CD27 Antibody Dimer Stability via Fc Mutations

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Solution Overview

Problem

Current CD27 antibodies have limitations in terms of affinity, specificity, and stability, which affect their ability to effectively activate NF-κB activity and stimulate T cell proliferation and IFN-γ secretion, and they may not remain in dimer form during storage.

Innovation Solution

Development of an antibody or antigen binding fragment with high affinity for CD27, specifically binding to human and monkey CD27, activating NF-κB activity, stimulating T cell proliferation, and maintaining stability, including a monoclonal, chimeric, humanized, or bispecific antibody that remains in dimer form during storage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CD27 antibodies are used, then they can bind to CD27 and activate T cells, but they have low affinity, poor stability, and may not remain in dimer form during storage

Engineering Contradiction:

Improvestability of antibodyVSAvoidcomplexity of antibody structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the antibody structure to include Fc region mutations (e.g., L234A/L235A in IgG1 or L234A/L235A/L243A in IgG2) that enhance dimer stability. These parameter changes in the amino acid sequence improve the antibody's ability to maintain dimer form during storage while preserving its binding and activating functions.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CD27 antibodies are designed to have high affinity and activate NF-κB activity, then they can stimulate T cell proliferation and IFN-γ secretion, but they may lose dimerization capability during storage

Engineering Contradiction:

Improveability to activate NF-κB and stimulate T cellsVSAvoiddimer form stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent merges two functional requirements: maintaining dimerization capability and achieving high affinity for CD27 activation. By combining Fc region mutations that stabilize dimers with variable regions that bind CD27 with high affinity, the antibody simultaneously achieves both dimer stability and strong NF-κB activation, stimulating T cell proliferation and IFN-γ secretion effectively.

Inventive Principle:

Principle #5Merging (Combining)

3Measurement precision

If existing CD27 antibodies are used, then they show some binding activity, but they lack sufficient affinity (KD > 10^-8 M) and do not specifically bind to human and monkey CD27

Engineering Contradiction:

Improvebinding affinity to CD27VSAvoiddifficulty in producing high-affinity antibody

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The patent achieves high binding affinity (KD ≤ 10^-8 M) through parameter changes in the variable regions of the antibody, specifically optimizing CDR sequences for human and monkey CD27 binding. The Fc region mutations (L234A/L235A or L234A/L235A/L243A) further enhance stability without compromising affinity, making the antibody both highly effective and manufacturable.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11795230B2Anti-CD27 antibodies and use thereof

Publication Date: 2023.10.24 SHIHUIDA PHARMACEUTICALS GROUP (JILIN) LTD

AI summary

The present disclosure provides an antibody, or an antigen binding fragment or variant thereof, which binds to CD27 and exhibits at least one of the following properties: specifically binds to CD27 with a KD of 10−8 M or less; activates and/or increases CD27 mediated NF-κB activity; stimulates CD4+ and/or CD8+ T cell proliferation; binds to human CD27 expressed on a cell surface; stimulates secretion of IFN-γ by CD4+ and/or CD8+ T cells. The present disclosure also provides a method for preparing and using said antibody.