This technology uses a novel chemical tagging method to identify intestinal receptors that transport biologic drugs across the gut barrier, enabling more effective oral delivery of large protein therapeutics that were previously only injectable.
Background
Oral delivery of biologic drugs, such as therapeutic proteins and antibodies, represents a major goal in pharmaceutical development due to its potential to improve patient compliance and accessibility. However, the gastrointestinal tract poses a formidable barrier to these large, hydrophilic molecules. The intestinal epithelium, characterized by tight junctions and selective cellular membranes, is highly effective at preventing the passage of macromolecules from the gut lumen into the bloodstream. While small, lipophilic drugs can often cross this barrier via passive diffusion, biologics require specialized active transport mechanisms, such as receptor-mediated transcytosis, to achieve systemic absorption. The identification of suitable transcytosis receptors on the intestinal epithelium is therefore critical for enabling efficient oral delivery of these advanced therapeutics.
Despite significant research efforts, current approaches to identifying and exploiting intestinal transcytosis pathways have met with limited success. The few known receptors, such as the transferrin receptor (TFRC), neonatal Fc receptor (FcRn), and vitamin B12 receptor, suffer from drawbacks including low expression on the apical surface of intestinal cells, widespread distribution in non-target tissues, and slow or inefficient transport kinetics. Traditional proteomics and membrane profiling methods often fail to distinguish between receptors that are actively involved in transcytosis and those that are recycled or degraded, leading to high rates of false positives and inefficient downstream screening. As a result, the development of orally bioavailable biologics remains severely constrained by the lack of robust, selective, and high-throughput methods for identifying functional transcytosis receptors specific to the intestinal barrier.
Technology Description
The technology described is a chemical proteomics platform called "Tag-and-Click," which is designed to identify and characterize intestinal transcytosis receptors to enhance the oral delivery of biologic drugs. This method leverages polarized Caco-2 intestinal epithelial cells grown on Transwell inserts to mimic the human intestinal barrier. The process involves selectively tagging apical membrane proteins with SulfoNHS-DBCO, inducing transcytosis with galectin-3, and then specifically labeling proteins that reach the basolateral membrane with azide-PEG-biotin. These doubly tagged proteins are isolated and identified via mass spectrometry, allowing researchers to pinpoint receptors that actively mediate transcytosis rather than those destined for recycling or degradation. The platform has led to the discovery and validation of several novel gut-specific receptors, such as MUC13, ACE, CDHR5, SLC3A1, basigin, and CD98hc, which have demonstrated superior transport capabilities in both in vitro and in vivo models.
What differentiates this technology is its unique ability to selectively identify only those receptors that are functionally involved in apical-to-basolateral transcytosis, offering a level of spatial and functional specificity not achieved by previous methods. Traditional approaches often profile membrane proteins based on abundance or tissue localization, resulting in extensive downstream screening to identify functional transporters. In contrast, the Tag-and-Click platform directly labels and isolates receptors actively engaged in transcytosis, streamlining the discovery process and accelerating the identification of promising therapeutic targets. This selectivity not only reduces the experimental burden but also uncovers previously unknown receptors with higher transport efficiency, paving the way for more effective oral biologic drug delivery. The method’s adaptability to other polarized barriers, such as the blood-brain barrier, and its compatibility with standard laboratory equipment further enhance its commercial and scientific appeal, positioning it as a transformative tool in targeted drug delivery research.
Benefits
- Enables identification of intestinal receptors that actively medcytose biologic drugs, overcoming the intestinal epithelial barrier.
- Selective chemical tagging distinguishes transcytosing receptors from those degraded or recycled, improving target discovery accuracy.
- Facilitates discovery of novel gut-specific receptors with superior transport efficiency compared to existing standards.
- Validated in vitro and in vivo, demonstrating enhanced oral bioavailability potential for large biologic molecules.
- Streamlines screening and accelerates development of oral biologic drug delivery systems.
- Adaptable to other polarized tissue barriers, broadening therapeutic delivery applications.
- Utilizes commercially available reagents and standard laboratory equipment, supporting easy implementation.
Commercial Applications
- Oral delivery of protein therapeutics
- Targeted oral vaccines development
- Screening novel transcytosis drug targets
- Blood-brain barrier drug delivery
Additional Information
This chemical proteomics platform, "Tag-and-Click," identifies intestinal transcytosis receptors. It selectively tags apical proteins on polarized Caco-2 cells, then labels those traversing to the basolateral membrane. Mass spectrometry identifies these actively transported proteins. This approach discovers novel targets to enhance oral delivery of biologics by overcoming the intestinal barrier.
Patent
Provisional patent filed 01/05/2026
