Key Points
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Five antibodies are now approved for cancer therapy with more approvals anticipated from among the 20 or so antibodies currently in oncology trials.
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The pressing clinical need to enhance the efficacy of anticancer antibodies is being met by the exploration of a plethora of strategies. Combination treatment of antibodies with chemotherapy is already benefiting some oncology patients.
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Chemically coupling antibodies to toxins or radionuclides is the most widely investigated means for increasing their antitumour activity. In Mylotarg, the anti-CD33–calicheamicin conjugate is already approved for cancer therapy, and two anti-CD20 radioimmunoconjugates, Bexxar (tositumomab; 131iodine) and Zevalin (ibritumomab tituxetan; 90yttrium), are poised for regulatory approval.
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Interactions between antibody Fc regions and their Fcγ receptors are crucial to the in vivo antitumour activity of at least four antitumour antibodies, including trastuzumab (Herceptin) and rituximab (Rituxan). Tumour-cell killing in vitro has been enhanced by point mutations in Fc that improve binding to FcγRIII and, alternatively, by cellular engineering of antibody production hosts to manipulate antibody glycoforms.
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Pre-targeting of radionuclides and prodrugs to tumours might greatly reduce the systemic toxicity of conventional radioimmunotherapy and cytotoxic chemotherapy, respectively. Pre-targeting strategies must overcome many remaining obstacles for them to provide significant new treatment options for cancer patients.
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Targeting tumour neovasculature and angiogenic growth factors (e.g. VEGF) and receptors are promising alternative and potentially complementary strategies to direct tumour targeting. A humanized anti-VEGF antibody, bevacizumab (Avastin), is now in Phase III oncology trials.
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Liposomal formulations of doxorubicin and daunorubicin have been approved in recent years for the treatment of Kaposi's sarcoma. Attaching antibody fragments to the surface of such liposomes allows them to be specifically targeted to tumours.
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Antibody–cytokine fusion proteins (immunocytokines) create high intratumour concentrations of cytokines to stimulate the antitumour immune response. An IL-2-containing immunocytokine eliminated established metastases in a syngeneic mouse tumour model, boding well for ongoing clinical studies with two different immunocytokines.
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Bispecific antibodies binding two different antigens might selectively deliver cytotoxic machinery, such as immune effector cells, radionuclides, drugs and toxins, to tumour cells in vivo. Any future clinical success with bispecific antibodies will probably require a deeper understanding of underwhelming clinical trial data combined with powerful new production technologies for these complex molecules.
Abstract
A quarter of a century after their advent, monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies.
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References
Quan, M. P. & Carter, P. in Lung Biology in Health and Disease (eds Jardieu, P. M. & Fick, R. Jr) (Marcel Dekker, New York, 2001).
Glennie, M. J. & Johnson, P. W. Clinical trials of antibody therapy. Immunol. Today 21, 403–410 (2000).
Hoogenboom, H. R. & Chames, P. Natural and designer binding sites made by phage display technology. Immunol. Today 21, 371–378 (2000).
Little, M., Kipriyanov, S. M., Le Gall, F. & Moldenhauer, G. Of mice and men: hybridoma and recombinant antibodies. Immunol. Today 21, 364–370 (2000).
Halin, C. & Neri, D. Antibody-based targeting of angiogenesis. Crit. Rev. Ther. Drug Carrier Syst. 18, 299–339 (2001).
Reff, M. E. et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83, 435–445 (1994).
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).Pivotal Phase III trial that led to the approval of Rituxan for the treatment of low-grade or follicular non-Hodgkin's lymphoma.
Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285–4289 (1992).
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).
Yang, X. D. 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).
Agus, D. B. et al. A potential role for activated HER-2 in prostate cancer. Semin. Oncol. 27, 76–83 (2000).
Fitzpatrick, V. D., Pisacane, P. I., Vandlen, R. L. & Sliwkowski, M. X. Formation of a high affinity heregulin binding site using the soluble extracellular domains of ErbB2 with ErbB3 or ErbB4. FEBS Lett. 431, 102–106 (1998).
Pietras, R. J. et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9, 1829–1838 (1994).
Pietras, R. J., Pegram, M. D., Finn, R. S., Maneval, D. A. & Slamon, D. J. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17, 2235–2249 (1998).
Baselga, J., Norton, L., Albanell, J., Kim, Y. M. & Mendelsohn, J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58, 2825–2831 (1998).
Pegram, M. et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18, 2241–2251 (1999).
Pietras, R. J. et al. Monoclonal antibody to HER-2/neu receptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 59, 1347–1355 (1999).
Mann, M. et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology 120, 1713–1719 (2001).Combination treatment with an anti-ERBB2 antibody (Herceptin or 2C4) and a cyclooxygenase inhibitor, celecoxib, reduces colorectal tumour growth more effectively than either agent alone, warranting further preclinical and perhaps clinical evaluation of this new novel strategy.
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).Pivotal Phase III clinical trial that, together with reference 9 , led to the approval of Herceptin for the treatment of ERBB2 overexpressing metastatic breast cancer.
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).
Pegram, M. D. 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).
Slamon, D. & Pegram, M. Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin. Oncol. 28, 13–19 (2001).
Demidem, A. et al. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother. Radiopharm. 12, 177–186 (1997).
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).
Vose, J. M. et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J. Clin. Oncol. 19, 389–397 (2001).
Riethmüller, G. et al. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. German Cancer Aid 17-1A Study Group. Lancet 343, 1177–1183 (1994).
Riethmüller, G. et al. Monoclonal antibody therapy for resected Dukes' C colorectal cancer: seven-year outcome of a multicenter randomized trial. J. Clin. Oncol. 16, 1788–1794 (1998). Together with reference 26 , this study provides evidence for the therapeutic benefit of using anti-cancer antibodies to treat minimal residual and micrometastatic disease.
Farah, R. A., Clinchy, B., Herrera, L. & Vitetta, E. S. The development of monoclonal antibodies for the therapy of cancer. Crit. Rev. Eukaryot. Gene Expr. 8, 321–356 (1998).
Herlyn, M., Steplewski, Z., Herlyn, D. & Koprowski, H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc. Natl Acad. Sci. USA 76, 1438–1442 (1979).
Mellstedt, H. et al. The therapeutic use of monoclonal antibodies in colorectal carcinoma. Semin. Oncol. 18, 462–477 (1991).
Clynes, R., Takechi, Y., Moroi, Y., Houghton, A. & Ravetch, J. V. Fc receptors are required in passive and active immunity to melanoma. Proc. Natl Acad. Sci. USA 95, 652–656 (1998). First demonstration that the antitumour activity of an antibody can be critically dependent on interaction between its Fc region and Fcγ receptors. Similar findings have subsequently been made with several other antibodies, including the clinically important Herceptin and Rituxan (reference 32).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Med. 6, 443–446 (2000).
Sampson, J. H. et al. Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors. Proc. Natl Acad. Sci. USA 97, 7503–7508 (2000).
Shields, R. L. et al. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276, 6591–6604 (2001).
Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K. S. & Foeller, C. Sequences of Proteins of Immunological Interest, 5th edn (NIH, Bethesda, Maryland, 1991).
Deisenhofer, J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-Å resolution. Biochemistry 20, 2361–2370 (1981).
Wright, A. & Morrison, S. L. Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol. 15, 26–32 (1997).
Lifely, M. R., Hale, C., Boyce, S., Keen, M. J. & Phillips, J. Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and grown under different culture conditions. Glycobiology 5, 813–822 (1995).
Umaña, P., Jean-Mairet, J., Moudry, R., Amstutz, H. & Bailey, J. E. Engineered glycoforms of an antineuro-blastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nature Biotechnol. 17, 176–180 (1999).Cellular engineering of production host to modify glycoforms of the antibody produced to enhance the capacity to support antibody-dependent cellular cytotoxicity.
Idusogie, E. E. et al. Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J. Immunol. 164, 4178–4184 (2000).
Idusogie, E. E. et al. Engineered antibodies with increased activity to recruit complement. J. Immunol. 166, 2571–2575 (2001).
Gorter, A. & Meri, S. Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol. Today 20, 576–582 (1999).
Heitner, T. et al. Selection of cell binding and internalizing epidermal growth factor receptor antibodies from a phage display library. J. Immunol. Methods 248, 17–30 (2001).
Poul, M. A., Becerril, B., Nielsen, U. B., Morisson, P. & Marks, J. D. Selection of tumor-specific internalizing human antibodies from phage libraries. J. Mol. Biol. 301, 1149–1161 (2000).
Trail, P. A. et al. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261, 212–215 (1993).
Tolcher, A. W. et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484 (1999).
Ajani, J. A., Kelsen, D. P., Haller, D., Hargraves, K. & Healey, D. A multi-institutional phase II study of BMS-182248-01 (BR96-doxorubicin conjugate) administered every 21 days in patients with advanced gastric adenocarcinoma. Cancer J. 6, 78–81 (2000).
Sedalacek, H.-H. et al. Antibodies as Carriers of Cytotoxicity Vol. 43 (Karger, Munich, Germany, 1992).
Hinman, L. M. et al. Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res. 53, 3336–3342 (1993).
Lode, H. N. et al. Targeted therapy with a novel enediyene antibiotic calicheamicin θI1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma. Cancer Res. 58, 2925–2928 (1998).
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).
Sievers, E. L. et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J. Clin. Oncol. 19, 3244–3254 (2001).
Liu, C. et al. Eradication of large colon tumor xenografts by targeted delivery of maytansinoids. Proc. Natl Acad. Sci. USA 93, 8618–8623 (1996).Compelling demonstration of the in vivo antitumour efficacy of an antibody armed with maystansine, even against tumours that are very large or heterogeneous in antigen expression.
Baker, T. S. et al. in Antigen and Antibody Molecular Engineering in Breast Cancer Diagnosis and Treatment (ed. Ceriani, R. L.) (Plenum, New York, 1994).
Pietersz, G. A. et al. Comparison of the biological properties of two anti-mucin-1 antibodies prepared for imaging and therapy. Cancer Immunol. Immunother. 44, 323–328 (1997).
Pastan, I. Targeted therapy of cancer with recombinant immunotoxins. Biochim. Biophys. Acta 1333, C1–C6 (1997).
Kreitman, R. J. et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol. 18, 1622–1636 (2000).Most clinically efficacious recombinant immunotoxin so far: one complete response and seven partial responses from 35 patients treated.
Pai, L. H., Wittes, R., Setser, A., Willingham, M. C. & Pastan, I. Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin. Nature Med. 2, 350–353 (1996).
Tsutsumi, Y. et al. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc. Natl Acad. Sci. USA 97, 8548–8553 (2000).
Rybak, S. M. et al. Humanization of immunotoxins. Proc. Natl Acad. Sci. USA 89, 3165–3169 (1992).
Suzuki, M. et al. Engineering receptor-mediated cytotoxicity into human ribonucleases by steric blockade of inhibitor interaction. Nature Biotechnol. 17, 265–270 (1999).5000-fold increase in in vitro cytotoxic activity of human ribonucleases by specific targeting to tumour cells plus steric blockade of the interaction with a prevalent ribonuclease inhibitor.
Zalutsky, M. R. & Vaidyanathan, G. Astatine-211-labeled radiotherapeutics: an emerging approach to targeted α-particle radiotherapy. Curr. Pharm. Des. 6, 1433–1455 (2000).
Goldenberg, D. M. in Clinical Uses of Antibodies (eds Baum, R. P. et al.) 1–13 (Kluwer Academic, The Netherlands, 1991).
Jurcic, J. G. & Scheinberg, D. A. Recent developments in the radioimmunotherapy of cancer. Curr. Opin. Immunol. 6, 715–721 (1994).
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).
Press, O. W. et al. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346, 336–340 (1995).
Kaminski, M. S. et al. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J. Clin. Oncol. 14, 1974–1981 (1996).
Witzig, T. E. The use of ibritumomab tiuxetan radioimmunotherapy for patients with relapsed B-cell non-Hodgkin's lymphoma. Semin. Oncol. 27, 74–78 (2000).
Knox, S. J. et al. Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin. Cancer Res. 2, 457–470 (1996).
Zalutsky, M. R. & Bigner, D. D. Radioimmunotherapy with α-particle emitting radioimmunoconjugates. Acta Oncol. 35, 373–379 (1996).
McDevitt, M. R. et al. Radioimmunotherapy with α-emitting nuclides. Eur. J. Nucl. Med. 25, 1341–1351 (1998).
Lode, H. N. & Reisfeld, R. A. Targeted cytokines for cancer immunotherapy. Immunol. Res. 21, 279–288 (2000).
Lode, H. N., Xiang, R., Becker, J. C., Gillies, S. D. & Reisfeld, R. A. Immunocytokines: a promising approach to cancer immunotherapy. Pharmacol. Ther. 80, 277–292 (1998).
Penichet, M. L. & Morrison, S. L. Antibody-cytokine fusion proteins for the therapy of cancer. J. Immunol. Methods 248, 91–101 (2001).
Lasic, D. D. & Papahadjopoulos, D. Liposomes revisited. Science 267, 1275–1276 (1995).
Park, J. W. et al. Development of anti-p185HER2 immunoliposomes for cancer therapy. Proc. Natl Acad. Sci. USA 92, 1327–1331 (1995).
Park, J. W. et al. Anti-HER2 immunoliposomes for targeted therapy of human tumors. Cancer Lett. 118, 153–160 (1997).
Park, J. W., Hong, K., Kirpotin, D. B., Papahadjopoulos, D. & Benz, C. C. Immunoliposomes for cancer treatment. Adv. Pharmacol. 40, 399–435 (1997).
Bendas, G. Immunoliposomes: a promising approach to targeting cancer therapy. BioDrugs 15, 215–224 (2001).
Segal, D. M., Weiner, G. J. & Weiner, L. M. Bispecific antibodies in cancer therapy. Curr. Opin. Immunol. 11, 558–562 (1999).
Koelemij, R. et al. Bispecific antibodies in cancer therapy, from the laboratory to the clinic. J. Immunother. 22, 514–524 (1999).
van Spriel, A. B., van Ojik, H. H. & van de Winkel, J. G. Immunotherapeutic perspective for bispecific antibodies. Immunol. Today 21, 391–397 (2000).
Lamers, C. H., Bolhuis, R. L., Warnaar, S. O., Stoter, G. & Gratama, J. W. Local but no systemic immunomodulation by intraperitoneal treatment of advanced ovarian cancer with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. Int. J. Cancer 73, 211–219 (1997).
Plückthun, A. & Pack, P. New protein engineering approaches to multivalent and bispecific antibody fragments. Immunotechnology 3, 83–105 (1997).
Merchant, A. M. et al. An efficient route to human bispecific IgG. Nature Biotechnol. 16, 677–681 (1998).First efficient and broadly applicable method for preparing bispecific human IgG that is potentially suitable for human therapy.
Niculescu-Duvaz, I., Friedlos, F., Niculescu-Duvaz, D., Davies, L. & Springer, C. J. Prodrugs for antibody- and gene-directed enzyme prodrug therapies (ADEPT and GDEPT). Anticancer Drug Des. 14, 517–538 (1999).
Syrigos, K. N. & Epenetos, A. A. Antibody directed enzyme prodrug therapy (ADEPT): a review of the experimental and clinical considerations. Anticancer Res. 19, 605–613 (1999).
Sharma, S. K., Bagshawe, K. D., Melton, R. G. & Sherwood, R. F. Human immune response to monoclonal antibody-enzyme conjugates in ADEPT pilot clinical trial. Cell Biophys. 21, 109–120 (1992).
Bosslet, K., Czech, J. & Hoffmann, D. Tumor-selective prodrug activation by fusion protein-mediated catalysis. Cancer Res. 54, 2151–2159 (1994).First targeted prodrug system to use human enzyme and humanized antibody to minimize the risk of immunogenicity. First demonstration that targeted prodrug can simultaneously achieve higher intra-tumour and lower extratumour drug concentrations as compared with free drug given at its maximum tolerated dose.
Bosslet, K. et al. Elucidation of the mechanism enabling tumor selective prodrug monotherapy. Cancer Res. 58, 1195–1201 (1998).
Smith, G. K. et al. Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate. J. Biol. Chem. 272, 15804–15816 (1997).
Wolfe, L. A. et al. Antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1: in vitro and in vivo studies with prodrugs of methotrexate and the thymidylate synthase inhibitors GW1031 and GW1843. Bioconjug. Chem. 10, 38–48 (1999).
Shabat, D. et al. In vivo activity in a catalytic antibody-prodrug system: antibody catalyzed etoposide prodrug activation for selective chemotherapy. Proc. Natl Acad. Sci. USA 98, 7528–7533 (2001).Important milestone on the road to developing a catalytic antibody for targeted prodrug therapy.
Stoldt, H. S. et al. Pretargeting strategies for radio-immunoguided tumour localisation and therapy. Eur. J. Cancer 33, 186–192 (1997).
Wu, A. M. Tools for pretargeted radioimmunotherapy. Cancer Biother. Radiopharm. 16, 103–108 (2001).
Cremonesi, M. et al. Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients. Eur. J. Nucl. Med. 26, 110–120 (1999).
Paganelli, G. et al. Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy. Eur. J. Nucl. Med. 25, 1336–1339 (1998).
Chinol, M. et al. Biochemical modifications of avidin improve pharmacokinetics and biodistribution and reduce immunogenicity. Br. J. Cancer 78, 189–197 (1998).
Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).
Boulianne, G. L., Hozumi, N. & Shulman, M. J. Production of functional chimaeric mouse/human antibody. Nature 312, 643–646 (1984).
Morrison, S. L., Johnson, M. J., Herzenberg, L. A. & Oi, V. T. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl Acad. Sci. USA 81, 6851–6855 (1984).
Jones, P. T., Dear, P. H., Foote, J., Neuberger, M. S. & Winter, G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525 (1986).
Riechmann, L., Clark, M., Waldmann, H. & Winter, G. Reshaping human antibodies for therapy. Nature 332, 323–327 (1988).First clinically relevant antibody to be humanized — Campath.
Verhoeyen, M., Milstein, C. & Winter, G. Reshaping human antibodies: grafting an antilysozyme activity. Science 239, 1534–1536 (1988).
Vaughan, T. J., Osbourn, J. K. & Tempest, P. R. Human antibodies by design. Nature Biotechnol. 16, 535–539 (1998).
de Haard, H. J. et al. A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies. J. Biol. Chem. 274, 18218–18230 (1999).
Knappik, A. et al. Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J. Mol. Biol. 296, 57–86 (2000).
Sheets, M. D. et al. Efficient construction of a large nonimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens. Proc. Natl Acad. Sci. USA 95, 6157–6162 (1998).
Vaughan, T. J. et al. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nature Biotechnol. 14, 309–314 (1996).
Griffiths, A. D. et al. Isolation of high affinity human antibodies directly from large synthetic repertoires. EMBO J. 13, 3245–3260 (1994).
Griffiths, A. D. et al. Human anti-self antibodies with high specificity from phage display libraries. EMBO J. 12, 725–734 (1993).
Fishwild, D. M. et al. High avidity human IgGκ monoclonal antibodies from a novel strain of minilocus transgenic mice. Nature Biotechnol. 14, 845–851 (1996).
Mendez, M. J. et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nature Genet. 15, 146–156 (1997).
Nicholson, I. C. et al. Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and κ and λ light chain yeast artificial chromosomes. J. Immunol. 163, 6898–6906 (1999).
Clark, M. Antibody humanization: a case of the 'Emperor's new clothes'? Immunol. Today 21, 397–402 (2000).
Schier, R. et al. Isolation of picomolar affinity anti-c-erbB2 single-chain Fv by molecular evolution of the complementarity determining regions in the center of the antibody binding site. J. Mol. Biol. 263, 551–567 (1996).
Yang, W.-P. et al. CDR walking mutagenesis for the affinity maturation of a potent human anti-HIV-1 antibody into the picomolar range. J. Mol. Biol. 254, 392–403 (1995).
Hanes, J., Schaffitzel, C., Knappik, A. & Plückthun, A. Picomolar affinity antibodies from a fully synthetic naive library selected and evolved by ribosome display. Nature Biotechnol. 18, 1287–1292 (2000).
Jermutus, L., Honegger, A., Schwesinger, F., Hanes, J. & Plückthun, A. Tailoring in vitro evolution for protein affinity or stability. Proc. Natl Acad. Sci. USA 98, 75–80 (2001).
Boder, E. T., Midelfort, K. S. & Wittrup, K. D. Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity. Proc. Natl Acad. Sci. USA 97, 10701–10705 (2000).
Adams, G. P. et al. Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies. Cancer Res. 58, 485–490 (1998).
Adams, G. P. et al. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61, 4750–4755 (2001).Important study on the influence of the antigen-binding affinity of single-chain fragments on their ability to target tumours.
Fujimori, K., Covell, D. G., Fletcher, J. E. & Weinstein, J. N. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J. Nucl. Med. 31, 1191–1198 (1990).
Adams, G. P. et al. Highly specific in vivo tumor targeting by monovalent and divalent forms of 741F8 anti-c-erbB2 single-chain Fv. Cancer Res. 53, 4026–4034 (1993).
Begent, R. H. et al. Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library. Nature Med. 2, 979–984 (1996).
Ghetie, M. A. et al. Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor cells. Proc. Natl Acad. Sci. USA 94, 7509–7514 (1997).
Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).First demonstration that anti-vascular endothelial growth factor therapy can inhibit angiogenesis and suppress tumour growth in vivo.
Ferrara, N. & Davis-Smyth, T. The biology of vascular endothelial growth factor. Endocr. Rev. 18, 4–25 (1997).
Borgstrom, P., Hillan, K. J., Sriramarao, P. & Ferrara, N. Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 56, 4032–4039 (1996).
Presta, L. G. et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593–4599 (1997).
Dvorak, H. F., Nagy, J. A. & Dvorak, A. M. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3, 77–85 (1991).
Burrows, F. J. & Thorpe, P. E. Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc. Natl Acad. Sci. USA 90, 8996–9000 (1993).Shows the antitumour activity of an immunotoxin that targets tumour vasculature. The greatest efficacy is achieved by combining this immunotoxin with one that directly targets the tumour.
Huang, X. et al. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275, 547–550 (1997).
Nilsson, F., Kosmehl, H., Zardi, L. & Neri, D. Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res. 61, 711–716 (2001).In vivo antitumour efficacy of immunotoxin targeted to a natural marker of angiogenesis — the ED domain of fibronectin — that is expressed in most aggressive solid tumours, but undetectable in normal blood vessels and tissues.
Kamigaki, T. et al. Therapy and imaging of pancreatic carcinoma xenografts with radioiodine-labeled chimeric monoclonal antibody A10 and its Fab fragment. Jpn J. Cancer Res. 86, 1216–1223 (1985).
Yokota, T., Milenic, D. E., Whitlow, M. & Schlom, J. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 52, 3402–3408 (1992).
Caron, P. C. et al. Engineered humanized dimeric forms of IgG are more effective antibodies. J. Exp. Med. 176, 1191–1195 (1992).
Ghetie, M. A., Bright, H. & Vitetta, E. S. Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin. Blood 97, 1392–1398 (2001).
Wolff, E. A., Schreiber, G. J., Cosand, W. L. & Raff, H. V. Monoclonal antibody homodimers: enhanced antitumour activity in nude mice. Cancer Res. 53, 2560–2565 (1993).
Acknowledgements
The author thanks L. Weiner, D. Liebowitz and J. Smothers for critical review of this manuscript and G. Yarranton and M. Pegram for kindly sharing unpublished data.
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Glossary
- PHAGE DISPLAY
-
Technology for displaying a protein (or peptide) on the surface of a bacteriophage, which contains the gene(s) that encodes the displayed protein(s), thereby physically linking the genotype and phenotype.
- VALENCY
-
For antibody-derived molecules, this refers to the number of binding sites for the cognate antigen(s).
- COMPLETE RESPONSE
-
No remaining tumour can be detected by visual inspection or by clinical imaging technologies. This does not mean that the disease has been cured.
- PARTIAL RESPONSE
-
≥ 50% reduction in tumour with no new lesions or increase in size of an existing lesion.
- RESPONSE DURATION
-
Time from the first response until disease progression or death.
- OVERALL RESPONSE RATE
-
Sum of partial and complete responses.
- TUMOUR XENOGRAFT
-
Commonly refers to the growth of human tumour cells as tumours in immuno-compromised mice.
- RIBOSOME DISPLAY
-
Technology for displaying a nascent protein, which is physically linked to its encoding mRNA, that relies on in vitro transcription and translation.
- DNA SHUFFLING
-
Process for creating molecular diversity by homologous recombination of DNA in vitro.
- YEAST DISPLAY
-
Technology for displaying a protein on the surface of a yeast cell that contains the gene(s) that encodes the displayed protein(s).
- EXTRAVASATION
-
Movement out of the vasculature compartment into interstitial spaces.
- MINIMAL RESIDUAL DISEASE
-
Tumour remaining in patients following debulking by surgery and/or chemotherapy and/or radiotherapy.
- MICROMETASTATIC DISEASE
-
Metastatic disease that can be detected by immuno-histochemistry of tissue biopsies, but involves too few tumour cells to be directly imaged in patients.
- DUKE'S STAGE C COLORECTAL CANCER
-
Cancer that has spread from the colon to nearby lymph nodes, but not to other parts of the body.
- FC REGION
-
For an IgG, this comprises the CH2 and CH3 domains (Box 1).
- KABAT NUMBERING SCHEME
-
Immunoglobulin amino-acid residue numbering scheme, devised by the late Elvin Kabat, that accommodates sequence insertions and deletions.
- BISECTED COMPLEX OLIGOSACCHARIDES
-
Branched carbohydrate that might include several different kinds of monosaccharides, including N-acetylglucosamine between main branches.
- PANNING
-
Process of separating target-binding clones from nonbinding clones for phage display library.
- CURE
-
Tumour does not reappear for a prolonged time period — deemed sufficient for regrowth of any residual tumour — following anticancer therapies.
- VASCULAR LEAK SYNDROME
-
Involves damage to vascular endothelial cells, extravasation of fluids and proteins resulting in weight gain and, in its most severe form, kidney damage and pulmonary oedema.
- PEGYLATION
-
Chemical modification of a protein with one or more molecules of polyethylene glycol.
- BYSTANDER CELLS
-
Cells in the immediate vicinity of a cell that has a bound antibody-based targeting agent.
- MYELOABLATIVE
-
Elimination of myeloid cells and their progenitors.
- AUTOLOGOUS STEM-CELL SUPPORT
-
Harvesting of a patient's haematological stem cells before myeloablative anticancer therapy, followed by rescue by engraftment of the stem cells back into the patient.
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Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1, 118–129 (2001). https://doi.org/10.1038/35101072
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DOI: https://doi.org/10.1038/35101072
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