Multivalent Molecules Recruit Phosphatases to SIRPα
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Solution Overview
Problem
Current therapeutic strategies for antagonizing SIRPα are limited by polymorphisms in the CD47-binding domain and are ineffective in eliminating basal intracellular signaling, necessitating alternative approaches to directly reduce or eliminate intracellular signaling of SIRPα beyond extracellular ligand blocking mechanisms.
Innovation Solution
Development of multivalent protein-binding molecules that specifically bind to SIRPα and recruit membrane phosphatases, such as CD45, to antagonize SIRPα signaling through phosphatase recruitment, thereby reducing both resting and ligand-activated signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If extracellular ligand blocking antibodies are used to antagonize SIRPα, then binding to SIRPα is achieved, but basal intracellular signaling cannot be eliminated
Solution Approach 1:
The patent introduces a bivalent protein molecule as an intermediary that bridges SIRPα and phosphatase. This molecule has a first binding domain that binds to SIRPα and a second binding domain that binds to phosphatase, thereby recruiting phosphatase to dephosphorylate SIRPα and eliminate basal signaling. This mediator approach resolves the limitation of conventional antibodies that cannot directly eliminate basal signaling.
Solution Approach 2:
The patent changes the mechanism of action from单纯的 ligand blocking to phosphatase recruitment that directly modifies the phosphorylation state of SIRPα. By altering the parameter of intracellular signaling activity through enzymatic dephosphorylation, the patent achieves complete elimination of basal signaling that cannot be accomplished by extracellular blocking alone.
2Reliability
If CD47-targeted therapies are used, then anti-cancer immunity is enhanced, but safety and efficacy are limited due to ubiquitous CD47 expression
Solution Approach 1:
The patent shifts the target from ubiquitous CD47 to SIRPα which is specifically expressed on myeloid cells. This local quality change ensures that the therapeutic effect is concentrated on immune cells involved in phagocytosis and anti-tumor immunity, while sparing other tissues from off-target effects, thereby improving both safety and efficacy.
Solution Approach 2:
Instead of blocking the ligand (CD47) that is overexpressed on tumors, the patent inverts the approach by targeting the receptor (SIRPα) on immune cells. This inversion allows the therapy to act on the immune system side of the interaction, enhancing immune cell function without interfering with normal tissue CD47 expression.
3Adaptability or versatility
If polymorphism-resistant anti-SIRPα antibodies are developed, then broader patient coverage is achieved, but development complexity increases
Solution Approach 1:
The patent segments the therapeutic molecule into a bivalent structure with distinct binding domains: one for SIRPα and one for phosphatase. This segmentation allows each domain to be optimized independently, simplifying the development process while maintaining broad applicability across different patient populations with varying SIRPα polymorphisms.
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 approach effectively enhances macrophage phagocytosis and promotes dendritic cell maturation, potentially improving anti-cancer immunity and immune responses by directly modulating SIRPα signaling.
Implementation Method 1
The binding of a first polypeptide module and/or a first antibody binding module to a signal regulatory protein α (SIRPα) molecule induces dephosphorylation of an intracellular domain of the SIRPα molecule
Data Source
AI summary
The present disclosure relates generally to compositions and methods for modulating cell surface receptor signaling by specifically recruiting membrane phosphatases, in cis, to a spatial proximity of a signal regulatory protein α (SIRPα) molecule. More particularly, the disclosure provides novel multivalent protein-binding molecules that specifically bind SIRPα and antagonize the SIRPα-mediated signaling through recruitment of a phosphatase activity to dephosphorylate the intracellular domain of SIRPα. Also provided are compositions and methods useful for producing such molecules, methods for promoting maturation dendritic cells and for production of vaccine, as well as methods for the prevention and/or treatment of health conditions associated with the inhibition of signal transduction mediated by SIRPα and/or CD47.