Anti-TNF Antibody FcRn Binding Modification
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Solution Overview
Problem
Current therapeutic antibodies, such as adalimumab, require frequent administration due to their short half-life, necessitating injections every two weeks, which can be inconvenient and may require loading doses, affecting patient compliance and treatment efficacy.
Innovation Solution
Development of novel anti-TNF antibodies with increased half-life by introducing specific amino acid substitutions in the FcRn binding portion of the human IgG1 constant domain, specifically at residues 252, 254, and 256, enhancing FcRn binding affinity and resulting in a longer serum retention, allowing for administration every four to eight weeks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If frequent administration is used to maintain therapeutic efficacy, then treatment effectiveness is improved, but patient compliance and convenience deteriorate
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the antibody Fc region (specifically residues 252, 254, and 256) to alter its binding affinity to FcRn. This biochemical parameter change extends the antibody's half-life from approximately 2 weeks to 4-8 weeks, thereby reducing dosing frequency while maintaining therapeutic effectiveness and improving patient compliance
2Reliability
If frequent administration is required, then therapeutic concentrations are maintained, but treatment complexity and burden increase
Solution Approach 1:
By changing the amino acid parameters in the Fc region (M252Y, S254T, T256E substitutions), the antibody achieves extended half-life that maintains therapeutic concentrations for 4-8 weeks without requiring complex dosing schedules or loading doses, thereby simplifying the treatment regimen
3Duration of action of moving object
If amino acid substitutions are introduced to extend half-life, then dosing frequency is reduced, but antibody structure complexity increases
Solution Approach 1:
The patent applies local quality by introducing amino acid substitutions only in the Fc region (residues 252, 254, and 256) rather than throughout the entire antibody structure. This localized modification achieves extended half-life through improved FcRn binding while minimizing overall structural complexity changes
Solution Approach 2:
Specific amino acid parameter changes (M252Y, S254T, T256E) in the Fc region alter the biochemical properties to enhance FcRn binding affinity, extending half-life without requiring complex structural redesign of the entire antibody molecule
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 antibodies achieve a 2- to 6-fold increase in half-life, maintaining therapeutic concentrations between 4-7 µg/ml for extended periods, reducing clearance and enabling less frequent dosing while maintaining effective TNF-alpha binding and neutralization activity.
Implementation Method 1
FcRn, also known as the neonatal Fc receptor, plays a key role in maintaining serum antibody levels by acting as a protective receptor that binds and salvages antibodies of the IgG isotype from degradation
Implementation Method 2
amino acid substitution at one or more of the amino acids selected from number 252, 254, 256, 309, 311 or 315 in the CH2 domain or 433 or 434 in the CH3 domain
Data Source
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AI summary
The present invention provides antigen binding proteins which bind specifically to TNF-alpha. For example novel variants of anti-TNF antibodies such as adalimumab which show increased binding to the FcRn receptor or increased half life compared to adalimumab. Also provided are compositions comprising the antigen binding proteins and uses of such compositions in treatment of disorders and disease.