Chimeric Complement Regulator with Flexible Linker for Host Cell Specificity

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Solution Overview

Problem

Current regulators of the alternative pathway of complement activation, such as Factor H, face challenges in effectively controlling complement activation on host cells while avoiding indiscriminate deposition on foreign surfaces, leading to potential tissue damage and limitations in treating diseases associated with abnormal complement regulation.

Innovation Solution

A complement regulator comprising a complement regulating region connected by a flexible linker to a multifunctional binding region, enabling binding to C3b activation/inactivation products, oxidation end products, and polyanionic surface markers on host cells, thereby regulating AP-mediated complement activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Factor H is used to regulate complement activation, then complement control on host cells is achieved, but indiscriminate deposition on foreign surfaces occurs causing tissue damage

Engineering Contradiction:

Improvecomplement control effectivenessVSAvoidindiscriminate deposition on foreign surfaces

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The regulator is designed with distinct functional regions: an N-terminal complement regulatory region (SCR 1-4) that controls complement activation and a C-terminal host recognition region (SCR 19-20) that specifically binds to polyanionic markers on host cells. This spatial separation of functions ensures that complement regulation occurs only where host cell markers are present, preventing indiscriminate deposition on foreign surfaces while maintaining effective complement control on host cells.

Inventive Principle:

Principle #3Local quality

2Reliability

If Factor H binds to C3b products, then complement activation is regulated, but affinity and specificity are insufficient compared to the invention

Engineering Contradiction:

Improvecomplement activation regulationVSAvoidbinding affinity and specificity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The invention merges the complement regulatory function (SCR 1-4) with the host recognition function (SCR 19-20) into a single unified regulator molecule connected by a flexible linker. This combination ensures that the regulator simultaneously binds to C3b activation/inactivation products and polyanionic host surface markers with high affinity, providing enhanced specificity and reliability in regulating complement activation only on host cells.

Inventive Principle:

Principle #5Merging (Combining)

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 described complement regulator efficiently targets and protects host cells by simultaneous recognition of complement activation/inactivation products and polyanionic host surface markers, providing enhanced control over AP-mediated complement activation with improved affinity and specificity compared to existing regulators.

Implementation Method 1

The polypeptide binds to C3b, iC3b, C3dg and C3d through its multifunctional binding region that recognizes thioester domains (TEDs) of these complement fragments

Methodology Applied

Scientific EffectThioester domain binding:

Implementation Method 2

The polypeptide binds to polyanionic surface markers on host cells including glycosaminoglycans (GAGs) such as heparin, heparan sulfate, chondroitin sulfate, dermantan sulfate, keratan sulfate and hyaluronan

Methodology Applied

Scientific EffectElectrostatic interaction:

Implementation Method 3

The polypeptide binds to oxidation end products including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), carboxyethylpyrrole (CEP), oxidized phosphatidylserine (OxPS), oxidized cardiolipin (OxCL) and phosphocholine (PC)

Methodology Applied

Scientific EffectOxidation product binding:

Implementation Method 4

The complement regulatory region is linked by a flexible linker to a multifunctional binding region, enabling simultaneous or sequential binding to multiple targets

Methodology Applied

Scientific EffectFlexible linker conformation:

Data Source

PatentUS9540626B2Regulator of complement activation and uses thereof

Publication Date: 2017.01.10 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

A potent complement regulator is disclosed. The complement regulator comprises a complement regulatory region connected by a flexible linker to a multifunctional binding region that enables binding to C3b activation/inactivation products and/or oxidation end products, as well as to polyanionic surface markers on host cells. An embodiment of the invention utilizes factor H SCRs 1-4 as the complement regulatory region and factor H SCRs 19 and 20 as the multifunctional binding region, linked together by a poly-Gly linker at least 12 residues in length. Pharmaceutical compositions comprising the complement regulator and methods of using the complement regulator are also disclosed.