Antibody Variants with Localized Charge Mutations
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antibody therapeutic molecules face challenges in modulating pharmacokinetic properties, particularly for CD40-targeting antibodies, due to the interdependence of protein properties, making intentional charge modification complex and prone to unintended effects.
Innovation Solution
Development of variant antibodies with specific mutations in the heavy and light chain variable regions, such as mutating residues at positions 12, 13, 19, 23, 38, 57, 63, 67, and 74 in the heavy chain and 45, 54, 61, and 107 in the light chain, to improve pharmacokinetic properties without exhibiting CD40 agonist activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If charge modification of antibody is performed to modulate pharmacokinetics, then pharmacokinetic properties can be influenced, but unintended and undesirable effects occur due to interdependence of protein properties
Solution Approach 1:
The patent applies local quality by making specific point mutations at defined positions (e.g., L234, L235, L236 in the heavy chain) rather than global charge modification. This localized approach allows precise control over charge distribution at the Fc region while maintaining overall protein structure and function, thereby improving pharmacokinetics without causing unintended effects throughout the entire antibody molecule.
Solution Approach 2:
The patent systematically changes charge parameters by substituting amino acids with different charge properties at specific positions. For example, replacing neutral or positively charged residues with negatively charged residues (aspartic acid, glutamic acid) or vice versa, allowing fine-tuned adjustment of the antibody's charge characteristics to optimize pharmacokinetic properties while avoiding destabilization.
2Duration of action of moving object
If multiple mutations are introduced to improve pharmacokinetics, then charge distribution can be optimized, but manufacturing complexity increases
Solution Approach 1:
The patent segments the antibody structure into specific mutable regions (primarily the Fc region of the heavy chain) and focuses mutations only on these segments. By concentrating modifications on defined positions (L234-L236, L242-L244, L249-L251) rather than distributing mutations throughout the entire antibody, the patent simplifies manufacturing while achieving the desired pharmacokinetic optimization.
Solution Approach 2:
The patent extracts the essential pharmacokinetic control function to a specific subset of amino acid positions in the Fc region. By identifying and modifying only these critical positions that most strongly influence charge-dependent interactions and pharmacokinetics, the patent reduces manufacturing complexity while maintaining or improving therapeutic effectiveness.
Data Source
AI summary
The disclosure provides variants of an antibody wherein the variant antibodies have modified net charge properties relative to the corresponding unmodified antibody. Certain variants have improved pharmacokinetic properties relative to the corresponding unmodified antibody. Certain antibody variants bind CD40. Compositions and methods of use of the same are also provided.