Fc Region Mutations for Stable Oligomerization Without Effector Activation
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Solution Overview
Problem
Current antibodies with enhanced Fc-Fc interactions for increased effector functions, such as CDC and ADCC, can inadvertently activate effector cells like T cells or NK cells, leading to unwanted immune responses, necessitating a solution that enhances Fc-Fc interactions without inducing these effector functions.
Innovation Solution
Introducing a second mutation at amino acid positions K322 or P329 in the Fc region of antibodies with a first mutation at E430, E345, or S440, specifically S440Y or S440W, to maintain enhanced oligomerization while reducing C1q binding and FcγR interactions, thereby decreasing CDC and ADCC activities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Fc-Fc interactions are enhanced through mutations in the Fc region, then effector functions such as CDC and ADCC are improved, but unwanted immune activation of effector cells like T cells and NK cells occurs
Solution Approach 1:
The patent applies local quality by making different parts of the Fc region have different functions: mutations at specific positions (E345, E430, S440) enhance Fc-Fc interactions and oligomerization locally, while mutations at other positions (K322, P329) selectively reduce C1q binding and effector functions. This allows the Fc region to simultaneously achieve stable oligomerization while minimizing unwanted immune activation.
Solution Approach 2:
The patent uses parameter changes by introducing multiple amino acid mutations at specific positions in the Fc region to precisely control the balance between Fc-Fc interaction strength and effector function activation. By changing the chemical and physical properties of amino acids at key positions, the patent achieves enhanced oligomerization without proportional enhancement of harmful effector functions.
2Stability of the object's composition
If mutations are introduced to enhance Fc-Fc interactions and oligomerization, then stable Fc region interactions are achieved, but C1q binding and FcγR interactions are increased leading to enhanced CDC and ADCC
Solution Approach 1:
The patent segments the Fc region into distinct functional zones: positions E345, E430, and S440 are optimized for Fc-Fc interactions and oligomerization stability, while positions K322 and P329 are optimized for reducing C1q binding and effector function activation. This segmentation allows independent optimization of different Fc region functions without compromise.
Solution Approach 2:
Different regions of the Fc region are given different functional properties through targeted mutations. The patent creates a local quality gradient where some residues promote stable oligomerization while others specifically inhibit C1q binding and effector cell activation, achieving a balanced functional profile.
3Productivity
If a single mutation is introduced to enhance Fc-Fc interactions, then oligomerization is improved, but effector functions such as CDC and ADCC are also enhanced
Solution Approach 1:
The patent merges multiple mutations into a single Fc region construct, combining Fc-Fc interaction enhancing mutations (E345R, E430G, S440Y/W) with effector function reducing mutations (K322E, P329D). This combination allows the simultaneous achievement of enhanced oligomerization and reduced harmful effector functions in a single therapeutic antibody.
Solution Approach 2:
The patent converts the potentially harmful effect of Fc region mutations into a beneficial balance by using multiple mutations to achieve enhanced oligomerization while simultaneously reducing C1q binding and effector function activation. The net effect is a therapeutic advantage where stable Fc interactions occur without proportional enhancement of harmful effector functions.
Data Source
AI summary
Described herein are polypeptides and antibodies comprising a variant Fc region. The variant Fc region provides for stabilized Fc-Fc interactions when the polypeptide(s), antibody or antibodies are bound to its target, antigen or antigens on the surface of a cell, while at the same time also having decreased complement-dependent cytotoxicity (CDC) and may also have decreased activation of other effector functions resulting from one or more amino acid modifications in the Fc region.