Use of Anti-sclerostin antibodies in treatment of osteogenesis imperfecta

Abstract

To provide methods for treating osteogenesis imperfecta.SOLUTION: Disclosed are methods for treating a patient suffering from osteogenesis imperfecta comprising administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. Methods for increasing bone formation and reducing bone resorption in an osteogenesis imperfecta patient by administering to the patient a therapeutically effective amount of an anti-sclerostin antibody are also disclosed. Further disclosed are compositions for increasing bone formation and reducing bone resorption in an osteogenesis imperfecta patient. The compositions comprise a therapeutically effective amount of an anti-sclerostin antibody. The invention also provides an anti-sclerostin antibody for use in the treatment of osteogenesis imperfecta.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to antibodies and their use as pharmaceutical compositions, more particularly to bone formation The present invention relates to the use of anti-sclerostin antibodies in the treatment of sclerostin deficiency.

[0002] [Sequence table] This application contains a sequence listing that has been submitted in ASCII format via EFS-Web. and is incorporated herein by reference in its entirety. The ASCII copy is named P069492US_SeqListing.txt. It is 153 kilobytes in size. [Background technology]

[0003] Osteogenesis imperfecta (OI) is a condition characterized by bone fragility and reduced bone mass that results in connective tissue dysfunction. OI is a rare genetic disorder of the skeletal muscle that primarily, but not always, encodes type I collagen. It includes a group of inherited disorders resulting from mutations in genes that cause I One of two genes (COL1A1 and COL1A2) that encode type 1 collagen Clinically, OI is characterized by weak bones that fracture easily and without trauma. In addition, patients with OI may experience muscle weakness, hearing loss, fatigue, joint laxity, Brachymetics, bowed bones, spinal stenosis, blue sclerosis, dentinogenesis imperfecta, and short stature Mostly.

[0004] Clinical classification systems categorize OI into types I–V. Patients with type I OI usually have Patients with this condition suffer from a mild, non-deforming disease that is often associated with a premature stop codon in gene 1. results in a decrease in the rate of type I collagen production and quantitatively less collagen in the bone. Patients with type II OI usually present with respiratory failure as a result of multiple severe fractures involving the rib cage. OI types III and IV are caused by the COL1A1 and COL1 Three polypeptides of type I collagen, often associated with glycine substitutions in A2 A qualitative defect that prevents the chains from properly intertwining and forming the normal triple alpha-helical structure Type III OI is the most severe form of OI in those children who survive infancy. Although type IV is the most severe form of OI, patients with type IV have mild to moderate bone deformities. is rare. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for therapeutic methods and agents for the treatment of OI. [Means for solving the problem]

[0006] The present inventors have surprisingly found that anti-sclerosis is associated with increased risk of developing osteogenesis imperfecta (OI) in patients with osteogenesis imperfecta (OI). In the following examples, we confirm that the Rostin antibody can both increase bone formation and decrease bone resorption. As established by these findings, human patients with OI can be successfully treated with anti-sclerostin antibodies. The inventors have discovered that the present invention can be used to treat Nos. 7,879,322, 8,246,953, and 6,246,953, both of which are incorporated herein by reference. In No. 8,486,661, a high affinity, neutralizing, fully human anti-sclerostin monoclonal antibody Human anti-sclerostin monoclonal antibodies (collectively, "human anti-sclerostin monoclonal antibodies") and their They disclosed potent in vitro and in vivo activity of.

[0007] In one aspect, the invention provides a method for treating a patient comprising administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. In one embodiment, the present invention provides a method for treating a patient suffering from osteogenesis imperfecta, comprising: In a patient with osteogenesis imperfecta, by administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. In another aspect, the present invention provides a method for increasing bone formation and decreasing bone resorption in a bone The present invention provides an anti-sclerostin antibody for use in treating sclerostin hypoplasia. In one embodiment, Anti-sclerostin antibodies increase bone formation and / or decrease bone resorption. The embodiment applies to both of the above aspects. In one embodiment, the anti-sclerostin antibody is In the order of hypervariable regions, heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, SEQ ID NO: No. 15, and a heavy chain variable region CDR2 comprising the amino acid sequence described in SEQ ID NO: 26. At least one immunoglobulin heavy chain comprising a heavy chain variable region CDR3 comprising the amino acid sequence a) a variable domain (VH); and b) a hypervariable region, each having the amino acid sequence set forth in SEQ ID NO:37. a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:48; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59. , and at least one immunoglobulin light chain variable domain (VL). The anti-sclerostin antibody comprises: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; ) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26; (d) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37 (e) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:59. at least one or more complementary sequences selected from the group consisting of a light chain variable region CDR3 comprising In one embodiment, the anti-sclerostin antibody comprises a sequence identical to SEQ ID NO:2. 6. The anti-sclerostin antibody contains all six of the aforementioned CDRs.

[0008] In another embodiment, the anti-sclerostin antibody has (a) the amino acid sequence set forth in SEQ ID NO:4. (b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) SEQ ID NO: 48; and (f) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 59. or (a) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:4. (b) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 15; (c) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) An anti-sclerostin antibody comprising a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59. In a related embodiment, the anti-sclerostin antibody binds to the same epitope as the human sclerostin antibody. The sclerostin antibody has a VL polypeptide sequence having the amino acid sequence set forth in SEQ ID NO:81. and an anti-scan comprising a VH polypeptide sequence having the amino acid sequence set forth in SEQ ID NO: 70. In another embodiment, the anti-sclerostin antibody binds to the same epitope as the rerostin antibody. has a full-length light chain amino acid sequence having the amino acid sequence set forth in SEQ ID NO: 125 and SEQ ID NO: 114. An anti-sclerostin antibody comprising a full-length heavy chain amino acid sequence having the amino acid sequence set forth in claim 114. In one embodiment, the anti-sclerostin antibody binds to the same epitope as SEQ ID NO: 17. 3 and the full-length light chain amino acid sequence of SEQ ID NO: 172. The same epitope as the anti-sclerostin antibody containing the full-length heavy chain amino acid sequence Bind to. In one embodiment, the anti-sclerostin antibody has the following human sclerostin sequence: CGPA RLLPNAIGRGKWWRPSGPDFRC ("Loop 2 epitope"; SEQ ID NO: 1 74) and / or DVSEYCRELHFTR SAKPVTELVCSGQCGP ARWWRPSGPDFRCIPDRYR LVASCKCKRLTR("T20.6E Thus, in one embodiment, The anti-sclerostin antibodies of the invention bind to / within the Loop 2 epitope. In this study, anti-sclerostin antibodies bind to / within the T20.6 epitope. Anti-sclerostin antibodies that bind to / within the T20.6 epitope region are known in the art. For example, see International Publication No. WO 00 / 32773 and International Publication No. WO 2005 / 003158. No. 2005 / 014650, No. 2006 / 119107, No. Publication No. 2006 / 119062, International Publication No. 2009 / 039175 and International Publication No. See WO 2008 / 061013. The antibody " Ab-A, Ab-B, Ab-C, Ab-D, and Ab-1 are The six CDRs, heavy and light chain variable sequences of these antibodies are expressly incorporated by reference in this disclosure. In one embodiment, the anti-sclerotic antibody of the present invention expressly includes the full length heavy and light chain sequences. The stin antibody has a VL polypeptide sequence having the amino acid sequence set forth in SEQ ID NO: 176 and and an anti-sclerotic agent comprising a VH polypeptide sequence having the amino acid sequence set forth in SEQ ID NO: 177. In another embodiment, the anti-sclerostin antibody of the present invention binds to the same epitope as the anti-sclerostin antibody. The antibodies include Ab-A, Ab-B, Ab-C, and or binds to the same epitope as Ab-D.

[0009] In one embodiment, the anti-sclerostin antibody is selected from brosozumab.

[0010] In another embodiment, the anti-sclerostin antibody has at least one amino acid sequence similar to that set forth in SEQ ID NO:70. At least 90 (e.g., at least 95, 98, or 99 or 100) percent In yet another embodiment, the anti-sclerostin antibody comprises a VH having the identity No. 81 and at least 90 (e.g., at least 95, 98, or In yet another embodiment, the VL has 99 or 100 percent identity to the VL. Anti-sclerostin antibodies may have a sequence similar to that of SEQ ID NO: 70 but which is at least 90% identical (e.g. , at least 95, 98, or 99 or 100) percent identity; and the amino acid sequence set forth in SEQ ID NO: 81 and at least 90 (e.g., at least 95, 98, or 99 or 100 percent identity. In embodiments, the anti-sclerostin antibody has a VH having the amino acid sequence set forth in SEQ ID NO:70. and a VL having the amino acid sequence set forth in SEQ ID NO: 81. The anti-sclerostin antibody has at least one amino acid sequence similar to that of SEQ ID NO: 114 or 172. At least 90 (e.g., at least 95, 98, or 99 or 100) percent heavy chain having identity and / or the amino acid sequence set forth in SEQ ID NO: 125 or 173 Column and at least 90 (e.g., at least 95, 98, or 99 or 100) percent In one embodiment, the anti-sclerostin antibody comprises a light chain having the sequence identity of SEQ ID NO: 172 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 173. It contains a light chain having

[0011] In one embodiment, a therapeutically effective amount of an anti-sclerostin antibody is about 1 / kg body weight of a human patient. The antibody is about 1 to 50 mg.

[0012] Another aspect of the present invention is to increase bone formation and decrease bone resorption in patients with osteogenesis imperfecta. In some embodiments, the composition comprises a) a pharmaceutical composition comprising the sequence A heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an amino acid sequence set forth in SEQ ID NO: 15 heavy chain variable region CDR2 comprising the amino acid sequence set forth in sequence number 26; at least one immunoglobulin heavy chain variable domain (VH) comprising the variable region CDR3; and b) a light chain variable region C comprising, in order of hypervariable region, the amino acid sequence set forth in SEQ ID NO: 37. DR1, a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and SEQ ID NO: At least one immunogen comprising a light chain variable region CDR3 comprising the amino acid sequence described in No. 59. It contains an anti-sclerostin antibody that contains a globulin light chain variable domain (VL).

[0013] In another embodiment, the anti-sclerostin antibody in the pharmaceutical composition is the antibody set forth in SEQ ID NO: 70. The VH has at least 95 percent identity to the amino acid sequence. Thus, the anti-sclerostin antibody has at least 95 copies of the amino acid sequence set forth in SEQ ID NO:81. The VL has a central identity.

[0014] In yet another embodiment, the anti-sclerostin antibody has the amino acid sequence set forth in SEQ ID NO:70. and a VH having at least 95 percent identity to the amino acid sequence set forth in SEQ ID NO: 81. In yet another embodiment, the VL has at least 95 percent identity to the amino acid sequence. The anti-sclerostin antibody comprises a VH having the amino acid sequence set forth in SEQ ID NO: 70, and a VH having the amino acid sequence set forth in SEQ ID NO: 71. In yet another embodiment, the anti-scan antibody comprises a VL having the amino acid sequence set forth in sequence number 81. The rerostin antibody has a heavy chain having the amino acid sequence set forth in SEQ ID NO: 114 or 172; and / or a light chain having the amino acid sequence set forth in SEQ ID NO: 125 or 173. .

[0015] In one aspect, the invention provides a pharmaceutical composition comprising an anti-sclerostin antibody disclosed herein. In one embodiment, the pharmaceutical composition may be used in the methods / uses described herein. [Brief description of the drawings]

[0016] [Figure 1]FIG. 1 is a table showing the results of one-sample t-test results of bone turnover biomarkers. [Diagram 2] FIG. 2 is a table showing the results of two-sample t-tests of bone turnover biomarkers. [Diagram 3] FIG. 3 is a graph showing the ratio of PINP geometric mean (plus or minus SD) to baseline. [Figure 4] FIG. 4 is a graph showing the ratio of PICP geometric mean (plus or minus SD) to baseline. [Diagram 5] FIG. 5 is a graph showing the ratio of BSAP to baseline in geometric mean (plus or minus SD). [Figure 6] FIG. 6 is a graph showing the ratio of OC geometric mean (plus or minus SD) to baseline. [Figure 7] FIG. 7 is a graph showing the Bayesian posterior probability of the ratio of BMD of lumbar spine (measured by DXA) data to baseline. [Figure 8] FIG. 8 is a graph showing the ratio of baseline to geometric mean (plus or minus SD) of CTX-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention relates to a method for treating osteogenesis imperfecta (OI) in human patients with osteogenesis imperfecta (OI) by the administration of anti-sclerostin antibodies. Based on the unexpected and surprising discovery that anti-sclerotic drugs can be successfully administered to human OI patients, Administration of a stin antibody increases bone formation and decreases bone resorption, as shown in the Examples. .

[0018] Background: Sclerostin is expressed in humans by the SOST gene. Scleostin is a naturally occurring protein that is encoded by a C-terminal cysteine ​​knot-like (CTCK) domain and bone morphogenetic protein (BMP) antagonist DAN (di differential screening-selected gene aberr ative in neuroblastoma; differential screening Secretory proteins with sequence similarity to a family of genes abnormal in selected neuroblastomas It is a glycoprotein.

[0019] As shown for the first time by the present inventors, the inhibition of sclerostin by anti-sclerostin antibodies Inhibition of ribonuclease boosts bone formation and bone density, providing beneficial effects in the treatment of OI in humans. anabolic hormones prior to using GH or PTH to increase bone turnover Unlike treatment with anti-sclerostin antibodies, treatment with anti-sclerostin antibodies stimulates bone formation in patients with OI offers the advantage of inhibiting bone resorption. Bone formation is a therapeutic effect in diseases characterized by a severe lack of bone matrix, human This includes the treatment of osteogenesis imperfecta.

[0020] Thus, the present invention provides methods of using anti-sclerostin antibodies in the treatment of OI. The present invention is directed to compositions comprising anti-sclerostin antibodies for use in treating OI. In one embodiment, the present invention relates to the treatment of osteogenesis imperfecta types I, III, or IV. Thus, the present invention relates to a method for the treatment of OI, preferably type I, type III, or type IV OI. In one embodiment, the present invention provides an anti-sclerostin antibody for use in treating rheumatoid arthritis, the rheumatoid arthritis, and a pharmaceutical composition comprising said antibody. In one embodiment, the anti-sclerostin antibody of the present invention is a monoclonal anti-sclerostin antibody. In embodiments, the anti-sclerostin antibodies of the invention are human or humanized monoclonal anti-sclerostin antibodies. Alternatively, the antibody may be, for example, a chimeric antibody.

[0021] The methods and uses of anti-sclerostin antibodies of the present invention are directed to the finding that antibody treatment in OI patients reduces bone formation This was unexpected and surprising since it resulted in both an increase in bone mass and a decrease in bone resorption.

[0022] In order that the present invention may be more readily understood, certain terms are first defined. Further definitions are provided below. This will be described throughout the detailed description.

[0023] The term "comprising" encompasses "including" as well as "consisting of." For example, a composition "comprising" X may consist of X alone, or of something additional, e.g. For example, it may include X+Y.

[0024] The term "about" in relation to a numerical value x means, for example, x±10%.

[0025] The term sclerostin refers to human sclerostin as defined in SEQ ID NO:155. Recombinant human sclerostin can be obtained from R&D Systems (Minn. eapolis, Minn., USA; 2006 Catalog No. 1406-ST-025 In addition, recombinant mouse sclerostin / SOST is commercially available from R&D Systems. (Minneapolis, Minn., USA; 2006 Catalog No. 1 589-ST-025). U.S. Patent Nos. 6,395,511 and 6,803,453 No. 20040009535 and U.S. Patent Application Publication No. 200501066. No. 83 describes generally anti-sclerostin antibodies.

[0026] As used herein, the term "antibody" refers to whole antibodies and any antigen-binding fragments thereof (i.e. A naturally occurring "antibody" may comprise a single chain, an "antigen-binding portion," or a single chain. A glycoprotein that contains at least two heavy (H) chains and two light (L) chains interconnected by Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region (CCL). The light chain constant region consists of one domain, CL. The VL and VL regions are further subdivided into regions of hypervariability called complementarity determining regions (CDRs). They are interspersed with regions that are more conserved and called framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, The sequences are arranged in the following order to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3. , CDR3, FR4. The variable regions of the heavy and light chains form a binding domain that interacts with an antigen. The constant region of an antibody is involved in the functioning of various cells of the immune system (e.g., effector cells and Delivery of immunoglobulins to host tissues or factors, including the first component of the classical complement system (C1q). In one embodiment, references herein to antibodies refer to isolated, monoclonal antibodies. Includes clonal, human and humanized monoclonal antibodies.

[0027] The term "antigen-binding portion" of an antibody (or simply "antigen portion"), as used herein, refers to In this case, the full length or partial length of the antibody that retains the ability to specifically bind to an antigen (e.g., sclerostin) is refers to one or more fragments. The antigen-binding function of an antibody is performed by a fragment of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include: Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; F(ab)2 A fragment, comprising two Fab fragments linked by a disulfide bridge at the hinge region. a monovalent fragment; an Fd fragment consisting of the VH and CH1 domains; a VL and Fv fragment consisting of the VH domain and dAb fragment consisting of the VH domain (Ward et al., 198 9 Nature 341:544-546); as well as isolated complementarity determining regions (CDRs).

[0028] Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes. However, they are considered to be single protein chains in which the VL and VH regions pair to form monovalent molecules. The nucleotide sequences are joined using recombinant methods by synthetic linkers that allow the nucleotide sequences to be generated in a manner similar to that described above. (known as single-chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:42 3-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding region" of an antibody. These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments have similar properties to intact antibodies. Screen for use in the same manner.

[0029] As used herein, an "isolated antibody" refers to an antibody that is isolated from other antibodies having different antigen specificities. An isolated antibody that specifically binds sclerostin is substantially free of There are virtually no antibodies that specifically bind to antigens other than sclerostin. The isolated antibodies that specifically bind to clerostin can be used to bind to sclerostin molecules from other species, e.g. In addition, the isolated antibodies may be cross-reactive with other cellular material and / or other antigens. In one embodiment, references herein to antibodies include those that are isolated. The term "antibody" refers to an antibody that has been

[0030] As used herein, the term "monoclonal antibody" or "monoclonal antibody combination" refers to a "Composition" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition is particularly Each antibody exhibits a single binding specificity and affinity for a defined epitope.

[0031] As used herein, the term "human antibody" refers to an antibody in which both the framework and CDR regions are It is intended to include antibodies having variable regions derived from sequences of human origin. When constant regions are included, the constant regions may also be human sequences, e.g., human germline sequences. or variants of the human germline sequence or Knappik, et al. (2000. J Mol Biol 296, 5 7-86) It is derived from the framework sequence.

[0032] Human antibodies may include amino acid residues that are not encoded by human sequences (e.g., in Random or site-directed mutagenesis in vitro or somatic cells in vivo However, as used herein, the term "human antibody" refers to a human antibody that is " refers to a CDR sequence derived from the germline of another mammalian species, e.g., mouse, that is cloned into a human framework. It is not intended to include antibodies that have been grafted onto the sequence.

[0033] The term "human monoclonal antibody" refers to an antibody in which both the framework and CDR regions are human. In one embodiment, the antibody is an antibody that exhibits a single binding specificity and has variable regions derived from a human The monoclonal antibodies are made by combining human heavy and light chain transgenes fused to immortalized cells. Transgenic non-human animals having a genome including a gene, e.g., transgenic mice It is produced by a hybridoma containing B cells obtained from a mouse.

[0034] As used herein, the term "recombinant human antibody" refers to an antibody prepared, expressed, or processed by recombinant means. All human antibodies currently produced or isolated, e.g., human immunoglobulin gene transcripts, transgenic or transchromosomal animals (e.g., mice) or The antibody isolated from the hybridoma prepared from the human antibody transformed to express the human antibody. Antibodies isolated from host cells, e.g., transfectomas, recombinant, combinatorial Antibodies isolated from an alhuman antibody library and human immunoglobulin gene sequences Prepared by any other means, including splicing all or part of the gene to another DNA sequence. Such recombinant human antibodies include antibodies that have been produced, expressed, generated or isolated using a framework. The variable regions are derived from human germline immunoglobulin sequences, and the CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are modified in vitro. Allogeneic (or in vivo, when animals transgenic for human Ig sequences are used) in vivo somatic mutagenesis) and thus the VH and VV of the recombinant antibody can be The amino acid sequences of the L regions are derived from and related to human germline VH and VL sequences, but These are sequences that cannot naturally occur in the human antibody germline repertoire in vivo.

[0035] In one embodiment, and as used herein, an antibody that binds sclerostin (e.g., Antibodies, such as anti-sclerostin antibodies, are known to specifically bind to sclerostin polypeptides. "Specifically binds to a sclerostin polypeptide" means 1×10 -8 More than M Bottom, 1×10 -9 M or less, or 1×10 -10 K below M D Sclerostin Polypeptide As used herein, the term "K" is intended to refer to an antibody that binds to a K D "teeth, Intended to refer to the dissociation constant, K d Against K a The ratio of (i.e., K d / K a ) and is obtained by mole It is expressed as a concentration (M). K D Values ​​are calculated using methods established in the art. The K of the antibody can be determined by D The method for determining the By using a biosensor system such as the Biacore® system, evening.

[0036] Standard assays to assess the binding ability of antibodies to sclerostin from various species are available in the art. These techniques are well known in the art and include, for example, ELISA, Western blot and RIA. Suitable assays are described in detail in WO 2009 / 047356. Antibody Binding Kinetics (e.g., binding affinity) may also be determined by the assay, e.g., by Biacore analysis. The functional properties of sclerostin can be assessed by standard assays known in the art. Assays to evaluate the efficacy of antibodies (e.g., receptor binding, osteolysis prevention or amelioration) are available internationally. Further details are described in Publication No. 2009 / 047356.

[0037] As used herein, the percent identity between two sequences is the best fit between the two sequences. The number of gaps that need to be introduced for alignment, and the length of each gap. It is a function of the number of identical positions shared by the sequences (i.e., % identity = identical positions) (# of positions / total # of positions × 100). Sequence comparison and percent identity between two sequences Gender determination may be accomplished using a mathematical algorithm, as described in the non-limiting examples below. .

[0038] The percent identity between two amino acid sequences was determined using the ALIGN program (version 2. 0) by E. Meyers and W. Miller (Comput. Appl. Bios ci., 4:11-17, 1988) algorithm to generate the PAM120 weight residue table ( weight residue table), with a gap length penalty of 12 and a gap penalty of 4 Additionally, the percent identity between two amino acid sequences can be determined using the GCG software. The GAP program is incorporated into the GCG software package (available at http: / / www.gcg.com). The algorithm of Needleman and Wunsch (J. Mol. Biol. 48:444-453, 1970) is used. Use either the Blossom62 matrix or the PAM250 matrix , as well as gap weights 16, 14, 12, 10, 8, 6 or 4 and long weights 1, 2, 3, 4, 5 or 6 may be used to determine.

[0039] Additionally or alternatively, the protein sequences of the present invention may be further used to identify, for example, related sequences. The sequence is used as a "query sequence" to perform searches against public databases. Such searches can be performed using the XBL method of Altschul, et al., 1990 J. Mol. Biol. 215:403-10. This can be performed using the AST program (version 2.0). BLAST Proteins The search was performed with the XBLAST program, score=50, word length=3. Amino acid sequences homologous to the antibody molecule of interest can be obtained. To obtain the above compound, the method described in Altschul et al., 1997 Nucleic Acids Res. 25(17):3389-3402 was used. For example, Gapped BLAST can be used. When using the LAST program, each program (e.g., XBLAST and Default parameters of the NCBI and NBLAST can be used. See gov.

[0040] Various aspects of the invention are described in further detail in the following subsections. Methods and uses of anti-sclerostin antibody treatment in treating OI

[0041] In one aspect, the invention provides a method of treating an OI patient with an anti-sclerostin antibody or The present invention relates to the use of anti-sclerostin antibodies in the treatment of OI. Treatment with this agent can both increase bone formation and decrease bone resorption in OI patients. The present invention provides anti-sclerostin antibodies for use in treating OI. Suitable anti-sclerostin antibodies for use in the present invention are disclosed herein.

[0042] In some embodiments, the present invention provides a method for increasing bone formation and bone resorption in OI patients. The method comprises administering to a patient a therapeutically effective amount of an anti-sclerostin antibody. In one embodiment, treatment of an OI patient with an anti-sclerostin antibody of the invention comprises Increasing bone formation and / or decreasing bone resorption in patients with OI.

[0043] In one embodiment, the VH amino acid sequence of the anti-sclerostin antibody is set forth in SEQ ID NOs: 69-77. The VL amino acid sequences of the anti-sclerostin antibodies are shown in SEQ ID NOs: 80 to 88, respectively. The corresponding full-length heavy chain amino acid sequences of sclerostin antibodies are shown in SEQ ID NOs:113-121. The corresponding full-length light chain amino acid sequences of the anti-sclerostin antibodies are shown in SEQ ID NOs: 124 to 13, respectively. In another embodiment, the anti-sclerostin antibody is mutated in the CDR region. still have at least 60, 70, 80, 90 or more amino acid sequences corresponding to the CDR regions shown in the above sequences. In yet another embodiment, the amino acid sequence has 95 percent or more identity to the amino acid sequence. In one embodiment, the anti-sclerostin antibody has, when compared to the CDR regions shown in the sequences above: Mutated amino acid sequences with only 1, 2, 3, 4 or 5 amino acid mutations in the CDR regions Includes.

[0044] In some embodiments, the parent nucleotide sequence of the variable heavy chain of an anti-sclerostin antibody is The parent nucleotide sequence of the variable heavy chain of the anti-sclerostin antibody is shown in SEQ ID NO: The full-length light chain nucleotide sequence optimized for expression in mammalian cells is shown in The full-length heavy chain nucleotides optimized for expression in mammalian cells are shown in SEQ ID NOs: 146 to 154. The light chain sequences are shown in SEQ ID NOs: 135 to 143. The full-length light chain amino acid sequences to be encoded are shown in SEQ ID NOs: 124 to 132. The full-length heavy chain amino acid sequence encoded by the octide sequence is shown in SEQ ID NOs: 113 to 121. In other embodiments, the anti-sclerostin antibody is mutated but still has at least one similar sequence to the above. having at least 60, 70, 80, 90 or 95 percent or more identity In some embodiments, the anti-sclerostin antibody comprises an amino acid or nucleic acid that binds to the When compared to the variable regions shown in the sequence above, only 1, 2, 3, or 4 or 5 amino acid mutated but retaining substantially the same therapeutic activity. .

[0045] In other embodiments, the VH, VL, full-length light chain, and full-length heavy chain sequences (nucleotide sequences The sequences (i.e., sequences and amino acid sequences) can be "mixed and matched." Sclerostin binding of the "mixed and matched" antibodies is described above and in the Examples. The chains can be mixed and tested using a binding assay (e.g., ELISA) that uses When matching, the VH sequence from a particular VH / VL pair is structurally similar to the VH sequence. Similarly, the full-length heavy chain sequence from a particular full-length heavy chain / full-length light chain pair should be replaced with The sequence should be replaced with a structurally similar full-length heavy chain sequence. The VL sequence from the VL pair should be replaced with a structurally similar VL sequence. In particular, a full-length light chain sequence from a particular full-length heavy chain / full-length light chain pair may be replaced with a structurally similar full-length light chain sequence. Therefore, in one aspect, the present invention provides SEQ ID NOs: 69 to 77 a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 80 to 88; An isolated monoclonal antibody having a light chain variable region comprising an amino acid sequence selected from the group consisting of: The present invention provides a cloned antibody or antigen-binding region thereof, the antibody specifically binding to sclerostin. do.

[0046] In some embodiments, the anti-sclerostin antibody is selected from the group consisting of (i) SEQ ID NOs: 113-121 The amino acid sequence optimized for expression in mammalian cells is selected from the group consisting of: full length heavy chain; and SEQ ID NOs: 124 to 132 in a mammalian cell. An isolated monoclonal antibody having a full-length light chain that contains an amino acid sequence optimized for expression in a mammalian cell line. or (ii) a functional protein comprising an antigen-binding portion thereof.

[0047] In other embodiments, the anti-sclerostin antibody consists of (i) SEQ ID NOs: 135-143. A total of nucleotide sequences optimized for expression in mammalian cells selected from the group consisting of: long heavy chain; and a mammalian cell selected from the group consisting of SEQ ID NOs: 146-154 An isolated monoclonal antibody having a full-length light chain comprising a nucleotide sequence optimized for expression by or (ii) a functional protein containing an antigen-binding portion thereof.

[0048] In yet another embodiment, the anti-sclerostin antibody comprises the heavy and light chain CDR1, CD Amino acids of VH CDR1, CDR2, and CDR3, or a combination thereof, of the antibody The sequences are shown in SEQ ID NOs: 1 to 11. The amino acid sequence of the VH CDR2 of the antibody is shown in SEQ ID NO: 1. The amino acid sequences of the VH CDR3 of the antibody are shown in SEQ ID NOs: 23 to 33. The amino acid sequences of the VL CDR1 of the antibody are shown in SEQ ID NOs: 34 to 44. The amino acid sequences of R2 are shown in SEQ ID NOs: 45 to 55. The sequences are shown in SEQ ID NOs: 56 to 66. The CDR regions were determined according to the Kabat system (Kabat, EA, et al. , 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, US Depa The Department of Health and Human Services, NIH Publication No. 91-3242) can be.

[0049] In some embodiments, the anti-sclerostin antibody comprises the VH CDR1, 2 and 3 sequences and VL CDR1, 2 and 3 sequences created after "mixing and matching" (i.e., CDRs from different antibodies can be mixed and matched). Sclerostin binding of such "mixed and matched" antibodies is described above and in the Examples. The VH can be tested using a binding assay (e.g., ELISA) as described in When mixing and matching CDR sequences, the CDR1, CDR2 and / or the CDR3 sequence should be replaced with a structurally similar CDR sequence. Similarly, when mixing and matching VL CDR sequences, the CDRs from a particular VL sequence may The DR1, CDR2 and / or CDR3 sequences are replaced with structurally similar CDR sequences. The new VH and VL sequences should be The CDR region sequences are shown herein for the monoclonal antibodies of the invention. It will be readily apparent to those skilled in the art that the present invention can be produced by substituting a structurally similar sequence derived from the It is understood.

[0050] For example, the anti-sclerostin antibody may comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12 to 22; heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 23 to 33; heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 44 a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45 to 55; and a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 56 to 66; The antibody can have a light chain variable region CDR3 comprising a selected amino acid sequence, It specifically binds to rostin.

[0051] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:3; Heavy chain variable region CDR2 of SEQ ID NO: 14; heavy chain variable region CDR3 of SEQ ID NO: 25; 36; light chain variable region CDR2 of SEQ ID NO:47; and SEQ ID NO:5 8 light chain variable region CDR3.

[0052] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:4; Heavy chain variable region CDR2 of SEQ ID NO: 15; heavy chain variable region CDR3 of SEQ ID NO: 26; 37; the light chain variable region CDR2 of SEQ ID NO:48; and SEQ ID NO:5 9 light chain variable region CDR3.

[0053] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:5; Heavy chain variable region CDR2 of SEQ ID NO: 16; heavy chain variable region CDR3 of SEQ ID NO: 27; 38; the light chain variable region CDR2 of SEQ ID NO:49; and SEQ ID NO:6 0 light chain variable region CDR3.

[0054] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:6; Heavy chain variable region CDR2 of SEQ ID NO: 17; heavy chain variable region CDR3 of SEQ ID NO: 28; 39; light chain variable region CDR2 of SEQ ID NO:50; and SEQ ID NO:6 It contains the light chain variable region CDR3 of 1.

[0055] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:7; Heavy chain variable region CDR2 of SEQ ID NO: 18; heavy chain variable region CDR3 of SEQ ID NO: 29; 40; the light chain variable region CDR2 of SEQ ID NO:51; and SEQ ID NO:6 It contains the light chain variable region CDR3 of 2.

[0056] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:8; Heavy chain variable region CDR2 of SEQ ID NO: 19; heavy chain variable region CDR3 of SEQ ID NO: 30; 41; the light chain variable region CDR2 of SEQ ID NO:52; and SEQ ID NO:6 3 light chain variable region CDR3.

[0057] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:9; Heavy chain variable region CDR2 of SEQ ID NO: 20; heavy chain variable region CDR3 of SEQ ID NO: 31; 42; the light chain variable region CDR2 of SEQ ID NO:53; and SEQ ID NO:6 4 light chain variable region CDR3.

[0058] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO: 10. ; Heavy chain variable region CDR2 of SEQ ID NO: 21; Heavy chain variable region CDR3 of SEQ ID NO: 32; No. 43; the light chain variable region CDR1 of SEQ ID NO: 54; and the light chain variable region CDR2 of SEQ ID NO: Contains 65 light chain variable region CDR3.

[0059] In certain embodiments, the anti-sclerostin antibody comprises the heavy chain variable region CDR1 of SEQ ID NO:11. ; Heavy chain variable region CDR2 of SEQ ID NO: 22; Heavy chain variable region CDR3 of SEQ ID NO: 33; No. 44; the light chain variable region CDR2 of SEQ ID NO: 55; and SEQ ID NO: It contains 66 light chain variable region CDR3s.

[0060] In certain embodiments, the anti-sclerostin antibody has the amino acid sequence set forth in SEQ ID NO:70. The VH polypeptide comprises a VH polypeptide amino acid sequence having at least 95 percent identity.

[0061] In certain embodiments, the anti-sclerostin antibody has the amino acid sequence set forth in SEQ ID NO:81. The VL polypeptide amino acid sequence has at least 95 percent identity.

[0062] In certain embodiments, the anti-sclerostin antibody has the amino acid sequence set forth in SEQ ID NO:70. VH polypeptide amino acid sequences with at least 95 percent identity and SEQ ID NO: 81. A VL polypeptide having at least 95 percent identity to the amino acid sequence set forth in Contains the amino acid sequence.

[0063] In certain embodiments, the anti-sclerostin antibody comprises the VH polypeptide set forth in SEQ ID NO:70. The VL polypeptide amino acid sequence set forth in SEQ ID NO:81 is also included.

[0064] In certain embodiments, the anti-sclerostin antibody is set forth in SEQ ID NO: 114 or 172. The heavy chain polypeptide amino acid sequence and the light chain polypeptide set forth in SEQ ID NO: 125 or 173 It contains the amino acid sequence of the tide.

[0065] In a preferred embodiment, the anti-sclerostin antibody is a human anti-sclerostin monoclonal antibody. The antibody BPS804 is a monoclonal antibody. BPS804 has the following CDRs: Heavy chain variable region CDR1 of SEQ ID NO: 15; heavy chain variable region CDR2 of SEQ ID NO: 26 light chain variable region CDR3 of SEQ ID NO: 37; light chain variable region CDR1 of SEQ ID NO: 48 2; and the light chain variable region CDR3 of SEQ ID NO: 59. VH and VL of BPS804 The sequences are the VH polypeptide amino acid sequence set forth in SEQ ID NO:70 and the VH polypeptide amino acid sequence set forth in SEQ ID NO:81. The heavy and light chain sequences of BPS804 comprise the VL polypeptide amino acid sequence of SEQ ID NO: The heavy chain polypeptide amino acid sequence set forth in SEQ ID NO:172 and the light chain polypeptide amino acid sequence set forth in SEQ ID NO:173 Contains a peptide amino acid sequence.

[0066] Further features of the anti-sclerostin antibodies of the invention, such as BPS804, are described in the disclosure and discussion therein. and WO 2009 / 047356, the data of which are incorporated herein by reference. By way of example only, antibodies of the invention may exhibit at least one of the following functional properties: Antibodies inhibit the inhibitory effect of sclerostin in a cell-based wnt signaling assay Blocking antibodies inhibit the inhibitory effect of sclerostin in a cell-based calcification assay Blocking antibodies inhibit the inhibitory effect of sclerostin in the Smad1 phosphorylation assay blocking, antibodies that inhibit the binding of sclerostin to LRP-6, and antibodies As mentioned above, these properties are consistent with those described in WO 02 / 06336. This is described in detail in US Pat. No. 2009 / 047356.

[0067] "Blocking the inhibitory effects of sclerostin in a cell-based wnt signaling assay" For an antibody that blocks the agonist, this means an IC50 of less than 1 mM, 100 nM, 20 nM, , 10 nM or less cell-based super top flash In the STF (top flash) assay, the presence of sclerostin inhibited the wnt-induced signaling pathway. The term "antibody" is intended to refer to an antibody that restores signal transmission. No. 5,333,636 describes the wnt STF assay.

[0068] Antibodies that "block the inhibitory effects of sclerostin in a cell-based mineralization assay" For the body, this means IC50s of less than 1 mM, 500 nM, 100 nM, 10 nM , 1 nM or less in the presence of sclerostin in cell-based assays It is intended to refer to an antibody that restores BMP2-induced calcification.

[0069] Antibodies that block the inhibitory effect of sclerostin in the Smad1 phosphorylation assay For the body, this means IC50s of less than 1 mM, 500 nM, 100 nM, 10 nM , 1 nM or less in the presence of sclerostin in cell-based assays It is intended to refer to an antibody that restores BMP6-induced Smad1 phosphorylation.

[0070] For antibodies that "inhibit sclerostin binding to LRP-6," this is an IC is 1mM, 500nM, 100nM, 10nM, 5nM, 3nM, 1nM or more It is intended to refer to antibodies that inhibit the binding of sclerostin to small LRP-6.

[0071] With respect to antibodies that "increase bone formation and bone mass and bone density," this refers to bone formation, bone mass and and bone mineral density at high anabolic doses, such as daily intermittent treatment with 100 μg / kg hPTH. is intended to refer to an antibody capable of reaching the levels of daily intermittent treatment with PTH. can be.

[0072] In one embodiment, the anti-sclerostin antibodies of the invention increase bone formation and / or Decreases bone resorption. Medication Regimen

[0073] Dosage regimens are adjusted to provide the optimum desired response (eg, a therapeutic response). For example, a single bolus may be administered, or several divided doses may be administered over time, or or as indicated by the exigencies of the therapeutic situation, the dosage may be proportionally reduced or increased. Parenteral compositions are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the dosage unit form is advantageously formulated to Refers to physically discrete units suited as unitary dosages for subjects; each unit may A predetermined amount calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier. The specifications of the dosage unit forms of the present invention are based on the unique characteristics of the active compound. and the specific therapeutic effect to be achieved, as well as the therapeutic sensitivity in the individual. The present invention is regulated by and directly depends on the inherent limitations of the technology for formulating such active compounds. In one embodiment, the dosage unit form of the invention contains 10 to 5000 mg of anti-sclerostin antibody, or 10~4000mg, 10~3000mg, 10~2000mg, 10~1000mg, 10~500mg, 10~400mg, 10~300mg, 10~200mg, 10~1 50mg, 10~100mg, 10~80mg, 10~60mg, 10~50mg, 10 ~40mg, 10~35mg, 10~30mg, 10~25mg, 10~20mg, if In one embodiment, the dosage unit form contains 150 mg of an anti-sclerosing agent. In another embodiment, the dosage unit form contains 210 mg of anti-sclerostin antibody. Includes.

[0074] In one embodiment, the anti-sclerostin antibody in the dosage unit form is lyophilized and in powder form. In another embodiment, the anti-sclerostin antibody dosage unit form is in solution. In one embodiment, the dosage unit form of the present invention is contained within a container such as a vial. In an embodiment, the container is a syringe.

[0075] In addition to the active agent (i.e., anti-sclerostin antibody), the dosage unit form may contain one or more It may contain multiple additional substances and / or excipients. In one embodiment, the dosage unit form is , the following: sucrose, arginine hydrochloride, L-histidine, polysorbate 80, hydrochloric acid and and water for injection (WFI).

[0076] In one aspect, the invention provides an anti-sclerostin antibody of the invention or a pharmaceutical composition of the invention; Alternatively, a kit comprising the lyophilisate of the invention or the dosage unit form of the invention is provided. Optionally, the kit may further comprise, for example, a patient information leaflet, instructions for reconstitution of the lyophilisate, and / or instructions for administration. The syringe includes one or more therapeutically effective doses of an anti-sclerostin antibody. The anti-sclerostin antibody in the range may be in liquid or lyophilized form. Solutions for reconstitution of lysates and / or infusion fluids (e.g., 5% dextromethorphan in sterile water) The composition may further include a base.

[0077] For administration of anti-sclerostin antibodies, dosages are as described above per kilogram of patient body weight. From about 1 milligram (herein referred to as "mg / kg" throughout this application) to 50 mg / kg of antibody kg, more typically about 1 to 30 mg / kg, and even more typically about 1 to 2 For example, dosages range from about 5 mg / kg body weight to about 10 mg / kg Body weight, about 20 mg / kg body weight, or within the range of about 5-20 mg / kg.

[0078] In another embodiment of the invention, the anti-sclerostin antibody is administered at a dose of 1-50 mg / kg of patient body weight. g, for example 2-50, 3-50, 5-50, 8-50 mg / kg.

[0079] In one embodiment, the anti-sclerostin antibody is administered at a dose of 2-50 mg / kg of patient body weight. The dose is, for example, 2-45, 2-40, 2-35, or 2-30 mg / kg.

[0080] In one embodiment, the anti-sclerostin antibody is administered at a dose of 3 to 50 mg / kg of patient body weight. The dose is, for example, 3-45, 3-40, 3-35, or 3-30 mg / kg.

[0081] In one embodiment, the anti-sclerostin antibody is administered at a dose of 5-50 mg / kg of patient body weight. The dose may be, for example, 5-45, 5-40, 5-35, or 5-30 mg / kg.

[0082] In one embodiment, the anti-sclerostin antibody is administered at a dose of 8 to 50 mg per kg of patient body weight. The dose is, for example, 8-45, 8-40, 8-35, or 8-30 mg / kg.

[0083] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-50 mg / kg of patient body weight. Administered at doses, e.g., 10-45, 10-40, 10-35, 10-30 mg / kg .

[0084] In one embodiment, the anti-sclerostin antibody is administered at a dose of 11-50 mg / kg of patient body weight. Administered at doses, e.g., 11-45, 11-40, 11-35, 11-30 mg / kg .

[0085] In one embodiment, the anti-sclerostin antibody is administered at a dose of 12-50 mg / kg of patient body weight. Administered at doses, e.g., 12-45, 12-40, 12-35, 12-30 mg / kg .

[0086] In one embodiment, the anti-sclerostin antibody is administered at a dose of 15-50 mg / kg of patient body weight. Administered at doses, e.g., 15-45, 15-40, 15-35, 15-30 mg / kg .

[0087] In one embodiment, the anti-sclerostin antibody is administered at a dose of 18-50 mg / kg of patient body weight. Administered at doses, e.g., 18-45, 18-40, 18-35, 18-30 mg / kg .

[0088] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20-50 mg / kg of patient body weight. Administered at doses, e.g., 20-45, 20-40, 20-35, 20-30 mg / kg .

[0089] In one embodiment, the anti-sclerostin antibody is administered at a dose of 5-20 mg / kg of patient body weight. The dose is, for example, 8-20, 10-20, 12-20, or 15-20 mg / kg.

[0090] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 mg / kg of patient body weight, or administered at 1, 2, 3, 4, 5, 6, 7, 8, or 9 mg / kg.

[0091] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20 mg / kg of patient body weight, or 11, 12, 13, 14, 15, 17, 18, or 19 mg / kg.

[0092] In one embodiment, the anti-sclerostin antibody is administered at a dose of 30 mg / kg of patient body weight, or 21, 22, 23, 24, 25, 26, 27, 28, or 29 mg / kg .

[0093] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 mg / kg of patient body weight. In a related embodiment, the anti-sclerostin antibody is administered at a dose of 8 to 12 mg / kg. It is administered at a dose of 8 to 15 mg / kg.

[0094] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20 mg / kg of patient body weight. In a related embodiment, the anti-sclerostin antibody is administered at a dose of 18-22 mg / kg. dose, or 15-25 mg / kg.

[0095] In another embodiment of the invention, the anti-sclerostin antibody is administered at a dose of 10 to 5000 mg. In one embodiment, the anti-sclerostin antibody is administered in an amount of 10 to 4000 mg, 10 to 3000 mg, or mg, 10~2000mg, 10~1000mg, 10~500mg, 10~400mg , 10~300mg, 10~200mg, 10~150mg, 10~100mg, 10~ 80mg, 10~60mg, 10~50mg, 10~40mg, 10~35mg, 10~ Administered in doses of 30 mg, 10-25 mg, 10-20 mg, or 10-15 mg In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 to 3500 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 to 3000 mg. In an embodiment, the anti-sclerostin antibody is administered at a dose of 10 to 2000 mg. In one embodiment, the anti-sclerostin antibody is administered in a dose of 10 to 1500 mg. In one embodiment, the anti-sclerostin antibody is administered in a dosage of 10 to 1000 mg.

[0096] Exemplary treatment regimens include once per week, once every two weeks, once every three weeks, once every four weeks, Once every hour, once every month, once every 5 weeks, once every 6 weeks, once every 7 weeks once every 8 weeks, once every 2 months (i.e., every other month), once every 3 months (i.e., , 4 times a year), once every 3 to 6 months, every 6 months, or annually under dosing schedules such as Multiple doses may be administered, which may be the same or different dosages, for example, in the range of about 5 to 20 mg / kg. In some embodiments, multiple doses are administered once per week, twice per week, or in combination with a single dose. Once per week, once per 3 weeks, once per 4 weeks, once per month, once per month, once per 5 weeks once every 6 weeks, once every 7 weeks, once every 8 weeks, or once every 2 months (i.e. , bimonthly), once every 3 months, once every 3 to 6 months, semiannually, or annually. Under the current rule, 2 to 20 doses are administered, more commonly 2 to 10 doses, and even more commonly 3 to 5 doses. There may be 5 doses, and even more commonly 3 doses.

[0097] In another aspect of the invention, the anti-sclerostin antibody is administered daily, weekly, biweekly, monthly, bimonthly, yearly, or at a dose of 100 mg / kg / day. It may be administered to patients four times or annually.

[0098] In one embodiment, the anti-sclerostin antibody is administered to the patient weekly. , administration occurs every 2, 3, 4, 5, 6, or 7 weeks.

[0099] In one embodiment, the anti-sclerostin antibody is administered to the patient monthly. , administration occurs every 2, 3, 4, 5, or 6 months.

[0100] In one embodiment, the anti-sclerostin antibody is administered to the patient every three months (i.e., four times a year). In the event of more frequent dosing regimens, for example weekly or daily dosing, A route of administration that allows the patient to self-administer is preferred. Examples include subcutaneous, topical, or oral routes of administration. Facilitate self-administration of anti-sclerostin antibodies and eliminate the need to visit a doctor / hospital to receive treatment There may be cases where it is no longer necessary.

[0101] Another exemplary treatment regimen is to administer the treatment until a treatment target is achieved or reached in the patient, e.g. Multiple doses may be administered, which may be the same or different dosages, for example, in the range of about 5 to 20 mg / kg. A treatment target is achieved or reached after a certain number of doses are administered. Treatment targets are complete normalization of bone mineral density, partial normalization of bone mineral density, or reduction in fracture incidence. decreased frequency of bone formation markers, increased levels of bone resorption markers, or Thus, in one embodiment, the invention relates to a method for treating sclerostin-related of use in the treatment of OI, reducing fracture rates in a patient / patient population compared to a The present invention provides an anti-sclerostin antibody for the treatment of sclerostin deficiency. Also 10, 20, 30, 35, 40, 50, 60, 70, 80, or 90 percent bone In one embodiment, the anti-sclerostin antibody reduces the rate of remission of sclerostin by at least 30 percent. Reduces fracture rates. In one embodiment, fractures are defined as peripheral or spinal fractures (severe Includes all major, minor, and clinical spinal fractures; those without clinical symptoms and detected only by investigative means. In one embodiment, the fracture is confirmed by radiological examination. The fracture rate is related to the patient population. The patient population and the control patient population are preferably statistically The size is such that meaningful comparisons can be made.

[0102] In one aspect of the invention, the treatment regimen comprises a first administration regimen, optionally followed by a second administration regimen. The administration regimen includes the dose to be administered and the frequency of administration. These may be selected from any of the above doses and administration frequencies, depending on the clinical condition of the patient. The dosages and administration frequencies disclosed above may be varied according to the specific needs of the patient. is expressly incorporated herein by reference.

[0103] By way of example, in one embodiment, the first dosing regimen comprises 1 to 50 mg / kg of patient body weight. mg, or 2-50 mg / kg, or 3-50 mg / kg, or 5-50 mg / kg g, or 8-50 mg / kg, or 3-30 mg / kg, 5-30 mg / kg, or 8-30mg / kg, 10-30mg / kg, 12-30mg / kg, or or 15-30 mg / kg, or 12-25 mg / kg, or 15-25 mg / kg In another exemplary embodiment, the first dosing regimen is 10 to 20 mg / month. The dose is 5000mg per month.

[0104] In one embodiment, the first dosing regimen comprises 1-50 mg / kg of patient body weight monthly. The aim is to administer

[0105] In one embodiment, the first dosing regimen comprises 2-50 mg / kg of patient body weight monthly. The aim is to administer

[0106] In one embodiment, the first dosing regimen comprises 2-30 mg / kg of patient body weight monthly. The aim is to administer

[0107] In one embodiment, the first dosing regimen comprises 3-50 mg / kg of patient body weight monthly. The aim is to administer

[0108] In one embodiment, the first dosing regimen comprises 3-30 mg / kg of patient body weight monthly. The aim is to administer

[0109] In one embodiment, the first dosing regimen comprises 5-30 mg / kg of patient body weight monthly. The aim is to administer

[0110] In one embodiment, the first dosing regimen comprises 5-25 mg / kg of patient body weight monthly. The aim is to administer

[0111] In one embodiment, the first dosing regimen is 12-25 mg / kg of patient body weight per day. The dose is given monthly.

[0112] In one embodiment, the first dosing regimen is 20 mg / kg of patient body weight administered monthly. To do so.

[0113] In another exemplary embodiment, the first dosing regimen comprises 1 to 50 mg / kg of patient body weight. mg, or 2-50 mg / kg, or 3-50 mg / kg, or 5-50 mg / kg g, or 8-50 mg / kg, or 8-30 mg / kg, or 10-30 mg / kg g, or 12-30 mg / kg, or 15-30 mg / kg, or 12-25 mg / kg, or 15-25 mg / kg administered four times a year. In this condition, the first dosing regimen is 10 to 5000 mg administered four times a year.

[0114] In one embodiment, the first dosing regimen is 2-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0115] In one embodiment, the first dosing regimen is 3-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0116] In one embodiment, the first dosing regimen is 5-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0117] In one embodiment, the first dosing regimen is 5-25 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0118] In one embodiment, the first dosing regimen comprises 12-25 mg / kg of patient body weight per year. It is administered four times.

[0119] In one embodiment, the first dosing regimen is 20 mg / kg patient body weight administered four times a year. The purpose is to give.

[0120] In one embodiment, and by way of example only, the second dosing regimen comprises 1-50 mg / kg, or 2-50 mg / kg, or 3-50 mg / kg, or 5-5 0 mg / kg, or 8 to 50 mg / kg, or 3 to 30 mg / kg, 5 to 30 mg / kg, or 8-30 mg / kg, or 10-30 mg / kg, or 12-30 mg / kg, or 12-25mg / kg, or 15-30mg / kg, or 15-25 In another exemplary embodiment, the second dosing regimen is The recommended dosage is 10 to 5,000 mg per month.

[0121] In one embodiment, the second dosing regimen is 1-50 mg / kg of patient body weight monthly. The aim is to administer

[0122] In one embodiment, the second dosing regimen is 2-50 mg / kg of patient body weight monthly. The aim is to administer

[0123] In one embodiment, the second dosing regimen is 2-30 mg / kg of patient body weight monthly. The aim is to administer

[0124] In one embodiment, the second dosing regimen is 3-50 mg / kg of patient body weight monthly. The aim is to administer

[0125] In one embodiment, the second dosing regimen is 3-30 mg / kg of patient body weight monthly. The aim is to administer

[0126] In one embodiment, the second dosing regimen is 5-30 mg / kg of patient body weight monthly. The aim is to administer

[0127] In one embodiment, the second dosing regimen is 5-25 mg / kg of patient body weight monthly. The aim is to administer

[0128] In one embodiment, the second dosing regimen is 12-25 mg / kg of patient body weight per day. The dose is given monthly.

[0129] In one embodiment, the second dosing regimen is 20 mg / kg of patient body weight administered monthly. To do so.

[0130] In another embodiment, the second dosing regimen is 1-50 mg / kg of patient body weight, or or 2-50 mg / kg, or 3-50 mg / kg, or 5-50 mg / kg, or 8-50mg / kg, 3-30mg / kg, 5-30mg / kg, or 8-3 0 mg / kg, or 10-30 mg / kg, or 12-30 mg / kg, or 12 ~25mg / kg, or 15-30mg / kg, or 15-25mg / kg every other month In another exemplary embodiment, the second dosing regimen is 10 to 500 The recommended dose is 100 mg every other month.

[0131] In one embodiment, the second dosing regimen is 1-50 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0132] In one embodiment, the second dosing regimen is 2-50 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0133] In one embodiment, the second dosing regimen is 2-30 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0134] In one embodiment, the second dosing regimen is 3-50 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0135] In one embodiment, the second dosing regimen is 3-30 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0136] In one embodiment, the second dosing regimen is 5-30 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0137] In one embodiment, the second dosing regimen is 5-25 mg / kg of patient body weight every other month. The best way to administer this is to administer it at 100 mg / kg / day.

[0138] In one embodiment, the second dosing regimen is administered every 12 to 25 mg / kg of patient body weight. The dose is given once a month.

[0139] In one embodiment, the second dosing regimen is 20 mg / kg patient body weight administered every other month. The purpose is to give.

[0140] In another exemplary embodiment, the second dosing regimen comprises 1 to 50 mg / kg of patient body weight. mg, or 2-50 mg / kg, 3-50 mg / kg, or 5-50 mg / kg, or or 8-50 mg / kg, or 8-30 mg / kg, or 10-30 mg / kg, or or 12-30mg / kg, or 12-25mg / kg, or 15-30mg / kg or 15-25 mg / kg administered four times a year. The second dosing regimen is 10 to 5,000 mg given four times a year.

[0141] In one embodiment, the second dosing regimen is 2-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0142] In one embodiment, the second dosing regimen is 3-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0143] In one embodiment, the second dosing regimen is 5-30 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0144] In one embodiment, the second dosing regimen is 5-25 mg / kg of patient body weight four times a year. The aim is to administer the drug once.

[0145] In one embodiment, the second dosing regimen is 12-25 mg / kg of patient body weight per year. It is administered four times.

[0146] In one embodiment, the second dosing regimen is 20 mg / kg patient body weight administered four times a year. The purpose is to give.

[0147] In a related embodiment, the first dosing regimen is 20 mg / kg of patient body weight per day. monthly, and the second dosing regimen is 20 mg / kg of patient body weight every other month. or given four times a year.

[0148] The duration of administration of the first and second dosing regimens will vary depending on the clinical needs of the patient. Thus, the first dosing regimen may be administered for a first period of time and the second dosing regimen may be administered for a second period of time. It is administered for a period of 2.

[0149] Thus, and by way of example, the first and second periods may be 1 month, 6 months, 12 months, or any other period of time.

[0150] In one embodiment, the anti-sclerostin antibody is administered to the patient monthly initially for one year, followed by It may be administered every other month or four times a year for at least one year (eg, two or more years).

[0151] Thus, in one embodiment, the first dosing regimen comprises 2 doses per kg of body weight of a human patient. 0 mg per month for one year, and the second dosing regimen may be 20 mg per kg every other month or 4 times a year for at least 1 year (e.g., 2 years or more) It may be by administering.

[0152] The drug-free period, i.e., the period during which anti-sclerostin antibodies are not administered, also had a clinically significant effect on patients. The present invention contemplates the use of anti-sclerotic agents in accordance with the above-mentioned needs. Treatment with the stimulant antibody may be continued for one month or more (e.g., 2, 3, 4, 5, 6, 8, 1 0, 12 or more) or even a year or more.

[0153] Measurement of targets is known in the art. For example, bone mineral density can be measured using dual energy X-ray absorptiometry. Conventional (DXA), single-energy X-ray absorptiometry (SXA), quantitative computed tomography DXA can be measured by bone imaging (CT), and ultrasound. It is the standard X-ray technique for density measurement. It can be used to measure any skeletal region. However, clinical judgment is usually made on the lumbar spine and hips. Portable DXA machines have been developed to measure bones (vertebrae) or fingers (phalanges), and DXA can also be used to measure body composition. As a result, T scores can be used to relate results to "normal" values. Standardized implementation will be used and individual results will be compared with a race- and sex-matched younger cohort. Instead, Z-scores compare individual outcomes across years that are also matched for race and gender. Compare with that of an age-matched population. So, for example, a Z score of -1 (average for age) A 60-year-old woman with a T score of -2.5 (1 SD lower than the mean of the young control group) 2.5 SD lower).

[0154] Yet another exemplary treatment regimen includes administering the same or different dosages, e.g., about 5 to 10 mg of each of the same or different doses. In the 20 mg / kg range, long-term use with no specific timeline for stopping administration was considered. This requires the administration of multiple doses, which may be repeated at any one time. This is because the doses are sufficient to maintain improved symptoms on an ongoing basis. The treatment regimen may be followed as needed to maintain the condition.

[0155] In other embodiments, the dosing regimen of the anti-sclerostin antibody comprises a time period between two consecutive doses. Sequential intravenous administration at intervals of 1 to 3 weeks, preferably 2 weeks, at the same dosage, e.g. Includes three doses at 5 mg / kg body weight, 10 mg / kg body weight, or 20 mg / kg body weight. In other embodiments, the dosing regimen of the anti-sclerostin antibody comprises between two consecutive doses Three different doses of the drug are administered intravenously, successively at intervals of 1 to 3 weeks, preferably 2 weeks. Amounts, for example, first 5 mg / kg body weight, then 10 mg / kg body weight, and finally 20 mg In yet another embodiment, the administration of the anti-sclerostin antibody comprises three doses at 100 mg / kg body weight. The drug regimen should be sequential with an interval of 1-3 weeks, preferably 2 weeks, between two successive doses. Three different doses, e.g., 20 mg / kg body weight, then 10 mg / kg body weight, administered intravenously. mg / kg body weight, and finally three doses at 5 mg / kg body weight.

[0156] In some embodiments, the anti-sclerostin antibody and one with a different binding specificity Alternatively, multiple monoclonal antibodies may be administered simultaneously or sequentially, in which case The dosage of each antibody is within the ranges indicated. In one embodiment, one or more additional monoclonal antibodies Clonal antibodies are also anti-sclerostin antibodies. The antibodies are usually administered multiple times. The interval between doses may be, for example, weekly, monthly, every two months (i.e., every other month), every three months, or every The intervals may also be years. In some methods, the dosage may be irregular, as indicated by the plasma Antibody concentrations of about 1-1000 μg / ml, and in some methods about 25-300 μg / m In one embodiment, the dosing of the anti-sclerostin antibody of the invention is adjusted to achieve The dose achieves a plasma antibody concentration of about 1-1000 μg / ml or about 25-300 μg / ml. The input is adjusted to

[0157] Alternatively, in some embodiments, the anti-sclerostin antibody is administered as a sustained release formulation. In this case, the frequency of administration may be less. The dosage and frequency are This varies depending on the half-life of the antibody in the patient. Generally, human antibodies have the longest half-life. The figures show the dosing and administration of antibodies, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The frequency can vary depending on whether the treatment is prophylactic or therapeutic. A relatively low dosage is administered at relatively infrequent intervals for a long period of time. In therapeutic applications, relatively high dosages are administered at relatively short intervals to treat the disease. The patient is then given a partial or complete recovery from the symptoms of the disease. Patients may be required to undergo prophylaxis until complete improvement is observed. It can be done.

[0158] In some embodiments, the actual dosage level of the anti-sclerostin antibody is determined based on the specific OI. A method for administering a compound that is effective to achieve a desired therapeutic response to a patient, composition, and mode of administration without toxicity to the patient. The dosage level selected may be varied to obtain an amount of anti-sclerostin antibody that is free of the activity of the particular composition of the invention used, the route of administration, the time of administration, the particular In combination with the rate of excretion of the anti-sclerostin antibody, the duration of treatment, and the particular composition used. Other drugs, compounds and / or substances used, the age, sex, weight, condition of the patient to be treated Various pharmacokinetic factors, including the patient's condition, general health and medical history, and similar factors well known in the pharmaceutical arts, will be considered. Depends on the form factor.

[0159] A "therapeutically effective amount" of an anti-sclerostin antibody is one that reduces the severity of disease symptoms, reduces the frequency of asymptomatic disease, To prevent the increase in severity and duration of, or impairment or inconvenience due to, the suffering of a disease. It is possible.

[0160] Anti-sclerostin antibody compositions may be prepared using one or more of a variety of methods known in the art. The composition may be administered by one or more routes of administration, as will be understood by those of skill in the art. As such, the route and / or mode of administration will vary depending upon the desired results. The route of administration of the antibody can be, for example, by injection or infusion, intravenously, intramuscularly, intradermally, intraperitoneally, This includes subcutaneous, spinal, or other parenteral routes of administration. In one embodiment, administration is via the intravenous route. In one embodiment, administration is via injection. In the present specification, the phrase "parenteral administration" generally refers to administration by injection. means any mode of administration other than enteral and topical administration, including intravenous, intramuscular, intra-arterial, intrathecal, Intracavitary, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, intravenous Including, but not limited to, intrathecal, subarachnoid, intrathecal, epidural and intrasternal injections and infusions. I can't.

[0161] Alternatively, the anti-sclerostin antibody can be administered by a route other than parenteral, such as topical, epithelial, or mucosal. by a route of administration, for example, intranasally, orally, vaginally, rectally, sublingually, or topically. It can be administered. Anti-sclerostin antibodies are available as implants, transdermal patches, and microencapsulated delivery systems. The compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation comprising Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, Uses polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid Many methods for the preparation of such formulations are patented or publicly available. These are generally known to those skilled in the art. For example, see Sustained and Controlled Release Drug Delivery See Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. patient group

[0162] In one embodiment, the methods and uses described herein comprise the anti-sclerosing agents described herein. The current study is aimed at treating osteogenesis imperfecta using tyrosine kinase antibodies. OI is a treatment for osteogenesis imperfecta that depends on the genetics and severity of the disease. Classified by Van Dijk and Sillence (the entire contents of which are incorporated herein by reference). 2014, Am J Med Genet Part A 164A:1470-1481 and Van Dijk and S According to the classification of OI type I and OI type I (Illence, 2014, Am J Med Genet Part A 167A:1178), OI can be classified as type I, type III, type IV, or type V. The classification is based on clinical The combination of evaluation / diagnosis, biochemical analysis, and molecular genetic testing provides a method for determining whether a patient is a candidate for the disease, as is routinely done by those skilled in the art. As used herein, the nomenclature / classification of OIs is as referenced in the above publications. , as proposed by Van Dijk and Sillence.

[0163] In 80% to 90% of people with OI, OI is caused by the alpha 1 and 2 forms of type I collagen. The COL1A1 and COL1A2 genes encoding the alpha 2 chain (17q21, respectively) It is caused by mutations in 7q.33 and 7q.22.3. A comprehensive database of known mutations along with genotype-phenotype correlations is published (https: / / oi.gene.le.ac.uk / home.php; accessed 12 December 2016). Other genes, e.g. For example, mutations in CRTAP, LEPRE1 or PPIB are also known. Molecular genetic testing for mutations in the COL1A1 and COL1A2 genes is known to those of skill in the art. For example, Korkko et al. (1998) reported that the COL1A1 gene and the COL PCR amplification of the 1A2 gene followed by conformational sensitive gel electrophoresis (CSGE (Am. J. Hum. Genet. 62:98-110, 1998). (2010) described multiplex ligation-dependent probe amplification (MLPA) technology. (Genet Med 12(11):736-741) described detection of COL1A1 mutations using COL1A1 ELISA. Arvai, K. et al. (2016) describe a next-generation sequencing method (Sci. Rep. 6, 28417), which references are incorporated herein by reference.

[0164] In one embodiment, the methods and uses described herein are directed to treating a deficiency in type I collagen, e.g. For the treatment of patients with OI types I-IV. As a result, collagen fibrils and hydrolases The normal structure of bone, which consists of hydroxyapatite crystals, is altered, causing brittleness. In some embodiments, the methods and uses herein are directed to detecting a gene that is involved in the expression of COL1A1 and / or COL1A2. The present invention is for the treatment of human OI patients characterized by one or more mutations in the

[0165] In one embodiment, the methods and uses described herein include those comprising the steps I, III and / or IV In one embodiment, OI types I, III and IV are treated with DNA testing, This is confirmed by detection of COL1A1 / COL1A2 mutations. In embodiments, the methods and uses herein are directed to COL1A1 and / or COL1A2. Types I, III and / or IV O characterized by one or more mutations in It is for the treatment of I.

[0166] In some embodiments, the methods and uses of anti-sclerostin antibodies are directed to treating mild to severe cases of OI. In another embodiment of the method and use of the anti-sclerostin antibody, In one embodiment, the patient under treatment has OI type I, OI type II, OI type III, or OI type IV. In yet other embodiments of the anti-sclerostin antibody methods and uses, the OI patient is 18 years of age or older. In still other embodiments of the methods and uses of anti-sclerostin antibodies, In particular, the OI patient is a pediatric patient. Pediatric patients as defined herein include, for example, 2-17, 3- As used herein, the term includes children aged 0 to 17 years, such as 17, 4 to 17, or 5 to 17 years. When used herein, the term patient refers to a human patient. Pharmaceutical Compositions

[0167] In another aspect, the present invention provides a method for increasing bone formation in a patient suffering from osteogenesis imperfecta. and a pharmaceutical composition for reducing bone resorption, the composition comprising an anti-sclerostin compound as described above. The pharmaceutical composition may be formulated with a pharma- ceutical acceptable carrier. In one embodiment, the present invention provides a pharmaceutical composition comprising an anti-sclerostin antibody as disclosed herein. In one embodiment, a pharmaceutical composition comprising an anti-sclerostin antibody is provided for use in the treatment of OI. This is for use in

[0168] As used herein, a "pharmaceutically acceptable carrier" refers to any physiologically compatible All solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delay agents Carriers include agents and the like that are administered intravenously (e.g., by injection or infusion), intramuscularly, subcutaneously, parenterally, The anti-sclerosing agent should be suitable for oral, spinal or epidermal administration. The antibody was used to protect the compound from the effects of acids and other natural conditions that may render the compound inactive. The material may be coated with a substance to enhance the adhesion.

[0169] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the presence of microorganisms can be achieved by sterilization procedures and the use of various antibacterial and antifungal agents, For example, the inclusion of parabens, chlorobutanol, phenol sorbic acid, etc. It is also possible to include isotonic agents, for example, sugars, sodium chloride, and the like in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by administering drugs that delay absorption. This can be achieved by the inclusion of agents such as aluminum monostearate and gelatin.

[0170] Pharmaceutically acceptable carriers include any suitable carrier for the extemporaneous preparation of sterile injectable solutions or dispersions. Such vehicles for pharma- ceutically active substances include sterile aqueous solutions or dispersions and sterile powders. The use of such media and agents in combination with the active compounds is well known in the art. Except where incompatible, their use in the pharmaceutical compositions of the present invention is contemplated. Active compounds can also be incorporated into the compositions.

[0171] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. do not have.

[0172] Sterile injectable solutions may be prepared by incorporating the active compounds in the required amounts in an appropriate solvent, as listed above. They can be formulated one or a combination and then prepared by sterile microfiltration when necessary. Typically, the dispersion contains a basic dispersion medium and other necessary components from those listed above. Sterile injectable solutions are prepared by incorporating the active compound in a sterile vehicle having In the case of sterile powders for the preparation of + Vacuum drying and freeze drying (freezing) to obtain a powder of any further desired ingredients Thus, in one embodiment, the anti-sclerostin antibody of the invention / the anti-sclerostin antibody of the invention The pharmaceutical composition is formulated as a lyophilized powder. In a related embodiment, the lyophilizate is It is reconstituted prior to administration. Suitable liquids for reconstitution include water for injection (wfi).

[0173] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form is This will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that can be produced in a single dosage form is usually determined by the amount of the composition that produces a therapeutic effect. Typically, out of 100 percent, this amount is the amount of a pharma- ceutically acceptable carrier. The combination contains from about 0.01 percent to about 99 percent of the active ingredient, and from about 0.1 percent to about 99 percent of the active ingredient. range from about one percent to about 70 percent, or from about 1 percent to about 30 percent. do.

[0174] The pharmaceutical compositions of the invention and the antibodies of the invention may also be used in combination therapy, i.e. in combination with other active agents. For example, the combination therapy may include at least one other anti-inflammatory agent or Combination therapy may include an anti-sclerostin antibody of the invention in combination with an anti-osteoporosis agent. Examples of therapeutic agents that may be used in the treatment of rheumatoid arthritis include bisphosphonates (e.g., alendronate, risedronate, etc.). Sodium tartrate, ibandronic acid, zoledronic acid, olpadronic acid, neridronic acid, Kelid, Bonefos), parathyroid hormone (e.g., teriparatide (rDNA ori gin injection), calcium receptor antagonists (calcilytics), calcium receptor agonists (calcilytics) alcimimetics (e.g., cinacalcet), statins, anabolic steroids, lanthanides The present invention includes fluoride, fluorine and strontium salts, and sodium fluoride. The anti-sclerostin antibodies of the present invention are directed to calcitonin or its analogs or derivatives. , e.g. salmon, eel, or human calcitonin, calcium receptor antagonists, calcium receptor agonists (e.g., cinacalcet); steroid hormones, e.g., estrogen; Partial estrogen agonists or combinations of estrogen and progesterone, SERMs (selected selective estrogen receptor modulators), e.g. raloxifene, lasofoxifene , bazedoxifene, arzoxifene, FC1271, tibolone (Livial (registered trademark), SARMs (selective androgen receptor modulators), RANKL antibodies (e.g. denosumab), cathepsin K inhibitors, vitamin D or their analogs, or PT H, PTH fragments or PTH derivatives, such as PTH(1-84) (e.g., Preos( (trademark) (parathyroid hormone 1-84)), PTH(1-34) (e.g., Forteo (trademark) Target) (Teriparatide (rdna origin) injection)), PTH (1-36), PTH (1-38), PTH(1-31)NH2 or PTS893 According to another embodiment, the antibody of the present invention may be administered in combination with a viscous Sulfonates (e.g., Fosamax® (alendronic acid), Actonel® ( (risedronate sodium), Bonviva(TM) (ibandronate), Zom eta™ (zoledronic acid), Aclasta™ / Reclast™ ( Zoledronic acid), olpadronic acid, neridronic acid, skelid, bonefos), statins , anabolic steroids, lanthanum and strontium salts, and sodium fluoride These drugs may be used in combination with other current osteoporosis treatment approaches, including chemotherapy.

[0175] In one embodiment, the antibodies of the invention are LRP4 modulators, i.e., LRP4 expression or activity. The LRP4 receptor may be administered in combination with a sex-regulating agent, such as an LRP4 neutralizing antibody.

[0176] In one embodiment, the antibodies of the invention are LRP5 modulators, i.e., LRP5 expression or activity. The drug may be administered in combination with a sex-regulating agent, such as an LRP5 neutralizing antibody.

[0177] In another embodiment, the antibodies of the invention are DKK1 modulators, i.e., inhibitors of Wnt signaling. Agents that interfere with or neutralize Dkk-1 mediated antagonism, such as DKK1 neutralizing antibodies. They may be administered in combination.

[0178] In one embodiment, the antibodies of the invention are administered in combination with bisphosphonates, e.g., alendronate, risedronate, sodium tartrate, ibandronic acid, zoledronic acid, olpadronic acid, nephronate It may be administered in combination with lidronate, skelid, and bonefos.

[0179] In one embodiment, the antibody of the invention is a combination of (i) zoledronic acid, (ii) an anti-DKK1 antibody, (iii) alendronate, (iv) anti-LRP4 antibody, (v) hPTH and / or (v i) It may be administered in combination with a parathyroid hormone releasing agent (calcium receptor antagonist).

[0180] Other agents that may be administered in combination with the anti-sclerostin antibodies of the invention include vitamin D and In one embodiment, the compound contains vitamin D and / or calcium. is administered if the patient is vitamin D and / or calcium deficient.

[0181] In one embodiment, the antibody of the invention may be administered in combination with another agent, such as an agent described above, in sequence (e.g., In one embodiment, the anti-sclerostin antibody is administered The dosage and frequency of administration are as described above. The appropriate dosage of the combination therapy will depend on the clinical condition of the patient. This may be changed according to specific needs.

[0182] The compositions are preferably formulated at physiological pH.

[0183] Therapeutic compositions can be administered by medical devices known in the art. In embodiments, the therapeutic compositions of the invention are administered in a needleless hypodermic injection device, such as those described in U.S. Pat. No. 9,163; No. 5,383,851; No. 5,312,335; No. 5,064,41 No. 3; No. 4,941,880; No. 4,790,824 or No. 4,596,556 The well-known implants and modules useful in the present invention may be administered by the devices shown in An example of a tool is an implantable microinfusion pump for delivering drugs at a controlled rate. U.S. Pat. No. 4,487,603, which shows a therapeutic device for administering drugs through the skin. U.S. Patent No. 4,486,194 showing a drug delivery system for delivering drugs at precise infusion rates; U.S. Patent No. 4,447,233 showing an infusion pump; variable flow rate for continuous drug delivery. U.S. Patent No. 4,447,224 showing an implantable infusion device; multiple chamber co U.S. Pat. No. 4,439,196, which shows an osmotic drug delivery system having compartments; and and U.S. Patent No. 4,475,196, which shows an osmotic drug delivery system. The present invention is incorporated herein by reference in its entirety. In one embodiment, the therapeutic composition of the present invention is administered by a syringe. It can be administered by

[0184] In certain embodiments, the antibodies of the invention are It can be formulated into

[0185] In one aspect, the present invention provides an anti-sclerosing agent for the manufacture of a medicament for the treatment of osteogenesis imperfecta. All other aspects / embodiments described herein are in accordance with the present invention. This rule applies equally to the specific aspects of the

[0186] In another aspect, the invention provides an anti-sclerostin antibody for use in treating osteogenesis imperfecta. All other aspects / embodiments described herein relate to this particular aspect of the invention. Apply equally.

[0187] In one aspect, the present invention provides a method for determining the incidence of fractures occurring in a clinical trial population at interim time points during a clinical trial. and comparing the number of fractures to the predicted number of fractures at said interval in said clinical trial population. Anti-sclerostin antibodies are provided for use in clinical trials for osteogenesis imperfecta.

[0188] In a related aspect, the present invention provides a method for determining whether a patient is at increased risk of developing a pulmonary hypertension or increased risk of developing a pulmonary hypertension. and comparing the number of fractures to the number of fractures predicted at said interval in said clinical trial population. The present invention provides a method for conducting a clinical trial of osteogenesis imperfecta with an anti-sclerostin antibody, comprising: In one embodiment of the aforementioned aspect, the aspect further comprises determining the number of fractures in the clinical trial population at an interim time point. If the number of fractures in the clinical trial population is less than the expected number, then additional patients are added to the clinical trial population. In one embodiment, the method further comprises recruiting a patient in an interim clinical trial population. If the number of fractures occurring during the clinical trial is less than the expected number of fractures in the clinical trial population, In another embodiment, the number of fractures in the clinical trial population at the time point is A higher than expected number of fractures in the clinical trial population will shorten the duration of the clinical trial. The population consisted of patients receiving anti-sclerostin antibodies and a control group of patients receiving a placebo. An advantage of these aspects / embodiments is that clinical trial duration is timed according to clinical occurrence. This will ultimately result in more efficient and cost-effective clinical trials that benefit patients. The projected number of fractures is based on historical data and / or the start of the clinical trial period. This can be calculated from baseline fracture rates, which can be derived from data from previous clinical trial populations. In embodiments, the anti-sclerostin antibody is an anti-sclerostin antibody as defined herein. Interval time points may be varied and selected according to where statistically significant comparisons are made. The clinical trial period begins with administration of anti-sclerostin antibody or placebo and continues until the end of the The study will be terminated once the final dose of sclerostin antibody / placebo has been administered and relevant data have been collected. do.

[0189] BPS804 H chain sequence (SEQ ID NO:172):

[0190] [ka]

[0191] BPS804 light chain sequence (SEQ ID NO: 173):

[0192] [ka] EXAMPLES

[0193] Modes for carrying out the invention

[0194] [Example 1] This example evaluates the use of anti-sclerostin antibodies in the treatment of adult patients with OI. This paper describes a clinical trial to determine whether the drug is effective in treating chronic conditions. Patients received 100 mg of the drug as an intravenous infusion, 2 weeks apart from each dose. The study was conducted in a randomized controlled trial of 11 patients treated with three sequential intrapatient escalating doses of the anti-sclerostin antibody BPS804. An untreated reference group was also randomly assigned to study participants with regard to changes in bone biomarker profiles. Patients were enrolled for monitoring and observation of natural OI disease progression. A randomized, open-label, within-patient study with an untreated reference group in 14 adult patients with I This was a dose-escalation study of 100 mg / kg / day ...

[0195] Patients received escalating doses of anti-sclerostin antibody every 2 weeks: Week 1: 5 mg / kg g, week 3: 10 mg / kg and week 5: 20 mg / kg. Treatment duration was approximately 3.6 months. At screening, patients were randomized to the untreated reference group and followed for a follow-up period of 10 days. Patients were admitted to the study facility only on Study Day 43, Week 7, and at the end of the study.

[0196] A description of the study drug BPS804 is presented in Table 1. BPS804 solutions for infusion were prepared as desired. was administered as an infusion at a flow rate of approximately 2 mL / min until a dose of 100 mg / kg was delivered.

[0197] Type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal pro Peptide (PICP), bone-specific alkaline phosphatase (BSAP), osteocalc Biomarkers of bone metabolism, including bone mineral density (OC), and bone mineral density (BMD) (measured by DXA) were also included. Markers were assayed at baseline, days 43 and 141.

[0198] [Table 1]

[0199] Of the 14 patients enrolled in the study, 9 patients were treated with anti-sclerostin antibodies. The overall mean age of patients in the anti-sclerostin antibody group was 27.4 years compared with the reference group. The overall mean weight and height between the two groups were significantly higher (30.7 years). A summary of patient demographics is presented in Table 2. Overall median lumbar spine z-scores The CORE was relatively low in the anti-sclerostin antibody group. Considering the relative size of the number of patients in each group, comparisons between groups are not possible, see Table 3.

[0200] [Table 2]

[0201] [Table 3]

[0202] Assay results of bone turnover biomarkers for the study are presented in Figure 1. Day 43 PI The geometric mean ratios of NP, PICP, BSAP, and OC were P 1.84, 1.5 for values ​​<0.001, 0.003, <0.001, and 0.012 The ratios of the geometric means of BMD at day 141 were P value 0.3, 1.59, and 1.44. It was .038 and 1.04.

[0203] Bayesian analyses of the changes from baseline in PINP, PICP, and BSAP were performed with a small Approximately 9% for an increase of at least 70% (PINP) or 30% (PICP, BSAP) The Bayesian analysis of BMD showed a posterior probability of 0% or higher. and 87% posterior probability for at least a 2% increase. For details of the INP, PICP, BSAP, OC, and BMD results, see Figures 3, 4, and See Figures 5, 6 and 7.

[0204] The geometric mean results for CTX-1 from days 8 to 43 were based on CTX-1 concentration levels. Figure 8 shows a reduction in bone mineral density, which, together with the results of bone formation biomarkers, supports bone anabolism. At day 43, baseline values ​​in the BPS804 group were The ratio from the line was 56% of baseline, thus a decrease of 44%. Concentration levels increased gradually from day 1 to day 85, and then slightly at days 113 and 141. It decreased.

[0205] Comparison of the ratios with the matched ratios in the reference group was performed using a planned two-sample t-test (one-sided). A P value of less than 0.1 in this comparison was considered evidence in favor of efficacy. Based on two-sample t-test analysis, PINP, PICP, BSAP, and For OC and OC, the P values ​​were <0.001, 0.014, 0.006, and 0.015. The p-value for the BMD treatment group comparison was 0.1, with no significant difference in the reference group. The evidence also supports that the increase was greater in the presence of anti-sclerostin antibodies than in the absence of anti-sclerostin antibodies. See Figure 2. These analyses showed that the mean mean age of the control group was 18.1 years for all three biomarker data and BMD data. We found evidence of a greater increase in anti-sclerostin antibodies in the control group than in the control group.

[0206] After administration of anti-sclerostin antibody, median PINP, PICP, BSAP activity, and O C levels increased by 84%, 53%, 59%, and 44%, respectively, on day 43, but In the treatment control group, the corresponding biomarkers remained unchanged or were modestly decreased. Furthermore, after administration of the anti-sclerostin antibody, CTX-1 levels increased from baseline to 43 days 44% decrease from baseline. Bone formation biomarkers (PINP, PICP, BSAP and OC) Increased levels of sclerosing agent and decreased levels of bone resorption biomarker (CTX-1) were associated with anti-sclerosing agent This is in line with the observed increase in lumbar spine BMD of approximately 4% at day 141 in the antibody-treated group. , and therefore the bone anabolic effects of anti-sclerostin antibodies in patients with osteogenesis imperfecta. Review the initial clinical evidence.

[0207] Furthermore, the study demonstrated that anti-sclerostin antibodies are safe and effective in adult patients with OI. The most commonly reported AEs were headache, influenza The AEs reported were nausea, arthralgia, and fatigue. There were no AEs reported that were considered related to the study drug. There was one mild SAE (goiter) reported in one patient in the reference group. The SAEs were considered serious due to hospitalization. The SAEs resolved before the end of the study. No signs of organ toxicity were observed. Three bone fractures were reported during the study (subject 5103-47 days). (Subject 5109-Day 4, Subject 5113-Day 4). There were no clinically significant abnormalities in bed chemistry, urinalysis, ECG or vital sign data.

[0208] Clinical trial results show that osteoanabolic treatments such as BPS804 have demonstrated bone formation and osteoanabolic activity. Sexuality can be stimulated in patients with OI. Increases in BMD lead to improved bone quality. Genotyping may be used to determine the risk of developing osteoporosis and bone fractures, thereby resulting in reduced fracture rates and risks. Identification or prediction of OI patients who will most benefit from the strategy may be warranted.

[0209] [Example 2] Combination of clinical trial data and publicly available data on other anti-sclerostin antibodies Based on the results, the pharmacokinetic (PK) and metabolic effects of circulating sclerostin after BPS804 administration were In addition to the pharmacokinetic (PK) model, a pharmacodynamic (PD) model for BPS804 was also developed. A PK-PD model was developed to evaluate the proposed dosing regimen of BPS804. The model was linked to existing systems pharmacology models. Provides guidance on dose selection and dosing intervals over 1-2 years of treatment of patients with chronic OI These are the first year (e.g., dosage and QM (i.e., monthly) vs. Q3M (i.e., Comparison of different dosing conditions (i.e., four times a year) and the following year (e.g., QM to Q3M dosing) The study included scenarios for the conditions of switching to the

[0210] result: Data show that the BPS804 dosing regimen that results in near-maximal (>75%) inhibition of sclerostin is , circulating sclerostin, bone turnover markers (BTM), and lumbar bone mineral density (BMD) ) provides a near-maximal response. A range of doses from to 20 mg / kg were administered QM (i.e. monthly) and The simulation was performed using Q3M (i.e., quarterly) and Q3M (i.e., quarterly) intervals. The results are for all BPS804 Exposure was hypothesized to act on sclerostin and evaluated for maximum inhibition. The 20 mg / kg QM dose approached the maximum sclerostin response. Maximal level of inhibition was reached by both monthly and quarterly dosing regimens, as well as QM and Q3 Both M 20 mg / kg dosing regimens reached maximum inhibitory levels.

[0211] Modeling results suggest that BPS804 may be a potent inhibitor of sclerostin, due to its longer-lasting inhibition. Therefore, the BPS804 20mg / kg QM dose had similar or similar efficacy compared with the Q3M dose. It has further been shown to provide significantly higher 12-month BMD gains.

[0212] After one year of treatment with BPS804 20 mg / kg QM, the maximum peaks were almost the same. A clerostin response can also be achieved with a 20 mg / kg dose administered four times a year. This potential change in dosing regimen following administration of sclerostin inhibitors was This may reflect the attainment of a new steady state in the bone remodeling system. Therefore, less frequent dosing after the first year of treatment may maintain the BMD gains from the first year of treatment. It may be possible.

[0213] In summary, modeling data indicates that BPS804 20 mg / kg QM dose provides a maximum These results suggest that the BMD response is predicted to be associated with near-maximal inhibition of sclerostin expression. In addition, extended dosing intervals for long-term treatment (e.g., every 2 months after 1 year of QM) are also possible. The effect of switching to Q2M or Q3M on bone turnover markers after the first year of treatment was This may be advantageous given the changes observed in

[0214] The patents and publications cited herein describe ordinary skill in the art. In the event of any conflict between said references and this specification, the present specification shall control. In describing the embodiments, specific terminology is used for the sake of clarity. The disclosure is not intended to be limited to the particular terminology so selected. The present invention should not be construed as limiting the scope of the present invention. The above embodiments are illustrative and non-limiting as would be recognized by one of ordinary skill in the art in light of the above teachings. Thus, modifications and variations can be made without departing from the invention. and to the full extent of their equivalents, the invention may be practiced otherwise than as specifically described. is understood.

Claims

1. administering to the human patient a therapeutically effective amount of an anti-sclerostin antibody. A method for treating osteogenesis imperfecta (OI) using a method comprising administering to said patient a therapeutically effective amount of the compound.

2. The method of claim 1, wherein the OI is type I OI, type III OI, or type IV OI. Law.

3. The human patient has one or more The method of claim 1 or 2, which has multiple mutations.

4. The anti-sclerostin antibody, (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59 contains; or (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59 Anti-sclerostin antibodies that bind to the same epitope as anti-sclerostin antibodies comprising The method according to any one of claims 1 to 3, comprising:

5. The anti-sclerostin antibody comprises a VL polypeptide having the amino acid sequence set forth in SEQ ID NO:

81. and a VH polypeptide sequence having the amino acid sequence set forth in SEQ ID NO:

70. The method of claim 4, wherein the antibody binds to the same epitope as an anti-sclerostin antibody.

6. The anti-sclerostin antibody has a full length light chain having the amino acid sequence set forth in SEQ ID NO:

173. The amino acid sequence and the full length heavy chain amino acid sequence having the amino acid sequence set forth in SEQ ID NO: 172 The method of claim 5, wherein the antibody binds to the same epitope as an anti-sclerostin antibody comprising

7. The anti-sclerostin antibody, (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59 The present invention relates to a method for the preparation of a nucleic acid sequence comprising administering to a patient a nucleic acid sequence comprising administering to said ... The method according to any one of items 1 to 3.

8. The anti-sclerostin antibody comprises at least the amino acid sequence set forth in SEQ ID NO:

26. The method of claim 7, comprising the heavy chain variable region CDR3.

9. The anti-sclerostin antibody, (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59 The method of claim 7 or 8, comprising:

10. The anti-sclerostin antibody, a) having at least 90 percent sequence identity with the amino acid sequence set forth in SEQ ID NO: 70 and / or a VH polypeptide sequence comprising b) having at least 90 percent sequence identity with the amino acid sequence set forth in SEQ ID NO:81; VL polypeptide sequence The method according to any one of claims 7 to 9, comprising:

11. The anti-sclerostin antibody comprises a VL polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

81. A VH polypeptide sequence comprising the amino acid sequence set forth in SEQ ID NO: 70, The method of claim 10.

12. Anti-sclerostin antibodies a) having at least 90 percent sequence identity with the amino acid sequence set forth in SEQ ID NO: 172; and / or a full length heavy chain amino acid sequence b) having at least 90 percent sequence identity with the amino acid sequence set forth in SEQ ID NO: 173; Full-length light chain amino acid sequence The method according to any one of claims 7 to 11, comprising:

13. The anti-sclerostin antibody comprises a full-length light chain amino acid sequence set forth in SEQ ID NO:

173. and a full-length heavy chain amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO:

172. The method of claim 12 .

14. The anti-sclerostin antibody is selected from SEQ ID NO: 174 and / or SEQ ID NO:

175. The method according to any one of claims 1 to 3, wherein the nucleic acid sequence is a sequence that is to be detected by the nucleic acid sequence analysis.

15. The anti-sclerostin antibody has a VL polypeptide having the amino acid sequence set forth in SEQ ID NO:

176. Peptide sequences and VH polypeptide sequences having the amino acid sequence set forth in SEQ ID NO:177 15. The method according to claim 1, wherein the antibody binds to the same epitope as an anti-sclerostin antibody comprising The method according to any one of claims 1 to 5.

16. The method according to any one of claims 1 to 3, wherein the anti-sclerostin antibody is brosozumab. How to.

17. The anti-sclerostin antibody is administered at a dose of 1 to 50 mg / kg of body weight of the human patient. The method according to any one of claims 1 to 16, wherein the

18. The anti-sclerostin antibody is administered at a dose of 10-30 mg / kg of body weight of the human patient. The method according to any one of claims 1 to 17, wherein the administration is

19. 1 to 1, wherein the anti-sclerostin antibody is administered at a dose of 10 to 5000 mg.

7. The method according to any one of claims 6 to 6.

20. The anti-sclerostin antibody is administered in a dose of 100 to 3000 mg.

20. The method of any one of claims 16 or 19.

21. The anti-sclerostin antibody is administered to the human The method of any one of claims 1 to 20, which is administered to a patient.

22. 22. The method of claim 1, wherein the anti-sclerostin antibody is administered to the human patient monthly. The method according to any one of claims 1 to 5.

23. 12. The method of claim 1, wherein the anti-sclerostin antibody is administered to the human patient every other month or quarterly.

23. The method according to any one of claims 1 to 22.

24. The treatment regimen includes a first administration regimen, optionally followed by a second administration regimen. The method according to any one of claims 1 to 23.

25. the first dosing regimen comprises administering 1-50 mg / kg of body weight of the human patient monthly; 25. The method of claim 24,

26. The first dosing regimen comprises administering 20 mg / kg of body weight of the human patient monthly. The method of claim 25,

27. The second dosing regimen comprises administering 1 to 50 mg / kg of body weight of the human patient every other month or The method of any one of claims 24 to 26, wherein the administration is four times a year.

28. The second dosing regimen comprises administering 20 mg / kg of body weight of the human patient every other month or yearly. The method according to any one of claims 24 to 27, wherein the administration is four times.

29. The first dosing regimen comprises administering 20 mg / kg of body weight of the human patient monthly. and wherein the second dosing regimen is administered every 20 mg / kg of the human patient's body weight.

29. The method of any one of claims 24 to 28, wherein the administration is quarterly or quarterly.

30. The first dosing regimen comprises administering 20 mg / kg of body weight of the human patient monthly for one year. and said second dosing regimen is 20 mg / kg of body weight of said human patient.

30. The method of claim 29, wherein the dose is 20 g every other month or four times a year for at least one year.

31. 2. The method of claim 1, wherein the first dosing regimen is a monthly administration of 10 to 5000 mg.

5. The method according to claim 4.

32. The second dosing regimen is 10 to 5000 mg administered every other month or four times a year. The method of claim 24 or 31,

33. The first dosing regimen is 10 to 5000 mg administered monthly, and the second dosing regimen is The dosage regimen of claim 1 is 10 to 5000 mg administered every other month or four times a year.

24. The method according to claim 24.

34. The first dosing regimen is 10 to 5000 mg administered monthly for one year, The second dosing regimen comprises administering 10 to 5000 mg every other month or four times a year for at least one year. The method of claim 33,

35. 35. The method of claim 1, wherein the anti-sclerostin antibody is administered intravenously. How to.

36. Bisphosphonates, parathyroid hormone, calcium receptor antagonists, calcium receptor agonists Veterinary drugs (e.g. cinacalcet), statins, anabolic steroids, lanthanum and stron and / or administering additional therapeutic agents such as sodium fluoride, sodium thium salts, and / or sodium fluoride. The method according to any one of claims 1 to 35.

37. A lyophilisate comprising an anti-sclerostin antibody as defined in any one of claims 1 to 16.

38. Sucrose, arginine hydrochloride, L-histidine, polysorbate 80, and hydrochloric acid The lyophilisate of claim 37 further comprising:

39. An anti-sclerostin antibody as defined in any one of claims 1 to 16, or claim 37.

38. A dosage unit form comprising the lyophilisate according to claim 37.

40. 40. The dosage unit of claim 39, comprising 10 to 5000 mg of the anti-sclerostin antibody. Dosage form.

41. An anti-sclerostin antibody as defined in any one of claims 1 to 16, or an anti-sclerostin antibody as defined in claim 37 or 38 or the dosage unit form according to claim 39 or 40. ,kit.

42. Bisphosphonates, parathyroid hormone, calcium receptor antagonists, calcium receptor agonists Veterinary drugs (e.g. cinacalcet), statins, anabolic steroids, lanthanum and stron and / or additional therapeutic agents such as co-therapeutic agents such as sodium fluoride.

42. The kit of claim 41 comprising:

43. A composition according to any one of claims 1 to 16 for use in a method according to any one of claims 1 to 36.

39. The anti-sclerostin antibody according to any one of claims 37 to 38, 41 or 42. Kit included.

44. 2. A method, anti-sclerostin antibody, lyophilized Dry products, unit dosage forms, kits, and / or uses.

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