Immune-complex deposition and Fcγ receptor (FcγR)-mediated activation of inflammatory responses by such immune complexes is a central pathogenic process in a variety of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and vasculitis. A new study reports the development of a humanized anti-FcγRIIA antibody (VIB9600) that might function as a broad-spectrum therapy for these and other diseases.

Credit: Springer Nature Limited

“Although it has been known for some time that targeting FcγRIIA is a potential therapeutic strategy for these autoimmune diseases, difficulties relating to the development of an effective and specific antibody have prevented clinical translation,” notes Bo Chen, a corresponding author of the new study.

The researchers now show that VIB9600 can inhibit immune-complex responses in a variety of contexts, but importantly without also targeting the highly homologous (but inhibitory) FcγRIIB and without activating antibody-dependent or complement-dependent cytotoxicity.

VIB9600 inhibited immune-complex-induced production of type 1 interferon by plasmacytoid dendritic cells, and TNF and IL-6 by monocytes, which are inflammatory pathways known to be central to SLE and RA, respectively.

VIB9600 also inhibited autoantibody-induced production of reactive oxygen species by neutrophils, a pathway known to contribute to vasculitis pathogenesis.

The researchers also showed that, aside from blocking its target Fc receptor, VIB9600 can reduce expression of FcγRIIA by neutrophils and platelets in FcγRIIA-transgenic mice. Consequently, these mice were resistant to thrombocytopenia as well as to neutrophil-mediated nephritis and arthritis, in part owing to a reduction in immune-complex signalling.

Finally, the researchers showed that the antibody meets clinical expectations for pharmacokinetics and pharmacodynamics when injected into cynomolgus monkeys, and no adverse events were recorded during a 3-month multiple-dose GLP toxicology study and a subsequent 8-week follow-up period. The pharmacology and safety of VIB9600 are now under investigation in humans in a phase I clinical trial conducted by Viela Bio.