Lysosomal Enzyme Fusion Proteins With IGF-II Tag for Targeted Uptake

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Solution Overview

Problem

Existing enzyme replacement therapies for lysosomal storage diseases face inefficiencies in delivering lysosomal enzymes to lysosomes due to reliance on mannose-6-phosphate-dependent mechanisms, which can be improved by using a peptide-based targeting technology that reduces binding affinity for the IGF-1 and insulin receptors and is resistant to furin cleavage.

Innovation Solution

Development of targeted therapeutic fusion proteins comprising a lysosomal enzyme, a peptide tag with reduced binding affinity for the IGF-1 and insulin receptors, and a spacer peptide, such as IGF-II mutein, to enhance lysosomal enzyme delivery and uptake.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If mannose-6-phosphate-dependent mechanisms are used for enzyme delivery, then lysosomal enzymes can be targeted to lysosomes, but delivery efficiency is insufficient

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidtargeting accuracy

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces a peptide-based targeting technology that acts as an intermediary mechanism between the lysosomal enzyme and the lysosome. This peptide tag serves as a mediator that binds to receptors on the lysosomal membrane, facilitating more efficient and reliable enzyme delivery compared to the traditional mannose-6-phosphate pathway.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the targeting parameters by changing from carbohydrate-based targeting (mannose-6-phosphate) to peptide-based targeting. This parameter change enables improved delivery efficiency and targeting accuracy by altering the molecular recognition mechanism at the lysosomal membrane.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If peptide-based targeting technology is used, then delivery efficiency is improved, but binding affinity for IGF-1 and insulin receptors increases

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidbinding affinity for off-target receptors

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality modification by creating a peptide tag with specific amino acid sequences that have different binding properties at different locations. The peptide is designed to bind strongly to lysosomal receptors while having reduced binding affinity for other receptors like IGF-1 and insulin receptors, achieving selective targeting.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of designing a peptide that binds to multiple receptors, the patent inverts the approach by creating a peptide that specifically avoids binding to off-target receptors while maintaining binding to the correct lysosomal receptor. This inversion of the binding specificity problem resolves the contradiction between delivery efficiency and off-target binding.

Inventive Principle:

Principle #13The other way round (Inversion)

3Productivity

If peptide-based targeting is used, then lysosomal enzyme uptake is enhanced, but susceptibility to furin cleavage increases

Engineering Contradiction:

Improveenzyme uptakeVSAvoidpeptide stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by designing the peptide tag to be resistant to furin cleavage from the outset. The peptide sequence is carefully selected to lack furin recognition sites or to have modified sequences that prevent furin binding and cleavage, thereby protecting the peptide from degradation while maintaining its targeting function.

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The patent converts the potential harm of furin cleavage into a benefit by designing the peptide tag to be inherently resistant to furin. This resistance ensures the peptide remains stable and functional in the cellular environment, transforming a potential vulnerability into a strength that enhances peptide reliability.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 fusion proteins exhibit improved production and uptake into lysosomes, potentially treating lysosomal storage diseases like Mucopolysaccharidosis Type IIIB with enhanced efficacy.

Implementation Method 1

The peptide tag binds to the cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner

Methodology Applied

Scientific EffectReceptor binding:

Data Source

PatentUS20250388644A1Targeted therapeutic lysosomal enzyme fusion proteins and uses thereof

Publication Date: 2025.12.25 BIOMARIN PHARMACEUTICAL INC

AI summary

The present invention relates in general to therapeutic fusion proteins useful to treat lysosomal storage diseases and methods for treating such diseases. Exemplary therapeutic fusion proteins comprise a lysosomal enzyme, a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide. Also provided are compositions and methods for treating Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome), comprising a targeted therapeutic fusion protein comprising alpha-N-acetylglucosaminidase (Naglu), a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide.