WO2017123642A1 - Méthodes et utilisations du récepteur associé à l'ostéoclaste (oscar) pour la prévention et le traitement de l'arthrose - Google Patents

Méthodes et utilisations du récepteur associé à l'ostéoclaste (oscar) pour la prévention et le traitement de l'arthrose Download PDF

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WO2017123642A1
WO2017123642A1 PCT/US2017/013030 US2017013030W WO2017123642A1 WO 2017123642 A1 WO2017123642 A1 WO 2017123642A1 US 2017013030 W US2017013030 W US 2017013030W WO 2017123642 A1 WO2017123642 A1 WO 2017123642A1
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Prior art keywords
fusion protein
immunoglobulin
domain
oscar
subject
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Inventor
Yongwon Choi
Soo Young Lee
Doo Ri PARK
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Ewha Womans University
University of Pennsylvania Penn
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Ewha Womans University
University of Pennsylvania Penn
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    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • Osteoarthritis is one of the most common forms of arthritis and is characterized by the gradual destruction of cartilage.
  • Current treatments include pain relievers, anti-inflammatories, physical therapy and surgery.
  • Osteoclasts are giant multinucleated cells derived from the cell fusion of mononuclear phagocyte precursors. While the resorptive activity of osteoclasts is essential for bone remodeling, it is also implicated in the pathological bone loss observed in autoimmune diseases, such as osteoporosis and rheumatoid arthritis, as well as bone cancers and other clinical disorders. Osteoclast differentiation is induced by the RANKL cytokine and costimulatory signals generated by the transmembrane immunoreceptor tyrosine-based activation motif (ITAM) adaptors, DNAX-activating protein of 12 kDa (DAP 12) and Fc receptor common ⁇ (FcRy).
  • ITAM transmembrane immunoreceptor tyrosine-based activation motif
  • Osteoclast-associated receptor is specifically expressed by
  • OSCAR binds to specific motifs within fibrillar collagens in the extracellular matrix (ECM) that become revealed on nonquiescent bone surfaces in which osteoclasts undergo maturation and terminal differentiation.
  • ECM extracellular matrix
  • OSCAR is a collagen receptor that can costimulate osteoclastogenesis.
  • the present invention relates to compositions and methods for treating osteoarthritis.
  • One aspect of the invention includes a method of treating
  • the method comprises administering to the subject a therapeutically effective amount of a fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment.
  • OSCAR osteoclast associated receptor
  • the invention includes a method of preventing the onset of osteoarthritis in a subject, comprising administering to the subject a therapeutically effective amount of a fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an
  • immunoglobulin or a functional fragment thereof.
  • the invention includes a method of delaying the progression of osteoarthritis in a subject.
  • the method comprises administering to the subject a
  • a recombinant fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof.
  • OSCAR osteoclast associated receptor
  • the invention provides a recombinant fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand- binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof, wherein the OSCAR comprises SEQ ID NO: 1.
  • the invention provides a recombinant fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof, wherein the extracellular domain of the OSCAR comprises SEQ ID NO: 8.
  • the invention provides a recombinant fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof, wherein the OSCAR comprises SEQ ID NO: 2.
  • the invention provides a recombinant fusion protein comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof, wherein the OSCAR comprises SEQ ID NO: 3.
  • the invention includes a recombinant fusion protein comprising
  • the invention includes a recombinant fusion protein comprising SEQ ID NO: 11. In still another aspect, the invention includes a recombinant fusion protein comprising SEQ ID NO: 9. In another aspect, the invention includes a recombinant fusion protein comprising SEQ ID NO: 10.
  • the invention provides a nucleic acid encoding a fusion protein of the present invention.
  • the invention includes an expression vector comprising a nucleic acid encoding a fusion protein of the present invention.
  • the invention provides an isolated host cell transformed with an expression vector of comprising a nucleic acid encoding a fusion protein of the present invention.
  • the invention provides a pharmaceutical composition comprising a recombinant fusion protein of the present invention and a pharmaceutically acceptable excipient.
  • the invention includes a method of treating osteoarthritis comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof.
  • Another aspect of the invention includes a method of preventing the onset of osteoarthritis comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof.
  • Yet another aspect of the invention includes a method of delaying the progress of osteoarthritis comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof.
  • a fusion protein of the present invention is administered by injection.
  • a pharmaceutical composition of the present invention is administered by injection.
  • the fusion protein is administered twice per week.
  • the pharmaceutical composition is administered twice per week.
  • the subject is a human. In other embodiments, the subject is a dog.
  • the OSCAR comprises SEQ ID NO: 1.
  • the extracellular domain of the OSCAR comprises SEQ ID NO: 8.
  • the OSCAR is a mouse OSCAR.
  • the mouse OSCAR comprises SEQ ID NO: 2.
  • the OSCAR is a dog OSCAR.
  • the dog OSCAR comprises SEQ ID NO: 3.
  • the immunoglobulin of the fusion protein is a human immunoglobulin. In other embodiments, the immunoglobulin is a mouse immunoglobulin. In other embodiments, the immunoglobulin is a dog immunoglobulin. In one embodiment, the immunoglobulin is an IgG. In anther embodiment, the immunoglobulin Fc domain is a human IgGl Fc domain. In yet another embodiment, the immunoglobulin Fc domain is a mouse IgG2a Fc domain. In still another embodiment, the immunoglobulin Fc domain is a mouse IgG Fc domain. In another embodiment, the immunoglobulin Fc domain comprises SEQ ID NO: 4.
  • the fusion protein further comprises a linker sequence between the extracellular domain of an OSCAR and the Fc domain.
  • the linker comprises SEQ ID NO: 5.
  • the fusion protein further comprises a signal sequence at its N-terminus.
  • the signal sequence comprises SEQ ID NO: 6.
  • Figures 1 A- IB are a series of images illustrating two mouse models of osteoarthritis.
  • Figure 1 A depicts collagenase injection into the knee.
  • Figure IB depicts surgical destabilization of the medial meniscus (DMM).
  • DDM medial meniscus
  • Figures 2A-2B are a series of images and graphs illustrating OSCAR knock-out mice exhibited reduced cartilage destruction in both the collagenase (Figure 2A) and DMM (Figure 2B) osteoarthritis models.
  • Figures 3A-3B are a series of images and graphs showing the stabilization of subchondral bone microarchitecture in OSCAR knock-out mice for both the collagenase ( Figure 3A) and DMM ( Figure 3B) osteoarthritis models.
  • Figures 4A-4B are a series of images depicting generation of a human OSCAR-Fc
  • Figures 5A-5B are a series of images showing the expression (Figure 5A) and purification (Figure 5B) of hOSCAR-Fc.
  • Figure 5A illustrates expression of hOSCAR-Fc (lane 1 :EV, lane 2: pcDNA-mOSCAR-Fc, lane 3: pVITRO-mOSCAR-Fc, lanes 4,5,6: pVITRO- hOSCAR-Fc) 12 well/293 T cell (DNA ⁇ ⁇ ).
  • Figure 5B illustrates purification of hOSCAR-Fc.
  • 293F cell were transfected (DNA;pVITRO-hOSCAR-Fc 200 ⁇ 3 ⁇ 4 PEI 130ul / 100ml), harvested 6 days after later and purified. Final yields: 0.7-1 mg hOSCAR-Fc/100 ⁇ g DNA/100 ml culture volume). hOSCAR-Fc fusion proteins were identified by Coomassi blue staining.
  • Figures 6A-6B are a series of graphs and images showing hOSCAR-Fc blocks articular cartilage degeneration in both collagenase ( Figure 6A) and DMM ( Figure 6B) osteoarthritis mouse models.
  • Figure 7 is a series of images and graphs showing hOSCAR-Fc attenuates the progression of osteoarthritis in the collagenase osteoarthritis mouse model.
  • Figure 8 is a series of graphs and images showing hOSCAR-Fc stabilizes subchondral bone microarchitecture in the collagenase osteoarthritis mouse model.
  • Figure 9 depicts the experimental scheme to deterimine the effect of hOSCAR-Fc in the DMM osteoarthritis mouse model.
  • Figures 1 OA- IOC are a series of images and graphs showing hOSCAR-Fc attenuates the progression of osteoarthritis (Figure 10A) and stabilizes subchondral bone microarchitecture (Figures 10B- IOC) in the DMM osteoarthritis mouse model.
  • the present invention relates to methods and compositions, such as fusion proteins derived from an osteoclast associated receptor (OSCAR), to treat, prevent the onset of, or delay the progress of osteoarthritis.
  • OSCAR osteoclast associated receptor
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a concentration, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1%, and still more preferably ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • animal refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds.
  • mammal includes both human and non-human mammals.
  • antibody refers to a polypeptide ligand comprising at least a light chain or heavy chain immunoglobulin variable region which specifically binds an epitope of a protein or a fragment of a protein.
  • Antibodies can include a heavy chain and a light chain, each of which has a variable region, termed the variable heavy (VH) region and the variable light (VL) region. Together, the VH region and the VL region are responsible for binding the antigen recognized by the antibody.
  • a scFv protein is a fusion protein in which a light chain variable region of an immunoglobulin and a heavy chain variable region of an immunoglobulin are bound by a linker, while in dsFvs, the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains.
  • the term also includes recombinant forms such as chimeric antibodies (for example, humanized murine antibodies), heteroconjugate antibodies (such as, bispecific antibodies).
  • classes There are five-major classes (isotypes) of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses,” e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of antibodies are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known to one skilled in the art.
  • binding refers to a specific interaction between two or more molecules, such as the binding of an antibody and an antigen (for example an antibody to an antigen).
  • specific binding is identified by a dissociation constant (Kd).
  • binding affinity is calculated by a modification of the Scatchard method described by Frankel et al, Mol. Immunol, 16: 101-106, 1979.
  • binding affinity is measured by an antigen/antibody dissociation rate.
  • a high binding affinity is measured by a competition radioimmunoassay (RIA).
  • a high binding affinity is at least about 1 x 10 " M.
  • a high binding affinity is at least about 1.5 x 10 "8 , at least about 2.0 x 10 "8 , at least about 2.5 x 10 "8 , at least about 3.0 x 10 "8 , at least about 3.5 x 10 "8 , at least about 4.0 x 10 "8 , at least about 4.5 x 10 "8 , or at least about 5.0 x 10 "8 M.
  • the disclosed antibodies have a binding affinity for the antigen of at least 10 nM.
  • telomere binding By the term “specifically binds,” as used herein, is meant a molecule, such as an antibody or a small molecule, which recognizes and binds to another molecule or feature, but does not substantially recognize or bind other molecules or features in a sample. Specific binding can be detected, for example, by ELISA, immunoprecipitation, coprecipitation, with or without chemical crosslinking, two-hybrid assays and the like. Appropriate controls can be used to distinguish between "specific” and “non-specific” binding.
  • an effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result. Such results may include, but are not limited to, the treatment of a disease or condition as determined by any means suitable in the art.
  • immunoglobulin herein is meant a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes. Immunoglobulins include but are not limited to antibodies. Immunoglobulins may have a number of structural forms, including but not limited to full-length antibodies, antibody fragments, and individual immunoglobulin domains including but not limited to VH, Oyl, Cy2, Cy3, VL, and CL.
  • "Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition and/or compound of the invention in a kit.
  • the instructional material of the kit may, for example, be affixed to a container that contains the compound and/or composition of the invention or be shipped together with a container which contains the compound and/or composition.
  • the term “subject” may refer to an animal, which is the object of treatment, observation, or experiment. Examples of subjects include but are not limited to dogs, cats, pigs, cows, sheep, horses, goats, horses, rats, mice, birds, humans and other primates. Preferably, the subject is a human.
  • promoter/regulatory sequence means a nucleic acid sequence which is required for expression of a gene product, such as the fusion proteins described herein, operably linked to the promoter/regulatory sequence.
  • this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product.
  • the promoter/regulatory sequence may, for example, be one which expresses the gene product in a spatially or temporally restricted manner.
  • therapeutic agent refers to a substance that demonstrates some therapeutic effect by restoring or maintaining health, such as by alleviating the symptoms associated with a disease or physiological disorder, or delaying (including preventing) progression or onset of a disease.
  • the therapeutic agent is a chemical or pharmaceutical agent, or a prodrug.
  • a therapeutic agent may be an agent which prevents or inhibits one or more signs or symptoms or laboratory findings associated with fungal infection.
  • a "therapeutically effective amount” or “effective amount” or “therapeutically effective dose” is that amount or dose sufficient to inhibit or prevent onset or advancement, to treat outward symptoms, or to cause regression, of a disease.
  • the therapeutically effective amount or dose also can be considered as that amount or dose capable of relieving symptoms caused by the disease.
  • a therapeutically effective amount or dose of an anti-fungal agent is that amount or dose sufficient to achieve a stated therapeutic effect.
  • the therapeutically effective amount may vary depending the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • treatment refers to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • the present invention relates to the unexpected finding that administering an
  • OSCAR-Fc fusion protein to a subject delays, prevents, and/or treats osteoarthritis in the subject.
  • OSCAR costimulates a pathway involved in osteoclastogenesis, the development of osteoclasts. Osteoclasts are important for bone homeostasis and bone resorption. However, bone resorption is not believed to be a mediator of osteoarthritis, and thus the relationship between OSCAR and osteoarthritis is an unexpected finding that is presented herein.
  • the invention includes methods of treating, preventing the onset of, or delaying the progress of osteoarthritis by administering to a subject in need thereof a therapeutically effective amount of a fusion protein comprising an OSCAR extracellular domain or a ligand-binding fragment thereof fused to an immunoglobulin Fc domain or a functional fragment thereof.
  • the invention provides recombinant fusion proteins comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof.
  • OSCAR osteoclast associated receptor
  • nucleic acids and expression vectors encoding the foregoing fusion proteins are also contemplated.
  • compositions including a recombinant fusion protein of an OSCAR extracellular domain or a ligand-binding fragment thereof fused to an immunoglobulin Fc domain or a functional fragment thereof.
  • the present invention provides fusion proteins comprising an extracellular domain of an osteoclast associated receptor (OSCAR) or a ligand-binding fragment thereof fused to an Fc domain of an immunoglobulin or a functional fragment thereof.
  • the fusion proteins of the present invention are useful for methods of treating, preventing the onset of, or delaying the progress of osteoarthritis, by administering to a subject in need thereof.
  • Nucleic acids and expression vectors encoding the fusion proteins are included in the invention, as well as host cells transformed with an expression vector encoding the fusion proteins.
  • Pharmaceutical compositionsl of the fusion proteins are also provided in the present invention.
  • the OSCAR is a human OSCAR
  • hOSCAR comprises the following amino acid sequence:
  • the extracellular domain of the hOSCAR comprises the following amino acid sequence: DITPSVAIIVPPASYHPKPWLGAQPATWTPGWVTLRCRAPQPAWRFGLFKPGEIAPLLF RDVSSELAEFFLEEVT PAQGGS YRCCYRRPDWGPG SQPSDVLELLVTEELPRPSLVALP GPWGPGANVSLRCAGRLR MSFVLYREGVAAPLQYRHSAQPWADFTLLGARAPGTYSCYY HT P S AP YVL S QRS E VL VI S WE D S GS S D YTRGNLVRLGLAGL V
  • the OSCAR is a mouse OSCAR (mOSCAR).
  • mOSCAR may have the following amino acid sequence:
  • the OSCAR is a canine OSCAR.
  • canine is a canine OSCAR.
  • canine is a canine OSCAR.
  • OSCAR may have the following amino acid sequence:
  • the immunoglobulin Fc domain is a human IgGl Fc domain.
  • the human IgGl Fc domain may have the following amino acid sequence:
  • the fusion protein has a linker sequence (e.g., GQAGQEPKSS (SEQ ID NO: 5)) between the OSCAR extracellular domain and the immunoglobulin Fc domain.
  • the fusion protein has a signal sequence (e.g., METDTLLLWVLLLWVPGS G (SEQ ID NO: 6)).
  • the signal sequence is at the N-terminus of the fusion protein.
  • the fusion protein has the following amino acid sequence:
  • each of the two Ig superfamily domains in the extracellular domain of human OSCAR (see Figure 4B) is underlined and the human IgG lFc domain is in bold.
  • the human OSCAR-Fc comprises the following nucleic acid sequence:
  • the canine OSCAR-Fc comprises the following nucleic acid sequence:
  • the canine OSCAR-Fc comprises the following amino acid sequence:
  • the immunoglobulin portion of the fusion protein can be of any class or subclass and from any species suitable for the present invention.
  • the immunoglobulin can be a human, mouse, or dog immunoglobulin.
  • the immunoglobulin is an IgG
  • the Fc domain can derive from any species and class or subclass.
  • the immunoglobulin Fc domain can be a human IgGl Fc domain, a mouse IgG Fc domain, a mouse IgG2a Fc domain.
  • a fusion protein comprising an OSCAR extracellular domain or a ligand-binding fragment thereof fused to an immunoglobulin Fc domain or a functional fragment thereof.
  • an effective amount or "a therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • compositions described herein may be administered to a patient subcutaneously,
  • the proteins of the present invention are administered to a subject by intradermal or subcutaneous injection. In another embodiment, the proteins of the present invention are administered by i.v. injection. In another embodiment, the fusion protein of the present invention is injected locally around the joint. In another embodiment, the fusion protein is injected directly into the joint.
  • the proteins of the invention may be administered acutely for acute treatment of temporary conditions, or may be administered chronically, especially in the case of progressive, recurrent, or degenerative disease.
  • one or more compounds of the invention may be administered simultaneously, or in some embodiments, they may be administered in a staggered fashion.
  • the staggered fashion may be dictated by the stage or phase of the disease.
  • the fusion protein is administered twice per week.
  • fusion proteins and pharmaceutical compositions thereof are fusion proteins and pharmaceutical compositions thereof. It will be appreciated that the fusion proteins and compositions, according to the methods of the present invention, may be administered using an amount and a route of administration effective for the treatment, prevention, or delay of osteoarthritis. The exact amount administered will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular therapeutic agent, its mode and/or route of administration, and the like.
  • the fusion proteins and expression vectors are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated.
  • the total daily usage of the fusion proteins and expression vectors and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and its severity; the activity of the specific fusion protein employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific fusion protein employed; the duration of the treatment; drugs used in combination or coincidental with the specific fusion protein employed; and like factors well known in the medical arts.
  • compositions comprising any of the fusion proteins or expression vectors described herein are encompassed.
  • chemically modified derivatives of fusion proteins of the invention which may provide additional advantages such as increased solubility, stability and in vivo or in vitro circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337).
  • the chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers,
  • compositions of this invention comprise a fusion protein, alone or in combination with a second pharmaceutically active agent.
  • pharmaceutically active agent refers to any medicament which satisfies the indicated purpose. Examples of pharmaceutically active agents include, but are not limited to, pain relievers, anti-inflammatories, and the like.
  • compositions include “pharmaceutically acceptable” and
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which can be, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • These terms refer to the use of buffered formulations as well, wherein the pH is maintained at a particular desired value, ranging from pH 4.0 to pH 9.0, in accordance with the stability of the compounds and route of administration.
  • the terms include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration.
  • Such formulations can be contained in a liquid; emulsion, suspension, syrup or elixir, or solid form; tablet (coated or uncoated), capsule (hard or soft), powder, granule, crystal, or microbead.
  • Supplementary active compounds ⁇ e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions.
  • compositions can be formulated to be compatible with a particular local or systemic route of administration.
  • pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by particular routes.
  • routes of administration for compositions of the invention include parenteral, intraarticular, intravenous, intradermal, subcutaneous, transdermal (topical), administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as as
  • compositions for injection include sterile aqueous solutions
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • Fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid and thimerosal.
  • Isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride can be included in the composition.
  • Including an agent which delays absorption, for example, aluminum monostearate and gelatin can prolong absorption of injectable compositions.
  • Sterile injectable solutions can be prepared by incorporating the active agent in the required amount in an appropriate solvent with one or a combination of above ingredients followed by filtered sterilization.
  • dispersions are prepared by incorporating the active agent into a sterile vehicle containing a basic dispersion medium and other ingredients as above.
  • methods of preparation include, for example, vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the invention also provides transformed cells and progeny thereof into which a nucleic acid molecule encoding a protein, has been introduced by means of recombinant DNA techniques in vitro, ex vivo or in vivo.
  • the transformed cells can be propagated and the introduced nucleic acid transcribed, or encoded protein expressed.
  • a progeny cell may not be identical to the parental cell, since there may be mutations that occur during replication.
  • Transformed cells include but are not limited to prokaryotic and eukaryotic cells such as bacteria, fungi, plant, insect, and animal ⁇ e.g., mammalian, including human) cells.
  • the cells may be present in culture, in a cell, tissue or organ ex vivo or present in a subject.
  • vector refers to a plasmid, virus, such as a viral vector, or other vehicle known in the art that can be manipulated by insertion or incorporation of a nucleic acid, for genetic manipulation (i.e., "cloning vectors"), or can be used to transcribe or translate the inserted polynucleotide (i.e., "expression vectors").
  • cloning vectors can be used to transcribe or translate the inserted polynucleotide
  • expression vectors are useful for introducing nucleic acids, including a nucleic acid that encodes a humanized antibody operably linked with an expression control element, and expressing the encoded protein in vitro ⁇ e.g., in solution or in solid phase), in cells or in vivo.
  • the expression vectors provided herein may be transferred to a host cell by conventional techniques and the transformed cells are then cultured by conventional techniques to produce a fustion protein of the invention.
  • the invention includes host cells containing polynucleotide(s) encoding a fusion protein of the invention operably linked to a heterologous promoter.
  • host-expression vector systems may be utilized to express the antibody molecules of the invention.
  • Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express a fusion protein of the invention in situ.
  • These include, but are not limited to, bacteriophage particles engineered to express proteins, microorganisms such as bacteria ⁇ e.g., E. coli, B.
  • subtilis transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing protein coding sequences; yeast ⁇ e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing protein coding sequences; insect cell systems infected with recombinant virus expression vectors ⁇ e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3, NSO cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter)

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Abstract

L'invention concerne des méthodes et des compositions, telles que des protéines de fusion dérivées d'un récepteur associé à l'ostéoclaste (OSCAR), pour traiter, prévenir l'apparition et retarder la progression de l'arthrose.
PCT/US2017/013030 2016-01-12 2017-01-11 Méthodes et utilisations du récepteur associé à l'ostéoclaste (oscar) pour la prévention et le traitement de l'arthrose Ceased WO2017123642A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2020111527A1 (fr) * 2018-11-30 2020-06-04 이화여자대학교 산학협력단 Composition pour cribler un inhibiteur d'interaction protéine-collagène oscar, kit la comprenant et procédé de criblage l'utilisant
WO2020246760A1 (fr) * 2019-06-04 2020-12-10 이화여자대학교 산학협력단 Anticorps anti-oscar pour la prévention ou le traitement de l'arthrose
EP4257598A4 (fr) * 2020-12-03 2024-10-30 Immunoforge Co., Ltd. Protéine de fusion comprenant un agoniste du récepteur glp-1 et un anticorps anti-oscar, et utilisation associée

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US20050003391A1 (en) * 1996-12-23 2005-01-06 Immunex Corporation Kits for detecting rankl proteins or nucleic acids
WO2013011062A2 (fr) * 2011-07-18 2013-01-24 Novo Nordisk A/S Antagonistes oscar
US20130236456A1 (en) * 2012-03-08 2013-09-12 Georgia Health Sciences University Research Institute, Inc. IMMUNOGLOBULIN Fc FRAGMENT TAGGING ACTIVATION OF ENDOGENOUS CD4 AND CD8 T CELLS AND ENHANCEMENT OF ANTITUMOR EFFECTS OF LENTIVECTOR IMMUNIZATION
US20130280273A1 (en) * 2008-10-06 2013-10-24 Cambridge Enterprise Limited Modulation of the Activity and Differentiation of Cells Expressing the Osteoclast-Associated Receptor
US20140199302A1 (en) * 2011-01-19 2014-07-17 The General Hospital Compositions for regulating iron homeostasis and methods of using same
US20150037333A1 (en) * 2012-02-22 2015-02-05 Nvip Pty Ltd Tumour necrosis factor receptor fusion proteins and methods of using the same

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US20050003391A1 (en) * 1996-12-23 2005-01-06 Immunex Corporation Kits for detecting rankl proteins or nucleic acids
US20040092714A1 (en) * 2000-09-05 2004-05-13 Yongwon Choi Osteoclast-associated receptor
US20130280273A1 (en) * 2008-10-06 2013-10-24 Cambridge Enterprise Limited Modulation of the Activity and Differentiation of Cells Expressing the Osteoclast-Associated Receptor
US20140199302A1 (en) * 2011-01-19 2014-07-17 The General Hospital Compositions for regulating iron homeostasis and methods of using same
WO2013011062A2 (fr) * 2011-07-18 2013-01-24 Novo Nordisk A/S Antagonistes oscar
US20150037333A1 (en) * 2012-02-22 2015-02-05 Nvip Pty Ltd Tumour necrosis factor receptor fusion proteins and methods of using the same
US20130236456A1 (en) * 2012-03-08 2013-09-12 Georgia Health Sciences University Research Institute, Inc. IMMUNOGLOBULIN Fc FRAGMENT TAGGING ACTIVATION OF ENDOGENOUS CD4 AND CD8 T CELLS AND ENHANCEMENT OF ANTITUMOR EFFECTS OF LENTIVECTOR IMMUNIZATION

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020111527A1 (fr) * 2018-11-30 2020-06-04 이화여자대학교 산학협력단 Composition pour cribler un inhibiteur d'interaction protéine-collagène oscar, kit la comprenant et procédé de criblage l'utilisant
KR20200065542A (ko) * 2018-11-30 2020-06-09 이화여자대학교 산학협력단 오스카 단백질-콜라겐 상호작용 저해제 스크리닝용 조성물, 이를 포함하는 키트, 및 이를 이용한 스크리닝 방법
KR102316299B1 (ko) * 2018-11-30 2021-10-22 이화여자대학교 산학협력단 오스카 단백질-콜라겐 상호작용 저해제 스크리닝용 조성물, 이를 포함하는 키트, 및 이를 이용한 스크리닝 방법
WO2020246760A1 (fr) * 2019-06-04 2020-12-10 이화여자대학교 산학협력단 Anticorps anti-oscar pour la prévention ou le traitement de l'arthrose
EP4257598A4 (fr) * 2020-12-03 2024-10-30 Immunoforge Co., Ltd. Protéine de fusion comprenant un agoniste du récepteur glp-1 et un anticorps anti-oscar, et utilisation associée

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