Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists.
Open accessAbstract
Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): “conventional,” TCR signaling–dependent costimulatory mAbs and “superagonistic” mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C′′D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C′′D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C′′D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor κB pathway without inducing phosphorylation of either TCRζ or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs.
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TGN1412 was called a superagonist because it could activate T-cells without prior engagement of the T-cell receptor complex.
“TGN1412 was called a 'superagonist' because it could activate T-cells without the need for prior engagement of the T-cell receptor complex (Tacke et al., 1997;Lühder et al., 2003).”
From Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 <sup>+</sup> effector memory T‐cells (2010) · cites this paper as Lühder et al., 2003
The Introduction defines anti-CD28 superagonists as antibodies that fully activate resting T cells without TCR signaling, and the Figure 4 caption describes human T-cell stimulation without TCR triggering. Our copy does not identify TGN1412, so it supports the reason for the label but not the claim about that specific antibody. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCD28 superagonists bind to a laterally exposed loop within the extracellular domain of CD28.
“While conventional CD28 mAbs bind CD28 close to the binding site of the natural CD28 ligands, CD80 and CD86, CD28 superagonists bind to a laterally exposed loop within the extracellular domain of CD28 [8].”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [8]
Conventional CD28 mAbs bind CD28 close to the binding site of natural ligands CD80 and CD86.
“While conventional CD28 mAbs bind CD28 close to the binding site of the natural CD28 ligands, CD80 and CD86, CD28 superagonists bind to a laterally exposed loop within the extracellular domain of CD28 [8].”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [8]
CD28 superagonists bind laterally to both subunits of the CD28 homodimer, unlike conventional CD28-specific antibodies that bind monovalently at the top, and this permits extensive CD28 crosslinking.
“In particular, we showed that in contrast to conventional CD28-specific mAbs, which bind monovalently at the top of the homodimeric CD28 molecule, CD28SA bind laterally to both subunits [8,9] allowing extensive CD28 crosslinking”
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 [8]
TGN1412's Fc-independent activity probably arises from lateral binding to the CD28 homodimer, which permits large-scale aggregation through lattice formation.
“This Fcindependent effect of the antibody is most likely due to its ability to laterally bind to the CD28 homodimer, thereby allowing its large-scale aggregation by lattice formation [8,9].”
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 [8]
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References 54 · Cited by 193
- Authors
- Lühder, F., Huang, Y., Dennehy, K. M., Guntermann, C., Müller, I., Winkler, E., Kerkau, T., Ikemizu, S., Davis, S. J., Hanke, T., & Hünig, T.
- Affiliations
- 1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
- University of Würzburg (DE)
- 2TeGenero ImmunoTherapeutics AG, D-97076 Würzburg, Germany
- Kumamoto University (JP)
- University of Oxford (GB)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-04-21
- Volume
- 197
- Issue
- 8
- Pages
- 955-966
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2193880
- OpenAlex
- W2122700509
- Cited by
- 193
- References
- 54
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 11 · 2017: 8 · 2016: 2 · 2015: 11 · 2014: 6 · 2013: 11 · 2012: 6
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 465)
- Bundesministerium für Bildung und Forschung
- Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD28, anti-CD28 monoclonal antibody, superagonists, T cell activation, costimulation, T cell receptor, NF-κB signaling, T cell hybridomas
- MeSH terms
- Animals, Antibodies, Monoclonal, Epitopes, Humans, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Molecular, Protein Conformation, Protein-Tyrosine Kinases, Rats, Inbred Lew, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, T-Lymphocytes, Signal Transduction, NF-kappa B, CD28 Antigens, Mice, Rats, ZAP-70 Protein-Tyrosine Kinase
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