Toward experimental assessment of receptor occupancy: TGN1412 revisited
Open accessAbstract
In March 2006, 6 healthy volunteers experienced serious adverse reactions during a first-in-human clinical trial of the superagonistic anti-CD28 mAb TGN1412. A first investigation excluded contaminations of the drug product or protocol irregularities as the root cause. Later, an expert scientific group convened in the United Kingdom to develop recommendations pertinent to minimizing risks of first-in-human clinical trials. The expert scientific group concluded from in silico calculations that at the initial dose of 0.1 mg/kg, which was adjusted on the basis of the no observed adverse effect level, approximately 86.2% to 90.9% CD28 receptor occupancy was obtained. Here we developed a flow cytometric method that revealed receptor occupancy of approximately 45% to 80% under the above conditions. Thus we present a method to experimentally determine receptor occupancy that can be taken as one parameter to define the minimal anticipated biological effect level as the basis for calculating safer starting doses for first-in-human clinical trials for products in which a potential risk has been identified. Additional measures are being discussed that will help to significantly improve safety of first-in-human clinical trials.
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The 0.1 mg/kg dose correlated with 45-80% receptor occupancy in man and a near maximum immunostimulatory dose in vitro.
“In reality, this dose correlated with 45–80% receptor occupancy in man and a near maximum immunostimulatory dose in vitro (Stebbings et al., 2007; Waibler et al., 2008).”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Waibler et al., 2008
The Abstract and Experimental Determination of Receptor Occupancy section report an estimated 45–80% CD28 receptor occupancy at 0.1 mg/kg, based on an in vitro binding assay and assumptions about plasma volume. Our copy does not report that this dose produced near-maximal immunostimulation in vitro; its measurements concern receptor binding, not immunostimulatory effect. Page numbers are unavailable in the indexed passages. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe calculation of a safe starting dose in man based upon pre-clinical safety testing of TGN1412 in cynomolgus macaques was flawed.
“Moreover, the calculation of a safe starting dose in man based upon pre-clinical safety testing of TGN1412 in cynomolgus macaques was flawed.”
From After TGN1412: Recent developments in cytokine release assays (2013) · cites this paper as Waibler et al., 2008
The Abstract says the TGN1412 starting dose was based on the no-observed-adverse-effect level, that six volunteers had serious adverse reactions, and that this dose-calculation approach was subsequently questioned. It does not identify cynomolgus macaques as the preclinical model or explicitly establish that the calculation itself was flawed. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe concentration corresponding to the first-in-human dose of 100 μg/kg achieved over 60% receptor occupancy.
“the antibody concentration extrapolated from the dose applied at the FIH trial-100 lgÁkg À1 body weight-translated not only into more than 60% receptor occupancy, as had been shown by Ulrich Kalinke 0 s group at the Paul Ehrlich Institute, the German regulatory body for drug development [52]”
From The rise and fall of the <scp>CD</scp> 28 superagonist <scp>TGN</scp> 1412 and its return as <scp>TAB</scp> 08: a personal account (2016) · cites this paper as [52]
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Cites
Pharmacokinetic aspects of biotechnology products.
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TGN1412—a regulator's perspective
Schneider, C. K., Kalinke, U., & Löwer, J. (2006) · Nature Biotechnology · doi:10.1038/nbt0506-493 · Cited by 60 · see citing works
Self-citationRishi, S. (2024) · Institute of Physics eBooks · doi:10.1088/978-0-7503-6462-1ch1 · Cited by 1 · see citing works
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The storm has cleared: lessons from the CD28 superagonist TGN1412 trial
Hünig, T. (2012) · Nature Reviews Immunology · doi:10.1038/nri3192 · Cited by 194 · see citing works
Römer, P. S., Berr, S., Avota, E., Na, S.-Y., Battaglia, M., ten Berge, I., Einsele, H., & Hünig, T. (2011) · Blood · doi:10.1182/blood-2010-12-319780 · Cited by 153 · see citing works
Tabares, P., Berr, S., Römer, P. S., Chuvpilo, S., Matskevich, A. A., Tyrsin, D., Fedotov, Y., Einsele, H., Tony, H., & Hünig, T. (2014) · European Journal of Immunology · doi:10.1002/eji.201343967 · Cited by 97 · see citing works
After TGN1412: Recent developments in cytokine release assays
Stebbings, R., Eastwood, D., Poole, S., & Thorpe, R. (2013) · Journal of Immunotoxicology · doi:10.3109/1547691x.2012.711783 · Cited by 73 · see citing works
“In reality, this dose correlated with 45–80% receptor occupancy in man and a near maximum immunostimulatory dose in vitro (Stebbings et al., 2007; Waibler et al., 2008).”
BackgroundSafety of biologics, lessons learnt from TGN1412
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Hünig, T. (2016) · The FEBS Journal · doi:10.1111/febs.13754 · Cited by 47 · see citing works
ICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation
Weissmüller, S., Semmler, L. Y., Kalinke, U., Christians, S., Müller-Berghaus, J., & Waibler, Z. (2012) · Blood · doi:10.1182/blood-2011-12-401083 · Cited by 26 · see citing works
Self-citation
- Authors
- Waibler, Z., Sender, L. Y., Kamp, C., Müller-Berghaus, J., Liedert, B., Schneider, C. K., Löwer, J., & Kalinke, U.
- Affiliations
- Paul Ehrlich Institut (DE)
- Center for Experimental and Clinical Infection Research (DE)
- Corresponding author
- Kalinke, Ulrich
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 122
- Issue
- 5
- Pages
- 890-892
- ISSN
- 0091-6749 (ISSN-L)
- OpenAlex
- W2012811079
- Semantic Scholar
- 27fb6bedbf750927fdd92ec199ca237409110094
- Cited by
- 40
- References
- 3
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 1 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 8
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- TGN1412, receptor occupancy, CD28, drug safety, flow cytometry, adverse drug reactions
- MeSH terms
- Antibodies, Monoclonal, Dose-Response Relationship, Drug, Dose-Response Relationship, Immunologic, Flow Cytometry, Humans, Receptors, Immunologic, CD28 Antigens, Toxicity Tests, No-Observed-Adverse-Effect Level, Antibodies, Monoclonal, Humanized
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