Cetuximab, used alone or with salvage chemotherapy, produces clinically meaningful anti-tumor responses in patients with chemotherapy-refractory cancers of the colon and rectum. In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer. These exciting recent results provide optimism for the development of mAbs that bind novel targets, exploit novel mechanisms of action or possess improved tumor targeting. Progress in the clinical use of radioimmunoconjugates remains hindered by complexity of administration, toxicity concerns and insufficiently selective tumor targeting.

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Figure 1: ADCC-mediated adaptive immunity switch.

Katie Ris

Figure 2: Complement-directed cytotoxicity.

Katie Ris

Figure 3: Examples of antibody-mediated signaling inhibition.

Katie Ris

Figure 4: Antibody-directed enzyme prodrug therapy (ADEPT).

Katie Ris

Figure 5: Potential targets for antibody therapy of cancer.

Katie Ris

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References

  1. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  CAS  PubMed  Google Scholar 

  2. Badger, C., Anasetti, C., Davis, J. & Berstein, I. Treatment of malignancy with unmodified antibody. Pathol. Immunopathol. Res. 6, 419–434 (1987).

    CAS  PubMed  Google Scholar 

  3. Khazaeli, M.B., Conry, R.M. & LoBuglio, A.F. Human immune response to monoclonal antibodies. J. Immunother. 15, 42–52 (1994).

    CAS  Google Scholar 

  4. Lee, J., Fenton, B.M., Koch, C.J., Frelinger, J.G. & Lord, E.M. Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment. Cancer Res. 58, 1478–1485 (1998).

    CAS  PubMed  Google Scholar 

  5. Miller, R.A., Maloney, D.G., Warnke, R. & Levy, R. Teatment of B-cell lymphoma with monoclonal anti-idiotype antibody. Medical Intelligence 306, 517–522 (1982).

    CAS  Google Scholar 

  6. McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16, 2825–2833 (1998).

    CAS  PubMed  Google Scholar 

  7. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    CAS  PubMed  Google Scholar 

  8. Leonard, J.P. & Link, B.K. Immunotherapy of non-Hodgkin's lymphoma with hLL2 (epratuzumab, an anti-CD22 monoclonal antibody) and Hu1D10 (apolizumab). Semin. Oncol. 29, 81–86 (2002).

    CAS  PubMed  Google Scholar 

  9. Witzig, T.E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 20, 2453–2463 (2002).

    CAS  PubMed  Google Scholar 

  10. Kaminski, M.S. et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 96, 1259–1266 (2000).

    CAS  PubMed  Google Scholar 

  11. Lundin, J. et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100, 768–773 (2002).

    CAS  PubMed  Google Scholar 

  12. Sievers, E.L. et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93, 3678–3684 (1999).

    CAS  PubMed  Google Scholar 

  13. Kreitman, R.J. et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N. Engl. J. Med. 345, 241–247 (2001).

    CAS  PubMed  Google Scholar 

  14. Cobleigh, M.A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).

    CAS  PubMed  Google Scholar 

  15. Vogel, C.L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719–726 (2002).

    CAS  PubMed  Google Scholar 

  16. Slamon, D.J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  PubMed  Google Scholar 

  17. Robert, F. et al. Phase I study of anti–epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J. Clin. Oncol. 19, 3234–3243 (2001).

    CAS  PubMed  Google Scholar 

  18. Foon, K.A. et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int. J. Radiat. Oncol. Biol. Phys. 58, 984–990 (2004).

    CAS  PubMed  Google Scholar 

  19. Egen, J.G., Kuhns, M.S. & Allison, J.P. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat. Immunol. 3, 611–618 (2002).

    CAS  PubMed  Google Scholar 

  20. Sanderson, K. et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J. Clin. Oncol. 23, 741–750 (2005).

    CAS  PubMed  Google Scholar 

  21. Steplewski, Z., Lubeck, M.D. & Koprowski, H. Human macrophages armed with murine immunoglobulin G2a antibodies to tumors destroy human cancer cells. Science 221, 865–867 (1983).

    CAS  PubMed  Google Scholar 

  22. Heijnen, I.A. & van de Winkel, J.G. Human IgG Fc receptors. Int. Rev. Immunol. 16, 29–55 (1997).

    CAS  PubMed  Google Scholar 

  23. Sulica, A., Morel, P., Metes, D. & Herberman, R.B. Ig-binding receptors on human NK cells as effector and regulatory surface molecules. Int. Rev. Immunol. 20, 371–414 (2001).

    CAS  PubMed  Google Scholar 

  24. Clynes, R.A., Towers, T.L., Presta, L.G. & Ravetch, J.V. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Shields, R.L. et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J. Biol. Chem. 276, 6591–6604 (2001).

    CAS  PubMed  Google Scholar 

  26. Ghetie, V. & Ward, E.S. Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu. Rev. Immunol. 18, 739–766 (2000).

    CAS  PubMed  Google Scholar 

  27. Umana, P., Jean-Mairet, J., Moudry, R., Amstutz, H. & Bailey, J.E. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17, 176–180 (1999).

    CAS  PubMed  Google Scholar 

  28. Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99, 754–758 (2002).

    CAS  PubMed  Google Scholar 

  29. Weng, W.K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).

    CAS  PubMed  Google Scholar 

  30. Janeway, C. & Travers, P. Immunobiology, vol. 3 (Current Biology, London, 1997).

    Google Scholar 

  31. Di Gaetano, N. et al. Complement activation determines the therapeutic activity of rituximab in vivo. J. Immunol. 171, 1581–1587 (2003).

    CAS  PubMed  Google Scholar 

  32. Golay, J. et al. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 98, 3383–3389 (2001).

    CAS  PubMed  Google Scholar 

  33. Gelderman, K.A., Tomlinson, S., Ross, G.D. & Gorter, A. Complement function in mAb-mediated cancer immunotherapy. Trends Immunol. 25, 158–164 (2004).

    CAS  PubMed  Google Scholar 

  34. Sunada, H., Magun, B.E., Mendelsohn, J. & MacLeod, C.L. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc. Natl. Acad. Sci. USA 83, 3825–3829 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, S. et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7, 301–311 (2005).

    CAS  PubMed  Google Scholar 

  36. Franklin, M.C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004).

    CAS  PubMed  Google Scholar 

  37. Arteaga, C.L. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin. Oncol. 29, 3–9 (2002).

    CAS  PubMed  Google Scholar 

  38. Austin, C.D. et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell 15, 5268–5282 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. May, K.F.J., Chen, L., Zheng, P. & Liu, Y. Anti-4–1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells. Cancer Res. 62, 3459–3465 (2002).

    CAS  PubMed  Google Scholar 

  40. Hirano, F.K.K. et al. Blockade of B7–H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65, 1089–1096 (2005).

    CAS  PubMed  Google Scholar 

  41. Wu, A.M. & Senter, P.D. Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotechnol. 23, 1137–1146 (2005).

    CAS  PubMed  Google Scholar 

  42. Gordon, L.I. et al. Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma. Clin. Lymphoma 5, 98–101 (2004).

    CAS  PubMed  Google Scholar 

  43. Kaminski, M.S. et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N. Engl. J. Med. 352, 441–449 (2005).

    CAS  PubMed  Google Scholar 

  44. Behr, T.M. et al. Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer 94, 1373–1381 (2002).

    CAS  PubMed  Google Scholar 

  45. Scott, A.M. et al. A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake. Clin. Cancer Res. 11, 4810–4817 (2005).

    CAS  PubMed  Google Scholar 

  46. Chong, G. et al. Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma. Clin. Cancer Res. 11, 4818–4826 (2005).

    CAS  PubMed  Google Scholar 

  47. Francis, R.J. et al. A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours. Br. J. Cancer 87, 600–607 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Mayer, A. et al. Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT). Br. J. Cancer 90, 2402–2410 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Cobleigh, M. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).

    CAS  PubMed  Google Scholar 

  50. Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737–744 (1996).

    CAS  PubMed  Google Scholar 

  51. Slamon, D. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  PubMed  Google Scholar 

  52. Norton, L., Slamon, D. & Leyland-Jones, B. in Proceedings of the American Society of Clinical Oncology vol. 18, 127a (ASCO Publications, Alexandria, Virginia, USA, 1999).

    Google Scholar 

  53. Baselga, J. Clinical trials of HerceptinR (trastuzumab). Eur. J. Cancer 37, S18–S24 (2001).

    CAS  PubMed  Google Scholar 

  54. Pegram, M.D. et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2 positive advanced breast cancer. J. Natl. Cancer Inst. 96, A759–A769 (2004).

    Google Scholar 

  55. Pegram, M. et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185her2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659–2671 (1998).

    CAS  PubMed  Google Scholar 

  56. Miller, K.D. et al. Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. Oncology (suppl. 3) 15, S38–S40 (2001).

    Google Scholar 

  57. Modjtahedi, H., Komurasaki, T., Toyoda, H. & Dean, C. Anti-EGFR monoclonal antibodies which act as EGF, TGF alpha, HB-EGF and BTC antagonists block the binding of epiregulin to EGFR-expressing tumours. Int. J. Cancer 75, 310–316 (1998).

    CAS  PubMed  Google Scholar 

  58. Teramoto, T., Onda, M., Tokunaga, A. & Asano, G. Inhibitory effect of anti-epidermal growth factor receptor antibody on a human gastric cancer. Cancer 77, 1639–1645 (1996).

    CAS  PubMed  Google Scholar 

  59. Arteaga, C.L., Coronado, E. & Osborne, C.K. Blockade of the epidermal growth factor receptor inhibits transforming growth factor alpha-induced but not estrogen-induced growth of hormone-dependent human breast cancer. Mol. Endocrinol. 2, 1064–1069 (1988).

    CAS  PubMed  Google Scholar 

  60. Hoffmann, T., Hafner, D., Ballo, H., Haas, I. & Bier, H. Antitumor activity of anti-epidermal growth factor receptor monoclonal antibodies and cisplatin in ten human head and neck squamous cell carcinoma lines. Anticancer Res. 17, 4419–4425 (1997).

    CAS  PubMed  Google Scholar 

  61. Fan, Z., Baselga, J., Masui, H. & Mendelsohn, J. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res. 53, 4637–4642 (1993).

    CAS  PubMed  Google Scholar 

  62. Baselga, J. et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J. Natl. Cancer Inst. 85, 1327–1333 (1993).

    CAS  PubMed  Google Scholar 

  63. Sunada, H., Yu, P., Peacock, J.S. & Mendelsohn, J. Modulation of tyrosine, serine, and threonine phosphorylation and intracellular processing of the epidermal growth factor receptor by antireceptor monoclonal antibody. J. Cell. Physiol. 142, 284–292 (1990).

    CAS  PubMed  Google Scholar 

  64. Fan, Z., Masui, H., Altas, I. & Mendelsohn, J. Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 53, 4322–4328 (1993).

    CAS  PubMed  Google Scholar 

  65. Baselga, J. et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J. Clin. Oncol. 18, 904–914 (2000).

    CAS  PubMed  Google Scholar 

  66. Saltz, L.B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004).

    CAS  PubMed  Google Scholar 

  67. Starling, N. & Cunningham, D. Monoclonal antibodies against vascular endothelial growth factor and epidermal growth factor receptor in advanced colorectal cancers: present and future directions. Curr. Opin. Oncol. 16, 385–390 (2004).

    CAS  PubMed  Google Scholar 

  68. Herbst, R. & Langer, C. Epidermal Growth Factor Receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin. Oncol. 29, 27–36 (2002).

    CAS  PubMed  Google Scholar 

  69. Mendez, M. et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Genet. 15, 146–156 (1997).

    CAS  PubMed  Google Scholar 

  70. Yang, X. et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243 (1999).

    CAS  PubMed  Google Scholar 

  71. Vanhoefer, U. et al. Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J. Clin. Oncol. 22, 175–184 (2004).

    CAS  PubMed  Google Scholar 

  72. Johns, T.G. et al. Identification of the epitope for the epidermal growth factor receptor-specific monoclonal antibody 806 reveals that it preferentially recognizes an untethered form of the receptor. J. Biol. Chem. 279, 30375–30384 (2004).

    CAS  PubMed  Google Scholar 

  73. Shankar, S. et al. Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent. Nucl. Med. Biol. 31, 909–919 (2004).

    CAS  PubMed  Google Scholar 

  74. Haga, Y., Sivinski, C., Woo, D. & Tempero, M. Dose related comparison of antibody-dependent cellular cytotoxicity with chimeric and native monoclonal antibody 17–1A. Improved cytolysis of pancreatic cancer cells with chimeric 17–1A. Int. J. Pancreatol. 15, 43–50 (1994).

    CAS  PubMed  Google Scholar 

  75. Meredith, R. & et al. Pharmacokinietics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/human IgG1 17–1A monoclonal antibody. J. Nucl. Med. 32, 1162–1168 (1991).

    CAS  PubMed  Google Scholar 

  76. Hartung, G. et al. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie 28, 347–350 (2005).

    CAS  PubMed  Google Scholar 

  77. Gold, P. & Freedman, S.O. Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J. Exp. Med. 12 1, 439–462 (1965).

    Google Scholar 

  78. Wong, J.Y.C. et al. A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies. Clin. Cancer Res. 6, 3855–3863 (2000).

    CAS  PubMed  Google Scholar 

  79. Juweid, M.E. et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J. Nucl. Med. 41, 93–103 (2000).

    CAS  PubMed  Google Scholar 

  80. Mayer, A. et al. Radioimmunoguided surgery in colorectal cancer using a genetically engineered anti-CEA single-chain Fv antibody. Clin. Cancer Res. 6, 1711–1719 (2000).

    CAS  PubMed  Google Scholar 

  81. Pukac, L. et al. HGS ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br. J. Cancer 92, 1430–1441 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Loo, D. et al. The monoclonal antibody RAV12 induces oncotic cell death in vitro and exhibits potent anti-tumor activity in human tumor xenografts. Proc. Am. Assoc. Cancer Res. 46, 558 (2005).

    Google Scholar 

  83. Nadler, L. et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 40, 3147–3154 (1980).

    CAS  PubMed  Google Scholar 

  84. Miller, R., Maloney, D., Warnke, R. & Levy, R. Treatment of B-cell lymphoma with monocolonal anti-idiotype antibody. N. Engl. J. Med. 306, 517–522 (1982).

    CAS  PubMed  Google Scholar 

  85. Vuist, W., Levy, R. & Maloney, D. Lymphoma regression induced by monoclonal anti-idiotypic antibodies correlates with their ability to induce Ig signal transduction and is not prevented by tumor expression of high levels of bcl-2 protein. Blood 83, 899–906 (1994).

    CAS  PubMed  Google Scholar 

  86. Swisher, E. et al. Expression of shared idiotypes in chronic lymphocytic leukemia and small lymphocytic lymphoma. Blood 77, 1977–1982 (1991).

    CAS  PubMed  Google Scholar 

  87. Bowen, A. et al. Subcutaneous CAMPATH-1H in fludarabine-resistant/relapsed chronic lymphocytic and B-prolymphocytic leukaemia. Br. J. Haematol. 96, 617–619 (1997).

    CAS  PubMed  Google Scholar 

  88. Lundin, J. et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma. J. Clin. Oncol. 16, 3257–3263 (1998).

    CAS  PubMed  Google Scholar 

  89. Hale, G. et al. Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood 92, 4581–4590 (1998).

    CAS  PubMed  Google Scholar 

  90. Naparstek, E. et al. Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies. Exp. Hematol. 27, 1210–1218 (1999).

    CAS  PubMed  Google Scholar 

  91. Maloney, D. et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J. Clin. Oncol. 15, 3266–3274 (1997).

    CAS  PubMed  Google Scholar 

  92. Maloney, D. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997).

    CAS  PubMed  Google Scholar 

  93. Shan, D., Ledbetter, J. & Press, O. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol. Immunother. 48, 673–683 (2000).

    CAS  PubMed  Google Scholar 

  94. McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16, 2825–2833 (1998).

    CAS  PubMed  Google Scholar 

  95. Bernstein, N. et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann. Oncol. 9, 995–1001 (1988).

    Google Scholar 

  96. Piro, L.D. et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann. Oncol. 10, 655–661 (1999).

    CAS  PubMed  Google Scholar 

  97. Coiffier, B. et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92, 1927–1932 (1998).

    CAS  PubMed  Google Scholar 

  98. Czuczman, M.S. et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J. Clin. Oncol. 17, 268–276 (1999).

    CAS  PubMed  Google Scholar 

  99. Coiffier, B. Rituximab in the treatment of diffuse large B-cell lymphomas. Semin. Oncol. 29, 30–35 (2002).

    CAS  PubMed  Google Scholar 

  100. Davis, T.A., Czerwinski, D.K. & Levy, R. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin. Cancer Res. 5, 611–615 (1999).

    CAS  PubMed  Google Scholar 

  101. Byrd, J. et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J. Clin. Oncol. 17, 791–795 (1999).

    CAS  PubMed  Google Scholar 

  102. Tai, Y.T. et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res. 64, 2846–2852 (2004).

    CAS  PubMed  Google Scholar 

  103. Uckun, F.M. et al. Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells. Blood 76, 2449–2456 (1990).

    CAS  PubMed  Google Scholar 

  104. Murphy, W.J. et al. Antibodies to CD40 prevent Epstein- Barr virus-mediated human B-cell lymphomagenesis in severe combined immune deficient mice given human peripheral blood lymphocytes. Blood 86, 1946–1953 (1995).

    CAS  PubMed  Google Scholar 

  105. Francisco, J.A. et al. In vivo efficacy and toxicity of a single-chain immunotoxin targeted to CD40. Blood 89, 4493–4500 (1997).

    CAS  PubMed  Google Scholar 

  106. Funakoshi, S., Longo, D.L. & Murphy, W.J. Differential in vitro and in vivo antitumor effects mediated by anti-CD40 and anti-CD20 monoclonal antibodies against human B-cell lymphomas. J. Immunother. Emphasis Tumor Immunol. 19, 93–101 (1996).

    CAS  PubMed  Google Scholar 

  107. van Mierlo, G.J. et al. CD40 stimulation leads to effective therapy of CD40(+) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc. Natl. Acad. Sci. USA 99, 5561–5566 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Czuczman, M.S. et al. Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma. J. Clin. Oncol. 23, 4390–4398 (2005).

    CAS  PubMed  Google Scholar 

  109. Leonard, J.P. et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin's lymphoma: phase I/II clinical trial results. Clin. Cancer Res. 10, 5327–5334 (2004).

    CAS  PubMed  Google Scholar 

  110. Leonard, J.P. et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma. J. Clin. Oncol. 21, 3051–3059 (2003).

    CAS  PubMed  Google Scholar 

  111. Cheng, J.D. et al. Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol. Cancer Ther. 4, 351–360 (2005).

    CAS  PubMed  Google Scholar 

  112. Scott, A.M. et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).

    CAS  Google Scholar 

  113. Garin-Chesa, P., Old, L.J. & Rettig, W.J. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc. Natl. Acad. Sci. USA 87, 7235–7239 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Reardon, D.A. et al. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J. Clin. Oncol. 20, 1389–1397 (2002).

    CAS  PubMed  Google Scholar 

  115. Rizzieri, D.A. et al. Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma. Blood 104, 642–648 (2004).

    CAS  PubMed  Google Scholar 

  116. Oh, P. et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 429, 629–635 (2004).

    CAS  PubMed  Google Scholar 

  117. Santimaria, M. et al. Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. Clin. Cancer Res. 9, 571–579 (2003).

    CAS  PubMed  Google Scholar 

  118. Chang, S.S. et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 59, 3192–3198 (1999).

    CAS  PubMed  Google Scholar 

  119. Gordon, M. et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J. Clin. Oncol. 19, 843–850 (2001).

    CAS  PubMed  Google Scholar 

  120. Kabbinavar, F.F. et al. Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial. J. Clin. Oncol. 23, 3697–3705 (2005).

    CAS  PubMed  Google Scholar 

  121. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    CAS  PubMed  Google Scholar 

  122. Willett, C.G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10, 145–147 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Miller, K.D. et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).

    CAS  PubMed  Google Scholar 

  124. Zhu, Z. et al. Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. Leukemia 17, 604–611 (2003).

    CAS  PubMed  Google Scholar 

  125. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  PubMed  Google Scholar 

  126. Lin, M.I. & Sessa, W.C. Antiangiogenic therapy: creating a unique “window” of opportunity. Cancer Cell 6, 529–531 (2004).

    CAS  PubMed  Google Scholar 

  127. Gutheil, J.C. et al. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin. Cancer Res. 6, 3056–3061 (2000).

    CAS  PubMed  Google Scholar 

  128. Byrd, J.C. et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J. Clin. Oncol. 17, 791–795 (1999).

    CAS  PubMed  Google Scholar 

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Correspondence to Louis M Weiner.

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G.P.A. is a consultant, scientific advisory board member and shareholder of EvoGenix and has received support for a research program from General Electric Global Research. L.M.W. is a consultant to Abgenix.

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Adams, G., Weiner, L. Monoclonal antibody therapy of cancer. Nat Biotechnol 23, 1147–1157 (2005). https://doi.org/10.1038/nbt1137

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