Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.

A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery.

Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.

The neonatal Fc receptor in mucosal immune regulation.

The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism. These processes secure distribution and high levels of both IgG and albumin throughout the body. At mucosal sites, FcRn transports IgG across polarized epithelial cells where it retrieves IgG in complex with luminal antigens that is delivered to tissue-localized immune cells. In dendritic cells (DCs), FcRn orchestrates processing of IgG-opsonized immune complexes (ICs) in concert with classical Fcγ receptors, which results in antigen presentation and cross-presentation of antigenic peptides on MHC class II and I to CD4+ and CD8+ T cells, respectively. Hence, FcRn regulates transport of the ligands within and across different types of cells, but also processing of IgG-ICs by immune cells. As such, the receptor is involved in immune surveillance and protection against infections. In this brief review, we highlight how FcRn expressed by hematopoietic and non-hematopoietic cells contributes to immune regulation at mucosal barriers-biology that can be utilized in development of biologics and subunit vaccines for non-invasive delivery.