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US-20260125437-A1 - FUSION PROTEIN COMPRISING IL13

US20260125437A1US 20260125437 A1US20260125437 A1US 20260125437A1US-20260125437-A1

Abstract

The invention is concerned with a fusion protein comprising interleukin 13 and a regulatory cytokine, for example, an interleukin chosen from interleukin 4, interleukin 10, interleukin 27, interleukin 33, transforming growth factor beta 1, transforming growth factor beta 2, and interleukin 13, a nucleic acid molecule encoding such fusion protein, a vector comprising such nucleic acid molecule, and a host cell comprising such nucleic acid molecule or such vector. The invention further pertains to a method for producing such fusion protein. The fusion protein or a gene therapy vector encoding the fusion protein may be used in the prevention or treatment of a condition characterized by pathological pain, chronic pain, neuro-inflammation and/or or neurodegeneration.

Inventors

  • Niels EIJKELKAMP
  • Cornelis Erik Hack
  • Judith PRADO SANCHEZ
  • Jelena POPOV-CELEKETIC
  • Sabine VERSTEEG

Assignees

  • SYNERKINE PHARMA B.V.

Dates

Publication Date
20260507
Application Date
20250616
Priority Date
20190419

Claims (19)

  1. 1 . A nucleic acid molecule comprising a polynucleotide sequence that encodes a fusion protein, the fusion protein comprising: (a) a first cytokine that is IL13; (b) a second cytokine that: (i) is IL4; (ii) is IL10; (iii) is IL13; (iv) is IL33; (v) is TGFβ1; (vi) is TGFβ2; or (vii) is IL27; and (c) optionally a linker.
  2. 2 . The nucleic acid molecule of claim 1 , wherein the first cytokine and the second cytokine are joined by the linker.
  3. 3 . The nucleic acid molecule of claim 1 , wherein a C terminus of the first cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the second cytokine.
  4. 4 . The nucleic acid molecule of claim 1 , wherein a C terminus of the second cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the first cytokine.
  5. 5 . The nucleic acid molecule of claim 1 , wherein the second cytokine is the IL4.
  6. 6 . The nucleic acid molecule of claim 5 , wherein a C terminus of the first cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the second cytokine.
  7. 7 . The nucleic acid molecule of claim 5 , wherein a C terminus of the second cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the first cytokine.
  8. 8 . The nucleic acid molecule of claim 1 , wherein the second cytokine is the IL10.
  9. 9 . The nucleic acid molecule of claim 8 , wherein a C terminus of the first cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the second cytokine.
  10. 10 . The nucleic acid molecule of claim 8 , wherein a C terminus of the second cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the first cytokine.
  11. 11 . The nucleic acid molecule of claim 1 , wherein the second cytokine is the IL13.
  12. 12 . The nucleic acid molecule of claim 11 , wherein a C terminus of the first cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the second cytokine.
  13. 13 . The nucleic acid molecule of claim 11 , wherein a C terminus of the second cytokine is joined to an N terminus of the linker and a C terminus of the linker is joined to an N terminus of the first cytokine.
  14. 14 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule is DNA.
  15. 15 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule is RNA.
  16. 16 . A cell comprising the nucleic acid molecule of claim 1 .
  17. 17 . A fusion protein comprising a first cytokine that is IL13 and a second cytokine that IL10 or IL13.
  18. 18 . The fusion protein of claim 17 , wherein the second cytokine is the IL10.
  19. 19 . The fusion protein of claim 17 , wherein the second cytokine is the IL13.

Description

CROSS REFERENCE This application is a divisional of U.S. patent application Ser. No. 17/693,956 filed Mar. 14, 2022 which is a divisional of U.S. patent application Ser. No. 17/158,785 filed Jan. 26, 2021, now U.S. Pat. No. 11,312,757 issued on Apr. 26, 2022, which is a continuation of International Application No. PCT/EP2020/060910, filed Apr. 17, 2020, which claims the benefit of Dutch Patent Application No. 2022982, filed Apr. 19, 2019, and Dutch Patent Application No. 2022984, filed Apr. 19, 2019, each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING STATEMENT The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 12, 2025, is named 56780-702_402_SL.xml and is 52,747 bytes in size. FIELD OF THE INVENTION The present invention is in the field of neuro-immunology and pharmacology, particularly for treatment of chronic pain, neuro-inflammatory and neurodegenerative diseases, and inflammatory disorders. The invention particularly relates to a novel fusion protein comprising interleukin 13 (IL13) and a regulatory cytokine, for example, without limitation, an interleukin chosen from interleukin 4 (IL4), interleukin 10 (IL10), interleukin 27 (IL27), interleukin 33 (IL33), transforming growth factor beta 1 (TGFβ1), transforming growth factor beta 2 (TGFβ2), and IL13 itself, either or not physically fused together through a linker sequence. Particularly, the present invention provides an IL4/IL13, IL10/IL13, IL27/IL13, IL33/IL13, TGFβ1/IL13, TGFβ2/IL13, or IL13/IL13 fusion protein endowed with a superior analgesic, neuro-protective, and anti-inflammatory activity over a combination of the individual cytokines, or over a fusion protein of IL4 and IL10. The present invention also provides nucleic acid sequences encoding a fusion protein, for example, an IL4/IL13 fusion protein, IL10/IL13 fusion protein, IL27/IL13 fusion protein, IL33/IL13 fusion protein, TGFβ1/IL13 fusion protein, TGFβ2/IL13 fusion protein, or IL13/IL13 fusion protein, expression vectors comprising such nucleic acid sequences, host cells or host organisms altered to harbour the nucleic acid sequence encoding the IL4/IL13 fusion protein, IL10/IL13 fusion protein, IL27/IL13 fusion protein, IL33/IL13 fusion protein, TGFβ1/IL13 fusion protein, TGFβ2/IL13 fusion protein, IL/13/IL13 fusion protein, and the fusion protein itself. The invention further provides methods for producing an IL4/IL13, IL10/IL13, IL27/IL13, IL33/IL13, TGFβ1/IL13, TGFβ2/IL13, or IL13/IL13 fusion protein using a cell or organism harbouring such nucleic acid sequences. Transgenic organisms comprising the nucleic acid sequence of the invention are also provided. The present invention also relates to pharmaceutical compositions comprising for example, the IL4/IL13 or IL10/IL13 or IL27/IL13 or IL33/IL13 or TGFβ1/IL13 or TGFβ2/IL13 or IL13/IL13 fusion protein. Finally, the use of the IL4/IL13 or IL10/IL13 or IL27/IL13 or IL33/IL13 or TGFβ1/IL13 or TGFβ2/IL13 or IL13/IL13 fusion protein as a medicament, in particular for the prevention and/or treatment of chronic pain and of conditions characterized by neuro-inflammation, neuro-degeneration, or inflammation is taught herein. BACKGROUND OF THE INVENTION Chronic pain affects millions of people and constitutes the largest unmet need of modern medicine1-4. In 2016, an estimated 20.4% of U.S. adults (50.0 million) had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain5. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) constitute the main classes of drugs to combat pain. However, these analgesics (“pain-killers”) are often ineffective and have severe side effects (addiction, gastrointestinal bleeding, cardiovascular, other). It is estimated that ˜50% of chronic pain patients (˜5-10% of the total population) do not receive adequate pain relief6. People with chronic pain suffer from spontaneous pain, hyperalgesia (a heightened experience of pain to a noxious stimulus) and allodynia (pain caused by a normally non-painful stimulus). Pain has multiple causes and results from biological processes at various anatomic levels7-10: the generation of stimuli that trigger sensory nerve endings in the periphery; the stimulation, sensitization, and dysfunction of peripheral sensory neurons that transmit action potentials to the spinal cord; neurons and glial cells in the dorsal horn of the spinal cord where action potentials from peripheral neurons are transmitted to spinal pain neurons via synapses; and finally central mechanisms in the brain. The contribution of all of these processes to different types of chronic pain varies. Depending on this contribution pain is discriminated in several types, including nociceptive pain, peripheral and central neuropathic pain, and mixed types of pain. Analgesic drugs used in the clinic, target pain at only one l