Fc Variant Polypeptides Reducing Effector Function
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Solution Overview
Problem
Current monoclonal antibodies with Fc regions exhibit unwanted effector functions such as ADCC, ADCP, and CDC, which can lead to toxicity and tissue targeting issues, necessitating a reduction in these functions for therapeutic antibodies.
Innovation Solution
Development of Fc region variants with specific amino acid substitutions, particularly at position Pro329, combined with other mutations like L234A and L235A, to reduce affinity to FcγRIIIA and C1q, thereby decreasing ADCC and CDC activities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type Fc region is used, then effector functions (ADCC, ADCP, CDC) are maintained, but toxicity and tissue targeting issues occur
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the Fc region (positions 234, 235, and 329) to alter the biological activity parameters. The L234A, L235A, and P329G mutations change the chemical structure to reduce affinity for Fcγ receptors and C1q, thereby decreasing effector functions and associated toxicity while preserving antigen binding capability.
2Object-affected harmful factors
If Fc region variants with reduced effector function are created, then toxicity is minimized, but affinity to FcγRIIIA and C1q is reduced
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions (234, 235, 329) within the Fc region while leaving the rest of the antibody structure unchanged. This localized modification approach reduces effector function through decreased receptor affinity at these specific sites while preserving the overall antibody structure and antigen binding capabilities.
3Object-affected harmful factors
If multiple amino acid substitutions are introduced, then ADCC activity is reduced to 20% of wild-type levels, but structural complexity increases
Solution Approach 1:
The patent systematically changes multiple parameters (amino acid identities at positions 234, 235, and 329) to achieve the desired reduction in ADCC activity to 20% of wild-type levels. Despite introducing three mutations, the overall structural complexity remains manageable because the mutations are confined to a specific region and use conservative amino acid substitutions that maintain protein folding and stability.
Data Source
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AI summary
The invention relates to engineered polypeptides comprising Fc variants and their uses. More specifically, Fc variants are described exhibiting reduced effector function. These variants cause a benefit for a patient suffering from a disease which could be treated with an antibody for which it is desirable to reduce the effector function elicited by antibodies.