Altering IgG Half-Life via FcRn Binding Modifications

Solution Overview

Problem

The persistence of immunoglobulins in circulation affects the efficacy and frequency of dosing in immunotherapies and diagnostics, with rapid clearance leading to adverse effects and increased costs, while slow clearance may be undesirable in certain procedures.

Innovation Solution

Modifying the IgG constant domain or FcRn-binding fragments with amino acid substitutions, insertions, or deletions to alter the binding affinity for the neonatal Fc receptor (FcRn), thereby modifying the serum half-life of immunoglobulins and other molecules.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immunoglobulins are administered for therapeutic use, then therapeutic efficacy is improved, but rapid clearance leads to increased dosing frequency and medical costs

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidserum half-life

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent applies parameter changes by modifying amino acid residues in the Fc region of immunoglobulins (specifically positions 252, 254, and 256) to alter binding affinity to FcRn. The YTE mutation (M252Y/S254T/T256E) changes the chemical properties of the Fc region to enhance interaction with FcRn at acidic pH, thereby extending serum half-life and reducing dosing frequency while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If immunoglobulins are administered for diagnostic procedures, then diagnostic capability is improved, but rapid clearance may be undesirable

Engineering Contradiction:

Improvediagnostic capabilityVSAvoidserum persistence

Core Design Contradiction:

Measurement precisionVSLoss of time

Solution Approach 1:

The patent applies parameter changes by modifying amino acid residues in the Fc region of immunoglobulins (specifically positions 252, 254, and 256) to alter binding affinity to FcRn. The YTE mutation (M252Y/S254T/T256E) changes the chemical properties of the Fc region to enhance interaction with FcRn at acidic pH, thereby extending serum half-life and reducing dosing frequency while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If dosing frequency is increased to compensate for rapid clearance, then therapeutic coverage is improved, but adverse effects increase and medical costs rise

Engineering Contradiction:

Improvetherapeutic coverageVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying amino acid residues in the Fc region of immunoglobulins (specifically positions 252, 254, and 256) to alter binding affinity to FcRn. The YTE mutation (M252Y/S254T/T256E) changes the chemical properties of the Fc region to enhance interaction with FcRn at acidic pH, thereby extending serum half-life and reducing dosing frequency while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

4Loss of time

If FcRn binding affinity is increased to extend half-life, then serum persistence is improved, but binding specificity may be affected

Engineering Contradiction:

Improveserum half-lifeVSAvoidbinding specificity

Core Design Contradiction:

Loss of timeVSReliability

Solution Approach 1:

The patent applies local quality by making site-specific amino acid substitutions only in the Fc region (positions 252, 254, 256) while leaving the antigen-binding Fab regions unchanged. This localized modification ensures that enhanced FcRn binding does not interfere with antigen specificity, as the variable regions responsible for antigen recognition remain intact.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies parameter changes by modifying amino acid residues in the Fc region of immunoglobulins (specifically positions 252, 254, and 256) to alter binding affinity to FcRn. The YTE mutation (M252Y/S254T/T256E) changes the chemical properties of the Fc region to enhance interaction with FcRn at acidic pH, thereby extending serum half-life and reducing dosing frequency while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

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 modified molecules exhibit altered in vivo half-lives, allowing for reduced dosing frequencies and improved pharmacokinetic properties, such as extended or shortened serum persistence, depending on the application, enhancing therapeutic and diagnostic efficacy.

Implementation Method 1

Modifying the IgG constant domain or FcRn-binding fragments with amino acid substitutions, insertions, or deletions to alter the binding affinity for the neonatal Fc receptor (FcRn), thereby modifying the serum half-life of immunoglobulins and other molecules.

Methodology Applied

Scientific EffectFcRn-mediated binding:

Data Source

PatentUS20240124612A1Molecules with altered neonate fc receptor binding having enhanced therapeutic and diagnostic properties

Publication Date: 2024.04.18 MEDIMMUNE LLC

AI summary

The present invention provides molecules, including proteins, more particularly, immunoglobulins whose in vivo half-lives are altered (increased or decreased) by the presence of an IgG constant domain, or FcRn binding fragment thereof (e.g., an Fc region or hinge-Fe region) (e.g., from a human IgG, e.g., human IgG1), that have modifications of one or more of amino acid residues in at least the CH3 domain.