Toxin-Derived Delivery Constructs for Oral Biologic Transcytosis
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Solution Overview
Problem
The challenge of efficiently delivering large molecule biologics across the gut epithelium for oral administration is hindered by their inability to diffuse through the barrier or be transported into the body, leading to degradation in lysosomes and reduced patient compliance due to systemic side effects.
Innovation Solution
Development of a delivery construct comprising a carrier derived from the domain I of an exotoxin, lacking domains II and III, which interacts with specific receptors on epithelial cells to facilitate transcytosis, endocytosis, and delivery to supranuclear regions, using chimeric carriers coupled to heterologous cargos like cytokines and therapeutic antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If large molecule biologics are orally administered, then patient convenience and compliance are improved, but the biologics cannot diffuse across the gut epithelium and are degraded in lysosomes
Solution Approach 1:
The patent uses a carrier molecule as an intermediary to facilitate the transport of large molecule biologics across the gut epithelium. The carrier binds to the biologic and mediates its transcytosis through the epithelial barrier, preventing lysosomal degradation and enabling systemic delivery via the oral route.
Solution Approach 2:
The delivery system is segmented into distinct functional components: a carrier molecule with specific binding properties, a targeting domain for epithelial cell recognition, and the therapeutic biologic cargo. This segmentation allows each component to perform its specialized function in the delivery process.
2Reliability
If systemic administration is used to deliver biologics, then delivery reliability is improved, but side effects increase and patient compliance decreases
Solution Approach 1:
The oral delivery system uses the carrier molecule as a mediator to achieve reliable biologic delivery through the gut epithelium, providing an alternative to systemic administration. This approach maintains delivery reliability while avoiding the harmful side effects associated with systemic injection or infusion routes.
3Productivity
If biologics are taken up by endocytosis, then cellular uptake is achieved, but the biologics are degraded in lysosomes rather than transported into the body
Solution Approach 1:
The carrier molecule is designed with specific local qualities: a binding domain for attaching to the biologic, a targeting domain for recognizing epithelial cell receptors, and a transcytosis-promoting structure. These localized functional regions enable the carrier to direct the biologic through endocytosis and facilitate its transport across the epithelium without lysosomal degradation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The delivery construct effectively transports biologics across epithelial cells, enhancing oral administration by avoiding lysosomal degradation and systemic side effects, thereby improving patient compliance and therapeutic efficacy.
Implementation Method 1
The delivery construct can deliver the heterologous cargo according to one or more of the following: across an epithelial cell via transcytosis
Implementation Method 2
to the interior of the epithelial cell via endocytosis
Data Source
AI summary
The present disclosure relates to isolated non-naturally occurring delivery constructs comprising a bacterial toxin-derived delivery construct coupled to a biologically active therapeutic cargo; wherein the delivery construct is capable of delivering the biologically active cargo via transcytosis transport across an epithelial cell; and wherein the delivery construct does not comprise a bacterial toxin-derived translocation domain or a bacterial toxin-derived catalytic (cytotoxic) domain.