IP Library › Granted Patent US 12,258,383
Granted Patent B2
US 12,258,383 · App. 17/810,128 · Granted Mar 25, 2025

Multi-functional and multi-valent interleukin-TGF-beta receptor fusion polypeptides

Inventor: Claudia Ania Penafuerte Diaz (Montreal, CA)
Assignee: Cura Therapeutics Inc.
C07K14/71A61P35/00C07K14/5443C07K14/55C07K19/00A61K38/00C07K2317/31C07K2317/622C07K2319/30C07K2319/31C07K2319/32
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Quick Facts
Patent No.
US 12,258,383
App. No.
17/810,128
Granted
Mar 25, 2025
Kind
B2
Abstract

Provided are multi-functional and multi-valent fusion polypeptides comprising an interleukin polypeptide and two or more TGFβ ligand-binding polypeptides. The compositions and methods provided herein are useful in the application of preventing tumorigenesis and treating cancer.

Claims (20)

1. A method of inhibiting or reducing tumor growth, tumor progression, or both, in a subject having a solid tumor, the method comprising: administering to the subject a fusion polypeptide comprising:

(a) an interleukin-2 (IL-2) polypeptide comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 2 or SEQ ID NO: 3;

(b) a first soluble TGFβ receptor II (sTBRII) polypeptide comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8 or SEQ ID NO: 9; and

(c) a second soluble TGFβ receptor II (sTBRII) polypeptide comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8 or SEQ ID NO: 9,

thereby inhibiting or reducing tumor growth, tumor progression, or both, in the subject.

2. The method of claim 1 , wherein inhibiting or reducing tumor growth or tumor progression comprises inhibiting or reducing angiogenesis.

3. The method of claim 1 , wherein the solid tumor is a metastatic tumor.

4. The method of claim 1 , wherein the solid tumor is selected from the group consisting of: a breast tumor, a heart tumor, a lung tumor, a small intestine tumor, a colon tumor, a spleen tumor, a kidney tumor, a bladder tumor, a head tumor, a neck tumor, an ovarian tumor, a prostate tumor, a brain tumor, a pancreatic tumor, a skin tumor, a bone tumor, a bone marrow tumor, a thymus tumor, a uterine tumor, a testicular tumor, and a liver tumor.

5. The method of claim 1 , wherein the solid tumor is a colorectal tumor.

6. The method of claim 1 , wherein the solid tumor is melanoma.

7. The method of claim 1 , wherein the administering comprises systemic administration.

8. The method of claim 1 , wherein the administering comprises intravenous administration.

9. The method of claim 1 , wherein the first sTBRII polypeptide, the second sTBRII polypeptide, or both, comprises an N terminus truncation, a C terminus truncation, or both, relative to SEQ ID NO: 8 or SEQ ID NO: 9.

10. The method of claim 1 , wherein the fusion polypeptide further comprises a linker polypeptide or a linker molecule attaching the first sTBRII polypeptide and the second sTBRII polypeptide.

11. The method of claim 1 , wherein the fusion polypeptide further comprises a pharmacokinetic modulator.

12. The method of claim 11 , wherein the pharmacokinetic modulator comprises an immunoglobulin constant (Fc) region polypeptide or an albumin polypeptide.

13. The method of claim 1 , wherein the fusion polypeptide comprises an amino acid sequence having at least 95% 90% sequence identity to any one of SEQ ID NOs: 10-22.

14. The method of claim 1 , wherein the subject is a human.

15. The method of claim 1 , wherein the fusion polypeptide is included in a pharmaceutical composition.

16. The method of claim 15 , wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, pharmaceutically acceptable diluents, or any combination thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 29, 2022
From: PENAFUERTE DIAZ, CLAUDIA ANIA
To: CURA THERAPEUTICS, INC.
Reel/Frame 061654/0417 →
Continuity (4)
Division 17574479 · Jan 12, 2022
Continuation PCTUS2021055646 · Oct 19, 2021
Provisional Application 63094277 · Oct 20, 2020
Related Publication 20230023954A1 · Jan 26, 2023
References Cited (52)
US 8283449B2 · Galipeau et al. · 2012 [cited by applicant]
US 8574548B2 · O'Connor-McCourt et al. · 2013 [cited by applicant]
US 11407814B2 · Penafuerte Diaz · 2022 [cited by applicant]
US 20110150828A1 · Galipeau et al. · 2011 [cited by applicant]
US 20180155439A1 · Galipeau et al. · 2018 [cited by applicant]
US 20200002425A1 · Li et al. · 2020 [cited by applicant]
US 20200231652A1 · Zwaagstra et al. · 2020 [cited by applicant]
US 20220127332A1 · Penafuerte Diaz · 2022 [cited by applicant]
US 20220257712A1 · Penafuerte Diaz · 2022 [cited by applicant]
WO WO2009152610A1 · 2009 [cited by applicant]
WO WO2016200881A1 · 2016 [cited by applicant]
WO WO2020047473A1 · 2020 [cited by applicant]
WO WO2021041886A1 · 2021 [cited by applicant]
WO WO2021096275A1 · 2021 [cited by applicant]
WO WO2022086988A1 · 2022 [cited by applicant]
WO WO2022178033A1 · 2022 [cited by applicant]
Penafuerte-Diaz et al. (Sep. 2008) “Chimeric Fusokines Borne of the Marriage of the TGFß Receptor II Ectodomain and Pro-Inflammatory Cytokines IL2 and GMCSF for Breast Cancer Immunotherapy”, Cytokine, 43(3), pp. 311. [cited by applicant]
Ng et al. (Oct. 1, 2016) “Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFß-Neutralizing Fusion Protein”, Cancer Research, 76(19):5683-5695. [cited by applicant]
Cesana et al.: Low-dose interleukin-2 administered pre-operatively to patients with gastric cancer activates peripheral and peritumoral lymphocytes but does not affect prognosis. Annals of surgical oncology. 14(4): 1295… [cited by applicant]
Dammeijer et al.: Rationally combining immunotherapies to improve efficacy of immune checkpoint blockade in solid tumors. Cytokine Growth Factor Rev. 36:5-15 (2017). [cited by applicant]
Dong et al.: The type III TGF-beta receptor suppresses breast cancer progression. The Journal of clinical investigation. 117(1):206-217 (2007) https://doi.org/10.1172/JCI29293. [cited by applicant]
Frieman et al.: SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog. 6(4):e1000849 (2010). [cited by applicant]
Heldin et al.: Signaling receptors for TGFBeta famly members. Cold Spring Harbor Perspectives in Biology. doi:10.1101/csjhperspect.a022053. p. 1-33 (2016). [cited by applicant]
Jamilloux et al.: Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 19(7):102567 (2020). [cited by applicant]
Kim et al.: TGF-Beta sensitivity is determined by N-linked glycosylation of the type II TGF-Beta receptor. Biochem J. 445:403-411 (2012). [cited by applicant]
Kint et al.: Infectious Bronchitis Coronavirus Inhibits STAT1 Signaling and Requires Accessory Proteins for Resistance to Type I Interferon Activity. J Virol. 89(23):12047-57 (2015). [cited by applicant]
Kopecky-Bromberg et al.: Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol. 81(2):548-57 (2007). [cited by applicant]
Malek et al.: Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004;4(9):665-74. [cited by applicant]
Marabondo et al.: High-dose interleukin-2 (IL-2) for the treatment of melanoma: safety considerations and future directions. Expert Opin Drug Saf. 16(12):1347-57 (2017). [cited by applicant]
Massagué, J.: TGFBeta signaling in context. Nat Rev Mol Cell Biol 13:616-630 (2012). [cited by applicant]
Mendy et al.: Factors Associated with Hospitalization and Disease Severity in a Racially and Ethnically Diverse Population of COVID-19 Patients. medRxiv. (2020). [cited by applicant]
Muraoka et al.: Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. The Journal of clinical investigation. 109(12):1551-1559 (2002) https://doi.org/10.1172/JCI15234). [cited by applicant]
PCT/US2021/055646 International Search Report and Written Opinion dated Jan. 11, 2022. [cited by applicant]
PCT/US2022/016662 International Search Report and Written Opinion dated May 13, 2022. [cited by applicant]
Penafuerte Al.: Novel TGF-Beta Antagonist Inhibits Tumor Growth and Angiogenesis by Inducing IL-2 Receptor-Driven STAT1 Activation. Journal of Immunology. 186(12):6933-6944 (2011). [cited by applicant]
Penafuerte et al.: B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of TGF-b Receptor II Induce Potent Antitumor Immunity. Cancer Research. 72(5):1210-1220 (2012). [cited by applicant]
Penafuerte et al.: FIST, a sword and shield fusokine for cancer immunotherapy. Oncolmmunology. 1(2):224-226 (2012). [cited by applicant]
Rafei et al.: A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex. Blood. 109(5):2234-2242 (2007) https://doi.org/10.1182/bloo… [cited by applicant]
Spolski et al.: Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 18:648-659 (2018). [cited by applicant]
Stauber et al.: Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 103(8):2788-93 (2006). [cited by applicant]
Totura et al.: SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol. 2(3):264-275 (2012). [cited by applicant]
Tzai et al.: Antisense oligonucleotide specific for transforming growth factor-beta 1 inhibit both in vitro and in vivo growth of MBT-2 murine bladder cancer. Anticancer research. 18(3A):1585-1589 (1998). [cited by applicant]
U.S. Appl. No. 17/673,691 Office Action dated Jul. 1, 2022. [cited by applicant]
U.S. Appl. No. 17/574,479 Office Action dated Jun. 10, 2022. [cited by applicant]
U.S. Appl. No. 17/574,479 Restriction Requirement dated Apr. 15, 2022. [cited by applicant]
U.S. Appl. No. 17/574,479 Restriction Requirement dated Mar. 7, 2022. [cited by applicant]
U.S. Appl. No. 17/673,691 Restriction Requirement dated May 18, 2022. [cited by applicant]
Wang et al.: An oncolytic adenovirus expressing soluble transforming growth factor-beta type II receptor for targeting breast cancer: in vitro evaluation. Molecular cancer therapeutics. 5(2):367-373 (2006) https://doi.o… [cited by applicant]
Wrangle et al.: IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res. 38(2):45-68 (2018). [cited by applicant]
Yakymovych et al.: Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase. Biochemistry. 41(36):… [cited by applicant]
Zhang et al.: Interleukin 2 receptor signaling regulates the perforin gene through signal transducer and activator of transcription (Stat)5 activation of two enhancers. J Exp Med. 190(9):1297-308 (1999). [cited by applicant]
Zwaagstra et al.: Engineering and therapeutic application of single-chain bivalent TGF-beta family traps. Mol Cancer Ther. 11(7):1477-87 (2012). [cited by applicant]