Soluble MIC Proteins for Targeted NK Cell Activation
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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, as they are not recognized by NK cells and certain T-cells due to lack of MIC protein expression on their surface.
Innovation Solution
Development of non-natural, monomeric, soluble MHC class I chain-related (MIC) molecules with a modified α3 domain containing heterologous peptides that bind target molecules on malignant or virus-infected cells, allowing the α1-α2 platform domain to recruit and activate NK cells and T-cells for targeted attack.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If malignant cells avoid expression of MIC proteins, then they escape immune detection and exhibit aggressive behavior, but they lose the ability to interact with the innate immune system through natural MIC-NKG2D recognition
Solution Approach 1:
The patent uses engineered MIC molecules as intermediaries that bridge the gap between malignant cells lacking natural MIC expression and NK cells requiring MIC recognition. These soluble MIC molecules contain heterologous peptides that bind to target cell molecules while presenting the α1-α2 platform domain to NKG2D receptors on NK cells, thereby mediating immune recognition of previously invisible target cells
Solution Approach 2:
The invention modifies the MIC protein structure by changing its parameters: converting from transmembrane to soluble form, altering the α3 domain to contain heterologous peptide sequences, and removing polymorphism to create a universal binder. These parameter changes enable the molecule to simultaneously bind target cells via heterologous peptides and activate NK cells via the conserved α1-α2 platform domain
2Reliability
If natural MIC proteins are used for immune recognition, then NK cells can be activated, but the polymorphic nature of natural MICA and MICB limits broad target recognition
Solution Approach 1:
The engineered MIC molecules achieve universality by replacing the polymorphic α3 domain with heterologous peptide sequences that can bind multiple different target molecules. The conserved α1-α2 platform domain maintains universal recognition by NKG2D receptors, while the customizable α3 domain provides versatility in targeting different malignant or virus-infected cells through heterologous peptide selection
Solution Approach 2:
The invention changes the polymorphism parameter to uniformity by using identical or homologous α1-α2 platform domains across all engineered MIC molecules, ensuring consistent NKG2D binding. Simultaneously, it introduces variability in the heterologous peptide sequences within the α3 domain to enable recognition of diverse target cells, thus resolving the contradiction between reliability and adaptability
3Measurement precision
If soluble MIC molecules are engineered with heterologous peptides in the α3 domain, then target cell specificity is enhanced, but molecular complexity increases
Solution Approach 1:
The engineered MIC molecule is segmented into distinct functional domains: the α1-α2 platform domain for NKG2D binding, the α3 domain for target cell recognition via heterologous peptides, and a signal peptide for secretion. This segmentation allows independent optimization of each domain's function while maintaining overall molecular integrity and simplifying the design process
Solution Approach 2:
The invention applies local quality by concentrating the complexity only where needed: the heterologous peptide sequences are inserted specifically within the α3 domain's solvent-exposed loops (positions 190-199 or 250-258), while the α1-α2 platform domain remains simple and conserved. This localized complexity enhancement achieves target specificity without unnecessarily complicating the entire molecule
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
The modified MIC molecules effectively direct NK cells and T-cells to bind and destroy target cells by presenting the α1-α2 platform domain to NKG2D-bearing immune cells, enhancing immune recognition and attack on previously immune-evasive cells.
Implementation Method 1
The human NKG2D molecule possesses a C-type lectin-like extracellular domain that binds to its cognate ligands, the 84% sequence identical or homologous, monomeric MICA and MICB
Implementation Method 2
the heterologous peptides direct the binding of the targeting motif to a target molecule on a target cell
Data Source
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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 a1-a2 platform domain, to the intended target cell specifically. The a1-a2 domain is contiguous with a heterologous a3 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 a3 domain can include a portion of an antibody, another protein molecule or portion thereof, a peptide, or a non-natural, modified a3 domain of a MIC protein.