Protease-Resistant TNFR1 Antagonists for Inflammatory Disease
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Solution Overview
Problem
Current therapeutic peptides and polypeptides used in medical applications are often rapidly degraded by proteases present in physiological states such as inflammatory conditions and cancer, leading to limited efficacy due to accelerated degradation and inactivation.
Innovation Solution
Development of protease-resistant immunoglobulin single variable domains and TNFα receptor type 1 (TNFR1) antagonists that are resistant to proteolytic degradation, maintaining biological activity and functionality by incorporating specific amino acid sequences and structural modifications, such as the DOM1h-131-206 sequence with an aspartic acid at position 53, and forming fusion proteins or conjugating with larger hydrodynamic entities to enhance serum half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic peptides and polypeptides are administered to treat disease, then biological activity is achieved, but they are rapidly degraded and inactivated by proteases
Solution Approach 1:
The patent applies parameter changes by modifying amino acid sequences to create protease-resistant variants. Specific amino acid substitutions are introduced to alter the polypeptide structure in ways that prevent protease recognition and degradation, thereby extending half-life while maintaining biological activity
Solution Approach 2:
The patent creates composite structures by fusing protease-resistant polypeptides with carrier proteins or forming multivalent complexes. These composite structures provide both protease resistance and enhanced biological activity, resolving the contradiction between stability and functionality
2Duration of action of moving object
If protease-resistant polypeptides are designed to extend half-life, then duration of action is improved, but selection and development complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-selecting and characterizing protease-resistant variants before in vivo application. Libraries of protease-resistant polypeptides are created and screened in advance, allowing selection of optimal candidates with extended half-life without requiring complex real-time optimization
Solution Approach 2:
The patent employs self-service mechanisms where protease-resistant polypeptides are selected through their own functional properties. Variants that naturally resist protease degradation are identified through functional assays, allowing the molecules to 'select themselves' based on their inherent stability rather than requiring complex external selection processes
3Power
If multivalent agents bind TNFR1 to induce clustering and signal transduction, then agonist activity is achieved, but antagonist efficacy is reduced
Solution Approach 1:
The patent applies local quality by designing monovalent agents that bind to specific local epitopes on TNFR1 without inducing overall receptor clustering. By targeting specific local regions of the receptor, these agents can block antagonist binding sites or signal transduction domains while avoiding the formation of multivalent complexes that would activate signaling pathways
Data Source
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AI summary
The invention relates to anti-TNFR1 polypeptides and antibody single variable domains (dAbs) that are resistant to degradation by a protease, as well as antagonists comprising these. The polypeptides, dAbs and antagonists are useful for as therapeutics and/or prophylactics that are likely to encounter proteases when administered to a patient, for example for pulmonary administration, oral administration, delivery to the lung and delivery to the GI tract of a patient, as well as for treating inflammatory disease, such as arthritis or COPD.