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+ | <h class="highlight-title dark-blue">SwordS enables antigen density dependent </br>tri-response for therapeutic applications</br></h> | ||
+ | <p></br>SwordS consists of two main modules, SynNotch and Stripe, and one supportive module, SynTF-SynPro<font color="#004a84">(Figure 3)</font>. </br></br> | ||
+ | </p> | ||
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+ | <img width="800" src="https://static.igem.org/mediawiki/2017/5/59/Figure3.jpg"> | ||
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+ | <div class="block main-text main-text"> | ||
+ | <h class="highlight-title dark-blue">Module 1: SynNotch</br></h> | ||
+ | <h class="bold-text">SynNotch,an engineered transmembrane receptor, bridges intra and extracellularinformation.</h> | ||
+ | <p></br>Synthetic Notch (SynNotch)<sup>(17)</sup>consists of three parts, the synthetic extracellular recognition domain (SynECD, e.g.scFv), the core transmembrane domain of wild Notch receptor<sup>(18)</sup>, and the synthetic intracellular transcriptional domain (SynICD, e.g.SynTF). When the SynECD binds to itstargeting surface antigen, induced cleavagestake place on the core transmembrane domain of SynNotch, releasing the SynICD. The SynICDwould be transported into nucleus and activate the transcription of its corresponding promoter <font color="#004a84">(Figure 4)</font>. </br> | ||
+ | </p> | ||
+ | <h class="bold-text">SynNotch is an ideal platform for customized antigen sensing behavior. </h> | ||
+ | <p> | ||
+ | SynNotch provides us an exciting platform for sensing and treating tumorbecause its SynECD and SynICD are both customizable. SynECDcan be designed based on current available scFvs for different tumors such as α-GPC3 for HCC<sup>(11, 19)</sup>,α-Her2 for glioma<sup>(4)</sup>,α-CD19for acute lymphoid leukemia<sup>(20)</sup>, etc.SynICD will trigger customized output after SynECD recognition. | ||
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Revision as of 15:25, 30 October 2017
The expression of the antigen on individual cells within a given tumor is different or heterogeneous. A solid tumor mass consists of numerous tumor cells. In these tumor cells, some may express relatively less tumor antigens, others may express relatively more tumor antigens. Meanwhile, a given tumor antigen is not only expressed on malignant cells, but may also be expressed on normal cells at a low level (Figure 1A). Thus, normal cells expressing low level of tumor antigens subsequently should not be targeted, otherwise would casuse complications. Carefully control the on-target/off-tumor effect is critical for the success of immunotherapy. (Figure 1B)
Carcinogenesis is a gradual progress driven by the accumulation of mutations. Tumor cells are highly heterogeneous in their surface tumor antigen expression(1), thus immune resistance(2), sensitivity to the treatment and so on. Meanwhile, efficient recognition by immunotherapy, as one of the fundamental challenges for solid tumors, is still in the way comparing with exciting results shown in treating hematological cancers(3).Currently, most existing immunotherapies exhaust in trying multiple methods to improve recognition(4-6), without considerating tumor heterogeneity. They focus narrowly on finding an ideal tumor antigen as the target and hope to generate a effective therapeutic response – monotonic response.We believe these conventional one-size-fits-all immunotherapies cannot adapt itself to all complex disease occasions in various types of tumors.(Figure 1B)
Tumor in different states need different treatments. To develop rational combined therapy, the key question is how to accurately manifest tumors’ condition. Fortunately, with improved understanding of oncogenesis and emerging therapies, clinical trials of rational combined therapy have become possible(14,15). Through investigation, we found that antigen density heterogeneity, tumor antigen level and expression pattern are associated with disease progression(16).Thus, Antigen density heterogeneity could be used to develop rational combined immunotherapy.
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SwordS consists of two main modules, SynNotch and Stripe, and one supportive module, SynTF-SynPro(Figure 3).
Synthetic Notch (SynNotch)(17)consists of three parts, the synthetic extracellular recognition domain (SynECD, e.g.scFv), the core transmembrane domain of wild Notch receptor(18), and the synthetic intracellular transcriptional domain (SynICD, e.g.SynTF). When the SynECD binds to itstargeting surface antigen, induced cleavagestake place on the core transmembrane domain of SynNotch, releasing the SynICD. The SynICDwould be transported into nucleus and activate the transcription of its corresponding promoter (Figure 4).
SynNotch provides us an exciting platform for sensing and treating tumorbecause its SynECD and SynICD are both customizable. SynECDcan be designed based on current available scFvs for different tumors such as α-GPC3 for HCC(11, 19),α-Her2 for glioma(4),α-CD19for acute lymphoid leukemia(20), etc.SynICD will trigger customized output after SynECD recognition.