Variant IgG Fc Domains Reducing Effector Function
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Solution Overview
Problem
There is no naturally occurring immunoglobulin that completely lacks effector functions, and existing methods to engineer antibodies with reduced effector function often compromise stability and other important properties.
Innovation Solution
Development of recombinant polypeptides with variant IgG Fc domains containing specific amino acid substitutions, such as Phenylalanine at position 234, Glutamine at position 235, and Glutamine at position 322, which reduce effector function while maintaining stability and increasing plasma half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If amino acid substitutions are introduced to reduce effector function, then effector function is diminished, but stability is compromised
Solution Approach 1:
The patent applies parameter changes by systematically modifying specific amino acid residues at defined positions in the Fc domain (e.g., positions 234, 235, 322, 331) to alter the molecular properties. These targeted substitutions change the local chemical environment to reduce effector function while preserving overall structural stability, resolving the contradiction between reducing harmful effector effects and maintaining compositional stability.
Solution Approach 2:
The invention employs local quality by introducing substitutions at specific localized positions within the Fc domain rather than throughout the entire molecule. By targeting particular residues (e.g., L234F, L235Q, P331G) that are critical for effector function but not for overall stability, the patent achieves reduced effector activity while maintaining the structural integrity and stability of the antibody molecule.
2Object-generated harmful factors
If amino acid substitutions are introduced to reduce effector function, then effector function is diminished, but half-life is reduced
Solution Approach 1:
The patent uses parameter changes to simultaneously optimize multiple properties by selecting amino acid substitutions that specifically affect effector function interactions while preserving or enhancing FcRn binding. The targeted modifications at positions such as 234, 235, 322, and 331 are chosen to reduce effector function without compromising the parameters that govern half-life, thereby resolving the contradiction between reducing harmful effects and maintaining prolonged duration of action.
Solution Approach 2:
The invention applies local quality by making targeted substitutions at specific residues that are involved in effector function binding interfaces but are distinct from the regions critical for FcRn interaction and half-life determination. This localized modification strategy allows the patent to reduce effector function while preserving the molecular features that extend half-life.
3Object-generated harmful factors
If multiple amino acid substitutions are introduced, then effector function is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by defining a finite set of approved amino acid substitutions at specific positions (e.g., F or A at position 234; Q, N, F, V, or A at position 235; Q, D, E, H, N, or A at position 322; A or G at position 331). This structured approach to parameter modification simplifies manufacturing by providing clear, predetermined options rather than requiring optimization of unlimited possibilities, thereby reducing manufacturing complexity while achieving reduced effector function.
Solution Approach 2:
The invention employs local quality by limiting substitutions to specific, well-defined positions in the Fc domain rather than allowing random or widespread modifications. This focused approach concentrates the manufacturing effort on a small number of critical residues, making the production process more manageable and less complex while still achieving the desired reduction in effector function through targeted local changes.
Data Source
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AI summary
Provided are polypeptides comprising a variant IgG Fc domain, wherein the polypeptides exhibit reduced or ablated effector functions (e.g., ADCC and/or CDC) and increased stability and plasma half-life compared to a parent polypeptide. Also provided are compositions, methods of treatment, and methods to diminish Fc-induced effector function in a parent polypeptide.