Engineered SIRPα Variants for Selective CD47 Disruption

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Solution Overview

Problem

Current cancer therapies targeting the CD47/SIRPα pathway face challenges in balancing efficacy against immune cell protection, necessitating the development of engineered SIRPα variants with reduced toxicity.

Innovation Solution

Engineered SIRPα polypeptides with specific amino acid mutations in loops such as BC, C′D, and DE, enhancing their ability to disrupt the CD47 interaction while minimizing off-target effects on healthy cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional SIRPα targeting therapies are used to enhance cancer cell recognition and phagocytosis, then tumor growth inhibition is improved, but toxicity to healthy immune cells (red blood cells, platelets, lymphocytes) increases

Engineering Contradiction:

Improvecancer therapy efficacyVSAvoidtoxicity to healthy immune cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific amino acid mutations at targeted locations (BC loop, C'D loop, DE loop) within the SIRPα protein structure. These localized changes modify the protein's binding properties selectively, enhancing affinity for tumor-associated CD47 while preserving or reducing interaction with CD47 on healthy cells, thereby achieving differentiated therapeutic effects.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying amino acid sequences at specific positions (e.g., positions 24-36, 53-56, 61-78) to optimize binding characteristics. Through mutational analysis and selection of variants with modified kinetic parameters (affinity, specificity), the therapy achieves enhanced efficacy against cancer cells while minimizing off-target effects on healthy immune cells.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If SIRPα-CD47 interaction is blocked to enhance phagocytosis of tumor cells, then anti-tumor activity is improved, but protection of healthy cells from phagocytosis is reduced

Engineering Contradiction:

Improvephagocytosis rate of tumor cellsVSAvoidprotection of healthy cells

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies segmentation by dividing the CD47-SIRPα interaction interface into distinct regions (BC loop, C'D loop, DE loop) and introducing mutations specifically in these segments. This segmented approach allows selective disruption of tumor cell protection while preserving or modulating protection of healthy cells, as each loop region contributes differently to binding specificity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The engineered SIRPα variants act as intermediaries that selectively modulate the CD47-SIRPα interaction. By introducing specific amino acid changes, these variants serve as modified mediators that preferentially disrupt binding to tumor cells while maintaining or reducing interaction with healthy cells, thereby achieving selective therapeutic effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250288643A1Engineered SIRPá variants and methods of use thereof

Publication Date: 2025.09.18 FBD BIOLOGICS LTD

AI summary

This disclosure relates to engineered SIRPα variants, and methods of use thereof.