Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies

• Published in: PloS one Vol. 3; no. 3; p. e1708
• Main Authors: Waibler, Zoe, Sender, Linda Y, Merten, Camilla, Hartig, Roland, Kliche, Stefanie, Gunzer, Matthias, Reichardt, Peter, Kalinke, Ulrich, Schraven, Burkhart
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.03.2008; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; Animal models; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Autoimmune diseases; Blotting, Western; Calcium; Calcium - metabolism; Calcium signalling; CD28 antigen; CD28 Antigens - immunology; CD3 antigen; CD4 antigen; Cell activation; Cell Proliferation; Cytokines; Flow Cytometry; Human behavior; Humans; Immunological memory; Immunology; Immunology/Leukocyte Activation; Immunology/Leukocyte Signaling and Gene Expression; Immunoregulation; Inflammation; Interferon; Interferon-gamma - metabolism; Interleukin 2; Interleukin-2 - metabolism; Intracellular signalling; Kinases; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Macaca fascicularis; Macaca mulatta; Medical treatment; Memory cells; Molecular modelling; Perturbation methods; Phosphotransferases; Primates; Quinuclidines - immunology; Quinuclidines - pharmacology; Reagents; Rodents; Side effects; Signal Transduction - immunology; src-Family Kinases - metabolism; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; γ-Interferon; United Kingdom > UK; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001708

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-gamma and TNF-alpha. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-gamma and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.