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JP-7857029-B2 - CXCL8 binding nucleic acid

JP7857029B2JP 7857029 B2JP7857029 B2JP 7857029B2JP-7857029-B2

Inventors

  • ヘーリッヒ，カイ
  • ヴェイター，アクセル
  • プシェク，ヴューヌ
  • ズボラルスキ，ダーク
  • マアシュ，クリスチアン

Assignees

  • アプタリオン バイオテック エージー

Dates

Publication Date
20260512
Application Date
20240711
Priority Date
20181112

Claims (15)

  1. An L-nucleic acid molecule that can bind to human CXCL8 , The L-nucleic acid molecule comprises a nucleotide sequence selected from the group of SEQ ID NOs: 14, 16, 17, 20, 25, 26, 39-44. The nucleotide sequences of sequence numbers 14, 16, 17, 20, 25, 26, and 39-44 are shown in the table below: An L nucleic acid molecule, configured in such a way.
  2. The L-nucleic acid molecule contains a modifying group. The L-nucleic acid molecule according to claim 1 .
  3. The excretion rate of the L-nucleic acid molecule containing the modifying group from an organism is reduced compared to the excretion rate of the L-nucleic acid molecule without the modifying group, and/or the retention time of the L-nucleic acid molecule containing the modifying group is increased compared to the retention time of the L-nucleic acid molecule without the modifying group. The L nucleic acid molecule according to claim 2 .
  4. The modifying group is selected from the group consisting of biodegradable modifications and non-biodegradable modifications. The L nucleic acid molecule according to claim 2 or 3 .
  5. The L-nucleic acid molecule according to claim 4, wherein the modifying group is selected from the group consisting of polyethylene glycol, linear polyethylene glycol, branched polyethylene glycol, hydroxyethyl starch, peptide, protein, polysaccharide, sterol, polyoxypropylene, polyoxyamide, and poly( 2 -hydroxyethyl)-L-glutamine.
  6. The L-nucleic acid molecule according to claim 1 , wherein the L-nucleic acid molecule includes a modifying group, the modifying group is for immobilizing the L-nucleic acid molecule, or the modifying group enables the detection of the L-nucleic acid molecule.
  7. An L nucleic acid molecule according to any one of claims 1 to 6 , for use in a method for treating and/or preventing a disease.
  8. An L nucleic acid molecule according to any one of claims 1 to 6 , used in a method for detecting CXCL8.
  9. An L nucleic acid molecule according to any one of claims 1 to 6 for manufacturing a detection means or biosensor.
  10. A pharmaceutical composition comprising an L-nucleic acid molecule as defined in any one of claims 1 to 6 , and optionally further components, wherein the further components are selected from pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically active agents.
  11. Use of an L-nucleic acid molecule according to any one of claims 1 to 6 for manufacturing a pharmaceutical product.
  12. Use of an L-nucleic acid molecule according to any one of claims 1 to 6 for manufacturing a diagnostic agent, a diagnostic means, or a biosensor.
  13. Use of an L-nucleic acid molecule according to any one of claims 1 to 6 for detecting CXCL8.
  14. A kit for detecting CXCL8, the kit comprising an L-nucleic acid molecule according to any one of claims 1 to 6 , and at least an instruction manual or a reaction vessel.
  15. A complex comprising an L-nucleic acid molecule and CXCL8 as described in any one of claims 1 to 6 .

Description

The present invention relates to nucleic acid molecules capable of binding to CXCL8, nucleic acid molecules for use in methods for treating and/or preventing diseases, nucleic acid molecules for use in methods for detecting CXCL8, detection means, or nucleic acid molecules for manufacturing biosensors, pharmaceutical compositions containing nucleic acid molecules, use of nucleic acid molecules for manufacturing pharmaceuticals, diagnostic agents, diagnostic means, or use of nucleic acid molecules for manufacturing biosensors, use of nucleic acid molecules for detecting CXCL8, kits containing nucleic acid molecules, methods for detecting CXCL8 using nucleic acid molecules, complexes containing nucleic acid molecules, methods for screening antagonists of CXCL8-mediated activity using nucleic acid molecules, and methods for detecting nucleic acid molecules. CXCL8 (UniProtKB/Swiss-Prot P10145, IL8_HUMAN; SEQ ID NO: 2) (also known as interleukin 8 (abbreviated IL-8)), neutrophil-activating protein 1 (abbreviated NAP-1), monocyte-derived neutrophil chemotactic factor (abbreviated MDNCF), or granulocyte chemotactic protein 1 (abbreviated GCP-1) is a small basic protein belonging to the subfamily of CXC chemokines, characterized by a glutamate-leucine-arginine (abbreviated ELR) motif at its N-terminus and possessing pro-inflammatory and pro-angiogenic properties. ELR-positive chemokines CXCL1 (also known as growth regulatory alpha protein, Gro-alpha, melanoma growth stimulating activity, MGSA, or NAP-3), CXCL2 (also known as Gro-beta or macrophage inflammatory protein 2-alpha, MIP2-alpha), CXCL3 (also known as Gro-gamma or MIP2-beta), CXCL5 (also known as epithelial neutrophil-activating protein 78, ENA-78, or small inducible cytokine B5), CX CL6 (also known as chemokine alpha 3, CKA-3, granulocyte chemotactic protein 2, GCP-2, or small inducible cytokine B6), CXCL7 (also known as platelet basic protein, PBP, leukocyte-derived growth factor, LDGF, macrophage-derived growth factor, MDGF, or small inducible cytokine B7), and CXCL8 are agonists of the receptor CXCR2 (also known as IL8RB, IL8R type 2, CD182, CDw128b, or GRO/MGSA receptor). CXCL6, CXCL7, and CXCL8 are agonists of the receptor CXCR1 (also known as IL8RA, IL8R type 1, CD181, or CDw128a). CXCL8 binds to receptors CXCR1 and CXCR2 with similar affinity of approximately 4 nM. CXCL8 binding to CXCR1/2 triggers a Gαi-dependent signaling pathway, inducing, for example, neutrophil migration, degranulation, and oxidative bursts. Receptor sensitivity can be modulated by phosphorylation, beta-arrestin recruitment, and receptor internalization (Ha, Theranostics 2017). CXCL7 has the highest homology to CXCL8, sharing 33 identical amino acids. CXCL8 from non-human primates (rhesus monkeys, cynomolgus monkeys) shares 95% identity with human CXCL8 (73 of 77 amino acids are identical). There are no orthologues of CXCL8 in mice or rats. CXCL8 is secreted by various cell types, including monocytes, macrophages, fibroblasts, endothelial cells, and epithelial cells, in response to pathogen-associated molecular patterns (PAMP) molecules (e.g., LPS), pro-inflammatory mediators (e.g., IL-1, IL-6, and TNF-α), hypoxia, reactive oxygen species, or environmental stressors (e.g., cigarette smoke) (Ha, Theranosticz 2017). CXCL8 functions as a chemotactic and activating cytokine in neutrophils and monocytes, playing a crucial physiological role in host defense. CXCL8 is used as a biomarker for the diagnosis, disease status, prognosis, and therapeutic efficacy of infections accompanied by elevated CXCL8 levels, as described in viral infections (e.g., respiratory syncytial virus, herpes simplex virus, hepatitis viruses B and C, human cytomegalovirus), bacterial infections (e.g., Streptococcus pneumoniae and Mycobacterium tuberculosis), and fungal infections (e.g., Candida albicans and Aspergillus fumigatus). In pediatric respiratory syncytial virus (RSV) infection, CXCL8 plasma levels correlate with disease severity. Therefore, CXCL8 can function as a biomarker to assess the severity of RSV infection and guide clinical management. The accuracy is improved by combining it with other immunological biomarkers, namely lymphocyte count and CCL5 plasma levels (Brand, Pediatrir Res 2013). Further examples of using CXCL8 as a biomarker for infection include neonatal sepsis (Zhou, PLOS One 2015), bacterial meningitis (Yao, Int J Clin Exp Med 2015), pneumonia (Morris, Thorax 2009), and neurosyphilis (Wang, Sci Rep 2016). CXCL8 can also be used as a biomarker for inflammatory diseases such as chronic prostatitis, acute pyelonephritis, cystic fibrosis, and various autoimmune diseases (Shahzad, Int Arch Med 2010). In cancer patients, CXCL8 levels are correlated with worsening tumor burden and outcomes (Sanmamed, Clin Cancer Res 2014). For example, CXCL8 is correlated with shorter survival in breast cancer (Fang, Anticancer Res 2017), pancreatic cancer (Chen, World J Gastroenterol 2012), and pediatric