SIRPα Antibody Epitope Engineering for Selective Tumor Phagocytosis

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current anti-SIRPα antibodies face challenges such as limited binding affinity, cross-reactivity with non-target SIRP family members, and potential toxicity due to broad histological distribution, necessitating the development of antibodies with improved specificity and efficacy for cancer treatment.

Innovation Solution

Development of a chimeric or fully human monoclonal antibody that specifically binds to human SIRPα isoforms 1, 2, and 8 with high affinity, while avoiding cross-reactivity with SIRPβ and SIRPγ, and inducing phagocytosis of tumor cells by macrophages, with potential applications in bispecific molecules, immunoconjugates, and chimeric antigen receptors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If anti-SIRPα antibodies are used to block CD47-SIRPα interaction and promote phagocytosis of tumor cells, then anti-tumor efficacy is improved, but toxicity increases due to harm to normal CD47-expressing hematopoietic and non-hematopoietic cells

Engineering Contradiction:

Improveanti-tumor efficacyVSAvoidtoxicity to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The antibody is engineered to recognize a specific epitope on SIRPα that is selectively targeted on tumor cells while sparing normal cells. This localized specificity allows the antibody to block CD47-SIRPα interaction only where needed (on tumor cells), promoting phagocytosis of cancer cells without harming normal hematopoietic and non-hematopoietic cells that express CD47.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of blocking CD47 on normal cells to prevent toxicity, the invention inverts the approach by targeting SIRPα specifically on tumor cells. This reversal allows the antibody to promote phagocytosis of cancer cells while leaving normal cell CD47-SIRPα interactions intact, thereby achieving anti-tumor efficacy without toxicity to normal cells.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If anti-SIRPα antibodies are designed to bind with high affinity to SIRPα, then phagocytosis induction is enhanced, but cross-reactivity with SIRPβ and SIRPγ may occur

Engineering Contradiction:

Improvephagocytosis inductionVSAvoidspecificity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The antibody is designed to recognize a unique epitope region on SIRPα that is structurally distinct from SIRPβ and SIRPγ. This localized epitope recognition ensures high-affinity binding to SIRPα and robust phagocytosis induction while maintaining strict specificity and avoiding cross-reactivity with other SIRP family members.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The antibody binding interface is engineered to interact with a specific segment or region of the SIRPα protein structure. This segmented approach to epitope recognition allows the antibody to achieve high affinity for SIRPα through multiple localized interactions while the unique structural features of this segment prevent binding to SIRPβ and SIRPγ.

Inventive Principle:

Principle #1Segmentation

3Productivity

If current anti-SIRPα antibodies are used, then some phagocytosis activity is achieved, but binding affinity and blocking activity are limited

Engineering Contradiction:

Improvephagocytosis activityVSAvoidbinding affinity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The antibody undergoes affinity maturation and engineering to optimize binding parameters. Through systematic variation of amino acid residues in the complementarity-determining regions (CDRs), the antibody achieves significantly enhanced binding affinity to SIRPα compared to prior art antibodies. This parameter optimization translates to improved blocking activity against CD47-SIRPα interaction and enhanced induction of phagocytosis by macrophages.

Inventive Principle:

Principle #35Parameter changes

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 antibody demonstrates enhanced binding and blocking activity compared to prior art antibodies, inducing phagocytosis of tumor cells and showing in vivo anti-tumor activity with reduced toxicity, applicable for treating various cancers.

Implementation Method 1

an isolated monoclonal antibody (e.g., a chimeric or fully human antibody), or an antigen-binding portion thereof, that binds SIRPα with high affinity

Methodology Applied

Scientific EffectAntibody-antigen binding:

Implementation Method 2

inducing FcR-mediated phagocytosis of these tumor cells

Methodology Applied

Scientific EffectPhagocytosis:

Implementation Method 3

capable of inducing FcR-mediated phagocytosis

Methodology Applied

Scientific EffectFc receptor-mediated endocytosis:

Data Source

PatentUS20250250355A1Antibodies targeting SIRP-alpha and uses thereof

Publication Date: 2025.08.07 BIOSION INC

AI summary

The present disclosure provides an isolated monoclonal antibody that specifically binds human SIRPα, or an antigen-binding portion thereof. A nucleic acid molecule encoding the antibody or the antigen-binding portion thereof, an expression vector, a host cell and a method for expressing the antibody or the antigen-binding portion thereof are also provided. The present disclosure further provides a bispecific molecule, an immunoconjugate, a chimeric antigen receptor, an oncolytic virus and a pharmaceutical composition comprising the antibody or the antigen-binding portion thereof, as well as a treatment method using an anti-SIRPα antibody or the antigen-binding portion thereof.