Skip to main content
SpringerLink
Log in

Bispecific Antibodies and Trispecific Immunocytokines for Targeting the Immune System Against Cancer

Preparing for the Future

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Monoclonal anti-tumor antibodies (mAbs) that are clinically effective usually recruit, via their constant fragment (Fc) domain, Fc receptor (FcR)-positive accessory cells of the immune system and engage these additionally against the tumor. Since T cells are FcR negative, these important cells are not getting involved. In contrast to mAbs, bispecific antibodies (bsAbs) can be designed in such a way that they involve T cells. bsAbs are artificially designed molecules that bind simultaneously to two different antigens, one on the tumor cell, the other one on an immune effector cell such as CD3 on T cells. Such dual antibody constructs can cross-link tumor cells and T cells. Many such bsAb molecules at the surface of tumor cells can thus build a bridge to T cells and aggregate their CD3 molecules, thereby activating them for cytotoxic activity. BsAbs can also contain a third binding site, for instance a Fc domain or a cytokine that would bind to its respective cytokine receptor. The present review discusses the pros and cons for the use of the Fc fragment during the development of bsAbs using either cell-fusion or recombinant DNA technologies. The recombinant antibody technology allows the generation of very efficient bsAbs containing no Fc domain such as the bi-specific T-cell engager (BiTE). The strong antitumor activity of these molecules makes them very interesting new cancer therapeutics. Over the last decade, we have developed another concept, namely to combine bsAbs and multivalent immunocytokines with a tumor cell vaccine. The latter are patient-derived tumor cells modified by infection with a virus. The virus—Newcastle Disease Virus (NDV)—introduces, at the surface of the tumor cells, viral molecules that can serve as general anchors for the bsAbs. Our strategy aims at redirecting, in an Fc-independent fashion, activities of T cells and accessory cells against autologous tumor antigens. It creates very promising perspectives for a new generation of efficient and safe cancer therapeutics that should confer long-lasting anti-tumor immunity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7.

    Article  PubMed  Google Scholar 

  2. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–45.

    PubMed  CAS  Google Scholar 

  3. Mayes S, Brown N, Illidge TM. New antibody drug treatments for lymphoma. Expert Opin Biol Ther. 2011;11(5):623–40.

    Article  PubMed  CAS  Google Scholar 

  4. Reichert JM. Metrics for antibody therapeutics development. MAbs. 2010;2(6):2695–700.

    Google Scholar 

  5. Reichert JM. Antibodies to watch in 2010. MAbs. 2010;2(1):84–100.

    Article  PubMed  Google Scholar 

  6. Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6(5):343–57.

    Article  PubMed  CAS  Google Scholar 

  7. Presta LG. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol. 2008;20(4):460–70.

    Article  PubMed  CAS  Google Scholar 

  8. Segal DM, Weiner GJ, Weiner LM. Bispecific antibodies in cancer therapy. Curr Opin Immunol. 1999;11:558–62.

    Article  PubMed  CAS  Google Scholar 

  9. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–7.

    Article  PubMed  CAS  Google Scholar 

  10. Maletz M, Kufer P, Mack M, Raum T, Pantel K, Riethmüller G, Gruber R. Bispecific single-chain antibodies as effective tools for eliminating epithelial cancer cells from human stem cell preparations by redirected cell cytotoxicity. Int J Cancer. 2001;93:409–16.

    Article  PubMed  CAS  Google Scholar 

  11. Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature. 1985;314(6012):628–31.

    Article  PubMed  CAS  Google Scholar 

  12. Fanger MW, Segal DM, Romet-Lemonne JL. Bispecific antibodies and targeted cellular cytotoxicity. Immunol Today. 1991;12(2):51–4.

    Article  PubMed  CAS  Google Scholar 

  13. Kufer P, Lutterbuse R, Baeuerle PA. A revival of bispecific antibodies. Trends Biotechnol. 2004;22:238–44.

    Article  PubMed  CAS  Google Scholar 

  14. Cao Y, Lam L. Bispecific antibody conjugates in therapeutics. Adv Drug Deliv Rev. 2003;55(2):171–97.

    Article  PubMed  CAS  Google Scholar 

  15. Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature. 1985;316(6026):354–6.

    Article  PubMed  CAS  Google Scholar 

  16. Müller D, Kontermann RE. Bispecific antibodies for cancer immunotherapy: current perspectives. BioDrugs. 2010;24(2):89–98.

    Article  PubMed  Google Scholar 

  17. Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 2009;1(6):539–47.

    Article  PubMed  Google Scholar 

  18. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.

    Article  PubMed  CAS  Google Scholar 

  19. Gelderman KA, Tomlinson S, Ross GD, Gorter A. Complement function in mAb-mediated cancer immunotherapy. Trends Immunol. 2004;25(3):158–64.

    Article  PubMed  CAS  Google Scholar 

  20. Abès R, Gélizé E, Fridman WH, Teillaud JL. Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. Blood. 2010;116(6):926–34.

    Article  PubMed  CAS  Google Scholar 

  21. Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell. 2010;18(2):160–70.

    Article  PubMed  CAS  Google Scholar 

  22. Jefferis R. Glycosylation of recombinant antibody therapeutics. Biotechnol Prog. 2005;21:11–6.

    Article  PubMed  CAS  Google Scholar 

  23. Helenius A, Aebi M. Intracellular functions of N-linked glycans. Science. 2001;291(5512):2364–9.

    Article  PubMed  CAS  Google Scholar 

  24. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer. 2001;1:118–29.

    Article  PubMed  CAS  Google Scholar 

  25. Clynes RA, Takechi RY, Moroi Y, Houghton A, Ravetch JV. Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci USA. 1998;95:652–6.

    Article  PubMed  CAS  Google Scholar 

  26. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443–6.

    Article  PubMed  CAS  Google Scholar 

  27. Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002;105:9–19.

    Article  PubMed  CAS  Google Scholar 

  28. Li Y, Beckman RA. Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development. Biotechniques. 2005;39:565–8.

    Article  CAS  Google Scholar 

  29. Staerz UD, Bevan MJ. Hybrid hybridoma producing a bispecific monoclonal antibody that can focus effector T-cell activity. Proc Natl Acad Sci USA. 1986;83(5):1453–7.

    Article  PubMed  CAS  Google Scholar 

  30. Lindhofer H, Mocikat R, Steipe B, Thierfelder S. Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas: implications for a single-step purification of bispecific antibodies. J Immunol. 1995;155(1):219–25.

    PubMed  CAS  Google Scholar 

  31. Shen J, Zhu Z. Catumaxomab, a rat/murine hybrid trifunctional bispecific monoclonal antibody for the treatment of cancer. Curr Opin Mol Ther. 2008;10(3):273–84.

    PubMed  CAS  Google Scholar 

  32. Kiewe P, Thiel E. Ertumaxomab: a trifunctional antibody for breast cancer treatment. Expert Opin Investig Drugs. 2008;17(10):1553–8.

    Article  PubMed  CAS  Google Scholar 

  33. Stanglmaier M, Faltin M, Ruf P, Bodenhausen A, Schröder P, Lindhofer H. Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti-CD20 × anti-CD3), mediates efficient killing of B-cell lymphoma cells even with very low CD20 expression levels. Int J Cancer. 2008;123(5):1181–9.

    Article  PubMed  CAS  Google Scholar 

  34. Zeidler R, Mysliwietz J, Csánady M, Walz A, Ziegler I, Schmitt B, et al. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer. 2000;83(2):261–6.

    Article  PubMed  CAS  Google Scholar 

  35. Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, Schmitt B, Lindhofer H. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol. 1999;163(3):1246–52.

    PubMed  CAS  Google Scholar 

  36. Ruf P, Lindhofer H. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood. 2001;98:2526–34.

    Article  PubMed  CAS  Google Scholar 

  37. Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36(6):458–67.

    Article  PubMed  CAS  Google Scholar 

  38. Riesenberg R, Buchner A, Pohla H, Lindhofer H. Lysis of prostate carcinoma cells by trifunctional bispecific antibodies (aEpCAM/aCD3). J Histochem Cytochem. 2001;49:911–7.

    Article  PubMed  CAS  Google Scholar 

  39. Boss MA, Kenten JH, Wood CR, Emtage JS. Assembly of functional antibodies from immunoglobulin heavy and light chains synthesised in Escherichia coli. Nucleic Acids Res. 1984;12(9):3791–806.

    Article  PubMed  CAS  Google Scholar 

  40. Kontermann RE, Müller R. Intracellular and cell surface displayed single-chain diabodies. J Immunol Methods. 1999;226(1–2):179–88.

    Article  PubMed  CAS  Google Scholar 

  41. Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. BioDrugs. 2009;23(2):93–109.

    Article  PubMed  CAS  Google Scholar 

  42. Ridgway JB, Presta LG, Carter P. ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617–21.

    Article  PubMed  CAS  Google Scholar 

  43. Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol. 1997;270:26–35.

    Article  PubMed  CAS  Google Scholar 

  44. Merchant AM, Zhu Z, Yuan JQ, Goddard A, Adams CW, Presta LG, Carter P. An efficient route to human bispecific IgG. Nat Biotechnol. 1998;16(7):677–81.

    Article  PubMed  CAS  Google Scholar 

  45. Orcutt KD, Ackerman ME, Cieslewicz M, Quiroz E, Slusarczyk AL, Frangioni JV, Wittrup KD. A modular IgG-scFv bispecific antibody topology. Protein Eng Des Sel. 2010;23:221–8.

    Article  PubMed  CAS  Google Scholar 

  46. Michaelson JS, Demarest SJ, Miller B, Amatucci A, Snyder WB, Wu X, et al. Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTbetaR. MAbs. 2009;1:128–41.

    Article  PubMed  Google Scholar 

  47. Dimasi N, Gao C, Fleming R, Woods RM, Yao XT, Shirinian L, et al. The design and characterization of oligospecific antibodies for simultaneous targeting of multiple disease mediators. J Mol Biol. 2009;393(3):672–92.

    Article  PubMed  CAS  Google Scholar 

  48. Wu C, Ying H, Grinnell C, Bryant S, Miller R, Clabbers A, et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 2007;25:1290–7.

    Article  PubMed  CAS  Google Scholar 

  49. Gunasekaran K, Pentony M, Shen M, Garrett L, Forte C, Woodward A, et al. Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J Biol Chem. 2010;285(25):19637–46.

    Article  PubMed  CAS  Google Scholar 

  50. Davis JH, Aperlo C, Li Y, Kurosawa E, Lan Y, Lo KM, Huston JS. SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng Des Sel. 2010;23:195–202.

    Article  PubMed  CAS  Google Scholar 

  51. Wu AM, Chen W, Raubitschek A, Williams LE, Neumaier M, Fischer R, et al. Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers. Immunotechnology. 1996;2(1):21–36.

    Article  PubMed  CAS  Google Scholar 

  52. Kontermann RE. Recombinant bispecific antibodies for cancer therapy. Acta Pharmacol Sin. 2005;26(1):1–9.

    Article  PubMed  CAS  Google Scholar 

  53. Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today. 2005;10(18):1237–44.

    Article  PubMed  CAS  Google Scholar 

  54. Haas C, Krinner E, Brischwein K, Hoffmann P, Lutterbüse R, Schlereth B, et al. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology. 2009;214(6):441–53.

    Article  PubMed  CAS  Google Scholar 

  55. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol. 2006;43(6):763–71.

    Article  PubMed  CAS  Google Scholar 

  56. Bluemel C, Hausmann S, Fluhr P, Sriskandarajah M, Stallcup WB, Baeuerle PA, Kufer P. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunol Immunother. 2010;59(8):1197–209.

    Article  PubMed  CAS  Google Scholar 

  57. Hoffmann P, Hofmeister R, Brischwein K, Brandl C, Crommer S, Bargou R, et al. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19- /CD3-bispecific single-chain antibody construct. Int J Cancer. 2005;115(1):98–104.

    Article  PubMed  CAS  Google Scholar 

  58. Dreier T, Baeuerle PA, Fichtner I, Grün M, Schlereth B, Lorenczewski G, et al. T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3-bispecific single-chain antibody construct. J Immunol. 2003;170(8):4397–402.

    PubMed  CAS  Google Scholar 

  59. Schlereth B, Quadt C, Dreier T, Kufer P, Lorenczewski G, Prang N, et al. T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immunother. 2006;55(5):503–14.

    Article  PubMed  CAS  Google Scholar 

  60. Lutterbuese R, Raum T, Kischel R, Lutterbuese P, Schlereth B, Schaller E, et al. Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA. J Immunother. 2009;32(4):341–52.

    Article  PubMed  CAS  Google Scholar 

  61. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69(12):4941–4.

    Article  PubMed  CAS  Google Scholar 

  62. Schirrmacher V, Fournier P. Newcastle Disease Virus: a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol Biol. 2009;542:565–605.

    Article  PubMed  CAS  Google Scholar 

  63. Fiola C, Peeters B, Fournier P, Arnold A, Bucur M, Schirrmacher V. Tumor selective replication of Newcastle disease virus: association with defects of tumor cells in antiviral defence. Int J Cancer. 2006;119(2):328–38.

    Article  PubMed  CAS  Google Scholar 

  64. Wilden H, Fournier P, Zawatzky R, Schirrmacher V. Expression of RIG-I, IRF3, IFN-beta and IRF7 determines resistance or susceptibility of cells to infection by Newcastle Disease Virus. Int J Oncol. 2009;34(4):971–82.

    PubMed  CAS  Google Scholar 

  65. Haas C, Lulei M, Fournier P, Arnold A, Schirrmacher V. T-cell triggering by CD3- and CD28-binding molecules linked to a human virus-modified tumor cell vaccine. Vaccine. 2005;23(19):2439–53.

    Article  PubMed  CAS  Google Scholar 

  66. Haas C, Lulei M, Fournier P, Arnold A, Schirrmacher V. A tumor vaccine containing anti-CD3 and anti-CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes. Int J Cancer. 2006;118(3):658–67.

    Article  PubMed  CAS  Google Scholar 

  67. Schirrmacher V, Haas C, Bonifer R, Ahlert T, Gerhards R, Ertel C. Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther. 1999;6(1):63–73.

    Article  PubMed  CAS  Google Scholar 

  68. Schulze T, Kemmner W, Weitz J, Wernecke KD, Schirrmacher V, Schlag PM. Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother. 2009;58(1):61–9.

    Article  PubMed  CAS  Google Scholar 

  69. Bortoletto N, Scotet E, Myamoto Y, D’Oro U, Lanzavecchia A. Optimizing anti-CD3 affinity for effective T cell targeting against tumor cells. Eur J Immunol. 2002;32(11):3102–7.

    Article  PubMed  CAS  Google Scholar 

  70. Traunecker A, Lanzavecchia A, Karjalainen K. Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV infected cells. EMBO J. 1991;10(12):3655–9.

    PubMed  CAS  Google Scholar 

  71. Fournier P, Schirrmacher V. Tumor antigen-dependent and tumor antigen-independent activation of antitumor activity in T cells by a bispecific antibody-modified tumor vaccine. Clin Dev Immunol 2010: 423781; Epub 2011 Mar 1.

  72. Fournier P, Arnold A, Wilden H, Schirrmacher V. Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity. Int J Oncol. 2012;40(3):840–50.

    PubMed  CAS  Google Scholar 

  73. Aigner M, Janke M, Lulei M, Beckhove P, Fournier P, Schirrmacher V. An effective tumor vaccine optimized for costimulation via bispecific and trispecific fusion proteins. Int J Oncol. 2008;32(4):777–89.

    PubMed  CAS  Google Scholar 

  74. Fournier P, Aigner M, Schirrmacher V. Targeting of IL-2 and GM-CSF immunocytokines to a tumor vaccine leads to increased anti-tumor activity. Int J Oncol. 2011;38(6):1719–29.

    PubMed  CAS  Google Scholar 

  75. Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science. 2004;305:200–5.

    Article  PubMed  CAS  Google Scholar 

  76. Porgador A, Mandelboim O, Restifo NP, Strominger JL. Natural killer cell lines kill autologous beta2-microglobulin-deficient melanoma cells: implications for cancer immunotherapy. Proc Natl Acad Sci USA. 1997;94(24):13140–5.

    Article  PubMed  CAS  Google Scholar 

  77. Brittenden J, Heys SD, Ross J, Eremin O. Natural killer cells and cancer. Cancer. 1996;77(7):1226–43.

    Article  PubMed  CAS  Google Scholar 

  78. Solá RJ, Griebenow K. Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs. 2010;24(1):9–21.

    Article  PubMed  Google Scholar 

  79. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018–28.

    Article  PubMed  CAS  Google Scholar 

  80. Dayan CM, Wraith DC. Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412. Clin Exp Immunol. 2008;151(2):231–4.

    Article  PubMed  CAS  Google Scholar 

  81. Schirrmacher V. Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory. Cancer Immunol Immunother. 2005;54(6):587–98.

    Article  PubMed  CAS  Google Scholar 

  82. Fournier P, Schirrmacher V. Randomized clinical studies of anti-tumor vaccination: state of the art in 2008. Expert Rev Vaccines. 2009;8(1):51–66.

    Article  PubMed  Google Scholar 

  83. Kubota T, Niwa R, Satoh M, Akinaga S, Shitara K, Hanai N. Engineered therapeutic antibodies with improved effector functions. Cancer Sci. 2009;100:1566–72.

    Article  PubMed  CAS  Google Scholar 

  84. Labrijn AF, Aalberse RC, Schuurman J. When binding is enough: nonactivating antibody formats. Curr Opin Immunol. 2008;20:479–85.

    Article  PubMed  CAS  Google Scholar 

  85. Jefferis R, Lund J. Interaction sites on human IgG-Fc for FcgammaR: current models. Immunol Lett. 2002;82:57–65.

    Article  PubMed  CAS  Google Scholar 

  86. Krapp S, Mimura Y, Jefferis R, Huber R, Sondermann P. Structural analysis of human IgGFc glycoforms reveals a correlation between glycosylation and structural integrity. J Mol Biol. 2003;325:979–89.

    Article  PubMed  CAS  Google Scholar 

  87. Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol. 2007;25:21–50.

    Article  PubMed  CAS  Google Scholar 

  88. Scanlan CN, Burton DR, Dwek RA. Making autoantibodies safe. Proc Natl Acad Sci USA. 2008;105:4081–2.

    Article  PubMed  CAS  Google Scholar 

  89. Lum LG, Davol PA, Lee RJ. The new face of bispecific antibodies: targeting cancer and much more. Exp Hematol. 2006;34(1):1–6.

    Article  PubMed  CAS  Google Scholar 

  90. Renner C, Hartmann F, Pfreundschuh M. Treatment of refractory Hodgkin’s disease with an anti-CD16/CD30 bispecific antibody. Cancer Immunol Immunother. 1997;45(3–4):184–6.

    Article  PubMed  CAS  Google Scholar 

  91. De Gast GC, Van Houten AA, Haagen IA, Klein S, De Weger RA, Van Dijk A, et al. Clinical experience with CD3 × CD19 bispecific antibodies in patients with B cell malignancies. J Hematother. 1995;4(5):433–7.

    Article  PubMed  Google Scholar 

  92. Hartmann F, Renner C, Jung W, Pfreundschuh M. Anti-CD16/CD30 bispecific antibodies as possible treatment for refractory Hodgkin’s disease. Leuk Lymphoma. 1998;31(3–4):385–92.

    PubMed  CAS  Google Scholar 

  93. Lum LG, Rathore R, Cummings F, Colvin GA, Radie-Keane K, Maizel A, et al. Phase I/II study of treatment of stage IV breast cancer with OKT3 × trastuzumab-armed activated T cells. Clin Breast Cancer. 2003;4(3):212–7.

    PubMed  CAS  Google Scholar 

  94. Hombach A, Tillmann T, Jensen M, Heuser C, Sircar R, Diehl V, et al. Specific activation of resting T cells against CA19-9+ tumor cells by an anti-CD3/CA19-9 bispecific antibody in combination with a costimulatory anti-CD28 antibody. J Immunother. 1997;20(5):325–33.

    Article  PubMed  CAS  Google Scholar 

  95. Repp R, van Ojik HH, Valerius T, Groenewegen G, Wieland G, Oetzel C, et al. Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer. Br J Cancer. 2003;89:2234–43.

    Article  PubMed  CAS  Google Scholar 

  96. Pullarkat V, Deo Y, Link J, Spears L, Marty V, Curnow R, et al. A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu. Cancer Immunol Immunother. 1999;48:9–21.

    Article  PubMed  CAS  Google Scholar 

  97. Sebastian M, Passlick B, Friccius-Quecke H, Jäger M, Lindhofer H, Kanniess F, et al. Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM × anti-CD3): a phase I study. Cancer Immunol Immunother. 2007;56(10):1637–44.

    Article  PubMed  CAS  Google Scholar 

  98. Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. J Cancer Treat Rev. 2010;36(6):458–67.

    Article  CAS  Google Scholar 

  99. Burges A, Wimberger P, Kümper C, Gorbounova V, Sommer H, Schmalfeldt B, et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM × anti-CD3 antibody: a phase I/II study. Clin Cancer Res. 2007;13(13):3899–905.

    Article  PubMed  CAS  Google Scholar 

  100. Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer. 2010;127(9):2209–21.

    Article  PubMed  CAS  Google Scholar 

  101. Borchmann P, Schnell R, Fuss I, Manzke O, Davis T, Lewis LD, et al. Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma. Blood. 2002;100(9):3101–7.

    Article  PubMed  CAS  Google Scholar 

  102. Kroesen BJ, Buter J, Sleijfer DT, Janssen RA, van der Graaf WT, The TH, et al. Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2. Br J Cancer. 1994;70(4):652–61.

    Article  PubMed  CAS  Google Scholar 

  103. Canevari S, Stoter G, Arienti F, Bolis G, Colnaghi MI, Di Re EM, et al. Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. J Natl Cancer Inst. 1995;87(19):1463–9.

    Article  PubMed  CAS  Google Scholar 

  104. Bolhuis RL, Lamers CH, Goey SH, Eggermont AM, Trimbos JB, Stoter G, et al. Adoptive immunotherapy of ovarian carcinoma with bs-MAb-targeted lymphocytes: a multicenter study. Int J Cancer Suppl. 1992;7:78–81.

    PubMed  CAS  Google Scholar 

  105. Valone FH, Kaufman PA, Guyre PM, Lewis LD, Memoli V, Ernstoff MS, et al. Clinical trials of bispecific antibody MDX-210 in women with advanced breast or ovarian cancer that overexpresses HER-2/neu. J Hematother. 1995;4:471–5.

    Article  PubMed  CAS  Google Scholar 

  106. Fury MG, Lipton A, Smith KM, Winston CB, Pfister DG. A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors. Cancer Immunol Immunother. 2008;57:155–63.

    Article  PubMed  CAS  Google Scholar 

  107. Hartmann F, Renner C, Jung W, Deisting C, Juwana M, Eichentopf B, et al. Treatment of refractory Hodgkin’s disease with an anti-CD16/CD30 bispecific antibody. Blood. 1997;89:2042–7.

    PubMed  CAS  Google Scholar 

  108. Wu C, Ying H, Bose S, Miller R, Medina L, Santora L, Ghayur T. Molecular construction and optimization of anti-human IL-1alpha/beta dual variable domain immunoglobulin (DVD-Ig) molecules. MAbs. 2009;1(4):339–47.

    Article  PubMed  Google Scholar 

  109. Choi BD, Cai M, Bigner DD, Mehta AI, Kuan CT, Sampson JH. Bispecific antibodies engage T cells for antitumor immunotherapy. Expert Opin Biol Ther. 2011;11(7):843–53.

    Article  PubMed  CAS  Google Scholar 

  110. Grosse-Hovest L, Hartlapp I, Marwan W, Brem G, Rammensee HG, Jung G. A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killing. Eur J Immunol. 2003;33:1334–40.

    Article  PubMed  CAS  Google Scholar 

  111. Robinson MK, Alpaugh RK, Borghaei H. Naptumomab estafenatox: a new immunoconjugate. Expert Opin Biol Ther. 2010;10(2):273–9.

    Article  PubMed  CAS  Google Scholar 

  112. Denkberg G, Reiter Y. Recombinant antibodies with T-cell receptor-like specificity: novel tools to study MHC class I penetration. Autoimmun Rev. 2006;5(4):252–7.

    Article  PubMed  CAS  Google Scholar 

  113. Kipriyanov SM, Moldenhauer G, Schuhmacher J, Cochlovius B, Von der Lieth CW, Matys ER, Little M. Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J Mol Biol. 1999;293(1):41–56.

    Article  PubMed  CAS  Google Scholar 

  114. Reusch U, Le Gall F, Hensel M, Moldenhauer G, Ho AD, Little M, Kipriyanov SM. Effect of tetravalent bispecific CD19xCD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells. Int J Cancer. 2004;112(3):509–18.

    Article  PubMed  CAS  Google Scholar 

  115. Moore PA, Zhang W, Rainey J, Burke S, Huang L, Li H, et al. Application of a novel bispecific antibody-based scaffold for optimal redirected T-cell killing of cancer cells [abstract no 5629]. 101st Annual meeting of the American Association for Cancer Research 2010 Apr 17–21, Washington, DC.

  116. Stork R, Zettlitz KA, Müller D, Rether M, Hanisch FG, Kontermann RE. N-glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J Biol Chem. 2008;283(12):7804–12.

    Article  PubMed  CAS  Google Scholar 

  117. Stork R, Campigna E, Robert B, Müller D, Kontermann RE. Biodistribution of a bispecific single-chain diabody and its half-life extended derivatives. J Biol Chem. 2009;284(38):25612–9.

    Article  PubMed  CAS  Google Scholar 

  118. Allan B. Variant Fc regions. Applied Molecular Evolution. Patent PCT/US2006/025276; 2010.

  119. Hansen G et al. Altered antibody Fc regions and uses thereof. Diversa/Medarex. Patent PCT/US2006/011048; 2010.

  120. Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA. 2006;103:4005–10.

    Article  PubMed  CAS  Google Scholar 

  121. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem. 2001;276:6591–604.

    Article  PubMed  CAS  Google Scholar 

  122. Stavenhagen J, Vijh S, Rankin C, Gorlatov S, Huang L. Macrogenics: identification and engineering of antibodies with variant Fc regions and methods of using same. Patent USSN 10/902,588; 2004 Jul 28.

  123. Beck A, Wagner-Rousset E, Bussat MC, Lokteff M, Klinguer-Hamour C, Haeuw JF, et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol. 2008;9:482–501.

    Article  PubMed  CAS  Google Scholar 

  124. Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci. 2009;30:356–62.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the members of the former team at DKFZ, Heidelberg for their dedication and the IOZK, Köln, for financial support. The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Philippe Fournier & Volker Schirrmacher

  2. IOZK, Medical Centre for Immunology and Oncology, Cologne, Germany

    Volker Schirrmacher

Authors
  1. Philippe Fournier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Schirrmacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippe Fournier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fournier, P., Schirrmacher, V. Bispecific Antibodies and Trispecific Immunocytokines for Targeting the Immune System Against Cancer. BioDrugs 27, 35–53 (2013). https://doi.org/10.1007/s40259-012-0008-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-012-0008-z

Keywords

Search

Navigation