Potent Control of Tumor Growth by CEA/CD3-bispecific Single-chain Antibody Constructs That Are Not Competitively Inhibited by Soluble CEA
Abstract
Carcinoembryonic antigen (CEA, CD66e) is a well-characterized tumor-associated antigen that is frequently overexpressed in tumors. Phospholipases release CEA from tumor cells resulting in high circulating serum levels of soluble CEA (sCEA) that has been validated as marker for progression of colorectal, breast, and lung cancers. sCEA also acts as a competitive inhibitor for anticancer strategies targeting membrane-bound CEA. As a novel therapeutic approach for treatment of tumors expressing CEA on their cell surface, we constructed a series of bispecific single-chain antibodies (bscAb) combining various single-chain variable fragments recognizing human CEA with a deimmunized single-chain variable fragments recognizing human CD3. CEA/CD3-bscAbs redirected human T cells to lyse CEA-expressing tumor cells in vitro and in vivo. Efficient tumor cell lysis was achieved in vitro at bscAb concentrations from 1 pg/mL (19 fM) to 8.9 pg/mL with preactivated CD8 T cells, and 200 to 500 pg/mL with unstimulated peripheral blood mononuclear cell. The cytotoxic activity of a subset of CEA/CD3-bscAbs was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. Treatment with CEA/CD3-bscAbs prevented the growth of human colorectal cancer lines in a severe combined immunodeficiency mouse model modified to show human T cell killing of tumors. A murine surrogate CEA/CD3-bscAb capable of recruiting murine T cells for redirected tumor lysis in immunocompetent mice prevented the growth of lung tumors expressing human CEA. Together, our results reveal a unique opportunity for targeting cytotoxic T cells toward CEA-expressing tumors without being competitively inhibited by sCEA and establish CEA/CD3-bscAb as a promising and potent therapeutic approach.
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Lutterbuese et al. found that the cytotoxic activity of some anti-CEA x anti-CD3 BiTEs was not competitively inhibited by sCEA at concentrations exceeding levels found in the serum of most cancer patients.
“Lutterbuese et al. compared the activity of several anti-CEA x anti-CD3 BiTE in the absence or presence of sCEA, and found that the cytotoxic activity of some of these molecules was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. 59”
From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [59]
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- Authors
- Lutterbuese, R., Raum, T., Kischel, R., Lutterbuese, P., Schlereth, B., Schaller, E., Mangold, S., Rau, D., Meier, P., Kiener, P. A., Mulgrew, K., Oberst, M. D., Hammond, S. A., Baeuerle, P. A., & Kufer, P.
- Corresponding author
- Lutterbuese, Ralf
- Raum, Tobias
- Kischel, Roman
- Lutterbuese, Petra
- Schlereth, Bernd
- Schaller, Evelyne
- Mangold, Susanne
- Rau, Doris
- Meier, Petra
- Baeuerle, Patrick A.
- Kufer, Peter
- ORCID
- Venue
- Journal of Immunotherapy
- Published
- 2009-05
- Volume
- 32
- Issue
- 4
- Pages
- 341-352
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W1981572061
- Cited by
- 77
- References
- 45
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 10
- FWCI
- 7.29
- 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 › Toxin Mechanisms and Immunotoxins
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- carcinoembryonic antigen, CD3, bispecific single-chain antibody, T cell redirection, tumor-associated antigens, colorectal cancer, lung cancer, adoptive T cell therapy, tumor growth inhibition
- MeSH terms
- Animals, Carcinoembryonic Antigen, Cricetulus, Cricetinae, Humans, Immunotherapy, Recombinant Fusion Proteins, Tetrahydrofolate Dehydrogenase, Colorectal Neoplasms, CHO Cells, Mice, SCID, CD3 Complex, Antibodies, Bispecific, CD8-Positive T-Lymphocytes, Mice
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