Soluble Non-Natural MIC Proteins for NK Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Malignant cells and virus-infected cells often evade the innate immune system by avoiding expression of MIC proteins, leading to aggressive behavior and immune evasion.
Innovation Solution
Development of soluble, monomeric, non-natural MIC molecules with a modified α3 domain containing heterologous peptides that bind target molecules on malignant or virus-infected cells, recruiting NK cells and T-cells for attack by delivering the NKG2D-binding α1-α2 platform domain to these cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural MIC proteins are expressed on malignant cells, then NK cell recognition and activation occurs, but malignant cells evade immune detection by avoiding MIC protein expression
Solution Approach 1:
The patent uses a soluble MIC protein as an intermediary that bridges the gap between NK cells and malignant cells. The soluble MIC protein contains an NKG2D-binding domain that activates NK cells and a targeting domain that binds to specific antigens on malignant cells, thereby mediating NK cell recruitment and activation against targets that would otherwise evade immune detection
Solution Approach 2:
The invention creates a soluble copy of the MIC protein that lacks the transmembrane domain, allowing it to circulate freely rather than being restricted to cell surface expression. This soluble copy replicates the antigen-binding and NK cell recruitment functions of natural MIC proteins while enabling targeted delivery to malignant cells through heterologous peptide incorporation
2Measurement precision
If soluble MIC proteins are engineered with heterologous peptides for targeted binding, then specificity to malignant cells increases, but molecular complexity of the protein structure increases
Solution Approach 1:
The soluble MIC protein is segmented into distinct functional domains: an NKG2D-binding domain (α1-α2 platform) that activates NK cells, a linking region that connects domains, and a targeting domain (α3 with heterologous peptides) that binds malignant cell antigens. This segmentation allows each domain to perform its specific function while maintaining overall protein functionality
Solution Approach 2:
The soluble MIC protein serves multiple functions simultaneously: it acts as an NK cell activator through the NKG2D-binding domain, a targeting molecule through the heterologous peptide-containing domain, and a bridge connecting immune cells to malignant targets. This multi-functionality reduces the need for separate molecules for each function
Data Source
AI summary
This invention describes soluble, monovalent, non-natural protein molecules that can activate NK cells and certain T-cells to attack specific cellular target cells by attaching the NKG2D-binding portions of monovalent MICA or MICB protein, i.e. their α1-α2 platform domain, to the intended target cell specifically. The α1-α2 domain is contiguous with a heterologous α3 domain that has been genetically modified to bind directly or indirectly to the extracellular aspect of the target cell, thereby serving as the targeting domain. The genetic modification to create a non-natural and non-terminal targeting motif within the α3 domain can include a portion of an antibody, another protein molecule or portion thereof, a peptide, or a non-natural, modified α3 domain of a MIC protein.