The deglycosylated form of 1E12 inhibits platelet activation and prothrombotic effects induced by VITT antibodies.

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.

• Authors: Caroline Vayne, Raghavendra Palankar, Sandra Billy, Stefan Handtke, Thomas Thiele, Charlotte Cordonnier, Claire Pouplard, Andreas Greinacher, Yves Gruel, Jérôme Rollin
• Journal: Haematologica (Haematologica) Vol. 107 Issue 10 Pg. 2445-2453 (10 01 2022) ISSN: 1592-8721 [Electronic] Italy
• PMID: 35385923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COVID-19 Vaccines
• Epitopes
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Receptors, IgG
• Platelet Factor 4
• Fibrin

Topics

• Animals
• COVID-19
• COVID-19 Vaccines (adverse effects)
• Epitopes
• Fibrin
• Humans
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Mice
• Platelet Activation
• Platelet Factor 4 (adverse effects, metabolism)
• Purpura, Thrombocytopenic, Idiopathic (chemically induced)
• Receptors, IgG (genetics, metabolism)
• Thrombocytopenia (chemically induced)
• Thrombosis (pathology)