pH-Sensitive Adalimumab Antibodies for Reduced Dosing

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Solution Overview

Problem

Current therapeutic antibodies, such as adalimumab, often require frequent and high-dose administration due to limited antigen-binding efficiency, leading to high production costs and administration burdens, as they typically bind to only one antigen molecule during their plasma lifetime and suffer from 'antibody buffering' effects that prolong antigen persistence.

Innovation Solution

Engineering anti-TNFα antibodies, like adalimumab, with pH-sensitive antigen binding by introducing histidine residues in the complementary determining regions (CDRs) to enhance antigen dissociation and recycling, allowing the antibody to bind multiple antigen molecules and extend its serum half-life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If conventional therapeutic antibodies are used, then antigen binding is achieved, but the antibody binds to only one antigen molecule during its plasma lifetime and requires frequent high-dose administration

Engineering Contradiction:

Improveserum half-lifeVSAvoidantigen-binding efficiency

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The patent introduces histidine residues at specific positions in the CDR domains of the antibody variable regions. These histidine residues create pH-dependent binding characteristics, allowing the antibody to bind antigen at physiological pH (7.4) but dissociate at acidic pH (6.0) within endosomes. This parameter change in binding affinity based on pH enables the antibody to be released from endosomes and recycled, extending its serum half-life while maintaining antigen-binding efficiency.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If conventional antibodies are used, then antigen blocking is achieved, but antibody buffering effects prolong antigen persistence and reduce therapeutic efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidantigen persistence

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent creates a dynamic binding system where the antibody's affinity for antigen changes based on the local pH environment. In circulation at physiological pH, the antibody binds antigen with high affinity. Upon internalization into endosomes where pH drops to 6.0, the histidine residues become protonated, causing the antibody to release the antigen. This dynamic pH-dependent behavior prevents antibody buffering by ensuring antigen release in the endosome, allowing the antigen to be degraded and eliminating the persistence problem.

Inventive Principle:

Principle #15Dynamics

3Reliability

If high-dose frequent administration is used, then therapeutic effect is maintained, but production costs and administration burden increase

Engineering Contradiction:

Improvetherapeutic effectVSAvoidproduction cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

By introducing pH-dependent binding characteristics through histidine residue substitution, the antibody can now bind and release antigen cyclically, extending its functional lifetime in circulation. This enables less frequent dosing intervals while maintaining therapeutic efficacy, thereby reducing both production costs and administration burden without compromising therapeutic effect.

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 pH-sensitive binding variants of adalimumab exhibit significantly improved therapeutic efficacy, enabling reduced dosing frequencies and costs by increasing antigen dissociation rates and maintaining effective binding affinity, thus prolonging the therapeutic effect.

Implementation Method 1

anti-TNFα antibodies which are engineered to exhibit a pH-sensitive antigen binding

Methodology Applied

Scientific EffectpH-dependent binding:

Implementation Method 2

modifications of amino acid sequence within the variable regions. Specifically, the invention relates to adalimumab or biologically active variants or fragments thereof, wherein the CDR domains are modified by replacing one or more amino acid residues by histidine residues

Methodology Applied

Scientific EffectHistidine protonation:

Implementation Method 3

the Fc-portion of an IgG1 interacts in a pH-dependent manner with the neonatal Fc-receptor (FcRn) that leads to antibody capture in the acidified endosome

Methodology Applied

Scientific EffectFcRn-mediated recycling:

Implementation Method 4

the Fc-portion of an IgG1 interacts in a pH-dependent manner with the neonatal Fc-receptor (FcRn)

Methodology Applied

Scientific EffectpH-dependent interaction:

Data Source

PatentUS10183994B2Anti-TNFα antibodies with pH-dependent antigen binding for improved target clearence

Publication Date: 2019.01.22 MERCK PATENT GMBH

AI summary

The invention relates to anti-TNFα antibodies which are engineered to exhibit a pH-sensitive antigen binding. The invention is preferably directed to anti-TNFα antibody adalimumab (Humira®) or biologically active variants and fragments thereof, wherein the original adalimumab antibody or variant or fragment thereof is engineered by modifications of amino acid sequence within the variable regions. Specifically, the invention relates to adalimumab or biologically active variants or fragments thereof, wherein the CDR domains are modified by replacing one or more amino acid residues by histidine residues.