Primate testing of TGN1412: right target, wrong cell

Area of Science:

• Immunology
• Pharmacology
• Toxicology

Background:

• The first-in-human study of TGN1412, a CD28-specific monoclonal antibody, resulted in severe cytokine release syndrome.
• Preclinical toxicity studies in non-human primates failed to predict this adverse event, leaving the cause unexplained.

Purpose of the Study:

• To identify the specific subset of human T-lymphocytes responsible for cytokine release syndrome during TGN1412 administration.
• To investigate the presence of the CD28 target molecule on this T-lymphocyte subset in cynomolgus monkeys.

Main Methods:

• Flow cytometry and cytokine analysis were used to characterize human T-lymphocyte subsets.
• Immunohistochemistry and flow cytometry were employed to assess CD28 expression on cynomolgus monkey T-lymphocytes.

Main Results:

• The effector memory subset of human T-lymphocytes was identified as the primary source of pro-inflammatory cytokines.
• This critical T-lymphocyte subset was found to lack CD28 expression in cynomolgus monkeys.

Conclusions:

• The absence of CD28 on the relevant T-lymphocyte subset in cynomolgus monkeys explains the failure of preclinical models to predict TGN1412 toxicity.
• This finding has significant implications for the preclinical evaluation of biological drugs, particularly monoclonal antibodies targeting T-cell co-stimulatory molecules.