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'Cytokine Storm' May Explain U.K. Clinical Trial Disaster

TGN1412 may trigger production of inflammatory molecules in humans but not in test animals

MONDAY, April 17 (HealthDay News) -- The experimental antibody drug TGN1412 that caused organ failure in six British men but not in test animals may have triggered a "cytokine storm" immune reaction, according to a news report published in the April 13 issue of Nature.

Because TGN1412 was designed to target the CD28 antibody receptor, which is identical in humans and monkeys, researchers believed it would have similar effects in both species.

"With hindsight, it might be no surprise that the compound, dubbed a 'superagonist' antibody by its creators, could run amok in the immune system," writes Nature reporter Michael Hopkin. He notes that TGN1412 "was designed to circumvent the usual checks and balances that prevent T cells from overreacting in the course of their normal duties," and as a result, the six men may have been hit by a 'cytokine storm,' or an onslaught of inflammatory molecules released by helper T cells.

"One possible source of the difference between the animal and human trials is that the 'tail' of the antibody molecule at the opposite end from the CD28-binding site may not be the same in humans and monkeys," writes Hopkin. "Antibody tails can undergo a process called crosslinking, which amplifies an immune response by recruiting more immune cells or antibodies. Therapeutic antibodies are modified so that they have the same overall structure as a generic human antibody, but doing this may also have prevented the full extent of TGN1412's activity from showing up in animal tests."

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