Avimer Therapeutics for Sclerostin Inhibition and Bone Density

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Solution Overview

Problem

Current therapeutics for treating disorders associated with low bone mineral density, such as those involving sclerostin and DKK1, face challenges in stability, immunogenicity, and production efficiency, and have limited ability to inhibit these proteins effectively.

Innovation Solution

Development of avimers, which are proteins comprising specific monomer domains that bind to sclerostin or DKK1, including LDL receptor class A domains with disulfide bonds, designed to be stable, non-immunogenic, and capable of high-efficiency production, potentially used alone or in combination with antibodies or other drugs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutics are used to treat bone mineral density disorders, then they can inhibit sclerostin and DKK1, but they have poor stability, short half-life, and high immunogenicity

Engineering Contradiction:

ImprovestabilityVSAvoidhalf-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent employs a composite molecular structure consisting of a stable backbone framework combined with functional binding regions. This composite architecture integrates the structural stability of engineered protein domains with the target-binding capability, thereby achieving both prolonged half-life and reduced immunogenicity while maintaining therapeutic efficacy against sclerostin and DKK1

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent utilizes systematic parameter optimization including amino acid sequence modifications, glycosylation patterns, and structural conformation adjustments to enhance protein stability. These parameter changes result in therapeutics with improved pharmacokinetic properties, extended serum half-life, and reduced immunogenicity without sacrificing binding affinity to targets

Inventive Principle:

Principle #35Parameter changes

2Productivity

If current therapeutics are used to inhibit sclerostin and DKK1, then bone density effects are achieved, but production efficiency is limited

Engineering Contradiction:

Improveproduction efficiencyVSAvoidmanufacturability

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent divides the therapeutic molecule into modular domains with distinct functions: a stable backbone region optimized for expression and a functional binding region for target interaction. This segmentation allows independent optimization of each module, enabling high-efficiency production while maintaining manufacturability and therapeutic activity

Inventive Principle:

Principle #1Segmentation

3Reliability

If current therapeutics are used, then some bone density improvement is achieved, but the ability to effectively inhibit sclerostin and DKK1 is limited

Engineering Contradiction:

Improveinhibition efficiencyVSAvoidbone loss

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs structure-based design to create high-affinity binding interfaces that precisely replicate and enhance the natural interaction between Wnt ligands and their receptors. By copying and optimizing key structural features, the therapeutics achieve superior inhibition of sclerostin and DKK1, effectively blocking their harmful effects on bone density while maintaining physiological Wnt signaling

Inventive Principle:

Principle #26Copying

Data Source

PatentUS9708375B2Inhibitory polypeptides specific to WNT inhibitors

Publication Date: 2017.07.18 AMGEN INC

AI summary

The present application is directed to avimers and peptides and various combinations thereof in addition to methods of making and using them.