Cytokine release assays for the prediction of therapeutic mAb safety in first-in man trials — Whole blood cytokine release assays are poorly predictive for TGN1412 cytokine storm

Autor: R. Stebbings, David Eastwood, Swaminathan Sethu, Sandrine Vessillier, Susan J. Thorpe, Thomas Dougall, Jean G. Sathish, Bernard Fox, Robin Thorpe
Rok vydání: 2015
Předmět:
IL-17
interleukin-17
Daclizumab
Erythrocytes
genetic structures
Cytokine release assay
medicine.medical_treatment
WBC
white blood cells
Fluoroimmunoassay
GYPA
glycophorin A
Therapeutic mAb
Immunology and Allergy
Glycophorins
SP
Solid Phase
Alemtuzumab
RBCs
Red Blood Cells
Whole blood
IL-8
interleukin-8
IL-13
interleukin-13
TCR
T cell receptor
Antibodies
Monoclonal
CRS
cytokine release syndrome
TGN1412
Group size
Cytokine release syndrome
Cytokine
Cytokines
IL-2R
interleukin-2 receptor
medicine.drug
medicine.drug_class
Immunology
WB
whole blood
TNFα
tumor necrosis factor alpha
Antineoplastic Agents
Biology
Antibodies
Monoclonal
Humanized
Monoclonal antibody
Peripheral blood mononuclear cell
Article
AQ
Aqueous Phase
PBS
phosphate buffered saline
IL-2
interleukin-2
medicine
Humans
mAb
monoclonal antibody
PBMCs
peripheral blood mononuclear cells
PBMC
HDC
high density culture
medicine.disease
IFNγ
interferon gamma
Immunoglobulin G
Leukocytes
Mononuclear
Cytokine storm
CRA
cytokine release assay
Zdroj: Journal of Immunological Methods
ISSN: 0022-1759
DOI: 10.1016/j.jim.2015.04.020
Popis: The therapeutic monoclonal antibody (mAb) TGN1412 (anti-CD28 superagonist) caused near-fatal cytokine release syndrome (CRS) in all six volunteers during a phase-I clinical trial. Several cytokine release assays (CRAs) with reported predictivity for TGN1412-induced CRS have since been developed for the preclinical safety testing of new therapeutic mAbs. The whole blood (WB) CRA is the most widely used, but its sensitivity for TGN1412-like cytokine release was recently criticized. In a comparative study, using group size required for 90% power with 5% significance as a measure of sensitivity, we found that WB and 10% (v/v) WB CRAs were the least sensitive for TGN1412 as these required the largest group sizes (n = 52 and 79, respectively). In contrast, the peripheral blood mononuclear cell (PBMC) solid phase (SP) CRA was the most sensitive for TGN1412 as it required the smallest group size (n = 4). Similarly, the PBMC SP CRA was more sensitive than the WB CRA for muromonab-CD3 (anti-CD3) which stimulates TGN1412-like cytokine release (n = 4 and 4519, respectively). Conversely, the WB CRA was far more sensitive than the PBMC SP CRA for alemtuzumab (anti-CD52) which stimulates FcγRI-mediated cytokine release (n = 8 and 180, respectively). Investigation of potential factors contributing to the different sensitivities revealed that removal of red blood cells (RBCs) from WB permitted PBMC-like TGN1412 responses in a SP CRA, which in turn could be inhibited by the addition of the RBC membrane protein glycophorin A (GYPA); this observation likely underlies, at least in part, the poor sensitivity of WB CRA for TGN1412. The use of PBMC SP CRA for the detection of TGN1412-like cytokine release is recommended in conjunction with adequately powered group sizes for dependable preclinical safety testing of new therapeutic mAbs.
Highlights • Sensitivity of different CRA formats determined by power analysis of group sizes. • PBMC solid phase CRAs were highly predictive for TGN1412 but not alemtuzumab. • Whole blood CRAs were predictive for alemtuzumab but poorly predictive for TGN1412. • TGN1412 cytokine release was inhibited by glycophorin A and red blood cells.
Databáze: OpenAIRE
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