Immunotherapy has emerged as an alternative strategy to treat malignancies in addition to conventional radio- and chemotherapy. There has been a plethora of evidence that the immune system is able to control tumor outgrowth and a number of strategies have been put forward to utilize this ability for immunotherapy. However, some of these strategies have not been very efficient and their success has been limited by tumor evasion mechanisms. A promising approach to engage effector cells of the immune system overcoming some of the escape mechanisms has been introduced more than two decades ago. This approach is based on bispecific antibodies. Here we summarize the evolution of bispecific antibodies, their improvement, remaining obstacles and some controversial reports.
References
[1]
Ehrlich, P. Ueber den jetzigen stand der Karzinomforschung. Ned. Tijdschr. Geneeskd. 1909, 273–290.
[2]
Burnet, M. Cancer: A biological approach. I. The processes of control. Br. Med. J. 1957, 1, 779–786, doi:10.1136/bmj.1.5022.779.
[3]
Thomas, L. Reactions to homologous tissue antigens in relation to hypersensitivity [Discussion]. In Cellular and Humoral Aspects of the Hypersensitive States; Lawrence, H.S., Ed.; Hoeber-Harper: New York, NY, USA, 1959; pp. 529–533.
[4]
Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. Cancer immunoediting: From immunosurveillance to tumor escape. Nat. Immunol. 2002, 3, 991–998, doi:10.1038/ni1102-991.
[5]
Parish, C.R. Cancer immunotherapy: The past, the present and the future. Immunol. Cell Biol. 2003, 81, 106–113, doi:10.1046/j.0818-9641.2003.01151.x.
[6]
Dighe, A.S.; Richards, E.; Old, L.J.; Schreiber, R.D. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1994, 1, 447–456, doi:10.1016/1074-7613(94)90087-6.
[7]
van den Broek, M.E.; Kagi, D.; Ossendorp, F.; Toes, R.; Vamvakas, S.; Lutz, W.K.; Melief, C.J.; Zinkernagel, R.M.; Hengartner, H. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 1996, 184, 1781–1790, doi:10.1084/jem.184.5.1781.
[8]
Kaplan, D.H.; Shankaran, V.; Dighe, A.S.; Stockert, E.; Aguet, M.; Old, L.J.; Schreiber, R.D. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl. Acad. Sci. USA 1998, 95, 7556–7561, doi:10.1073/pnas.95.13.7556. 9636188
[9]
Smyth, M.J.; Thia, K.Y.; Street, S.E.; Cretney, E.; Trapani, J.A.; Taniguchi, M.; Kawano, T.; Pelikan, S.B.; Crowe, N.Y.; Godfrey, D.I. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 2000, 191, 661–668, doi:10.1084/jem.191.4.661.
[10]
Smyth, M.J.; Thia, K.Y.; Street, S.E.; MacGregor, D.; Godfrey, D.I.; Trapani, J.A. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 2000, 192, 755–760, doi:10.1084/jem.192.5.755.
[11]
Shankaran, V.; Ikeda, H.; Bruce, A.T.; White, J.M.; Swanson, P.E.; Old, L.J.; Schreiber, R.D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410, 1107–1111, doi:10.1038/35074122.
[12]
Dunn, G.P.; Old, L.J.; Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21, 137–148, doi:10.1016/j.immuni.2004.07.017.
Halliday, G.M.; Patel, A.; Hunt, M.J.; Tefany, F.J.; Barnetson, R.S. Spontaneous regression of human melanoma/nonmelanoma skin cancer: Association with infiltrating CD4+ T cells. World J. Surg. 1995, 19, 352–358, doi:10.1007/BF00299157.
[15]
Iihara, K.; Yamaguchi, K.; Nishimura, Y.; Iwasaki, T.; Suzuki, K.; Hirabayashi, Y. Spontaneous regression of malignant lymphoma of the breast. Pathol. Int. 2004, 54, 537–542, doi:10.1111/j.1440-1827.2004.01652.x.
[16]
Penn, I. Tumors of the immunocompromised patient. Annu. Rev. Med. 1988, 39, 63–73, doi:10.1146/annurev.me.39.020188.000431.
Clemente, C.G.; Mihm, M.C., Jr.; Bufalino, R.; Zurrida, S.; Collini, P.; Cascinelli, N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996, 77, 1303–1310, doi:10.1002/(SICI)1097-0142(19960401)77:7<1303::AID-CNCR12>3.0.CO;2-5.
[19]
Scanlan, M.J.; Simpson, A.J.; Old, L.J. The cancer/testis genes: Review, standardization, and commentary. Cancer Immun. 2004, 4, 1. 14738373
[20]
Haanen, J.B.; Baars, A.; Gomez, R.; Weder, P.; Smits, M.; de Gruijl, T.D.; von Blomberg, B.M.; Bloemena, E.; Scheper, R.J.; van Ham, S.M.; et al. Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol. Immunother. 2006, 55, 451–458, doi:10.1007/s00262-005-0018-5.
[21]
Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: Integrating immunity's roles in cancer suppression and promotion. Science 2011, 331, 1565–1570, doi:10.1126/science.1203486. 21436444
[22]
Smyth, M.J.; Dunn, G.P.; Schreiber, R.D. Cancer immunosurveillance and immunoediting: The roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol. 2006, 90, 1–50, doi:10.1016/S0065-2776(06)90001-7.
[23]
Swann, J.B.; Smyth, M.J. Immune surveillance of tumors. J. Clin. Invest. 2007, 117, 1137–1146, doi:10.1172/JCI31405.
Sims, G.P.; Rowe, D.C.; Rietdijk, S.T.; Herbst, R.; Coyle, A.J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 2010, 28, 367–388, doi:10.1146/annurev.immunol.021908.132603.
[26]
Dunn, G.P.; Bruce, A.T.; Sheehan, K.C.; Shankaran, V.; Uppaluri, R.; Bui, J.D.; Diamond, M.S.; Koebel, C.M.; Arthur, C.; White, J.M.; et al. A critical function for type I interferons in cancer immunoediting. Nat. Immunol. 2005, 6, 722–729, doi:10.1038/ni1213.
[27]
Smith, P.L.; Lombardi, G.; Foster, G.R. Type I interferons and the innate immune response—More than just antiviral cytokines. Mol. Immunol. 2005, 42, 869–877, doi:10.1016/j.molimm.2004.11.008.
[28]
Guerra, N.; Tan, Y.X.; Joncker, N.T.; Choy, A.; Gallardo, F.; Xiong, N.; Knoblaugh, S.; Cado, D.; Greenberg, N.M.; Raulet, D.H. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008, 28, 571–580, doi:10.1016/j.immuni.2008.02.016.
[29]
Smyth, M.J.; Godfrey, D.I.; Trapani, J.A. A fresh look at tumor immunosurveillance and immunotherapy. Nat. Immunol. 2001, 2, 293–299, doi:10.1038/86297.
[30]
Chan, C.W.; Housseau, F. The 'kiss of death' by dendritic cells to cancer cells. Cell Death Differ. 2008, 15, 58–69, doi:10.1038/sj.cdd.4402235.
[31]
Appay, V. The physiological role of cytotoxic CD4(+) T-cells: The holy grail? Clin. Exp. Immunol. 2004, 138, 10–13, doi:10.1111/j.1365-2249.2004.02605.x.
[32]
Quezada, S.A.; Simpson, T.R.; Peggs, K.S.; Merghoub, T.; Vider, J.; Fan, X.; Blasberg, R.; Yagita, H.; Muranski, P.; Antony, P.A.; et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 2010, 207, 637–650, doi:10.1084/jem.20091918. 20156971
[33]
Law, T.M.; Motzer, R.J.; Mazumdar, M.; Sell, K.W.; Walther, P.J.; O'Connell, M.; Khan, A.; Vlamis, V.; Vogelzang, N.J.; Bajorin, D.F. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995, 76, 824–832, doi:10.1002/1097-0142(19950901)76:5<824::AID-CNCR2820760517>3.0.CO;2-N.
[34]
Imai, C.; Iwamoto, S.; Campana, D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 2005, 106, 376–383, doi:10.1182/blood-2004-12-4797.
[35]
Morgan, R.A.; Dudley, M.E.; Wunderlich, J.R.; Hughes, M.S.; Yang, J.C.; Sherry, R.M.; Royal, R.E.; Topalian, S.L.; Kammula, U.S.; Restifo, N.P.; et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006, 314, 126–129, doi:10.1126/science.1129003. 16946036
[36]
Ljunggren, H.G.; Malmberg, K.J. Prospects for the use of NK cells in immunotherapy of human cancer. Nat. Rev. Immunol. 2007, 7, 329–339, doi:10.1038/nri2073.
[37]
Cartellieri, M.; Bachmann, M.; Feldmann, A.; Bippes, C.; Stamova, S.; Wehner, R.; Temme, A.; Schmitz, M. Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. J. Biomed. Biotechnol. 2010, 2010, doi:10.1155/2010/956304.
[38]
Cartellieri, M.; Michalk, I.; von Bonin, M.; Kruger, T.; Stamova, S.; Koristka, S.; Arndt, C.; Feldmann, A.; Schmitz, M.; Wermke, M.; et al. Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Acute Myeloid Leukemia. Blood 2011, 118, 1124–1125.
[39]
Mellman, I.; Coukos, G.; Dranoff, G. Cancer immunotherapy comes of age. Nature 2011, 480, 480–489, doi:10.1038/nature10673. 22193102
[40]
Park, T.S.; Rosenberg, S.A.; Morgan, R.A. Treating cancer with genetically engineered T cells. Trends Biotechnol. 2011, 29, 550–557, doi:10.1016/j.tibtech.2011.04.009.
[41]
Schwartzentruber, D.J.; Lawson, D.H.; Richards, J.M.; Conry, R.M.; Miller, D.M.; Treisman, J.; Gailani, F.; Riley, L.; Conlon, K.; Pockaj, B.; et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 2011, 364, 2119–2127, doi:10.1056/NEJMoa1012863. 21631324
[42]
Stroncek, D.F.; Berger, C.; Cheever, M.A.; Childs, R.W.; Dudley, M.E.; Flynn, P.; Gattinoni, L.; Heath, J.R.; Kalos, M.; Marincola, F.M.; et al. New directions in cellular therapy of cancer: A summary of the summit on cellular therapy for cancer. J. Transl. Med. 2012, 10, 48, doi:10.1186/1479-5876-10-48.
[43]
Rivoltini, L.; Canese, P.; Huber, V.; Iero, M.; Pilla, L.; Valenti, R.; Fais, S.; Lozupone, F.; Casati, C.; Castelli, C.; et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: How can we tilt the balance towards immune-mediated cancer control? Expert Opin. Biol. Ther. 2005, 5, 463–476, doi:10.1517/14712598.5.4.463.
[44]
Ferrone, S.; Whiteside, T.L. Tumor microenvironment and immune escape. Surg. Oncol. Clin. N. Am. 2007, 16, 755–774, viii, doi:10.1016/j.soc.2007.08.004.
[45]
Rabinovich, G.A.; Gabrilovich, D.; Sotomayor, E.M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 2007, 25, 267–296, doi:10.1146/annurev.immunol.25.022106.141609.
[46]
Groth, A.; Kloss, S.; von Strandmann, E.P.; Koehl, U.; Koch, J. Mechanisms of tumor and viral immune escape from natural killer cell-mediated surveillance. J. Innate Immun. 2011, 3, 344–354, doi:10.1159/000327014.
Raju, T.S. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. 2008, 20, 471–478, doi:10.1016/j.coi.2008.06.007.
[49]
Chan, A.C.; Carter, P.J. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 2010, 10, 301–316, doi:10.1038/nri2761.
[50]
Jiang, X.R.; Song, A.; Bergelson, S.; Arroll, T.; Parekh, B.; May, K.; Chung, S.; Strouse, R.; Mire-Sluis, A.; Schenerman, M. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat. Rev. Drug Discov. 2011, 10, 101–111, doi:10.1038/nrd3365. 21283105
[51]
Kohler, G.; Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975, 256, 495–497, doi:10.1038/256495a0.
[52]
Neuberger, M.S.; Williams, G.T.; Mitchell, E.B.; Jouhal, S.S.; Flanagan, J.G.; Rabbitts, T.H. A hapten-specific chimaeric IgE antibody with human physiological effector function. Nature 1985, 314, 268–270, doi:10.1038/314268a0. 2580239
[53]
Jones, P.T.; Dear, P.H.; Foote, J.; Neuberger, M.S.; Winter, G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 1986, 321, 522–525, doi:10.1038/321522a0.
[54]
Hoogenboom, H.R.; Chames, P. Natural and designer binding sites made by phage display technology. Immunol. Today 2000, 21, 371–378, doi:10.1016/S0167-5699(00)01667-4.
[55]
Lonberg, N. Human monoclonal antibodies from transgenic mice. Handb. Exp. Pharmacol. 2008, 69–97, doi:10.1007/978-3-540-73259-4_4.
[56]
Reichert, J.M.; Rosensweig, C.J.; Faden, L.B.; Dewitz, M.C. Monoclonal antibody successes in the clinic. Nat. Biotechnol. 2005, 23, 1073–1078, doi:10.1038/nbt0905-1073.
[57]
Chames, P.; Van Regenmortel, M.; Weiss, E.; Baty, D. Therapeutic antibodies: Successes, limitations and hopes for the future. Br. J. Pharmacol. 2009, 157, 220–233, doi:10.1111/j.1476-5381.2009.00190.x.
[58]
Cheson, B.D. Radioimmunotherapy of non-Hodgkin's lymphomas. Curr. Drug Targets 2006, 7, 1293–1300, doi:10.2174/138945006778559157.
[59]
Carter, P.J.; Senter, P.D. Antibody-drug conjugates for cancer therapy. Cancer J. 2008, 14, 154–169, doi:10.1097/PPO.0b013e318172d704.
[60]
Lum, L.G.; Thakur, A. Targeting T cells with bispecific antibodies for cancer therapy. BioDrugs 2011, 25, 365–379, doi:10.2165/11595950-000000000-00000.
[61]
McLaughlin, P.; Grillo-Lopez, A.J.; Link, B.K.; Levy, R.; Czuczman, M.S.; Williams, M.E.; Heyman, M.R.; Bence-Bruckler, I.; White, C.A.; Cabanillas, F.; et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J. Clin. Oncol. 1998, 16, 2825–2833. 9704735
[62]
Witzig, T.E.; White, C.A.; Gordon, L.I.; Wiseman, G.A.; Emmanouilides, C.; Murray, J.L.; Lister, J.; Multani, P.S. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J. Clin. Oncol. 2003, 21, 1263–1270, doi:10.1200/JCO.2003.08.043. 12663713
Cobleigh, M.A.; Vogel, C.L.; Tripathy, D.; Robert, N.J.; Scholl, S.; Fehrenbacher, L.; Wolter, J.M.; Paton, V.; Shak, S.; Lieberman, G.; et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 1999, 17, 2639–2648. 10561337
[65]
Romond, E.H.; Perez, E.A.; Bryant, J.; Suman, V.J.; Geyer, C.E., Jr.; Davidson, N.E.; Tan-Chiu, E.; Martino, S.; Paik, S.; Kaufman, P.A.; et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 2005, 353, 1673–1684, doi:10.1056/NEJMoa052122.
[66]
Lundin, J.; Kimby, E.; Bjorkholm, M.; Broliden, P.A.; Celsing, F.; Hjalmar, V.; Mollgard, L.; Rebello, P.; Hale, G.; Waldmann, H.; et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002, 100, 768–773, doi:10.1182/blood-2002-01-0159.
[67]
Rhee, J.; Hoff, P.M. Angiogenesis inhibitors in the treatment of cancer. Expert Opin. Pharmacother. 2005, 6, 1701–1711, doi:10.1517/14656566.6.10.1701.
[68]
Snyder, L.C.; Astsaturov, I.; Weiner, L.M. Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. Clin. Colorectal. Cancer 2005, 5 (Suppl. 2), S71–S80, doi:10.3816/CCC.2005.s.010.
[69]
Patel, D.K. Clinical use of anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer. Pharmacotherapy 2008, 28, 31S–41S, doi:10.1592/phco.28.11-supp.31S.
[70]
Chames, P.; Baty, D. Bispecific antibodies for cancer therapy: The light at the end of the tunnel? MAbs 2009, 1, 539–547, doi:10.4161/mabs.1.6.10015.
[71]
Beckman, R.A.; Weiner, L.M.; Davis, H.M. Antibody constructs in cancer therapy: Protein engineering strategies to improve exposure in solid tumors. Cancer 2007, 109, 170–179, doi:10.1002/cncr.22402.
[72]
Shinkawa, T.; Nakamura, K.; Yamane, N.; Shoji-Hosaka, E.; Kanda, Y.; Sakurada, M.; Uchida, K.; Anazawa, H.; Satoh, M.; Yamasaki, M.; et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 2003, 278, 3466–3473. 12427744
[73]
Preithner, S.; Elm, S.; Lippold, S.; Locher, M.; Wolf, A.; da Silva, A.J.; Baeuerle, P.A.; Prang, N.S. High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Mol. Immunol. 2006, 43, 1183–1193, doi:10.1016/j.molimm.2005.07.010.
[74]
Cartron, G.; Dacheux, L.; Salles, G.; Solal-Celigny, P.; Bardos, P.; Colombat, P.; Watier, H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002, 99, 754–758, doi:10.1182/blood.V99.3.754.
[75]
Weng, W.K.; Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 2003, 21, 3940–3947, doi:10.1200/JCO.2003.05.013.
[76]
Nimmerjahn, F.; Ravetch, J.V. Antibodies, Fc receptors and cancer. Curr. Opin. Immunol. 2007, 19, 239–245, doi:10.1016/j.coi.2007.01.005.
[77]
Xie, H.; Blattler, W.A. In vivo behaviour of antibody-drug conjugates for the targeted treatment of cancer. Expert Opin. Biol. Ther. 2006, 6, 281–291, doi:10.1517/14712598.6.3.281.
[78]
Steiner, M.; Neri, D. Antibody-radionuclide conjugates for cancer therapy: Historical considerations and new trends. Clin. Cancer Res. 2011, 17, 6406–6416, doi:10.1158/1078-0432.CCR-11-0483.
[79]
Staerz, U.D.; Kanagawa, O.; Bevan, M.J. Hybrid antibodies can target sites for attack by T cells. Nature 1985, 314, 628–631, doi:10.1038/314628a0.
[80]
Kontermann, R.E. Recombinant bispecific antibodies for cancer therapy. Acta Pharmacol. Sin. 2005, 26, 1–9, doi:10.1111/j.1745-7254.2005.00008.x.
[81]
Muller, D.; Kontermann, R.E. Bispecific antibodies for cancer immunotherapy: Current perspectives. BioDrugs 2010, 24, 89–98, doi:10.2165/11530960-000000000-00000.
[82]
Singer, H.; Kellner, C.; Lanig, H.; Aigner, M.; Stockmeyer, B.; Oduncu, F.; Schwemmlein, M.; Stein, C.; Mentz, K.; Mackensen, A.; et al. Effective elimination of acute myeloid leukemic cells by recombinant bispecific antibody derivatives directed against CD33 and CD16. J. Immunother. 2010, 33, 599–608, doi:10.1097/CJI.0b013e3181dda225.
[83]
Silla, L.M.; Chen, J.; Zhong, R.K.; Whiteside, T.L.; Ball, E.D. Potentiation of lysis of leukaemia cells by a bispecific antibody to CD33 and CD16 (Fc gamma RIII) expressed by human natural killer (NK) cells. Br. J. Haematol. 1995, 89, 712–718. 7772507
[84]
Cochlovius, B.; Kipriyanov, S.M.; Stassar, M.J.; Christ, O.; Schuhmacher, J.; Strauss, G.; Moldenhauer, G.; Little, M. Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells. J. Immunol. 2000, 165, 888–895. 10878363
[85]
Blanco, B.; Holliger, P.; Vile, R.G.; Alvarez-Vallina, L. Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells. J. Immunol. 2003, 171, 1070–1077. 12847281
[86]
Schlereth, B.; Fichtner, I.; Lorenczewski, G.; Kleindienst, P.; Brischwein, K.; da Silva, A.; Kufer, P.; Lutterbuese, R.; Junghahn, I.; Kasimir-Bauer, S.; et al. Eradication of tumors from a human colon cancer cell line and from ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct. Cancer Res. 2005, 65, 2882–2889, doi:10.1158/0008-5472.CAN-04-2637.
[87]
Muller, D.; Kontermann, R.E. Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr. Opin. Mol. Ther. 2007, 9, 319–326. 17694444
[88]
Kiessling, A.; Fussel, S.; Wehner, R.; Bachmann, M.; Wirth, M.P.; Rieber, E.P.; Schmitz, M. Advances in specific immunotherapy for prostate cancer. Eur. Urol. 2008, 53, 694–708, doi:10.1016/j.eururo.2007.11.043. 18061335
[89]
Arndt, C.; Feldmann, A.; Koristka, S.; Michalk, I.; Cartellieri, M.; Stamova, S.; von Bonin, M.; Bornhauser, M.; Ehninger, G.; Bachmann, M. Redirection of Immune Effector Cells by Bispecific Antibody Systems for the Treatment of Acute Myeloid Leukemia. Blood 2011, 118, 663–664.
[90]
Feldmann, A.; Stamova, S.; Bippes, C.C.; Bartsch, H.; Wehner, R.; Schmitz, M.; Temme, A.; Cartellieri, M.; Bachmann, M. Retargeting of T cells to prostate stem cell antigen expressing tumor cells: Comparison of different antibody formats. Prostate 2011, 71, 998–1011, doi:10.1002/pros.21315.
[91]
Fortmuller, K.; Alt, K.; Gierschner, D.; Wolf, P.; Baum, V.; Freudenberg, N.; Wetterauer, U.; Elsasser-Beile, U.; Buhler, P. Effective targeting of prostate cancer by lymphocytes redirected by a PSMA x CD3 bispecific single-chain diabody. Prostate 2011, 71, 588–596, doi:10.1002/pros.21274.
[92]
Stamova, S.; Cartellieri, M.; Feldmann, A.; Bippes, C.C.; Bartsch, H.; Wehner, R.; Schmitz, M.; von Bonin, M.; Bornhauser, M.; Ehninger, G.; et al. Simultaneous engagement of the activatory receptors NKG2D and CD3 for retargeting of effector cells to CD33-positive malignant cells. Leukemia 2011, 25, 1053–1056, doi:10.1038/leu.2011.42. 21415850
[93]
Milstein, C.; Cuello, A.C. Hybrid hybridomas and their use in immunohistochemistry. Nature 1983, 305, 537–540, doi:10.1038/305537a0.
[94]
Kufer, P.; Lutterbuse, R.; Baeuerle, P.A. A revival of bispecific antibodies. Trends Biotechnol. 2004, 22, 238–244, doi:10.1016/j.tibtech.2004.03.006.
[95]
Segal, D.M.; Weiner, G.J.; Weiner, L.M. Bispecific antibodies in cancer therapy. Curr. Opin. Immunol. 1999, 11, 558–562, doi:10.1016/S0952-7915(99)00015-1. 10508714
Holliger, P.; Prospero, T.; Winter, G. "Diabodies": Small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. USA 1993, 90, 6444–6448, doi:10.1073/pnas.90.14.6444. 8341653
[98]
Lawrence, L.J.; Kortt, A.A.; Iliades, P.; Tulloch, P.A.; Hudson, P.J. Orientation of antigen binding sites in dimeric and trimeric single chain Fv antibody fragments. FEBS Lett. 1998, 425, 479–484, doi:10.1016/S0014-5793(98)00292-0.
[99]
Volkel, T.; Korn, T.; Bach, M.; Muller, R.; Kontermann, R.E. Optimized linker sequences for the expression of monomeric and dimeric bispecific single-chain diabodies. Protein Eng. 2001, 14, 815–823, doi:10.1093/protein/14.10.815.
[100]
Bippes, C.C.; Feldmann, A.; Stamova, S.; Cartellieri, M.; Schwarzer, A.; Wehner, R.; Schmitz, M.; Rieber, E.P.; Zhao, S.; Schakel, K.; et al. A novel modular antigen delivery system for immuno targeting of human 6-sulfo LacNAc-positive blood dendritic cells (SlanDCs). PLoS One 2011, 6, e16315, doi:10.1371/journal.pone.0016315. 21283706
[101]
Kontermann, R.E.; Korn, T.; Jerome, V. Recombinant adenoviruses for in vivo expression of antibody fragments. Methods Mol. Biol. 2003, 207, 421–433. 12412489
[102]
Ren-Heidenreich, L.; Davol, P.A.; Kouttab, N.M.; Elfenbein, G.J.; Lum, L.G. Redirected T-cell cytotoxicity to epithelial cell adhesion molecule-overexpressing adenocarcinomas by a novel recombinant antibody, E3Bi, in vitro and in an animal model. Cancer 2004, 100, 1095–1103, doi:10.1002/cncr.20060.
[103]
Stamova, S.; Cartellieri, M.; Feldmann, A.; Arndt, C.; Koristka, S.; Bartsch, H.; Bippes, C.C.; Wehner, R.; Schmitz, M.; von Bonin, M.; et al. Unexpected recombinations in single chain bispecific anti-CD3-anti-CD33 antibodies can be avoided by a novel linker module. Mol. Immunol. 2011, 49, 474–482, doi:10.1016/j.molimm.2011.09.019.
[104]
Stamova, S.; Feldmann, A.; Cartellieri, M.; Arndt, C.; Koristka, S.; Apel, F.; Wehner, R.; Schmitz, M.; Bornhauser, M.; von Bonin, M.; et al. Generation of single-chain bispecific green fluorescent protein fusion antibodies for imaging of antibody-induced T cell synapses. Anal. Biochem. 2012, 423, 261–268, doi:10.1016/j.ab.2011.12.042. 22274538
[105]
Rossi, E.A.; Goldenberg, D.M.; Cardillo, T.M.; McBride, W.J.; Sharkey, R.M.; Chang, C.H. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc. Natl. Acad. Sci. USA 2006, 103, 6841–6846, doi:10.1073/pnas.0600982103. 16636283
[106]
Saerens, D.; Ghassabeh, G.H.; Muyldermans, S. Single-domain antibodies as building blocks for novel therapeutics. Curr. Opin. Pharmacol. 2008, 8, 600–608, doi:10.1016/j.coph.2008.07.006.
[107]
Ward, E.S.; Gussow, D.; Griffiths, A.D.; Jones, P.T.; Winter, G. Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 1989, 341, 544–546, doi:10.1038/341544a0. 2677748
Harmsen, M.M.; De Haard, H.J. Properties, production, and applications of camelid single-domain antibody fragments. Appl. Microbiol. Biotechnol. 2007, 77, 13–22, doi:10.1007/s00253-007-1142-2.
[110]
Gill, D.S.; Damle, N.K. Biopharmaceutical drug discovery using novel protein scaffolds. Curr. Opin. Biotechnol. 2006, 17, 653–658, doi:10.1016/j.copbio.2006.10.003.
[111]
Gebauer, M.; Skerra, A. Engineered protein scaffolds as next-generation antibody therapeutics. Curr. Opin. Chem. Biol. 2009, 13, 245–255, doi:10.1016/j.cbpa.2009.04.627.
[112]
Friedman, M.; Lindstrom, S.; Ekerljung, L.; Andersson-Svahn, H.; Carlsson, J.; Brismar, H.; Gedda, L.; Frejd, F.Y.; Stahl, S. Engineering and characterization of a bispecific HER2 × EGFR-binding affibody molecule. Biotechnol. Appl. Biochem. 2009, 54, 121–131, doi:10.1042/BA20090096.
[113]
Kipriyanov, S.M.; Cochlovius, B.; Schafer, H.J.; Moldenhauer, G.; Bahre, A.; Le Gall, F.; Knackmuss, S.; Little, M. Synergistic antitumor effect of bispecific CD19 × CD3 and CD19 x CD16 diabodies in a preclinical model of non-Hodgkin's lymphoma. J. Immunol. 2002, 169, 137–144. 12077238
[114]
Asano, R.; Sone, Y.; Makabe, K.; Tsumoto, K.; Hayashi, H.; Katayose, Y.; Unno, M.; Kudo, T.; Kumagai, I. Humanization of the bispecific epidermal growth factor receptor × CD3 diabody and its efficacy as a potential clinical reagent. Clin. Cancer Res. 2006, 12, 4036–4042, doi:10.1158/1078-0432.CCR-06-0059.
[115]
Buhler, P.; Wolf, P.; Gierschner, D.; Schaber, I.; Katzenwadel, A.; Schultze-Seemann, W.; Wetterauer, U.; Tacke, M.; Swamy, M.; Schamel, W.W.; et al. A bispecific diabody directed against prostate-specific membrane antigen and CD3 induces T-cell mediated lysis of prostate cancer cells. Cancer Immunol. Immunother. 2008, 57, 43–52, doi:10.1007/s00262-007-0348-6.
[116]
Grosse-Hovest, L.; Hartlapp, I.; Marwan, W.; Brem, G.; Rammensee, H.G.; Jung, G. A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killing. Eur. J. Immunol. 2003, 33, 1334–1340, doi:10.1002/eji.200323322.
[117]
Otz, T.; Grosse-Hovest, L.; Hofmann, M.; Rammensee, H.G.; Jung, G. A bispecific single-chain antibody that mediates target cell-restricted, supra-agonistic CD28 stimulation and killing of lymphoma cells. Leukemia 2009, 23, 71–77, doi:10.1038/leu.2008.271.
[118]
Suntharalingam, G.; Perry, M.R.; Ward, S.; Brett, S.J.; Castello-Cortes, A.; Brunner, M.D.; Panoskaltsis, N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 2006, 355, 1018–1028, doi:10.1056/NEJMoa063842.
[119]
Grosse-Hovest, L.; Wick, W.; Minoia, R.; Weller, M.; Rammensee, H.G.; Brem, G.; Jung, G. Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo. Int. J. Cancer 2005, 117, 1060–1064, doi:10.1002/ijc.21294.
[120]
Mack, M.; Riethmuller, G.; Kufer, P. A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc. Natl. Acad. Sci. USA 1995, 92, 7021–7025, doi:10.1073/pnas.92.15.7021.
[121]
Loffler, A.; Kufer, P.; Lutterbuse, R.; Zettl, F.; Daniel, P.T.; Schwenkenbecher, J.M.; Riethmuller, G.; Dorken, B.; Bargou, R.C. A recombinant bispecific single-chain antibody, CD19 × CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000, 95, 2098–2103. 10706880
[122]
Baeuerle, P.A.; Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009, 69, 4941–4944, doi:10.1158/0008-5472.CAN-09-0547.
[123]
Nagorsen, D.; Baeuerle, P.A. Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab. Exp. Cell Res. 2011, 317, 1255–1260, doi:10.1016/j.yexcr.2011.03.010.
[124]
Bargou, R.; Leo, E.; Zugmaier, G.; Klinger, M.; Goebeler, M.; Knop, S.; Noppeney, R.; Viardot, A.; Hess, G.; Schuler, M.; et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008, 321, 974–977, doi:10.1126/science.1158545. 18703743
[125]
Topp, M.S.; Kufer, P.; Gokbuget, N.; Goebeler, M.; Klinger, M.; Neumann, S.; Horst, H.A.; Raff, T.; Viardot, A.; Schmid, M.; et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J. Clin. Oncol. 2011, 29, 2493–2498, doi:10.1200/JCO.2010.32.7270. 21576633
[126]
Molhoj, M.; Crommer, S.; Brischwein, K.; Rau, D.; Sriskandarajah, M.; Hoffmann, P.; Kufer, P.; Hofmeister, R.; Baeuerle, P.A. CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis. Mol. Immunol. 2007, 44, 1935–1943, doi:10.1016/j.molimm.2006.09.032. 17083975
[127]
Feldmann, A.; Arndt, C.; T？pfer, K.; Stamova, S.; Krone, C.M.; Koristka, S.; Michalk, I.; Lindemann, D.; Schmitz, M.; Temme, A.; et al. Novel humanized and highly efficient bispecific antibodies mediate killing of prostate stem cell antigen-expressing tumor cells by CD8+ and CD4+ T Cells. J. Immunol. 2012. in press.
[128]
Haagen, I.A.; de Lau, W.B.; Bast, B.J.; Geerars, A.J.; Clark, M.R.; de Gast, B.C. Unprimed CD4+ and CD8+ T cells can be rapidly activated by a CD3 × CD19 bispecific antibody to proliferate and become cytotoxic. Cancer Immunol. Immunother. 1994, 39, 391–396, doi:10.1007/BF01534426.
[129]
Dreier, T.; Lorenczewski, G.; Brandl, C.; Hoffmann, P.; Syring, U.; Hanakam, F.; Kufer, P.; Riethmuller, G.; Bargou, R.; Baeuerle, P.A. Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int. J. Cancer 2002, 100, 690–697, doi:10.1002/ijc.10557.
[130]
Buhler, P.; Molnar, E.; Dopfer, E.P.; Wolf, P.; Gierschner, D.; Wetterauer, U.; Schamel, W.W.; Elsasser-Beile, U. Target-dependent T-cell activation by coligation with a PSMA × CD3 diabody induces lysis of prostate cancer cells. J. Immunother. 2009, 32, 565–573, doi:10.1097/CJI.0b013e3181a697eb.
[131]
Offner, S.; Hofmeister, R.; Romaniuk, A.; Kufer, P.; Baeuerle, P.A. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol. Immunol. 2006, 43, 763–771, doi:10.1016/j.molimm.2005.03.007.
Koristka, S.; Cartellieri, M.; Theil, A.; Feldmann, A.; Arndt, C.; Stamova, S.; Michalk, I.; Topfer, K.; Temme, A.; Kretschmer, K.; et al. Retargeting of human regulatory T cells by single-chain bispecific antibodies. J. Immunol. 2012, 188, 1551–1558, doi:10.4049/jimmunol.1101760. 22184723
[134]
Hoffmann, P.; Hofmeister, R.; Brischwein, K.; Brandl, C.; Crommer, S.; Bargou, R.; Itin, C.; Prang, N.; Baeuerle, P.A. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int. J. Cancer 2005, 115, 98–104, doi:10.1002/ijc.20908.
[135]
Boesteanu, A.C.; Katsikis, P.D. Memory T cells need CD28 costimulation to remember. Semin. Immunol. 2009, 21, 69–77, doi:10.1016/j.smim.2009.02.005.
[136]
Koristka, S.; Cartellieri, M.; Theil, A.; Arndt, C.; Feldmann, A.; Michalk, I.; Schmitz, M.; Kretschmer, K.; Bornhauser, M.; Ehninger, G.; et al. Antigen-Specific Redirection of Human Regulatory T Cells by Bispecific Antibodies. Blood 2011, 118, 1725–1726.
[137]
Hombach, A.A.; Kofler, D.; Rappl, G.; Abken, H. Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity. Gene Ther. 2009, 16, 1088–1096, doi:10.1038/gt.2009.75.
Moretta, L.; Moretta, A. Unravelling natural killer cell function: Triggering and inhibitory human NK receptors. EMBO J. 2004, 23, 255–259, doi:10.1038/sj.emboj.7600019.
[140]
Salih, H.R.; Rammensee, H.G.; Steinle, A. Cutting edge: Down-regulation of MICA on human tumors by proteolytic shedding. J. Immunol. 2002, 169, 4098–4102. 12370336
[141]
Fuertes, M.B.; Girart, M.V.; Molinero, L.L.; Domaica, C.I.; Rossi, L.E.; Barrio, M.M.; Mordoh, J.; Rabinovich, G.A.; Zwirner, N.W. Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. J. Immunol. 2008, 180, 4606–4614. 18354183
[142]
Diefenbach, A.; Jensen, E.R.; Jamieson, A.M.; Raulet, D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001, 413, 165–171, doi:10.1038/35093109. 11557981
[143]
Germain, C.; Larbouret, C.; Cesson, V.; Donda, A.; Held, W.; Mach, J.P.; Pelegrin, A.; Robert, B. MHC class I-related chain A conjugated to antitumor antibodies can sensitize tumor cells to specific lysis by natural killer cells. Clin. Cancer Res. 2005, 11, 7516–7522, doi:10.1158/1078-0432.CCR-05-0872. 16243826
[144]
von Strandmann, E.P.; Hansen, H.P.; Reiners, K.S.; Schnell, R.; Borchmann, P.; Merkert, S.; Simhadri, V.R.; Draube, A.; Reiser, M.; Purr, I.; et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. Blood 2006, 107, 1955–1962, doi:10.1182/blood-2005-05-2177. 16210338
[145]
Nausch, N.; Cerwenka, A. NKG2D ligands in tumor immunity. Oncogene 2008, 27, 5944–5958, doi:10.1038/onc.2008.272. 18836475
[146]
Groh, V.; Rhinehart, R.; Randolph-Habecker, J.; Topp, M.S.; Riddell, S.R.; Spies, T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat. Immunol. 2001, 2, 255–260, doi:10.1038/85321.
[147]
Kim, Y.J.; Han, M.K.; Broxmeyer, H.E. 4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells. Blood 2008, 111, 1378–1386. 18024793
[148]
Doubrovina, E.S.; Doubrovin, M.M.; Vider, E.; Sisson, R.B.; O'Reilly, R.J.; Dupont, B.; Vyas, Y.M. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J. Immunol. 2003, 171, 6891–6899. 14662896
[149]
Kim, Y.J.; Stringfield, T.M.; Chen, Y.; Broxmeyer, H.E. Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. Blood 2005, 105, 274–281, doi:10.1182/blood-2003-12-4343.
[150]
Parmiani, G.; Rivoltini, L.; Andreola, G.; Carrabba, M. Cytokines in cancer therapy. Immunol. Lett. 2000, 74, 41–44, doi:10.1016/S0165-2478(00)00247-9.
[151]
Masztalerz, A.; Van Rooijen, N.; Den Otter, W.; Everse, L.A. Mechanisms of macrophage cytotoxicity in IL-2 and IL-12 mediated tumour regression. Cancer Immunol. Immunother. 2003, 52, 235–242. 12669248
[152]
Emminger, W.; Emminger-Schmidmeier, W.; Peters, C.; Susani, M.; Hawliczek, R.; Hocker, P.; Gadner, H. Capillary leak syndrome during low dose granulocyte-macrophage colony-stimulating factor (rh GM-CSF) treatment of a patient in a continuous febrile state. Blut 1990, 61, 219–221, doi:10.1007/BF01744134.
[153]
Stern, A.C.; Jones, T.C. The side-effect profile of GM-CSF. Infection 1992, 20 (Suppl. 2), S124–S127, doi:10.1007/BF01705031.
[154]
Schwartz, R.N.; Stover, L.; Dutcher, J. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park) 2002, 16, 11–20.
Ott, M.G.; Marme, F.; Moldenhauer, G.; Lindhofer, H.; Hennig, M.; Spannagl, R.; Essing, M.M.; Linke, R.; Seimetz, D. Humoral response to catumaxomab correlates with clinical outcome: Results of the pivotal phase II/III study in patients with malignant ascites. Int. J. Cancer 2012, 130, 2195–2203, doi:10.1002/ijc.26258. 21702044
[160]
Meredith, R.F.; Khazaeli, M.B.; Plott, W.E.; Saleh, M.N.; Liu, T.; Allen, L.F.; Russell, C.D.; Orr, R.A.; Colcher, D.; Schlom, J.; et al. Phase I trial of iodine-131-chimeric B72.3 (human IgG4) in metastatic colorectal cancer. J. Nucl. Med. 1992, 33, 23–29. 1730991
[161]
Steffens, M.G.; Boerman, O.C.; Oosterwijk-Wakka, J.C.; Oosterhof, G.O.; Witjes, J.A.; Koenders, E.B.; Oyen, W.J.; Buijs, W.C.; Debruyne, F.M.; Corstens, F.H.; et al. Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J. Clin. Oncol. 1997, 15, 1529–1537. 9193349
[162]
Pavlinkova, G.; Colcher, D.; Booth, B.J.; Goel, A.; Wittel, U.A.; Batra, S.K. Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-TAG-72 single-chain Fvs. Int. J. Cancer 2001, 94, 717–726, doi:10.1002/ijc.1523.
[163]
Verhoeyen, M.; Milstein, C.; Winter, G. Reshaping human antibodies: Grafting an antilysozyme activity. Science 1988, 239, 1534–1536, doi:10.1126/science.2451287. 2451287
Marks, J.D.; Hoogenboom, H.R.; Bonnert, T.P.; McCafferty, J.; Griffiths, A.D.; Winter, G. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 1991, 222, 581–597, doi:10.1016/0022-2836(91)90498-U.
[166]
Vaughan, T.J.; Williams, A.J.; Pritchard, K.; Osbourn, J.K.; Pope, A.R.; Earnshaw, J.C.; McCafferty, J.; Hodits, R.A.; Wilton, J.; Johnson, K.S. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat. Biotechnol. 1996, 14, 309–314, doi:10.1038/nbt0396-309.
[167]
Weiner, L.M. Fully human therapeutic monoclonal antibodies. J. Immunother. 2006, 29, 1–9, doi:10.1097/01.cji.0000192105.24583.83.
[168]
Kontermann, R.E. Strategies to extend plasma half-lives of recombinant antibodies. BioDrugs 2009, 23, 93–109, doi:10.2165/00063030-200923020-00003.
[169]
Muller, D.; Karle, A.; Meissburger, B.; Hofig, I.; Stork, R.; Kontermann, R.E. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J. Biol. Chem. 2007, 282, 12650–12660, doi:10.1074/jbc.M700820200. 17347147
[170]
Stork, R.; Muller, D.; Kontermann, R.E. A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G. Protein Eng. Des. Sel. 2007, 20, 569–576, doi:10.1093/protein/gzm061.
[171]
Stork, R.; Campigna, E.; Robert, B.; Muller, D.; Kontermann, R.E. Biodistribution of a bispecific single-chain diabody and its half-life extended derivatives. J. Biol. Chem. 2009, 284, 25612–25619, doi:10.1074/jbc.M109.027078. 19628871
[172]
Holt, L.J.; Basran, A.; Jones, K.; Chorlton, J.; Jespers, L.S.; Brewis, N.D.; Tomlinson, I.M. Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs. Protein Eng. Des. Sel. 2008, 21, 283–288, doi:10.1093/protein/gzm067.
[173]
Tijink, B.M.; Laeremans, T.; Budde, M.; Stigter-van Walsum, M.; Dreier, T.; de Haard, H.J.; Leemans, C.R.; van Dongen, G.A. Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: Taking advantage of modular Nanobody technology. Mol. Cancer Ther. 2008, 7, 2288–2297, doi:10.1158/1535-7163.MCT-07-2384.
[174]
Marvin, J.S.; Zhu, Z. Recombinant approaches to IgG-like bispecific antibodies. Acta Pharmacol. Sin. 2005, 26, 649–658, doi:10.1111/j.1745-7254.2005.00119.x.
[175]
Stork, R.; Zettlitz, K.A.; Muller, D.; Rether, M.; Hanisch, F.G.; Kontermann, R.E. N-Glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J. Biol. Chem. 2008, 283, 7804–7812, doi:10.1074/jbc.M709179200. 18211902
[176]
Chapman, A.P. PEGylated antibodies and antibody fragments for improved therapy: A review. Adv. Drug Deliv. Rev. 2002, 54, 531–545, doi:10.1016/S0169-409X(02)00026-1.
[177]
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, 458–467, doi:10.1016/j.ctrv.2010.03.001.
