C1s Antigen-Binding Molecules With pH-Dependent FcRn Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing therapeutic antibodies targeting C1s have limitations in antigen binding capacity and pharmacokinetics, leading to high dosage requirements and high production costs, and conventional antibodies can only neutralize a maximum of two targets per molecule due to their two binding sites.
Innovation Solution
Development of antigen-binding molecules with specific amino acid modifications in the heavy chain variable region, light chain variable region, and Fc region to enhance binding affinity and stability at different pH levels, allowing for increased target neutralization and reduced immunogenicity, while also inhibiting C1s activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional therapeutic antibodies are used to target C1s, then antigen binding is achieved, but the dosage requirement is high and production cost is high due to limited antigen binding capacity and pharmacokinetics
Solution Approach 1:
The patent combines multiple functional capabilities into a single antibody molecule by engineering it to bind to multiple C1s molecules simultaneously. The bivalent or multivalent binding configuration allows one antibody to neutralize more than two C1s targets, effectively merging multiple binding functions into one molecular entity, thereby reducing the quantity of antibody substance required for therapeutic effect.
Solution Approach 2:
The patent extends the binding capacity beyond the conventional two-site limitation by creating multivalent binding configurations. This dimensional expansion from bivalent to multivalent binding increases the number of C1s targets that can be neutralized per antibody molecule, addressing the antigen binding capacity limitation without requiring proportionally higher dosages.
2Adaptability or versatility
If conventional antibodies are used, then two binding sites are available, but only a maximum of two targets can be neutralized per molecule
Solution Approach 1:
The engineered antibody is designed to perform multiple binding functions simultaneously, with each antibody molecule capable of binding to and neutralizing multiple C1s targets. This multi-functionality extends the neutralization capacity beyond the conventional two-target limit, making the single antibody molecule universally effective against multiple antigen targets.
3Reliability
If standard Fc region is used, then basic pharmacokinetics are achieved, but binding affinity to FcRn and immunogenicity can be optimized further
Solution Approach 1:
The patent applies local quality optimization by introducing specific amino acid modifications at particular positions within the Fc region. These localized changes at specific residues enhance binding affinity to FcRn and modulate immunogenicity without altering the overall antibody structure or function, thereby optimizing pharmacokinetics while maintaining target binding capability.
Solution Approach 2:
The patent optimizes pharmacokinetic parameters by modifying the Fc region's amino acid sequence to alter its binding characteristics. Specific amino acid substitutions change the physical-chemical parameters of the Fc region, enhancing FcRn binding affinity and improving half-life and other pharmacokinetic properties while controlling immunogenicity.
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 antigen-binding molecules effectively reduce plasma C1s concentration by up to 20% and can be administered at a lower dose, providing therapeutic benefits for complement-mediated disorders with improved pharmacokinetics and reduced production costs.
Implementation Method 1
the heavy chain variable region and/or the light chain variable region comprise at least one amino acid that can increase the ratio of KD value of the antigen-binding molecule to C1s in acidic pH range to KD value of the antigen-binding molecule to C1s in neutral pH range
Implementation Method 2
the Fc region comprises at least one amino acid that can increase binding ability of the antigen-binding molecule to FcRn in acidic pH range
Data Source
AI summary
The present invention relates to antigen-binding molecules, pharmaceutical compositions, and methods. The present invention provides antigen-binding molecules that bind to C1s and comprise a heavy chain variable region, a light chain variable region and an Fc region.