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Recombinant Bispecific Antibodies for Cancer Therapy

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Antibody Expression and Production

Part of the book series: Cell Engineering ((CEEN,volume 7))

Abstract

Bispecific antibodies are molecules capable of simultaneously binding to two different antigens. While initially bispecific antibodies have been developed mainly for cellular cancer immunotherapy through retargeting of effector cells to tumor cells, recent developments include also dual targeting strategies and the retargeting of effector molecules, e.g. in radioimmunotherapy. In addition to various applications, a plethora of bispecific antibody formats have been developed, including small recombinant bispecific molecules comprising only the variable domains of two antibodies and tetravalent IgG-like bispecific antibodies. In this chapter we will focus on the most relevant bispecific antibody formats, explaining the therapeutic concepts, the methodology involved in their production and the preclinical and clinical achievements, so far.

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References

  • Alt M, Müller R, Kontermann RE. (1999) Novel tetravalent and bispecific IgG-like antibody molecules combining single-chain diabodies with the immunoglobulin g1 Fc or CH3 region. FEBS Lett. 454(1–2):90–4.

    Google Scholar 

  • Asano R, Kudo T, Nishimura Y, Makabe K, Hayashi H, Suzuki M, Tsumoto K, Kumagai I. (2002) Efficient construction of a diabody using a refolding system: anti-carcinoembryonic antigen recombinant antibody fragment. J Biochem. 132(6):903–9.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M, Einsele H, Brandl C, Wolf A, Kirchinger P, Klappers P, Schmidt M, Riethmüller G, Reinhardt C, Baeuerle PA, Kufer P. (2008) Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 321(5891):974–7.

    Article  PubMed  CAS  Google Scholar 

  • Blanco B, Holliger P, Vile RG, Alvarez-Vallina L. (2003) 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. 171(2):1070–7.

    PubMed  CAS  Google Scholar 

  • Bluemel C, Hausmann S, Fluhr P, Sriskandarajah M, Stallcup WB, Baeuerle PA, Kufer P. (2010) 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. 59(8):1197–209.

    Article  PubMed  CAS  Google Scholar 

  • Brandão JG, Scheper RJ, Lougheed SM, Curiel DT, Tillman BW, Gerritsen WR, van den Eertwegh AJ, Pinedo HM, Haisma HJ, de Gruijl TD. (2003) CD40-targeted adenoviral gene transfer to dendritic cells through the use of a novel bispecific single-chain Fv antibody enhances cytotoxic T cell activation. Vaccine. 21(19–20):2268–72.

    Article  PubMed  Google Scholar 

  • Bruenke J, Barbin K, Kunert S, Lang P, Pfeiffer M, Stieglmaier K, Niethammer D, Stockmeyer B, Peipp M, Repp R, Valerius T, Fey GH. (2005) Effective lysis of lymphoma cells with a stabilised bispecific single-chain Fv antibody against CD19 and FcgammaRIII (CD16). Br J Haematol. 130(2):218–28.

    Article  PubMed  CAS  Google Scholar 

  • Brüsselbach S, Korn T, Völkel T, Müller R, Kontermann RE. (1999) Enzyme recruitment and tumor cell killing in vitro by a secreted bispecific single-chain diabody. Tumor Targeting. 4:115–23.

    Google Scholar 

  • Chames P, Baty D. (2009) Bispecific antibodies for cancer therapy. Curr Opin Drug Discov Devel. 12(2):276–83.

    PubMed  CAS  Google Scholar 

  • Chan JK, Hamilton CA, Cheung MK, Karimi M, Baker J, Gall JM, Schulz S, Thorne SH, Teng NN, Contag CH, Lum LG, Negrin RS. (2006) Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin Cancer Res. 12(6):1859–67.

    Article  PubMed  CAS  Google Scholar 

  • Cochlovius B, Kipriyanov SM, Stassar MJ, Christ O, Schuhmacher J, Strauss G, Moldenhauer G, Little M. (2000) Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells. J Immunol. 165(2):888–95.

    PubMed  CAS  Google Scholar 

  • Davis JH, Aperlo C, Li Y, Kurosawa E, Lan Y, Lo KM, Huston JS. (2010) 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. 23(4):195–202.

    Article  PubMed  CAS  Google Scholar 

  • Dreier T, Baeuerle PA, Fichtner I, Grün M, Schlereth B, Lorenczewski G, Kufer P, Lutterbüse R, Riethmüller G, Gjorstrup P, Bargou RC. (2003) 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. 170(8):4397–402.

    PubMed  CAS  Google Scholar 

  • FitzGerald K, Holliger P, Winter G. (1997) Improved tumour targeting by disulphide stabilized diabodies expressed in Pichia pastoris. Protein Eng. 10(10):1221–5.

    Article  PubMed  CAS  Google Scholar 

  • Gall JM, Davol PA, Grabert RC, Deaver M, Lum LG. (2005) T cells armed with anti-CD3 x anti-CD20 bispecific antibody enhance killing of CD20+ malignant B cells and bypass complement-mediated rituximab resistance in vitro. Exp Hematol. 33(4):452–9.

    Article  PubMed  CAS  Google Scholar 

  • Grabert RC, Cousens LP, Smith JA, Olson S, Gall J, Young WB, Davol PA, Lum LG. (2006) Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. Clin Cancer Res. 12(2):569–76.

    Article  PubMed  CAS  Google Scholar 

  • Graziano RF, Guptill P. (2004) Chemical production of bispecific antibodies. Methods Mol Biol. 283:71–85.

    PubMed  CAS  Google Scholar 

  • Grosse-Hovest L, Müller S, Minoia R, Wolf E, Zakhartchenko V, Wenigerkind H, Lassnig C, Besenfelder U, Müller M, Lytton SD, Jung G, Brem G. (2004) Cloned transgenic farm animals produce a bispecific antibody for T cell-mediated tumor cell killing. Proc Natl Acad Sci USA. 101(18):6858–63.

    Article  PubMed  CAS  Google Scholar 

  • Guettinger Y, Barbin K, Peipp M, Bruenke J, Dechant M, Horner H, Thierschmidt D, Valerius T, Repp R, Fey GH, Stockmeyer B. (2010) A recombinant bispecific single-chain fragment variable specific for HLA class II and Fc alpha RI (CD89) recruits polymorphonuclear neutrophils for efficient lysis of malignant B lymphoid cells. J Immunol. 184(3):1210–17.

    Article  PubMed  CAS  Google Scholar 

  • Gunasekaran K, Pentony M, Shen M, Garrett L, Forte C, Woodward A, Ng SB, Born T, Retter M, Manchulenko K, Sweet H, Foltz IN, Wittekind M, Yan W. (2010) Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J Biol Chem. 285(25):19637–46.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hayashi H, Asano R, Tsumoto K, Katayose Y, Suzuki M, Unno M, Kodama H, Takemura S, Yoshida H, Makabe K, Imai K, Matsuno S, Kumagai I, Kudo T. (2004) A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells. Cancer Immunol Immunother. 53(6):497–509.

    Article  PubMed  CAS  Google Scholar 

  • Hayden MS, Linsley PS, Gayle MA, Bajorath J, Brady WA, Norris NA, Fell HP, Ledbetter JA, Gilliland LK. (1994) Single-chain mono- and bispecific antibody derivatives with novel biological properties and antitumour activity from a COS cell transient expression system. Ther Immunol. 1(1):3–15.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Holliger P, Prospero T, Winter G. (1993) “Diabodies”: small bivalent and bispecific antibody fragments. Proc Natl Acad Sci USA. 90(14):6444–8.

    Article  PubMed  CAS  Google Scholar 

  • Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, Zhang W, Tuaillon N, Rainey J, Barat B, Yang Y, Jin L, Ciccarone V, Moore PA, Koenig S, Bonvini E. (2010) Effector Cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol. 399(3):436–49.

    Article  PubMed  CAS  Google Scholar 

  • Kashentseva EA, Douglas JT, Zinn KR, Curiel DT, Dmitriev IP. (2009) Targeting of adenovirus serotype 5 pseudotyped with short fiber from serotype 41 to c-erbB2-positive cells using bispecific single-chain diabody. J Mol Biol. 388(3):443–61.

    Article  PubMed  CAS  Google Scholar 

  • Kellner C, Bruenke J, Stieglmaier J, Schwemmlein M, Schwenkert M, Singer H, Mentz K, Peipp M, Lang P, Oduncu F, Stockmeyer B, Fey GH. (2008) A novel CD19-directed recombinant bispecific antibody derivative with enhanced immune effector functions for human leukemic cells. J Immunother. 31(9):871–84.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Korn T, Nettelbeck DM, Völkel T, Müller R, Kontermann RE. (2004) Recombinant bispecific antibodies for the targeting of adenoviruses to CEA-expressing tumour cells: a comparative analysis of bacterially expressed single-chain diabody and tandem scFv. J Gene Med. 6(6):642–51.

    Article  PubMed  CAS  Google Scholar 

  • Kou G, Shi J, Chen L, Zhang D, Hou S, Zhao L, Fang C, Zheng L, Zhang X, Liang P, Zhang X, Li B, Guo Y. (2010) A bispecific antibody effectively inhibits tumor growth and metastasis by simultaneous blocking vascular endothelial growth factor A and osteopontin. Cancer Lett. 299(2):130–6.

    Article  PubMed  CAS  Google Scholar 

  • Kufer P, Mack M, Gruber R, Lutterbüse R, Zettl F, Riethmüller G. (1997) Construction and biological activity of a recombinant bispecific single-chain antibody designed for therapy of minimal residual colorectal cancer. Cancer Immunol Immunother. 45(3–4):193–7.

    Article  PubMed  CAS  Google Scholar 

  • Kügler M, Stein C, Kellner C, Mentz K, Saul D, Schwenkert M, Schubert I, Singer H, Oduncu F, Stockmeyer B, Mackensen A, Fey GH. (2010) A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br J Haematol. 150(5):574–86.

    Article  PubMed  Google Scholar 

  • Le Gall F, Reusch U, Little M, Kipriyanov SM. (2004) Effect of linker sequences between the antibody variable domains on the formation, stability and biological activity of a bispecific tandem diabody. Protein Eng Design Sel. 17:357–66.

    Article  CAS  Google Scholar 

  • Li B, Zhang X, Shi S, Zhao L, Zhang D, Qian W, Zheng L, Gao J, Wang H, Guo Y. (2010) Construction and characterization of a bispecific anti-CD20 antibody with potent antitumor activity against B-cell lymphoma. Cancer Res. 70(15):6293–302.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Liu R, Jiang W, Yang M, Guo H, Zhang Y, Wang J, Zhu H, Shi R, Fan D, Yang C, Zhu Z, Xie Y, Xiong D. (2010) Efficient inhibition of human B-cell lymphoma in SCID mice by synergistic antitumor effect of human 4-1BB ligand/anti-CD20 fusion proteins and anti-CD3/anti-CD20 diabodies. J Immunother. 33(5):500–9.

    Article  PubMed  Google Scholar 

  • Löffler A, Kufer P, Lutterbüse R, Zettl F, Daniel PT, Schwenkenbecher JM, Riethmüller G, Dörken B, Bargou RC. (2000) A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood. 95(6):2098–103.

    PubMed  Google Scholar 

  • Lu D, Zhang H, Koo H, Tonra J, Balderes P, Prewett M, Corcoran E, Mangalampalli V, Bassi R, Anselma D, Patel D, Kang X, Ludwig DL, Hicklin DJ, Bohlen P, Witte L, Zhu Z. (2005) A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity. J Biol Chem. 280(20):19665–72.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lutterbuese R, Raum T, Kischel R, Lutterbuese P, Schlereth B, Schaller E, Mangold S, Rau D, Meier P, Kiener PA, Mulgrew K, Oberst MD, Hammond SA, Baeuerle PA, Kufer P. (2009) Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA. J Immunother. 32(4):341–52.

    Article  PubMed  CAS  Google Scholar 

  • Marvin JS, Zhu Z. (2006) Bispecific antibodies for dual-modality cancer therapy: killing two signaling cascades with one stone. Curr Opin Drug Discov Develop. 9(2):184–93.

    CAS  Google Scholar 

  • McCall AM, Shahied L, Amoroso AR, Horak EM, Simmons HH, Nielson U, Adams GP, Schier R, Marks JD, Weiner LM. (2001) Increasing the affinity for tumor antigen enhances bispecific antibody cytotoxicity. J Immunol. 166(10):6112–17.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Michaelson JS, Demarest SJ, Miller B, Amatucci A, Snyder WB, Wu X, Huang F, Phan S, Gao S, Doern A, Farrington GK, Lugovskoy A, Joseph I, Bailly V, Wang X, Garber E, Browning J, Glaser SM. (2009) Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTbetaR. MAbs. 1(2):128–41.

    Article  PubMed  Google Scholar 

  • Milstein C, Cuello AC. (1983) Hybrid hybridomas and their use in immunohistochemistry. Nature. 305(5934):537–40.

    Article  PubMed  CAS  Google Scholar 

  • Müller D, Frey K, Kontermann RE. (2008) A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother. 31(8):714–22.

    Article  PubMed  Google Scholar 

  • Müller D, Karle A, Meissburger B, Höfig I, Stork R, Kontermann RE. (2007) Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem. 282(17):12650–60.

    Article  PubMed  Google Scholar 

  • Müller D, Kontermann RE. (2007) Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr Opin Mol Ther. 9(4):319–26.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Nagorsen D, Bargou R, Ruttinger D, Kufer P, Baeuerle PA, Zugmaier G. (2009) Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab. Leuk Lymphoma. 50(6):886–91.

    Article  PubMed  CAS  Google Scholar 

  • Orcutt KD, Ackerman ME, Cieslewicz M, Quiroz E, Slusarczyk AL, Frangioni JV, Wittrup KD. (2010) A modular IgG-scFv bispecific antibody topology. Protein Eng Des Sel. 23(4):221–8.

    Article  PubMed  CAS  Google Scholar 

  • Ranft K, Thepen T, Fischer R, Barth S, Stöcker M. (2009) Recombinant bispecific single chain antibody fragments induce Fc gamma-receptor-mediated elimination of CD30+ lymphoma cells. Cancer Lett. 282(2):187–94.

    Article  PubMed  CAS  Google Scholar 

  • Ren-Heidenreich L, Davol PA, Kouttab NM, Elfenbein GJ, Lum LG. (2004) 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. 100(5):1095–103.

    Article  PubMed  CAS  Google Scholar 

  • Reusch U, Sundaram M, Davol PA, Olson SD, Davis JB, Demel K, Nissim J, Rathore R, Liu PY, Lum LG. (2006) Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Clin Cancer Res. 12(1):183–90.

    Article  PubMed  CAS  Google Scholar 

  • Schlereth B, Quadt C, Dreier T, Kufer P, Lorenczewski G, Prang N, Brandl C, Lippold S, Cobb K, Brasky K, Leo E, Bargou R, Murthy K, Baeuerle PA. (2006a) T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immunother. 55(5):503–14.

    Article  PubMed  CAS  Google Scholar 

  • Schlereth B, Kleindienst P, Fichtner I, Lorenczewski G, Brischwein K, Lippold S, da Silva A, Locher M, Kischel R, Lutterbüse R, Kufer P, Baeuerle PA. (2006b) Potent inhibition of local and disseminated tumor growth in immunocompetent mouse models by a bispecific antibody construct specific for Murine CD3. Cancer Immunol Immunother. 55(7):785–96.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sen M, Wankowski DM, Garlie NK, Siebenlist RE, Van Epps D, LeFever AV, Lum LG. (2001) Use of anti-CD3 x anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors. J Hematother Stem Cell Res. 10(2):247–60.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Singer H, Kellner C, Lanig H, Aigner M, Stockmeyer B, Oduncu F, Schwemmlein M, Stein C, Mentz K, Mackensen A, Fey GH. (2010) Effective elimination of acute myeloid leukemic cells by recombinant bispecific antibody derivatives directed against CD33 and CD16. J Immunother. 33(6):599–608.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Vallera D, Chen H, Sichender AR, Panoskaltsis-Mortari A, Taras EP. (2009) Genetic alteration of a bispecific ligand-directed toxin targeting human C19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancies. Leuk Res. 33:1233–42.

    Article  PubMed  CAS  Google Scholar 

  • Vallera D, OH S, Chen H, Shu Y, Frankel AE. (2010) Bioengineering a unique deimmunized bispecific targetred toxin that simultaneously recognizes human CD22 and CD19 receptors in a mouse model of B-cell malignancies. Mol Cancer Ther. 9(6):1872–83.

    Google Scholar 

  • Vallera D, Todhunter DA, Kuroki DW, Shu Y, Sichender A, Chen H. (2005) A bispecific recombinant immunotoxin, DT2219, targeting human CD199 and CD22 receptors in mouse xenograft model of B-cell leukemia/lymphoma. Clin Cancer Res. 11(10):3879–88.

    Article  PubMed  CAS  Google Scholar 

  • Völkel T, Korn T, Bach M, Müller R, Kontermann RE. (2001) Optimized linker sequences for the expression of monomeric and dimeric bispecific single-chain diabodies. Protein Eng. 14:815–23.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Wu C, Ying H, Grinnell C, Bryant S, Miller R, Clabbers A, Bose S, McCarthy D, Zhu RR, Santora L, Davis-Taber R, Kunes Y, Fung E, Schwartz A, Sakorafas P, Gu J, Tarcsa E, Murtaza A, Ghayur T. (2007) Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 25(11):1290–7.

    Article  PubMed  CAS  Google Scholar 

  • Zhu Z, Presta LG, Zapata G, Carter P. (1997) Remodeling domain interfaces to enhance heterodimer formation. Protein Sci. 6(4):781–8.

    Article  PubMed  CAS  Google Scholar 

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  1. Institut für Zellbiologie und Immunologie, Universität Stuttgart, 70569, Stuttgart, Germany

    Dafne Müller & Roland E. Kontermann

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  1. Dafne Müller
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  2. Roland E. Kontermann
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Correspondence to Roland E. Kontermann .

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  1. Dept. Chemical & Biochemical, Engineering, University College, Dublin, Belfield, Dublin 4, Ireland

    Mohamed Al-Rubeai

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Müller, D., Kontermann, R.E. (2011). Recombinant Bispecific Antibodies for Cancer Therapy. In: Al-Rubeai, M. (eds) Antibody Expression and Production. Cell Engineering, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1257-7_11

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