TGN1412 - What the hell happened?

NEJM has published an article which chronicles the events in the 30 days after dosing with the experimental drug, TGN1412, in six healthy volunteers. All went into multi-organ failure.

Pre-clinical studies in monkeys showed two mild side effects: irritation at the injection site and a mild swelling of the lymph nodes in some animals. These effects were mils, despite the fact that they received considerably higher concentrations of the drug.

Compare that to the long list of effects shown in Table 3 of the NEJM article! These include:

Capillary leak
Hemodynamic instability
Lactic acidemia
Early acute renal impairment
Acute pulmonary changes (six patients)
Met criteria for acute lung injury (two patients)
Met criteria for acute respiratory distress syndrome (one patient)
Lymphopenia
Monocytopenia
Thrombocytopenia
Disseminated intravascular coagulation
Normochromic, normocytic anemia
Delirium
Partial amnesia
Paresthesia or localized numbness
Difficulty concentrating (late)
Headaches (early and late)
Nausea or vomiting

Differences between humans and the animals used in preclinical studies are identified as factors that ultimately lead to this disaster - because the effects were not predicted by the results of the animal experiments.

Link to full article below.

NEJM -- Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412