CR2-FH Fusion Protein Targeting Complement Activation Sites

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Solution Overview

Problem

Current treatments for diseases involving the alternative complement pathway, such as macular degeneration and systemic lupus erythematosus, face challenges due to the high concentration of Factor H in plasma and the belief that complement activation sites are already fully covered, limiting the effectiveness of therapies.

Innovation Solution

A CR2-FH molecule comprising a complement receptor 2 (CR2) portion and a Factor H (FH) portion, either fused or linked, is used to target and inhibit the alternative complement pathway activation, providing enhanced therapeutic efficacy by specifically binding to CR2 ligands and regulating complement activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If native Factor H is used to inhibit the alternative complement pathway, then complement regulation is provided in the fluid phase, but the therapeutic effectiveness is limited because complement activation sites are already fully covered by the high concentration of Factor H in plasma

Engineering Contradiction:

Improvecomplement regulation effectivenessVSAvoidFactor H concentration at activation site

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent uses CR2 (complement receptor 2) as an intermediary to deliver Factor H to complement activation sites. CR2 binds to C3d on the surface of activated complement sites, and the CR2-FH fusion protein is recruited to these sites through CR2-C3d interactions, thereby delivering Factor H directly where needed despite the low concentration of native FH at these locations

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs CR2, which naturally binds to C3d deposits formed during complement activation, to pre-position Factor H at activation sites before significant complement damage occurs. This preliminary positioning allows Factor H to exert its regulatory effect more effectively at the critical moment of complement activation

Inventive Principle:

Principle #10Preliminary action

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 CR2-FH molecule effectively targets and inhibits the alternative complement pathway, showing improved therapeutic outcomes in diseases like macular degeneration and systemic lupus erythematosus, surpassing the limitations of native Factor H by delivering targeted regulation of complement activation.

Implementation Method 1

The CR2 portion of the CR2-FH molecule is capable of binding to a CR2 ligand

Methodology Applied

Scientific EffectSpecific binding:

Implementation Method 2

It functions by competing with factor B for binding to C3b

Methodology Applied

Scientific EffectCompetition for binding:

Implementation Method 3

Binding of C3b to Factor H also leads to degradation of C3b by factor I to the inactive form C3bi

Methodology Applied

Scientific EffectEnzymatic degradation: Enzyme

Data Source

PatentEP2826788B1Targeting complement factor h for treatment of diseases by the use of CR2-FH molecules

Publication Date: 2017.12.13 THE REGENTS OF THE UNIVERSITY OF COLORADO

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AI summary

The invention provides a CR2-FH molecule comprising a CR2 portion comprising CR2 protein or a fragment thereof and a FH portion comprising a factor H protein or a fragment thereof, and pharmaceutical compositions comprising a CR2-FH molecule. Also provided are methods of using the compositions for treatment diseases in which the alternative complement pathway is implicated, such as age-related macular degeneration, rheumatoid arthritis, and ischemia reperfusion.