IP Library › Granted Patent US 12,577,323
Granted Patent B2
US 12,577,323 · App. 15/735,158 · Granted Mar 17, 2026

Compositions and conjugates comprising an interleukin and polypeptides that specifically bind TGF-beta

Inventors: Jacques Galipeau (Atlanta, GA); Spencer Ng (Atlanta, GA)
Assignees: Emory University; Children's Healthcare of Atlanta, Inc.
C07K16/32A61K38/179A61K38/1793A61K38/2086A61P35/00C07K14/495C07K14/54C07K14/5443C07K14/71C07K14/7155C07K16/30C12N15/63C07K2319/00
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Quick Facts
Patent No.
US 12,577,323
App. No.
15/735,158
Granted
Mar 17, 2026
Kind
B2
Abstract

This disclosure relates to compositions and conjugates comprising an interleukin, e.g., IL-15 and a polypeptide that specifically binds TGF-beta. Typically the polypeptide that specifically binds TGF-beta is a type II TGF-beta receptor. In certain embodiments, the type II TGF-beta receptor is a human isoform, fragment or variant thereof. Uses for treating or preventing cancer and infectious diseases are contemplated.

Claims (7)

1 . A conjugate comprising a polypeptide fragment of type II TGF-beta receptor that specifically binds TGF-beta; a polypeptide fragment of a sushi domain of the IL-15 receptor alpha chain that specifically binds IL-15; and a polypeptide fragment of IL-15, wherein the conjugate has greater than 90% sequence identity to TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECND NIIFSEEYNTSNPDGTGGSSGITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLT ECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSGGSGGGGSGGGSGGGGSLQNWVNVIS DLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSL SSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 21).

2 . A polynucleotide encoding a conjugate of claim 1 .

3 . A vector comprising a polynucleotide of claim 2 .

4 . An expression system comprising a vector of claim 3 .

5 . A method of treating cancer comprising administering an effective amount of a composition comprising a conjugate of claim 1 to a subject in need thereof.

6 . The method of claim 5 further comprising administering the conjugate in combination with checkpoint inhibitors, immunostimulatory cytokines, GM-CSF, anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CD40, anti-IL-7, or anti-IL-6 antibodies or combinations thereof.

7 . A conjugate comprising a polypeptide fragment of type II TGF-beta receptor that specifically binds TGF-beta; a polypeptide fragment of a sushi domain of the IL-15 receptor alpha chain that specifically binds IL-15; and a polypeptide fragment of IL-15, wherein the conjugate has greater than 90% sequence identity to TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCNISNCSITSICKPQE VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECND NIIFSEEYNTSNPDTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNC SITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMC SCSSDECNDIIFSEEYNTSNPDGTGGSSGITCPPPMSVEHADIWVKSYSLYSRERYICNSGFK RKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSGGSGGGGSGGGSGGGGS LQNWVNIVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASHDTVE NLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 27).

Assignments (1)
SECURITY INTEREST Recorded Jul 17, 2025
From: KIDDE-FENWAL, LLC
To: MGG INVESTMENT GROUP LP, AS COLLATERAL AGENT
Reel/Frame 072039/0358 →
Continuity (2)
Provisional Application 62173592 · Jun 10, 2015
Related Publication 20180155439A1 · Jun 7, 2018
References Cited (53)
US 7947265B2 · Galipeau · 2011 [cited by applicant]
US 8163879B2 · Wong · 2012 [cited by applicant]
US 8771664B2 · Lopez · 2014 [cited by applicant]
US 20050053579A1 · Galipeau · 2005 [cited by applicant]
US 20060269526A1 · Galipeau · 2006 [cited by applicant]
US 20100021421A1 · Galipeau · 2010 [cited by applicant]
US 20110177070A1 · Lofquist · 2011 [cited by applicant]
US 20170073387A1 · Galipeau · 2017 [cited by applicant]
EP 2511294A2 · 2012 [cited by applicant]
WO 2005100395 · 2005 [cited by applicant]
WO 2009152610 · 2009 [cited by applicant]
WO 2012040323 · 2012 [cited by applicant]
WO 2012175222 · 2012 [cited by applicant]
WO 2015018528 · 2015 [cited by applicant]
Wells, 1990, Biochemistry 29:8509-8517. [cited by examiner]
Bork, 2000, Genome Research 10:398-400. [cited by examiner]
Skolnick et al., 2000, Trends in Biotech. 18(1):34-39. [cited by examiner]
Doerks et al., 1998, Trends in Genetics 14:248-250. [cited by examiner]
Tokuriki and Tawflik, Current Opinion in Structural Biology 2009, 19: 596-604. [cited by examiner]
Benahmed et al. Inhibition of TGF-beta Signaling by IL-15: A New Role for IL-15 in the Loss of Immune Homeostasis in Celiac Disease, Gastroenterology 2007, 132:994-1008. [cited by applicant]
Bessard et al. High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer, Mol Cancer Ther 2009,8(9). [cited by applicant]
Chou et al. Effects of immunotherapy of IL-6 and IL-15 plasmids on transmissible venereal tumor in beagles, Veterinary Immunology and Immunopathology 130 (2009) 25-34. [cited by applicant]
Han et al. TGF-beta signaling and its targeting for glioma treatment, Am J Cancer Res 2015, 5(3):945-955. [cited by applicant]
Hurton, Tethered IL-15 to Augment the Therapeutic Potential of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, and Antitumor Activity, (2014). UT GSBS Dissertations and Theses (O… [cited by applicant]
Hurton et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells, Proc Natl Acad Sci U S A. 2016,113(48):E7788-E7797. [cited by applicant]
Lin et al. Combined immunogene therapy of IL-6 and IL-15 enhances anti-tumor activity through augmented NK cytotoxicity, Cancer Letters 272 (2008) 285-295. [cited by applicant]
Lucas et al. Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice, Blood. 2006, 108:2789-2795. [cited by applicant]
Mortier et al. Soluble Interleukin-15 Receptor alpha (IL-15Ralpha)-sushi as a Selective and Potent Agonist of IL-15 Action through IL-15Rbeta/gamma, J Biol Chem. 2006, 281(3):1612-9. [cited by applicant]
Ng et al. Activation of NK and CD8+ T-Cells with a Novel IL-15 and TGF-beta Receptor Fusion Protein Confers Anti-Tumor Immunity. Blood, 2015, 126:3421. [cited by applicant]
Ng et al. Novel TGF-beta antagonist and IL-15 fusion protein enhances formation of memory CD8+ T-cells and prevents the formation of regulatory CD4+ T-cells, Cytotherapy, vol. 17, Issue 6, Supplement, Jun. 2015, p. S19. [cited by applicant]
Ng et al. Stimulation of natural killer cell-mediated tumor immunity by an IL-15/TGF-beta neutralizing fusion protein, Cancer Res. 2016, 76(19): 5683-5695. [cited by applicant]
Rafei et al. AGMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex, Blood. 2007,109:2234-2242. [cited by applicant]
Rafei et al. GIFT15 fusokine to foil immunity's follies, Immunotherapy, 2009, 1(6), 913-915. [cited by applicant]
Rubinstein et al. Converting IL-15 to a superagonist by binding to soluble IL-15Ralpha, Proc Natl Acad Sci U S A. 2006, 103(24):9166-71. [cited by applicant]
Sanjabi et al. Opposing effects of TGF-? and IL-15 control the number of short lived effector CD8+ T cells, Immunity. 2009, 31(1): 131-144. [cited by applicant]
Seay et al. In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice, J Virol, 89:6264-6274, 2015. [cited by applicant]
Stoklasek et al. Combined IL-15/IL-15Ralpha Immunotherapy Maximizes IL-15 Activity In Vivo, J Immunol. 2006, 177(9): 6072-6080. [cited by applicant]
Zhang et al. Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer, Proc Natl Acad Sci U S A. 2009, 106(18):7513-7518. [cited by applicant]
Bork et al. Powers and Pitfalls in Sequence Analysis: The 70% Hurdle, Genome Res. 2000, 10: 398-400. [cited by applicant]
Doerks et al. Protein annotation: detective work for function prediction, TIG, 1998 vol. 14 No. 6, p. 248-250. [cited by applicant]
Kelley et al. The Phyre2 web portal for protein modeling, prediction and analysis, Nature Protocols, vol. 10, pp. 845-858 (2015). [cited by applicant]
MacKenzie et al. Tertiary alphabet for the observable protein structural universe, Proceedings of the National Academy of Sciences, 2016, 113 (47) E7438-E7447. [cited by applicant]
MacKenzie et al. Protein Structural Motifs in Prediction and Design, Curr Opin Struct Biol. 2017, 44: 161-167. [cited by applicant]
Marks et al. Protein structure prediction from sequence variation, Nat Biotechnol. 2012, 30(11): 1072-1080. [cited by applicant]
Ng et al. Concise Review: Engineering the Fusion of Cytokines for the Modulation of Immune Cellular Responses in Cancer and Autoimmune Disorders Stem Cells Translational Medicine, 2015, 4:66-73. [cited by applicant]
Penafuerte et al. Novel TGF-P Antagonist Inhibits Tumor Growth and Angiogenesis by Inducing IL-2 Receptor-Driven STAT1 Activation, J Immunol. 2011, 186(12):6933-6944. [cited by applicant]
Saldano et al. Evolutionary Conserved Positions Define Protein Conformational Diversity, PLoS Comput Biol, 2016, 12(3): e1004775. [cited by applicant]
Shihab et al. GTB—an online genome tolerance browser, Shihab et al. BMC Bioinformatics (2017) 18:20. [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, 18(1):34-39. [cited by applicant]
Tokuriki et al. Stability effects of mutations and protein evolvability, Curr Opin Struct Biol. 2009,19(5):596-604. [cited by applicant]
Wei et al. Recent Progress in Machine Learning-Based Methods for Protein Fold Recognition, Int. J. Mol. Sci. 2016, 17, 2118, 13 pages. [cited by applicant]
Wells, Additivity of Mutational Effects in Protein, Biochemistry, 1990, 29(37) 8509-8517. [cited by applicant]
Extended European Search Report, EP application No. 16808155.2 dated Sep. 25, 2018. [cited by applicant]