High Affinity CD47 Polypeptides Block SIRPα Interaction
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Solution Overview
Problem
Current modulators targeting the CD47-SIRPα interaction face challenges due to CD47's ubiquitous expression, leading to antigen sink and off-target effects, and existing strategies fail to effectively block the interaction to enhance phagocytosis of tumor cells.
Innovation Solution
Development of high-affinity CD47 polypeptides that specifically target SIRPα, with modifications such as extended N-termini and loop region changes, to increase binding affinity and prevent interaction with native CD47, allowing for enhanced phagocytosis of target cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing modulators target the ubiquitously expressed CD47 cell surface molecule, then the CD47-SIRPα interaction is blocked, but antigen sink and off-target effects occur due to CD47's ubiquitous expression
Solution Approach 1:
The patent applies local quality by modifying specific regions of the CD47 protein (N-terminal extension and loop region changes) to create high-affinity variants that selectively bind SIRPα on phagocytes while maintaining structural integrity. This localized modification approach enables targeted interaction enhancement without affecting CD47's ubiquitous expression pattern, thereby reducing off-target effects while improving blocking effectiveness
Solution Approach 2:
The patent employs parameter changes by engineering amino acid substitutions and extensions in the CD47 polypeptide sequence to increase binding affinity for SIRPα. Specifically, N-terminal extensions and loop region modifications alter the physical-chemical parameters of the CD47 binding interface, creating high-affinity variants that overcome the low affinity of native CD47-SIRPα interaction and reduce the antigen sink effect
2Reliability
If monomeric or dimeric high-affinity SIRPα variants are used to target CD47, then the interaction is blocked, but antigen sink occurs due to CD47's ubiquitous expression
Solution Approach 1:
The patent applies inversion by reversing the traditional targeting strategy instead of using anti-CD47 antibodies to block CD47-SIRPα interaction. The invention uses high-affinity CD47 variants that mimic native CD47 but with enhanced SIRPα binding, allowing these variants to competitively inhibit the interaction by binding to SIRPα on phagocytes. This inverted approach reduces antigen sink by using the ligand structure rather than targeting the receptor broadly
3Productivity
If native CD47 expression is blocked or lost, then phagocytosis of tumor cells is enhanced, but removal of live cells and non-aged erythrocytes occurs
Solution Approach 1:
The patent applies the intermediary principle by using high-affinity CD47 variants as mediators that selectively bind to SIRPα on phagocytes. These engineered variants serve as soluble competitors that block the interaction between native CD47 on tumor cells and SIRPα on phagocytes, enhancing phagocytosis of tumor cells without requiring complete loss of CD47 expression. The intermediary variants provide selective inhibition while preserving normal physiological functions, avoiding non-specific cell removal
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 high-affinity CD47 reagents significantly improve phagocytosis of tumor cells by blocking the CD47-SIRPα interaction, offering a more targeted and effective approach for cancer immunotherapy and diagnostic imaging.
Implementation Method 1
high-affinity CD47 molecules that target SIRPα rather than CD47... a library of CD47 binding domain variants was generated and screened for members having high affinity for multiple human SIRPα alleles
Data Source
AI summary
High affinity CD47 reagents are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for a SIRPα relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity CD47 reagent, which blocks the physiological binding interaction between SIRPα and a ligand, e.g., native CD47.