GITR Antibody Stability via Amino Acid Substitutions

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Solution Overview

Problem

There is a need for agents, such as antibodies, that can modulate the activity of glucocorticoid-induced tumor necrosis factor receptor (GITR), which is a costimulatory receptor expressed on regulatory T-cells and other immune cells, to enhance cancer immunotherapy and treat immune disorders.

Innovation Solution

The development of antibodies and antigen-binding fragments that specifically bind to GITR, which can be full-length or truncated, and are designed to minimize in vivo truncation, thereby effectively targeting immune cells expressing GITR.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antibodies are designed to target GITR on immune cells, then therapeutic efficacy is improved, but in vivo truncation of the antibody occurs

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidantibody structure stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by modifying the antibody's amino acid sequence, specifically introducing substitutions at positions 40 and 43 of the heavy chain variable domain. These parameter changes in the molecular structure prevent proteolytic cleavage while maintaining the antibody's ability to bind GITR and exert therapeutic effects.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates modified copies of the original antibody sequence with specific amino acid substitutions. These copied variants retain the therapeutic function of targeting GITR while having improved stability against truncation, effectively creating enhanced versions of the parent molecule.

Inventive Principle:

Principle #26Copying

2Duration of action of stationary object

If antibodies undergo in vivo truncation, then half-life is extended, but binding affinity and functionality are reduced

Engineering Contradiction:

Improveantibody half-lifeVSAvoidbinding affinity

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by pre-modifying the antibody sequence to prevent truncation before it occurs in vivo. The amino acid substitutions at positions 40 and 43 create resistance to proteolytic cleavage, thereby preventing the formation of truncated variants that would have reduced binding affinity.

Inventive Principle:

Principle #9Preliminary anti-action

3Loss of time

If conventional antibodies are used, then development time is reduced, but in vivo truncation occurs reducing therapeutic effectiveness

Engineering Contradiction:

Improvedevelopment timeVSAvoidtherapeutic effectiveness

Core Design Contradiction:

Loss of timeVSReliability

Solution Approach 1:

The patent applies preliminary action by incorporating stability-enhancing amino acid substitutions into the antibody sequence during the design and development phase. This preliminary modification ensures that the antibody is resistant to truncation from the outset, eliminating the need for subsequent optimization and ensuring therapeutic effectiveness without extending development time.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12331127B2Therapeutic uses of anti-GITR antibodies

Publication Date: 2025.06.17 REGENERON PHARMACEUTICALS INC

AI summary

Provided herein are antibodies, and antigen-binding fragments thereof that specifically bind glucocorticoid-induced tumor necrosis factor receptor (GITR), compositions comprising the antibodies or antigen-binding fragments thereof, and methods of using the same, including, e.g., methods of treatment using the same.