SIRP-Alpha Variants With pH-Sensitive Binding for Selective CD47 Targeting
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Solution Overview
Problem
Current therapeutic strategies targeting the interaction between SIRP-α and CD47 face challenges in selectively disrupting this interaction on diseased cells, as SIRP-α binds to CD47 on various cell types, necessitating the development of SIRP-α variants that preferentially bind to CD47 on diseased cells or sites, such as tumors.
Innovation Solution
Engineering SIRP-α variants with specific amino acid substitutions, attachment to blocking peptides or targeting moieties, and incorporation of cleavable linkers to enhance binding affinity under acidic pH and hypoxic conditions, ensuring selective interaction with CD47 on diseased cells while minimizing binding to non-diseased cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If SIRP-α is used to block CD47 interaction, then binding affinity to CD47 is improved, but selectivity for diseased cells deteriorates because SIRP-α binds to CD47 on many different cell types
Solution Approach 1:
The patent introduces pH-sensitive histidine residues at specific positions (e.g., H29, H30, H31, H32, H33, H34, H35, H52, H53, H54, H66, H67, H68, H69, H74, H93, H96, H97, H98, H100) in the SIRP-α protein structure. These localized modifications create pH-sensitive binding sites that maintain high affinity for CD47 only in acidic tumor microenvironments (pH < 7), while preventing binding at physiological pH (7.4) on healthy cells. This resolves the contradiction by making binding strength conditional on local environmental conditions.
Solution Approach 2:
The patent exploits changes in pH as a parameter to control binding affinity. By introducing histidine residues with pKa values around 6.0-6.5, the binding interaction becomes sensitive to pH changes. At tumor acidic pH (6.5-7.0), histidine residues are protonated and facilitate CD47 binding, while at physiological pH 7.4, they remain unprotonated and prevent binding. This parameter-based control allows selective targeting of diseased cells without affecting healthy cells.
2Reliability
If SIRP-α variants with higher CD47 binding affinity are engineered, then therapeutic efficacy is improved, but binding to non-diseased cells increases causing off-target effects
Solution Approach 1:
The patent creates a dynamic binding system where SIRP-α variants exhibit conditional binding affinity based on environmental pH. The histidine residue modifications enable the protein to dynamically adjust its binding state: high affinity in acidic tumor environments and low affinity at physiological pH in healthy tissues. This dynamic behavior ensures therapeutic efficacy at the target site while minimizing off-target effects on non-diseased cells.
Solution Approach 2:
The histidine residues act as intermediary elements that mediate the relationship between SIRP-α and CD47 based on pH conditions. These residues serve as pH-sensitive switches that control the binding interaction: when protonated in acidic environments, they facilitate binding; when unprotonated at physiological pH, they prevent binding. This intermediary mechanism enables selective therapeutic action.
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 SIRP-α variants demonstrate increased binding affinity to CD47 on diseased cells under conditions characteristic of tumors, such as acidic pH and hypoxia, allowing for targeted therapeutic interventions with reduced off-target effects.
Implementation Method 1
the SIRP-α variants bind with higher affinity to CD47 under acidic pH (e.g., less than around pH 7) than under physiological conditions
Implementation Method 2
the SIRP-α variants bind with higher affinity to CD47 under acidic pH (e.g., less than around pH 7) and/or under hypoxic condition than under physiological conditions
Data Source
AI summary
The invention relates to compositions and methods of constructs comprising a SIRP-α polypeptide, including SIRP-α variants. The 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 constructs of the invention may be used to treat various diseases, such as cancer, preferably solid tumor or hematological cancer.