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NEJM - Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry, M.R.C.P., Stephen Ward, F.R.C.A., Stephen J. Brett, M.D., Andrew Castello-Cortes, F.R.C.A., Michael D. Brunner, F.R.C.A., and Nicki Panoskaltsis, M.D., Ph.D.
http://content.nejm.org/cgi/content/abstract/NEJMoa063842
Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry, M.R.C.P., Stephen Ward, F.R.C.A., Stephen J. Brett, M.D., Andrew Castello-Cortes, F.R.C.A., Michael D. Brunner, F.R.C.A., and Nicki Panoskaltsis, M.D., Ph.D.
http://content.nejm.org/cgi/content/abstract/NEJMoa063842
ABSTRACT <vardef id="TEXT"> </vardef>
Six healthy young male volunteers at a contract research organization<sup> </sup>were enrolled in the first phase 1 clinical trial of TGN1412,<sup> </sup>a novel superagonist anti-CD28 monoclonal antibody that directly<sup> </sup>stimulates T cells. Within 90 minutes after receiving a single<sup> </sup>intravenous dose of the drug, all six volunteers had a systemic<sup> </sup>inflammatory response characterized by a rapid induction of<sup> </sup>proinflammatory cytokines and accompanied by headache, myalgias,<sup> </sup>nausea, diarrhea, erythema, vasodilatation, and hypotension.<sup> </sup>Within 12 to 16 hours after infusion, they became critically<sup> </sup>ill, with pulmonary infiltrates and lung injury, renal failure,<sup> </sup>and disseminated intravascular coagulation. Severe and unexpected<sup> </sup>depletion of lymphocytes and monocytes occurred within 24 hours<sup> </sup>after infusion. All six patients were transferred to the care<sup> </sup>of the authors at an intensive care unit at a public hospital,<sup> </sup>where they received intensive cardiopulmonary support (including<sup> </sup>dialysis), high-dose methylprednisolone, and an anti-interleukin-2<sup> </sup>receptor antagonist antibody. Prolonged cardiovascular shock<sup> </sup>and acute respiratory distress syndrome developed in two patients,<sup> </sup>who required intensive organ support for 8 and 16 days. Despite<sup> </sup>evidence of the multiple cytokine-release syndrome, all six<sup> </sup>patients survived. Documentation of the clinical course occurring<sup> </sup>over the 30 days after infusion offers insight into the systemic<sup> </sup>inflammatory response syndrome in the absence of contaminating<sup> </sup>pathogens, endotoxin, or underlying disease.
Notice: This article<sup> </sup>was published at www.nejm.org on August 14, 2006. It will appear<sup> </sup>in the September 7 issue of the Journal.
Click on "PDF" for<sup> </sup>the full text.
Six healthy young male volunteers at a contract research organization<sup> </sup>were enrolled in the first phase 1 clinical trial of TGN1412,<sup> </sup>a novel superagonist anti-CD28 monoclonal antibody that directly<sup> </sup>stimulates T cells. Within 90 minutes after receiving a single<sup> </sup>intravenous dose of the drug, all six volunteers had a systemic<sup> </sup>inflammatory response characterized by a rapid induction of<sup> </sup>proinflammatory cytokines and accompanied by headache, myalgias,<sup> </sup>nausea, diarrhea, erythema, vasodilatation, and hypotension.<sup> </sup>Within 12 to 16 hours after infusion, they became critically<sup> </sup>ill, with pulmonary infiltrates and lung injury, renal failure,<sup> </sup>and disseminated intravascular coagulation. Severe and unexpected<sup> </sup>depletion of lymphocytes and monocytes occurred within 24 hours<sup> </sup>after infusion. All six patients were transferred to the care<sup> </sup>of the authors at an intensive care unit at a public hospital,<sup> </sup>where they received intensive cardiopulmonary support (including<sup> </sup>dialysis), high-dose methylprednisolone, and an anti-interleukin-2<sup> </sup>receptor antagonist antibody. Prolonged cardiovascular shock<sup> </sup>and acute respiratory distress syndrome developed in two patients,<sup> </sup>who required intensive organ support for 8 and 16 days. Despite<sup> </sup>evidence of the multiple cytokine-release syndrome, all six<sup> </sup>patients survived. Documentation of the clinical course occurring<sup> </sup>over the 30 days after infusion offers insight into the systemic<sup> </sup>inflammatory response syndrome in the absence of contaminating<sup> </sup>pathogens, endotoxin, or underlying disease.
Notice: This article<sup> </sup>was published at www.nejm.org on August 14, 2006. It will appear<sup> </sup>in the September 7 issue of the Journal.
Click on "PDF" for<sup> </sup>the full text.