T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct
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BscCD19xCD3 is a bispecific single-chain antibody construct with exceptional cytotoxic potency in vitro and in vivo. Here, we have investigated the biological activity of bscCD19xCD3 in chimpanzee, the only animal species identified in which bscCD19xCD3 showed bispecific binding, redirected B-cell lysis and cytokine production comparable to human cells. Pharmacokinetic analysis following 2-h intravenous infusion of 0.06, 0.1 or 0.12 mug/kg of bscCD19xCD3 as part of a dose escalation study in a single female chimpanzee revealed a half-life of approximately 2 h and elimination of the bispecific antibody from circulation within approximately 8 h after the end of infusion. This short exposure to bscCD19xCD3 elicited a transient increase in serum levels of IFNgamma, IL-6, IL-2, soluble CD25, and transiently upregulated expression of CD69 and MHC class II on CD8-positive cells. Cytokine release and upregulation of T-cell activation markers were not observed with vehicle controls. A multiple-dose study using 5 weekly doses of 0.1 mug/kg in two animals also showed transient cytokine release and an activation of peripheral T cells with a first-dose effect, accompanied by a transient lymphopenia. While oscillations of T-cell counts were relatively even during repeated treatments, the amplitudes of peripheral B cells declined with every infusion, which was not observed in a vehicle control animal. Our data show that bscCD19xCD3 can be safely administered to chimpanzees at dose levels that cause fully reversible T-cell activation and, despite a very short exposure time, cumulative loss of peripheral B lymphocytes. A clinical trial testing prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing.
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Studies in chimpanzees showed repeated 2 h treatments with doses as low as 0.1 μg.kg-1 were well-tolerated and led to cumulative depletion of peripheral B cells due to fully reversible T cell activation.
“Later, studies performed in chimpanzees showed that repeated 2 h treatments with doses as low as 0.1 μg.kg -1 were welltolerated, and led to cumulative depletion of peripheral B cells due to fully reversible T cell activation. 53”
From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [53]
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- Authors
- 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, P. A.
- Affiliations
- Novartis (Switzerland) (CH)
- Ablynx (Belgium) (BE)
- Texas Biomedical Research Institute (US)
- Humboldt-Universität zu Berlin (DE)
- Corresponding author
- Baeuerle, Patrick A.
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2005-07-20
- Volume
- 55
- Issue
- 5
- Pages
- 503-514
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC11030059
- OpenAlex
- W2076787465
- Cited by
- 103
- References
- 28
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 6 · 2013: 7 · 2012: 8
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Immunology Immunotherapy (publishedVersion)
- PubMed Central (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 › Immunotoxicology and immune responses
- Keywords
- bispecific single-chain antibody, chimpanzees, T cell activation, B-cell depletion, lymphopenia, cytokine production, pharmacokinetics, dose escalation, CD8+ T cells, MHC class II upregulation, CD69
- MeSH terms
- Animals, B-Lymphocytes, Cells, Cultured, Pan troglodytes, Cytotoxicity Tests, Immunologic, Female, Flow Cytometry, Humans, Immunotherapy, Leukocytes, Mononuclear, Lymphocyte Depletion, Lymphocyte Activation, Male, T-Lymphocytes, CD3 Complex, Antibodies, Bispecific, Antigens, CD19, Cell Line, Tumor
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