Linked Antigen-Binding Domains for Protease-Resistant Agonist Activity

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Solution Overview

Problem

Existing antibody pharmaceuticals often fail to adequately enhance or regulate interactions between antigen molecules, and they are susceptible to protease cleavage, leading to potential side effects and reduced efficacy.

Innovation Solution

Development of antigen-binding molecules with two linked antigen-binding domains, either through covalent or non-covalent bonds, including disulfide bonds and crosslinking agents, to enhance agonist activity and resistance to protease digestion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antibodies are used as pharmaceuticals, then they bind to antigen and exhibit agonistic or antagonistic effects, but they are susceptible to protease cleavage leading to reduced efficacy and side effects

Engineering Contradiction:

Improveresistance to protease cleavageVSAvoidprotease cleavage

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent merges two antigen-binding domains (Fab regions) into a single continuous polypeptide chain through the hinge region, creating a bispecific antibody structure. This merging of functional domains provides enhanced stability and resistance to protease cleavage while maintaining the ability to bind two different antigens, thereby resolving the contradiction between pharmaceutical efficacy and protease susceptibility

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent creates a composite protein structure combining two different antigen-binding specificities within a single molecule. The bispecific antibody comprises an first antigen-binding domain specific for a first antigen and a second antigen-binding domain specific for a second antigen, integrated in a composite structure that resists proteolytic degradation while providing multiple therapeutic functions

Inventive Principle:

Principle #40Composite materials

2Productivity

If native IgG antibodies are used, then they are stable in blood plasma, but they do not sufficiently exert expected effects

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidagonist activity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the structural parameters of the antibody by creating a bisspecific configuration where two different antigen-binding domains are linked. This parameter change enables the antibody to simultaneously bind two different antigens, enhancing therapeutic efficacy by providing both agonistic and antagonistic activities that native single-specificity antibodies cannot achieve

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent endows the antibody molecule with multi-functionality by integrating two different antigen-specific binding capabilities. The bisspecific antibody can bind to both a first antigen (e.g., cancer cell surface protein) and a second antigen (e.g., T-cell or NK cell surface protein), enabling it to perform multiple therapeutic functions including direct tumor targeting and immune cell activation

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Productivity

If bisspecific antibodies are developed to bind two different antigens, then expected effects are enhanced, but structural complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmolecule structure

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent segments the antibody molecule into distinct functional domains: an first antigen-binding domain (Fab1) and a second antigen-binding domain (Fab2), each with specific binding specificities. This segmentation allows independent optimization of each binding site while maintaining overall molecular integrity through the hinge region connection, thereby achieving enhanced efficacy without excessive structural complexity

Inventive Principle:

Principle #1Segmentation

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 linked antigen-binding domains improve agonist activity and provide enhanced interaction regulation between antigen molecules, while also increasing resistance to protease cleavage, potentially reducing side effects and improving therapeutic efficacy.

Implementation Method 1

the two antigen-binding domains are linked with each other via one or more bonds

Methodology Applied

Scientific EffectCovalent bonding: Chemical Bonding

Implementation Method 2

including disulfide bonds and crosslinking agents

Methodology Applied

Scientific EffectDisulfide bond: Chemical Bonding

Implementation Method 3

Antibodies are proteins which specifically bind to an antigen with high affinity

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 4

increasing resistance of an antigen-binding molecule to protease cleavage

Methodology Applied

Scientific EffectProtease resistance:

Data Source

PatentUS12435137B2Antigen-binding molecule containing two antigen-binding domains that are linked to each other

Publication Date: 2025.10.07 CHUGAI PHARMA CO LTD

AI summary

In a non-limiting embodiment, the present invention relates to antigen-binding molecules comprising two or more antigen-binding domains which are linked with each other. In a non-limiting embodiment, the antigen-binding molecules of the present disclosure have activity of holding two or more antigen molecules at spatially close positions, activity of regulating interaction between two or more antigen molecules, activity of regulating activation of two or more antigen molecules which are activated by association with each other, resistance to protease cleavage, or such.