Dissecting the Functional Role of Mucosal IgA Clonal and Glycoprofiles for Effective Humoral Mucosal Protection

Introduction

Numerous mucosal vaccines and IgA-based monoclonal antibodies aimed at robust immunity within the respiratory tract are in development to combat viral endemics and pandemics. However, investigations into humoral immunity have predominantly focused on circulating antibodies, particularly those of the IgG isotype. This has left a significant void in our understanding of the role of mucosal IgA proteoforms in conveying effective immune protection. This crucial knowledge gap deprives vaccine and antibody development of essential determinants or immune characteristics to replicate.

Research Objectives

In response to this, we will conduct in-depth investigations of mucosal IgA, including:

1. In vitro functional evaluations
2. In vivo functional evaluations

We will capitalize on recent advances in liquid chromatography and mass spectrometry-based approaches for the detailed characterization of mucosal IgA clonal repertoires and glycosylation profiles, a field that has remained completely unexplored until now. Our methods will include:

• B-cell receptor sequencing
• Monoclonal IgA glycoengineering
• In vitro functional assays

Unique Approach

We will take advantage of our unparalleled biobank of human nasal secretion samples with clear documentation of infection outcomes on an individual level. What sets our approach apart is the unprecedented molecular-level characterization of IgA, directly linked to their in vitro functionality and pre-defined clinical outcomes, which clearly surpasses current state-of-the-art.

Expected Outcomes

By harnessing our in-depth characterization of mucosal IgA coupled with functional traits, we will generate IgA templates with:

• Enhanced binding and neutralization capabilities
• Functionally advantageous Fc effector potencies

Our overarching aim is to provide molecular-level blueprints for protective monoclonal IgA antibodies, enabling the fine-tuning of vaccine formulations and monoclonal antibody generation with a higher degree of accuracy, ultimately enhancing their efficacy and safety.