Split interleukin mimetics and their use

A non-naturally occurring conditionally active receptor agonist, comprising a first polypeptide component and a second polypeptide component, wherein the first polypeptide component and the second polypeptide component are not present in a fusion protein, wherein in total the first polypeptide component and the second polypeptide component comprise domains X1, X2, X3, and X4, wherein:

• (a) X1 is a peptide comprising the amino acid sequence at least 25%, 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% identical to the full length of peptide (PKKKIQ)LHAEHALYDAL(MILNI) (SEQ ID NO:
• 4);
• (b) X2 is any helical peptide domain;
• (c) X3 is a peptide comprising the amino acid sequence at least 25%, 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% identical to the full length of peptide (LE)DYAFNFELILEE((IARLFESG) (SEQ ID NO:5);
• and
• (d) X4 is a peptide comprising the amino acid sequence at least 25%, 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% identical to the full length of peptide (EDEQEEMANAI)ITILQSWIF(S) (SEQ ID NO:6).
• wherein:
• (i) amino acid residues in parentheses may be present or absent;
• (ii) the first polypeptide component comprises at least one of X1, X2, X3, and X4 but does not comprise each of X1, X2, X3, and X4;
• and
• (iii) the second polypeptide component comprises each of X1, X2, X3, and X4 that is not present in the first polypeptide component;
• wherein the first polypeptide component and the second polypeptide component are not active receptor agonists individually, and wherein the first polypeptide component and the second polypeptide interact to form an active agonist of IL-2 receptor βc heterodimer (IL-2Rβc), IL-4 receptor αcheterodimer (IL-4Rαc), IL-13 alpha, or IL-4Ralpha/IL13Ralpha heterodimer.