Fc Variant Amino Acid Modifications Reduce Effector Functions
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Solution Overview
Problem
Current antibody therapeutics face challenges in reducing effector functions such as ADCC and CDC, which can lead to unwanted side effects, particularly in treatments where these responses are not necessary, like graft rejection, due to high affinity to C1q and Fc gamma receptors.
Innovation Solution
Introducing specific amino acid modifications, such as deletion of amino acids at positions 294 or 293 within the Fc region of antibodies, significantly reduces binding to C1q and Fc gamma receptors, thereby minimizing effector functions like ADCC and CDC.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the Fc region of antibodies maintains high affinity for C1q and Fc gamma receptors to enable effector functions (ADCC, CDC), then the therapeutic effect against cancers and infectious diseases is improved, but unwanted side effects and IgG-cytotoxicity occur in treatments where these responses are not necessary
Solution Approach 1:
The patent applies local quality by making specific amino acid modifications at particular positions within the Fc region (such as positions 234, 235, 327, 330, 331) to selectively reduce binding affinity for C1q and Fc gamma receptors while preserving other important functions. This localized modification approach allows the antibody to have different binding characteristics at different interaction sites, enabling reduced effector functions without completely abolishing Fc region activity
Solution Approach 2:
The patent employs parameter changes by modifying amino acid sequences at specific positions in the Fc region to alter the binding affinity parameters. By changing amino acids at positions 234, 235, 327, 330, and 331, the patent adjusts the interaction strength between the Fc region and C1q/Fc gamma receptors, thereby controlling effector function activation levels to match therapeutic needs
2Object-affected harmful factors
If IgG4 subclass is used to reduce effector functions due to low affinity for C1q and Fc gamma receptors, then side effects are minimized, but in vivo instability and dynamics issues arise
Solution Approach 1:
The patent applies composite materials by creating hybrid Fc regions that combine elements from different IgG subclasses. Specifically, the patent constructs Fc variants with amino acid sequences that integrate characteristics of IgG1, IgG2, and IgG4 subclasses at different positions, thereby achieving a composite structure that simultaneously provides improved stability (from IgG1/IgG2) and reduced effector function activation (from IgG4-like properties at critical positions)
3Object-affected harmful factors
If amino acid modifications are introduced in the Fc region to reduce binding to C1q and Fc gamma receptors, then ADCC and CDC activities are decreased, but the complexity of antibody engineering increases
Solution Approach 1:
The patent applies segmentation by dividing the Fc region into distinct functional domains and identifying specific amino acid positions (234, 235, 327, 330, 331) that control C1q and Fc gamma receptor binding. By focusing modifications on these discrete segments rather than the entire Fc region, the patent reduces engineering complexity while achieving the desired reduction in effector function activation
Data Source
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AI summary
The invention relates to a method for producing a variant of a parent polypeptide comprising a Fc region, which variant exhibits reduced binding to the protein C1 q and to at least one receptor FcyR as compared to the said parent polypeptide.