Fc Region Modified Antibodies Eliminating Effector Functions
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Solution Overview
Problem
Current antibody therapies face challenges in reducing unwanted effector functions while maintaining pharmacokinetic properties, as previous modifications to the Fc region have not completely eliminated Fc-mediated activities and may impact immunogenicity and half-life.
Innovation Solution
Development of proteins with specific modifications in the Fc region, such as altering amino acids at positions L234, L235, and D265, to prevent interaction with Fc receptors and C1q, thereby inhibiting effector functions while maintaining a plasma clearance rate comparable to wild-type antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If the Fc region is modified to reduce effector functions, then unwanted effects (cytokine storm, platelet aggregation) are reduced, but Fc-mediated therapeutic efficacy may be compromised
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the Fc region (amino acid positions 234, 235, and 265) while leaving the rest of the antibody structure intact. This selective modification approach allows the antibody to retain overall Fc function while eliminating specific unwanted effector functions through targeted changes at these critical positions.
Solution Approach 2:
The patent changes the amino acid parameters at positions 234, 235, and 265 in the Fc region to alter the binding properties. By substituting specific amino acids (e.g., L234, L235, D265 in wild-type IgG1), the patent modifies the physical-chemical properties of the Fc region to prevent interaction with FcγRs and C1q, thereby changing the effector function profile while maintaining pharmacokinetic properties.
2Object-affected harmful factors
If antibody fragments are used to eliminate Fc-effector functions, then effector function activity is reduced, but in vivo half-life is shortened
Solution Approach 1:
The patent extracts the specific problematic binding capability from the Fc region by modifying amino acids at positions 234, 235, and 265. This extraction approach removes the ability to bind FcγRs and C1q (the unwanted effector functions) while preserving the Fc region's ability to engage FcRn for recycling, thereby maintaining long in vivo half-life without requiring full antibody fragments.
Solution Approach 2:
The patent creates a composite Fc region with mixed properties: it retains the structural framework and FcRn binding capability (for long half-life) while incorporating modified amino acid residues that eliminate FcγR and C1q binding. This composite approach combines beneficial properties (long circulation) while eliminating harmful properties (unwanted effector functions).
Data Source
AI summary
Described herein are, proteins comprising amino acid substitutions in at least one of a first and a second polypeptide chain. Furthermore, is described the uses and methods related to said proteins.