Autoreactivity of Broadly Neutralizing Influenza Human Antibodies to Human Tissues and Human Proteins.

Surender Khurana,Laura Klenow,Megan Hahn,Hana Golding

doi:10.3390/v12101140

Abstract

Broadly neutralizing monoclonal antibodies (bNAbs) against conserved domains in the influenza hemagglutinin are in clinical trials. Several next generation influenza vaccines designed to elicit such bNAbs are also in clinical development. One of the common features of the isolated bNAbs is the use of restricted IgVH repertoire. More than 80% of stem-targeting bNAbs express IgVH1-69, which may indicate genetic constraints on the evolution of such antibodies. In the current study, we evaluated a panel of influenza virus bNAbs in comparison with HIV-1 MAb 4E10 and anti-RSV MAb Palivizumab (approved for human use) for autoreactivity using 30 normal human tissues microarray and human protein (>9000) arrays. We found that several human bNAbs (CR6261, CR9114, and F2603) reacted with human tissues, especially with pituitary gland tissue. Importantly, protein array analysis identified high-affinity interaction of CR6261 with the autoantigen “Enhancer of mRNA decapping 3 homolog” (EDC3), which was not previously described. Moreover, EDC3 competed with hemagglutinin for binding to bNAb CR6261. These autoreactivity findings underscores the need for careful evaluation of such bNAbs for therapeutics and stem-based vaccines against influenza virus.

Highlights

Concerted efforts are underway to develop broadly protective therapeutic antibodies and cross-reactive vaccines against influenza
We produced a panel of previously described broadly neutralizing human monoclonal antibodies (bNAbs) whose targets were mapped either to the stem region (CR8020, CR6261, CR9114, F10, F16, and F2603) [4,5,12] or to the receptor-binding domain (CH65) [6] of the influenza virus hemagglutinin (HA)
A human tissues microarray with 30 different normal human tissues each from 3 different donors was used to determine the autoreactivity of the bNAbs (Supplementary Figure S1)

Summary

Introduction

Concerted efforts are underway to develop broadly protective therapeutic antibodies and cross-reactive vaccines against influenza. The development of such next-generation (or universal) vaccines was greatly energized by the isolation of broadly neutralizing human monoclonal antibodies (bNAbs) that target relatively conserved epitopes in the hemagglutinin (HA). Such bNAbs and vaccines designed to generate such antibodies could provide protection against drifting strains over longer periods compared with the current seasonal vaccines, as well as against avian influenza strains with pandemic potential [1,2,3]. IgVH 1-69 gene segment is associated with polyreactive responses in autoimmune pathologies and with certain B-cell

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