huTNFR1 Selective Antagonists for Inflammatory Disease Treatment
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Solution Overview
Problem
Current anti-TNF therapies targeting TNF itself have limited efficacy and are associated with significant side effects and immune suppression, leading to increased infectious risks and refractory responses in chronic inflammatory diseases, highlighting the need for receptor-specific targeting of TNF action.
Innovation Solution
Development of a huTNFR1-ligand comprising amino acid sequences of human origin to reduce immunogenicity and sequences of non-human origin for selective binding to huTNFR1, acting as an antagonist to TNF and LTα, thereby providing a receptor-specific therapeutic approach.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-TNF antibodies or soluble TNFR-Fc fusion proteins are used to target TNF, then therapeutic effect in chronic inflammatory diseases is improved, but immune suppression and side effects increase
Solution Approach 1:
The invention segments the TNF targeting approach by developing ligands that specifically target TNFR1 rather than TNF itself. This segmentation allows selective inhibition of TNFR1-mediated pathways while preserving TNFR2 function and overall immune regulation, thereby reducing immune suppression and side effects while maintaining therapeutic efficacy in chronic inflammatory diseases
Solution Approach 2:
The invention uses engineered ligands as intermediaries that bind selectively to TNFR1. These ligands serve as mediators between the therapeutic goal (inhibiting TNF pathology) and the receptor system, providing controlled and specific inhibition without the broad immune suppression associated with direct anti-TNF antibodies
2Measurement precision
If non-human amino acid sequences are used for selective binding to huTNFR1, then binding specificity is improved, but immunogenicity increases
Solution Approach 1:
The invention applies local quality by incorporating human amino acid sequences specifically at the immunogenic regions of the ligand structure, while maintaining non-human sequences in the binding regions. This localized approach preserves binding specificity to huTNFR1 while reducing overall immunogenicity by humanizing the immunologically exposed portions of the molecule
Solution Approach 2:
The invention creates composite ligand structures combining human and non-human amino acid sequences. This composite approach allows optimization of different regions for their specific functions: non-human sequences for high-affinity binding to TNFR1 and human sequences for reduced immunogenicity, achieving both binding specificity and low immunogenicity simultaneously
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
The huTNFR1-ligand effectively blocks TNF action with high affinity and specificity, reducing immunogenicity and adverse reactions, offering a superior therapeutic option for TNF-mediated disorders with improved safety and efficacy compared to existing anti-TNF strategies.
Implementation Method 1
one or more amino acid sequences capable of selectively binding to huTNFR1
Data Source
AI summary
The present invention relates to a ligand, which specifically binds to human tumor necrosis factor type 1 receptor (huTNFR1). The ligand includes one or more amino acid sequences of human origin capable of reducing the immunogenic response of the ligand in humans and one or more amino acid sequences capable of selectively binding to huTNFR1. The present invention also relates to a nucleic acid sequence encoding the ligand and to a pharmaceutical composition for the treatment of disorders related to huTNFR1.