Targeted Chimeric IFN-β Proteins With Reduced IFNAR2 Side Effects
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Solution Overview
Problem
The therapeutic use of interferon-beta (IFN-β) is associated with significant side effects such as pain, fever, chills, myalgias, and arthralgias, narrowing the therapeutic window and making patients more susceptible to other diseases, despite its benefits in treating various diseases and disorders.
Innovation Solution
Development of chimeric proteins comprising modified IFN-β with reduced affinity for the interferon-α/β receptor (IFNAR) subunits, combined with targeting moieties that specifically bind to immune cells or tumor cells, allowing for localized therapeutic action and reduced off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If interferon-beta is used to treat diseases, then therapeutic efficacy is improved, but side effects increase
Solution Approach 1:
The patent applies local quality by modifying the IFN-β molecule to have different binding affinities for different receptor subunits. The chimeric protein is designed with reduced affinity for IFNAR2 (to reduce side effects) while maintaining or enhancing affinity for IFNAR1 (to preserve therapeutic efficacy). This creates a non-uniform interaction profile with the receptor complex, allowing selective therapeutic action at the molecular level.
Solution Approach 2:
The invention segments the therapeutic action by separating the binding interactions with the two receptor subunits. By independently tuning the affinity for IFNAR1 versus IFNAR2 through structural modifications and chimeric design, the patent divides the overall therapeutic effect into distinct components: one for efficacy (IFNAR1-mediated) and one for side effect reduction (IFNAR2-mediated).
2Reliability
If interferon-beta binds to IFNAR receptor subunits, then therapeutic activity is achieved, but off-target effects increase
Solution Approach 1:
The patent changes the binding affinity parameters of the IFN-β molecule through structural modifications and chimeric protein design. Specifically, it alters the dissociation constant (Kd) for IFNAR2 binding to be higher (weaker affinity) while maintaining or improving the Kd for IFNAR1 binding. This parameter adjustment shifts the therapeutic window, allowing effective target engagement while minimizing off-target binding and associated harmful effects.
3Productivity
If high affinity binding to IFNAR2 is maintained, then receptor engagement is efficient, but side effects increase
Solution Approach 1:
The patent applies local quality by creating asymmetric binding properties within the receptor interaction. The chimeric IFN-β is designed to engage IFNAR1 with high affinity (maintaining efficiency) while having reduced affinity for IFNAR2 (reducing side effects). This localized differentiation in binding strength across the two interaction sites allows efficient therapeutic action without the harmful consequences of strong IFNAR2 binding.
Data Source
AI summary
The present invention relates, in part, to chimeric proteins comprising mutant interferon-β and their use as therapeutic agents.