I International Bureau (10) International Publication Number (43) International Publication Date 6 December 2012 ( )
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1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date 6 December 2012 ( ) WO 2012/ Al P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07K 16/24 ( ) A61P 19/10 ( ) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/EP2012/ KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 29 May 2012 ( ) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/491, May ( ) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicant (for all designated States except US): ABLYNX TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, NV [BE/BE]; Technologiepark 21, B-9052 Ghent-Zwijn- EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, aarde (BE). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventors; and ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): HOLZ, Josefln- Beate [DE/BE]; Vlaanderenstraat 119 Bus 601, B-9000 Published: Gent (BE). HEMERYCK, Alex [BE/BE]; Wolfputstraat 63 Bus 0101, B-9041 Oostakker (BE). with international search report (Art. 21(3)) before the expiration of the time limit for amending the (74) Agents: WIEDEMANN, Peter et al; Hoffmann Eitle, claims and to be republished in the event of receipt of Arabellastrasse 4, Munich (DE). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, with sequence listing part of description (Rule 5.2(a)) (54) Title: INHIBITION OF BONE RESORPTION WITH RANKL BINDING PEPTIDES o (57) Abstract: Methods are provided for inhibiting bone resorption and/or osteoclast activity. More specifically, methods are provided wherein polypeptides against RANK-L are administered to a subject less frequently and/or at lower dose, while still main taining effective inhibition of bone resorption and/or osteoclast activity in the subject at unexpectedly prolonged periods of time, particularly in view of the doses administered.
2 INHIBITION OF BONE RESORPTION WITH RANKL BINDING PEPTIDES FIELD O F THE INVENTION The present invention relates to methods for inhibiting bone resorption and/or osteoclast activity for prolonged periods of time using amino acid sequences that are directed against Receptor Activator of Nuclear factor Kappa B Ligand (RANK-L). More specifically, the present invention provides polypeptides directed against RAN K-L at specific dose ranges for inhibiting RANK-L mediated bone resorption o r osteoclast activity. BACKGROUND OF THE INVENTION Remodelling (turnover) of bone is the process by which the adult skeleton is continually being resorbed (removed) and formed (replaced). Bone remodeling involves the synthesis of bone matrix by osteoblasts and its resorption by osteoclast cells. Osteoclasts, derived from hematopoietic cells, are unique forms of tissue macrophages that have the capacity t o resorb bone tissue. Osteoblasts are specialized fibroblasts that have the capacity o f secreting bone collagen. There is an exquisite coordination among the activities of these bone cells that link the processes of bone formation and bone resorption. Bone remodelling is controlled by a balance between RAN K-L/RANK and the RANK-L decoy receptor OPG. RAN K-L and its receptor RANK are essentia l for the development and activation of osteoclasts. OPG, a secreted protein, is an effective inhibitor of osteoclast maturation and osteoclasts activation. In normal bone homeostasis, RAN K-L and OPG participate in a cytokine axis that tightly controls the generation of osteoclasts from monocyte precursors. RA K- L, expressed by osteoblasts and bone marrow stromal cells, binds t o its functional receptor, RAN K, t o stimulate differentiation of osteoclasts from precursor cells and the proliferation and activity of mature osteoclasts. OPG, which is expressed by osteoblasts, stromal cells, dendritic cells, and megakaryocytes, limits this process by acting as a soluble decoy receptor for RAN K-L. The TNF family molecule RANK-L is encoded by a single gene (rank!) at human chromosome 13ql4. RAN K-L m RNA is expressed at highest levels in bone and bone marrow, as well as in lymphoid tissues (lym ph node, thymus, spleen, fetal liver, and Peyer's patches) (Anderson et al. 1997, Nature 390: ; Wong et al. 1997, J. Biol. Chem. 272: ; Lacey et al. 1998, Cell 93: ; Yasuda et al. 1998, Proc. Natl. Acad. Sci. USA 95: ). Alternative splicing of RANK-L m RNA allows expression as a type II transmembrane glycoprotein of either 316 o r 270 amino acids or as a soluble ligand of 243 amino acids (Kong et al. 1999, Nature 397: ; Nagai et al. 2000, Biochem Biophys. Res. Cornmun. 269: ). In addition, RANK-L can be released from its membrane bound state by meta lloproteinases, including TNF-alpha convertase (Lum et al. 1999, J. Biol. Chem.
3 274: ). All four isoforms of RANK- L associate into trimeric molecules capable of triggering osteoclastogenesis. RANK (receptor activator of NFkappa B; also known as TRANCE-R, ODAR, o r TNFRSF11A), expressed o n preosteoclastic cells, is the sole receptor o n these cells for RANK-L (Li et al. 2000, Proc. Natl. Acad. Sci. USA 97: ). RAN K activation by RANK-L is followed by its interaction with TNF receptor-associated (TRAF) family members, activation of nuclear factor (NF)-kappaB and c-fos, JNK, c-src, and the serine/threonine kinase Akt/PKB (Anderson et al. 1997, Nature 390: ; Hsu et a!. 1999, Proc. Acad. Sci. USA 96: ). OPG (osteoprotegerin; "protector of the bone"; also known as osteoclastogenesis inhibitory factor (OCI F)) is a soluble, 110-kDa, disulfide-linked, homodimeric glycoprotein produced and released by activated osteoblast cells (Simonet et al. 1997, Cell 89: ) with homology t o the TNF receptor family, that functions as a decoy receptor for RANK-L and competes with RANK for RANK-L binding. Consequently, OPG is an effective inhibitor of osteoclast maturation and osteoclast activation (Simonet et al. 1997, Cell 89: ; Lacey et al. 1998, Cell 93: ; Kong et al. 1999, Nature 397: ), thereby reducing bone resorption. A more detailed overview of the OPG/RAN K-L/RANK system as the mediator of bone formation and destruction is presented in Khosla, (2001 Endocrinology 142: ), Holstead Jones et al. (2002, Ann. Rheum. Dis. 61 (Suppl II): ii32-ii39), Bezerra et al. (2005, Brazilia n J. Med. Biol. Res. 38: ) and McClung (2006, Current Osteoporosis Reports 4 : 28-33). Several bone disorders occur when there is an imbalance between the resorption and formation components of bone remodeling activity (uncoupling of bone homeostasis). Imbalances between osteoclast and osteoblast activities can arise from a wide variety of hormonal changes or perturbations of inflammatory and growth factors, such as e.g. an altered balance between OPG and RANK-L. When bone resorption is greater than bone formation, there is a net loss of bone over time. This ca n eventually result in low bone mass (osteopenia) or osteoporosis. When bone formation exceeds resorption, there is a net increase in bone mass (osteopetrosis). Excessive bone loss or destruction due t o higher RAN K-L, lower OPG o r both has been implicated in many disease states, including post-menopausal osteoporosis (Eghbali-Fatourechi et al. 2003, Journal of Clinical Investigation 111: ; Tsangari et al. 2004, Bone 35: ; Abdalla h et ai. 2005, Calcified Tissue International 76: 90-97). Pharmacological agents t o decrease risk of fracture have been available for more than ten years. Anticatabolic drugs (oestrogens, bisphosphonates, calcitonin and selective oestrogen receptor modulators) decrease bone resorption, while ana bolic agents, such as recombinant human parathyroid hormone (PTH), increase bone formation and bone size. The bisphosphonate class of drugs is the one most often used for the treatment of osteoporosis. Although this drug class is
4 generally very safe, oral dosing is complex and has been associated with gastrointestinal adverse events in a small percentage of clinical practice patients. Clinical trials are evaluating increasing intervals of intravenous bisphosphonate dosing. The recent discovery of the OPG/RANK-L/RAN system as pivotal regulatory factors in the pathogenesis of bone diseases and disorders like osteoporosis provides unique targets for therapeutic agents. In laboratory animals and in humans, administering forms of OPG markedly inhibited osteoclast activity and improved bone strength (Bekker et a. 2001, J. Bone Miner. Res. 16: ; Campagnuolo et al. 2002, Arthritis Rheum. 46: ; Bezerra e al. 2005, Brazilian J. Med. Biol. Res. 38: ; McClung 2006, Curre nt Osteoporosis Reports 4: 28-33). In early studies in humans, a fully human antibody against RANK-L (Denosumab) reduced bone turnover and improved bone density (Body et al. 2003, Cancer 97: ; Bekker et al. 2004, J. Bone Miner. Res. 19: ; McClung 2006, Current Osteoporosis Reports 4: 28-33; Lewiecki 2006, Expert Opin. Biol. Ther. 6: ; McClung et al. 2006, N. Engl. J. Med. 354: ). Such complete antibodies, however, face the drawbacks of full size antibodies such as high production costs, low stability, and their large size, which e.g. impedes their access t o certain hidden epitopes. SUMMARY OF THE INVENTION The Applicant has discovered that the administration t o human subjects of polypeptides as described herein that specifica lly bind RANKL (also referred t o herein as "polypeptide(s) of the invention") provides an unexpectiy sustained, prolonged effect o n bone resorption and/or osteoclast activity in the human subjects as observed through changes in relevant biomarkers (such as CTX-1, NTX-1 TRACPSb, PIN P, and/or BAP). For example, the change in one o r more markers of bone metabolism and/or bone homeostasis can be measured for at least 30 days after ad ministration. The change in the one or more markers of bone metabolism and/or bone homeostasis can persist for longer periods of time, such as at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 210 days, at least 240 days, at least 270 days, at least 300 days, at least 330 days, o r at least 360 days. This effect is also achieved rapidly, with the reductions in biomarkers observed, in some embodiments by 8 hours after administration of the polypeptide that specifically binds RAN KL. The unexpected sustained, prolonged effect o n RANK-L mediated bone resorption and osteoclast activity was mainly caused by the much better potency ( C 0 ) of the polypeptide of the invention in vivo than what was predicted based o n background art and preclinical information. Because of this better potency of the polypeptide of the invention, an unexpectedly sustained, prolonged effect on RANK-L mediated bone resorption and osteoclast activity in the human subjects was observed compared t o what was assessed based on pre-clinical modelling. As a consequence,
5 less therapeutic molecules (i.e. lower dose) need t o be administerd, or less frequent dosing of the therapeutic molecule need t o be applied in order t o obtaine the same effect on RANK-L mediated bone resorption and osteoclast activity (observed through changes in relevant biomarkers such as CTX-1, NTX-1, TRACPSb, PINP, and/or BAP). Therefore, the invention relates t o the use of the polypeptides described herein t o inhibit bone resorption and/or osteoclast activity in a subject for unexpectedly prolonged periods of time, particularly in view of the doses administered. The invention also provides for less frequent and/or lower dose administration t o a subject of the polypeptides described herein, while still maintaining effective inhibition of bone resorption and/or osteoclast activity in the subject at unexpectedly prolonged periods of time, particularly in view of the doses administered. In particular, the invention provides pharmacologically active agents, compositions, methods and/or dosing schedules that have certain advantages compared t o the agents, compositions, methods and/or dosing schedules that are currently used and/or known in the art, includ ing the ability t o dozes less frequently or t o adm inister lower doses t o obtain equivalent effects in inhibiting RAN K-L mediated bone resorption and/or osteoclast activity. According t o one aspect of the invention, methods for inhibiting bone resorption or osteoclast activity in a subject are provided. The methods include administering t o the subject a polypeptide that specifically binds Receptor Activator of Nuclear Factor kappa B Ligand (RANK-L) (also referred t o as "polypeptide of the invention"). The amount of the polypeptide ad ministered is effective t o change one or more markers of bone metabolism and/or bone homeostasis for at least 30 days after administration. In some embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 10 mg/kg. In some embodiments, the markers of bone metabolism are selected from cross-linking telopeptide of type collagen (CTX-1), N-terminal telopeptide of type collagen (NTX-1), tartrate-resistant acid phosphatase isoform 5b (TRACPSb), N-terminal propeptide of type I procollagen (PINP) and bone-specific alka line phosphatase (BAP). In some embodiments, one o r more of the CTX-1, NTX-1, TRACPSb, PINP and BAP is/are measured using an ELISA assay specific for CTX-1, NTX-1, or TRACPSb; a radioimm unoassay specific for PIN P, o r an immunoenzymetric assay specific for BAP, respectively. According t o another aspect of the invention, methods for inhibiting bone resorption o r osteoclast activity in a subject are provided. The methods include administering t o the subject a polypeptide that specifically binds Receptor Activator of Nuclear Factor kappa B Ligand (RANKL) (polypeptide of the invention). The amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 30%, compared t o pretreatment or normal levels, for at least 30 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast
6 activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least about 30 days after administration. In some embodiments, the polypeptide is administered in an amount of at least mg/kg. In some embodiments, the polypeptide is administered in an amount from about mg/kg t o about 0.03 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than o r equal to mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for at least 60 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting A N K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 60 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.01 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than o r equal t o 0.01 mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for at least 90 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 90 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.01 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 90 days after administration, and the polypeptide is administered in an amount of less than o r equal t o 0.01 mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for at least 120 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of
7 CTX-1 at at least 30% for at least 120 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.01 mg/kg. in certain em bodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 120 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.01 mg/kg. In some embodiments, the CTX-1 is red uced by at least 30%, compared t o pre-treatment or normal levels, for at least 150 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 150 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment o r normal levels, for about 150 days aft e administration, and the polypeptide is administered in an amount of less than o r equal t o 0.1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or norma l levels, for at least 180 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 180 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In some embodiments, the polypeptide is administered in an amount of at least 1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 10 mg/kg. In certain embodiments, the polypeptide is administered in a amount from about 0.1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 180 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 180 days after administration, and the polypeptide is administered in an amount of less than or equal t o 1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for at least 210 days after administration. Accordingly, the invention also relates to a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast
8 activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 210 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In some embodiments, the polypeptide is administered in an amount of at least 1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 10 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 210 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 210 days after administration, and the polypeptide is administered in an amount of less than or equal t o 1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for at least 270 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 30%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 30% for at least 270 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In some embodiments, the polypeptide is administered in an amount of at least 1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 10 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 270 days after ad ministration, and the polypeptide is administered in an amount of less tha n or equal to 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 30%, compared t o pre-treatment or normal levels, for about 270 days after administration, and the polypeptide is administered in an amount of less than or equal t o 1 mg/kg. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-1) by at least 45%, compared t o pre-treatment or normal levels, for at least about 30 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 45%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least about 30 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.01
9 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 0.1 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 3 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than or equa l t o 0.01 mg/kg. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 45%, compared t o pre-treatment or normal levels, for at least about 60 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 45%, compa red t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for a least about 60 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.01 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 0.01 mg/kg t o about 0.1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pretreatment o r normal levels, for about 60 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.01 mg/kg. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 45%, compared t o pre-treatment or normal levels, for at least about 90 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by a least 45%, compa red t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least about 90 days after adm inistration. In some embodiments, the polypeptide is administered in an amount of at least 0.03 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 0.03 mg/kg t o about 0.3 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pretreatment or normal levels, for about 90 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.03 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for about 30 days t o 3 months after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated osteoclast activity, wherein the amount of the polypeptide administered bone resorption and/or is effective t o reduce serum levels of CTX-1 by at least 45%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least about 30 days to 3 months after administration. In certa in
10 embodiments, the polypeptide is administered in a n amount from about 0.01 mg/kg t o about 0.3 mg/kg. In some embodiments, the polypeptide is administered in a n amount from about 0.03 mg/kg t o about 0.3 mg/kg. In some embodiments, the CTX-1 is red uced by at least 45%, compared t o pretreatment or normal levels, for about 30 days after administration, and the polypeptide is administered in an amount from about 0.03 mg/kg t o about 0.3 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.03 mg/kg. According to another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-1) by at least 45%, compared t o pre-treatment or normal levels, for at least about 120 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 45%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least about 120 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0. 1 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 0. 1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pretreatment o r normal levels, for about 120 days after administration, and the polypeptide is administered in an amount of less than or equal to 0.1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment o r normal levels, for at least 150 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 45%, compa red t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least 150 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 1 mg/kg t o about 10 mg/kg. In other embodiments, the CTX-1 is red uced by at least 45%, compared t o pre-treatment or normal levels, for about 150 days after administration, and the polypeptide is administered in an amount of less than or equal to 1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or norma l levels, for at least 180 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of
11 CTX-1 by at least 45%, compared t o pre-treatment o r normal levels, and t o maintain serum levels of CTX-1 at at least 45% for at least 180 days after administration. In some embodiments, the polypeptide is administered polypeptide is administered in an amount of at least 1 mg/kg. In certain embodiments, the in an amount from about 1 mg/kg t o about 10 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for about 180 days after administration, and the polypeptide is administered in an amount of less than or equal t o 1 mg/kg. in some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for about 3 months t o 6 months after ad ministration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide levels of CTX-1 by at least 45%, compared t o pre-treatment administered is effective t o reduce serum or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for about 3 months t o 6 months after administration. In some embodiments, the polypeptide is administered in an amount from about 0.3 mg/kg t o about 1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment o r norma! levels for about 3 months after administration, and the polypeptide is administered in a amount from about 0.3 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or norma! levels, for about 3 months after administration, and the polypeptide is administered in an amount of less than o r equal t o 0.3 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compared t o pre-treatment or normal levels, for at least 6 months t o 1 year after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 45%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 45% for about 6 months t o 1 year after administration. In some embodiments, the polypeptide is administered in an amount from about 1 mg/kg t o about 10 mg/kg. In some embodiments, the polypeptide is administered in an amount from about 1 mg/kg t o about 3 mg/kg. In some embodiments, the CTX-1 is reduced by at least 45%, compa red t o pre-treatment o r normal levels, for about 6 months after administration, and the polypeptide is administered in an amount from about 1 mg/kg t o about 3 mg/kg. In other embodiments, the CTX-1 is reduced by at least 45%, compa red t o pre-treatment or normal levels, for about 6 months after administration, and the polypeptide is administered in an amount of less than or equal t o 1 mg/kg. In some embodiments, CTX-1 is reduced by at least 50%, compared t o pre-treatment or normal levels, for at least 30 days after administration, such as for at least 60 days after administration, for at least 90 days after administration, for at least 120 days after administration,
12 for at least 150 days after administration, for at least 180 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 50%, compared t o pre-treatment o r normal levels, and t o maintain serum levels o CTX-1 at at least 50% for at least 60 days after administration, for at least 90 days after administration, for at least 120 days after administration, for at least 150 days after administration, for at least 180 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. In some embodiments, CTX-1 is reduced by at least 60%, compared t o pre-treatment or normal levels, for at least 30 days after administration, such as for at least 60 days after administration, for a least 90 days after administration, for at least 120 days after administration, for at least 150 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o red uce serum levels of CTX-1 by at least 60%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 60% for a least 60 days after administration, for at least 90 days after administration, for at least 120 days after administration, for at least 150 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. In some embodiments, CTX-1 is reduced by at least 70%, compared t o pre-treatment or normal levels, for at least 30 days after administration, such as for at least 60 days after administration, for at least 90 days after administration, for at least 120 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 70%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 70% for at least 60 days after administration, for at least 90 days after administration, for at least 120 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 70%,
13 compared t o pre-treatment or normal levels, for at least 30 days after administration. The invention thus also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 70%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 70% for at least about 30 days after administration. In some embodiments, the polypeptide is administered in an amount of at least mg/kg. in some embodiments, the polypeptide is administered in an amount from about mg/kg t o about 0. 3 mg/kg. In other embodiments, the CTX-1 is reduced by at least 70%, compared t o pre-treatment o r normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.03 mg/kg. In some embodiments, the CTX-1 is reduced by at least 70%, compared t o pre-treatment o r normal levels, for at least 60 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 70%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 70% for at least 60 days after administration. n some embodiments, the polypeptide is administered in an amo unt of at least 0.1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 1 mg/kg. In other em bodiments, the CTX-1 is reduced by at least 70%, compared t o pre-treatment o r normal levels, for about 30 days after administration, and the polypeptide is administered in an amount of less than or equa l t o 0.1 mg/kg. In some embodiments, the CTX-1 is reduced by at least 70%, com pared t o pre-treatment o r normal levels, for at least 90 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 70%, compared t o pre-treatment o r normal levels, and t o maintain serum levels of CTX-1 at at least 70% for at least 90 days after ad ministration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 70%, compared t o pre-treatment o r normal levels, for about 90 days after administration, and the polypeptide is administered in an amount of less tha n or equal t o 0.1 mg/kg. In some embodiments, the CTX- 1 is reduced by at least 70%, compared t o pre-treatment o r normal levels, for at least 120 days after administration. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast
14 activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 70%, compared t o pre-treatment or normal levels, and t o maintain serum levels of CTX-1 at at least 70% for at least 120 days after administration. In some embodiments, the polypeptide is administered in an amount of at least 0.1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0.1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 70%, compared t o pre-treatment or normal levels, for about 120 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0.1 mg/kg. In some embodiments, CTX-1 is reduced by at least 80%, compared t o pre-treatment or normal levels, for at least 30 days after administration, such as for at least 60 days after adm inistration, for at least 90 days after administration, for times intermediate t o these, o r longer as described elsewhere herein and as shown in the examples and figures presented herein. Accordingly, the invention also relates t o a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide administered is effective t o reduce serum levels of CTX-1 by at least 80%, compared t o pretreatment or normal levels, and t o maintain serum levels of CTX-1 at at least 80% for at least 60 days after administration, for at least 90 days after administration, for times intermediate t o these, or longer as described elsewhere herein and as shown in the examples and figures presented herein. In some embodiments, the polypeptide is administered in an amount of at least 0. 1 mg/kg. In certain embodiments, the polypeptide is administered in an amount from about 0. 1 mg/kg t o about 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 80%, compared t o pre-treatment or normal levels, for about 90 days after administration, and the polypeptide is administered in an amount of less than o r equal t o 0. 1 mg/kg. In other embodiments, the CTX-1 is reduced by at least 80%, compared t o pre-treatment or normal levels, for about 90 days after administration, and the polypeptide is administered in an amount of less than or equal t o 0. 3 mg/kg. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-1) by at least 30%, compared t o pre-treatment o r normal levels, for about 60 days after administration, and wherein the amount of the polypeptide administered is less than or equa l t o about mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than or equal t o about mg/kg every month and wherein serum levels of CTX-1 are reduced by at least 30%, compared t o pre-treatment or normal levels, and maintained at at least 30% for about 60 days after ad ministration.
15 According to another aspect of the invention, the amount of the polypeptide administered is effective to reduce serum level of cross-linking telopeptide of type collagen (CTX-1) by at least 30%, compared to pre-treatment or normal levels, for about 150 days after administration, and wherein the amount of the polypeptide administered is less than or equal t o about 0.01 mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than or equal t o about 0.01 mg/kg every month and wherein serum levels of CTX-1 are reduced by at least 30%, compared t o pre-treatment or normal levels, and maintained at at least 30% for about 150 days after administration. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 30%, compared t o pre-treatment or normal levels, for about 90 days after administration, and wherein the amount of the polypeptide administered is less than o r equal t o about 0.03 mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than or equal t o about 0.03 mg/kg every month and wherein serum levels of CTX-1 are reduced by at least 30%, compared t o pre-treatment or normal levels, a d maintained at at least 30% for about 90 days after administration. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type I collagen (CTX-1) by at least 30%, compared t o pre-treatment or normal levels, for about 210 days after administration, and wherein the amount of the polypeptide administered is less than or equal t o about 0.1 mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than or equal to about 0.1 mg/kg every month and wherein serum levels of CTX-1 are reduced by at least 30%, compared t o pre-treatment or normal levels, a nd maintained at at least 30% for about 210 days after administration. According to another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX- 1) by at least 30%, compared to pre-treatment o r normal levels, for about 210 days after administration, and wherein the amount of the polypeptide administered is less than o r equal t o about 0.3 mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RAN K-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than or equal to about 0. 3 mg/kg every month and wherein serum levels of CTX-1 are reduced by at
16 least 30%, compared t o pre-treatment o r normal levels, and maintained at at least 30% for about 210 days after administration. According t o another aspect of the invention, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-l) by at least 30%, compared t o pre-treatment o r normal levels, for about 270 days after administration, and wherein the amount of the polypeptide administered is less than o r equal t o about 1 mg/kg every month. The invention thus also provides a polypeptide of the invention for inhibiting RANK-L mediated bone resorption and/or osteoclast activity, wherein the polypeptide is administered in an amount less than o r equal t o about 1 mg/kg every month and wherein serum levels of CTX-l are reduced by at least 30%, compared t o pre-treatment or normal levels, and maintained at at least 30% for about 270 days after administration. In some embodiments, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-l) by at least 30% by 8 hours after administration. In some embodiments, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-l) by at least 45% by 8 hours after administration. In some embodiments, the amount of the polypeptide administered is effective t o reduce serum level of cross-linking telopeptide of type collagen (CTX-l) by at least 70% by 8 hours after administration. In some embodiments, the polypeptide is administered as a single dose. In some embodiments, the polypeptide is administered subcutaneously. In some embodiments, bone resorption is inhibited in the subject as determined by ELISA assay for CTX-l. In some embodiments, the subject has osteoporosis, for example a human subject, such as a female human subject, and in some particular embodiments a post-menopausal female human subject. According to another aspect of the invention, methods for inhibiting bone resorption or osteoclast activity in a subject are provided. The methods include administering to the subject a polypeptide that specifically binds Receptor Activator of Nuclear Factor kappa B Liga nd ( RAN KL) (polypeptide of the invention). The amount of the polypeptide administered is effective to reduce N- terminal telopeptide of type I collagen (NTX-1) by at least 30%, determined as ratio of NTX- 1 to creatinine in urine, compared t o pre-treatment or normal levels, for at least 30 days after administration. The invention thus also relates to a polypeptide of the invention for inhibiting RAN K- L mediated bone resorption and/or osteoclast activity, wherein the amount of the polypeptide
WO 2012/ A3. 15 November 2012 ( ) P O P C T
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