Anti-TNFR1 Variable Domains for Agonist-Free Stability
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Solution Overview
Problem
Current anti-TNFR1 immunoglobulin single variable domains and antagonists face challenges in storage stability and efficacy as therapeutics and diagnostic reagents, particularly in neutralizing TNFR1-mediated conditions effectively.
Innovation Solution
Development of anti-TNFα receptor type 1 (TNFR1) immunoglobulin single variable domains with specific amino acid sequences that maintain stability and potency, including sequences with less than 0.4 OD 320 after incubation in PBS at 40°C for 40 hours, and multispecific ligands combining TNFR1 and serum albumin binding domains for enhanced therapeutic and diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multivalent agents that bind TNFR1 are used to block TNF binding, then TNF binding is blocked, but TNFR1 clustering and signal transduction are induced causing agonist activity
Solution Approach 1:
The patent segments the antibody structure into single variable domains (dAbs) rather than using complete multivalent antibodies. This segmentation allows the binding function to be retained while eliminating the clustering effect that causes agonist activity. The monovalent dAbs bind TNFR1 without cross-linking or inducing receptor clustering.
Solution Approach 2:
Instead of using multivalent antibodies that naturally induce clustering, the patent inverts the approach by using monovalent single variable domains. This inversion of valency eliminates the harmful clustering effect while preserving the blocking function, transforming the molecule from an agonist to a pure antagonist.
2Reliability
If conventional anti-TNFR1 antibodies are used for therapeutic applications, then TNFR1 binding is achieved, but storage stability is insufficient
Solution Approach 1:
The patent extracts only the essential antigen-binding variable domains from complete antibodies, creating standalone dAbs. This extraction eliminates the constant regions and other structural elements that contribute to instability, resulting in a minimized, stable core structure that retains binding function.
Solution Approach 2:
The patent applies parameter changes by modifying the amino acid sequences of the variable domains through mutagenesis and selection processes. These sequence optimizations improve structural stability and resistance to degradation while maintaining binding affinity, enabling superior storage stability under various conditions.
3Device complexity
If single variable domains are used to reduce complexity, then molecule size is reduced, but half-life and AUC values are insufficient for therapeutic efficacy
Solution Approach 1:
The patent merges multiple single variable domains into multispecific ligands that can bind both TNFR1 and serum albumin. This combination leverages the long half-life of albumin to extend the circulation time of the therapeutic agent, achieving prolonged duration of action while maintaining the simplicity and monovalency of individual dAbs.
Solution Approach 2:
The patent creates multispecific ligands with dual functionality: one domain binds TNFR1 for therapeutic action while another domain binds serum albumin for pharmacokinetic optimization. This multi-functionality allows a single molecule to achieve both therapeutic efficacy and prolonged half-life without increasing overall molecular complexity.
Data Source
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AI summary
The invention relates to storage-stable anti-TNFR1 antibody single variable domains (d Abs), antagonists and multispecific ligands, as well as methods and uses of these. The anti-TNFR1 polypeptides, antibody single variable domains (d Abs), antagonists and multispecific ligands are useful for treating and/or preventing inflammatory disease, such as arthritis or COPD, as well as for pulmonary administration, oral administration, delivery to the lung and delivery to the GI tract of a patient.