The Fc Review: When does antibody bivalency help, and when can it work against you? A recent mAbs study explores the impact of antibody bivalency on antigen occupancy and cell surface opsonization, revealing that the same property can be advantageous or disadvantageous depending on the intended mechanism of action (MoA). Background: Most therapeutic antibodies are bivalent, meaning they can bind two target antigens simultaneously. This avidity effect is often viewed as beneficial because it increases apparent binding strength and can improve target engagement. However, therapeutic success is not always driven by target occupancy alone. For mechanisms that rely on Fc-mediated effector function, the number of antibodies decorating the target cell surface may be just as important. The study highlights: Bivalent antibodies achieved higher antigen occupancy than comparable monovalent antibodies across a range of affinities and antigen densities. At the same time, bivalency reduced the total number of antibodies bound per cell because a single antibody could occupy two antigens simultaneously. The authors describe an "avidity barrier," where achieving equivalent levels of cell surface opsonization requires substantially higher concentrations of a bivalent antibody. The optimal balance between occupancy and opsonization depended on factors including antibody affinity, valency, and target antigen density.

Abstract: Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in Long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluorescence, ELISA, human protein array, and mass spectrometry assays, we identified a broad range of AAB targets among individuals with LC. Individuals with neurocognitive symptoms showed increased AABs against central and peripheral nervous system proteins. Purified IgG reacted with human locus coeruleus, thalamus, adrenal gland, thyroid, and cross-reacted with mouse sciatic nerve and meninges. CNS-reactive AABs correlated with several neurological symptoms. MED20-targeting IgG from patients with LC showed enhanced antibody-dependent phagocytosis. Passive transfer of IgG from individuals with LC into mice induced fatigue-like behavior, loss of balance/coordination, thermal hyperalgesia, small fiber nerve damage, and increased pain-related neuronal activity, recapitulating patients’ symptoms. These findings suggest that targeting AABs might offer therapeutic benefits for this LC subgroup.