Enhancing IgG distribution to lung mucosal tissue improves protective effect of anti–Pseudomonas aeruginosa antibodies

Abstract

IgG antibodies are abundantly present in the vasculature but to a much lesser extent in mucosal tissues. This contrasts with antibodies of the IgA and IgM isotype that are present at high concentration in mucosal secretions due to active delivery by the polymeric Ig receptor (pIgR). IgG is the preferred isotype for therapeutic mAb development due to its long serum half-life and robust Fc-mediated effector function, and it is utilized to treat a diverse array of diseases with antigen targets located in the vasculature, serosa, and mucosa. As therapeutic IgG antibodies targeting the luminal side of mucosal tissue lack an active transport delivery mechanism, we sought to generate IgG antibodies that could be transported via pIgR, similarly to dimeric IgA and pentameric IgM. We show that an anti-Pseudomonas aeruginosa IgG fused with pIgR-binding peptides gained the ability to transcytose and be secreted via pIgR. Consistent with these results, pIgR-binding IgG antibodies exhibit enhanced localization to the bronchoalveolar space when compared with the parental IgG antibody. Furthermore, pIgR-binding mAbs maintained Fc-mediated functional activity and promoted enhanced survival compared with the parental mAb in a P. aeruginosa acute pneumonia model. Our results suggest that increasing IgG accumulation at mucosal surfaces by pIgR-mediated active transport can improve the efficacy of therapeutic mAbs that act at these sites.

In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains

“…Moreover, the higher doses of mAbs used in patients (e.g., ∼35 mg/kg for casirivimab and imdevimab [REGN mAbs]) could compensate for loss in neutralization potency. Generally, in mice and hamsters, mAb-mediated protection was better in the lung than in nasal washes, possibly because IgG levels in the respiratory mucosa are lower than in plasma 21,22 .…”

Discovery and characterization of single-domain antibodies for polymeric Ig receptor-mediated mucosal delivery of biologics

“…Previous studies have demonstrated that conferring pIgRbinding abilities to IgG and other biologic payloads can result in the transport of such molecules across the epithelial barrier. [15][16][17][18][19][20][21][22][23][24][25] Thus, we sought to generate VHHs that could be transported via pIgR for use as a delivery moiety in multi-specific antibodies.…”

“…15,19,23 In the most recent work, an anti-P. aeruginosa IgG fused with pIgR-binding peptides exhibited enhanced localization to the bronchoalveolar space, maintained Fc-mediated functional activity and promoted enhanced survival in an acute pneumonia model. 15 Given that the VHH scaffold is small (12-15 kDa) and wellrecognized for high stability, solubility, cleft recognition properties, low production costs and easy genetic cross-linking, 33,34 we generated VHHs against pIgR to develop a mucosal drug delivery platform. Following llama immunization, B-cell sorting and VHH gene isolation, we expressed, purified and screened a panel of 73 VHH-mFc molecules for binding to mpIgR and hpIgR ECD.…”

“…This results in very poor accumulation of IgG molecules in mucosa upon intravenous administration, which is undesirable for therapeutic IgG antibodies targeting mucosal organs (e.g., lungs, intestine) for treating respiratory, pulmonary and intestinal diseases. 15 Previous studies have shown that conferring pIgR-binding abilities to IgG molecules and other biologic payloads can result in the transcytosis of such molecules across the epithelial barrier. Other groups have generated pIgR-binding peptides, [15][16][17] IgG antibodies, antigen-binding fragments (Fabs), single-chain variable fragments, [18][19][20][21][22][23][24] and single-domain antibodies (VHH) 25 to capitalize on the transcytosis activity of pIgR.…”

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

“…In particular, bamlanivimab is an IgG 1 , and these immunoglobulins cannot be secreted to mucosal tissue like IgA and IgM. It has been demonstrated that systemically administered IgG levels in bronchoalveolar lavage (BAL) can be approximately 1,000 times lower than levels of IgG in serum [ 72 ]. Furthermore, the injury of the respiratory tissue by inflammatory processes probably determines a further limitation to bioavailability.…”