MHC Multimers for Tuberculosis T Cell Detection
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Solution Overview
Problem
The short half-life of peptide-MHC-T cell receptor ternary complexes and weak binding of MHC monomers pose challenges for therapeutic and vaccine applications, making it difficult to label specific T cells and employ MHC-peptide complexes effectively.
Innovation Solution
Development of MHC multimers, which are complexes with increased affinity and half-life, formed by covalently or non-covalently attaching multiple copies of MHC-peptide complexes to a multimerization domain, such as dimers, tetramers, pentamers, and streptamers, to enhance interaction stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If MHC monomers are used for T cell labeling and therapeutic applications, then the structure is simple and easy to manufacture, but the binding affinity and half-life are insufficient
Solution Approach 1:
The patent combines multiple MHC-peptide complexes into multimeric structures (dimers, tetramers, pentamers, streptamers) to enhance binding affinity and stability. This merging of multiple identical units creates a more reliable T cell labeling reagent while maintaining manufacturing feasibility through standardized production protocols.
Solution Approach 2:
The patent creates composite structures by associating multiple MHC-peptide complexes with multimerization domains (such as streptavidin-biotin systems or protein-protein interaction domains). This composite approach enhances the functional properties of the MHC complex while providing a systematic manufacturing pathway.
2Ease of manufacture
If MHC monomers are used for T cell detection, then the manufacturing process is simple, but the half-life of the complex is too short for effective therapeutic application
Solution Approach 1:
By merging multiple MHC-peptide complexes into multimeric structures, the patent extends the functional half-life of the T cell detection reagent. The multimeric configuration increases stability and persistence in biological systems, enabling effective therapeutic applications while maintaining a streamlined manufacturing process.
Solution Approach 2:
The patent creates multiple copies of the MHC-peptide complex within a single multimeric structure. This copying strategy enhances the duration of action by providing redundant binding sites and increasing overall stability, while the modular nature allows for efficient replication during manufacturing.
3Reliability
If multiple copies of MHC-peptide complexes are attached to form multimers, then the binding affinity and half-life are improved, but the device complexity increases
Solution Approach 1:
The patent employs multimerization domains as intermediary structures that facilitate the association of multiple MHC-peptide complexes. These intermediaries (such as streptavidin, coiled-coil domains, or other protein-protein interaction modules) simplify the overall architecture by providing a standardized platform for assembling multiple units, thereby reducing the effective complexity despite the increased number of components.
Solution Approach 2:
The multimerization domains serve multiple functions: they organize multiple MHC-peptide complexes, provide structural stability, enable controlled assembly, and facilitate purification. This multi-functionality reduces the need for additional specialized components, effectively managing complexity while enhancing binding affinity.
4Duration of action of stationary object
If MHC multimers are used for T cell detection and therapy, then the half-life and binding stability are improved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent employs preliminary action by pre-forming MHC-peptide complexes and pre-preparing multimerization domains separately, then combining them in a controlled assembly step. This staged approach allows each component to be optimized independently and simplifies the overall manufacturing process despite the complexity of the final multimeric structure, while ensuring the extended half-life is achieved.
Data Source
AI summary
The present invention relates to MHC-peptide complexes and uses thereof in the diagnosis of, treatment of or vaccination against a disease in an individual. More specifically the invention discloses MHC complexes comprising Mycobacterium tuberculosis antigenic peptides and uses there of.