IL-11 Muteins Modulating Signaling Specificity
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Solution Overview
Problem
Current therapies for IL-11-mediated conditions lack effective modulators that can specifically modulate IL-11 signaling, either enhancing or inhibiting it as needed, to treat a wide range of diseases including thrombocytopenia, inflammatory disorders, and bone metabolism issues.
Innovation Solution
Development of IL-11 muteins with specific amino acid mutations, such as replacing AMSAG with PAIDY or FMQIQ at positions 58 to 62 and inhibiting gp130 binding, to create agonists or antagonists with enhanced binding to the IL-11Rα chain, allowing for targeted modulation of IL-11 signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If wild-type IL-11 is used to treat IL-11-mediated conditions, then it can stimulate hematopoietic cell growth and differentiation, but it cannot specifically modulate IL-11 signaling to enhance or inhibit as needed for different disease states
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (e.g., W147A, H182Q, D186E) at critical positions in the IL-11 molecule. These mutations alter the binding parameters of IL-11 to gp130, converting wild-type IL-11 into muteins with reversed or enhanced signaling properties. This allows the same cytokine scaffold to produce both agonist and antagonist effects by changing specific molecular parameters.
Solution Approach 2:
The patent segments the IL-11 signaling function by identifying and mutating specific amino acid residues that are responsible for gp130 binding. By targeting individual critical residues (Trp147, His182, Asp186), the patent divides the overall signaling function into separable components, allowing independent modulation of signaling strength and direction without affecting other biological activities.
2Adaptability or versatility
If neutralizing antibodies or soluble receptor proteins are used to inhibit IL-11, then IL-11 signaling can be blocked, but these approaches cannot provide both agonist and antagonist functionality
Solution Approach 1:
The patent achieves universality by creating a family of IL-11 muteins derived from a single cytokine structure. By mutating specific residues, the same IL-11 scaffold can function as an agonist, antagonist, or hyperagonist depending on the mutation introduced. This multi-functional approach eliminates the need for separate neutralizing antibodies and soluble receptors, providing both inhibitory and stimulatory capabilities from one platform.
Solution Approach 2:
The patent applies inversion by creating muteins that reverse the normal agonist function of IL-11. The W147A mutation, for example, converts IL-11 into an antagonist that blocks signaling, while other mutations like H182Q and D186E create hyperagonists with enhanced activity. This inversion capability allows the same molecular platform to provide opposite therapeutic effects.
3Manufacturing precision
If IL-11 muteins with specific mutations are developed to modulate signaling, then affinity for IL-11Rα can be enhanced, but the complexity of identifying and creating effective mutations increases
Solution Approach 1:
The patent applies local quality by focusing mutations at specific critical locations in the IL-11 molecule rather than throughout the entire structure. The identified residues (Trp147, His182, Asp186) are localized to the gp130 binding interface, and mutations are introduced only at these strategic positions. This localized approach enhances binding affinity and signaling modulation while minimizing the complexity of screening and development.
Data Source
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AI summary
The present invention relates generally to the treatment of an interleukin-11 (IL-11)-mediated condition. More particularly, the present invention provides the use of modified forms of IL-11 which modulate IL-11 signaling in the treatment of IL-11-mediated conditions.