Skip to main content
SpringerLink
Log in

Application of Recombinant Antibodies in Cancer Patients

  • Protocol
Recombinant Antibodies for Cancer Therapy

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 207))

  • 933 Accesses

Abstract

As a consequence of the invention of the hybridoma technology by Köhler and Milstein (1), many monoclonal antibodies (MAbs) have been evaluated in clinical trials since the early 1980s. Clinical outcomes were generally poor (2–5), with the notable exception of marked tumor responses, including long-term remissions of patients with malignant B-cell lymphoma who were treated with patient-specific antiidiotypic antibodies (6–8). The main factors responsible for these initial shortcomings were related to the immunogenicity of the murine protein, to modulation of targeted antigens, and to the poor ability of these antibodies to sufficiently mediate antibody-dependent effector functions in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Köhler G. and Milstein C. (1975). Continuous culture of fused cells secreting antibody of predefined specifity. Nature 256, 495–497.

    PubMed  Google Scholar 

  2. Ritz J., Pesando J. M., Sallan S. E., Clavell L. A., Notis-McConarty J., Rosenthal P., and Schlossman S. F. (1981). Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood 58, 141–152.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. Oncol. 2, 881–891.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  6. Meeker T. C., Lowder J., Maloney D. G., Miller R. A., Thielemans K., Warnke R., and Levy R. (1985). A clinical trial of anti-idiotype therapy for B cell malignancy. Blood 65, 1349–1363.

    PubMed  CAS  Google Scholar 

  7. Brown S. L., Miller R. A., Horning S. J., Czerwinski D., Hart S. M., McElderry R., et al. (1989). Treatment of B-cell lymphomas with anti-idiotype antibodies alone and in combination with alpha interferon. Blood 73, 651–661.

    PubMed  CAS  Google Scholar 

  8. Davis T. A., Maloney D. G., Czerwinski D. K., Liles T. M., and Levy R. (1998). Antiidiotype antibodies can induce long-term complete remissions in non-Hodgkin’s lymphoma without eradicating the malignant clone. Blood 92, 1184–1190.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  11. Meselson M. and Yuan R. (1968). DNA restriction enzyme from E. coli. Nature 217, 1110–1114.

    PubMed  CAS  Google Scholar 

  12. Boulianne G. L., Hozumi N., and Shulman M. J. (1984). Production of functional chimaeric mouse/human antibody. Nature 312, 643–646.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  14. Neuberger M. S., Williams G. T., and Fox R. O. (1984). Recombinant antibodies possessing novel effector functions. Nature 312, 604–608.

    PubMed  CAS  Google Scholar 

  15. LoBuglio A. F., Wheeler R. H., Trang J., Haynes A., Rogers K., Harvey E. B., et al. (1989). Mouse/human chimeric antibody in man: kinetics and immune response. Proc. Natl. Acad. Sci. USA 86, 4220–4224.

    PubMed  CAS  Google Scholar 

  16. Khazaeli M. B., Saleh M. N., Liu T. P., Meredith R. F., Wheeler R. H., Baker T. S., 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.

    PubMed  CAS  Google Scholar 

  17. Maloney D. G., Liles T. M., Czerwinski D. K., Waldichuk C., Rosenberg J., Grillo-Lopez A., and Levy R. (1994). Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84, 2457–2466.

    PubMed  CAS  Google Scholar 

  18. Maloney D. G., Grillo-Lopez A. J., White C. A., Bodkin D., Schilder R. J., Neidhart J. 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.

    PubMed  CAS  Google Scholar 

  19. Davis T. A., White C. A., Grillo-Lopez A. J., Velasquez W. S., Link B., Maloney D. G., et al. (1999). Single-agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II trial of rituximab. J. Clin. Oncol. 17, 1851–1857.

    PubMed  CAS  Google Scholar 

  20. Maloney D. G., Grillo-Lopez A. J., Bodkin D. J., White C. A., Liles T. M., Royston I., 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.

    PubMed  CAS  Google Scholar 

  21. Berinstein N. L., Grillo-Lopez A. J., White C. A., Bence-Bruckler I., Maloney D., 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.

    PubMed  CAS  Google Scholar 

  22. Bruggemann M., Williams G. T., Bindon C. I., Clark M. R., Walker M. R., Jefferis R., et al. (1987). Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J. Exp. Med. 166, 1351–1361.

    PubMed  CAS  Google Scholar 

  23. 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.

    PubMed  CAS  Google Scholar 

  24. Abdullah N., Greenman J., Pimenidou A., Topping K. P., and Monson J. R. (1999). The role of monocytes and natural killer cells in mediating antibody-dependent lysis of colorectal tumour cells. Cancer Immunol. Immunother. 48, 517–524.

    PubMed  CAS  Google Scholar 

  25. Golay J., Zaffaroni L., Vaccari T., Lazzari M., Borleri G. M., Bernasconi S., 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.

    PubMed  CAS  Google Scholar 

  26. Steplewski Z., Sun L. K., Shearman C. W., Ghrayeb J., Daddona P., and Koprowski H. (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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  28. Jones P. T., Dear P. H., Foote J., Neuberger M. S., and Winter G. (1986). Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525.

    PubMed  CAS  Google Scholar 

  29. Chothia C. and Lesk A. M. (1987). Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901–917.

    PubMed  CAS  Google Scholar 

  30. Chothia C., Lesk A. M., Tramontano A., Levitt M., Smith-Gill S. J., Air G., et al. (1989). Conformations of immunoglobulin hypervariable regions. Nature 342, 877–883.

    PubMed  CAS  Google Scholar 

  31. Queen C., Schneider W. P., Selick H. E., Payne P. W., Landolfi N. F., Duncan J. F., et al. (1989). A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86, 10,029–10,033.

    PubMed  CAS  Google Scholar 

  32. Kettleborough C. A., Saldanha J., Heath V. J., Morrison C. J., and Bendig M. M. (1991). Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation. Protein Eng. 4, 773–783.

    PubMed  CAS  Google Scholar 

  33. Co M. S., Avdalovic N. M., Caron P. C., Avdalovic M. V., Scheinberg D. A., and Queen, C. (1992). Chimeric and humanized antibodies with specificity for the CD33 antigen. J. Immunol. 148, 1149–1154.

    PubMed  CAS  Google Scholar 

  34. Roberts S., Cheetham J. C., and Rees A. R. (1987). Generation of an antibody with enhanced affinity and specificity for its antigen by protein engineering. Nature 328, 731–734.

    PubMed  CAS  Google Scholar 

  35. Riechmann L., Clark M., Waldmann H., and Winter G. (1988). Reshaping human antibodies for therapy. Nature 332, 323–327.

    PubMed  CAS  Google Scholar 

  36. Roguska M. A., Pedersen J. T., Keddy C. A., Henry A. H., Searle S. J., Lambert J. M., et al. (1994). Humanization of murine monoclonal antibodies through variable domain resurfacing. Proc. Natl. Acad. Sci. USA 91, 969–973.

    PubMed  CAS  Google Scholar 

  37. Glennie M. J. and Johnson P. W. (2000). Clinical trials of antibody therapy. Immunol. Today 21, 403–410.

    PubMed  CAS  Google Scholar 

  38. Behr T. M., Wormann B., Gramatzki M., Riggert J., Gratz S., Behe 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.

    PubMed  CAS  Google Scholar 

  39. Juweid M. E., Stadtmauer E., Hajjar G., Sharkey R. M., Suleiman S., Luger S., et al. (1999). Pharmacokinetics, dosimetry, and initial therapeutic results with 131I-and (111)In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody in patients with relapsed, refractory non-Hodgkin’s lymphoma. Clin. Cancer Res. 5, 3292s–3303s.

    PubMed  CAS  Google Scholar 

  40. Sievers E. L., Appelbaum F. R., Spielberger R. T., Forman S. J., Flowers D., Smith F. O., et al. (1999). Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93, 3678–3684.

    PubMed  CAS  Google Scholar 

  41. Steffens M. G., Boerman O. C., de Mulder P. H., Oyen W. J., Buijs W. C., Witjes J. A., et al. (1999). Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250. Clin. Cancer Res. 5, 3268s–3274s.

    PubMed  CAS  Google Scholar 

  42. Tolcher A. W., Sugarman S., Gelmon K. A., Cohen R., Saleh M., Isaacs C., et al. (1999). Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484.

    PubMed  CAS  Google Scholar 

  43. Saleh M. N., Sugarman S., Murray J., Ostroff J. B., Healey D., Jones D., et al. (2000). Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors. J. Clin. Oncol. 18, 2282–2292.

    PubMed  CAS  Google Scholar 

  44. Miller J. L. (2000). FDA approves antibody-directed cytotoxic agent for acute myeloid leukemia. Am. J. Health Syst. Pharm. 57, 1202, 1204.

    Google Scholar 

  45. Shalaby M. R., Shepard H. M., Presta L., Rodrigues M. L., Beverley P. C., Feldmann M., and Carter P. (1992). Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J. Exp. Med. 175, 217–225.

    PubMed  CAS  Google Scholar 

  46. Zhu Z., Lewis G. D., and Carter P. (1995). Engineering high affinity humanized antip185HER2/anti-CD3 bispecific F(ab′)2 for efficient lysis of p185HER2 overexpressing tumor cells. Int. J. Cancer 62, 319–324.

    PubMed  CAS  Google Scholar 

  47. Luiten R. M., Coney L. R., Fleuren G. J., Warnaar S. O., and Litvinov S. V. (1996). Generation of chimeric bispecific G250/anti-CD3 monoclonal antibody, a tool to combat renal cell carcinoma. Br. J. Cancer 74, 735–744.

    PubMed  CAS  Google Scholar 

  48. Ridgway J. B., Presta L. G., and Carter P. (1996). ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 9, 617–621.

    PubMed  CAS  Google Scholar 

  49. Keler T., Graziano R. F., Mandal A., Wallace P. K., Fisher J., Guyre P. M., et al. (1997). Bispecific antibody-dependent cellular cytotoxicity of HER2/neu-overexpressing tumor cells by Fc gamma receptor type I-expressing effector cells. Cancer Res. 57, 4008–4014.

    PubMed  CAS  Google Scholar 

  50. van Ojik H. H., Repp R., Groenewegen G., Valerius T., and van de Winkel J. G. (1997). Clinical evaluation of the bispecific antibody MDX-H210 (anti-Fc gamma RI · anti-HER-2/neu) in combination with granulocyte-colony-stimulating factor (filgrastim) for treatment of advanced breast cancer. Cancer Immunol. Immunother. 45, 207–209.

    PubMed  Google Scholar 

  51. Posey J. A., Raspet R., Verma U., Deo Y. M., Keller T., Marshall J. L., et al. (1999). A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. J. Immunother. 22, 371–379.

    PubMed  CAS  Google Scholar 

  52. Lewis L. D., Cole B. F., Wallace P. K., Fisher J. L., Waugh M., Guyre P. M., et al. (2001). Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/neu. J. Immunol. Methods 248, 149–165.

    PubMed  CAS  Google Scholar 

  53. Skerra A. and Pluckthun A. (1988). Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science 240, 1038–1041.

    PubMed  CAS  Google Scholar 

  54. 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.

    PubMed  CAS  Google Scholar 

  55. Glockshuber R., Malia M., Pfitzinger I., and Plückthun A. (1990). A comparison of strategies to stabilize immunoglobulin Fv fragments. Biochemistry 29, 1362–1367.

    PubMed  CAS  Google Scholar 

  56. Huston J. S., Levinson D., Mudgett-Hunter M., Tai M. S., Novotny J., Margolies M. N., 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.

    PubMed  CAS  Google Scholar 

  57. Bird R. E., Hardman K. D., Jacobson J. W., Johnson S., Kaufman B. M., Lee S. M., et al. (1988). Single-chain antigen-binding proteins [published erratum appears in Science 1989 Apr 28;244(4903):409]. Science 242, 423–426.

    PubMed  CAS  Google Scholar 

  58. Brinkmann U., Reiter Y., Jung S. H., Lee B., and Pastan I. (1993). A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc. Natl. Acad. Sci. USA 90, 7538–7542.

    PubMed  CAS  Google Scholar 

  59. Reiter Y., Brinkmann U., Jung S. H., Lee B., Kasprzyk P. G., King C. R., and Pastan I. (1994). Improved binding and antitumor activity of a recombinant anti-erbB2 immunotoxin by disulfide stabilization of the Fv fragment. J. Biol. Chem. 269, 18,327–18,331.

    PubMed  CAS  Google Scholar 

  60. Chaudhary V. K., FitzGerald D. J., Adhya S., and Pastan I. (1987). Activity of a recombinant fusion protein between transforming growth factor type alpha and Pseudomonas toxin. Proc. Natl. Acad. Sci. USA 84, 4538–4542.

    PubMed  CAS  Google Scholar 

  61. Chaudhary V. K., Queen C., Junghans R. P., Waldmann T. A., FitzGerald D. J., and Pastan I. (1989). A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339, 394–397.

    PubMed  CAS  Google Scholar 

  62. 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.

    PubMed  CAS  Google Scholar 

  63. Brinkmann U., Pai L. H., FitzGerald D. J., Willingham M., and Pastan I. (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.

    PubMed  CAS  Google Scholar 

  64. Siegall C. B. (1995). Targeted therapy of carcinomas using BR96 sFv-PE40, a singlechain immunotoxin that binds to the Le(y) antigen. Semin. Cancer Biol. 6, 289–295.

    PubMed  CAS  Google Scholar 

  65. Newton D. L., Nicholls P. J., Rybak S. M., and Youle R. J. (1994). Expression and characterization of recombinant human eosinophil-derived neurotoxin and eosinophilderived neurotoxin-anti-transferrin receptor sFv. J. Biol. Chem. 269, 26,739–26,745.

    PubMed  CAS  Google Scholar 

  66. Newton D. L., Xue Y., Olson K. A., Fett J. W., and Rybak S. M. (1996). Angiogenin single-chain immunofusions: influence of peptide linkers and spacers between fusion protein domains. Biochemistry 35, 545–553.

    PubMed  CAS  Google Scholar 

  67. Zewe M., Rybak S. M., Dubel S., Coy J. F., Welschof M., Newton D. L., and Little M. (1997). Cloning and cytotoxicity of a human pancreatic RNase immunofusion. Immunotechnology 3, 127–136.

    PubMed  CAS  Google Scholar 

  68. Bosslet K., Czech J., Lorenz P., Sedlacek H. H., Schuermann M., and Seemann G. (1992). Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activation. Br. J. Cancer 65, 234–238.

    PubMed  CAS  Google Scholar 

  69. Goshorn S. C., Svensson H. P., Kerr D. E., Somerville J. E., Senter P. D., and Fell H. P. (1993). Genetic construction, expression, and characterization of a single chain anticarcinoma antibody fused to beta-lactamase. Cancer Res. 53, 2123–2127.

    PubMed  CAS  Google Scholar 

  70. Rodrigues M. L., Presta L. G., Kotts C. E., Wirth C., Mordenti J., Osaka G., et al. (1995). Development of a humanized disulfide-stabilized anti-p185HER2 Fv-betalactamase fusion protein for activation of a cephalosporin doxorubicin prodrug. Cancer Res. 55, 63–70.

    PubMed  CAS  Google Scholar 

  71. Michael N. P., Chester K. A., Melton R. G., Robson L., Nicholas W., Boden J. A., et. al. (1996). In vitro and in vivo characterisation of a recombinant carboxypeptidase G2:anti-CEA scFv fusion protein. Immunotechnology 2, 47–57.

    PubMed  CAS  Google Scholar 

  72. Haisma H. J., Sernee M. F., Hooijberg E., Brakenhoff R. H., vd Meulen-Muileman I. H., 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.

    PubMed  CAS  Google Scholar 

  73. Colcher D., Pavlinkova G., Beresford G., Booth B. J., and Batra S. K. (1999). Singlechain antibodies in pancreatic cancer. Ann. NY Acad. Sci. 880, 263–280.

    PubMed  CAS  Google Scholar 

  74. 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.

    PubMed  CAS  Google Scholar 

  75. Xu X., Clarke P., Szalai G., Shively J. E., Williams L. E., Shyr Y., Shi E., 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.

    PubMed  CAS  Google Scholar 

  76. Biragyn A., Tani K., Grimm M. C., Weeks S., and Kwak L. W. (1999). Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nature Biotechnol. 17, 253–258.

    CAS  Google Scholar 

  77. 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.

    PubMed  CAS  Google Scholar 

  78. Pack P. and Pluckthun 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.

    PubMed  CAS  Google Scholar 

  79. Holliger P., Prospero T., and Winter G. (1993). “Diabodies”: Small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. USA 90, 6444–6448.

    PubMed  CAS  Google Scholar 

  80. 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.

    PubMed  CAS  Google Scholar 

  81. Zhu Z., Presta L. G., Zapata G., and Carter P. (1997). Remodeling domain interfaces to enhance heterodimer formation. Protein Sci. 6, 781–788.

    PubMed  CAS  Google Scholar 

  82. Holliger P., Brissinck J., Williams R. L., Thielmans K., and Winter G. (1996). Specific killing of lymphoma cells by cytotoxic T-cells mediated by a bispecific diabody. Prot. Eng. 9, 299–305.

    CAS  Google Scholar 

  83. Zhu Z., Zapata G., Shalaby R., Snedecor B., Chen H., and Carter P. (1996). High-Level secretion of a humanized bispecific diabody from Escherichia coli. Biotechnology 14, 192–196.

    PubMed  CAS  Google Scholar 

  84. Kipriyanov S. M., Moldenhauer G., Srauss 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.

    PubMed  CAS  Google Scholar 

  85. Manzke O., Fitzgerald K. J., Holliger P., Klock J., Span M., Fleischmann B. H., et al. (1999). CD3X anti-nitrophenyl bispecific diabodies: universal Immunotherapeutic tools for retargeting T cells to tumors. Int. J. Cancer 82, 700–708.

    PubMed  CAS  Google Scholar 

  86. 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.

    PubMed  CAS  Google Scholar 

  87. Coloma M. J. and Morrison S. L. (1997). Design and production of novel tetravalent bispecific antibodies. Nature Biotechnol. 15, 159–163.

    CAS  Google Scholar 

  88. Alt M., Muller R., and Kontermann R. E. (1999). Novel tetravalent and bispecific IgGlike antibody molecules combining single-chain diabodies with the immunoglobulin gamma1 Fc or CH3 region. FEBS Lett. 454, 90–94.

    PubMed  CAS  Google Scholar 

  89. Kipriyanov S. M., Moldenhauer G., Schuhmacher J., Cochlovius B., Von der Lieth C. W., Matys E. R., and Little M. (1999). Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J. Mol. Biol. 293, 41–56.

    PubMed  CAS  Google Scholar 

  90. Gross G. and Eshhar Z. (1992). Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB J. 6, 3370–3378.

    PubMed  CAS  Google Scholar 

  91. 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.

    PubMed  CAS  Google Scholar 

  92. Hwu P., Shafer G. E., Treisman J., Schindler D. G., Gross G., Cowherd R., et al. (1993). Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J. Exp. Med. 178, 361–366.

    PubMed  CAS  Google Scholar 

  93. Hombach A., Heuser C., Sircar R., Tillmann T., Diehl V., Kruis W., 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.

    PubMed  CAS  Google Scholar 

  94. Hombach A., Schneider C., Sent D., Koch D., Willemsen R. A., Diehl V., 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.

    PubMed  CAS  Google Scholar 

  95. Kreitman R. J., Wilson W. H., Bergeron K., Raggio M., Stetler-Stevenson M., FitzGerald D. J., and Pastan I. (2001). Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N. Engl. J. Med. 26, 241–247.

    Google Scholar 

  96. Kreitman R. J., Wilson W. H., White J. D., Stetler-Stevenson M., Jaffe E. S., Giardina S., et al. (2000). Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol. 18, 1622–1636.

    PubMed  CAS  Google Scholar 

  97. Smith G. P. (1985). Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317.

    PubMed  CAS  Google Scholar 

  98. McCafferty J., Griffiths A. D., Winter G., and Chiswell D. J. (1990). Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554.

    PubMed  CAS  Google Scholar 

  99. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., and Arnheim N. (1985). Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230, 1350–1354.

    PubMed  CAS  Google Scholar 

  100. Orlandi R., Gussow D. H., Jones P. T., and Winter G. (1989). Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc. Natl. Acad. Sci. USA 86, 3833–3837.

    PubMed  CAS  Google Scholar 

  101. Sastry L., Alting-Mees M., Huse W. D., Short J. M., Sorge J. A., Hay B. N., et al. (1989). Cloning of the immunological repertoire in Escherichia coli for generation of monoclonal catalytic antibodies: construction of a heavy chain variable region-specific cDNA library. Proc. Natl. Acad. Sci. USA 86, 5728–5732.

    PubMed  CAS  Google Scholar 

  102. 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.

    PubMed  CAS  Google Scholar 

  103. Welschof M., Terness P., Kolbinger F., Zewe M., Dubel S., Dorsam H., 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.

    PubMed  CAS  Google Scholar 

  104. Barbas C. F., 3rd, 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.

    PubMed  CAS  Google Scholar 

  105. Breitling F., Dubel S., Seehaus T., Klewinghaus I., and Little M. (1991). A surface expression vector for antibody screening. Gene 104, 147–153.

    PubMed  CAS  Google Scholar 

  106. Hoogenboom H. R., Griffiths A. D., Johnson K. S., Chiswell D. J., Hudson P., and Winter G. (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.

    PubMed  CAS  Google Scholar 

  107. 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.

    PubMed  CAS  Google Scholar 

  108. Pereira S., Van Belle P., Elder D., Maruyama H., Jacob L., Sivanandham M., et al. (1997). Combinatorial antibodies against human malignant melanoma. Hybridoma 16, 11–16.

    PubMed  CAS  Google Scholar 

  109. Welschof M., Terness P., Kipriyanov S. M., Stanescu D., Breitling F., Dorsam H., et al. (1997). The antigen-binding domain of a human IgG-anti-F(ab′)2 autoantibody. Proc. Natl. Acad. Sci. USA 94, 1902–1907.

    PubMed  CAS  Google Scholar 

  110. Clackson T., Hoogenboom H. R., Griffiths A. D., and Winter G. (1991). Making antibody fragments using phage display libraries. Nature 352, 624–628.

    PubMed  CAS  Google Scholar 

  111. Chester K. A., Begent R. H. J., Robson L., Keep P., Pedley R. B., Boden J. A., et al. (1994). Phage libraries for generation of clinically useful antibodies. Lancet 343, 455–456.

    PubMed  CAS  Google Scholar 

  112. Kettleborough C. A., Ansell K. H., Allen R. W., Rosell-Vives E., Gussow D. H., and Bendig M. M. (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.

    PubMed  CAS  Google Scholar 

  113. Marks J. D., Hoogenboom H. R., Bonnert T. P., McCafferty J., Griffiths A. D., and Winter G. (1991). By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222, 581–597.

    PubMed  CAS  Google Scholar 

  114. Sheets M. D., Amersdorfer P., Finnern R., Sargent P., Lindquist E., Schier 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.

    PubMed  CAS  Google Scholar 

  115. de Haard H. J., van Neer N., Reurs A., Hufton S. E., Roovers R. C., Henderikx P., 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, 18,218–18,230.

    PubMed  Google Scholar 

  116. Little M., Welschof M., Braunagel M., Hermes I., Christ C., Keller A., et al. (1999). Generation of a large complex antibody library from multiple donors. J. Immunol. Methods 231, 3–9.

    PubMed  CAS  Google Scholar 

  117. Barbas C. F., 3rd, 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.

    PubMed  CAS  Google Scholar 

  118. 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.

    PubMed  CAS  Google Scholar 

  119. Garrard L. J. and Henner D. J. (1993). Selection of an anti-IGF-1 Fab from a Fab phage library created by mutagenesis of multiple CDR loops. Gene 128, 103–109.

    PubMed  CAS  Google Scholar 

  120. Griffiths A. D., Williams S. C., Hartley O., Tomlinson I. M., Waterhouse P., Crosby W. L., et al. (1994). Isolation of high affinity human antibodies directly from large synthetic repertoires. EMBO J. 13, 3245–3260.

    PubMed  CAS  Google Scholar 

  121. Nissim A., Hoogenboom H. R., Tomlinson I. M., Flynn G., Midgley C., Lane D., and Winter G. (1994). Antibody fragments from a’ single pot’ phage display library as immunochemical reagents. EMBO J. 13, 692–698.

    PubMed  CAS  Google Scholar 

  122. Braunagel M. and Little M. (1997). Construction of a semisynthetic antibody library using trinucleotide oligos. Nucleic Acids Res. 25, 4690–4691.

    PubMed  CAS  Google Scholar 

  123. Knappik A., Ge L., Honegger A., Pack P., Fischer M., Wellnhofer G., et al. (2000). Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucl otides. J. Mol. Biol. 296, 57–86.

    PubMed  CAS  Google Scholar 

  124. 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.

    PubMed  CAS  Google Scholar 

  125. 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.

    PubMed  CAS  Google Scholar 

  126. Hamers-Casterman C., Atarhouch T., Muyldermans S., Robinson G., Hamers C., Songa E. B., et al. (1993). Naturally occurring antibodies devoid of light chains. Nature 363, 446–448.

    PubMed  CAS  Google Scholar 

  127. Arbabi Ghahroudi M., Desmyter A., Wyns L., Hamers R., and Muyldermans S. (1997). Selection and identification of single domain antibody fragments from camel heavychain antibodies. FEBS Lett. 414, 521–526.

    PubMed  CAS  Google Scholar 

  128. 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.

    PubMed  CAS  Google Scholar 

  129. 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.

    PubMed  CAS  Google Scholar 

  130. Begent R. H., Verhaar M. J., Chester K. A., Casey J. L., Green A. J., Napier M. P., (1996). Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library. Nat. Med. 2, 979–984.

    PubMed  CAS  Google Scholar 

  131. Mayer A., Chester K. A., Flynn A. A., and Begent R. H. (1999). Taking engineered anti-CEA antibodies to the clinic. J. Immunol. Methods 231, 261–273.

    PubMed  CAS  Google Scholar 

  132. Carson D. A. and Freimark B. D. (1986). Human lymphocyte hybridomas and monoclonal antibodies. Adv. Immunol. 38, 275–311.

    PubMed  CAS  Google Scholar 

  133. Bruggemann M., Spicer C., Buluwela L., Rosewell I., Barton S., Surani M. A., and Rabbitts T. H. (1991). Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus. Eur. J. Immunol. 21, 1323–1326.

    PubMed  CAS  Google Scholar 

  134. Taylor L. D., Carmack C. E., Schramm S. R., Mashayekh R., Higgins K. M., Kuo C. C., et al. (1992). A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins. Nucleic Acids Res. 20, 6287–6295.

    PubMed  CAS  Google Scholar 

  135. Lonberg N., Taylor L. D., Harding F. A., Trounstine M., Higgins K. M., Schramm S. R., et al. (1994). Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859.

    PubMed  CAS  Google Scholar 

  136. Nicholson I. C., Zou X., Popov A. V., Cook G. P., Corps E. M., Humphries S., 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.

    PubMed  CAS  Google Scholar 

  137. Tomizuka K., Shinohara T., Yoshida H., Uejima H., Ohguma A., Tanaka S., 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.

    PubMed  CAS  Google Scholar 

  138. Stashenko P., Nadler L. M., Hardy R., and Schlossman S. F. (1980). Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125, 1678–1685.

    PubMed  CAS  Google Scholar 

  139. McLaughlin P., Grillo-Lopez A. J., Link B. K., Levy R., Czuczman M. S., Williams M. E., 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.

    PubMed  CAS  Google Scholar 

  140. Coiffier B., Haioun C., Ketterer N., Engert A., Tilly H., Ma D., et 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.

    PubMed  CAS  Google Scholar 

  141. Coiffier B., Lepage E., Herbrecht R., Tilly H., Solal-Celigny P., Munck J. N., et al. (2000). Mabthera (Rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large B-cell lymphoma (DLCL): Interim results of a randomized GELA trial. Abstract #950 American Society of Hematology (ASH).

    Google Scholar 

  142. Coiffier B., Lepage E., Gaulard P., Quesnel A., Bosly A., Christian B., et al. (2001). Prognostic factors affecting the efficacy of Rituximab plus CHOP (R-CHOP) therapy in elderly patients with diffuse large B-cell lymphoma (DLCL): results of a randomized GELA trial. Abstract #1131 Annual Meeting of American Society of Clinical Oncologists (ASCO).

    Google Scholar 

  143. Vose J. M., Link B. K., Grossbard M. L., Czuczman M., Grillo-Lopez A., Gilman P., et al. (2001). 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.

    PubMed  CAS  Google Scholar 

  144. Czuczman M. S., Grillo-Lopez A. J., White C. A., Saleh M., Gordon L., LoBuglio A. F., 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.

    PubMed  CAS  Google Scholar 

  145. Colombat P., Salles G., Brousse N., Eftekhari P., Soubeyran P., Delwail V., 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.

    PubMed  CAS  Google Scholar 

  146. Buckstein R., Imrie K., Spaner D., Potichnyj A., Robinson J. B., Nanji S., 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.

    PubMed  CAS  Google Scholar 

  147. Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., et al. (1985). Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230, 1132–1139.

    PubMed  CAS  Google Scholar 

  148. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., and McGuire W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182.

    PubMed  CAS  Google Scholar 

  149. Borg A., Tandon A. K., Sigurdsson H., Clark G. M., Ferno M., Fuqua S. A., et al. (1990). HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res. 50, 4332–4337.

    PubMed  CAS  Google Scholar 

  150. Hudziak R. M., Lewis G. D., Winget M., Fendly B. M., Shepard H. M., and Ullrich A. (1989). p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell Biol. 9, 1165–1172.

    PubMed  CAS  Google Scholar 

  151. Shepard H. M., Lewis G. D., Sarup J. C., Fendly B. M., Maneval D., Mordenti J., et al. (1991). Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J. Clin. Immunol. 11, 117–127.

    PubMed  CAS  Google Scholar 

  152. Carter P., Presta L., Gorman C. M., Ridgway J. B., Henner D., Wong W. L., et al. (1992). Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. USA 89, 4285–4289.

    PubMed  CAS  Google Scholar 

  153. Baselga J., Tripathy D., Mendelsohn J., Baughman S., Benz C. C., Dantis L., 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.

    PubMed  CAS  Google Scholar 

  154. Vici P., Belli F., Di Lauro L., Amodio A., Conti F., Foggi P., et al. (2001). Docetaxel in patients with anthracycline-resistant advanced breast cancer. Oncology 60, 60–65.

    PubMed  CAS  Google Scholar 

  155. Cobleigh M. A., Vogel C. L., Tripathy D., Robert N. J., Scholl S., Fehrenbacher L., 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.

    PubMed  CAS  Google Scholar 

  156. Baselga J., Norton L., Albanell J., Kim Y. M., and Mendelsohn J. (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.

    PubMed  CAS  Google Scholar 

  157. Pietras R. J., Pegram M. D., Finn R. S., Maneval D. A., and Slamon D. J. (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.

    PubMed  CAS  Google Scholar 

  158. Slamon D. J., Leyland-Jones B., Shak S., Fuchs H., Paton V., Bajamonde A., 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.

    PubMed  CAS  Google Scholar 

  159. Tan A. R. and Swain S. M. (2001). Adjuvant chemotherapy for breast cancer: an update. Semin. Oncol. 28, 359–376.

    PubMed  CAS  Google Scholar 

  160. Koprowski H., Herlyn D., Lubeck M., DeFreitas E., and Sears H. F. (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.

    PubMed  CAS  Google Scholar 

  161. LoBuglio A. F., Saleh M. N., Lee J., Khazaeli M. B., Carrano R., Holden H., and Wheeler R. H. (1988). Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects. J. Natl. Cancer Inst. 80, 932–936.

    PubMed  CAS  Google Scholar 

  162. Riethmuller G., Schneider-Gadicke E., Schlimok G., Schmiegel W., Raab R., Hoffken K., 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.

    PubMed  CAS  Google Scholar 

  163. Gruber R., van Haarlem L. J., Warnaar S. O., Holz E., and Riethmuller G. (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.

    PubMed  CAS  Google Scholar 

  164. Jerne N. K. (1974). Towards a network theory of the immune system. Ann. Immunol. (Paris) 125C, 373–389.

    CAS  Google Scholar 

  165. Frodin J. E., Faxas M. E., Hagstrom B., Lefvert A. K., Masucci G., Nilsson 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.

    PubMed  CAS  Google Scholar 

  166. Wagner U. A., Oehr P. F., Reinsberg J., Schmidt S. C., Schlebusch H. W., Schultes B., et al. (1992). Immunotherapy of advanced ovarian carcinomas by activation of the idiotypic network. Biotechnol. Ther. 3, 81–89.

    PubMed  CAS  Google Scholar 

  167. Cheung N. K., Cheung I. Y., Canete A., Yeh S. J., Kushner B., Bonilla M. A., et al. (1994). Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival. Cancer Res. 54, 2228–2233.

    PubMed  CAS  Google Scholar 

  168. Schmolling J., Reinsberg J., Wagner U., and Krebs D. (1997). Anti-TAG-72 antibody B72.3 — immunological and clinical effects in ovarian carcinoma. Hybridoma 16, 53–58.

    PubMed  CAS  Google Scholar 

  169. 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.

    PubMed  CAS  Google Scholar 

  170. Nadler L. M., Stashenko P., Hardy R., Kaplan W. D., Button L. N., Kufe D. W., et al. (1980). Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 40, 3147–3154.

    PubMed  CAS  Google Scholar 

  171. Miller R. A. and Levy R. (1981). Response of cutaneous T cell lymphoma to therapy with hybridoma monoclonal antibody. Lancet 2, 226–230.

    PubMed  CAS  Google Scholar 

  172. Cobbold S. P. and Waldmann H. (1984). Therapeutic potential of monovalent monoclonal antibodies. Nature 308, 460–462.

    PubMed  CAS  Google Scholar 

  173. Sahin U., Tureci O., Schmitt H., Cochlovius B., Johannes T., Schmits R., et al. (1995). Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 92, 11,810–11,813.

    PubMed  CAS  Google Scholar 

  174. Barth S., Weidenmuller U., Tur M. K., Schmidt M. F., and Engert A. (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.

    PubMed  CAS  Google Scholar 

  175. Chames P., Hufton S. E., Coulie P. G., Uchanska-Ziegler B., and Hoogenboom H. R. (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.

    PubMed  CAS  Google Scholar 

  176. Li J., Pereira S., Van Belle P., Tsui P., Elder D., Speicher D., et al. (2001). Isolation of the melanoma-associated antigen p23 using antibody phage display. J. Immunol. 166, 432–438.

    PubMed  CAS  Google Scholar 

  177. 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.

    PubMed  CAS  Google Scholar 

  178. 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.

    PubMed  CAS  Google Scholar 

  179. 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.

    PubMed  CAS  Google Scholar 

  180. 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.

    PubMed  CAS  Google Scholar 

  181. Herlyn D., Herlyn M., Ross A. H., Ernst C., Atkinson B., and Koprowski H. (1984). Efficient selection of human tumor growth-inhibiting monoclonal antibodies. J. Immunol. Methods 73, 157–167.

    PubMed  CAS  Google Scholar 

  182. 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.

    PubMed  CAS  Google Scholar 

  183. Liu A. Y., Robinson R. R., Murray E. D., Jr., Ledbetter J. A., Hellstrom I., and Hellstrom K. E. (1987). Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J. Immunol. 139, 3521–3526.

    PubMed  CAS  Google Scholar 

  184. Caron P. C., Co M. S., Bull M. K., Avdalovic N. M., Queen C., and Scheinberg D. A. (1992). Biological and Immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res. 52, 6761–6767.

    PubMed  CAS  Google Scholar 

  185. Ravetch J. V. and Clynes R. A. (1998). Divergent roles for Fc receptors and complement in vivo. Annu. Rev. Immunol. 16, 421–432.

    PubMed  CAS  Google Scholar 

  186. Bolland S. and Ravetch J. V. (1999). Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149–177.

    PubMed  CAS  Google Scholar 

  187. Cragg M. S., French R. R., and Glennie M. J. (1999). Signaling antibodies in cancer therapy. Curr. Opin. Immunol. 11, 541–547.

    PubMed  CAS  Google Scholar 

  188. 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.

    PubMed  CAS  Google Scholar 

  189. 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.

    PubMed  CAS  Google Scholar 

  190. Ghetie M. A., Podar E. M., Ilgen A., Gordon B. E., Uhr J. W., and Vitetta E. S. (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.

    PubMed  CAS  Google Scholar 

  191. Stout R. D., Suttles J., Xu J., Grewal I. S., and Flavell R. A. (1996). Impaired T cellmediated macrophage activation in CD40 ligand-deficient mice. J. Immunol. 156, 8–11.

    PubMed  CAS  Google Scholar 

  192. van Kooten C. and Banchereau J. (1997). Functions of CD40 on B cells, dendritic cells and other cells. Curr. Opin. Immunol. 9, 330–337.

    PubMed  Google Scholar 

  193. French R. R., Chan H. T., Tutt A. L., and Glennie M. J. (1999). CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat. Med. 5, 548–553.

    PubMed  CAS  Google Scholar 

  194. Pietras R. J., Poen J. C., Gallardo D., Wongvipat P. N., Lee H. J., and Slamon D. J. (1999). Monoclonal antibody to HER-2/neureceptor modulates repair of radiationinduced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 59, 1347–1355.

    PubMed  CAS  Google Scholar 

  195. Goldenberg D. M., Sharkey R. M., Goldenberg H., Hall T. C., Murthy S., Izon D. O., et al. (1990). Monoclonal antibody therapy of cancer. NJ Med. 87, 913–918.

    CAS  Google Scholar 

  196. Chester K. A. and Hawkins R. E. (1995). Clinical issues in antibody design. Trends Biotechnol. 13, 294–300.

    PubMed  CAS  Google Scholar 

  197. Adams G. P., Schier R., Marshall K., Wolf E. J., McCall A. M., Marks J. D., and Weiner L. M. (1998). Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies. Cancer Res. 58, 485–490.

    PubMed  CAS  Google Scholar 

  198. Purtell J. N., Pesce A. J., Clyne D. H., Miller W. C., and Pollak V. E. (1979). Isoelectric point of albumin: effect on renal handling of albumin. Kidney Int. 16, 366–376.

    PubMed  CAS  Google Scholar 

  199. Deen W. M., Bridges C. R., and Brenner B. M. (1983). Biophysical basis of glomerular permselectivity. J. Membr. Biol. 71, 1–10.

    PubMed  CAS  Google Scholar 

  200. Vaughn D. E., Milburn C. M., Penny D. M., Martin W. L., Johnson J. L., and Bjorkman P. J. (1997). Identification of critical IgG binding epitopes on the neonatal Fc receptor. J. Mol. Biol. 274, 597–607.

    PubMed  CAS  Google Scholar 

  201. 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.

    PubMed  CAS  Google Scholar 

  202. Ghetie V., Popov S., Borvak J., Radu C., Matesoi D., Medesan C., et al. (1997). Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat. Biotechnol. 15, 637–640.

    PubMed  CAS  Google Scholar 

  203. 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.

    PubMed  CAS  Google Scholar 

  204. 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.

    PubMed  CAS  Google Scholar 

  205. Milenic D. E., Yokota T., Filpula D. R., Finkelman M. A., Dodd S. W., Wood J. F., 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.

    PubMed  CAS  Google Scholar 

  206. Huston J. S., George A. J., Adams G. P., Stafford W. F., Jamar F., Tai M. S., et al. (1996). Single-chain Fv radioimmunotargeting. Q. J. Nucl. Med. 40, 320–333.

    PubMed  CAS  Google Scholar 

  207. Adams G. P., Schier R., McCall A. M., Crawford R. S., Wolf E. J., Weiner L. M., and Marks J. D. (1998). Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br. J. Cancer 77, 1405–1412.

    PubMed  CAS  Google Scholar 

  208. 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.

    PubMed  CAS  Google Scholar 

  209. Boerman O. C., Mijnheere E. P., Broers J. L., Vooijs G. P., and Ramaekers F. C. (1991). Biodistribution of a monoclonal antibody (RNL-1) against the neural cell adhesion molecule (NCAM) in athymic mice bearing human small-cell lung-cancer xenografts. Int. J. Cancer 48, 457–462.

    PubMed  CAS  Google Scholar 

  210. Kennel S. J., Falcioni R., and Wesley J. W. (1991). Microdistribution of specific rat monoclonal antibodies to mouse tissues and human tumor xenografts. Cancer Res. 51, 1529–1536.

    PubMed  CAS  Google Scholar 

  211. Clauss M. A. and Jain R. K. (1990). Interstitial transport of rabbit and sheep antibodies in normal and neoplastic tissues. Cancer Res. 50, 3487–3492.

    PubMed  CAS  Google Scholar 

  212. Colcher D., Bird R., Roselli M., Hardman K. D., Johnson S., Pope S., et al. (1990). In vivo tumor targeting of a recombinant single-chain antigen-bindin protein. J. Natl. Cancer Inst. 82, 1191–1197.

    PubMed  CAS  Google Scholar 

  213. Adams G. P., McCartney J. E., Tai M. S., Oppermann H., Huston J. S., Stafford W. F. D., 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.

    PubMed  CAS  Google Scholar 

  214. Kitamura K., Takahashi T., Yamaguchi T., Noguchi A., Takashina K., Tsurumi H., et al. (1991). Chemical engineering of the monoclonal antibody A7 by polyethylene glycol for targeting cancer chemotherapy. Cancer Res. 51, 4310–4315.

    PubMed  CAS  Google Scholar 

  215. Pedley R. B., Boden J. A., Boden R., Begent R. H., Turner A., Haines A. M., and King D. J. (1994). The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody. Br. J. Cancer 70, 1126–1130.

    PubMed  CAS  Google Scholar 

  216. Chapman A. P., Antoniw P., Spitali M., West S., Stephens S., and King D. J. (1999). Therapeutic antibody fragments with prolonged in vivo half-lives. Nature Biotechnol. 17, 780–783.

    CAS  Google Scholar 

  217. Abuchowski A., McCoy J. R., Palczuk N. C., van Es T., and Davis F. F. (1977). Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252, 3582–3586.

    PubMed  CAS  Google Scholar 

  218. Marks J. D., Griffiths A. D., Malmqvist M., Clackson T. P., Bye J. M., and Winter G. (1992). By-passing immunization: building high affinity human antibodies by chain shuffling. Biotechnology (NY) 10, 779–783.

    CAS  Google Scholar 

  219. Hawkins R. E., Russell S. J., Baier M., and Winter G. (1993). The contribution of contact and non-contact residues of antibody in the affinity of binding to antigen. The interaction of mutant D1.3 antibodies with lysozyme. J. Mol. Biol. 234, 958–964.

    PubMed  CAS  Google Scholar 

  220. Schier R., McCall A., Adams G. P., Marshall K. W., Merritt H., Yim M., 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.

    PubMed  CAS  Google Scholar 

  221. Schier R., Marks J. D., Wolf E. J., Apell G., Wong C., McCartney J. E., et al. (1995). In vitro and in vivo characterization of a human anti-c-erbB-2 single-chain Fv isolated from a filamentous phage antibody library. Immunotechnology 1, 73–81.

    PubMed  CAS  Google Scholar 

  222. Schier R., Bye J., Apell G., McCall A., Adams G. P., Malmqvist M., et 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.

    PubMed  CAS  Google Scholar 

  223. Adams G. P., Schier R., McCall A., Wolf E. J., Marks J. D., and Weiner L. M. (1996). Tumor targeting properties of anti-c-erb-2 single-chain Fv molecules over a wide range of affinities for the same epitope. Tumor Targeting 2, 154.

    Google Scholar 

  224. Weinstein J. N., Eger R. R., Covell D. G., Black C. D., Mulshine J., Carrasquillo J. A., et al. (1987). The pharmacology of monoclonal antibodies. Ann. NY Acad. Sci. 507, 199–210.

    PubMed  CAS  Google Scholar 

  225. Adams G. P., Schier R., McCall A. M., Simmons H. H., Horak E. M., Alpaugh R. K., Marks J. D., and Weiner L. M. (2001). High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61, 4750–4755.

    PubMed  CAS  Google Scholar 

  226. Crothers D. M. and Metzger H. (1972). The influence of polyvalency on the binding properties of antibodies. Immunochemistry 9, 341–357.

    PubMed  CAS  Google Scholar 

  227. Wu A. M., Chen W., Raubitschek A., Williams L. E., Neumaier M., Fischer R., et al. (1996). Tumor localization of anti-CEA single-chain Fvs: improved targeting by noncovalent dimers. Immunotechnology 2, 21–36.

    PubMed  CAS  Google Scholar 

  228. Goel A., Colcher D., Baranowska-Kortylewicz J., Augustine S., Booth B. J., Pavlinkova G., and Batra S. K. (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.

    PubMed  CAS  Google Scholar 

  229. 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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Cancer Institute at Frederick, Frederick, MD

    Jürgen Krauss & Michaela Arndt

  2. Universitätskliniken des Saarlandes, Innere Medizin I, Homburg, Germany

    Michael Pfreundschuh

Authors
  1. Jürgen Krauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michaela Arndt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Pfreundschuh
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Axaron Bioscience AG, Heidelberg, Germany

    Martin Welschof

  2. National Institutes of Health, National Cancer Institute, Frederick, MD

    Jürgen Krauss

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Humana Press Inc.

About this protocol

Cite this protocol

Krauss, J., Arndt, M., Pfreundschuh, M. (2003). Application of Recombinant Antibodies in Cancer Patients. In: Welschof, M., Krauss, J. (eds) Recombinant Antibodies for Cancer Therapy. Methods in Molecular Biology™, vol 207. Humana Press. https://doi.org/10.1385/1-59259-334-8:27

Download citation

  • DOI: https://doi.org/10.1385/1-59259-334-8:27

  • Publisher Name: Humana Press

  • Print ISBN: 978-0-89603-918-6

  • Online ISBN: 978-1-59259-334-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation