Topological Requirements and Signaling Properties of T Cell–activating, Anti-CD28 Antibody Superagonists

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  • Fred Lühder
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Yun Huang
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Kevin M. Dennehy
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Christine Guntermann
    2TeGenero ImmunoTherapeutics AG, D-97076 Würzburg, Germany
  • Ingrid Müller
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Erna Winkler
    2TeGenero ImmunoTherapeutics AG, D-97076 Würzburg, Germany
  • Thomas Kerkau
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Shinji Ikemizu
    3Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
  • Simon J. Davis
    4Nuffield Department of Medicine, The University of Oxford, Oxford OX3 9DU, United Kingdom
  • Thomas Hanke
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
  • Thomas Hünig
    1Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany

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<jats:p>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.</jats:p>

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