Fc-Optimized Anti-CD47 Antibodies Enhance Phagocytosis

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current anti-CD47 antibodies have limited clinical benefit in treating malignancies due to unclear mechanisms of antitumor activity, with no consensus on the ideal Fc format for maximizing therapeutic index.

Innovation Solution

Development of Fc-optimized anti-CD47 antibodies with specific mutations (G236A/A330L/1332E) that enhance binding to activating FcγRs, thereby boosting systemic antitumor immunity while minimizing toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional anti-CD47 antibodies are used to block CD47/SIRPα interaction, then antitumor activity is achieved, but therapeutic index is limited due to unclear mechanisms and lack of Fc optimization

Engineering Contradiction:

Improveantitumor activityVSAvoidFc format optimization

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by systematically modifying the Fc region amino acid sequences of anti-CD47 antibodies to optimize binding affinity to activating FcγRs. Specific mutations (e.g., E233K, M252Y, S254T, N297Q) were introduced to enhance FcγR engagement, transforming the antibody from a simple blocking agent to an immunomodulatory therapeutic with improved therapeutic index through controlled parameter optimization of the Fc domain.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If Fc mutations are introduced to enhance binding to activating FcγRs, then systemic antitumor immunity is boosted, but toxicity may increase

Engineering Contradiction:

Improvesystemic antitumor immunityVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific point mutations only in the Fc region while maintaining the original Fab domain structure. This localized modification approach allows enhancement of FcγR binding and antitumor immunity without altering the antigen-binding specificity, thereby minimizing off-target effects and reducing toxicity while achieving the desired immunomodulatory enhancement.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs feedback mechanisms through in vivo efficacy and toxicity assessment in preclinical models to iteratively optimize Fc mutations. By evaluating the balance between antitumor activity and toxicity outcomes, the research identified optimal mutation combinations that maximize therapeutic index, allowing feedback-driven refinement of the Fc region design to achieve enhanced immunity with acceptable safety profiles.

Inventive Principle:

Principle #23Feedback

3Productivity

If multiple Fc mutations are combined to maximize FcγR binding, then phagocytosis and immune cell infiltration are enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvephagocytosis and immune cell infiltrationVSAvoidantibody production

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent applies segmentation by dividing the antibody into distinct functional modules: the Fab domain for antigen binding and the Fc domain for immune engagement. This modular approach allows independent optimization of each region, with multiple Fc mutations introduced without affecting Fab domain expression or assembly, thereby enhancing phagocytosis and immune cell infiltration while maintaining relatively straightforward manufacturing processes through standardized recombinant antibody production.

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The Fc-optimized anti-CD47 antibodies demonstrate enhanced phagocytosis of cancer cells, increased infiltration of tumor-specific macrophages and T cells, and improved antitumor activity with reduced toxicity.

Implementation Method 1

interactions between the fragment crystallizable (Fc) and Fc gamma receptors (FcγRs) also contribute to their antitumor activity

Methodology Applied

Scientific EffectAntibody-Fc receptor binding:

Implementation Method 2

therapeutic antibodies that block the interaction between CD47 and SIRPα promote effective antitumor responses by enabling elimination of both hematologic and solid tumor cells by phagocytes

Methodology Applied

Scientific EffectProtein-protein interaction blocking:

Implementation Method 3

the antitumor activity of these antibodies relies solely on blocking the CD47/SIRPα interaction by the fragment antigen-binding (Fab) domain, or whether interactions between the fragment crystallizable (Fc) and Fc gamma receptors (FcγRs) also contribute to their antitumor activity

Methodology Applied

Scientific EffectPhagocytosis:

Data Source

PatentUS20250154253A1TARGETING CD47 WITH Fc-ENHANCED ACTIVITY

Publication Date: 2025.05.15 THE ROCKEFELLER UNIV

AI summary

This disclosure provides anti-CD47 antibodies or antigen-binding portions thereof comprising a modified Fc region that activates FcγRs and enhances in vivo antitumor activity. This disclosure further provides a humanized CD47/SIRPα/FcγR mouse model for evaluating anti-CD47 antibodies or antigen-binding portions thereof.