Some aspects of the recombinantly expressed humanised superagonist anti-CD28 mAb, TGN1412 trial catastrophe lessons to safeguard mAbs and vaccine trials.
We consider essential, still ignored, basic research aspects of the failed clinical trial (13 March 2006) of a recombinantly expressed humanised superagonist anti-CD28 mAb, TGN14122. Without hindsight, if for approval of the first ever recombinantly expressed anti-CD28 mAb use in humans attention had been paid to the physico-chemical factors and receptor saturation, the possible catastrophe will have been predictable and preventable. To understand what went wrong and, crucially, to prevent any future disasters to safeguard human health, safety and welfare, the information provided is likely to be of wide interest. We present calculations to show CD28 receptors on T cells of the six healthy volunteers by the anti-CD28 mAb superagonist, TGN1412. This led to the over activation of T cells and the violent cytokine storm precipitating the cascade and the release of endogenous molecules affecting other cells. Monocytes and plasma cells are likely to have been affected. We discuss briefly the role of neutrophils and activation releasing the surface-located sialidase affecting cell coats, such as, of T lymphocytes exposing galactose receptors that could have been involved in antigen presenting cell interactions. The role of the cell surface thiols of lymphocytes in forming mixed disulphides with endogenous ligands and in the REDOX system are briefly mentioned. Consideration of these various factors and a critical evaluation of the receptor occupancy data before injecting 0.1 mg/kg TGN1412 will have rung alarm bells about possible serious side effects and the catastrophe will have been averted.
Mehrishi
Jitendra N
JN
University of Cambridge, Cambridge, United Kingdom. jm45@cam.ac.uk
Szabó
Miklós
M
Bakács
Tibor
T
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism*; D002986:Clinical Trials as Topic / Q000592:standards*; D016207:Cytokines / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014612:Vaccines
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; D011994:Recombinant Proteins; D014612:Vaccines; C509303:TGN-1412