Soluble pMHC Multimers for Selective TCR Blockade in Multiple Sclerosis
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Solution Overview
Problem
Current treatments for multiple sclerosis (MS) do not effectively prevent or inhibit the adaptive immune response associated with the disease, leading to ongoing inflammation and tissue damage in the central nervous system.
Innovation Solution
The use of soluble peptide-major histocompatibility complex (pMHC) or multimers thereof, which compete with endogenous complexes for binding to MS-associated T-cell receptors (TCRs), along with agents that target and deplete T cells expressing these MS-associated TCRs, or induce tolerance to the antigens recognized by these TCRs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current immunomodulatory therapies are used for multiple sclerosis, then general immune suppression is achieved, but specific adaptive immune response associated with MS is not effectively prevented
Solution Approach 1:
The patent uses soluble peptide-MHC complexes as intermediaries that specifically bind to and block MS-associated TCRs, preventing pathogenic T cell activation without broadly suppressing the immune system. This intermediary approach allows selective intervention in the disease pathway while preserving normal immune function.
Solution Approach 2:
The invention extracts and targets the specific pathogenic component (MS-associated TCRs) from the broader immune system. By identifying and isolating the specific T cell receptors involved in MS pathology, the therapy can selectively remove or block only the harmful adaptive immune responses while leaving other immune functions intact.
2Object-generated harmful factors
If broad immunosuppression is applied, then general immune activity is reduced, but specific MS-associated adaptive immune response remains active
Solution Approach 1:
The therapy applies local quality by targeting specific MS-associated TCRs with high specificity rather than applying uniform immunosuppression across all immune cells. The soluble peptide-MHC complexes are designed to match specific antigen-MHC-TCR interactions involved in MS, creating a localized therapeutic effect at the molecular recognition level.
Solution Approach 2:
Soluble peptide-MHC complexes serve as intermediaries that specifically bridge the gap between the antigen and the pathogenic TCRs. These intermediaries allow selective blocking of MS-associated immune responses by mimicking the natural antigen presentation process but in a controlled, therapeutic manner that prevents pathogenic activation.
3Device complexity
If non-specific immunomodulatory agents are used, then treatment complexity is reduced, but measurement precision of immune response targeting is insufficient
Solution Approach 1:
The invention changes the parameter of specificity by designing soluble peptide-MHC complexes with precise amino acid sequences that match specific MS-associated antigen-TCR interactions. This parameter change enables highly specific targeting of pathogenic T cells while maintaining a relatively simple therapeutic approach using recombinant protein technology.
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 effectively prevents or inhibits the MS-associated adaptive immune response, reducing inflammation and potentially halting disease progression by targeting specific T cells involved in the autoimmune response.
Implementation Method 1
soluble peptide-major histocompatibility complex (pMHC) or multimers thereof, which compete with endogenous complexes for binding to MS-associated T-cell receptors (TCRs)
Data Source
AI summary
Provided are agents and methods for preventing or inhibiting a multiple sclerosis (MS)-associated adaptive immune response in a subject in need thereof. In some instances, the agents comprise or consist of a soluble peptide-major histocompatibility complex (pMHC) or multimer(s) thereof. The peptide of the pMHC is one identified as being targeted by MS-associated T-cell receptors (TCRs). The agents may be used alone or may be conjugated or fused to one or more moieties that result in the targeted depletion of T cells expressing the MS-associated TCRs. Other agents such as the MS-associated TCRs or binding domains thereof, and inhibitory immune cells expressing such TCRs are also provided. Aspects of the present disclosure further include methods of treating multiple sclerosis in a subject in need thereof via administration of an agent of the present disclosure.