Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

被引:66
作者
Waibler, Zoe [1 ]
Sender, Linda Y. [1 ]
Merten, Camilla [2 ]
Hartig, Roland [2 ]
Kliche, Stefanie [2 ]
Gunzer, Matthias [2 ]
Reichardt, Peter [2 ]
Kalinke, Ulrich [1 ]
Schraven, Burkhart [2 ]
机构
[1] Paul Ehrlich Inst, D-6070 Langen, Germany
[2] Otto von Guericke Univ, Inst Mol & Clin Immunol, Magdeburg, Germany
来源
PLOS ONE | 2008年 / 3卷 / 03期
关键词
D O I
10.1371/journal.pone.0001708
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 naive 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.
引用
收藏
页数:13
相关论文
共 47 条
[1]  
ABE R, 1995, J IMMUNOL, V154, P985
[2]   CD28-mediated co-stimulation: A quantitative support for TCR signalling [J].
Acuto, O ;
Michel, F .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (12) :939-951
[3]   CD28 superagonists put a break on autoimmunity by preferentially activating CD4+CD25+ regulatory T cells [J].
Beyersdorf, N ;
Hanke, T ;
Kerkau, T ;
Hünig, T .
AUTOIMMUNITY REVIEWS, 2006, 5 (01) :40-45
[4]   Superagonistic anti-CD28 antibodies:: potent activators of regulatory T cells for the therapy of autoimmune diseases [J].
Beyersdorf, N ;
Hanke, T ;
Kerkau, T ;
Hünig, T .
ANNALS OF THE RHEUMATIC DISEASES, 2005, 64 :91-95
[5]   Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis [J].
Beyersdorf, N ;
Gaupp, S ;
Balbach, K ;
Schmidt, J ;
Toyka, KV ;
Lin, CH ;
Hanke, T ;
Hünig, T ;
Kerkau, T ;
Gold, R .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (03) :445-455
[6]   Large-scale expansion of rat CD4+ CD25+ Treg cells in the absence of T-cell receptor stimulation [J].
Beyersdorf, Niklas ;
Balbach, Karen ;
Huenig, Thomas ;
Kerkau, Thomas .
IMMUNOLOGY, 2006, 119 (04) :441-450
[7]  
Bischof A, 2000, EUR J IMMUNOL, V30, P876, DOI 10.1002/1521-4141(200003)30:3<876::AID-IMMU876>3.0.CO
[8]  
2-M
[9]   Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome [J].
Dennehy, Kevin M. ;
Elias, Fernando ;
Na, Shin-Young ;
Fischer, Klaus-Dieter ;
Huenig, Thomas ;
Luehder, Fred .
JOURNAL OF IMMUNOLOGY, 2007, 178 (03) :1363-1371
[10]   Mitogenic signals through CD28 activate the protein kinase Cθ-NF-κB pathway in primary peripheral T cells [J].
Dennehy, KM ;
Kerstan, A ;
Bischof, A ;
Park, JH ;
Na, SY ;
Hünig, T .
INTERNATIONAL IMMUNOLOGY, 2003, 15 (05) :655-663