IP Library › Granted Patent US 12,428,466
Granted Patent B2
US 12,428,466 · App. 17/287,756 · Granted Sep 30, 2025

IL4/IL13 receptor molecule for veterinary use

Inventors: Hangjun Zhan (Foster City, CA); Lam Nguyen (Union City, CA); Fawn Qian (Burlingame, CA); Shyr Jiann Li (Millbrae, CA)
Assignee: Elanco US Inc.
C07K14/7155A61K38/1793A61K45/06G01N33/6869C07K2319/30C07K2319/32G01N2333/5406G01N2333/5437
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Quick Facts
Patent No.
US 12,428,466
App. No.
17/287,756
Granted
Sep 30, 2025
Kind
B2
Abstract

Provided are various embodiments relating to IL13R/IL4R heterodimeric proteins derived from companion animal species and that bind to IL13 and/or IL4. Such heterodimeric proteins can be used in methods to treat IL13 and/or IL4-induced conditions in companion animals, such as canines, felines, and equines.

Claims (46)

1. A heterodimeric protein comprising:

a) a first contiguous polypeptide comprising at least one IL13R extracellular domain (ECD) and a first Fc polypeptide,

wherein the amino acid sequence of the at least one IL13R ECD is SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 32, or SEQ ID NO: 34, SEQ ID NO: 36, and

b) a second contiguous polypeptide comprising at least one IL4R ECD and a second Fc polypeptide,

wherein the amino acid sequence of the at least one IL4R ECD is SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 33, SEQ ID NO: 35, or SEQ ID NO: 37, wherein the IL13R ECD and/or the IL4R ECD are derived from a companion animal species.

2. The heterodimeric protein of claim 1 , wherein the first contiguous polypeptide and/or the second contiguous polypeptide comprises one, two, three, or four IL4R ECDs and/or one, two, three, or four IL13R ECDs.

3. The heterodimeric protein of claim 1 , wherein the first contiguous polypeptide and/or the second contiguous polypeptide further comprises at least one binding partner other than IL4R ECD or IL13R ECD, and wherein the at least one binding partner comprises IL5, IL6, IL17, IL22, IL31, LFA-1, TNF-α, TSLP, and/or IgE.

4. The heterodimeric protein of claim 1 , wherein the heterodimeric protein binds to IL13 and/or IL4 with a dissociation constant (Kd) of less than 5×10 −6 M, less than 1×10 −6 M, less than 5×10 −7 M, less than 1×10 −7 M, less than 5×10 −8 M, less than 1×10 −8 M, less than 5×10 −9 M, less than 1×10 −9 M, less than 5×10 −10 M, less than 1×10 −10 M, less than 5×10 −11 M, less than 1×10 −11 M, less than 5×10 −12 M, or less than 1×10 −12 M, as measured by biolayer interferometry; and/or wherein the heterodimeric protein reduces IL13 and/or IL4 signaling in a companion animal species.

5. The heterodimeric protein of claim 1 , wherein the companion animal species is canine, feline, or equine.

6. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide and/or the second Fc polypeptide is:

a) a canine IgG-A, IgG-B, IgG-C, or IgG-D Fc polypeptide;

b) a feline IgG1a, IgG1b, or IgG2 Fc polypeptide; and/or

c) an equine IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, or IgG7 Fc polypeptide.

7. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises a knob mutation; and/or wherein the first Fc polypeptide or the second Fc polypeptide comprises a hole mutation.

8. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises:

a) SEQ ID NO: 38 with an amino acid substitution at position 138, SEQ ID NO: 39 with an amino acid substitution at position 137, SEQ ID NO: 40 with an amino acid substitution at position 137, or SEQ ID NO: 41 with an amino acid substitution at position 138; and/or

b) SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, or SEQ ID NO: 46, each with an amino acid substitution at position 154; and/or

c) SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, each with an amino acid substitution at position 130.

9. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises:

a) SEQ ID NO: 38 with a tryptophan at position 138, SEQ ID NO: 39 with a tryptophan at position 137, SEQ ID NO: 40 with a tryptophan at position 137, or SEQ ID NO: 41 with a tryptophan at position 138; and/or

b) SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, or SEQ ID NO: 46, each with a tryptophan at position 154; and/or

c) SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, each with a tryptophan at position 130.

10. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises:

a) SEQ ID NO: 38 or SEQ ID NO: 41, each with an amino acid substitution at position 138 and/or position 140 and/or position 181; ID NO: 39 or SEQ ID NO: 40, each with an amino acid substitution at position 137 and/or position 139 and/or position 180; and/or

b) SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, or SEQ ID NO: 46, each with an amino acid substitution at position 154 and/or position 156 and/or position 197; and/or

c) SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, each with an amino acid substitution at position 130 and/or position 132 and/or position 173.

11. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises:

a) SEQ ID NO: 38 with a serine at position 138 and/or an alanine at position 140 and/or a threonine at position 181; SEQ ID NO: 39 with a serine at position 137 and/or an alanine at position 139 and/or a threonine at position 180; SEQ ID NO: 40 with a serine at position 137 and/or an alanine at position 139 and/or a threonine at position 180; or SEQ ID NO: 41 with a serine at position 138 and/or an alanine at position 140 and/or a threonine at position 181; and/or

b) SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, or SEQ ID NO: 46, each with a serine at position 154 and/or an alanine at position 156 and/or a threonine at position 197; and/or

c) SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, each with a serine at position 130 and/or an alanine at position 132 and/or a threonine at position 173.

12. The heterodimeric protein of claim 1 , wherein the first Fc polypeptide or the second Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, or SEQ ID NO: 101.

13. The heterodimeric protein of claim 1 , wherein the first contiguous polypeptide comprises the amino acid sequence of SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, or SEQ ID NO: 113; and/or wherein the second contiguous polypeptide comprises the amino acid sequence of SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, or SEQ ID NO: 112.

14. A pharmaceutical composition comprising the heterodimeric protein of claim 1 and a pharmaceutically acceptable carrier.

15. A heterodimeric protein comprising:

a) a first polypeptide comprising at least one IL13R extracellular domain (ECD) and a first Fc polypeptide, and

b) a second polypeptide comprising at least one IL4R ECD and a second Fc polypeptide;

wherein the IL13R ECD and/or the IL4R ECD are derived from a canine;

wherein the IL13R ECD sequence is SEQ ID NO: 22;

wherein the IL4R ECD sequence is SEQ ID NO: 23;

wherein the first polypeptide is SEQ ID NO: 103;

wherein the second polypeptide is SEQ ID NO: 102;

wherein the first Fc polypeptide is SEQ ID NO 55; and

wherein the second Fc polypeptide is SEQ ID NO 59.

16. The heterodimeric protein of claim 15 , wherein the first polypeptide and/or the second polypeptide further comprises at least one binding partner other than IL4R ECD or IL13R ECD, and wherein the at least one binding partner comprises IL31.

17. The heterodimeric protein of claim 15 , wherein the heterodimeric protein binds to IL13 and/or IL4 with a dissociation constant (Kd) of less than 5×10 −6 M as measured by biolayer interferometry.

18. The heterodimeric protein of claim 15 , wherein the heterodimeric protein reduces IL13 and/or IL4 signaling in a companion animal species.

Assignments (4)
ASSIGNMENT OF SECURITY INTEREST IN PATENT RIGHTS, RECORDED ON OCTOBER 20, 2021, AT REEL/FRAME 057861/0905 Recorded Dec 3, 2025
From: GOLDMAN SACHS BANK USA, AS RETIRING COLLATERAL AGENT
To: JPMORGAN CHASE BANK, N.A., AS SUCCESSOR COLLATERAL AGENT
Reel/Frame 073815/0912 →
MERGER AND CHANGE OF NAME Recorded Oct 2, 2023
From: KINDRED BIOSCIENCES, INC.; ELANCO US INC.
To: ELANCO US INC.
Reel/Frame 065091/0055 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 9, 2023
From: ZHAN, HANGJUN; NGUYEN, LAM; QIAN, FAWN; LI, SHYR JIANN
To: KINDRED BIOSCIENCES, INC.
Reel/Frame 062933/0016 →
SECURITY INTEREST Recorded Oct 20, 2021
From: KINDRED BIOSCIENCES, INC.
To: GOLDMAN SACHS BANK USA, AS COLLATERAL AGENT
Reel/Frame 057861/0905 →
Continuity (2)
Provisional Application 62750782 · Oct 25, 2018
Related Publication 20210395340A1 · Dec 23, 2021
References Cited (69)
US 5599905A · Mosley et al. · 1997 [cited by applicant]
US 5705154A · Dalie et al. · 1998 [cited by applicant]
US 5844099A · Stahl et al. · 1998 [cited by applicant]
US 6846486B1 · Skurkovich et al. · 2005 [cited by applicant]
US 7078494B1 · Collins et al. · 2006 [cited by applicant]
US 7186809B2 · Pluenneke · 2007 [cited by applicant]
US 7229962B2 · Chung et al. · 2007 [cited by applicant]
US 7253264B1 · Lauffer et al. · 2007 [cited by applicant]
US 7378275B2 · Mccall et al. · 2008 [cited by applicant]
US 7410781B2 · Karow et al. · 2008 [cited by applicant]
US 8216805B2 · Carter et al. · 2012 [cited by applicant]
US 8722618B2 · Jacobs et al. · 2014 [cited by applicant]
US 20030104567A1 · Stahl et al. · 2003 [cited by applicant]
US 20050032164A1 · Watson et al. · 2005 [cited by applicant]
US 20050191730A1 · Karow · 2005 [cited by examiner]
US 20080287665A1 · Mccall et al. · 2008 [cited by applicant]
US 20090156421A1 · Yang et al. · 2009 [cited by applicant]
US 20100278827A1 · Chung et al. · 2010 [cited by applicant]
US 20110151515A1 · Heifetz et al. · 2011 [cited by applicant]
US 20130089893A1 · Hogarth et al. · 2013 [cited by applicant]
US 20140056920A1 · Ardeleanu et al. · 2014 [cited by applicant]
US 20140255407A1 · Koenig · 2014 [cited by applicant]
US 20150056162A1 · Garcia et al. · 2015 [cited by applicant]
US 20180134766A1 · Larson · 2018 [cited by examiner]
US 20200048325A1 · Zhan et al. · 2020 [cited by applicant]
US 20210395340A1 · Zhan et al. · 2021 [cited by applicant]
EP 1723173B1 · 2008 [cited by applicant]
EP 2674440A2 · 2013 [cited by applicant]
JP 2007161724A · 2007 [cited by applicant]
WO 1998023289A1 · 1998 [cited by applicant]
WO 2008073463A2 · 2008 [cited by applicant]
WO 2017019949A1 · 2017 [cited by applicant]
WO 2018064190A1 · 2018 [cited by applicant]
WO 2018195388A1 · 2018 [cited by applicant]
WO 2020086886A1 · 2020 [cited by applicant]
WO 2021216899A1 · 2021 [cited by applicant]
Arima K, Sato K, Tanaka G, Kanaji S, Terada T, Honjo E, Kuroki R, Matsuo Y, Izuhara K. Characterization of the interaction between interleukin-13 and interleukin-13 receptors. J Biol Chem. Jul. 1, 2005;280(26):24915-22.… [cited by examiner]
Kraich M, Klein M, Patiño E, Harrer H, Nickel J, Sebald W, Mueller TD. A modular interface of IL-4 allows for scalable affinity without affecting specificity for the IL-4 receptor. BMC Biol. Apr. 26, 2006;4:13. doi: 10.… [cited by examiner]
Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5thedition. New York: Garland Science; 2001. Section Structural variation in immunoglobulin constant regions. (Year: 20… [cited by examiner]
Vadnais, M.L., Criscitiello, M.F. and Smider, V.V. (2017). Antibodies from Other Species. In Protein Therapeutics (eds T. Vaughan, J. Osbourn and B. Jallal). https://doi.org/10.1002/9783527699124.ch4 (Year: 2017). [cited by examiner]
Gonzales AJ, Humphrey WR, Messamore JE, Fleck TJ, Fici GJ, Shelly JA, Teel JF, Bammert GF, Dunham SA, Fuller TE, McCall RB. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. V… [cited by examiner]
Elliott et al., “Antiparallel Conformation of Knob and Hole Aglycosylated Half-Antibody Homodimers Is Mediated by a CH2—CH3 Hydrophobic Interaction,” J. Mol. Biol., vol. 426, 2014, pp. 1947-1957. [cited by applicant]
International Search Report and Written Opinion in PCT/US2019/057922, dated Jan. 29, 2020, 12 pages. [cited by applicant]
Ridgway et al., “‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization,” Protein Engineering, vol. 9, No. 7, 1996, pp. 167-621. [cited by applicant]
Andrews et al., “IL-4 Receptor α Is an Important Modulator of IL-4 and IL-3 Receptor Binding: Implications for the Development of Therapeutic Targets,” J Immunol, (2006), vol. 176(12): 7456-61, 6 pages. [cited by applicant]
Bork, Peer, “Powers and Pitfalls in Sequence Analysis: The 70% Hurdle,” Genome Research, (2000), vol. 10: 398-400. [cited by applicant]
Burgess et al., “Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-binding (Acidic Fibroblast) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single… [cited by applicant]
Colman, P.M., “Effects of amino acid sequence changes on antibody-antigen interactions,” Res Immunol., (1994), vol. 145(1): 33-6. [cited by applicant]
Database UniProt [Online] Nov. 30, 2010, Database accession No. E2QZ78, 3 pages. [cited by applicant]
Database UniProt [Online] Jul. 27, 2011, Database accession No. F6BUHR5, 2 pages. [cited by applicant]
Database UniProt [Online] May 1, 2013, Database accession No. M3XOTO, 2 pages. [cited by applicant]
Extended European Search Report for Application No. 18788175.0, dated Nov. 27, 2020, 9 pages. [cited by applicant]
Extended European Search Report for Application No. 19875949.0, dated Jun. 15, 2022, 15 pages. [cited by applicant]
Hoffman et al., “Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with Cryopyrin-Associated Periodic Syndromes,” Arthritis & Rheumatism, (2008), vol. 58, No. 8: 2443-2452. [cited by applicant]
International Search Report for PCT/US2018/028507, dated Jul. 17, 2018, 15 pages. [cited by applicant]
International Search Report for PCT/US2021/28679, dated Oct. 4, 2021, 14 pages. [cited by applicant]
Kasaian et al., “Therapeutic activity of an interleukin-4/interleukin-13 dual antagonist on oxazolone-induced colitis in mice,” Immunology, (2014), vol. 143: 416-427. [cited by applicant]
Laporte et al., “Molecular and structural basis of cytokine receptor pleiotropy in the Interleukin-4/13 system,” Cell, (2008), vol. 132(2): 259-272, 25 pages. [cited by applicant]
Lupardus et al., “Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Rα2,” Structure, (2010), vol. 18(3): 332-342, 22 pages. [cited by applicant]
Mckenzie et al., “Decoy Receptors in the Regulation of T Helper Cell Type 2 Responses,” J. Exp. Med., (2003), vol. 197, No. 6: 675-679, 5 pages. [cited by applicant]
Miosge et al., “Comparison of predicted and actual consequences of missense mutations,” Proc Natl Acad Sci USA, (2015), vol. 112, No. 37: E5189-98. [cited by applicant]
Oh et al., “Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma,” Eur Respir Rev, (2010), vol. 19, No. 115: 46-54, 9 pages. [cited by applicant]
Press Release, Kindred Bio, “Kindred Biosciences Announces Positive Results from Pilot Field Efficacy Study of its IL-4/IL-13 Sink Molecule Being Developed for the Treatment of Atopic Dermatitis in Dogs,” (2020), 4 page… [cited by applicant]
Skolnick et al., “From genes to protein structure and function: novel applications of computational approaches in the genomic era,” Trends Biotechnol., (2000), vol. 18, No. 1: 34-39. [cited by applicant]
Takizawa et al., “Constitutive high-expression of interleukin-4/13A and GATA-3 in gill and skin of salmonid fishes suggest that these tissues form Th2-skewed immune environments,” Molecular Immunology, (2011), vol. 48: … [cited by applicant]
Tanaka et al., “Association analysis of non-synonymous polymorphisms of interleukin-4 receptor-α and Interleukin-13 genes in canine atopic dermatitis,” J. Vet. Med. Sci., (2020), vol. 82(9): 1253-1259. [cited by applicant]
Tang et al., “Expression and Characterization of Recombinant Canine IL-13 Receptor α2 Protein and its Biological Activity In Vitro,” Mol. Immun., (2003), vol. 39: 719-727. [cited by applicant]
Tang et al., “Recombinant canine IL-13 receptor α2-Fc fusion protein inhibits canine allergen-specific-IgE production in vitro by peripheral blood mononuclear cells from allergic dogs,” Veterinary Immunology and Immunop… [cited by applicant]
Tang, Liang, “Molecular cloning of canine IL-13 receptor α chain (α1 and α2) cDNAs and detection of corresponding mRNAs in canine tissues,” Veterinary Immunology and Immunopathology, (2001), vol. 79: 181-195. [cited by applicant]