Molecular Biotechnology

, Volume 25, Issue 1, pp 1–17 | Cite as

Recombinant antibodies for the diagnosis and treatment of cancer

  • Jürgen KraussEmail author


The advent of recombinant antibody technology led to an enormous revival in the use of antibodies as diagnostic and therapeutic tools for fighting cancer. This review provides a brief historical sketch of the development of recombinant antibodies for the diagnosis and immunotherapy of cancer and summarizes the most significant clinical data for the best established reagents to date. It also discusses clinically relevant aspects of the use of recombinant antibodies in cancer patients.

Index Entries

Cancer diagnosis and therapy clinical trial recombinant antibodies 


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  1. 1.
    Köhler, G., and Milstein, C. (1975) Continuous culture of fused cells secreting antibody of predefined specifity. Nature 256, 495–497.PubMedCrossRefGoogle Scholar
  2. 2.
    Ritz, J., Pesando, J. M., Sallan, S. E., et al. (1981) Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood 58, 141–152.PubMedGoogle Scholar
  3. 3.
    Miller, R. A., Oseroff, A. R., Stratte, P. T., and Levy, R. (1983) Monoclonal antibody therapeutic trials in seven patients with T-cell lymphoma. Blood 62, 988–995.PubMedGoogle Scholar
  4. 4.
    Dillman, R. O., Shawler, D. L., Dillman, J. B., and Royston, I. (1984) Therapy of chronic lymphocytic leukemia and cutaneous T-cell lymphoma with T101 monoclonal antibody. J. Clin. Oncoll. 2, 881–891.Google Scholar
  5. 5.
    Foon, K. A., Schroff, R. W., Bunn, P. A., Mayer, D., Abrams, P. G., Fer, M., et al. (1984) Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia. Blood 64, 1085–1093.PubMedGoogle Scholar
  6. 6.
    Meeker, T. C., Lowder, J., Maloney, D. G., et al. (1985) A clinical trial of anti-idiotype therapy for B cell malignancy. Blood 65, 1349–1363.PubMedGoogle Scholar
  7. 7.
    Brown, S. L., Miller, R. A., Horning, S. J., et al. (1989) Treatment of B-cell lymphomas with antiidiotype antibodies alone and in combination with alpha interferon. Blood 73, 651–661.PubMedGoogle Scholar
  8. 8.
    Davis, T. A., Maloney, D. G., Czerwinski, D. K., Liles, T. M., and Levy, R. (1998) Anti-idiotype antibodies can induce long-term complete remissions in non-Hodgkin’s lymphoma without eradicating the malignant clone. Blood 92, 1184–1190.PubMedGoogle Scholar
  9. 9.
    Brack, C., and Tonegawa, S. (1977) Variable and constant parts of the immunoglobulin light chain gene of a mouse myeloma cell are 1250 nontranslated bases apart. Proc. Natl. Acad. Sci. USA 74, 5652–5656.PubMedCrossRefGoogle Scholar
  10. 10.
    Tonegawa, S., Brack, C., Hozumi, N., and Schuller, R. (1977) Cloning of an immunoglobulin variable region gene from mouse embryo. Proc. Natl. Acad. Sci. USA 74, 3518–3522.PubMedCrossRefGoogle Scholar
  11. 11.
    Meselson, M., and Yuan, R. (1968) DNA restriction enzyme from E. coli. Nature 217, 1110–1114.PubMedCrossRefGoogle Scholar
  12. 12.
    Boulianne, G. L., Hozumi, N., and Shulman, M. J. (1984) Production of functional chimaeric mouse/human antibody. Nature 312, 643–646.PubMedCrossRefGoogle Scholar
  13. 13.
    Morrison, S. L., Johnson, M. J., Herzenberg, L. A., and Oi, V. T. (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. USA 81, 6851–6855.PubMedCrossRefGoogle Scholar
  14. 14.
    Neuberger, M. S., Williams, G. T., and Fox, R. O. (1984) Recombinant antibodies possessing novel effector functions. Nature 312, 604–608.PubMedCrossRefGoogle Scholar
  15. 15.
    Bruggemann, M., Williams, G. T., Bindon, C. I., et al. (1987) Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J. Exp. Med. 166, 1351–1361.PubMedCrossRefGoogle Scholar
  16. 16.
    Shaw, D. R., Khazaeli, M. B., and LoBuglio, A. F. (1988) Mouse/human chimeric antibodies to a tumor-associated antigen: biologic activity of the four human IgG subclasses. J. Natl. Cancer. Inst. 80, 1553–1559.PubMedCrossRefGoogle Scholar
  17. 17.
    Steplewski, Z., Sun, L. K., Shearman, C. W., et al. (1988) Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificity. Proc. Natl. Acad. Sci. USA 85, 4852–4856.PubMedCrossRefGoogle Scholar
  18. 18.
    LoBuglio, A. F., Wheeler, R. H., Trang, J., et al. (1989) Mouse/human chimeric antibody in man; Kinetics and immune response. Proc. Natl. Acad. Sci. USA 86, 4220–4224.PubMedCrossRefGoogle Scholar
  19. 19.
    Khazaeli, M. B., Saleh, M. N., Liu, T. P., et al. (1991) Pharmacokinetics and immune response of 131I-chimeric mouse/human B72.3 (human gamma 4) monoclonal antibody in humans. Cancer Res. 51, 5461–5466.PubMedGoogle Scholar
  20. 20.
    Maloney, D. G., Liles, T. M., Czerwinski, D. K., et al. (1994) Phase I clinical trial using escalating singledose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84, 2457–2466.PubMedGoogle Scholar
  21. 21.
    Stashenko, P., Nadler, L. M., Hardy, R., and Schlossman, S. F. (1980) Characterization of a human B lymphocytespecific antigen. J. Immunol. 125, 1678–1685.PubMedGoogle Scholar
  22. 22.
    Maloney, D. G., Grillo-Lopez, A. J., White, C. A., et al. (1997) IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90, 2188–2195.PubMedGoogle Scholar
  23. 23.
    McLaughlin, P., Grillo-Lopez, A. J., Link, B. K., et al. (1998) 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.PubMedGoogle Scholar
  24. 24.
    Berinstein, N. L., Grillo-Lopez, A. J., White, C. A., et al. (1998) 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.PubMedCrossRefGoogle Scholar
  25. 25.
    Coiffier, B., Haioun, C., Ketterer, N., Engert, Aet al. (1998) 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.PubMedGoogle Scholar
  26. 26.
    Coiffier, B., Lepage, E., Briere, J., et al. (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242.PubMedCrossRefGoogle Scholar
  27. 27.
    Czuczman, M. S., Grillo-Lopez, A. J., White, C. A., et al. (1999) 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.PubMedGoogle Scholar
  28. 28.
    Colombat, P., Salles, G., Brousse, N., et al. (2001) Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 97, 101–106.PubMedCrossRefGoogle Scholar
  29. 29.
    Behr, T. M., Wormann, B., Gramatzki, M., et al. (1999) Low-versus high-dose radioimmunotherapy with humanized anti-CD22 or chimeric anti-CD20 antibodies in a broad spectrum of B cell-associated malignancies. Clin. Cancer Res. 5, 3304s-3314s.PubMedGoogle Scholar
  30. 30.
    Buckstein, R., Imrie, K., Spaner, D., et al. (1999) Stem cell function and engraftment is not affected by “in vivo purging” with rituximab for autologous stem cell treatment for patients with low- grade non-Hodgkin’s lymphoma. Semin. Oncol. 26, 115–122.PubMedGoogle Scholar
  31. 31.
    Mangel, J., Buckstein, R., Imrie, K., et al. (2002) Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma. Semin. Oncol. 29, 56–69.PubMedCrossRefGoogle Scholar
  32. 32.
    Cheson, B. D. (2002) Rituximab: clinical development and future directions. Expert Opin. Biol. Ther. 2, 97–110.PubMedCrossRefGoogle Scholar
  33. 33.
    Prewett, M., Rockwell, P., Rockwell, R. F., et al. (1996) The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J. Immunother. Emphasis Tumor Immunol. 19, 419–427.PubMedGoogle Scholar
  34. 34.
    Baselga, J., Pfister, D., Cooper, M. R., et al. (2000) Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J. Clin. Oncol. 18, 904–914.PubMedGoogle Scholar
  35. 35.
    Shin, D. M., Donato, N. J., Perez-Soler, R., et al. (2001) Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin. Cancer Res. 7, 1204–1213.PubMedGoogle Scholar
  36. 36.
    Jones, P. T., Dear, P. H., Foote, J., et al. (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525.PubMedCrossRefGoogle Scholar
  37. 37.
    Chothia, C. and Lesk, A. M. (1987) Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901–917.PubMedCrossRefGoogle Scholar
  38. 38.
    Chothia, C., Lesk, A. M., Tramontano, A., et al. (1989) Conformations of immunoglobulin hypervariable regions. Nature 342, 877–883.PubMedCrossRefGoogle Scholar
  39. 39.
    Riechmann, L., Clark, M., Waldmann, H., and Winter, G. (1988) Reshaping human antibodies for therapy. Nature 332, 323–327.PubMedCrossRefGoogle Scholar
  40. 40.
    Queen, C., Schneider, W. P., Selick, H. E., et al. (1989) A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci USA 86, 10029–10033.PubMedCrossRefGoogle Scholar
  41. 41.
    Kettelborough, C. A., Saldanha, J., Heath, V. J., et al. (1991) Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation. Protein Eng. 4, 773–783.CrossRefGoogle Scholar
  42. 42.
    Co, M. S., Avdalovic, N. M., Caron, P. C., et al. (1992) Chimeric and humanized antibodies with specificity for the CD33 antigen. J. Immunol 148, 1149–1154.PubMedGoogle Scholar
  43. 43.
    Padlan, E. A. (1991) A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties. Mol. Immunol. 28, 489–498.PubMedCrossRefGoogle Scholar
  44. 44.
    Roguska, M. A., Pedersen, J. T., Keddy, C. A., et al. (1994) Humanization of murine monoclonal antibodies through variable domain resurfacing. Proc. Natl. Acad. Sci. USA 91, 969–973.PubMedCrossRefGoogle Scholar
  45. 45.
    Caldas, C., Coelho, V. P., Rigden, D. J., et al. (2000) Design and synthesis of germline-based hemi-humanized single-chain Fv against the CD18 surface antigen. Protein Eng. 13, 353–360.PubMedCrossRefGoogle Scholar
  46. 46.
    Tan, P., Mitchell, D. A., Buss, T. N., et al. (2002) “Superhumanized” Antibodies: Reduction of Immunogenic Potential by Complementarity-Determining Region Grafting with Human Germline Sequences: Application to an Anti-CD28. J. Immunol. 169, 1119–1125.PubMedGoogle Scholar
  47. 47.
    Iwahashi, M., Milenic, D. E., Padlan, E. A et al. (1999) CDR substitutions of a humanized monoclonal antibody (CC49): contributions of individual CDRs to antigen binding and immunogenicity. Mol. Immunol. 36, 1079–1091.PubMedCrossRefGoogle Scholar
  48. 48.
    Tamura, M., Milenic, D. E., Iwahashi, M., et al. (2000) Structural correlates of an anticarcinoma antibody: identification of specificity-determining residues (SDRs) and development of a minimally immunogenic antibody variant by retention of SDRs only. J. Immunol. 164, 1432–1441.PubMedGoogle Scholar
  49. 49.
    Carter, P., Presta, L., Gorman, C. M., et al. (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. USA 89, 4285–4289.PubMedCrossRefGoogle Scholar
  50. 50.
    Coussens, L., Yang-Feng, T. L., Liao, Y. C., et al. (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230, 1132–1139.PubMedCrossRefGoogle Scholar
  51. 51.
    Slamon, D. J., Clark, G. M., Wong, S. G., et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182.PubMedCrossRefGoogle Scholar
  52. 52.
    Borg, A., Tandon, A. K., Sigurdsson, H., et al. (1990) HER-2/neu amplification predicts poor survival in nodepositive breast cancer. Cancer Res 50, 4332–4337.PubMedGoogle Scholar
  53. 53.
    Baselga, J., Tripathy, D., Mendelsohn, J., et al. (1996) 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.PubMedGoogle Scholar
  54. 54.
    Cobleigh, M. A., Vogel, C. L., Tripathy, D., et al. (1999) 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.PubMedGoogle Scholar
  55. 55.
    Vici, P., Belli, F., Di Lauro, L., et al. (2001) Docetaxel in patients with anthracycline-resistant advanced breast cancer. Oncology 60, 60–65.PubMedCrossRefGoogle Scholar
  56. 56.
    Baselga, J., Norton, L., Albanell, J., et al. (1998) 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.PubMedGoogle Scholar
  57. 57.
    Pietras, R. J., Pegram, M. D., Finn, R. S., et al. (1998) Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17, 2235–2249.PubMedCrossRefGoogle Scholar
  58. 58.
    Slamon, D. J., Leyland-Jones, B., Shak, S., et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792.PubMedCrossRefGoogle Scholar
  59. 59.
    Seidman, A., Hudis, C., Pierri, M. Ket al. (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20, 1215–1221.PubMedCrossRefGoogle Scholar
  60. 60.
    Pegram, M. D., Lipton, A., Hayes, D. F., et al. (1998) 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.PubMedGoogle Scholar
  61. 61.
    Burstein, H. J., Kuter, I., Campos, S. M., et al. (2001) Clinical activity of trastuzumab and vinorelbine in women with HER2- overexpressing metastatic breast cancer. J. Clin. Oncol. 19, 2722–2730.PubMedGoogle Scholar
  62. 62.
    Jahanzeb, M., Mortimer, J. E., Yunus, Fet al. (2002) Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer. Oncologist 7, 410–417.PubMedCrossRefGoogle Scholar
  63. 63.
    Slamon, D., and Pegram, M. (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin. Oncol. 28, 13–19.PubMedCrossRefGoogle Scholar
  64. 64.
    Lundin, J., Kimby, E., Bjorkholm, M., et al. (2002) 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.PubMedCrossRefGoogle Scholar
  65. 65.
    Rai, K. R., Freter, C. E., Mercier, R. J., et al. (2002) Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J. Clin. Oncol. 20, 3891–3897.PubMedCrossRefGoogle Scholar
  66. 66.
    Hale, G., Slavin, S., Goldman, J. M., Mackinnon, S., et al. (2002) Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning? Bone Marrow Transplant 30, 797–804.PubMedCrossRefGoogle Scholar
  67. 67.
    Lundin, J., Hagberg, H., Repp, R., et al. (2003) Phase II study of alemtuzumab (anti-CD52 monoclonal antibody, Campath- 1H) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 23, 23.Google Scholar
  68. 68.
    Lundin, J., Osterborg, A., Brittinger, G., et al. (1998) 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.PubMedGoogle Scholar
  69. 69.
    Miller, J. L. (2000) FDA approves antibody-directed cytotoxic agent for acute myeloid leukemia. Am. J. Health Syst. Pharm. 57, 1202, 1204.Google Scholar
  70. 70.
    Better, M., Chang, C. P., Robinson, R. R., and Horwitz, A. H. (1988) Escherichia coli secretion of an active chimeric antibody fragment. Science 240, 1041–1043.PubMedCrossRefGoogle Scholar
  71. 71.
    Skerra, A., and Pluckthun, A. (1988) Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science 240, 1038–1041.PubMedCrossRefGoogle Scholar
  72. 72.
    Glockshuber, R., Malia, M., Pfitzinger, I., and Pluckthun, A. (1990) A comparison of strategies to stabilize immunoglobulin Fv-fragments. Biochemistry 29, 1362–1367.PubMedCrossRefGoogle Scholar
  73. 73.
    Bird, R. E., Hardman, K. D., Jacobson, J. W., et al. (1988) Single-chain antigen-binding proteins. Science 242, 423–426.PubMedCrossRefGoogle Scholar
  74. 74.
    Huston, J. S., Levinson, D., Mudgett-Hunter, M., et al. (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc. Natl. Acad. Sci. USA 85, 5879–5883.PubMedCrossRefGoogle Scholar
  75. 75.
    Brinkmann, U., Reiter, Y., Jung, S. H., et al. (1993) A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc. Natl. Acad. Sci. USA. 90, 7538–7542.PubMedCrossRefGoogle Scholar
  76. 76.
    Reiter, Y., Brinkmann, U., Jung, S. H., et al. (1994) Improved binding and antitumor activity of a recombinant anti-erbB2 immunotoxin by disulfide stabilization of the Fv fragment. J. Biol. Chem. 269, 18327–18331.PubMedGoogle Scholar
  77. 77.
    Chaudhary, V. K., Queen, C., Junghans, R. P., et al. (1989) A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339, 394–397.PubMedCrossRefGoogle Scholar
  78. 78.
    Batra, J. K., Fitzgerald, D. J., Chaudhary, V. K., and Pastan, I. (1991) Single-chain immunotoxins directed at the human transferrin receptor containing Pseudomonas exotoxin A or diphtheria toxin: anti-TFR(Fv)-PE40 and DT388-anti-TFR(Fv). Mol. Cell Biol. 11, 2200–2205.PubMedGoogle Scholar
  79. 79.
    Brinkmann, U., Pai, L. H., FitzGerald, D. J., et al. (1991) B3(Fv)-PE38KDEL, a single-chain immunotoxin that causes complete regression of a human carcinoma in mice. Proc. Natl. Acad. Sci. USA 88, 8616–8620.CrossRefGoogle Scholar
  80. 80.
    Newton, D. L., Nicholls, P. J., Rybak, S. M., and Youle, R. J. (1994) Expression and characterization of recombinant human eosinophil-derived neurotoxin and eosinophil-derived neurotoxin-anti-transferrin receptor sFv. J. Biol. Chem. 269, 26739–26745.PubMedGoogle Scholar
  81. 81.
    Newton, D. L., Xue, Y., Olson, K. A., et al. (1996) Angiogenin single-chain immunofusions: influence of peptide linkers and spacers between fusion protein domains. Biochemistry 35, 545–553.PubMedCrossRefGoogle Scholar
  82. 82.
    Zewe, M., Rybak, S. M., Dubel, S., et al. (1997) Cloning and cytotoxicity of a human pancreatic RNase immunofusion. Immunotechnology 3, 127–136.PubMedCrossRefGoogle Scholar
  83. 83.
    Bosslet, K., Czech, J., Lorenz, P., et al. (1992) Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activiation. Br. J. Cancer. 65, 234–238.PubMedGoogle Scholar
  84. 84.
    Rodrigues, M. L., Presta, L. G., Kotts, C. E., et al. (1995) Development of a humanized disulfide-stabilized anti-p185HER2 Fv-beta- lactamase fusion protein for activation of a cephalosporin doxorubicin prodrug. Cancer Res. 55, 63–70.PubMedGoogle Scholar
  85. 85.
    Haisma, H. J., Sernee, M. F., Hooijberg, E., et al. (1998) Construction and characterization of a fusion protein of single-chain anti-CD20 antibody and human beta-glucuronidase for antibody-directed enzyme prodrug therapy. Blood 92, 184–190.PubMedGoogle Scholar
  86. 86.
    Colcher, D., Pavlinkova, G., Beresford, G., et al. (1999) Single-chain antibodies in pancreatic cancer. Ann. NY Acad. Sci. 880, 263–280.PubMedCrossRefGoogle Scholar
  87. 87.
    Rosenblum, M. G., Horn, S. A., and Cheung, L. H. (2000) A novel recombinant fusion toxin targeting HER-2/NEU-over-expressing cells and containing human tumor necrosis factor. Int. J. Cancer 88, 267–273.PubMedCrossRefGoogle Scholar
  88. 88.
    Xu, X., Clarke, P., Szalai, G., et al. (2000) Targeting and therapy of carcinoembryonic antigen-expressing tumors in transgenic mice with an antibody-interleukin 2 fusion protein. Cancer Res. 60, 4475–4484.PubMedGoogle Scholar
  89. 89.
    Biragyn, A., Tani, K., Grimm, M. C., et al. (1999) Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat. Biotechnol. 17, 253–258.PubMedCrossRefGoogle Scholar
  90. 90.
    Kostelny, S. A., Cole, M. S., and Tso, J. Y. (1992) Formation of a bispecific antibody by the use of leucine zippers. J. Immunol. 148, 1547–1553.PubMedGoogle Scholar
  91. 91.
    Gruber, M., Schodin, B. A., Wilson, E. R., and Kranz, D. M. (1994) Efficient tumor cell lysis mediated by a bispecific single chain antibody expressed in Escherichia coli. J. Immunol. 152, 5368–5374.PubMedGoogle Scholar
  92. 92.
    Holliger, P., Brissinck, J., Williams, R. L., et al. (1996) Specific killing of lymphoma cells by cytotoxic T-cells mediated by a bispecific diabody. Prot. Eng. 9, 299–305.CrossRefGoogle Scholar
  93. 93.
    Zhu, Z., Zapata, G., Shalaby, R., et al. (1996) High-Level secretion of a humanized bispecific diabody from Escherichia coli. Biotechnology 14, 192–196.PubMedCrossRefGoogle Scholar
  94. 94.
    Kipriyanov, S. M., Moldenhauer, G., Srauss, G., and Little, M. (1998) Bispecific CD3 x CD19 diabody for T cell-mediated lysis of malignant human B cells. Int. J. Cancer 77, 763–772.PubMedCrossRefGoogle Scholar
  95. 95.
    Manzke, O., Fitzgerald, K. J., Holliger, P., et al. (1999) CD3X anti-nitrophenyl bispecific diabodies: universal immunotherapeutic tools for retargeting T cells to tumors. Int. J. Cancer 82, 700–708.PubMedCrossRefGoogle Scholar
  96. 96.
    Arndt, M. A., Krauss, J., Kipriyanov, S. M., Pfreundschuh, M., and Little, M. (1999) A bispecific diabody that mediates natural killer cell cytotoxicity against xenotransplantated human Hodgkin’s tumors. Blood 94, 2562–2568.PubMedGoogle Scholar
  97. 97.
    Coloma, M. J., and Morrison, S. L. (1997) Design and production of novel tetravalent bispecific antibodies. Nat. Biotechnol. 15, 159–163.PubMedCrossRefGoogle Scholar
  98. 98.
    Alt, M., Muller, R., and Kontermann, R. E. (1999) Novel tetravalent and bispecific IgG-like antibody molecules combining single-chain diabodies with the immunoglobulin gammal Fc or CH3 region. FEBS Lett. 454, 90–94.PubMedCrossRefGoogle Scholar
  99. 99.
    Kipriyanov, S. M., Moldenhauer, G., Schuhmacher, J., et al. (1999) Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J. Mol. Biol. 293, 41–56.PubMedCrossRefGoogle Scholar
  100. 100.
    Gross, G., and Eshhar, Z. (1992) Endowing T cells with antibody specificity using chimeric T cell receptors. Faseb J. 6, 3370–3378.PubMedGoogle Scholar
  101. 101.
    Eshhar, Z., Waks, T., Gross, G., and Schindler, D. G. (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl. Acad. Sci. USA 90, 720–724.PubMedCrossRefGoogle Scholar
  102. 102.
    Hombach, A., Heuser, C., Sircar, R., et al. (1997) T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope. Gastroenterology 113, 1163–1170.PubMedCrossRefGoogle Scholar
  103. 103.
    Hombach, A., Schneider, C., Sent, D., et al. (2000) An entirely humanized CD3 zeta-chain signaling receptor that directs peripheral blood t cells to specific lysis of carcinoembryonic antigen- positive tumor cells. Int. J. Cancer 88, 115–120.PubMedCrossRefGoogle Scholar
  104. 104.
    Kreitman, R. J., Wilson, W. H., Bergeron, K., et al. (2001) Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy- resistant hairy-cell leukemia. N. Engl. J. Med. 345, 241–247.PubMedCrossRefGoogle Scholar
  105. 105.
    Smith, G. P. (1985) Filamentous fusion phage: Novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317.PubMedCrossRefGoogle Scholar
  106. 106.
    McCafferty, J., Griffiths, A. D., Winter, G., and Chiswell, D. J. (1990) Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554.PubMedCrossRefGoogle Scholar
  107. 107.
    Saiki, R. K., Scharf, S., Faloona, F., et al. (1985) Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230, 1350–1354.PubMedCrossRefGoogle Scholar
  108. 108.
    Barbas, C. F., III, Kang, A. S., Lerner, R. A., and Benkovic, S. J. (1991) Assembly of combinatorial antibody libraries on phage surfaces: the gene III site. Proc. Natl. Acad. Sci. USA 88, 7978–7982.PubMedCrossRefGoogle Scholar
  109. 109.
    Breitling, F., Dubel, S., Seehaus, T., et al. (1991) A surface expression vector for antibody screening. Gene 104, 147–153.PubMedCrossRefGoogle Scholar
  110. 110.
    Hoogenboom, H. R., Griffiths, A. D., Johnson, K. S., et al. (1991) Multi-subunit proteins on the surface of filamentous phage: methodologies for displaying antibody (Fab) heavy and light chains. Nucleic Acids Res. 19, 4133–4137.PubMedCrossRefGoogle Scholar
  111. 111.
    Winter, G., Griffiths, A. D., Hawkins, R. E., and Hoogenboom, H. R. (1994) Making antibodies by phage display technology. Annu. Rev. Immunol. 12, 433–455.PubMedCrossRefGoogle Scholar
  112. 112.
    Cai, X., and Garen, A. (1995) Anti-melanoma antibodies from melanoma patients immunized with genetically modified autologous tumor cells: selection of specific antibodies from single-chain Fv fusion phage libraries. Proc. Natl. Acad. Sci. USA 92, 6537–6541.PubMedCrossRefGoogle Scholar
  113. 113.
    Welschof, M., Terness, P., Kipriyanov, S. M., et al. (1997) The antigen-binding domain of a human IgG-anti-F(ab)2 autoantibody. Proc. Natl. Acad. Sci. USA 94, 1902–1907.PubMedCrossRefGoogle Scholar
  114. 114.
    Clackson, T., Hoogenboom, H. R., Griffiths, A. D., and Winter, G. (1991) Making antibody fragments using phage display libraries. Nature 352, 624–628.PubMedCrossRefGoogle Scholar
  115. 115.
    Chester, K. A., Begent, R. H. J., Robson, L., et al. (1994) Phage libraries for generation of clinically useful antibodies. Lancet 343, 455–456.PubMedCrossRefGoogle Scholar
  116. 116.
    Kettleborough, C. A., Ansell, K. H., Allen, R. W., et al. (1994) Isolation of tumor cell-specific single-chain Fv from immunized mice using phage-antibody libraries and the re-construction of whole antibodies from these antibody fragments. Eur. J. Immunol. 24, 952–958.PubMedCrossRefGoogle Scholar
  117. 117.
    Marks, J. D., Hoogenboom, H. R., Bonnert, T. P et al. (1991) By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222, 581–597.PubMedCrossRefGoogle Scholar
  118. 118.
    Sheets, M. D., Amersdorfer, P., Finnern, R., et al. (1998) 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.PubMedCrossRefGoogle Scholar
  119. 119.
    de Haard, H. J., van Neer, N., Reurs, A., et al. (1999) 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.PubMedCrossRefGoogle Scholar
  120. 120.
    Little, M., Welschof, M., Braunagel, M., et al. (1999) Generation of a large complex antibody library from multiple donors. J. Immunol. Methods. 231, 3–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Barbas, C. F., III, Bain, J. D., Hoekstra, D. M., and Lerner, R. A. (1992) Semisynthetic combinatorial antibody libraries: Achemical solution to the diversity problem. Proc. Natl. Acad. Sci. USA 89, 4457–4461.PubMedCrossRefGoogle Scholar
  122. 122.
    Hoogenboom, H. R., and Winter, G. (1992) By-passing immunisation. Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J. Mol. Biol. 227, 381–388.PubMedCrossRefGoogle Scholar
  123. 123.
    Griffiths, A. D., Williams, S. C., Hartley, O., et al. (1994) Isolation of high affinity human antibodies directly from large synthetic repertoires. Embo J. 13, 3245–3260.PubMedGoogle Scholar
  124. 124.
    Braunagel, M., and Little, M. (1997) Construction of a semisynthetic antibody library using trinucleotide oligos. Nucleic Acids Res. 25, 4690–4691.PubMedCrossRefGoogle Scholar
  125. 125.
    Knappik, A., Ge, L., Honegger, A., et al. (2000) Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J. Mol. Biol. 296, 57–86.PubMedCrossRefGoogle Scholar
  126. 126.
    Hanes, J., and Pluckthun, A. (1997) In vitro selection and evolution of functional proteins by using ribosome display. Proc. Natl. Acad. Sci. USA 94, 4937–4942.PubMedCrossRefGoogle Scholar
  127. 127.
    He, M., and Taussig, M. J. (1997) Antibody-ribosome-mRNA (ARM) complexes as efficient selection particles for in vitro display and evolution of antibody combining sites. Nucleic Acids Res. 25, 5132–5134.PubMedCrossRefGoogle Scholar
  128. 128.
    Hamers-Casterman, C., Atarhouch, T., Muyldermans, S., et al. (1993) Naturally occurring antibodies devoid of light chains. Nature 363, 446–448.PubMedCrossRefGoogle Scholar
  129. 129.
    Arbabi Ghahroudi, M., Desmyter, A., Wyns, L., et al. (1997) Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett 414, 521–526.PubMedCrossRefGoogle Scholar
  130. 130.
    Muyldermans, S., and Lauwereys, M. (1999) Unique single-domain antigen binding fragments derived from naturally occurring camel heavy-chain antibodies. J. Mol. Recognit. 12, 131–140.PubMedCrossRefGoogle Scholar
  131. 131.
    Reiter, Y., Schuck, P., Boyd, L. F., and Plaksin, D. (1999) An antibody single-domain phage display library of a native heavy chain variable region: Isolation of functional single-domain VH molecules with a unique interface. J. Mol. Biol. 290, 685–698.PubMedCrossRefGoogle Scholar
  132. 132.
    Begent, R. H., Verhaar, M. J., Chester, K. A., et al. (1996) Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library. Nat. Med. 2, 979–984.PubMedCrossRefGoogle Scholar
  133. 133.
    Mayer, A., Tsiompanou, E., O’Malley, D., et al. (2000) Radioimmunoguided surgery in colorectal cancer using a genetically engineered anti-CEA single-chain Fv antibody. Clin. Cancer Res. 6, 1711–1719.PubMedGoogle Scholar
  134. 134.
    Carson, D. A., and Freimark, B. D. (1986) Human lymphocyte hybridomas and monoclonal antibodies. Adv. Immunol. 38, 275–311.PubMedGoogle Scholar
  135. 135.
    Bruggemann, M., Spicer, C., Buluwela, L., et al. (1991) Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus. Eur. J. Immunol. 21, 1323–1326.PubMedCrossRefGoogle Scholar
  136. 136.
    Taylor, L. D., Carmack, C. E., Schramm, S. R., et al. (1992) A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins. Nucleic Acids Res. 20, 6287–6295.PubMedCrossRefGoogle Scholar
  137. 137.
    Lonberg, N., Taylor, L. D., Harding, F. A., et al. (1994) Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859.PubMedCrossRefGoogle Scholar
  138. 138.
    Nicholson, I. C., Zou, X., Popov, A. V., et al. (1999) Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes. J. Immunol. 163, 6898–6906.PubMedGoogle Scholar
  139. 139.
    Tomizuka, K., Shinohara, T., Yoshida, H., et al. (2000) Double trans-chromosomic mice: maintenance of two individual human chromosome fragments containing Ig heavy and kappa loci and expression of fully human antibodies. Proc. Natl. Acad. Sci. USA 97, 722–727.PubMedCrossRefGoogle Scholar
  140. 140.
    Koprowski, H., Herlyn, D., Lubeck, M., et al. (1984) Human anti-idiotype antibodies in cancer patients: Is the modulation of the immune response beneficial for the patient? Proc. Natl. Acad. Sci. USA 81, 216–219.PubMedCrossRefGoogle Scholar
  141. 141.
    LoBuglio, A. F., Saleh, M. N., Lee, J., et al. (1988) Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects. J. Natl. Cancer Inst. 80, 932–936.PubMedCrossRefGoogle Scholar
  142. 142.
    Riethmuller, G., Schneider-Gadicke, E., Schlimok, G., et al. (1994) 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.PubMedCrossRefGoogle Scholar
  143. 143.
    Gruber, R., van Haarlem, L. J., Warnaar, S. O., et al. (2000) The human antimouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A. Cancer Res. 60, 1921–1926.PubMedGoogle Scholar
  144. 144.
    Jerne, N. K. (1974) Towards a network theory of the immune system. Ann. Immunol. (Paris) 125C, 373–389.Google Scholar
  145. 145.
    Frodin, J. E., Faxas, M. E., Hagstrom, B., et al. (1991) Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies in patients treated with the mouse monoclonal antibody 17-1A (ab1). Relation to the clinical outcome—an important antitumoral effector function? Hybridoma 10, 421–431.PubMedCrossRefGoogle Scholar
  146. 146.
    Cheung, N. K., Cheung, I. Y., Canete, A., et al. (1994) Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival. Cancer Res. 54, 2228–2233.PubMedGoogle Scholar
  147. 147.
    Cheung, N. K., Guo, H. F., Heller, G., and Cheung, I. Y. (2000) Induction of Ab3 and Ab3′ antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma. Clin. Cancer Res. 6, 2653–2660.PubMedGoogle Scholar
  148. 148.
    Nadler, L. M., Stashenko, P., Hardy, R., et al. (1980) Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 40, 3147–3154.PubMedGoogle Scholar
  149. 149.
    Miller, R. A., and Levy, R. (1981) Response of cutaneous T cell lymphoma to therapy with hybridoma monoclonal antibody. Lancet 2, 226–230.PubMedCrossRefGoogle Scholar
  150. 150.
    Cobbold, S. P., and Waldmann, H. (1984) Therapeutic potential of monovalent monoclonal antibodies. Nature 308, 460–462.PubMedCrossRefGoogle Scholar
  151. 151.
    Sahin, U., Tureci, O., Schmitt, H., et al. (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 92, 11810–11813.PubMedCrossRefGoogle Scholar
  152. 152.
    Barth, S., Weidenmuller, U., Tur, M. K., et al. (2000) Combining phage display and screening of cDNA expression libraries: a new approach for identifying the target antigen of an scFv preselected by phage display. J. Mol. Biol. 301, 751–757.PubMedCrossRefGoogle Scholar
  153. 153.
    Chames, P., Hufton, S. E., Coulie, P. G., et al. (2000) Direct selection of a human antibody fragment directed against the tumor T-cell epitope HLA-A1-MAGE-A1 from a nonimmunized phage-Fab library. Proc. Natl. Acad. Sci. USA 97, 7969–7974.PubMedCrossRefGoogle Scholar
  154. 154.
    Li, J., Pereira, S., Van Belle, P., et al. (2001) Isolation of the melanoma-associated antigen p23 using antibody phage display. J. Immunol. 166, 432–438.PubMedGoogle Scholar
  155. 155.
    Herlyn, D. M., Steplewski, Z., Herlyn, M. F., and Koprowski, H. (1980) Inhibition of growth of colorectal carcinoma in nude mice by monoclonal antibody. Cancer Res. 40, 717–721.PubMedGoogle Scholar
  156. 156.
    Hellstrom, I., Brown, J. P., and Hellstrom, K. E. (1981) Monoclonal antibodies to two determinants of melanoma-antigen p97 act synergistically in complement-dependent cytotoxicity. J. Immunol. 127, 157–160.PubMedGoogle Scholar
  157. 157.
    Herlyn, D., and Koprowski, H. (1982) IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc. Natl. Acad. Sci. USA 79, 4761–4765.PubMedCrossRefGoogle Scholar
  158. 158.
    Adams, D. O., Hall, T., Steplewski, Z., and Koprowski, H. (1984) Tumors undergoing rejection induced by monoclonal antibodies of the IgG2a isotype contain increased numbers of macrophages activated for a distinctive form of antibody-dependent cytolysis. Proc. Natl. Acad. Sci. USA 81, 3506–3510.PubMedCrossRefGoogle Scholar
  159. 159.
    Herlyn, D., Herlyn, M., Ross, A. H., et al. (1984) Efficient selection of human tumor growth-inhibiting monoclonal antibodies. J. Immunol. Methods 73, 157–167.PubMedCrossRefGoogle Scholar
  160. 160.
    Hellstrom, I., Beaumier, P. L., and Hellstrom, K. E. (1986) Antitumor effects of L6, an IgG2a antibody that reacts with most human carcinomas. Proc. Natl. Acad. Sci. USA 83, 7059–7063.PubMedCrossRefGoogle Scholar
  161. 161.
    Liu, A. Y., Robinson, R. R., Murray, E. D., Jr., et al. (1987) Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J. Immunol. 139, 3521–3526.PubMedGoogle Scholar
  162. 162.
    Caron, P. C., Co, M. S., Bull, M. K., et al. (1992) Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res. 52, 6761–6767.PubMedGoogle Scholar
  163. 163.
    Golay, J., Zaffaroni, L., Vaccari, T., et al. (2000) Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 95, 3900–3908.PubMedGoogle Scholar
  164. 164.
    Ravetch, J. V., and Clynes, R. A. (1998) Divergent roles for Fc receptors and complement in vivo. Annu. Rev. Immunol. 16, 421–432.PubMedCrossRefGoogle Scholar
  165. 165.
    Bolland, S., and Ravetch, J. V. (1999) Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149–177.PubMedCrossRefGoogle Scholar
  166. 166.
    Clynes, R. A., Towers, T. L., Presta, L. G., and Ravetch, J. V. (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat. Med. 6, 443–446.PubMedCrossRefGoogle Scholar
  167. 167.
    Cragg, M. S., French, R. R., and Glennie, M. J. (1999) Signaling antibodies in cancer therapy. Curr. Opin. Immunol. 11, 541–547.PubMedCrossRefGoogle Scholar
  168. 168.
    Shan, D., Ledbetter, J. A., and Press, O. W. (1998) Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91, 1644–1652.PubMedGoogle Scholar
  169. 169.
    Shan, D., Ledbetter, J. A., and Press, O. W. (2000) Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol. Immunother. 48, 673–683.PubMedCrossRefGoogle Scholar
  170. 170.
    Ghetie, M. A., Podar, E. M., Ilgen, A., et al. (1997) 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.PubMedCrossRefGoogle Scholar
  171. 171.
    Pietras, R. J., Poen, J. C., Gallardo, D., et al. (1999) Monoclonal antibody to HER-2/neureceptor modulates repair of radiation- induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 59, 1347–1355.PubMedGoogle Scholar
  172. 172.
    Lee, S., Yang, W., Lan, K. H., et al. (2002) Enhanced sensitization to taxol-induced apoptosis by herceptin pretreatment in ErbB2-overexpressing breast cancer cells. Cancer Res. 62, 5703–5710.PubMedGoogle Scholar
  173. 173.
    Goldenberg, D. M., Sharkey, R. M., Goldenberg, H., et al. (1990) Monoclonal antibody therapy of cancer. NJ Med. 87, 913–918.Google Scholar
  174. 174.
    Chester, K. A., and Hawkins, R. E. (1995) Clinical issues in antibody design. Trends Biotechnol. 13, 294–300.PubMedCrossRefGoogle Scholar
  175. 175.
    Adams, G. P., Schier, R., Marshall, K., et al. (1998) Increased affinity leads to improved selective tumor delivery of single- chain Fv antibodies. Cancer Res. 58, 485–490.PubMedGoogle Scholar
  176. 176.
    Deen, W. M., Bridges, C. R., and Brenner, B. M. (1983) Biophysical basis of glomerular permselectivity. J. Membr. Biol. 71, 1–10.PubMedCrossRefGoogle Scholar
  177. 177.
    Maloney, D. G., Grillo-Lopez, A. J., Bodkin, D. J., et al. (1997) IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J. Clin. Oncol. 15, 3266–3274.PubMedGoogle Scholar
  178. 178.
    Vaughn, D. E., Milburn, C. M., Penny, D. M., et al. (1997) Identification of critical IgG binding epitopes on the neonatal Fc receptor. J. Mol. Biol. 274, 597–607.PubMedCrossRefGoogle Scholar
  179. 179.
    Junghans, R. P., and Anderson, C. L. (1996) The protection receptor for IgG catabolism is the beta2-microglobulin- containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA 93, 5512–5516.PubMedCrossRefGoogle Scholar
  180. 180.
    Ghetie, V., Popov, S., Borvak, J., et al. (1997) Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat. Biotechnol. 15, 637–640.PubMedCrossRefGoogle Scholar
  181. 181.
    Ghetie, V., and Ward, E. S. (1997) FcRn: the MHC class I-related receptor that is more than an IgG transporter. Immunol. Today 18, 529–598.CrossRefGoogle Scholar
  182. 182.
    Zuckier, L. S., Chang, C. J., Scharff, M. D., and Morrison, S. L. (1998) Chimeric human-mouse IgG antibodies with shuffled constant region exons demonstrate that multiple domains contribute to in vivo half-life. Cancer Res. 58, 3905–3908.PubMedGoogle Scholar
  183. 183.
    Milenic, D. E., Yokota, T., Filpula, D. R., et al. (1991) Construction, binding properties, metabolism, and tumor targeting of a single-chain Fv derived from the pancarcinoma monoclonal antibody CC49. Cancer Res. 51, 6363–6371.PubMedGoogle Scholar
  184. 184.
    Weiner, L. M., Houston, L. L., Huston, J. S., et al. (1995) Improving the tumor-selective delivery of single-chain Fv molecules. Tumor Targeting 1, 51–60.Google Scholar
  185. 185.
    Adams, G. P., Schier, R., McCall, A. M., et al. (1998) Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br. J. Cancer 77, 1405–1412.PubMedGoogle Scholar
  186. 186.
    Nielsen, U. B., Adams, G. P., Weiner, L. M., and Marks, J. D. (2000) Targeting of bivalent anti-ErbB2 diabody antibody fragments to tumor cells is independent of the intrinsic antibody affinity. Cancer Res. 60, 6434–6440.PubMedGoogle Scholar
  187. 187.
    Yokota, T., Milenic, D. E., Whitlow, M., and Schlom, J. (1992) Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 52, 3402–3408.PubMedGoogle Scholar
  188. 188.
    Kitamura, K., Takahashi, T., Yamaguchi, T., et al. (1991) Chemical engineering of the monoclonal antibody A7 by polyethylene glycol for targeting cancer chemotherapy. Cancer Res. 51, 4310–4315.PubMedGoogle Scholar
  189. 189.
    Pedley, R. B., Boden, J. A., Boden, R., et al. (1994) The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody. Br. J. Cancer 70, 1126–1130.PubMedGoogle Scholar
  190. 190.
    Chapman, A. P., Antoniw, P., Spitali, M., et al. (1999) Therapeutic antibody fragments with prolonged in vivo half-lives. Nat. Biotechnol. 17, 780–783.PubMedCrossRefGoogle Scholar
  191. 191.
    Abuchowski, A., McCoy, J. R., Palczuk, N. C., et al. (1977) Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252, 3582–3586.PubMedGoogle Scholar
  192. 192.
    Marks, J. D., Griffiths, A. D., Malmqvist, M., et al. (1992) By-passing immunization: building high affinity human antibodies by chain shuffling. Biotechnology (NY) 10, 779–783.CrossRefGoogle Scholar
  193. 193.
    Hawkins, R. E., Russell, S. J., and Winter, G. (1992) Selection of phage antibodies by binding affinity. Mimicking affinity maturation. J. Mol. Biol. 226, 889–896.PubMedCrossRefGoogle Scholar
  194. 194.
    Schier, R., Marks, J. D., Wolf, E. J., et al. (1995) In vitro and in vivo characterization of a human anti-c-erbB2 single- chain Fv isolated from a filamentous phage antibody library. Immunotechnology 1, 73–81.PubMedCrossRefGoogle Scholar
  195. 195.
    Schier, R., Bye, J., Apell, Get al. (1996) Isolation of high-affinity monomeric human anti-c-erbB-2 single chain Fv using affinity-driven selection. J. Mol. Biol. 255, 28–43.PubMedCrossRefGoogle Scholar
  196. 196.
    Schier, R., McCall, A., Adams, G. P., et al. (1996) Isolation of picomolar affinity anti-c-erbB-2 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.PubMedCrossRefGoogle Scholar
  197. 197.
    Adams, G. P., Schier, R., McCall, A. M., et al. (2001) High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 61, 4750–4755.PubMedGoogle Scholar
  198. 198.
    Jackson, H., Bacon, L., Pedley, R. B., et al. (1998) Antigen specificity and tumour targeting efficiency of a human carcinoembryonic antigen-specific scFv and affinity-matured derivatives. Br. J. Cancer 78, 181–188.PubMedCrossRefGoogle Scholar
  199. 199.
    Crothers, D. M., and Metzger, H. (1972) The influence of polyvalency on the binding properties of antibodies. Immunochemistry 9, 341–357.PubMedCrossRefGoogle Scholar
  200. 200.
    Adams, G. P., McCartney, J. E., Tai, M. S., et al. (1993) Highly specific in vivo tumor targeting by monovalent and divalent forms of 741F8 anti-c-erbB-2 single-chain Fv. Cancer Res. 53, 4026–4034.PubMedGoogle Scholar
  201. 201.
    Wu, A. M., Chen, W., Raubitschek, A., et al. (1996) Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers. Immunotechnology 2, 21–36.PubMedCrossRefGoogle Scholar
  202. 202.
    Goel, A., Colcher, D., Baranowska-Kortylewicz, J., et al. (2000) Genetically engineered tetravalent single-chain Fv of the pancarcinoma monoclonal antibody CC49: improved biodistribution and potential for therapeutic application. Cancer Res. 60, 6964–6971.PubMedGoogle Scholar

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© Humana Press Inc 2003

Authors and Affiliations

  1. 1.SAIC Frederick, National Cancer Institute at FrederickFrederick

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