Background:
The α4β7 integrin plays an important role in the pathogenesis of HIV-1 infection. It is a heterodimeric receptor expressed on different immune cells. Expression of α4β7 on peripheral CD4+ T cells predicts HIV-1 acquisition and disease progression. Recent study showed that α4β7 is present on the envelope of HIV-1 virions, which suggests that α4β7 could be a highly conserved target for HIV-1 treatment.
Methods:
ABBV-382, a humanized mouse anti-human α4β7 mAb, has been evaluated in different biochemical, virological, immunosafety, and immunopeptidomics studies to characterize its properties and determine its mechanisms of action for HIV-1 intervention.
Results:
ABBV-382 demonstrated high binding affinity to α4β7 and blocked the interaction of α4β7 with its ligand MAdCAM-1. The binding profile of ABBV-382 to human FcγRs was similar to that of a typical human IgG1 mAb, but it did not induce ADCC or ADCP activity in vitro. ABBV-382 blocked the MAdCAM-1-mediated co-stimulation of CD4+ T cells, and HIV-1 replication in these treated cells. It also inhibited the interaction of α4β7 with HIV-1 gp120, and is therefore proposed to inhibit the cell-to-cell viral spread mediated by this interaction. Consistent with the report that α4β7 is present on the surface of HIV-1 virions, ABBV-382 could bind to virions from different HIV-1 strains to form immune complexes (ICs). These ICs could engage different FcγRs through the Fc domain of ABBV-382 in vitro. When the ICs were incubated with antigen presenting cells (APCs), they were phagocytosed in a Fc-dependent manner. Immunopeptidomics analyses demonstrated that the internalized ICs were processed, and HIV-1 peptides were presented by MHC class II on APCs, a mechanism that is proposed to enhance HIV-1 antigen presentation to T cells.
Conclusions:
Our study results provide evidence of the antiviral and immunomodulatory properties of ABBV-382 through two main mechanisms: (1) Direct antagonism of the interaction of α4β7 with its ligand MAdCAM-1 or HIV-1 gp120, leading to inhibition of HIV-1 replication or cell-to cell viral spread, respectively, and (2) Enhanced viral antigen presentation to T cells enabled by the Fc-dependent uptake of ICs (HIV-1 virions and ABBV-382) by APCs. Taken together, ABBV-382 demonstrates favorable biological characteristics and novel mechanistic properties supporting its clinical evaluation as an immune-based intervention for HIV-1 viral control. Disclosure: The design, study conduct, & financial support were provided by AbbVie.