Chimeric Receptor NK Cell Expansion via 4-1BB Signaling
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Solution Overview
Problem
Current methods for expanding NK cells for therapeutic use are limited by the inability to obtain sufficient pure NK cells and the expansion of T cells, which often results in residual T cells becoming prominent, making it challenging to achieve effective NK cell expansion without T cell expansion.
Innovation Solution
A chimeric receptor containing the signaling domain of 4-1BB is incorporated into NK cells, along with a single chain variable domain of an anti-CD19 monoclonal antibody and the transmembrane and cytoplasmic domains of CD8α and CD3ζ, allowing for specific expansion and activation of NK cells, and a method using a cell line expressing membrane-bound IL-15 and 4-1BB ligand to activate NK cells while avoiding T cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional NK cell expansion methods are used, then NK cell numbers increase, but T cells also expand and become prominent, reducing NK cell purity
Solution Approach 1:
The patent introduces a chimeric receptor as an intermediary element that specifically mediates NK cell activation and expansion. This receptor combines an anti-CD19 single chain variable domain with the signaling domain of 4-1BB, creating a selective activation pathway that does not engage T cells, thereby enabling NK cell expansion while maintaining purity
Solution Approach 2:
The patent changes the activation parameters by using a chimeric receptor that responds to CD19 antigen presentation. This parameter change (from conventional non-specific activation to CD19-specific activation) allows selective NK cell expansion without T cell contamination, as the chimeric receptor signaling pathway is specific to NK cells expressing this engineered receptor
2Productivity
If chimeric receptor is introduced into NK cells, then specific activation and expansion is achieved, but device complexity increases
Solution Approach 1:
The chimeric receptor is constructed by segmenting and combining functional domains from different sources: the antigen-binding domain (anti-CD19 single chain variable domain) is separated from the signaling domain (4-1BB signaling domain), and these segments are joined to create a functional hybrid receptor that confers specific activation capability to NK cells
Solution Approach 2:
The chimeric receptor performs multiple functions within a single molecular structure: it provides antigen recognition (via the anti-CD19 domain), transmembrane signaling (via the 4-1BB signaling domain), and enables both activation and expansion of NK cells. This multi-functionality achieves high productivity without requiring separate components for each function
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the specific and vigorous expansion of NK cells, overcoming HLA-mediated inhibitory signals and allowing cytotoxicity against NK-resistant cells, with enhanced cytotoxic activity and survival advantages for the NK cells, improving their therapeutic potential in treating cancers.
Implementation Method 1
The formation of the complex between the ligand and the extracellular portion of the receptor results in a conformational change in the cytoplasmic portion of the receptor which results in a signal transduced within the cell
Implementation Method 2
The human IL-15 gene was cloned into an expression vector, and the vector was introduced into a myeloid cell line, thereby providing the cell line with the capacity to express IL-15
Implementation Method 3
NK cells are capable of lysing virally-infected or tumor target cells
Data Source
AI summary
The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.