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US 12,029,778 B2Granted
Interleukin-18 mimics and methods of use
AssigneeYale University
InventorAaron Ring
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Abstract
The present disclosure provides methods of making and methods of using IL-18 mimic polypeptides for use in therapeutic and non-therapeutic applications. The synthetic IL-18 mimics an increase IL-18R signaling activity even in the presence of an inhibitory molecule such as IL-18BP.
Claims32
A method of making a mimic of a parent IL-18 protein, the method comprising:
- (a) computationally designing a polypeptide de novo from a parent IL-18 protein by:
- (i) defining as a template a structure of the IL-18 parent protein in a complex with at least human IL-18Rα, wherein the parent IL-18 protein is a decoy resistant (DR) IL-18 variant polypeptide of wild-type (WT) human IL-18;
- (ii) designating one or more hotspots in the template based on binding sites in the complex;
- (iii) inputting the template comprising the one or more designated hotspots into a mimetic design protocol to generate a de novo polypeptide backbone;
- and
- (iv) outputting an amino acid sequence for the de novo designed polypeptide;
- and
- (b) producing the de novo designed polypeptide that was computationally designed in step (a), wherein the amino acid sequence of the produced de novo designed polypeptide has 84% or less sequence identity with the WT human IL-18 SEQ ID NO:30, has a beta trefoil fold, specifically binds to human IL-18 receptor (IL-18R), and exhibits substantially reduced binding to human IL-18 binding protein (IL-18BP) as compared with WT human IL-18 with a KD for IL-18BP measured by SPR that is 10 nM or greater.
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A method of making a mimic of a parent IL-18 protein, the method comprising:
- (a) computationally designing a polypeptide de novo from a parent IL-18 protein by:
- (i) defining as a template a structure of the IL-18 parent protein in a complex with at least human IL-18BP, wherein the parent IL-18 protein:
- (i) is a decoy-to-the-decoy (D2D) IL-18 variant polypeptide of wild-type (WT) human IL-18;
- (ii) designating one or more hotspots in the template based on binding sites in the complex;
- (iii) inputting the template comprising the one or more designated hotspots into a mimetic design protocol to generate a de novo polypeptide backbone;
- and
- (iv) outputting an amino acid sequence for the de novo designed polypeptide;
- and
- (b) producing the de novo designed polypeptide that was computationally designed in step (a), wherein the amino acid sequence of the produced de novo designed polypeptide has 84% or less sequence identity with WT human IL-18 SEQ ID NO:30, has a beta trefoil fold, specifically binds to human IL-18BP, and exhibits 10% or less of the binding affinity to human IL-18 receptor (IL-18R) as compared with WT human IL-18.
6 more elements
Dependencies are inferred from the claim text.