Interleukin-18 mimics and methods of use

A method of making a nucleic acid encoding a mimic of a parent interleukin 18 (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 a nucleic acid that encodes the amino acid sequence for the de novo designed polypeptide that was computationally designed in step (a), wherein the amino acid sequence 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-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.

A method of making a polypeptide mimic of an interleukin 18 (IL-18) protein, or a nucleic acid encoding the polypeptide mimic, the method comprising:

• (a) computationally designing a polypeptide mimic by:
• (i) defining as a template a structure of an IL-18 protein in a complex with at least human IL-18Rα;
• (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 identify a polypeptide mimic backbone comprising an immunoglobulin domain;
• and
• (iv) outputting an amino acid sequence for the designed polypeptide mimic;
• and
• (b) producing the polypeptide mimic, or a nucleic acid that encodes the polypeptide mimic, computationally designed in step (a), wherein the produced polypeptide mimic comprises the immunoglobulin domain and specifically binds to human IL-18 receptor (IL-18R), and the amino acid sequence of the polypeptide mimic has less than 50% sequence identity with wild-type human IL-18 SEQ ID NO:30.