"Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics.
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.
Stebbings
Richard
R
Biotherapeutics Group, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
Findlay
Lucy
L
Edwards
Cherry
C
Eastwood
David
D
Bird
Chris
C
North
David
D
Mistry
Yogesh
Y
Dilger
Paula
P
Liefooghe
Emily
E
Cludts
Isabelle
I
Fox
Bernard
B
Tarrant
Gill
G
Robinson
Jane
J
Meager
Tony
T
Dolman
Carl
C
Thorpe
Susan J
SJ
Bristow
Adrian
A
Wadhwa
Meenu
M
Thorpe
Robin
R
Poole
Stephen
S
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
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C509303:TGN-1412