pIgR Stem Zone-Targeted Nanobodies as Apical-to-Basolateral Carriers for Inhaled Biologic Delivery Across Mucosal...

Area of Science:

• Biotechnology
• Pharmacology
• Immunology

Background:

• The mucosal barrier poses challenges for macromolecular drug delivery, leading to poor bioavailability and toxicity.
• The polymeric immunoglobulin receptor (pIgR) facilitates transcytosis via its stem domain.
• Targeting the pIgR stem domain may enable active drug transport across mucosal barriers.

Purpose of the Study:

• To develop a strategy for enhanced transmucosal delivery of biologics by targeting the pIgR stem domain.
• To investigate the efficacy of nanobody-mediated transport across mucosal barriers.

Main Methods:

• Phage display was used to identify nanobodies targeting human and murine pIgR.
• Lead nanobodies (3LTHMP-4, 3LTHMP-5) were tested for apical-to-basolateral transport in vitro and in vivo.
• Engineered bispecific antibodies were administered via inhalation in a murine asthma model.

Main Results:

• Two nanobodies demonstrated efficient transport across mucosal barriers.
• Bispecific antibodies showed significant therapeutic efficacy in a murine asthma model.
• HDX-MS confirmed specific binding of nanobodies to the pIgR stem domain (residues 578-612).

Conclusions:

• Stem domain-specific binding facilitates transport across the mucosal barrier.
• This strategy preserves native receptor physiology.
• Offers a potential approach for effective transmucosal delivery of biologics.