title: "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics.
abstract: The CD28-specific mAb TGN1412 rapidly caused a life-threatening "cytokine storm" in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates.
authors: Biotherapeutics Group, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
authors: Richard
authors: R
authors: Stebbings
authors: Lucy
authors: L
authors: Findlay
authors: Cherry
authors: C
authors: Edwards
authors: David
authors: D
authors: Eastwood
authors: Chris
authors: C
authors: Bird
authors: David
authors: D
authors: North
authors: Yogesh
authors: Y
authors: Mistry
authors: Paula
authors: P
authors: Dilger
authors: Emily
authors: E
authors: Liefooghe
authors: Isabelle
authors: I
authors: Cludts
authors: Bernard
authors: B
authors: Fox
authors: Gill
authors: G
authors: Tarrant
authors: Jane
authors: J
authors: Robinson
authors: Tony
authors: T
authors: Meager
authors: Carl
authors: C
authors: Dolman
authors: Susan J
authors: SJ
authors: Thorpe
authors: Adrian
authors: A
authors: Bristow
authors: Meenu
authors: M
authors: Wadhwa
authors: Robin
authors: R
authors: Thorpe
authors: Stephen
authors: S
authors: Poole
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D049109:Cell Proliferation; D017321:Clinical Trials, Phase I as Topic; D016207:Cytokines / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008213:Lymphocyte Activation; D008252:Macaca fascicularis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C509303:TGN-1412