Engineered NK Cell Compositions for Extended In Vivo Persistence
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Solution Overview
Problem
Natural killer (NK) cells have a relatively short lifespan and limited persistence in vivo, posing a challenge for their clinical application in cancer therapy, necessitating approaches for prolonged survival.
Innovation Solution
Engineering NK cells with chimeric polypeptides comprising ligand binding and signaling regions, such as MyD88 polypeptides, CD40 cytoplasmic polypeptides, and co-stimulatory signaling regions, along with IL-15 polypeptides, and optionally chimeric antigen receptors (CARs) or pro-apoptotic polypeptides, to enhance their survival and targeting capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NK cells are used for cancer therapy, then cytotoxicity against cancer cells is achieved, but lifespan and persistence in vivo are limited
Solution Approach 1:
The patent introduces chimeric polypeptides with ligand binding regions and signaling regions that are expressed before the NK cells encounter cancer cells. These pre-prepared signaling components (including MyD88, CD40 cytoplasmic regions, and co-stimulatory signaling regions) enable prolonged survival and persistence in vivo by providing sustained activation signals, thereby resolving the contradiction between immediate cytotoxicity and long-term persistence.
Solution Approach 2:
The patent modifies the biological parameters of NK cells by introducing engineered chimeric polypeptides that alter their signaling pathways. The chimeric polypeptides combine ligand binding regions with various signaling regions (MyD88, CD40, co-stimulatory molecules) to change the activation and survival parameters of NK cells, enabling extended lifespan and persistence while maintaining cancer-targeting capability.
2Duration of action of moving object
If NK cells are engineered with chimeric polypeptides to prolong survival, then persistence in vivo is enhanced, but device complexity increases
Solution Approach 1:
The patent segments the chimeric polypeptide into distinct functional regions: ligand binding regions and signaling regions. The signaling region is further divided into modular components (MyD88 polypeptide, CD40 cytoplasmic polypeptide, co-stimulatory signaling regions). This segmentation allows for systematic design and assembly of different polypeptide variants to achieve prolonged persistence while managing construction complexity through modular architecture.
Solution Approach 2:
The patent creates chimeric polypeptides that perform multiple functions simultaneously: ligand binding, signal transduction, and cell survival promotion. By integrating multiple signaling pathways (MyD88, CD40, co-stimulatory molecules) into a single polypeptide structure, the invention achieves multi-functionality that prolongs persistence without requiring separate components for each function, thereby managing overall system complexity.
Data Source
AI summary
The technology relates generally to the field of immunology and relates in part to compositions and methods for growing and storing modified natural killer cells, including for example, conditional chemical regulation of natural killer cell function. The technology further relates to pharmaceutical compositions and treatment of subjects using modified natural killer cells.