Anti-C5 Antibody pH-Dependent Binding for Complement Inhibition

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for paroxysmal nocturnal hemoglobinuria (PNH) and other complement-mediated disorders are limited in effectively inhibiting excessive activation of the complement cascade, leading to uncontrolled hemolysis and tissue damage.

Innovation Solution

Development of anti-C5 antibodies that bind specifically to the β chain of C5, particularly the MG1-MG2 domain, with enhanced affinity at neutral pH, inhibiting the activation of C5 and preventing the formation of the membrane attack complex, thereby reducing complement-mediated damage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing complement inhibitors are used, then complement activation is partially inhibited, but hemolysis and tissue damage continue due to insufficient inhibition

Engineering Contradiction:

Improveinhibition effectivenessVSAvoidhemolysis and tissue damage

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the binding parameters of the antibody by optimizing affinity at neutral pH (7.4) while reducing binding at acidic pH (5.8), creating pH-dependent binding characteristics that enhance inhibition effectiveness specifically during complement activation conditions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces non-specific complement inhibition with a highly specific antibody-mediated inhibition mechanism that targets the C5 β-chain with precision, replacing the mechanical/blunt approach of general inhibition with a targeted molecular lock

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Duration of action of stationary object

If non-pH dependent antibodies are used, then binding occurs at all pH levels, but plasma retention is reduced due to endosomal recycling

Engineering Contradiction:

Improveplasma retentionVSAvoidantibody recycling

Core Design Contradiction:

Duration of action of stationary objectVSLoss of energy

Solution Approach 1:

The patent fundamentally changes the binding parameter from pH-independent to pH-dependent, where the antibody binds strongly at neutral plasma pH but dissociates at acidic endosomal pH, preventing recycling and extending plasma retention

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses pH as an intermediary mechanism to control the antibody-antigen interaction, where the changing pH environment serves as a switch to prevent antibody recycling through endosomal compartments

Inventive Principle:

Principle #24Intermediary (Mediator)

3Duration of action of stationary object

If antibodies binding at acidic pH are used, then binding occurs in endosomes, but plasma retention is extended through FcRn recycling

Engineering Contradiction:

Improveplasma retentionVSAvoidinhibition effectiveness

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent inverts the conventional pH-dependent binding pattern by creating an antibody that binds at neutral pH but not at acidic pH, opposite to the typical pattern, thereby preventing recycling while maintaining plasma retention

Inventive Principle:

Principle #13The other way round (Inversion)

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 anti-C5 antibodies effectively inhibit C5 activation, reducing hemolysis and tissue damage in PNH and other complement-mediated disorders, providing a more targeted and efficient therapeutic approach compared to existing treatments.

Implementation Method 1

the antibody binds to C5 with a higher affinity at neutral pH than at acidic pH

Methodology Applied

Scientific EffectpH-dependent binding:

Implementation Method 2

an isolated anti-C5 antibody of the present invention binds to an epitope within the β chain of C5

Methodology Applied

Scientific EffectAntibody-antigen binding:

Data Source

PatentUS20240052021A1Anti-c5 antibodies and methods of use

Publication Date: 2024.02.15 CHUGAI PHARMA CO LTD

AI summary

An objective of the invention is to provide anti-C5 antibodies and methods of using the same. The invention provides anti-C5 antibodies and methods of using the same. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the β chain of C5 with a higher affinity at neutral pH than at acidic pH. The invention also provides isolated nucleic acids encoding an anti-C5 antibody of the present invention. The invention also provides host cells comprising a nucleic acid of the present invention. The invention also provides a method of producing an antibody comprising culturing a host cell of the present invention so that the antibody is produced. The invention further provides a method of producing an anti-C5 antibody comprising immunizing an animal against a polypeptide which comprises the MG1-MG2 domain of the β chain of C5. Anti-C5 antibodies of the present invention may be for use as a medicament. Anti-C5 antibodies of the present invention may be for use in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5. Anti-C5 antibodies of the present invention may be for use in enhancing the clearance of C5 from plasma.