Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Matthew R Gardner,Jeffrey D Lifson,Guangping Gao,Ronald C Desrosiers,Sebastian P Fuchs,Michael Farzan,Ina Fetzer,Jose M Martinez-Navio,Lisa M Kattenhorn,Barnett Alfant,Meredith E Davis-Gardner,Hema R Kondur,Jesse A Weber,Amber S Zhou

doi:10.1016/j.ymthe.2019.01.004

Abstract

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs.

Highlights

To date, no HIV-1 vaccine approaches have elicited potent broadly neutralizing antibodies in humans, but bNAbs emerge naturally in some HIV-1-positive individuals after several years of infection
Emergence of anti-drug antibody (ADA) Coincides with a Decrease in bNAb Expression Given their low expression, we investigated whether the rapid decline in bNAb titers was associated with the emergence of ADA
All HIV-1 vaccine candidates have so far failed to elicit bNAbs thought necessary for sterilizing protection of the global population

Summary

Introduction

No HIV-1 vaccine approaches have elicited potent broadly neutralizing antibodies (bNAbs) in humans, but bNAbs emerge naturally in some HIV-1-positive individuals after several years of infection (reviewed in Burton and Mascola[1]). These bNAbs target multiple epitopes of the HIV-1 envelope glycoprotein (Env), including the CD4-binding site, the N332 V3-glycan site, the V1V2 apex, the gp120/gp[41] interface, and the membrane-proximal external region (MPER). One way to bypass the need to develop bNAbs through vaccination is through the use of adeno-associated virus (AAV) vectors. More recent macaque studies made it clear that AAV1- and AAV8-delivered bNAbs are frequently targeted by host immune responses, limiting their expression and efficacy.[13,14,15] To develop an effective AAV-based HIV-1 vaccine alternative, it will, be necessary to minimize immune system-mediated clearance of the AAV-expressed transgene

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