Modified Peptide Ligands for Autoimmune Disorder Treatment
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Solution Overview
Problem
Current therapies for Multiple Sclerosis (MS) like interferons and glatiramer acetate have limited effectiveness and significant side effects, and there is a need for improved immunotherapeutic approaches that can effectively modulate the immune response to prevent disease progression.
Innovation Solution
Development of altered peptide ligands and conjugates, specifically modified versions of the MBP 83-99 peptide, which are either in linear or cyclic forms and conjugated with mannan, to divert immune responses from a Th1 to a Th2 profile, reducing inflammation and preventing autoimmune damage in MS.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current peptide therapies (interferons and glatiramer acetate) are used for MS treatment, then immune response modulation is achieved, but side effects increase and long-term effectiveness decreases
Solution Approach 1:
The patent modifies the MBP peptide sequence by substituting specific amino acids (e.g., position 91 in the MBP 83-99 epitope) to create altered peptide ligands that maintain immunogenicity while reducing cross-reactivity with native MBP, thereby improving long-term effectiveness and reducing side effects
Solution Approach 2:
The patent conjugates altered peptide ligands to carrier proteins (keyhole limpet hemocyanin, bovine serum albumin, or rat serum albumin) to create composite immunogenic compositions that enhance stability, immunogenicity, and therapeutic effectiveness while reducing adverse reactions
2Reliability
If orally administered antigens are used to suppress autoimmunity, then regulatory T-cell induction is improved, but peptide stability and cost-effectiveness deteriorate
Solution Approach 1:
The patent introduces non-natural amino acid substitutions in the peptide sequence to enhance resistance to proteolytic degradation, thereby improving oral stability while maintaining the ability to induce regulatory T-cells
Solution Approach 2:
The patent forms conjugates with carrier proteins to protect the peptide from degradation in the gastrointestinal tract, enabling stable oral administration and improving cost-effectiveness through enhanced bioavailability
3Reliability
If peptide analogues are designed to cross-react with native MBP for therapeutic effect, then immune suppression is achieved, but off-target effects and harmful factors increase
Solution Approach 1:
The patent introduces subtle local modifications at specific positions (e.g., position 91) in the peptide sequence that preserve binding to the target antigen-presenting cells while eliminating cross-reactivity with native MBP, thereby reducing off-target effects
Solution Approach 2:
The patent creates peptide analogues that copy the essential immunogenic features of native MBP epitopes while introducing modifications to prevent harmful cross-reactivity, achieving selective immune suppression
Data Source
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AI summary
One aspect of the invention relates to a peptide comprising the amino acid sequence of formula (I), ENPVVHFFK91NIVTP96RTP (I) wherein at least one of K91 and P96 is substituted by a natural or unnatural amino acid, wherein said peptide is in linear or cyclic form. Another aspect of the invention relates to a peptide comprising the amino acid sequence of formula (Ia), ENPWHFFK91NrVTP96RTP (Ia), wherein each of K91 and P96 is substituted by a natural or unnatural amino acid. Another aspect of the invention relates to a peptide comprising the amino acid sequence of formula (Ib), ENPVVHFFK91NIVTP96RTP (Ib) wherein at least one of K91 and P96 is substituted by an amino acid selected from R, E, F and Y. Yet another aspect of the invention relates to a peptide comprising the amino acid sequence of formula (II), VHFFK91NrVTP96RTP (II) wherein K91 is substituted by the amino acid A and P96 is substituted by the amino acid A, wherein said peptide is in linear or cyclic form. Further aspects of the invention relate to conjugates of the above described peptides with mannan, pharmaceutical compositions and methods of treating autoimmune disorders.