Abstract
Treatment with monoclonal antibodies of the human IgG1 and IgG2 isotypes have become a mainstay in cancer therapy, particularly, in hematological malignancies (Ball and Broome 2010). Engagement of Fcγ receptor-bearing immune effector cells, complement fixation, induction of apoptosis, and neutralization of growth factors are major modes of action of conventional monoclonal antibodies. A limited efficacy of such antibodies in oncology as monotherapy has prompted intense efforts in academia and industry to improve their clinical activity. One approach is defucosylation or the introduction of point mutations in the Fcγ1 domain of antibodies, which significantly improves antibody-dependent cellular cytotoxicity (ADCC) (Kubota et al. 2009). Several new antibodies with improved Fcγ receptor-binding properties are now in early-stage clinical development. Another technology to boost antibody efficacy is coupling of toxic payloads, such as chemotherapeutics or bacterial toxins (Alley et al. 2010). While the US market approval for the anti-CD33/calicheamycin conjugate Mylotarg®, the first marketed drug of this kind, has been retracted in 2010, a novel generation of antibody drug conjugates (ADC) is well advanced in development using new technologies for more stably conjugating payloads. For instance, an anti-CD30 for treatment of Hodgkin’s lymphoma called SGN-35, and an anti-Her-2/neu ADC called T-DM1 for treatment of metastatic breast cancer are in pivotal trials and have shown high response rates in patients exceeding those of the parental unconjugated antibodies.
Keywords
- Acute Lymphoblastic Leukemia
- Bispecific Antibody
- Antibody Drug Conjugate
- Prostate Stem Cell Antigen
- Target Cell Lysis
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Alley SC, Okeley NM, Senter PD (2010) Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol 14(4):529–537
Altenschmidt U, Klundt E, Groner B (1997) Adoptive transfer of in-vitro-targeted, activated lymphocytes results in total tumor regression. J Immunol 159(11):5509–5515
Amann M, Brischwein K, Lutterbuese P, Parr L, Petersen L, Lorenczewski G, Krinner E, Bruckmeier S, Lippold S, Kischel R, Lutterbuese R, Kufer P, Baeuerle PA, Schlereth B (2008) Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3. Cancer Res 68(1):143–151
Amann M, Friedrich M, Lutterbuese P, Vieser E, Lorenczewski G, Petersen L, Brischwein K, Kufer P, Kischel R, Baeuerle PA, Schlereth B (2009a) Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans. Cancer Immunol Immunother 58(1):95–109
Amann M, D'Argouges S, Lorenczewski G, Brischwein K, Kischel R, Lutterbuese R, Mangold S, Rau D, Volkland J, Pflanz S, Raum T, Münz M, Kufer P, Schlereth B, Baeuerle PA, Friedrich M (2009) Antitumor activity of an EpCAM/CD3-bispecific BiTE antibody during long-term treatment of mice in the absence of T-cell anergy and sustained cytokine release. J Immunother 32(5):452–464
Baeuerle PA, Reinhardt C, Kufer P (2008) BiTE – a new class of antibodies that recruit T cells. Drugs of the Future 33:137–147
Baeuerle PA, Reinhardt C (2009) Bispecific T cell engaging antibodies for cancer therapy. Cancer Res 69(12):4941–4944
Baeuerle PA, Kufer P, Bargou R (2009) BiTE: teaching antibodies to engage T cells. Curr Opin Mol Ther 11(1):22–30
Ball ED, Broome HE (2010) Monoclonal antibodies in the treatment of hemtologic malignancy. Best Pract Res Clin Haematol 23(3):403–416
Bargou R, Leo E, Zugmaier G, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M, Einsele H, Riethmüller G, Brandl C, Wolf A, Kirchinger P, Klappers P, Schmidt M, Klinger M, 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):974–977
Bargou R, Zugmaier G, Goekbuget N, Neumann S, Horst H-A, Raff T, Brueggemann M, Kneba M, Viardot A, Schmid M, Schaich M, Stelljes M, Goebeler M, Pfeifer H, Ottmann O, Burmeister T, Degenhard E, Schmidt M, Scheele J, Einsele H, Kufer P, Klinger M, Nagorsen D, Hoelzer D, Topp M (2010) Prolonged leukemia free survival following blinatumomab (anti-CD19 BiTE) treatment of patients with minimal residual disease (MRD) of B precursor ALL: updated results of a phase II study. Annual meeting of the European Hematology Association, Barcelona 2010, abstract no 598
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):1197–1209
Brandl C, Haas C, d' Argouges S, Fisch T, Kufer P, Brischwein K, Prang N, Bargou R, Suzich J, Baeuerle PA, Hofmeister R (2007) The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother 56(10):1551–1563
Brischwein K, Schlereth B, Guller B, Steiger C, Wolf A, Lutterbuese R, Offner S, Locher M, Urbig T, Raum T, Kleindienst P, Kimmig R, Fichtner I, Kufer P, da Silva AJ, Baeuerle PA (2006) MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating solid tumors. Mol Immunol 43(8):1129–1143
Brischwein K, Parr L, Pflanz S, Volkland J, Lumsden J, Klinger M, Locher M, Hammond SA, Kiener P, Kufer P, Schlereth B, Baeuerle PA (2007) Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J Immunother 30(8):798–807
Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan KM, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH (2009) Control of large, established tumor xenografts with genetically engineered human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106(9):3360–3365
Denkberg G, Reiter Y (2006) Recombinant antibodies with T-cell receptor-like specificity: novel tools to study MHC class I penetration. Autoimmun Rev 5(4):252–257
Dreier T, Lorenczewski G, Brandl C, Hoffmann P, Syring U, Hanakam F, Kufer P, Riethmuller G, Bargou R, Baeuerle PA (2002) Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int J Cancer 100(6):690–697
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):4397–4402
Fiedler WM, Ritter B, Seggewiss R, Bokemeyer C, Fettes P, Klinger M, Vieser E, Ruettinger D, Kaubitzsch S, Wolf M (2010) Phase I safety and pharmacology study of the EpCAM/CD3-bispecific BiTE antibody MT110 in patients with metastatic colorectal, gastric, or lung cancer. J Clin Oncol 28:15s, abstract no 2573
Goebeler M, Viardot A, Knop S, Topp M, Sökeler M, Kanz L, Krause S, Mackensen A, Noppeney R, Nagorsen D, Zugmaier G, Klinger M, Schmidt M, Scheele J, Klappers P, Kufer P, Einsele H, Bargou R (2010) Confirmation of safety, efficacy and response duration in non-Hodgkin lymphoma patients treated with 60 μg/m²/d of BiTE antibody blinatumomab. Annual meeting of the European Hematology Association, Barcelona 2010, abstract no 559
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):441–453
Hammond SA, Lutterbuese R, Roff S, Lutterbuese P, Schlereth B, Bruckheimer E, Kinch MS, Coats S, Baeuerle PA, Kufer P, Kiener PA (2007) Selective targeting and potent control of tumor growth using an EphA2/CD3-bispecific single-chain antibody construct. Cancer Res 67(8):3927–3935
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
Kischel R, Raum T, Hausmann S, Rau D, Bluemel C, Mangold S, Meier P, Ebert E, Kvesic M, Hoffman P, Baeuerle PA, Kufer P (2008) Characterization in primates of MCSP- and CD33-specific human BiTE antibodies for treatment of melanoma and AML. Proc Am Assoc Cancer Res 99: Abstract no 2404
Kischel R, Hausmann S, Klinger M, Baeuerle PA, Kufer P (2009) Effector memory T cells make a major contribution to redirected lysis by T cell-engaging BiTE antibody MT110. 100th meeting of the American Association for Cancer Research 2009, abstract no 3252
Kubota T, Niwa R, Satoh M, Akinaga S, Shitara K, hanai N (2009) Engineered therapeutic antibodies with improved effector functions. Cancer Sci 100(9):1566–1572
Kufer P, Lutterbuese R, Baeuerle PA (2004) A revival of bispecific antibodies. Trends Biotechnol 22:238–244
Kurschus FC, Jenne D (2010) Delivery and therapeutic potential of human granzyme B. Immunol Rev 235(1):159–171
Kurschus FC, Fellows E, Stegmann E, Jenne DE (2008) Granzyme B delivery via perforin is restricted by size, but not by heparan sulfate-dependent endocytosis. Proc Natl Acad Sci USA 105(37):13799–13804
Küsters S, Gantner F, Künstle G, Tiegs G (1996) Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. Gastroenterology 111(2):462–471
Küsters S, Tiegs G, Alexopoulo L, Pasparakis M, Douni E, Künstle G, Bluethmann H, Wendel A, Pfizenmaier K, Kollias G, Grell M (1997) In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol 27(11):2870–2905
Linke R, Klein A, Seimetz D (2010) Catumaxomab: clinical development and future directions. MAbs 2(2):129–136
Löffler A, Gruen M, Wuchter C, Schriever F, Kufer P, Dreier T, Hanakam F, Baeuerle PA, Bommert K, Karawajew L, Dörken B, Bargou RC (2003) Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Leukemia 17(5):900–909
Lum LG, Davol PA, Lee RJ (2006) The new face of bispecific antibodies: targeting cancer and much more. Exp Hematol 34(1):1–6
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):341–352
Lutterbuese R, Raum T, Kischel R, Hoffmann P, Mangold S, Rattel B, Friedrich M, Thomas O, Lorenczewski G, Rau D, Schaller E, Herrmann I, Wolf A, Urbig T, Baeuerle PA, Kufer P (2010) T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells. Proc Natl Acad Sci USA 107(28):12605–12610
Minguet S, Schamel WW (2008) A permissive geometry model for TCR-CD3 activation. Trends Biochem Sci 33(2):51–57
Molhoj M, Crommer S, Rau D, Sriskandarajah M, Kufer P, Brischwein K, Hofmeister R, Baeuerle PA (2007) CD19/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis. Mol Immunol 44(8):1945–1953
Moore PA, Zhang W, Rainey J, Burke S, Huang L, Li H, Veri C, Yang Y, He L, Ciccarone V, Gorlatov S, Aggarwal S, Alderson R, Koenig S, Bonvini E, Johnson S (2010) Application of a novel bispecific antibody-based scaffold for optimal redirected T-cell killing of cancer cells. 101st Annual meeting of the American Association for Cancer Research 2010, abstract no 5629
Morse MA, Whelan M (2010) A year of successful cancer vaccines points to a path forward. Curr Opin Mol Ther 12:11–13
Müller D, Kontermann RE (2007) Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr Opin Mol Ther 9(4):319–326
Müller D, Kontermann RE (2010) Bispecific antibodies for cancer immunotherapy: current perspectives. BioDrugs 24(2):89–98
Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69(14):5627–5629
Nagorsen D, Bargou R, Ruettinger D, Kufer P, Baeuerle PA, Zugmaier G (2009a) Immunotherapy of lymphoma and leukemia with T cell-engaging BiTE antibody blinatumomab. Leuk Lymphoma 50(6):1–6
Nagorsen D, Zugmaier G, Viardot A, Goebeler M, Noppeney R, Schmidt M, Klappers P, Baeuerle PA, Kufer P, Bargou RC (2009) Confirmation of safety, efficacy and response duration in non-Hodgkin lymphoma patients treated with 60 μg/m2/d of BiTE® antibody blinatumomab. Blood 114:4793 (ASH Annual Meeting Abstracts)
Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA (2006) Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 43(6):763–771
Osada T, Hsu D, Hammond S, Hobeika A, Devi G, Clay TM, Lyerly HK, Morse MA (2010) Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody. Br J Cancer 102(1):124–133
Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666
Purbhoo MA, Irvine DJ, Huppa JB, Davis MM (2004) T cell killing does not require the formation of a stable mature immunological synapse. Nat Immunol 5(5):524–530
Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296
Raum R, Rau D, Kischel R, Bluemel C, Hausmann S, Steiger C, Meier P, Ebert E, Mangold S, Hoffmann P, Strasser S, Cierpka R, Kvesic M, Baeuerle PA (2010) Novel primate-crossreactive BiTE antibodies that eliminate cancer cells expressing cMet, IGFR-1, FAP-alpha, PSCA, Endosialin, CAIX or Her2/neu. 101st Annual meeting of the American Association for Cancer Research 2010, abstract no 2434
Renner C, Jung W, Sahin U, Denfeld R, Pohl C, Trümper L, Hartmann F, Diehl V, van Lier R, Pfreundschuh M (1994) Cure of xenografted human tumors by bispecific monoclonal antibodies and human T cells. Science 264(5160):833–835
Reusch U, Le Gall F, Hensel M, Moldenhauer G, Ho AD, Little M, Kipriyanov SM (2004) Effect of tetravalent bispecific CD19 × CD3 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 112(3):509–518
Robinson MK, Alpaugh RK, Borghaei H (2010) Naptumomab estafenatox: a new immunoconjugate. Expert Opin Biol Ther 10(2):273–279
Roman K, Raum T, Hausmann S, Rau D, Bluemel C, Mangold S, Meier P, Ebert E, Kvesic M, Hoffman P, Baeuerle PA, Kufer P (2008) Characterization of novel CD33- and MCSP-specific BiTE antibodies for the treatment of acute myeloid leukemia and melanoma, respectively, that are fully human in sequence. 99th meeting of the American Association for Cancer Research 2008, abstract no 2404
Rosenberg SA, Restifo N, Yang JC, Morgan RA, Dudley ME (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8(4):299–308
Schlereth B, Fichtner I, Lorenczewski G, Kleindienst P, Brischwein K, Kufer P, Lutterbüse R, Wimberger P, Kimmig R, Baeuerle PA (2005) Eradication of tumors from a human colon cancer cell line and primary ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct. Cancer Res 65(7):2882–2889
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):273–284
Stork R, Campigna A, Robert B, Müller D, Kontermann RE (2009) Biodistribution of a bispecific single-chain diabody and its half-life extended derivatives. J Biol Chem 284(38):25612–25619
Topp MS, Zugmaier G, Goekbuet N, Kufer P, Goebeler M, Klinger M, Degenhard E, Baeuerle PA, Schmidt M, Nagorsen D, Neumann S, Horst HA, Raff T, Viardot A, Stelljes M, Schmid M, Ottmann OG, Burmeister T, Einsele H, Riethmueller G, Hoelzer D, Bargou RC (2009) Report of a phase II trial of single-agent BiTE antibody blinatumomab in patients with minimal residual disease (MRD) positive B-precursor acute lymphocytic leukemia (ALL). Blood 114:840 (ASH Annual Meeting Abstract)
Wahlin BE, Sander B, Christensson B, Kimby E (2007) CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res 13(2):388–397
Weber J (2009) Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother 58(8):823–830
Willems A, Schoonooghe S, Eeckhout D, De Jaeger G, Grooten J, Mertens N (2005) CD3 × CD28 cross-interacting bispecific antibodies improve tumor cell dependent T-cell activation. Cancer Immunol Immunother 54:1059–1071
Wimberger P, Xiang W, Mayr D, Diebold J, Dreier T, Baeuerle PA, Kimmig R (2003) Efficient tumor cell lysis by autologous, tumor-resident T lymphocytes in primary ovarian cancer samples by an EP-CAM-/CD3-bispecific antibody. Int J Cancer 105(2):241–248
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):339–347
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Baeuerle, P.A., Zugmaier, G., Rüttinger, D. (2011). Bispecific T Cell Engager for Cancer Therapy. In: Kontermann, R. (eds) Bispecific Antibodies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-20910-9_15
Download citation
DOI: https://doi.org/10.1007/978-3-642-20910-9_15
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-20909-3
Online ISBN: 978-3-642-20910-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)