Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses

Area of Science:

• Immunology
• Autoimmune Diseases
• Therapeutic Antibody Development

Background:

• Immune complexes (ICs) are central to the pathology of various autoimmune diseases.
• Fc gamma receptor IIA (FcγRIIA) plays a critical role in mediating cellular activation by ICs.

Purpose of the Study:

• To generate and characterize VIB9600, a first-in-class antibody targeting FcγRIIA.
• To evaluate VIB9600's potential to block IC-mediated cellular activation for clinical development.

Main Methods:

• Humanization and optimization of the IV.3 antibody to create VIB9600.
• In vitro assays (Biacore, ELISA, confocal microscopy, flow cytometry) to assess binding, specificity, and mechanism of action.
• In vitro cell-based assays and in vivo studies in FcγRIIA-transgenic mice to demonstrate efficacy.
• Pharmacokinetic, pharmacodynamic, and GLP toxicity studies in non-human primates.

Main Results:

• VIB9600 potently blocks FcγRIIA activation by preventing ligand engagement and inducing receptor internalization.
• Demonstrated inhibition of IC-induced inflammatory mediators (type I interferons, reactive oxygen species, TNF-α, IL-6) relevant to SLE, ANCA-associated vasculitis, and rheumatoid arthritis.
• Successfully suppressed IC-mediated pathologies in vivo, including thrombocytopenia, nephritis, and arthritis.
• Exhibited favorable pharmacokinetic and safety profiles in non-human primates.

Conclusions:

• VIB9600 is a specific, humanized antibody antagonist of FcγRIIA with null effector function.
• The antibody effectively blocks autoantibody and IC-mediated pro-inflammatory responses.
• VIB9600 warrants further clinical development for treating immune complex-mediated diseases.