Abstracts (complete list) - Wissenschaft Online

Linda Sender, Zoe Waibler, Camilla Merten, Roland Hartig, Matthias Gunzer, Peter
Reichardt, Ulrich Kalinke, Burkhart Schraven
An unusual signalling signature suggests a molecular basis
for the adverse side effects of anti-human CD28
superagonistic antibodies
Superagonistic CD28 antibodies (CD28SA) activate T-lymphocytes without concomitant
perturbation of the TCR/CD3-complex. In rats and mice they induce the preferential
expansion of regulatory T-cells and can be used for the treatment of autoimmune
diseases. Therefore, it was proposed that CD28SAs might also be applicable for
humans. However, a phase I clinical trial using the CD28 superagonist TGN1412 showed
that the reactivity of human T-cells towards CD28SA-mediated stimulation dramatically
differs from the response of mouse, rat and even monkey T-cells. The molecular basis
for the severe side effects of CD28SAs in humans is as yet unclear. Here we show that
two distinct CD28SAs (commercially available ANCD28.1 and original TGN1412) induce
a delayed and weak but extremely sustained calcium response in human, but not in
rhesus or cynomolgus monkey T-cells. The sustained Ca++-signal is accompanied by a
global and extended activation of the major intracellular signalling pathways. Together
these signals culminate in the synthesis of high amounts of pro-inflammatory cytokines,
most notably IFNgamma and TNFalpha but also IL-2, -4, -5 and -10. Our findings
suggest a molecular basis for the dramatic side effects that CD28 superagonists produce
when administered to humans.