WO2014206414A1 - Facteur h du complément destiné à l'utilisation dans le traitement de maladies osseuses - Google Patents

Facteur h du complément destiné à l'utilisation dans le traitement de maladies osseuses Download PDF

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Publication number
WO2014206414A1
WO2014206414A1 PCT/DK2014/050183 DK2014050183W WO2014206414A1 WO 2014206414 A1 WO2014206414 A1 WO 2014206414A1 DK 2014050183 W DK2014050183 W DK 2014050183W WO 2014206414 A1 WO2014206414 A1 WO 2014206414A1
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WO
WIPO (PCT)
Prior art keywords
bone
complement factor
factor
differentiation
cfh
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PCT/DK2014/050183
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English (en)
Inventor
Li Chen
Moustapha Kassem
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Region Syddanmark
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Publication of WO2014206414A1 publication Critical patent/WO2014206414A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • Complement Factor H for use in the treatment of bone diseases
  • This invention relates to human complement Factor H (CFH), which has now been found as a cytokine enhancing osteoblastic differentiation and bone formation, is a potential drug target to be effective for the therapy of bone diseases.
  • CSH human complement Factor H
  • the complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on.
  • the cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize the surface of a pathogen, marking it for destruction.
  • This deposition of complement can also kill cells directly by disrupting their plasma membrane.
  • Factor H has the ability to inactivate C3b molecules in the normal course of the mammalian metabolism. Factor H was earlier known as " ⁇ 1 ⁇ " [see e.g. Weiler et al.
  • Bone is a dynamic organ that turns over continually through bone resorption and bone formation. This remodelling process functions to maintain calcium balance, repair bone damaged from mechanical stresses, adjust for changes in mechanical load, and remove old bone material that has degraded with age. Bone mass is regulated by a delicate balance between bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts.
  • Osteoblasts are cells of mesenchymal origin and synthesize the precursors that form the organic extracellular matrix, also called the osteoid or ground substance, which are composed mainly of type I collagen and various non-collagen proteins such as osteocalcin, osteopontin, osteonectin, proteoglycans, and alkaline phosphatases. Once a layer of organic matrix is laid down by the osteoblasts, mineralization occurs through deposition of hydroxyapatite along and within the organic matrix. Osteocalcin, a protein produced by the osteoblasts, binds and concentrates the calcium in the matrix.
  • Consecutive layers of organic matrix added by the osteoblasts through cycles of osteoid secretion and mineralization (appositional growth) form sheets or rings of mineralized matrix, which fuse together to form a lattice structure of connected bone.
  • a proportion of osteoblasts becomes trapped as osteocytes in the lacunae, which is connected by a system of canaliculi.
  • the organic matrix is arranged in a weave-like form and results in a type of bone referred to as woven, immature, or primitive bone. Changes to stiffness of bone occurs by modulating the level of hydroxyapatite in the matrix, with higher mineral content providing stiffness and rigidity and a lower mineral content providing bone flexibility.
  • Osteoclasts the primary cells responsible for bone resorption, arise from hematopoietic cells of the macrophage/monocyte lineage and are multinucleated cells (i.e., polykaryons) that form by fusion of monocytes. Osteoclasts secrete various enzymes that act in dissolution of bone material. For example, tartrate resistant acid phosphatase (TRACP) decalcifies the bone while cathepsin K digests the bone matrix proteins. Osteoclasts also acidify the surrounding environment through vacuolar H+- ATPase activity, thereby further promoting bone resorption.
  • TRACP tartrate resistant acid phosphatase
  • osteoclasts are tightly coupled to the activity of osteoblasts, which secrete cellular factors affecting osteoclast differentiation and activity.
  • the osteoblast protein RANKL receptor for activating NFkB ligand
  • Osteoblasts also produce a decoy ligand, osteoprotegrin (OPG), which competes with RANKL and inhibits its activity.
  • OPG osteoprotegrin
  • Expression of RANKL is regulated by cytokines (e.g., IL-I, IL-6, IL-1 1 and TNF-alpha), glucocorticoids, and parathyroid hormone (PTH).
  • cytokines e.g., IL-I, IL-6, IL-1 1 and TNF-alpha
  • PTH parathyroid hormone
  • RANKL upregulators leads to enhanced bone resorption and a corresponding loss of bone mass.
  • OPG production is upregulated by cytokines IL-I and TNF-alpha, steroid hormone beta-estradiol, and mechanical stress, thereby stimulating bone formation.
  • glucocorticoids, and prostaglandins suppress production of OPG and thus enhance bone resorption.
  • This intricate interaction between the osteoblasts and osteoclasts provides a mechanism for adapting to conditions requiring additional bone mass (e.g., increased mechanical load) as well as maintenance of bone mass.
  • the abnormal regulation of osteoclast and osteoblast activities can lead to various bone disorders.
  • the clinical presentations of decreased bone formation and/or increased bone resorption include loss of bone mass and/or decrease in structural integrity of the bone matrix. Both conditions can lead to an increased risk of bone fractures.
  • the most common form of boneloss, primary osteoporosis is a significant health problem because nearly 5 to 20% of the human female population suffers from the condition. Although not as prevalent as in the female population, age-related osteoporosis also affects a significant percentage of males.
  • fracture in which bone regeneration is impaired.
  • up to 13% of fractures that occur in the tibia are associated with delayed healing or non-healing fractures.
  • treatment methods available which can be used either alone or in combination, for management of these complex clinical situations.
  • tissue-engineering approach is a promising strategy added in the field of bone regenerative medicine which aims to generate new, cell-driven, functional tissues.
  • bone-tissue engineering combines progenitor cells, such as human mesenchymal stem cells (hMSC) or mature cells (for osteogenesis) seeded in biocompatible scaffolds and ideally in three dimensional tissue-like structures (for osteoconduction and vascular in growth), with appropriate growth factors (for osteogenic induction), in order to generate and maintain bone.
  • progenitor cells such as human mesenchymal stem cells (hMSC) or mature cells (for osteogenesis) seeded in biocompatible scaffolds and ideally in three dimensional tissue-like structures (for osteoconduction and vascular in growth), with appropriate growth factors (for osteogenic induction), in order to generate and maintain bone.
  • hMSC human mesenchymal stem cells
  • osteogenesis mature cells
  • growth factors for osteogenic induction
  • WO 2012/044139 discloses a composition comprising cryptotanshinone for promoting the differentiation of mesenchymal stem cells into osteoblasts, and an osteogenesis promoter comprising cryptotanshinone and mesenchymal stem cells.
  • the differentiation of the mesenchymal stem cells into osteoblasts is promoted when the mesenchymal stem cells are treated with cryptotanshinone.
  • the thus-differentiated mesenchymal stem cells may be directly transplanted to a patient so as to promote osteogenesis in the patient.
  • the composition may be used for treating a patient having impairments requiring osteogenesis promotion, such as osteoporosis, bone fractures, and other bone defects.
  • WO 2012/044139 discloses a composition comprising cryptotanshinone for promoting the differentiation of mesenchymal stem cells into osteoblasts.
  • WO 2012/044139 does not specifically mention CFH's ability to enhance bone formation (via differentiation of mesenchymal stem cells).
  • WO 2012/044139 reports an increased level of CFH (among other proteins) this does not mean that CFH plays any role in the differentiation of MSC into osteoblasts.
  • complement factor H enhances the osteoblast differentiation in dose-dependent manner.
  • the factor can be considered as a potential gene target or drug for treatment of osteoporosis.
  • the present invention is thus based upon the discovery that the administration of exogenous Factor H to a mammalian, e.g. human, patient suffering from a bone disorder/disease, especially osteoporosis, will cure or alleviate the symptons of that disease.
  • the present invention provides Factor H for use in treating or preventing a degenerative bone disorder/disease.
  • the degenerative bone disorder is primary osteoporosis, optionally selected from postmenopausal osteoporosis, senile osteoporosis, and juvenile osteoporosis.
  • the degenerative bone disorder may be associated with an endocrinopathy, optionally selected from hypercorticolism, hypogonadism, hyperparathyroidism, hypoparathyroidism, or bone fracture, repair of bone defects, or repair of bone destruction following bone metastases.
  • the degenerative bone disorder is osteodystrophy; osteopenia or a degenerative bone disorder caused by an imbalance of osteoclast and osteoblast activity that results in net excess of bone resorption over bone formation.
  • the present invention further provides a method of treating or preventing a degenerative bone disorder by administering to an individual in need thereof a therapeutically effective amount of Complement Factor H.
  • the invention also relates to a method for obtaining osteoblasts from mesenchymal stem cells in vitro or ex vivo, comprising contacting the stem cells with CFH.
  • the inventors observed that they can differentiate a substantial fraction, e.g., a majority, of exposed stem cells toward the osteoblast phenotypes. Consequently, in an aspect the methods of the invention can be employed for obtaining osteoblasts or osteoblast phenotype cells per se.
  • cell populations resulting from the method may comprise further cell types, at least some of which can augment the useful characteristics of the osteoprogenitor or osteoblast phenotype cells present in such populations, in particular in the context of bone therapy.
  • a cell population resulting from the methods of the invention may also comprise endothelial cells or endothelial progenitors.
  • a method for differentiating mesenchymal stem cells into osteoblast by contacting the cells with Complement Factor H.
  • Such differentiated cells are useful for being inserted in bone fractures or diseased bone tissue thereby facilitating the osteogenic process.
  • CFH was identified as secreted factor in hMSCs.
  • Figure 1A CFH was identified in conditioned medium of hMSC during osteoblasitc differentiation by SI LAC mass spectrometric analysis
  • Figure 1 B the up-regulation of CFH during osteoblastic differentiation was confirmed by real time PCR in both 10% FBS and 2% FBS culturing.
  • Figure 1 C shows the protein level expression and secretion of CFH in hMSCs during osteoblastic differentiation confirmed by western blot analysis.
  • Figure 2 there is shown how knocking down the expression of complement factor H (CFH) inhibits osteoblastic differentiation of hMSCs.
  • C complement factor H
  • FIG. 2A shows that knocking down CFH expression by its siRNA reduce the alkaline phosphatase (ALP) staining and mineralization of cells stained by Alizarin red staining.
  • FIG 2B shows that knocking down the CFH expression in hMSCs by siRNA inhibits the expression of osteoblasts marker genes (OPN, ON, Coll , BSP) during osteoblastic differentiation (detected by real time PCRs).
  • ALP alkaline phosphatase
  • FIG. 3 there is shown how overexpression of complement factor H (CFH) enhances osteoblastic differentiation of hMSCs.
  • hMSCs overexpressed hCFH proteins by transfection with CFH expression plasmid (CFH) and vehicle transfection control cells (ctrl).
  • CFH CFH expression plasmid
  • ctrl vehicle transfection control cells
  • CFH overexpression enhances the mineralization of hMSC osteoblastic differentiation (stained by Alizarin red staining at Day 13 after osteoblastic induction).
  • FIG 3C there is shown that overexpression of CFH in hMSCs enhances the expression of osteoblasts marker genes (OPN, ON, Coll , BSP) during osteoblastic differentiation (detected by real time PCRs).
  • osteoblasts marker genes OPN, ON, Coll , BSP
  • CFH protein enhances the osteoblastic differentiation of hMSCs.
  • Human stromal stem cells were inducted into osteoblasts, purified CFH protein were added into induction medium in different concentrations (50ng/ml - 1 ug/ml).
  • Alzarin red staining were performed on day 13, indicated a dose- dependent promotion of minimizations of cells (Fig. 4A), and Alkaline phosphorase activity at Day 7 of induction is also dose-dependently increased by CFH (Fig. 4B), expression of osteoblasts marker genes (OPN, ON, Coll , BSP) detected by real time PCRs confirmed the effects (Fig. 4C).
  • therapeutically effective amount, effective amount or sufficient amount of Factor H is a quantity or activity sufficient to, when administered to the subject effect beneficial or desired results, including clinical results, and, as such, an effective amount or synonym thereof depends upon the context in which it is being applied.
  • therapeutically effective amounts of Factor H are used to treat, modulate, attenuate, reverse, or affect the bone loss disease or conditions.
  • An effective amount is intended to mean that amount of a compound that is sufficient to treat, prevent or inhibit such diseases or conditions.
  • a therapeutically effective amount of Factor H is an amount which prevents, inhibits, suppresses or reduces a bone loss disease or condition. As defined herein, a therapeutically effective amount of Factor H may be readily determined by one of ordinary skill by routine methods known in the art.
  • a treatment or prevention regime of a subject with a therapeutically effective amount of Factor H may consist of a single administration, or alternatively comprise a series of applications.
  • Factor H may be administered at least once a month.
  • Factor H may be administered to the subject from about one time per week to about a daily administration for a given treatment.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of Factor H.
  • the effective dosage used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • Exemplary formulations as used for parenteral administration include subcutaneous, intramuscular, intravenous or intraocular injection as, for example, a sterile solution or suspension.
  • Exemplary formulations for topical or mucosal administration including intranasal, intrabronchial or intraocular use include aqueous or oily suspensions or solutions, emulsions, eventually used as sprays, drops or ointment.
  • Determination of a therapeutically effective amount or a prophylactically effective amount of Factor H according to the invention can be readily made by one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a skilled artisan.
  • C3 Complement Factor H
  • C3b the active fragment of the third component of complement C3
  • C3 convertases a bimolecular enzymatic complex formed by active fragments of C3 and factor B [CFB]
  • CFH human mesenchymal stem cells
  • the present inventors knocked down CFH expression by its specific siRNAs, or overexpressed this gene in hMSCs to check the regulation of osteoblast differentiation in hMSCs. While the data indicated that this factor is a regulator for osteoblast differentiation, evidenced by inhibiting the expression thereby reducing osteoblastic differentiation of hMSCs in vitro (Fig. 2), overexpression the factor in cell culturing medium enhanced osteoblast differentiation (Fig. 3). Both data indicate thatCFH enhances osteoblast differentiation. In an additional experiment purified CFH factor was added into hMSC osteoblastic induction medium. The results show that adding CFH factor into cell culturing medium, it dose-dependently enhances the osteoblastic differentiation in hMSCs (Fig. 4).
  • CFH acts as a protein that is highly expressed and secreted by human mesenchymal stem cells. Its expression up- regulates during osteoblastic differentiation. Importantly CFH acts as a positive factor for osteoblatic differentiation of hMSCs, wherein the enhancement of osteoblastic differentiation is CFH dose-dependent (around 25-1000ng/ml in vitro). While the same concentration of the protein has no effects on osteoclast formation.
  • CFH can be used as a factor that assist bone healing or a factor that can be added into osteogenic induction medium to hMSCs in tissue engineering for bonehealing or growth in clinical stem cell transplantation.
  • the factor can also be injected to osteoporosis patients to improve the bone formation and keep bone density or a factor that can used preventively for age-related osteoporosis.
  • CFH has no effects at human osteoclast differentiation.
  • Human osteoclast precursors cells (Lonza) were cultured and induced to osteoclasts by M-CSF and RANKL for 5 days, medium change every 2 days.
  • Human CFH protein were added into induction medium at different doses (0-1000ng/ml).
  • Osteoclasts were stained by TRAP staining. The formation of osteoclasts was calculated by staining cells and areas.

Abstract

L'invention concerne le facteur H du complément destiné à la prévention ou au traitement de la perte osseuse et à la promotion de la différenciation des cellules mésenchymateuses en ostéoblastes.
PCT/DK2014/050183 2013-06-28 2014-06-23 Facteur h du complément destiné à l'utilisation dans le traitement de maladies osseuses WO2014206414A1 (fr)

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DKPA201370365 2013-06-28
DKPA201370365 2013-06-28

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151634A1 (fr) * 2008-06-12 2009-12-17 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs du complément en tant qu’agents thérapeutiques dans l’arthrite post-traumatique et dégénérative
WO2010043772A2 (fr) * 2008-10-15 2010-04-22 Suomen Punainen Risti, Veripalvelu Procédé de protection de cellules
WO2012024584A2 (fr) * 2010-08-20 2012-02-23 Fate Therapeutics, Inc. Composés oxystérol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151634A1 (fr) * 2008-06-12 2009-12-17 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs du complément en tant qu’agents thérapeutiques dans l’arthrite post-traumatique et dégénérative
WO2010043772A2 (fr) * 2008-10-15 2010-04-22 Suomen Punainen Risti, Veripalvelu Procédé de protection de cellules
WO2012024584A2 (fr) * 2010-08-20 2012-02-23 Fate Therapeutics, Inc. Composés oxystérol

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FEDARKO, N.S. ET AL.: "Factor H Binding to Bone Sialoprotein and Osteopontin Enables Tumor Cell Evasion of Complement-mediated Attack", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 275, no. 22, 2000, pages 16666 - 16672 *
GURKAN, U.A. ET AL.: "Immune and Inflammatory Pathways are Involved in Inherent Bone Marrow Ossification", CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, vol. 470, 14 July 2012 (2012-07-14), pages 2528 - 2540, XP035096474, DOI: doi:10.1007/s11999-012-2459-4 *
KRISTENSEN, L.P. ET AL.: "Temporal Profiling and Pulsed SILAC Labeling Identify Novel Secreted Proteins During Ex Vivo Osteoblast Differentiation of Human Stromal Cells", MOLECULAR AND CELLULAR PROTEOMICS, vol. 11, 16 July 2012 (2012-07-16), pages 989 - 1007 *
MITCHELL, E.J. ET AL.: "The Genetics of Heterotopic Ossification: Insight Into the Bone Remodeling Pathway", JOURNAL OF ORTHOPAEDIC TRAUMA, vol. 24, no. 9, 2010, pages 530 - 533 *

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