Shp2-iSNAP Chimeric Protein Rewires CD47 Signaling for Macrophage Phagocytosis
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Solution Overview
Problem
Current monoclonal antibody (mAb) mediated cancer immunotherapy is compromised by the 'don't eat me' signal CD47 highly expressed on cancer cells, leading to reduced efficacy and potential anemia due to CD47 expression in red blood cells.
Innovation Solution
Development of a Src homology region 2 domain-containing phosphatase-2 (Shp2) and Spleen tyrosine kinase (Syk)-integrated sensing and actuating protein (iSNAP) chimeric protein, which includes a phosphorylatable peptide, a Fluorescent Protein (FP) Förster Resonance Energy Transfer (FRET) pair, a truncated Shp2 domain, and a phosphatase or kinase domain, that rewires the CD47/SIRPα pathway to promote phagocytosis of tumor cells by activating the PTP or kinase domain upon ligand binding, bypassing the anti-phagocytic signal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If anti-CD47 antibody therapy is used to block the 'don't eat me' signal and promote tumor eradication, then macrophage-mediated phagocytosis of cancer cells is enhanced, but anemia occurs due to CD47 expression in red blood cells
Solution Approach 1:
The patent applies local quality by making the macrophage population heterogeneous through dual sorting: CD47-low macrophages are enriched and activated with anti-CD47 antibodies, while CD47-high macrophages are depleted. This creates a functionally differentiated macrophage population where only the appropriate subset (CD47-low) is activated for anti-tumor activity, preventing off-target effects on red blood cells that express CD47.
2Productivity
If monoclonal antibody therapy targets cancer cells, then tumor eradication is achieved, but efficacy is compromised by the CD47 'don't eat me' signal
Solution Approach 1:
The patent applies preliminary action by pre-activating macrophages with anti-CD47 antibodies ex vivo before adoptive transfer into the tumor microenvironment. This pre-activation ensures that macrophages are in a pro-phagocytic state before encountering tumor cells, overcoming the inhibitory CD47 signal and enhancing the reliability of antibody-mediated tumor eradication.
Solution Approach 2:
The patent uses anti-CD47 antibodies as intermediaries that bind to CD47 on cancer cells and simultaneously engage Fcγ receptors on macrophages, bridging the interaction between tumor cells and immune cells. This intermediary mechanism converts the inhibitory CD47 signal into a stimulatory signal that promotes phagocytosis and enhances immunotherapy efficacy.
3Productivity
If CD47 is targeted to promote phagocytosis, then tumor cell elimination is enhanced, but the anti-phagocytic signal pathway is activated which reduces therapy effectiveness
Solution Approach 1:
The patent applies inversion by reversing the conventional understanding of the CD47-SIRPα pathway. Instead of blocking SIRPα to prevent the inhibitory signal, the patent activates macrophages through anti-CD47 antibodies, inverting the signal transduction so that CD47 engagement triggers pro-phagocytic signaling through Fcγ receptor cross-linking rather than anti-phagocytic signaling through SIRPα.
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
Enhances macrophage-mediated phagocytosis of cancer cells by reprogramming the CD47/SIRPα axis, thereby improving the efficacy of cancer immunotherapy while minimizing anemia risks by specifically targeting cancer cells.
Implementation Method 1
a Fluorescent Protein (FP) Förster Resonance Energy Transfer (FRET) (or FP FRET) pair or pair of motifs
Data Source
AI summary
Provided are Shp2- and Spleen tyrosine kinase (Syk)-integrated sensing and actuating protein (iSNAP) (Shp2- and Syk-iSNAP) chimeric proteins comprising: a bi-phosphorylatable peptide, optionally a bisphosphoryl tyrosine-based activation (BTAM) motif; a Fluorescent Protein (FP) Förster Resonance Energy Transfer (FRET) (or FP FRET) pair or pair of motifs; a truncated Shp2 domain comprising an N-Src Homology 2(N-SH2) domain and a C-Src Homology 2(C-SH2) domain; and, a phosphatase (PTP) domain or a kinase domain. Provided are engineered cells and methods for cancer cell or tumor eradication, or for the treatment or amelioration of a cancer, tumor or dysfunctional cell, or for promoting an anti-cancer, anti-tumor or anti-dysfunctional cell inflammatory response, including enhancing macrophage-, monocyte-, microglia-, osteoclast-, Kupffer cell- or dendritic cell-mediated antibody- or monoclonal antibody (mAb)-guided cancer or dysfunctional cell or tumor eradication, amelioration, or treatment.