Fc Domain Mutations Enhance Antibody Agonism

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Solution Overview

Problem

There is a need for additional engineering approaches to modulate the Fc domain-mediated functions of antibodies and other Fc-domain containing therapeutic constructs, particularly for enhancing agonistic activity and therapeutic responses in anti-tumor necrosis factor receptor (TNFR) superfamily member antibodies.

Innovation Solution

Introduction of specific mutations such as T437R, T437R/K248E, and T437R/K338A in the Fc domain of anti-TNFR superfamily member antibodies to enhance agonistic activity and effector functions, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Fc domain engineering approaches are used to modulate antibody effector functions, then therapeutic response is improved, but additional engineering approaches are needed to further enhance agonistic activity

Engineering Contradiction:

Improvetherapeutic responseVSAvoidengineering approaches

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid mutations (T437R, T437R/K248E, T437R/K338A) in the Fc domain to modify antibody properties. These mutations change the biochemical parameters of the Fc domain to enhance agonistic activity and effector functions, providing a systematic approach to optimize therapeutic response through controlled parameter modification.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by making targeted mutations at specific positions (T437, K248, K338) within the Fc domain rather than modifying the entire antibody molecule. This localized engineering approach allows precise modulation of effector functions while maintaining other important antibody properties, enabling further enhancement of agonistic activity through site-specific modifications.

Inventive Principle:

Principle #3Local quality

2Reliability

If mutations are introduced to enhance agonistic activity, then anti-tumor immunity is improved, but complexity of antibody engineering increases

Engineering Contradiction:

Improveanti-tumor immunityVSAvoidantibody engineering

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses parameter changes to enhance anti-tumor immunity by introducing specific amino acid substitutions that modify Fc domain properties. These controlled parameter changes (T437R, T437R/K248E, T437R/K338A mutations) systematically improve agonistic activity and effector functions while providing a manageable engineering approach through defined mutation sets.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent reduces engineering complexity by applying local quality modifications at three specific positions in the Fc domain. This localized approach concentrates the engineering effort on key residues that control effector functions, avoiding the need for comprehensive antibody redesign and simplifying the overall engineering process while achieving enhanced anti-tumor immunity.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS10669344B2Engineered antibodies and other Fc-domain containing molecules with enhanced agonism and effector functions

Publication Date: 2020.06.02 JANSSEN BIOTECH INC

AI summary

The present invention relates to engineered antibodies and other Fc-domain containing molecules with enhanced agonism and effector functions.