The deglycosylated form of 1E12 inhibits platelet activation and prothrombotic effects induced by VITT antibodies.
Haematologica
; 107(10): 2445-2453, 2022 10 01.
Article
in English
| MEDLINE | ID: covidwho-1779916
ABSTRACT
In order to improve the safety of COVID-19 vaccines, there is an urgent need to unravel the pathogenesis of vaccineinduced immune thrombotic thrombocytopenia (VITT), a severe complication of recombinant adenoviral vector vaccines used to prevent COVID-19, and likely due to anti-platelet factor 4 (PF4) IgG antibodies. In this study, we demonstrated that 1E12, a chimeric anti-PF4 antibody with a human Fc fragment, fully mimics the effects of human VITT antibodies, as it activates platelets to a similar level in the presence of platelet factor 4 (PF4). Incubated with neutrophils, platelets and PF4, 1E12 also strongly induces NETosis, and in a microfluidic model of whole blood thrombosis, it triggers the formation of large platelet/leukocyte thrombi containing fibrin(ogen). In addition, a deglycosylated form of 1E12 (DG-1E12), which still binds PF4 but no longer interacts with Fcγ receptors, inhibits platelet, granulocyte and clotting activation induced by human anti-PF4 VITT antibodies. This strongly supports that 1E12 and VITT antibodies recognize overlapping epitopes on PF4. In conclusion, 1E12 is a potentially important tool to study the pathophysiology of VITT, and for establishing mouse models. On the other hand, DG-1E12 may help the development of a new drug that specifically neutralizes the pathogenic effect of autoimmune anti-PF4 antibodies, such as those associated with VITT.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Thrombocytopenia
/
Purpura, Thrombocytopenic, Idiopathic
/
COVID-19 Vaccines
/
COVID-19
Type of study:
Experimental Studies
Topics:
Vaccines
Limits:
Animals
/
Humans
Language:
English
Journal:
Haematologica
Year:
2022
Document Type:
Article
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