Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory...

Area of Science:

• Immunology
• Pharmacology
• Translational Medicine

Background:

• The CD28 superagonist monoclonal antibody (mAb) TGN1412 caused a life-threatening cytokine storm in humans during a phase I trial.
• Pre-clinical safety testing in animals failed to predict this severe adverse event.
• The exact reason for TGN1412's differential immunopharmacology across species remained unclear.

Purpose of the Study:

• To investigate the immunopharmacological differences of TGN1412 between humans and animal models.
• To identify the cellular mechanisms underlying the cytokine storm induced by TGN1412.
• To explain the failure of pre-clinical testing to predict TGN1412's toxicity.

Main Methods:

• Utilized polychromatic flow cytometry and intracellular cytokine staining.
• Analyzed TGN1412's in vitro immunopharmacology at the cellular level.
• Compared immune responses in humans versus species used for pre-clinical safety testing.

Main Results:

• Interleukin-2 (IL-2) and Interferon-gamma (IFN-γ) release from CD4+ effector memory T-cells were key indicators of the TGN1412 response.
• TGN1412 activates CD4+ effector memory T-cells, distinct from other therapeutic mAbs.
• Crucially, CD28 is not expressed on CD4+ effector memory T-cells in species used for TGN1412's pre-clinical testing, preventing TGN1412 stimulation.

Conclusions:

• Activation of human CD4+ effector memory T-cells by TGN1412 likely caused the cytokine storm.
• The absence of CD28 on these T-cells in animal models explains the failure to predict this adverse reaction.
• This species-specific difference in CD28 expression is critical for understanding TGN1412's immunopharmacology and improving future drug safety assessments.