Recombinant Exosomes Block CD47-SIRPα Interaction
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Solution Overview
Problem
Current anticancer agents targeting the CD47-SIRPα interaction are limited in their ability to stimulate phagocytosis and inhibit tumor growth effectively, as they often require high doses and may not be suitable for chemotherapy due to unsuitable binding affinity and immune evasion mechanisms employed by cancer cells.
Innovation Solution
Development of recombinant exosomes with SIRPα proteins clustered in lipid rafts on their surface, which have high binding activity to CD47 on cancer cells, enhancing phagocytic activity of macrophages and dendritic cells and stimulating an anti-cancer immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type SIRPα proteins or recombinant SIRPα proteins are used to block CD47-SIRPα interaction, then the interaction is blocked, but the binding affinity is weak and phagocytosis stimulation is insufficient
Solution Approach 1:
The patent modifies the SIRPα protein by introducing point mutations (e.g., L107P, L110P, L113P substitutions) to change its binding parameters and achieve high affinity for CD47. These parameter changes in the protein structure enable both strong binding affinity and effective phagocytosis stimulation, resolving the contradiction between weak binding and insufficient phagocytosis activation.
Solution Approach 2:
The patent creates composite structures by fusing SIRPα with Fc regions (SIRPα-Fc) or incorporating it into exosome membranes. This composite approach combines the CD47-binding capability of SIRPα with the immune-activating properties of Fc or exosome-associated molecules, achieving both high binding affinity and strong phagocytosis stimulation.
2Productivity
If high doses of anti-CD47 agents are administered to achieve therapeutic effect, then tumor growth inhibition is improved, but the treatment becomes unsuitable for chemotherapy due to toxicity and side effects
Solution Approach 1:
By engineering high-affinity SIRPα mutants, the patent achieves potent tumor growth inhibition at low doses. The enhanced binding affinity parameter allows the therapeutic agent to be effective at concentrations that avoid the toxicity and side effects associated with high-dose treatments, making it suitable for chemotherapy protocols.
Solution Approach 2:
The patent uses exosomes as intermediary carriers to deliver SIRPα to the tumor microenvironment. This intermediary approach allows for targeted delivery, reducing systemic exposure and toxicity while maintaining effective local concentrations for tumor growth inhibition.
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 recombinant exosomes effectively block the CD47-SIRPα interaction with a small amount, increasing phagocytosis of cancer cells and demonstrating significant antitumor effects in both immunodeficient and immunocompetent mouse models, thereby offering a novel approach for chemotherapy.
Implementation Method 1
increases the phagocytosis of cancer cells
Data Source
AI summary
The present invention provides a recombinant exosome and uses thereof. More particularly, the present invention provides a recombinant exosome wherein a phagocytosis promoting protein is presented on the surface of the exosome.