TNFR-1B Mutants for Ligand-Specific Screening

Solution Overview

Problem

Current treatments for diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, juvenile idiopathic arthritis, inflammation, autoimmune diseases, Crohn's disease, ulcerative colitis, and inflammatory bowel disease are limited in efficacy and specificity, particularly in modulating interactions between TNFR-1B and its ligands.

Innovation Solution

Development of methods to screen for candidate compounds that modulate the interaction between TNFR-1B and its ligands, including ICOS-L, MadCAM-1, ISLR2, and B7-1, and the creation of modified TNFR-1B compounds or mutants with altered binding affinities and selectivities to target specific diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used for autoimmune and inflammatory diseases, then treatment is provided, but efficacy and specificity are limited

Engineering Contradiction:

Improvetreatment efficacyVSAvoiddisease specificity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by creating TNFR-1B mutants with site-specific amino acid substitutions that selectively enhance binding to specific ligands (such as ICOS-L, MadCAM-1, or ISLR2) while maintaining or reducing binding to other ligands. This localized modification at specific molecular interaction sites enables the therapeutic compound to differentially modulate various disease pathways with improved specificity for particular autoimmune and inflammatory conditions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying the amino acid sequence of TNFR-1B through mutagenesis to alter binding affinity parameters. By changing specific residues in the ligand-binding domain, the patent generates variants with tuned binding characteristics that optimize both efficacy and disease-specific targeting, allowing differentiation between various TNFR-1B ligands involved in different pathological processes.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If TNFR-1B interactions are modulated to treat diseases, then treatment efficacy improves, but selectivity for specific ligands must be enhanced

Engineering Contradiction:

Improvetreatment efficacyVSAvoidligand binding selectivity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by creating TNFR-1B mutants with site-specific amino acid substitutions that selectively enhance binding to specific ligands (such as ICOS-L, MadCAM-1, or ISLR2) while maintaining or reducing binding to other ligands. This localized modification at specific molecular interaction sites enables the therapeutic compound to differentially modulate various disease pathways with improved specificity for particular autoimmune and inflammatory conditions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent replaces the natural, non-specific TNFR-1B binding mechanism with engineered mutants that use altered molecular recognition mechanisms. By substituting specific amino acids in the binding interface, the patent creates new interaction patterns that selectively recognize specific ligand epitopes, thereby achieving precise ligand discrimination through modified molecular mechanics rather than relying on the wild-type binding mechanism.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Productivity

If screening methods are developed for candidate compounds, then compound identification improves, but screening complexity increases

Engineering Contradiction:

Improvecompound screening efficiencyVSAvoidscreening method complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by pre-engineering a panel of TNFR-1B mutants with defined binding specificities for different ligands before the screening process. These pre-characterized mutants serve as ready-to-use tools that can directly assess compound selectivity for specific disease pathways. This preliminary preparation eliminates the need for complex real-time characterization during screening, as the mutant panel already encodes the selectivity requirements.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent employs universality by creating a multi-functional TNFR-1B mutant panel where each mutant serves multiple purposes: they can screen for compounds with different binding affinities, assess selectivity for various ligands, and evaluate potential therapeutic mechanisms. This universal panel approach allows a single screening system to address multiple drug discovery objectives simultaneously, reducing overall screening complexity while maintaining high productivity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS10717776B2Tumor necrosis factor 1B (TNF-1B) mutants and methods of use thereof to screen for candidate therapeutic compounds

Publication Date: 2020.07.21 ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV

AI summary

Disclosed are tumor necrosis factor receptor 1B (TNFR-1B) signaling targets and TNFR-1B mutants and their uses for treatment of diseases and disorders.