Klotho-FGF23 Fusion Polypeptide Serum Half-Life

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods lack effective solutions for preventing or treating age-related conditions and metabolic disorders, particularly in addressing the biological characteristics and tissue-specific metabolic activities associated with alpha-Klotho and beta-Klotho proteins.

Innovation Solution

Development of Klotho fusion polypeptides comprising a Klotho protein or its active fragment combined with a fibroblast growth factor, such as FGF23, and a modified Fc fragment, which are linked covalently or via a linker to enhance serum half-life and affinity for FGF receptors, allowing for the treatment of age-related conditions and metabolic disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If alpha-Klotho or beta-Klotho proteins are used alone, then they can bind to FGF receptors, but their serum half-life is limited and therapeutic activity is insufficient

Engineering Contradiction:

Improveserum half-lifeVSAvoidtherapeutic activity

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent combines Klotho protein with FGF23 and a modified Fc fragment to create a fusion polypeptide. This merging of multiple functional components achieves both extended serum half-life (through the Fc fragment) and enhanced therapeutic activity (through the synergistic Klotho-FGF23 combination that activates FGF receptors more effectively than either component alone).

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If FGF23 is used alone, then it can activate FGF receptors, but it requires Klotho as an obligatory partner for effective signaling

Engineering Contradiction:

Improvesignaling capabilityVSAvoidprotein combination requirement

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The fusion polypeptide merges Klotho and FGF23 into a single molecular entity, eliminating the need for separate protein components and complex protein-protein interactions. This ensures reliable FGF receptor signaling while simplifying the system architecture by incorporating the obligatory partner directly into the therapeutic molecule.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The modified Fc fragment acts as an intermediary component that bridges the Klotho-FGF23 complex to the FGF receptor, enhancing the interaction and signaling efficiency. The Fc fragment facilitates the binding and activation process while extending the circulation time of the therapeutic complex.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If tissue-specific expression of alpha-Klotho is maintained, then FGF23 signaling is restricted to specific tissues, but this limits the broad therapeutic application

Engineering Contradiction:

Improvetherapeutic application scopeVSAvoidtissue-specific signaling

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The fusion polypeptide design incorporates universal elements (modified Fc fragment with extended half-life) that enable broad therapeutic application across multiple tissue types and conditions. The Klotho-FGF23 combination maintains the ability to activate FGF receptors in various tissues, providing versatile therapeutic potential for age-related conditions, metabolic disorders, and bone diseases beyond the restriction of endogenous tissue-specific expression patterns.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 Klotho fusion polypeptides effectively activate FGF receptors, providing enhanced therapeutic activity for treating conditions like muscle wasting, metabolic disorders, and hyperphosphatemia by improving the binding and signaling capabilities of Klotho and FGF proteins.

Implementation Method 1

Klotho fusion polypeptides comprising a Klotho protein or its active fragment combined with a fibroblast growth factor, such as FGF23, and a modified Fc fragment, which are linked covalently or via a linker

Methodology Applied

Scientific EffectCovalent bonding: Chemical Bonding

Data Source

PatentUS9475857B2Methods and compositions using a Klotho-FGF23 fusion polypeptide

Publication Date: 2016.10.25 NOVARTIS AG

AI summary

The present invention is directed to methods, kits and compositions for preventing or treating age-related conditions or metabolic disorders. The Klotho fusion polypeptides of the invention include at least a Klotho protein or an active fragment thereof. In one embodiment, the fusion polypeptide comprises a Klotho polypeptide, a FGF (such as FGF23) and (optionally) a modified Fc fragment. The Fc fragment can, for example, have decreased binding to Fc-gamma-receptor and increased serum half-life. The Klotho fusion proteins are useful in the treatment and prevention of a variety of age-related conditions and metabolic disorders. In another embodiment, the fusion polypeptide comprises a FGF (such as FGF23) and a modified Fc fragment.