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WO-2026093764-A1 - P75NTR(NBP)-FC FUSION PROTEIN AND ITS MEDICAL USE

WO2026093764A1WO 2026093764 A1WO2026093764 A1WO 2026093764A1WO-2026093764-A1

Abstract

The present invention relates to a p75NTR neurotrophin binding protein (NBP)-Fc fusion protein comprising a p75NTR(NBP) portion and an immunoglobulin portion. In certain embodiments, the p75NTR(NBP)-Fc fusion protein is for use in the treatment of pain and/or a symptom of pain.

Inventors

  • WESTBROOK, SIMON

Assignees

  • LEVICEPT LIMITED

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (12)

  1. 1. a p75NTR neurotrophin binding protein (NBP)-Fc fusion protein, comprising: (a) a p75NTR(NBP) portion having 90% homology with Seq ID no 1; and (b) an immunoglobulin Fc portion; wherein, the p75NTR(NBP) and Fc portions are connected via a linker, the linker comprises a peptide of formula G x , where x is 1, 2, 3, 4, 5 or 6, wherein X represents an amino acid, each X independently selected from S or T.
  2. 2. The p75NTR(NBP)-Fc fusion protein according to claim 1 wherein p75NTR(NBP) portion has 95% homology with Seq ID no 1.
  3. 3. The p75NTR(NBP)-Fc fusion protein according to claim 1 wherein p75NTR(NBP) portion is Seq ID no 1.
  4. 4. The p75NTR(NBP)-Fc fusion protein according to claim 1-3 wherein the linker is GGG.
  5. 5. The p75NTR(NBP)-Fc fusion protein according to claim 1 or 4 wherein the Fc region is an Fc suitable for human use.
  6. 6. The p75NTR(NBP)-Fc fusion protein according to claim 1-5 wherein the Fc region is Fc selected from one of Seq ID no 20-24.
  7. 7. Use of the p75NTR(NBP)-Fc fusion protein as described in claims 1-6 for the treatment of pain.
  8. 8. A nucleic acid molecule encoding the p75NTR(NBP)-Fc fusion protein as described in claims 1-6.
  9. 9. A replicable expression vector for transfecting a cell, the vector comprising the nucleic acid molecule described in claim 8.
  10. 10. Use of the nucleic acid molecule as described in claim 5 or the vector as described in claim 9 for the treatment of pain.
  11. 11. Use of the p75NTR(NBP)-Fc fusion protein as described in claims 1-6, the nucleic acid molecule as described in claim 8, or the vector as described in claim 9 for use in the treatment of osteoarthritis.
  12. 12. A pharmaceutical composition, comprising the p75NTR(NBP)-Fc fusion protein as described in claims 1-6 the nucleic acid molecule as described in claim 8, or the vector as described in claim 9, and a pharmaceutically acceptable carrier and/or an excipient.

Description

FUSION PROTEIN Background to the invention The neurotrophins, neurotrophic growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/ 5 (NT-4/5) act via four receptors: the low affinity p75 neutrophic receptor (p75NTR), and the high affinity tyrosine kinase receptors; TrkA, TrkB, and TrkC. The low affinity receptor p75NTR binds and is activated by all four neurotrophins and has been reported to function independently from the other receptors. However, the Trk receptors are more selectively activated i.e. NGF is the selective ligand for TrkA, BDNF the ligand for TrkB and NT-3, 4/5 the ligands for TrkC. In addition it has been reported, when p75NTR and Trk proteins are coexpressed, they form complexes, which alter the signaling of both receptors (Huang and Reichardt, 2003, Annu Rev Biochem. 72:609-42). Indeed, it has been suggested that p75NTR facilitates the selectivity of each of the neutrophins for their respective Trk receptor. The p75NTR is a member of the tumor necrosis factor receptor superfamily (TNFR-SF) and was the first member of this superfamily to be characterized fully. The superfamily (encoded by some 30 genes in humans) is defined by ligand-binding domains consisting of one or more (typically four) repeats of a 40 amino acid cysteine-rich domain (CRD) that was first identified in p75NTR (Johnson et al., 1986 Cell 47:545-554; Radeke et al., 1987 Nature 325:593-597). In contrast, no sequence motif is shared by the intracellular domains of all TNFR-SF family members. Consequently, signaling mechanisms of TNFR-SF proteins vary significantly. An unusual feature of p75NTR structure is the existence of a disulfide-linked p75NTR dimer, formed via cysteinyl residues within the transmembrane domains. This disulfide linkage is required for effective neurotrophin-dependent signaling by p75NTR and plays an important role in the formation of an intracellular and extracellular domain (Vilar et al., 2009 Neuron 62:72-83). Neurotrophins exist physiologically as noncovalently associated dimers (Bothwell and Shooter, 1977 J Biol Chem. 252(23):8532-6.) with a distribution half-life of approximately 5 min (Tria et al., 1994 Exp Neurol. 127(2): 178-83). Neurotrophin-dependent p75NTR activation involves association of a neurotrophin dimer with CRDs 2-4 of the two extracellular domains of a p75NTR dimer (He and Garcia, 2004 Science 304:870-875). Recent studies support a model in which neurotrophin binding causes the two extracellular domains of p75NTR dimers to move closer together, forcing the intracellular domains to splay apart in a snail-tong-like motion centered on the disulfide bond and permitting association of the intracellular domains with the signaling adapter proteins, NRIF and TRAF6 (Vilar et al., 2009 J Cell Sci 122:3351-3357, Vilar et al., 2009 Neuron 62:72-83). Intra-transmembrane domain disulfide bonds, such as are present in p75NTR, have not been described previously in other TNFR-SF family members, or in any other membrane protein. p75NTR undergoes sequential proteolytic cleavage by a-secretase and y-secretase activities and matrix metalloproteinases (MMPs), releasing its intracellular domain (ICD) into the cytoplasm, in a manner analogous to the cleavage-dependent signaling pathway of Notch and p-amyloid precursor protein (Jung et al., 2003 J Biol Chem 278:42161-42169; Kanning et al., 2003 J Neuro- sci 23:5425- 5436). Cytoplasmic release of the p75NTR ICD by this pathway promotes signaling by associated NRIF (Kenchappa et al., 2006 Neuron 50:219-232). The role of the extracellular domain of p75NTR, following the proteolytic cleavage by a-secretase and y-secretase activities and MMPs isn’t fully understood. It has been documented that NGF and other neurotrophins (BDNF, NT-3 and NT-4/5) play a significant role in pathology for example pain due to osteoarthritis, pancreatitis, rheumatoid arthritis, psoriasis, pruritis and multiple sclerosis (Watanabe etal., 2008 J Neurosci Res. 86(16):3566-74; Raychaudhuri et al., 2011 Arthritis Rheum. 63( 11): 3243-52; Barthel et al., 2009 Arthritis Res Ther. 11(3):R82; Truzzi et al., 2011 Cell Death Differ. 18:948-58; McDonald et al., 2011 Curr Med Chem. 18:234-44; Yamaoka et al., 2007 J Dermatol Sci. 46( 1):41 -51). It was been demonstrated that selective antibodies to any of the neutrophins; either NGF or BDNF, NT-3 and NT-4/5 significantly reduce pain. Furthermore, antibodies directed to the neurotrophin receptors p75NTR Trk A, Trk B or Trk C have also been demonstrated to be efficacious in models of pain (Orita S et al., 2010 J Orthop Res. 28: 1614-20; Svensson P et al., 2010 Pain. 148:473-80; Iwakura et al., 2010 J Hand Surg Am. 35:267-73; Cirilio et al., 2010 Cell Mol Neurobiol. 30:51-62; Pezet et a/., 2010 Pain. 90: 113-25; Hayashi et al., 2011 J Pain. 12: 1059-68; Chu et al., 2011 Pain. 152: 1832-7; Ueda et a/., 2010 J Pharmacol Sci. ;112:438-43; Ghilardi et al., 2010 Bone. 48:389-98; Fukui et al., 2010 J Orth