Multi-Antigen CAR Composition for Lower-Toxicity Cancer Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current CAR therapies face challenges such as cytokine release syndrome (CRS), neurologic complications, tonic antigen-independent signaling leading to unrestrained cellular activation, immunogenicity of murine monoclonal antibodies, and limited efficacy due to targeting a single antigen or epitope, which can result in antigen loss and toxicity to normal tissues.
Innovation Solution
Development of genetically engineered effector cells, such as T cells and NK cells, equipped with chimeric antigen receptors (CARs) that include polynucleotides encoding antigen-specific domains, extracellular hinge regions, transmembrane domains, costimulatory domains, and intracellular signaling domains, targeting multiple antigens and epitopes, and utilizing human or humanized antibodies to enhance persistence and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If CARs target a single antigen or epitope, then the CAR-T cells can be rapidly generated and act as living drugs, but antigen loss and toxicity to normal tissues occur
Solution Approach 1:
The patent divides the targeting function into multiple segments by engineering CAR-T cells to recognize multiple different antigens (e.g., CD19, CD20, CD22, CD79b) simultaneously. This segmentation approach ensures that even if one antigen is lost or downregulated, the CAR-T cells can still target and eliminate tumor cells through alternative antigens, thereby reducing antigen loss resistance and toxicity to normal tissues.
Solution Approach 2:
The patent creates multi-functional CAR-T cells that can recognize and respond to multiple different tumor-associated antigens. By incorporating multiple antigen recognition specificities into a single CAR-T cell product, the system achieves universal targeting capability across different antigen backgrounds, preventing tumor escape mechanisms while maintaining selective toxicity against malignant cells.
2Adaptability or versatility
If CARs engage HLA-independent antigens, then CARs can recognize antigen on any HLA background, but the ability to target tumor cells with down-regulated HLA expression is limited
Solution Approach 1:
The patent employs a dynamic dual-pathway recognition system where CAR-T cells can switch between HLA-independent antigen recognition and HLA-dependent TCR recognition. This dynamic adaptability allows the immune system to respond effectively regardless of the tumor's HLA expression status, maintaining reliable tumor cell recognition through flexible mechanism selection.
Solution Approach 2:
The patent introduces TCRs as intermediary recognition elements that work in conjunction with CARs. While CARs provide HLA-independent antigen binding, TCRs serve as intermediaries that can recognize HLA-presented peptides, creating a bridging mechanism that enhances overall tumor cell recognition reliability across diverse HLA backgrounds.
3Duration of action of stationary object
If CARs incorporate costimulatory domains to enhance signaling strength, then T-cell expansion and persistence are improved, but cytokine release syndrome and neurologic complications occur
Solution Approach 1:
The patent modifies the signaling parameters of CARs by incorporating specific costimulatory domains (such as CD28 or 4-1BB) with optimized signaling characteristics. By carefully selecting and tuning the costimulatory signals, the patent achieves enhanced T-cell persistence and expansion while controlling the intensity and duration of cytokine release to prevent CRS and neurologic complications.
Solution Approach 2:
The patent employs periodic or controlled activation patterns where CAR-T cells are activated in a regulated manner rather than continuously. This periodic action allows for controlled cytokine release that maintains therapeutic efficacy while preventing excessive and sustained inflammatory responses that lead to CRS and neurologic toxicity.
4Productivity
If CARs are constructed with scFv-based antigen binding domains, then rapid tumor targeting is achieved, but the range of potential targets is limited compared to TCRs
Solution Approach 1:
The patent merges the advantages of both CAR and TCR systems by constructing hybrid receptors that combine scFv-based antigen binding domains with TCR chains. This merging approach enables the resulting CAR-T cells to achieve both rapid tumor targeting (from scFv) and expanded target range (from TCR's ability to recognize processed peptides), effectively combining the strengths of both recognition mechanisms.
Data Source
Figure 1
Figure 2A
Figure 2B~2D
AI summary
Provided herein is a composition comprising, a cell, comprising nucleic acids encoding a chimeric antigen receptor (CAR) and one or more of signaling proteins selected from K13-vFLIP, MC159-vFLIP, cFLIP-L, cFLIP-p22, HTLV1-Tax and HTLV2-Tax, wherein the CAR comprises an a) extracellular antigen specific domain, b) a transmembrane domain and c) an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM); wherein c) is located at the C-terminus of the chimeric receptor. In some embodiments, the CAR further comprises one or more co-stimulatory domains. Also provided herein are methods for treating diseases using the compositions described herein. Further provided herein is a kinase inhibitor for use in therapeutic methods described herein.