Enhancing FcγR-mediated antibody effector function during persistent viral infection

Area of Science:

• Immunology
• Virology
• Pharmacology

Background:

• Persistent viral infections can lead to excessive immune complex (IC) formation.
• This IC formation impairs Fc receptor gamma (FcγR)-mediated antibody effector functions.
• This impairment results in resistance to FcγR-dependent therapeutic antibodies.

Purpose of the Study:

• To investigate mechanisms by which therapeutic antibodies can overcome endogenous ICs.
• To identify strategies for efficient target cell depletion in persistent viral infections.

Main Methods:

• Utilized mice persistently infected with lymphocytic choriomeningitis virus (LCMV).
• Tested depleting antibodies targeting antigens with varying expression levels (CD90, CD20, CD4, CD8α).
• Compared fucosylated and afucosylated antibodies for FcγR binding affinity and in vivo efficacy.

Main Results:

• Efficient depletion required higher antibody binding to target cells or use of afucosylated antibodies with increased FcγR affinity.
• Antibodies targeting highly expressed antigens (CD90, CD20) were effective, while those against low-abundance antigens failed.
• Afucosylated antibodies against CD4 and CD8α demonstrated superior efficacy over fucosylated versions in infected mice.

Conclusions:

• Therapeutic antibodies can overcome endogenous ICs by targeting highly expressed antigens or possessing increased FcγR affinity.
• Afucosylation enhances antibody efficacy in the presence of competing ICs.
• Findings offer strategies for optimizing antibody therapies in persistent infections, autoimmune diseases, and cancer.