Strictly Target Cell-dependent Activation of T Cells by Bispecific Single-chain Antibody Constructs of the BiTE Class
Abstract
Bispecific antibodies have been extensively studied in vitro and in vivo for their use in redirected tumor cell lysis. A particular challenge of bispecific antibody constructs that recognize the invariant CD3 signaling complex is a controlled polyclonal activation of T cells that, ideally, is exquisitely dependent on the presence of target cells. Otherwise, overt production of inflammatory cytokines and secondary reactions may occur as side effects, as can be observed with constitutively T-cell activating monoclonal antibodies to CD3 or CD28, and with bispecific antibodies bearing Fc gamma portions. Here we analyzed 2 distinct bispecific single-chain antibody constructs of the BiTE class, called MT110 and MT103 (or MEDI-538), for conditional T-cell activation. In the presence of target-expressing cell lines, low picomolar concentrations of the BiTE molecules were sufficient to stimulate a high percentage of peripheral human T cells to express cytokines and surface activation markers, enter into cell cycle, and induce redirected lysis of target cells. However, in the absence of target cells, the 2 BiTE molecules even at high concentrations did not detectably activate T cells. Our data show that T cell activation by monomeric forms of MT110 and MT103 is highly conditional in that it is strictly dependent on the presence of cells expressing the proper target antigen. BiTE molecules therefore qualify for a highly controlled polyclonal T-cell therapy of cancer.
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Killing by BiTEs remains strictly target-cell dependent, and T cells cannot be activated in the absence of target cells, even at concentrations exceeding EC50 values by several thousand fold.
“Despite this extreme efficiency, the killing remains strictly target-cell dependent, and T cells cannot be activated in the absence of target cells, even at concentrations exceeding EC 50 values by several thousand fold. 48”
From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [48]
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- Authors
- Brischwein, K., Parr, L., Pflanz, S., Volkland, J., Lumsden, J., Klinger, M., Locher, M., Hammond, S. A., Kiener, P., Kufer, P., Schlereth, B., & Baeuerle, P. A.
- Corresponding author
- Brischwein, Klaus
- Parr, Larissa
- Pflanz, Stefan
- Volkland, Jörg
- Lumsden, John
- Klinger, Matthias
- Locher, Mathias
- Kufer, Peter
- Schlereth, Bernd
- Baeuerle, Patrick A.
- Venue
- Journal of Immunotherapy
- Published
- 2007-11
- Volume
- 30
- Issue
- 8
- Pages
- 798-807
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W1985561195
- Cited by
- 187
- References
- 31
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 5 · 2023: 7 · 2022: 16 · 2021: 22 · 2020: 10 · 2019: 11 · 2018: 5 · 2017: 12 · 2016: 5 · 2015: 13 · 2014: 8 · 2013: 7 · 2012: 14
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Immunotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- bispecific T-cell engagers, bites, bispecific single-chain antibody, CD3 signaling, T cell activation, cytokine production, cancer immunotherapy
- MeSH terms
- Epithelial Cell Adhesion Molecule, CD69 Antigens, Animals, Antigens, Differentiation, T-Lymphocyte, Antigens, Neoplasm, Cricetulus, Cricetinae, Humans, Immunoglobulin Fragments, Leukocytes, Mononuclear, Lymphocyte Activation, Macaca fascicularis, Recombinant Proteins, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Transfection, Antigens, CD, Cell Adhesion Molecules, Cytokines, CHO Cells, Muromonab-CD3, CD3 Complex, Antibodies, Bispecific, Antigens, CD19, Epitopes, T-Lymphocyte, Amino Acid Substitution, Lectins, C-Type, Cell Proliferation, Mice, Interleukin-2 Receptor alpha Subunit
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