Bridging Molecule Cell Therapy for Solid Tumor Targeting
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Solution Overview
Problem
Existing CAR T cell therapies face challenges in effectively targeting solid tumors due to insufficient activation, expansion, and persistence of CAR T cells, immunosuppressive tumor microenvironments, antigen-negative escape variants, and on-target, off-tumor toxicities, along with side effects like cytokine release syndrome and CAR T cell-related encephalopathy syndrome.
Innovation Solution
A two-component therapeutic approach involving immune cells expressing a receptor with an antigen-recognition domain and a signaling domain, combined with a bridging molecule that targets dysfunctional P2X7 receptors on tumor cells, allowing for multi-pronged targeting of cancer cells through multiple antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If mono-specific CAR T cells are used to target a single antigen, then the therapy is simpler to manufacture and administer, but it leads to antigen-negative escape variants and on-target off-tumor toxicities
Solution Approach 1:
The patent implements multi-specific CAR T cells that can recognize and bind to multiple different tumor antigens simultaneously. This multi-functionality allows the immune cells to target various cancer cells expressing different antigens, preventing escape variants while maintaining manageable manufacturing processes through standardized multi-antigen vector designs
2Adaptability or versatility
If CAR T cells are used to target solid tumors, then the therapeutic scope is expanded, but activation, expansion and persistence of CAR T cells is insufficient
Solution Approach 1:
The patent introduces bridging molecules that act as intermediaries between the CAR T cells and solid tumor cells. These bridging molecules bind to antigens on solid tumor cells that are not easily accessible to CAR T cells, facilitating effective recognition and killing while enhancing CAR T cell activation, expansion and persistence in the solid tumor microenvironment
3Measurement precision
If CAR T cells target antigens with low expression in healthy tissues, then tumor targeting is achieved, but severe on-target off-tumor toxicities occur
Solution Approach 1:
The patent employs multi-specific CAR T cells that target multiple antigens simultaneously, requiring the presence of multiple antigens on tumor cells for effective killing. This partial action approach reduces off-tumor toxicity because healthy tissues typically do not express multiple tumor-associated antigens simultaneously, even if they express individual antigens at low levels
Data Source
AI summary
The present invention relates to therapeutics, compositions, kits and methods of treatment comprising:(a) an immune cell or progenitor thereof, expressing a receptor comprising an antigen-recognition domain and a signalling domain, wherein the antigen-recognition domain binds to a tumour-specific antigen, preferably a dysfunctional P2X7 receptor, expressed on a cell surface; and(b) a bridging molecule comprising:(i) a targeting moiety that binds to a cell surface molecule on a target cell; and(ii) a tumour-specific epitope moiety, preferably a dysfunctional P2X7 receptor epitope moiety, that is bound by the antigen recognition domain.