SIRP-α Variant Constructs for Selective CD47 Binding
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Solution Overview
Problem
Current therapeutic strategies targeting the interaction between SIRP-α and CD47 face challenges in selectively binding to diseased cells, as SIRP-α can interact with CD47 on various cell types in the body, necessitating the development of SIRP-α variants that preferentially bind to CD47 on diseased cells or at diseased sites.
Innovation Solution
The creation of SIRP-α variant constructs attached to CD47-based blocking peptides via cleavable linkers, which are designed to have higher affinity for CD47 on diseased cells, particularly under acidic pH and hypoxic conditions, and include amino acid substitutions or modifications to enhance binding specificity, along with targeting moieties like antibodies to direct the variants to tumor sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If SIRP-α is used to bind CD47 on tumor cells, then therapeutic efficacy is improved, but non-specific binding to healthy cells increases causing off-target effects
Solution Approach 1:
The patent applies local quality by creating SIRP-α variants with modified binding properties that are specifically tailored to interact with CD47 under the unique conditions of the tumor microenvironment (acidic pH and hypoxia). The variants are designed to have enhanced binding affinity specifically in this localized environment while maintaining low affinity under normal physiological conditions, thus achieving selective targeting without widespread off-target effects.
Solution Approach 2:
The patent employs parameter changes by engineering SIRP-α variants whose binding affinity to CD47 is modulated by environmental parameters specific to tumor sites - namely acidic pH and hypoxic conditions. The amino acid substitutions are designed to make the binding interaction sensitive to these parameter changes, allowing the therapeutic agent to activate preferentially at the tumor site while remaining inactive in healthy tissues with normal pH and oxygen levels.
2Manufacturing precision
If SIRP-α variants with enhanced binding affinity are designed, then binding specificity to diseased cells is improved, but protein structure complexity increases
Solution Approach 1:
The patent applies segmentation by focusing mutations and modifications on specific functional domains of the SIRP-α protein, particularly the CD47-binding interface. Rather than redesigning the entire protein structure, the approach segments the modification effort to specific regions that control binding affinity and environmental sensitivity, thereby achieving enhanced specificity with minimal increase in overall structural complexity.
Solution Approach 2:
The patent employs composite material principles by creating chimeric SIRP-α variants that combine elements from different SIRP-α isoforms or species with optimized binding interfaces. These composite proteins integrate functional domains that provide both high affinity for CD47 and sensitivity to tumor microenvironment conditions, achieving complex functionality through controlled combination of simpler structural elements.
Data Source
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AI summary
The invention relates to compositions and methods of SIRP-α variant constructs including SIRP-α variants. The SIRP-α variant constructs may be engineered in a variety of ways to respond to environmental factors, such as pH, hypoxia, and/or the presence of tumor-associated enzymes or tumor-associated antigens. The SIRP-α variant constructs of the invention may be used to treat various diseases, such as cancer, preferably solid tumor or hematological cancer.