TGN1412 (theralizumab) is a humanized CD28 super-agonist that stimulates T cells. It was supposed to treat B cell chronic lymphocytic leukemia and rheumatoid arthritis. In clinical trial Phase I, TGN1412 caused severe cytokine release syndrome (CRS) and multi-organ failure in six healthy recipients. However, we found that: 

1) In preclinical safety testing, in vitro incubation of freshly isolated human peripheral blood mononuclear cells (PBMCs) with soluble TGN1412 did not induce the release of pro-inflammatory cytokines.

2) No CRS was observed in mice during preclinical testing.

3) Cynomolgus macaques, another preclinical animal model, were treated with TGN1412 at a much. higher dose than that given to the trial participants and again, no CRS was observed. Explain the potential reasons.

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The observed differences in the response to TGN1412 between preclinical safety testing and clinical trial Phase I in humans as well as the lack of cyt... View the full answer