Engineered Fc Polypeptides With G236A/A330L/I332E Mutations

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Solution Overview

Problem

Existing antibodies and immunoglobulin Fc domains face challenges in optimizing interactions with immune system proteins like FcγRs and complement C1q, affecting immune response outcomes such as activation or suppression against pathogens.

Innovation Solution

Engineered polypeptides with specific Fc modifications, such as G236A/A330L/I332E mutations, enhance binding to FcγRIIA and FcγRIIIA, reduce binding to FcγRIIB, and increase C1q binding, leading to improved immune response activation and therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type Fc polypeptide is used, then natural immune response is maintained, but binding affinity to FcγRs and C1q is insufficient for optimized therapeutic efficacy

Engineering Contradiction:

Improvebinding affinityVSAvoidimmune response activation

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid mutations (G236A, A330L, I332E) at defined positions in the Fc polypeptide sequence. These mutations alter the binding parameters of the Fc region to FcγRs and C1q, optimizing affinity and effector function activation while maintaining structural integrity of the antibody molecule.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If Fc modifications are introduced to enhance binding to FcγRIIA and FcγRIIIA, then immune response activation is improved, but binding to FcγRIIB may be adversely affected

Engineering Contradiction:

Improvebinding affinityVSAvoidadverse binding effect

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by making specific, targeted mutations at precise locations within the Fc polypeptide sequence (positions 236, 330, and 332). Each mutation is strategically placed to influence binding to specific FcγR subtypes (enhancing FcγRIIA and FcγRIIIA while controlling FcγRIIB interaction), thereby achieving subtype-selective effector function modulation.

Inventive Principle:

Principle #3Local quality

3Reliability

If multiple Fc mutations are combined to optimize binding characteristics, then therapeutic efficacy is enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmutation combination

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple beneficial mutations (G236A, A330L, I332E) into a single Fc polypeptide sequence, creating a composite engineered Fc region that simultaneously achieves enhanced binding to FcγRIIA, FcγRIIIA, and C1q. This combination approach consolidates multiple functional improvements into one integrated molecular construct, simplifying production compared to generating separate antibody variants.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250296986A1Engineered polypeptides

Publication Date: 2025.09.25 VIR BIOTECHNOLOGY INC

AI summary

Provided herein are engineered polypeptides (e.g., Fc polypeptides, Fc polypeptide fragments, Fc fusion proteins, antibodies, and the like) that comprise a variant of an IgG Fc polypeptide (or a portion or fragment thereof), which variants (and the polypeptides that comprise these variants) have one or more improved characteristics over known Fc polypeptides.