Primary NK CAR Constructs for PDL1 Tumor Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
NK cells face limitations in reaching tumor tissues, altered receptor-ligand interactions, and a suppressive tumor microenvironment, hindering their effectiveness in treating solid tumors and cancers.
Innovation Solution
Development of recombinant nucleic acids and modified NK cells with chimeric antigen receptors (CARs) targeting tumor antigens like PDL1, using RNA constructs with T7 promoter, 5′-UTR, signal peptide, single chain antibody fragments, hinge and transmembrane domains, and intracellular signaling sequences for enhanced cytotoxic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NK cells are used as therapeutic entities isolated from peripheral blood and expanded in cell culture, then moderate effectiveness is achieved in ex vivo therapy and in vivo treatment, but poor ability to reach tumor tissues limits their application as therapies for solid tumors
Solution Approach 1:
The patent modifies NK cells by introducing chimeric antigen receptors (CARs) with altered binding parameters to tumor antigens like PDL1. This changes the recognition parameters of NK cells, enabling them to effectively target and reach tumor tissues that were previously inaccessible, thereby resolving the contradiction between therapeutic effectiveness and ability to reach tumor tissues
Solution Approach 2:
The patent uses chimeric antigen receptors as intermediaries that bridge NK cells and tumor antigens. The CAR structure includes an antibody variable region that specifically binds to tumor antigens, serving as a mediator that directs NK cells to tumor tissues, thus overcoming the limitation of poor tissue penetration while maintaining therapeutic effectiveness
2Ease of operation
If NK cells rely on natural receptor-ligand interactions, then non-specific killing of targeted cells occurs without prior immune sensitization, but changes in NK cell-activating receptors and their ligands in tumors lead to decreased therapeutic response and tumor progression
Solution Approach 1:
The patent creates dynamic chimeric antigen receptors that can adapt to changing tumor conditions. The CAR design allows NK cells to dynamically respond to tumor antigens even as natural receptor-ligand interactions change during tumor progression, maintaining reliable therapeutic response while preserving the ease of operation through engineered specificity
Solution Approach 2:
The patent fundamentally changes the binding parameters of NK cells by replacing natural receptors with engineered chimeric antigen receptors. These CARs have optimized binding affinity and specificity for tumor antigens like PDL1, ensuring reliable therapeutic response that is not affected by changes in natural ligand expression during tumor progression
3Productivity
If NK cells are transferred adoptively into subjects, then treatment of cancer is attempted, but the tumor microenvironment remains a major barrier through suppressive immune cells and immunosuppressive cytokines
Solution Approach 1:
The patent applies preliminary anti-action by engineering NK cells with chimeric antigen receptors that are pre-configured to resist suppression from the tumor microenvironment. The CAR design includes co-stimulatory domains that provide inherent resistance to immunosuppressive signals, allowing NK cells to maintain productivity despite the presence of suppressive immune cells and cytokines in the tumor microenvironment
Data Source
AI summary
Disclosed herein are recombinant nucleic acids, comprising a 5′ untranslated (5′-UTR) sequence portion, a signal peptide sequence portion, a single chain antibody fragment sequence portion, a hinge region sequence portion, a transmembrane domain sequence portion, and one or more intracellular domain sequence portions. Also disclosed herein are modified natural killer (NK) cells comprising the recombinant nucleic acid described above. Further disclosed herein are methods of treating a tumor in a subject by administering the modified NK cells.