Split interleukin mimetics and their use

Patent metadata

Field	Value
Publication number	US-12234572-B2
Application number	US-201917294807-A
Country	US
Kind code	B2
Filing date	Nov 19, 2019
Priority date	Nov 20, 2018
Publication date	Feb 25, 2025
Grant date	Feb 25, 2025

Abstract

Conditionally active receptor agonists that, when activated, bind to IL-2 receptor β c heterodimer (IL-2Rβ c ), IL-4 receptor α c heterodimer (IL-4Rα c ), or IL-13 receptor a subunit (IL˜13 Rα) are disclosed, as are components of the conditionally active receptor agonists and methods for using the conditionally active receptor agonists.

First claim

We claim:

1. 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 an amino acid sequence at least 75% identical to the amino acid sequence (PKKKIQ) LHA E HA LYD A L (MILNI) (SEQ ID NO: 4);
(b) X2 is any helical peptide domain;
(c) X3 is a peptide comprising an amino acid sequence at least 75% identical to the amino acid sequence ( L E) D Y AF N FE LI LEE( I ARLFESG) (SEQ ID NO:5); and
(d) X4 is a peptide comprising an amino acid sequence at least 75% identical to the amino acid sequence (EDEQEEMANAI) I TIL Q S W IF(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 β c heterodimer (IL-2Rβ c ), or IL-4 receptor α c heterodimer (IL-4Rα c ).

2. The conditionally active receptor agonist of claim 1 , wherein:
(a) X1 is a peptide comprising an amino acid sequence at least 85% identical to the amino acid sequence PKKKIQLHA E HA LYD A L MILNI (SEQ ID NO: 4) or QLHA E HA LYD A L MILNI (SEQ ID NO:320);
(b) X3 is a peptide comprising an amino acid sequence at least 85% identical to the amino acid sequence L ED Y AF N FE LI LEE I ARLFESG (SEQ ID NO:5) or L ED Y AF N FE LI LEE I ARLFES (SEQ ID NO:321); and
(c) X4 is a peptide comprising an amino acid sequence at least 85% identical to the amino acid sequence EDEQEEMANAI I TIL Q S W IF(S) (SEQ ID NO:6) or DEQEEMANAI I TIL Q S W IF(S) (SEQ ID NO:322).

3. The conditionally active receptor agonist of claim 1 , wherein:
X2 is a peptide comprising an amino acid sequence at least 75% identical to the amino acid sequence KDEAEKAKRMKE W MKRIK(T) (SEQ ID NO:7), wherein amino acid residues in parentheses may be present or absent.

4. The conditionally active receptor agonist of claim 1 , wherein:
(i) the first polypeptide component includes one of X1, X2, X3, and X4, and the second polypeptide component includes the three of X1, X2, X3, and X4 that are not present in the first polypeptide component; or
ii) the first polypeptide component includes two of X1, X2, X3, and X4, and the second polypeptide component includes the two of X1, X2, X3, and X4 that are not present in the first polypeptide component.

5. The conditionally active receptor agonist of claim 1 , wherein
(i) the first polypeptide comprises X1 and the second polypeptide comprises X2, X3, and X4;
(ii) the first polypeptide comprises X2 and the second polypeptide comprises X1, X3, and X4;
(iii) the first polypeptide comprises X3 and the second polypeptide comprises X1, X2, and X4;
(iv) the first polypeptide comprises X4 and the second polypeptide comprises X1, X2, and X3;
(v) the first polypeptide comprises X1 and X2, and the second polypeptide comprises X3 and X4;
(vi) the first polypeptide comprises X1 and X3, and the second polypeptide comprises X2 and X4;
(vii) the first polypeptide comprises X1 and X4, and the second polypeptide comprises X2 and X3;
(viii) the first polypeptide comprises X2 and X3, and the second polypeptide comprises X1 and X4;
(ix) the first polypeptide comprises X2 and X4, and the second polypeptide comprises X1 and X3;
(x) the first polypeptide comprises X3 and X4, and the second polypeptide comprises X1 and X2;
(xi) the first polypeptide comprises X1, X2, and X3 and the second polypeptide comprises X4;
(xii) the first polypeptide comprises X1, X2, and X4 and the second polypeptide comprises X3;
(xiii) the first polypeptide comprises X1, X3, and X4 and the second polypeptide comprises X2; or
(xiv) the first polypeptide comprises X2, X3, and X4 and the second polypeptide comprises X1.

6. The conditionally active receptor agonist of claim 1 , wherein:
(a) the first polypeptide comprises X1 and excludes X2, X3, and X4; and the second polypeptide is a fusion protein comprising X3-Z1-X2-Z2-X4 and excluding X1;
(b) the first polypeptide comprises X4 and excludes X1, X2, and X3; and the second polypeptide is a fusion protein comprising X1-Z1-X3-Z2-X2 and excluding X4; or
(c) the first polypeptide is a fusion protein comprising X1-Z1-X3 and excluding X2 and X4; and the second polypeptide is a fusion protein comprising X2-Z1-X4 and excluding X1 and X3;
wherein each of Z1 and Z2 independently are an optional amino acid linker.

7. The conditionally active receptor agonist of claim 1 , wherein the first polypeptide and the second polypeptide comprise an amino acid sequence at least 75% identical to the amino acid sequence of a pair of first and second polypeptides selected from options (i)-(xiii), wherein (underlined residues or “X” residues” are optional and each optional residue, when present, may comprise any amino acid):

(i)

First polypeptide X1 (Neo2A)

(SEQ ID NO: 256)

PKKKIQLHAEHALYDALMILNI VKTNS

and

Second polypeptide: X3-X2′-X4 (Neo2B)

(SEQ ID NO: 257)

TNSPPAEEK LEDYAFNFELILEEIARLFESG DQ KDEAEKAKRMKEWMKRI

KT TAS EDEQEEMANAIITILQSWIFS

(ii)

First polypeptide X1-X3-X2′

(SEQ ID NO: 258)

PKKKIQLHAEHALYDALMILNI VKTNSPPAEEK LEDYAFNFELILEEIAR

LFESG DQ KDEAEKAKRMKEWMKRIKTTAS

and

Second polypeptide X4

(SEQ ID NO: 259)

TTASE DEQEEMANAIITILQSWIFS;

(iii)

First polypeptide X1-X3

(SEQ ID NO: 260)

PKKKIQLHAEHALYDALMILNI VKTNSPPAEEK LEDYAFNFELILEEIAR

LFES GD

and

Second polypeptide X2-X4

(SEQ ID NO: 261)

DQKDEAEKAKRMKEWMKRIKT TAS EDEQEEMANAIITILQSWIFS

(iv)

First polypeptide X1 (Neo4A)

(SEQ ID NO: 262)

PKKKIQIMAEEALKDALSILNI VKTNS

Assignees

• Univ Washington

Inventors

• Quijano Rubio Alfredo
• Silva Manzano Daniel Adriano
• Baker David
• Ulge Umut
• Lajoie Marc Joseph

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title