Multivalent CD47 Amphiphilic Compositions for Macrophage Immunotherapy
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Solution Overview
Problem
Tumor-associated macrophages (TAMs) in solid tumors exist in a pro-tumorigenic M2 phenotype, supporting tumor growth and metastasis due to immunosuppressive cytokines and the CD47-SIRPα interaction, which hinders macrophage phagocytosis of cancer cells.
Innovation Solution
Development of engineered amphiphilic compositions comprising multivalent CD47 proteins and amphiphiles, which bind to SIRPα to activate macrophages and enhance phagocytosis, combined with anti-PDL1 antibodies to stimulate T cell-cancer cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD47-SIRPα interaction is blocked to enhance macrophage phagocytosis, then anti-tumor immunity is improved, but tumor growth suppression is limited due to M2 phenotype persistence
Solution Approach 1:
The patent segments the macrophage activation process into two distinct functional components: (1) CD47 multivalent binding to block the 'don't eat me' signal and enable phagocytosis, and (2) M2-to-M1 phenotype conversion to eliminate pro-tumorigenic functions. This segmentation allows each component to be optimized independently while working synergistically.
Solution Approach 2:
The patent merges two therapeutic mechanisms into a single amphiphilic composition: multivalent CD47 binding capability and M2-to-M1 phenotype conversion activity. The engineered composition simultaneously delivers both functions through its dual-targeting design, achieving synergistic anti-tumor effects that neither mechanism could achieve alone.
2Object-generated harmful factors
If M2-to-M1 phenotype conversion is achieved to reduce pro-tumorigenic support, then tumor growth is inhibited, but macrophage phagocytic activity may be insufficient without CD47 blocking
Solution Approach 1:
The patent applies preliminary action by first blocking the CD47-SIRPα interaction to remove the inhibitory 'don't eat me' signal before macrophages can effectively phagocytose tumor cells. This preliminary blocking action prepares the macrophages for enhanced phagocytic activity that follows M2-to-M1 conversion, ensuring that phagocytic capacity is not limited by CD47 signaling.
Solution Approach 2:
The amphiphilic composition acts as an intermediary that mediates both CD47 binding and M2-to-M1 conversion simultaneously. The multivalent CD47 on the composition surface serves as an intermediary that bridges macrophage activation and phenotype conversion, coordinating both functions through a single therapeutic agent.
3Device complexity
If single-function macrophage activators are used to simplify treatment, then device complexity is reduced, but therapeutic efficacy is limited due to inability to address both phagocytosis and phenotype conversion
Solution Approach 1:
The patent implements universality by designing an amphiphilic composition that performs multiple therapeutic functions simultaneously: multivalent CD47 binding to block inhibitory signals, M2-to-M1 phenotype conversion to eliminate pro-tumorigenic support, and enhancement of macrophage phagocytosis. This multi-functional design consolidates what would traditionally require multiple separate agents into a single universal therapeutic platform.
Solution Approach 2:
The patent uses composite material principles by combining amphiphilic molecules with multivalent CD47 proteins into a single integrated composition. The amphiphilic structure provides both the scaffold for multivalent CD47 display and the mechanism for M2-to-M1 conversion, creating a composite therapeutic material that leverages the synergistic properties of its components.
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 engineered compositions convert TAMs from M2 to M1 phenotype, enhancing macrophage phagocytosis and inducing a synergistic anti-tumor response, effectively inhibiting tumor growth.
Implementation Method 1
the engineered amphiphilic composition comprises multiple CD47 proteins (mCD47/multivalent) and at least one amphiphile, wherein the engineered amphiphilic composition binds SIRP-alpha protein
Implementation Method 2
The engineered compositions convert TAMs from M2 to M1 phenotype, enhancing macrophage phagocytosis
Implementation Method 3
enhancing the phagocytic function of macrophages comprising contacting, in vitro or in vivo, said macrophages by contacting a cancer cell with the engineered amphiphilic composition
Data Source
AI summary
The present disclosure provides an engineered amphiphilic composition (for example, a lipid nanoparticle) comprising multiple CD47 proteins and at least one amphiphile. The disclosure further provides methods for enhancing the phagocytic function of macrophages by contacting the macrophages with macrophages with the engineered amphiphilic composition. The disclosure further provides methods for treating cancer by administering the engineered amphiphilic composition to a patient in need thereof.