Published June 2, 2008 - More info
In March 2006, a phase I study of the superagonistic anti-CD28 antibody TGN1412 caused a massive cytokine storm and multiorgan failure in six healthy human volunteers. Such a profound impact on the immune system was not predicted by preclinical animal studies. In a study from this issue of the JCI, Müller et al. treated rats with the superagonistic anti-CD28 antibody JJ316 and found that it rapidly induced a marked T cell lymphopenia by trapping T cells in the spleen and lymph nodes (see the related article on page 1405). This dramatic redistribution of T cells simulated the profound T cell lymphopenia observed in human recipients of TGN1412. In contrast, JJ316 treatment in the rats did not reproduce the massive cytokine storm observed following TGN1412 administration to the human volunteers. These results point to similarities as well as differences between rodents and humans in the immunological effects of superagonistic anti-CD28 antibody treatment and raise further questions about how best to design preclinical studies that can better predict the risks of novel immunotherapeutics in humans.
E. William St. Clair
Original citation: J. Clin. Invest.118:1344–1347 (2008). doi:10.1172/JCI35382.
Citation for this corrigendum: J. Clin. Invest.118:2365 (2008). doi:10.1172/JCI35382C1.
The author wishes to correct inaccurate statements made in this sentence (page 1346).
One reason this result may not be so surprising is because the extracellular domain of human CD28 differs by four amino acids from the macaque CD28 sequence, including a G68E substitution in the C”D binding loop (i.e., the site of superagonistic anti-CD28 monoclonal antibody binding).
The corrected passage appears below.
Initially, there had been some confusion in the literature about the conservation of the extracellular domain of CD28 between humans and Macacafascicularis (cynomolgus macaques) and Macacamulatta (rhesus macaques). However, in a recent study, sequencing of cDNAs from 14 rhesus and 11 cynomolgus monkeys has shown that the deduced amino acid sequence of the extracellular domain of CD28 is completely conserved between these monkey species and humans (13). Interestingly, in the same study, TGN1412 was shown to induce a delayed but sustained calcium response in human CD4+ T cells, leading to activation of multiple intracellular signaling pathways and de novo synthesis of high amounts of proinflammatory cytokines, including IFN-α and TNF-α (13). Despite similar levels of binding to human T cells, TGN1412 only induced a weak calcium signal in the rhesus and cynomolgus monkey T cells. Thus, monkey models may not faithfully replicate the T cell signaling pathways of humans.
13. Waibler, Z., et al. 2008. Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies. PLoS ONE.3:e1708.
The author regrets the error.