MHC Oligomers With Rigid Linking Segments
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Solution Overview
Problem
Existing MHC multimers face challenges in achieving high avidity for T cell receptors due to low affinity and incomplete oligomerization, leading to decreased specificity and increased background binding, with existing methods like biotin-streptavidin systems being inefficient and difficult to control.
Innovation Solution
The development of MHC oligomers with a rigid and extended linking segment connected to a core structure, allowing for controlled oligomerization of MHC peptide complexes, which enhances the binding capability and specificity to T cell receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MHC multimers are formed using conventional methods (biotin-streptavidin or chemical crosslinking), then multimerization is achieved, but the binding affinity and specificity to T cell receptors deteriorates due to incomplete oligomerization and uncontrolled valency
Solution Approach 1:
The MHC multimer is segmented into discrete monomeric units, each comprising an MHC molecule bound to a specific peptide. This segmentation allows independent optimization of each monomer's binding properties while maintaining overall multimeric structure, resolving the contradiction between achieving multimerization and maintaining precise control over oligomerization.
Solution Approach 2:
The patent applies preliminary action by pre-assembling monomeric MHC-peptide complexes with defined structures and binding specificities before forming the multimer. This preliminary assembly ensures that each monomer is fully functional and properly folded before oligomerization, thereby maintaining high binding affinity and specificity while achieving controlled multimerization.
2Reliability
If existing MHC multimerization methods are used, then multimeric structure is formed, but the valency and steric conformation are uncontrolled, leading to decreased specificity
Solution Approach 1:
The patent applies local quality by赋予 each monomeric unit within the multimer specific local properties, including defined peptide sequences, MHC alleles, and binding specificities. This allows different regions of the multimer to have specialized functions, thereby achieving high specificity while maintaining manageable complexity through modular design.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying key parameters such as peptide sequence, MHC allele type, and oligomerization valency to optimize the multimer's binding characteristics. This controlled parameter variation enables precise tuning of specificity and affinity while maintaining structural integrity and manageable complexity.
3Quantity of substance
If soluble MHC complexes are incubated with molar excess of peptide, then peptide binding is achieved, but oligomerization is incomplete and multiple peptide sections remain unbound
Solution Approach 1:
The patent applies preliminary action by pre-assembling monomeric MHC-peptide complexes with defined structures and binding specificities before forming the multimer. This preliminary assembly ensures that each monomer is fully functional and properly folded before oligomerization, thereby maintaining high binding affinity and specificity while achieving controlled multimerization.
Solution Approach 2:
The patent uses an intermediary approach by introducing a multivalent platform or crosslinking agent that facilitates controlled oligomerization of pre-formed MHC-peptide monomers. This intermediary mechanism ensures complete and uniform oligomerization without requiring molar excess of peptide, thereby achieving both quantitative peptide binding and complete oligomerization.
Data Source
Figure 1(a)~1(c)
Figure 2
Figure 3~4
AI summary
The present invention relates to an MHC binding polymer suitable for the oligomerisation of individual MHC monomers. The MHC binding polymer comprises a first segment and a second segment, wherein the first segment comprises a peptide capable of binding in a binding groove of an MHC molecule, and wherein the second segment comprises a linking segment and a recognition site for coupling the MHC binding polymer with a specific partner. The linking segment is a polymer with a length of at least 10 Angstrom in its native conformation. Further it relates to an MHC oligomer containing such MHC binding polymers. Individual functional MHC complex monomers are oligomerised via their peptides bound in the peptide binding groove of the complex. Moreover, it relates to a method of making such MHC binding polymer and oligomer and various methods using the same.