TNF Mutein Receptor Selectivity for Lower-Toxicity Tumor Targeting
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Solution Overview
Problem
Existing TNF therapies for increasing tumour vasculature permeability are associated with severe adverse side effects due to non-selective binding to TNFR1 and TNFR2 receptors, necessitating the development of TNF muteins that selectively bind to TNFR1 to minimize toxicity while maintaining therapeutic efficacy.
Innovation Solution
Development of TNF muteins with specific amino acid substitutions at positions 84, 85, 88, and 89 to enhance selective binding to TNFR1, reducing or eliminating binding to TNFR2, thereby minimizing cytotoxic side effects while maintaining or enhancing TNFR1-mediated responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TNF is used to increase tumour vasculature permeability, then therapeutic efficacy is improved, but severe adverse side effects occur due to non-selective binding to both TNFR1 and TNFR2
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at positions 84, 85, 88, and 89 of the TNF molecule. These localized changes modify the binding interface to achieve selective affinity for TNFR1 while reducing binding to TNFR2, thereby maintaining therapeutic efficacy at the target site while minimizing harmful effects on non-target tissues.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequence parameters of TNF through multiple substitutions at specific positions. This modifies the binding characteristics of the molecule, transforming it from non-selective (wild-type) to selective (mutein), thereby resolving the contradiction between efficacy and toxicity by changing the molecular parameters that determine receptor specificity.
2Object-affected harmful factors
If TNF binds selectively to TNFR1, then cytotoxic side effects are minimized, but binding affinity and biological activity must be maintained
Solution Approach 1:
The patent uses parameter changes by introducing four specific amino acid substitutions (K84E, S85T, N88D, T89S) that collectively modify the binding parameters of TNF. These changes reduce affinity for TNFR2 (minimizing side effects) while preserving or enhancing affinity for TNFR1 (maintaining biological activity), thus resolving the contradiction through precise parameter optimization.
Solution Approach 2:
The patent applies local quality by making targeted amino acid changes only at the receptor-binding interface (positions 84-89), leaving the rest of the molecule unchanged. This localized modification approach selectively alters binding properties without affecting other functional aspects of the TNF molecule, thereby maintaining biological activity while reducing cytotoxicity.
3Reliability
If multiple amino acid substitutions are introduced in TNF, then selectivity for TNFR1 is enhanced, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by concentrating all modifications within a specific region (amino acid positions 84-89) of the TNF molecule. This localized approach enhances selectivity through targeted changes while minimizing overall molecular complexity by leaving the rest of the 157-amino acid sequence unchanged, thus resolving the contradiction between selectivity and complexity.
Solution Approach 2:
The patent employs segmentation by dividing the TNF molecule into functional regions, with modifications confined to the binding interface segment (positions 84-89). This segmentation allows independent optimization of binding selectivity without affecting other functional segments, thereby achieving high selectivity with minimal increase in overall molecular complexity.
Data Source
AI summary
The present invention relates to tumour necrosis factor (TNF) muteins with improved properties, and in particular to TNF muteins which are agonists of, and bind selectively to, tumour necrosis factor receptor 1 (TNFR1). Compositions comprising the TNF muteins, which may additionally comprise appropriate anticancer agents or imaging agents are provided. The use of the muteins of the invention in methods of treating or detecting a tumour are also provided. The invention also provides nucleic acids (e.g. vectors) encoding the TNF muteins and host cells comprising the nucleic acids.