Fc Conjugate Non-Peptidyl Linker FcRn Binding Affinity

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Solution Overview

Problem

Existing protein conjugates face challenges in maintaining the binding affinity of immunoglobulin Fc fragments for FcRn without reducing the activity of physiologically active polypeptides, and in efficiently dissociating from FcRn at neutral pH, which limits the serum half-life of protein drugs.

Innovation Solution

A physiologically active polypeptide-immunoglobulin Fc fragment conjugate linked via a non-peptidyl linker maintains the intrinsic binding affinity for FcRn, with a binding ratio within ±6% at pH 6.0 and pH 7.4, allowing easy dissociation at neutral pH, thereby enhancing the serum half-life of the polypeptide.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If an immunoglobulin Fc fragment is linked to a physiologically active substance to increase serum half-life, then the serum half-life is extended, but the binding affinity of the Fc fragment for FcRn is reduced

Engineering Contradiction:

Improveserum half-lifeVSAvoidbinding affinity for FcRn

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

A non-peptidyl linker is introduced as an intermediary component between the physiologically active substance and the immunoglobulin Fc fragment. This linker mediates the connection while preserving the FcRn-binding capability of the Fc fragment, thereby maintaining both extended serum half-life and reliable FcRn binding affinity simultaneously

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The conjugate is segmented into distinct functional modules: the physiologically active substance, the non-peptidyl linker, and the immunoglobulin Fc fragment. This segmentation allows each component to perform its specific function independently, with the Fc fragment maintaining its native FcRn-binding properties while the linker provides the connection without interfering with this critical interaction

Inventive Principle:

Principle #1Segmentation

2Stability of the object's composition

If a conventional linker is used to connect the polypeptide to the Fc fragment, then the conjugate is stable, but the dissociation from FcRn at neutral pH is impaired

Engineering Contradiction:

Improveconjugate stabilityVSAvoiddissociation from FcRn at neutral pH

Core Design Contradiction:

Stability of the object's compositionVSEase of operation

Solution Approach 1:

The non-peptidyl linker is designed with specific chemical parameters that enable pH-responsive behavior. The linker maintains stable conjugation at physiological pH while allowing efficient dissociation from FcRn at neutral pH, optimizing both conjugate stability and release efficiency through precise parameter control

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The conjugate system exhibits dynamic behavior in response to pH changes. The non-peptidyl linker provides stable connection under physiological conditions but enables efficient dissociation at neutral pH, allowing the system to adapt its state based on environmental conditions to achieve both stability and ease of separation

Inventive Principle:

Principle #15Dynamics

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 conjugate effectively maintains the immunoglobulin Fc fragment's binding affinity for FcRn while ensuring easy dissociation at neutral pH, leading to an increased in vivo half-life of the physiologically active polypeptide without reducing its activity.

Implementation Method 1

IgG and FcRn strongly bind to each other at a weak acidic pH and dissociate from each other at a neutral pH

Methodology Applied

Scientific EffectpH-dependent binding:

Implementation Method 2

IgG and FcRn strongly bind to each other at a weak acidic pH and dissociate from each other at a neutral pH

Methodology Applied

Scientific EffectpH-dependent dissociation:

Data Source

PatentUS20220380437A1Immunoglobulin fc conjugate which maintains binding affinity of immunoglobulin fc fragment to fcrn

Publication Date: 2022.12.01 HANMI PHARM CO LTD

AI summary

A physiologically active polypeptide-immunoglobulin Fc fragment conjugate and a method for making the conjugate are disclosed. The conjugate contains a physiologically active polypeptide linked via a non-peptidyl linker to an immunoglobulin Fc fragment having an FcRn-binding region and maintains the intrinsic binding affinity of the immunoglobulin Fc fragment. A method of maintaining the intrinsic binding affinity of the conjugate for FcRn, and a composition containing the conjugate, which maintains the intrinsic binding affinity of the immunoglobulin Fc fragment for FcRn are also disclosed.