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WO2014139539A1 - Inhibiteur de dpysl3/crmp4 pour le traitement d'une perte osseuse - Google Patents

Inhibiteur de dpysl3/crmp4 pour le traitement d'une perte osseuse Download PDF

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Publication number
WO2014139539A1
WO2014139539A1 PCT/DK2014/050063 DK2014050063W WO2014139539A1 WO 2014139539 A1 WO2014139539 A1 WO 2014139539A1 DK 2014050063 W DK2014050063 W DK 2014050063W WO 2014139539 A1 WO2014139539 A1 WO 2014139539A1
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Prior art keywords
crmp4
bone
bone loss
seq
antibody
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Moustapha Kassem
Basem ABDALLAH
Kenneth HAUBERG
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Syddansk Universitet
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Syddansk Universitet
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency

Definitions

  • the present invention relates to the inhibition of CRMP4 thereby increasing osteogenic differentiation.
  • the present invention provides an antibody and siRNA for use in treating or preventing bone loss in a patient.
  • disorders in humans and other mammals involve or are associated with abnormal bone remodelling.
  • disorders include, but are not limited to, senile and postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, periodontitis, tooth loss, osteoarthritis, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
  • senile and postmenopausal osteoporosis include, but are not limited to, senile and postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, periodontitis, tooth loss, osteoarthritis, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma
  • Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone loss.
  • hMSC Bone marrow-derived human mesenchymal (stromal, skeletal) stem cells
  • stromal, skeletal stem cells are a population of self-renewing, multipotent cells that have significant clinical potential in cellular therapies for skeletal tissue and other tissue regeneration.
  • hMSC can differentiate along several mesodermal lineages, including the osteogenic lineage, in response to stimulation by multiple exogenous factors.
  • Dihydropyrimidinase-like protein 3 a member of TUC (TOAD-64/Ulip/CRMP)
  • DBP-3 dihydropyrimidinase related protein 3
  • CRMP-4 collapsing response- mediated protein-4
  • TUC-4 unc-33-like phosphoprotein
  • CRMP4 is strongly expressed throughout the developing central and peripheral nervous systems and was shown to mediate the signaling pathway of Sema 3A/collapsin-induced growth cone collapse and to play an important role in neuronal differentiation and axonal outgrowth (2,3). Furthermore, CRMP4 was shown to have a regulatory function in the cytoskeletal dynamics of neuronal cells via interaction with GAP-43 (4) and regulating F- actin bundling (5).
  • CRMP4 contains a number of consensus phosphorylation sites and serves as physiological substrates for the signaling molecule glycogen synthase kinase 3 ⁇ ( ⁇ 8 ⁇ 3 ⁇ ) after priming phosphorylation by Dual specificity tyrosine-phosphorylation- regulated kinase (DYRK2) and Cyclin-dependent kinase 5 (Cdk5) (6,7).
  • DYRK2 Dual specificity tyrosine-phosphorylation- regulated kinase
  • Cdk5 Cyclin-dependent kinase 5
  • WO 2007/098198 A2 discloses agents for increasing osteoblast differentiation and for treating or preventing osteoporosis.
  • the agents may be antibodies against the Ror-2 protein resulting in dimerization and thereby activation of the Ror-2 protein, which then phosphorylates and inactivates the 14-3-3 ⁇ protein. This inactivation results in an increase in osteoblast differentiation at about 85% (osteoblast formation) and an increase in bone mass at about 50%.
  • the agent may also be a shRNA or a siRNA against the 14-3-3 ⁇ gene for the purpose of inhibiting the expression of said gene. It is shown that shRNA against the 14-3-3 ⁇ gene results in an increase in osteoblast differentiation at about 60% (osteoblast formation) and increase in bone mass at about 50%.
  • the effects of said antibody and said shRNA were not additive or synergistic indicating the same pathway of differentiation.
  • De Jong et al disclose osteoblast differentiation induced by BMP-2 and/or ⁇ , of which the CRMP4 ("DPYSL3") gene among 26 genes is demonstrated to be up- regulates by BMP-2 during said differentiation (tablel).
  • the CRMP4 gene is among 7 genes selected for further investigation, where it is shown that 5 of said selected genes were specifically regulated by BMP-2, of which 5 selected genes the CRMP4 gene is the only gene not previously disclosed to play a role in osteoblast differentiation.
  • De Jong, et al (10) disclose BMP2-induced osteoblast differentiation, where the CRMP4 gene is one gene among several genes which are up-regulated during said differentiation. Thus, said up-regulated genes are sorted in 6 clusters depending on their expression pattern during said differentiation.
  • CRMP4 is one gene among 17 genes in cluster 1 showing a linear expression level when plot against time.
  • hMSC human MSC
  • the present inventors have found that inhibition of CRMP4 by e.g. an antibody markedly increases osteogenic differentiation.
  • the present invention provides an antibody, fragments hereof, or derivatives hereof, which specifically blocks CRMP4 phosphorylation sites at the c-terminal end (including Phosphothreonine, Phosphoserine) by targeting the epitope having the sequence: VFDLTTTPKGGTPAGSARGSPTRPNPPVRNLHSGFSLSGTQVDEGVRSA (SEQ ID 1) for use in treating or preventing bone loss in a patient.
  • the antibody is selected from the group consisting of an isolated polyclonal antiserum, a preparation of purified polyclonal antibodies, and a preparation containing one or more monoclonal antibodies.
  • the bone loss may be associated with ankylosing spondylitis, renal osteodystrophy, osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover due to other conditions e.g. periodontitis, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), or bone loss associated with renal tubular disorders, or bone loss associated with prolonged immobilization.
  • the bone loss is associated with osteoporosis.
  • the present invention is directed at the use of an siRNA to block the transcription of all CRMP4 variants mRNA by targeting the following DNA sequence of the gene GTGTTGATGACGTACGTTA (SEQ ID 2).
  • the present invention provides a method for treating or preventing bone loss in a patient comprising the steps of providing an antibody of the present invention and administering said one or more nucleic acids to the patient.
  • Figure 1 shows a schematic diagram of the microarray approach used to select for DPYSL3/CRMP4.
  • Figure 2 shows exclusive expression and regulation of CRMP4 during osteoblast differentiation of MSC.
  • Figure 3 shows tissue distribution of CRMP4 mRNA expression in adult mouse organs and bone related cells.
  • Figure 4 shows that CRMP4 expression and phosphorylation is regulated during osteoblast differentiation of MSC.
  • Figure 5 shows paraffin embedded sections of mouse embryos at different gestations and new born pups.
  • Figure 6 shows expression of CRMP4 by bone lining osteoblasts during endochondral bone development.
  • Figure 7 shows expression of CRMP4 by osteoblast lining cells in adult mouse bone.
  • Figure 8 shows expression of CRMP4 by proliferating chondrocyte and osteoblast during mouse bone fracture healing.
  • Figure 9 shows increased bone mineral density in CRMP4 knockout mice.
  • Figure 10 shows increased trabecular and cortical bone volume/total volume (BV/TV) in CRMP4-/- mice.
  • Figure 11 shows results from the bone cellular phenotype of CRMP4-/- mice.
  • Figure 12 shows the effect of different signalling molecules on osteoblast differentiation of CRMP ⁇ ' O versus WT OB.
  • Figure 13 shows WT and CRMP4-/- OB induced to osteoblast differentiation in the presence of different BMPs.
  • Figure 14 shows WT and CRMP4 '1' OB induced with different concentration of BMP-2.
  • Figure 15 shows WT and CRMP4-/- MSC isolated from the bone marrow of 2 months old mice and cultured in osteogenic media.
  • Figure 16 shows WT and CRMP4-/- OB induced with BMP-2 and western blot was performed for the indicated proteins of canonical and non-canonical BMP2 signals.
  • Figure 17 shows the effect of specific BMP-type I receptor inhibitor LDN-193189 on BMP2 -induced osteoblast differentiation.
  • Figure 18 shows BMP2-induced migration of CRMP4-/- OB in response to BMP2.
  • the present inventors used a comparative microarray analysis to screen for non- canonical osteogenic factors controlling the osteoblast differentiation of mesenchymal stem cells (MSC) and identified CRMP4, as a novel neuro-protein to be expressed and control the early commitment of MSC into osteoblast lineage.
  • MSC mesenchymal stem cells
  • CRMP4 a novel neuro-protein to be expressed and control the early commitment of MSC into osteoblast lineage.
  • the results demonstrated a novel function of CRMP4 in regulating osteoblast differentiation of MSC and osteoprogenitors.
  • preliminary skeletal analysis of CRMP4 knockout mice revealed significant increased bone mass in CRMP4-/- mice over wild type controls.
  • CRMP4 gene as the only member of CRMP osteoblast differentiation is provided.
  • the inventors screened for non-canonical osteogenic factors by comparing the transcriptome of previously established bone marrow-derived pre-osteogenic (MSC-bone) and pre-adipogenic (MSC-adipo) cell lines (8) during their differentiation course into osteoblast and adipocyte lineages respectively.
  • FIG. 1 shows a schematic diagram of the microarray approach used to select for DPYSL3/CRMP4.
  • Two clonal mouse bone marrow-derived mesenchymal stem cells (MSC) with opposite differentiation potential were used to screen for novel factor involved in regulating bone formation, using comparative microarray analysis.
  • -mMSC- bone denotes mMSC cells only differentiated into osteoblast and chondrocyte lineages
  • -mMSC-Adipo corresponds to mMSC cells only differentiated into adipocyte lineage.
  • Microarray analysis was performed at different time points (day 0, 3, 6 and 10) during osteoblast differentiation of MSC-Bone and adipocyte differentiation of MSC- Adipo.
  • CRMP4 mRNA was shown to be expressed by BM-MSC during their early osteoblast differentiation, while its expression was down-regulated afterwards.
  • Figure 2 there is shown exclusive expression and regulation of CRMP4 during osteoblast differentiation of MSC as shown by (A) microarray analysis and fluorescent immune staining for CRMP4.
  • B Real time PCR analysis during the time course of differentiation. For quantitative RT-PCR, CRMP4 mRNA expression was represented as relative expression to b-actin. Values are mean ⁇ SD of three replicates in three independent experiments.
  • FIG 3 tissue distribution of CRMP4 mRNA expression in adult mouse organs and bone related cells.
  • A Different tissues were dissected from 2 months old mice and homogenized to isolate RNA.
  • CRMP4 expression and phosphorylation is regulated during osteoblast differentiation of MSC.
  • ST2 cell line was induced to osteoblast differentiation for 12-20 days and both protein extract and RNA were purified at the indicated time points.
  • A) shows quantitative PCR for CRMP4 mRNA expression. The expression level of CRMP4 is up-regulated during early OB diff and then down-regulated during matrix mineralization.
  • B) shows protein extracts were subjected to Western blot analysis. The phosphorylation of CRMP4 appears to increase at day6 during OB diff and then decline after day 9.
  • the regulation of CRMP4-p indicates the role of CRMP4 phosphorylation in OB diff.
  • CRMP4 The phosphorylation of CRMP4 is inhibited by blocking the up-stream signal of GSK3b and Cdk5 kinases activity in osteoprogenitor cells. Since CRMP4 was identified as a phosphorylated brain-specific substrate for GSK3 upon priming by DYRK2 and Cdk5 (6,7), the inventors aimed to investigate whether the CRMP4 phosphorylation mediates its effect on osteoblast differentiation.
  • -Calvaria cells were isolated from 2-3 days pups and treated without (control) or with inhibitors of GSK3b kinase (CHIR-99021 , SB216763), or Cdk5 kinase inhibitor (purvalanol). -Western blots were performed after 2 days of induction.
  • FIG. 5 there is shown paraffin embedded sections of mouse embryos at different gestations and new born pups (1 day) were immune-stained with mouse specific CRMP4 antibody. Immune-histochemical staining for CRMP4 showed the expression of CRMP4 protein by proliferating chondrocyte (red arrows) and osteoblast (blue arrows) during mouse ribs development (flat bone).
  • FIG. 6 there is shown expression of CRMP4 by bone lining osteoblasts during endochondral bone development.
  • Paraffin embedded sections of mouse embryonic femur derived from embryos at different gestations and new born pups (1 day) were stained with a CRMP4 specific antibody. Immunehistochemical staining for CRMP4 showed the expression of CRMP4 protein during endochondral ossification of mouse femur bone.
  • FIG. 7 there is shown expression of CRMP4 by osteoblast lining cells in adult mouse bone. Immune-histochemical staining for CRMP4 in the paraffin embedded sections of 2 months old mouse distal femur. Almost all osteoblastic lining cells of cancellous and endostial cortical bone surface were staining positive for CRMP4.
  • FIG. 8 there is shown expression of CRMP4 by proliferating chondrocyte and osteoblast during mouse bone fracture healing.
  • the expression of CRMP4 was studied during bone union-fracture healing in mice at different time points. Results showed that CRMP4 is expressed early during callus formation by proliferating chondrocyte and later by osteoblasts. This expression pattern is similar to the expression of CRMP4 during embryonic bone formation.
  • FIG. 9 there is shown increased bone mineral density in CRMP4 knockout mice.
  • A) X-ray radiographs show the increasing bone mass in the 2 months old CRMP4- /- tibia vs wild type controls.
  • BMD total bone mineral density;
  • BMC total bone mineral content and
  • B area total bone area.
  • FIG. 10 there is shown increased trabecular and cortical bone volume/total volume (BV/TV) in CRMP4-/- mice.
  • Micro-computed tomography analysis was performed on the proximal tibia of 2-months-old tibia obtained from DPYSL3- /- and wild type control mice.
  • FIG. 11 results from the bone cellular phenotype of CRMP4-/- mice.
  • Osteoprogenitor cells (OB) were isolated from both WT, heterozygote and CRMP4-/- neonatel calvaria (2-3 days old) and cultured in vitro.
  • B) OB cells were differentiate into osteoblastic lineage with b-glycerophosphate and Ascorbic acid for 7 days and alkaline phosphatase activity was measure and normalized to cell viability. It is herewith demonstrated that CRMP4 deficiency promotes osteoblast differentiation in vitro.
  • FIG. 12 there is shown the effect of different signalling molecules on osteoblast differentiation of CRMP ⁇ ' O versus WT OB.
  • WT, CRMP4 +/ ⁇ OB and CRMP4 ' OB were induced to osteoblast differentiation in the presence of different signalling molecules that are known to be involved in osteogenesis including BMP-2,-4,- 7, TGFb1 &2, Inhibitors for GSK3b kinase, Wnt3a conditioned media (Wnt CM) and Sema3A.
  • BMPs signalling pathway is involved in mediating the regulatory function of CRMP4 on osteoblast differentiation.
  • CRMP4 deficiency increases the responsiveness of osteoblast to BMPs-induced ALP activity.
  • WT and CRMP4-/- OB were induced to osteoblast differentiation in the presence of different BMPs for 12 days and matrix mineralization in cultured cells was stained with Alizarin Red and eluted for quantification. Based thereon it may be concluded that CRMP4 deficiency increases the responsiveness of osteoblast to BMPs- induced matrix mineralization.
  • WT and CRMP4 OB were induced with different concentration of BMP-2 for 24h and qPCR analysis was performed for the indicated genes. Based thereon it may be concluded that several of BMP2-responsive genes were shown to be up-regulated in CRMP4 ' OB.
  • WT and CRMP4-/- MSC cells were isolated from the bone marrow of 2 months old mice and cultured in osteogenic media.
  • FIG. 17 there is shown the effect of specific BMP-type I receptor inhibitor LDN-193189 on BMP2 -induced osteoblast differentiation.
  • A WT and CRMP4-/- OB were treated with BMP2 in the presence of different concentrations of LDN-193189 for 6 days during osteoblast differentiation.
  • B Cells were incubated with different concentration of LDN for 30 min and then induced with BMP2 for 10 min. Western blot was performed for the indicated proteins. Based thereon it may be concluded that BMP- type I receptor is partially involved in mediating the activation of BMP2 signalling in CRMP4-/- OB cells.
  • FIG. 18 there is shown the BMP2-induced migration of CRMP4-/- OB in response to BMP2.
  • A) OrisTM Cell Migration Assay was used to study the dose- dependent effect of BMP2 on cellular migration of CRMP4-/- OB vs WT OB. Imaging analysis and quantification of cell layer area of migrated cells was analyzed by high content Operetta imaging system.

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Abstract

La présente invention concerne un anticorps, des fragments de celui-ci, ou des dérivés de celui-ci, qui bloquent spécifiquement CRMP4 pour utilisation dans le traitement ou la prévention de la perte osseuse chez un patient. L'anticorps peut être choisi parmi un antisérum polyclonal isolé, une préparation d'anticorps polyclonaux purifiés, et une préparation contenant un ou plusieurs anticorps monoclonaux. L'invention concerne en outre l'utilisation d'ARNsi pour bloquer l'expression génique de CRMP4.
PCT/DK2014/050063 2013-03-15 2014-03-14 Inhibiteur de dpysl3/crmp4 pour le traitement d'une perte osseuse Ceased WO2014139539A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005608A1 (fr) * 2016-06-28 2018-01-04 Northeast Ohio Medical University Compositions et procédés de prévention de la perte osseuse et/ou de stimulation de la guérison osseuse
US12409221B2 (en) 2018-12-24 2025-09-09 Grand Theravac Life Sciences (Nanjing) Co., Ltd. Pharmaceutical preparation for treating hepatitis b, preparation method therefor and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050106143A1 (en) * 2001-09-07 2005-05-19 Pascale Giraudon Use of a protein of the crmp family for treating diseases related to the immune system
WO2007109819A1 (fr) * 2006-03-24 2007-10-04 Trumpf Maschinen Austria Gmbh & Co. Kg Procédé et dispositif de pliage de pièces métalliques plates
WO2008000512A2 (fr) * 2006-06-30 2008-01-03 Schwarz-Pharma Ag Procédé d'identification de modulateurs des crmp

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050106143A1 (en) * 2001-09-07 2005-05-19 Pascale Giraudon Use of a protein of the crmp family for treating diseases related to the immune system
WO2007109819A1 (fr) * 2006-03-24 2007-10-04 Trumpf Maschinen Austria Gmbh & Co. Kg Procédé et dispositif de pliage de pièces métalliques plates
WO2008000512A2 (fr) * 2006-06-30 2008-01-03 Schwarz-Pharma Ag Procédé d'identification de modulateurs des crmp

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Title
BALINT, E. ET AL.: "Phenotype discovery by gene expression profiling: mapping of biological processes linked to BMP-2-mediated osteoblast differentiation.", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 89, 2003, pages 401 - 426, XP009123770, DOI: doi:10.1002/jcb.10515 *
DE JONG, D.S. ET AL.: "Identification of novel regulators associated with early- phase osteoblast differentiation.", JOURNAL OF BONE AND MINERAL RESEARCH, vol. 19, no. 6, 2004, pages 947 - 958, XP009033033, DOI: doi:10.1359/JBMR.040216 *
DE JONG, D.S. ET AL.: "Regulation of Notch signaling genes during BMP2- induced differentiation of osteoblast precursor cells.", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 320, no. 1, 2004, pages 100 - 107, XP004519071, DOI: doi:10.1016/j.bbrc.2004.05.150 *
ELEUTERIO, E. ET AL.: "Proteome of human stem cells from periodontal ligament and dental pulp.", PLOS ONE, vol. 8, no. 8, 2013, pages E71101 *
MROZIK, K. ET AL.: "Proteomic Characterization of Mesenchymal Stem Cell -Like Populations Derived from Ovine Periodontal Ligament, Dental Pulp, and Bone Marrow: Analysis of Differentially Expressed Proteins.", STEM CELLS AND DEVELOPMENT, vol. 19, no. 10, 2010, pages 1485 - 1499 *
PRASHAR, P. ET AL.: "Microarray meta-analysis identifies evolutionary conserved BMP signaling targets in developing long bones.", DEVELOPMENTAL BIOLOGY, vol. 389, 2014, pages 192 - 207, XP028844505, DOI: doi:10.1016/j.ydbio.2014.02.015 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018005608A1 (fr) * 2016-06-28 2018-01-04 Northeast Ohio Medical University Compositions et procédés de prévention de la perte osseuse et/ou de stimulation de la guérison osseuse
US12409221B2 (en) 2018-12-24 2025-09-09 Grand Theravac Life Sciences (Nanjing) Co., Ltd. Pharmaceutical preparation for treating hepatitis b, preparation method therefor and use thereof

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