The calm after the cytokine storm: lessons from the TGN1412 trial

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.