CAR T Cell Polyprotein for Localized Tumor Microenvironment Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current CAR T cell therapies face challenges in effectively targeting tumor-associated antigens and Treg-associated antigens within the tumor microenvironment, leading to systemic toxicity and limited efficacy in treating cancers like glioblastoma.
Innovation Solution
Development of chimeric antigen receptor (CAR) T cells that express a polyprotein encoding both a CAR and a therapeutic agent, which are cleaved to generate separate molecules, allowing for targeted delivery of a bispecific T cell engager to both tumor-associated and Treg-associated antigens, reducing systemic toxicity by localizing treatment to the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to target tumor-associated antigens, then therapeutic efficacy is improved, but systemic toxicity increases
Solution Approach 1:
The patent applies local quality by designing CAR T cells that selectively concentrate therapeutic activity at the tumor microenvironment through localized expression of the bispecific T cell engager. The CAR T cells are engineered to express the bispecific molecule only when activated by tumor-associated antigens, creating a localized therapeutic effect at the tumor site while minimizing systemic exposure and toxicity to healthy tissues.
Solution Approach 2:
The patent uses the bisspecific T cell engager as an intermediary molecule that mediates between the CAR T cell and both tumor-associated antigens and Treg-associated antigens. This intermediary enables the CAR T cell to simultaneously engage tumor cells and regulatory T cells, enhancing therapeutic efficacy while the localized expression strategy controls systemic toxicity.
2Reliability
If CAR T cells target both tumor-associated antigens and Treg-associated antigens, then treatment specificity is improved, but device complexity increases
Solution Approach 1:
The patent merges the CAR and the bisspecific T cell engager into a single polyprotein structure encoded by one nucleic acid molecule. This combining approach allows simultaneous expression of both functional components from a single genetic construct, simplifying the delivery mechanism while enabling the CAR T cell to target both tumor-associated antigens and Treg-associated antigens through the bispecific molecule.
Solution Approach 2:
The patent applies segmentation by including a cleavable moiety within the polyprotein structure that separates the CAR and the bisspecific T cell engager into distinct functional molecules after translation. This segmentation allows the two components to function independently while being co-expressed from a single nucleic acid molecule, achieving treatment specificity for multiple antigens without the complexity of separate delivery systems.
3Manufacturing precision
If a polyprotein encoding both CAR and therapeutic agent is used, then manufacturing precision is improved, but device complexity increases
Solution Approach 1:
The patent merges the coding sequences for the CAR and the therapeutic agent (bisspecific T cell engager) into a single nucleic acid molecule that encodes a polyprotein. This merging ensures that both proteins are co-expressed from a single genetic construct, improving manufacturing precision by eliminating variability associated with separate delivery systems, while the polyprotein structure represents the complexity trade-off.
Solution Approach 2:
The patent incorporates a cleavable moiety as a segmented element within the polyprotein sequence, allowing the single polyprotein to be processed into multiple functional proteins. This segmentation strategy enables precise co-expression control from one nucleic acid molecule while the cleavable linker adds a controlled complexity element that facilitates proper protein function and localization.
Data Source
Figure 1~2B
Figure 3A~4B
Figure 5A~5D
AI summary
The invention provides methods and compositions for use in treating cancer, which advantageously may be achieved by targeting of the tumor microenvironment.