Advertisement

Molecular Biotechnology

, Volume 26, Issue 1, pp 39–60 | Cite as

Generation and production of engineered antibodies

  • Sergey M. Kipriyanov
  • Fabrice Le Gall
Review

Abstract

Various forms of recombinant monoclonal antibodies are being used increasingly, mainly for therapeutic purposes. This review specifically focuses on what is now called antibody engineering, and discusses the generation of chimeric, humanized, and fully human recombinant antibodies, immunoglobulin fragments, and artificial antigen-binding molecules. Since the production of recombinant antibodies is a limiting factor in their availability, and a shortage is expected in the future, different expression systems for recombinant antibodies and transgenic organisms as bioreactors are also discussed, along with their advantages and drawbacks.

Index Entries

Recombinant antibody humanization single-chain Fv fragment phage display antibody library expression bioreactor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Köhler, G., and Milstein, C. (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497.PubMedCrossRefGoogle Scholar
  2. 2.
    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
  3. 3.
    Terness, P., Welschof, M., Moldenhauer, G., et al. (1997) Idiotypic vaccine for treatment of human B-cell lymphoma. Construction of IgG variable regions from single malignant B cells. Hum. Immunol. 56, 17–27.PubMedCrossRefGoogle Scholar
  4. 4.
    Green, L. L. (1999) Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. J. Immunol. Methods 231, 11–23.PubMedCrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    Borrebaeck, C. A., Danielsson, L., and Moller, S. A. (1988) Human monoclonal antibodies produced by primary in vitro immunization of peripheral blood lymphocytes. Proc. Natl. Acad. Sci. USA 85, 3995–3999.PubMedCrossRefGoogle Scholar
  7. 7.
    Little, M., Kipriyanov, S. M., Le Gall, F., and Moldenhauer, G. (2000) Of mice and men: hybridoma and recombinant antibodies. Immunol. Today 21, 364–370.PubMedCrossRefGoogle Scholar
  8. 8.
    Marks, J. D., Tristem, M., Karpas, A., and Winter, G. (1991) Oligonucleotide primers for polymerase chain reaction amplification of human immunoglobulin variable genes and design of family-specific oligonucleotide probes. Eur. J. Immunol. 21, 985–991.PubMedCrossRefGoogle Scholar
  9. 9.
    Welschof, M., Terness, P., Kolbinger, F., et al. (1995) Amino acid sequence based PCR primers for amplification of rearranged human heavy and light chain immunoglobulin variable region genes. J. Immunol. Methods 179, 203–214.PubMedCrossRefGoogle Scholar
  10. 10.
    Kipriyanov, S. M., Kupriyanova, O. A., Little, M., and Moldenhauer, G. (1996) Rapid detection of recombinant antibody fragments directed against cell-surface antigens by flow cytometry. J. Immunol. Methods 196, 51–62.PubMedCrossRefGoogle Scholar
  11. 11.
    Lagerkvist, A. C., Furebring, C., and Borrebaeck, C. A. (1995) Single, antigen-specific B cells used to generate Fab fragments using CD40-mediated amplification or direct PCR cloning. Biotechniques 18, 862–869.PubMedGoogle Scholar
  12. 12.
    Dreher, M. L., Gherardi, E., Skerra, A., and Milstein, C. (1991) Colony assays for antibody fragments expressed in bacteria. J. Immunol. Methods 139, 197–205.PubMedCrossRefGoogle Scholar
  13. 13.
    de Wildt, R. M., Mundy, C. R., Gorick, B. D., and Tomlinson, I. M. (2000) Antibody arrays for high-throughput screening of antibody-antigen interactions. Nat. Biotechnol. 18, 989–994.PubMedCrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    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
  16. 16.
    Khazaeli, M. B., Conry, R. M., and LoBuglio, A. F. (1994) Human immune response to monoclonal antibodies. J. Immunother. 15, 42–52.CrossRefGoogle Scholar
  17. 17.
    McLaughlin, P., Hagemeister, F. B., and Grillo-Lopez, A. J. (1999) Rituximab in indolent lymphoma: The single-agent pivotal trial. Semin. Oncol. 26, 79–87.PubMedGoogle Scholar
  18. 18.
    Maloney, D. G. (1999) Preclinical and phase I and II trials of rituximab. Semin. Oncol. 26, 74–78.PubMedGoogle Scholar
  19. 19.
    Press, O. W. (1999) Radiolabeled antibody therapy of B-cell lymphomas. Semin. Oncol. 26, 58–65.PubMedGoogle Scholar
  20. 20.
    Padlan, E. A. (1994) Anatomy of the antibody molecule. Mol. Immunol. 31, 169–217.PubMedCrossRefGoogle Scholar
  21. 21.
    Jones, P. T., Dear, P. H., Foote, J., et al. (1986) Replacing the complementarity-determing regions in a human antibody with those from a mouse. Nature 321, 522–525.PubMedCrossRefGoogle Scholar
  22. 22.
    Verhoeyen, M., Milstein, C., and Winter, G. (1988) Reshaping human antibodies: grafting an anti-lysozyme activity. Science 239, 1534–1536.PubMedCrossRefGoogle Scholar
  23. 23.
    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
  24. 24.
    Co, M. S., and Queen, C. (1991) Humanized antibodies for therapy. Nature 351, 501–502.PubMedCrossRefGoogle Scholar
  25. 25.
    Roguska, M. A., Pedersen, J. T., Henry, A. H., et al. (1996) A comparison of two murine monoclonal antibodies humanized by CDR-grafting and variable domain resurfacing. Protein Eng. 9, 895–904.PubMedCrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    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, 1079–91.PubMedCrossRefGoogle Scholar
  28. 28.
    De Pascalis, R., Iwahashi, M., Tamura, M., et al. (2002) Grafting of “abbreviated” complementarity-determining regions containing specificity-determining residues essential for ligand contact to engineer a less immunogenic humanized monoclonal antibody. J. Immunol. 169, 3076–3084.PubMedGoogle Scholar
  29. 29.
    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
  30. 30.
    Sliwkowski, M. X., Lofgren, J. A., Lewis, G. D., et al. (1999) Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin. Oncol. 26, 60–70.PubMedGoogle Scholar
  31. 31.
    Bookman, M. A., Darcy, K. M., Clarke-Pearson, D., et al. (2003) Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the gynecologic oncology group. J. Clin. Oncol. 21, 283–290.PubMedCrossRefGoogle Scholar
  32. 32.
    Horton, J. (2002) Trastuzumab use in breast cancer: clinical issues. Cancer Control 9, 499–507.PubMedGoogle Scholar
  33. 33.
    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
  34. 34.
    Pedersen, J. T., Henry, A. H., Searle, S. J., et al. (1994) Comparison of surface accessible residues in human and murine immunoglobulin Fv domains. Implication for humanization of murine antibodies. J. Mol. Biol. 235, 959–973.PubMedCrossRefGoogle Scholar
  35. 35.
    Mark, G. E., and Padlan, E. A. (1994) Humanization of monoclonal antibodies. In: Handbook of Experimental Pharmacology, Vol. 113: The Pharmacology of Monoclonal Antibodies (Rosenberg, M. and Moore, G. P., eds.) Springer-Verlag, Berlin, Heidelberg, pp. 105–134.Google Scholar
  36. 36.
    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
  37. 37.
    Altuvia, Y., Schueler, O., and Margalit, H. (1995) Ranking potential binding peptides to MHC molecules by a computational threading approach. J. Mol. Biol. 249, 244–2450.PubMedCrossRefGoogle Scholar
  38. 38.
    Schueler-Furman, O., Altuvia, Y., Sette, A., and Margalit, H. (2000) Structure-based prediction of binding peptides to MHC class I molecules: application to a broad range of MHC alleles. Protein Sci. 9, 1838–1846.PubMedCrossRefGoogle Scholar
  39. 39.
    Ghetie, V., and Ward, E. S. (1997) FcRn: the MHC class I-related receptor that is more than an IgG transporter. Immunol. Today 18, 592–598.PubMedCrossRefGoogle Scholar
  40. 40.
    Liu, A. Y., Robinson, R. R., Hellström, K. E., et al. (1987) Chimeric mouse-human IgG1 antibody that can mediate lysis of cancer cells. Proc. Natl. Acad. Sci. USA 84, 3439–3443.PubMedCrossRefGoogle Scholar
  41. 41.
    Riechmann, L., Clark, M., Waldmann, H., and Winter, G. (1988) Reshaping human antibodies for therapy. Nature 332, 323–327.PubMedCrossRefGoogle Scholar
  42. 42.
    Woodle, E. S., Thistlethwaite, J. R., Jolliffe, L. K., et al. (1992) Humanized OKT3 antibodies: successful transfer of immune modulating properties and idiotype expression. J. Immunol. 148, 2756–2763.PubMedGoogle Scholar
  43. 43.
    Alegre, M. L., Collins, A., Pulito, V. L., et al. (1992) Effect of a single amino acid mutation on the activating and immunosuppressive properties of a “humanized” OKT3 monoclonal antibody. J. Immunol. 148, 3461–3468.PubMedGoogle Scholar
  44. 44.
    Alegre, M. L., Peterson, L. J., Xu, D., et al. (1994) A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 57, 1537–1543.PubMedGoogle Scholar
  45. 45.
    Cole, M. S., Anasetti, C., and Tso, J. Y. (1997) Human IgG2 variants of chimeric anti-CD3 are nonmitogenic to T cells. J. Immunol. 159, 3613–3621.PubMedGoogle Scholar
  46. 46.
    Armour, K. L., Clark, M. R., Hadley, A. G., and Williamson, L. M. (1999) Recombinant human IgG molecules lacking Fcγ receptor I binding and monocyte triggering activities. Eur. J. Immunol. 29, 2613–2624.PubMedCrossRefGoogle Scholar
  47. 47.
    Kipriyanov, S. M., and Little, M. (1999) Generation of recombinant antibodies. Mol. Biotechnol. 12, 173–201.PubMedCrossRefGoogle Scholar
  48. 48.
    Kretzschmar, T., and von Rüden, T. (2002) Antibody discovery: Phage display. Curr. Opin. Biotechnol. 13, 598–602.PubMedCrossRefGoogle Scholar
  49. 49.
    Kellermann, S. A., and Green, L. L. (2002) Antibody discovery: The use of transgenic mice to generate human monoclonal antibodies for therapeutics. Curr. Opin. Biotechnol. 13, 593–597.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuroiwa, Y., Kasinathan, P., Choi, Y. J., et al. (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat. Biotechnol. 20, 889–894.PubMedCrossRefGoogle Scholar
  51. 51.
    Fishwild, D. M., O’Donnell, S. L., Bengoechea, T., et al. (1996) High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat. Biotechnol. 14, 845–851.PubMedCrossRefGoogle Scholar
  52. 52.
    Mendez, M. J., Green, L. L., Corvalan, J. R et al. (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Genet. 15, 146–156.PubMedCrossRefGoogle Scholar
  53. 53.
    Yang, X. D., Jia, X. C., Corvalan, J. R., et al. (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243.PubMedGoogle Scholar
  54. 54.
    Tomizuka, K., Yoshida, H., Uejima, H., et al. (1997) Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nat. Genet. 16, 133–143.PubMedCrossRefGoogle Scholar
  55. 55.
    Clark, M. (2000) Antibody humanization: A case of the “Emperor’s new clothes”? Immunol. Today 21, 397–402.PubMedCrossRefGoogle Scholar
  56. 56.
    Borrebaeck, C. A. (1999) Human monoclonal antibodies: The emperor’s new clothes? Nat. Biotechnol. 17, 621.PubMedCrossRefGoogle Scholar
  57. 57.
    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
  58. 58.
    Skerra, A., and Plückthun, A. (1988) Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science 240, 1038–1041.PubMedCrossRefGoogle Scholar
  59. 59.
    Russell, S. J., Hawkins, R. E., and Winter, G. (1993) Retroviral vectors displaying functional antibody fragments. Nucleic Acids Res. 21, 1081–1085.PubMedCrossRefGoogle Scholar
  60. 60.
    Boublik, Y., Di Bonito, P., and Jones, I. M. (1995) Eukaryotic virus display: Engineering the major surface glycoprotein of the Autographa californica nuclear polyhedrosis virus (AcNPV) for the presentation of foreign proteins on the virus surface. Biotechnology (NY) 13, 1079–1084.CrossRefGoogle Scholar
  61. 61.
    Boder, E. T., and Wittrup, K. D. (1997) Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15, 553–557.PubMedCrossRefGoogle Scholar
  62. 62.
    Feldhaus, M. J., Siegel, R. W., Opresko, L. K., et al. (2003) Flow-cytometric isolation of human antibodies from a nonimmune Saccharomyces cerevisiae surface display library. Nat. Biotechnol. 21, 163–170.PubMedCrossRefGoogle Scholar
  63. 63.
    Chen, W., and Georgiou, G. (2002) Cell-Surface display of heterologous proteins: From high-throughput screening to environmental applications. Biotechnol. Bioeng. 79, 496–503.PubMedCrossRefGoogle Scholar
  64. 64.
    Amstutz, P., Forrer, P., Zahnd, C., and Plückthun, A. (2001) In vitro display technologies: novel developments and applications. Curr. Opin. Biotechnol. 12, 400–405.PubMedCrossRefGoogle Scholar
  65. 65.
    Smith, G. P. (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317.PubMedCrossRefGoogle Scholar
  66. 66.
    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
  67. 67.
    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
  68. 68.
    McGuinness, B. T., Walter, G., FitzGerald, K., et al. (1996) Phage diabody repertoires for selection of large numbers of bispecific antibody fragments. Nat. Biotechnol. 14, 1149–1154.PubMedCrossRefGoogle Scholar
  69. 69.
    Persson, M. A., Caothien, R. H., and Burton, D. R. (1991) Generation of diverse high-affinity human monoclonal antibodies by repertoire cloning. Proc. Natl. Acad. Sci. U S A 88, 2432–2436.PubMedCrossRefGoogle Scholar
  70. 70.
    Burton, D. R., Barbas, C. F., Persson, M. A., et al. (1991) A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Natl. Acad. Sci. USA 88, 10134–10137.PubMedCrossRefGoogle Scholar
  71. 71.
    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
  72. 72.
    Dörsam, H., Rohrbach, P., Kurschner, T., et al. (1997) Antibodies to steroids from a small human naive IgM library. FEBS Lett. 414, 7–13.PubMedCrossRefGoogle Scholar
  73. 73.
    Barbas, C. F., Bain, J. D., Hoekstra, D. M., and Lerner, R. A. (1992) Semisynthetic combinatorial antibody libraries: A chemical solution to the diversity problem. Proc. Natl. Acad. Sci. USA 89, 4457–4461.PubMedCrossRefGoogle Scholar
  74. 74.
    Nissim, A., Hoogenboom, H. R., Tomlinson, I. M., et al. (1994) Antibody fragments from a “single pot” phage display library as immunochemical reagents. EMBO J. 13, 692–698.PubMedGoogle Scholar
  75. 75.
    Hoogenboom, H. R. and Chames, P. (2000) Natural and designer binding sites made by phage display technology. Immunol. Today 21, 371–378.PubMedCrossRefGoogle Scholar
  76. 76.
    Huls, G. A., Heijnen, I. A., Cuomo, M. E., et al. (1999) A recombinant, fully human monoclonal antibody with antitumor activity constructed from phage-displayed antibody fragments. Nat. Biotechnol. 17, 276–281.PubMedCrossRefGoogle Scholar
  77. 77.
    McCafferty, J. and Glover, D. R. (2000) Engineering therapeutic proteins. Curr. Opin. Struct. Biol. 10, 417–420.PubMedCrossRefGoogle Scholar
  78. 78.
    Bird, R. E., Hardman, K. D., Jacobson, J. W., et al. (1988) Single-chain antigen-binding proteins. Science 242, 423–426.PubMedCrossRefGoogle Scholar
  79. 79.
    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
  80. 80.
    Glockshuber, R., Malia, M., Pfitzinger, I., and Plückthun, A. (1990) A comparison of strategies to stabilize immunoglobulin Fv-fragments. Biochemistry 29, 1362–1367.PubMedCrossRefGoogle Scholar
  81. 81.
    Zhu, Z., Presta, L. G., Zapata, G., and Carter, P. (1997) Remodeling domain interfaces to enhance heterodimer formation. Protein Sci. 6, 781–788.PubMedCrossRefGoogle Scholar
  82. 82.
    Kipriyanov, S. M., and Little, M. (1997) Affinity purification of tagged recombinant proteins using immobilized single chain Fv fragments. Anal. Biochem. 244, 189–191.PubMedCrossRefGoogle Scholar
  83. 83.
    Arnold-Schild, D., Kleist, C., Welschof, M., et al. (2000) One-step single-chain Fv recombinant antibody-based purification of gp96 for vaccine development. Cancer Res. 60, 4175–4178.PubMedGoogle Scholar
  84. 84.
    Reiter, Y., Brinkmann, U., Jung, S. H., et al. (1995) Disulfide stabilization of antibody Fv: computer predictions and experimental evaluation. Protein Eng. 8, 1323–1331.PubMedCrossRefGoogle Scholar
  85. 85.
    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
  86. 86.
    Ward, E. S., Gussow, D., Griffiths, A. D., et al. (1989) Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 341, 544–546.PubMedCrossRefGoogle Scholar
  87. 87.
    Davies, J., and Riechmann, L. (1996) S2ingle antibody domains as small recognition units: design and in vitro antigen selection of camelized, human VH domains with improved protein stability. Protein Eng. 9, 531–537.PubMedCrossRefGoogle Scholar
  88. 88.
    Greenberg, A. S., Avila, D., Hughes, M., et al. (1995) A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 374, 168–173.PubMedCrossRefGoogle Scholar
  89. 89.
    Nuttall, S. D., Krishnan, U. V., Hattarki, M., et al. (2001) Isolation of the new antigen receptor from wobbegong sharks, and use as a scaffold for the display of protein loop libraries. Mol. Immunol. 38, 313–326.PubMedCrossRefGoogle Scholar
  90. 90.
    Riechmann, L., and Muyldermans, S. (1999) Single domain antibodies: Comparison of camel VH and camelised human VH domains. J. Immunol. Methods 231, 25–38.PubMedCrossRefGoogle Scholar
  91. 91.
    Hansson, M., Ringdahl, J., Robert, A., et al. (1999) An in vitro selected binding protein (affibody) shows conformation-dependent recognition of the respiratory syncytial virus (RSV) G protein. Immunotechnology 4, 237–252.PubMedCrossRefGoogle Scholar
  92. 92.
    McConnell, S. J., and Hoess, R. H. (1995) Tendamistat as a scaffold for conformationally constrained phage peptide libraries. J. Mol. Biol. 250, 460–470.PubMedCrossRefGoogle Scholar
  93. 93.
    Koide, A., Bailey, C. W., Huang, X., and Koide, S. (1998) The fibronectin type III domain as a scaffold for novel binding proteins. J. Mol. Biol. 284, 1141–1151.PubMedCrossRefGoogle Scholar
  94. 94.
    Beste, G., Schmidt, F. S., Stibora, T., and Skerra, A. (1999) Small antibody-like proteins with prescribed ligand specificities derived from the lipocalin fold. Proc. Natl. Acad. Sci. USA 96, 1898–1903.PubMedCrossRefGoogle Scholar
  95. 95.
    Hufton, S. E., van Neer, N., van den Beuken, T., et al. (2000) Development and application of cytotoxic T lymphocyte-associated antigen 4 as a protein scaffold for the generation of novel binding ligands. FEBS Lett. 475, 225–231.PubMedCrossRefGoogle Scholar
  96. 96.
    Skerra, A. (2000) Engineered protein scaffolds for molecular recognition. J. Mol. Recognit. 13, 167–187.PubMedCrossRefGoogle Scholar
  97. 97.
    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
  98. 98.
    Kipriyanov, S. M., Dübel, S., Breitling, F., et al. (1994) Recombinant single-chain Fv fragments carrying C-terminal cysteine residues: production of bivalent and biotinylated miniantibodies. Mol. Immunol. 31, 1047–1058.PubMedCrossRefGoogle Scholar
  99. 99.
    Holliger, P., Prospero, T., and Winter, G. (1993) “Diabodies”: Small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. USA 90, 6444–6448.PubMedCrossRefGoogle Scholar
  100. 100.
    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
  101. 101.
    Kortt, A. A., Lah, M., Oddie, G. W., et al. (1997) Single-chain Fv fragments of anti-neuraminidase antibody NC10 containing five- and ten-residue linkers form dimers and with zero-residue linker a trimer. Protein Eng. 10, 423–433.PubMedCrossRefGoogle Scholar
  102. 102.
    Le Gall, F., Kipriyanov, S. M., Moldenhauer, G., and Little, M. (1999) Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19: Effect of valency on cell binding. FEBS Lett. 453, 164–168.PubMedCrossRefGoogle Scholar
  103. 103.
    Pack, P. and Plückthun, A. (1992) Miniantibodies: Use of amphipathic helices to produce functional, flexibly linked dimeric Fv fragments with high avidity in Escherichia coli. Biochemistry 31, 1579–1584.PubMedCrossRefGoogle Scholar
  104. 104.
    Hu, S., Shively, L., Raubitschek, A., Sherman, M., et al. (1996) Minibody: a novel engineered anticarcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res. 56, 3055–3061.PubMedGoogle Scholar
  105. 105.
    Kipriyanov, S. M., Little, M., Kropshofer, H., et al. (1996) Affinity enhancement of a recombinant antibody: formation of complexes with multiple valency by a single-chain Fv fragment-core streptavidin fusion. Protein Eng. 9, 203–211.PubMedCrossRefGoogle Scholar
  106. 106.
    van Spriel, A. B., van Ojik, H. H., and van De Winkel, J. G. (2000) Immunotherapeutic perspective for bispecific antibodies. Immunol. Today 21, 391–397.PubMedCrossRefGoogle Scholar
  107. 107.
    Milstein, C. and Cuello, A. C. (1983) Hybrid hybridomas and their use in immunohistochemistry. Nature 305, 537–540.PubMedCrossRefGoogle Scholar
  108. 108.
    Dall’Acqua, W. and Carter, P. (1998) Antibody engineering. Curr. Opin. Struct. Biol. 8, 443–450.PubMedCrossRefGoogle Scholar
  109. 109.
    Merchant, A. M., Zhu, Z., Yuan, J. Q., et al. (1998) An efficient route to human bispecific IgG. Nat. Biotechnol. 16, 677–681.PubMedCrossRefGoogle Scholar
  110. 110.
    Shalaby, M. R., Shepard, H. M., Presta, L., et al. (1992) Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J. Exp. Med. 175, 217–225.PubMedCrossRefGoogle Scholar
  111. 111.
    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
  112. 112.
    de Kruif, J. and Logtenberg, T. (1996) Leucine zipper dimerized bivalent and bispecific scFv antibodies from a semi-synthetic antibody phage display library. J. Biol. Chem. 271, 7630–7634.PubMedCrossRefGoogle Scholar
  113. 113.
    Müller, K. M., Arndt, K. M., Strittmatter, W., and Plückthun, A. (1998) The first constant domain (CH1 and CL) of an antibody used as heterodimerization domain for bispecific miniantibodies. FEBS Lett. 422, 259–264.PubMedCrossRefGoogle Scholar
  114. 114.
    Zuo, Z., Jimenez, X., Witte, L., and Zhu, Z. (2000) An efficient route to the production of an IgG-like bispecific antibody. Protein Eng. 13, 361–367.PubMedCrossRefGoogle Scholar
  115. 115.
    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
  116. 116.
    Kurucz, I., Titus, J. A., Jost, C. R., et al. (1995) Retargeting of CTL by an efficiently refolded bispecific single-chain Fv dimer produced in bacteria. J. Immunol. 154, 4576–4582.PubMedGoogle Scholar
  117. 117.
    Schmiedl, A., Breitling, F., and Dübel, S. (2000) Expression of a bispecific dsFv-dsFv’ antibody fragment in Escherichia coli. Protein Eng. 13, 725–734.PubMedCrossRefGoogle Scholar
  118. 118.
    Holliger, P., Brissinck, J., Williams, R. L., et al. (1996) Specific killing of lymphoma cells by cytotoxic T-cells mediated by a bispecific diabody. Protein Eng. 9, 299–305.PubMedCrossRefGoogle Scholar
  119. 119.
    Kipriyanov, S. M., Moldenhauer, G., Strauss, G., and Little, M. (1998) Bispecific CD3 × CD19 diabody for T cell-mediated lysis of malignant human B cells. Int. J. Cancer 77, 763–772.PubMedCrossRefGoogle Scholar
  120. 120.
    Perisic, O., Webb, P. A., Holliger, P., et al. (1994) Crystal structure of a diabody, a bivalent antibody fragment. Structure 2, 1217–1226.PubMedCrossRefGoogle Scholar
  121. 121.
    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
  122. 122.
    Cochlovius, B., Kipriyanov, S. M., Stassar, M. J. J. G., et al. (2000) Treatment of human B cell lymphoma xenografts with a CD3 × CD19 diabody and T cells. J. Immunol. 165, 888–895.PubMedGoogle Scholar
  123. 123.
    Arndt, M. A., Krauss, J., Kipriyanov, S. M., et al. (1999) A bispecific diabody that mediates natural killer cell cytotoxicity against xenotransplanted human Hodgkin’s tumors. Blood 94, 2562–2568.PubMedGoogle Scholar
  124. 124.
    Kipriyanov, S. M., Cochlovius, B., Schafter, H. J., et al. (2002) Synergistic antitumor effect of bispecific CD19 × CD3 and CD19 × CD16 diabodies in a preclinical model of non-Hodgkin’s lymphoma. J. Immunol. 169, 137–144.PubMedGoogle Scholar
  125. 125.
    FitzGerald, K., Holliger, P., and Winter, G. (1997) Improved tumour targeting by disulphide stabilized diabodies expressed in Pichia pastoris. Protein Eng. 10, 1221–1225.PubMedCrossRefGoogle Scholar
  126. 126.
    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
  127. 127.
    Kontermann, R. E. and Müller, R. (1999) Intracellular and cell surface displayed single-chain diabodies. J. Immunol. Methods 226, 179–188.PubMedCrossRefGoogle Scholar
  128. 128.
    Coloma, M. J. and Morrison, S. L. (1997) Design and production of novel tetravalent bispecific antibodies. Nat. Biotechnol. 15, 159–163.PubMedCrossRefGoogle Scholar
  129. 129.
    Schoonjans, R., Willems, A., Schoonooghe, S., et al. (2000) Fab chains as an efficient heterodimerization scaffold for the production of recombinant bispecific and trispecific antibody derivatives. J. Immunol. 165, 7050–7057.PubMedGoogle Scholar
  130. 130.
    Alt, M., Müller, R., and Kontermann, R. E. (1999) Novel tetravalent and bispecific IgG-like antibody molecules combining single-chain diabodies with the immunoglubulin gammal Fc or CH3 region. FEBS Lett. 454, 90–94.PubMedCrossRefGoogle Scholar
  131. 131.
    Müller, K. M., Arndt, K. M., and Plückthun, A. (1998) A dimeric bispecific miniantibody combines two specificities with avidity. FEBS Lett. 432, 45–49.PubMedCrossRefGoogle Scholar
  132. 132.
    Völkel, T., Korn, T., Bach, M., et al. (2001) Optimized linker sequences for the expression of monmoeric and dimeric bispecific single-chain diabodies. Protein Eng. 14, 815–823.PubMedCrossRefGoogle Scholar
  133. 133.
    Cochlovius, B., Kipriyanov, S. M., Stassar, M. J., et al. (2000) Cure of Burkitt’s lymphoma in severe combined immunodeficiency mice by T cells, tetravalent CD3 × CD19 tandem diabody, and CD28 costimulation. Cancer Res. 60, 4336–4341.PubMedGoogle Scholar
  134. 134.
    Andersen, D. C. and Krummen, L. (2002) Recombinant protein expression for therapeutic applications. Curr. Opin. Biotechnol. 13, 117–123.PubMedCrossRefGoogle Scholar
  135. 135.
    Meissner, P., Pick, H., Kulangara, A., et al. (2001) Transient gene expression: Recombinant protein production with suspension-adapted HEK293-EBNA cells. Biotechnol. Bioeng. 75, 197–203.PubMedCrossRefGoogle Scholar
  136. 136.
    Grabenhorst, E., Schlenke, P., Pohl, S., et al. (1999) Genetic engineering of recombinant glycoproteins and the glycosylation pathway in mammalian host cells. Glycoconj. J. 16, 81–97.PubMedCrossRefGoogle Scholar
  137. 137.
    Pollock, D. P., Kutzko, J. P., Birck-Wilson, E., et al. (1999) Transgenic milk as a method for the production of recombinant antibodies. J. Immunol. Methods 231, 147–157.PubMedCrossRefGoogle Scholar
  138. 138.
    Baguisi, A., Behboodi, E., Melican, D. T., et al. (1999) Production of goats by somatic cell nuclear transfer. Nat. Biotechnol. 17, 456–461.PubMedCrossRefGoogle Scholar
  139. 139.
    Hiatt, A., Cafferkey, R., and Bowdish, K. (1989) Production of antibodies in transgenic plants. Nature 342, 76–78.PubMedCrossRefGoogle Scholar
  140. 140.
    Ma, J. K., Hiatt, A., Hein, M., et al. (1995) Generation and assembly of secretory antibodies in plants. Science 268, 716–719.PubMedCrossRefGoogle Scholar
  141. 141.
    Peeters, K., De Wilde, C., De Jaeger, G., et al. (2001) Production of antibodies and antibody fragments in plants. Vaccine 19, 2756–2761.PubMedCrossRefGoogle Scholar
  142. 142.
    Fischer, R., Schumann, D., Zimmermann, S., et al. (1999) Expression and characterization of bispecific single-chain Fv fragments produced in transgenic plants. Eur. J. Biochem. 262, 810–816.PubMedCrossRefGoogle Scholar
  143. 143.
    Vaquero, C., Sack, M., Schuster, F., et al (2002) A carcinoembryonic antigen-specific diabody produced in tobacco. FASEB J. 16, 408–410.PubMedGoogle Scholar
  144. 144.
    Conrad, U. and Fiedler, U. (1998) Compartment-specific accumulation of recombinant immunoglobulins in plant cells: an essential tool for antibody production and immunomodulation of physiological functions and pathogen activity. Plant Mol. Biol. 38, 101–109.PubMedCrossRefGoogle Scholar
  145. 145.
    Vaquero, C., Sack, M., Chandler, J., et al. (1999) Transient expression of a tumor-specific single-chain fragment and a chimeric antibody in tobacco leaves. Proc. Natl. Acad. Sci. USA 96, 11128–11133.PubMedCrossRefGoogle Scholar
  146. 146.
    Hendy, S., Chen, Z. C., Barker, H., et al. (1999) Rapid production of single-chain Fv fragments in plants using a potato virus X episomal vector. J. Immunol. Methods 231, 137–146.PubMedCrossRefGoogle Scholar
  147. 147.
    Mayfield, S. P., Franklin, S. E., and Lerner, R. A. (2003) Expression and assembly of a fully active antibody in algae. Proc. Natl. Acad. Sci. USA 100, 438–442.PubMedCrossRefGoogle Scholar
  148. 148.
    Venturi, M., Seifert, C., and Hunte, C. (2002) High level production of functional antibody Fab fragments in an oxidizing bacterial cytoplasm. J. Mol. Biol. 315, 1–8.PubMedCrossRefGoogle Scholar
  149. 149.
    Jurado, P., Ritz, D., Beckwith, J., et al. (2002) Production of functional single-chain Fv antibodies in the cytoplasm of Escherichia coli. J. Mol. Biol. 320, 1–10.PubMedCrossRefGoogle Scholar
  150. 150.
    Kipriyanov, S. M., Moldenhauer, G., Martin, A. C. R., et al. (1997) Two amino acid mutations in an antihuman CD3 single chain Fv antibody fragment that affect the yield on bacterial secretion but not the affinity. Protein Eng. 10, 445–453.PubMedCrossRefGoogle Scholar
  151. 151.
    Duenas, M., Vazquez, J., Ayala, M., et al. (1994) Intra-and extracellular expression of an scFv antibody fragment in E. coli: Effect of bacterial strains and pathway engineering using GroES/L chaperonins. Biotechniques 16, 476–477.PubMedGoogle Scholar
  152. 152.
    Knappik, A., Krebber, C., and Plückthun, A. (1993) The effect of folding catalysts on the in vivo folding process of different antibody fragments expressed in Escherichia coli. Biotechnology 11, 77–83.PubMedCrossRefGoogle Scholar
  153. 153.
    Bothmann, H. and Plückthun, A. (2000) The periplasmic Escherichia coli peptidylprolyl cis, trans-isomerase FkpA. I. Incrased functional expression of antibody fragments with and without cis-prolines. J. Biol. Chem. 275, 17100–17105.PubMedCrossRefGoogle Scholar
  154. 154.
    Bothmann, H. and Plückthun, A. (1998) Selection for a periplasmic factor improving phage display and functional periplasmic expression. Nat. Biotechnol. 16, 376–380.PubMedCrossRefGoogle Scholar
  155. 155.
    Skerra, A., and Plückthun, A. (1991) Secretion and in vivo folding of the Fab fragment of the antibody McPC603 in Escherichia coli: Influence of disulphides and cis-prolines. Protein Eng. 4, 971–979.PubMedCrossRefGoogle Scholar
  156. 156.
    Kipriyanov, S. M., Moldenhauer, G., and Little, M. (1997) High level production of soluble single chain antibodies in small-scale Escherichia coli cultures. J. Immunol. Methods 200, 69–77.PubMedCrossRefGoogle Scholar
  157. 157.
    Simmons, L. C., Reilly, D., Klimowski, L., et al. (2002) Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies. J. Immunol. Methods 263, 133–147.PubMedCrossRefGoogle Scholar
  158. 158.
    Minshull, J. and Stemmer, W. P. (1999) Protein evolution by molecular breeding. Curr. Opin. Chem. Biol. 3, 284–290.PubMedCrossRefGoogle Scholar
  159. 159.
    Holt, L. J., Enever, C., de Wildt, R. M., and Tomlinson, I. M. (2000) The use of recombinant antibodies in proteomics. Curr. Opin. Biotechnol. 11, 445–449.PubMedCrossRefGoogle Scholar
  160. 160.
    Lal, S. P., Christopherson, R. I., and dos Remedios, C. G. (2002) Antibody arrays: An embryonic but rapidly growing technology. Drug. Discovery Today 7, S143-S149.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Affimed Therapeutics AG, TechnologieparkHeidelbergGermany

Personalised recommendations