Furin-Cleavable Delivery Constructs for Epithelial Transport

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Solution Overview

Problem

Current methods for administering large therapeutic molecules like proteins across epithelial barriers, such as the gut or respiratory epithelium, are limited due to their inability to diffuse or cross intact epithelial layers, leading to low efficacy and side effects with parenteral administration routes.

Innovation Solution

A furin-cleavable delivery construct is developed, comprising a transcytosing element from a mono-ADP-ribosyl transferase domain I, a heterologous cargo, and a furin-cleavable cleavage site, allowing for transcytosis across epithelial cells with subsequent release of the cargo by furin protease cleavage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If parenteral administration (intravenous or subcutaneous) is used to deliver therapeutic proteins, then delivery efficacy is improved, but side effects increase and patient convenience decreases

Engineering Contradiction:

Improvedelivery efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs a transcytosing element as an intermediary carrier protein that mediates the transport of therapeutic cargo across the epithelial barrier. This intermediary mechanism allows therapeutic proteins to cross the blood-brain barrier without requiring direct parenteral injection, thereby reducing side effects while maintaining delivery efficacy through the intermediary's ability to facilitate controlled transport.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If therapeutic proteins are administered orally or respiratorily, then patient convenience is improved, but delivery efficacy decreases due to inability to cross intact epithelial barriers

Engineering Contradiction:

Improvepatient convenienceVSAvoiddelivery efficacy

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The transcytosing element utilizes the cell's own endocytic and transcytotic machinery to transport the therapeutic cargo across the epithelial barrier. By harnessing the cell's self-service transport mechanisms rather than requiring external intervention, the system enables oral or respiratory administration (improving convenience) while achieving effective delivery (improving efficacy) through the cell's intrinsic transport capabilities.

Inventive Principle:

Principle #25Self-service

3Reliability

If therapeutic proteins enter epithelial cells, then delivery across barrier is achieved, but proteins are degraded in lysosomes

Engineering Contradiction:

Improvedelivery across barrierVSAvoidprotein degradation

Core Design Contradiction:

ReliabilityVSLoss of substance

Solution Approach 1:

The patent extracts the therapeutic cargo from the transcytosing element's protective domain I structure after successful transcytosis. By removing or exposing the cargo at the appropriate stage (post-transcytosis, pre-lysosomal degradation), the system enables delivery across the barrier while preventing protein degradation in lysosomes through timely cargo release before the cargo is subjected to lysosomal enzymes.

Inventive Principle:

Principle #2Taking out (Extraction)

4Reliability

If a transcytosing element is used to transport cargo across epithelium, then delivery efficacy is improved, but device complexity increases

Engineering Contradiction:

Improvedelivery efficacyVSAvoidconstruct complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The transcytosing element is segmented into functional domains: domain I (transcytosing function), domain II (structural support), and domain III (cargo binding). This segmentation allows each domain to perform its specific function efficiently while maintaining overall system simplicity. The modular architecture enables the transcytosing element to achieve effective delivery without requiring overly complex interactions between components.

Inventive Principle:

Principle #1Segmentation

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

This approach enables efficient and targeted delivery of therapeutic proteins across epithelial cells, enhancing bioavailability and reducing side effects by utilizing endogenous trafficking pathways and avoiding lysosomal degradation.

Implementation Method 1

a furin-cleavable cleavage site, wherein the furin-cleavable cleavage site has a scissile bond that is positioned between the transcytosing element and the heterologous cargo such that cleavage of the scissile bond by a furin protease releases the heterologous cargo from the transcytosing element

Methodology Applied

Scientific EffectProteolytic cleavage: Enzyme

Implementation Method 2

a transcytosing element derived from a domain I of a mono-ADP-ribosyl transferase (mART); a heterologous cargo coupled to the transcytosing element

Methodology Applied

Scientific EffectTranscytosis:

Data Source

PatentUS20250099599A1Furin-cleavable delivery constructs

Publication Date: 2025.03.27 THORNHILL THERAPEUTICS INC

AI summary

The present disclosure provides furin-cleavable delivery constructs that include a transcytosing element that is derived from a mono-ADP-ribosyl transferase and a heterologous cargo that is coupled to the carrier. The carrier is capable of facilitating transport of the heterologous cargo across an epithelial cell via transcytosis. The heterologous cargo may be released from a remaining portion of the delivery construct upon cleavage by a furin protease. The constructs may be used to facilitate delivery of a cargo to a basolateral side of an epithelial membrane.