AU2015264940A1 - Antibodies to OPGL - Google Patents

Abstract

Antibodies that interact with osteoprotegerin ligand (OPGL) are described. Methods of treating osteopenic disorders by administering a pharmaceutically effective amount of antibodies to OPGL are described. Methods of detecting the amount of OPGL in a sample using antibodies to OPGL are described.

Description

ANTIBODIES TO OPGL The present application is a divisional application of Australian Application No. 2012216429, which is incorporated in its entirety herein by reference. [001] This application claims priority to U.S. Provisional Application Serial No. 60/301, 172, filed June 26, 2001 , which is incorporated herein by reference for any purpose. FIELD OF THE INVENTION [002] The present invention relates to antibodies that bind osteoprotegerin ligand (OPGL). Compositions and methods for the treatment of bone diseases, such as osteoporosis, bone loss from arthritis, Paget's disease, and osteopenia, are also described. BACKGROUND OF THE INVENTION [003] Bone tissue provides support for the body and includes mineral (including calcium and phosphorous), a matrix of collagenous and noncollagenous proteins, and cells. Living bone tissue exhibits a dynamic equilibrium between formation of bone, which is called deposition, and breakdown of bone, which is called resorption. Three types of cells found in bone, osteocytes, osteoblasts and osteoclasts, are involved in this equilibrium. Osteoblasts promote formation of bone tissue whereas osteoclasts are associated with resorption. Resorption, or the dissolution of bone matrix and mineral, is a fast and efficient process compared to bone formation and can release large amounts of mineral from bone. Osteoclasts are involved in the regulation of the normal remodeling of skeletal tissue and in resorption induced by homoe, Fristne reooiissimla by the sceinO pa rath-yrocid hQ'oroe in response toderangccnttisofalumonn extaceluar luis.In contrast, inhton of resorpton is a functon of calcitonin. In addition, metaboites of n te the espos ness of bone o parath.,yroid hormone anidcaitin Soseoprotenoger qd P wh a member af the TNF family of cvfoiries, p:rnootes fo'aino secat through binding to the actiatior teceptor or ODA) Osteoprotagerdn (GO), on the oter hand, nhs th a of a by equestern P and preventing OPG association with ODA Thus he amontof CPGL associated wih ODAR correl th the eiibumetenbon.e de position and . resrpon [00Q) After skeletal 1 mat'urit-y, thre am ntff bone in the seeo reflects he b aneombance one oraion and bone resorpt a bone mass occurs after skeleta maturty prior to the fourth decade Between he fo~urth" and fifth decaes, the equyridum shif3ts an'd bone resopti nmiates. The i tabe decease in bone massitadan years stat elir femals thn tooes and is ditnt aclrte fe mnpue nsm emales (prcipaAy those of Caucasan and sian descent [006] Osteopenia is a condition relahng generay to any decrease In bonems to belw ormral levels.Suc a codiio my rse frm decrease in e rate of bne synhess or an rease n the rate of bone r noth common fom of o iis pray sto S aoO referred to as postmenopausal and senile osteoporosis. This form of osteoporosis is a consequence of the universal loss of bone with age and is often result of increase inbone resorptin wih a norma te of bone formal Man e females in the Unied State develop symptomatic osteoporos. A direc reltonship exists be ae steopoross and" thecidenc of hiNp, eo neck and interochanterc facture in wornen 45 ars and older, Edery males may deveop symptoaic osteoporosis betweerdhe ages o0 and 70, teoors my ce i instances, result frm increased eves aci of OPGL hu, twoud be useful to have molecules that can ragulate the actiy Qf OP in tQ0 Several factors have been identiied Nh may contrbute to poeenopusl arnd sernie osteoporosis. They nude aterationimone level CCompning agihg and Inadequde c i consumpti atributed to decreased intestinalabsorption of calkum and othermerals Certan treatments have icleAd omone therapy or dietary supplements in tempt to retard the process -More receniy antresorpte agents such a sphosphonates an selotveestogen reetrtnodifers (SERMs havr~e emrgdorte peeto and treatmentrif reduced bone massb Tus it may be useful to co bine those treatments with molecuesthat can regulate the activity of PGL in treating certain osteopenic disorders.

OOS} In certain embodiments the invention provdes for an O ~ ~ ~ ~ ~ ~ ~ V~e pfnxna20a nea yn8T a e atody, compsing a heavy chain and a ig where the heavy etha begcomprisesarn amno aci d sequent nSEQ N 2 or afagment thereof and the light chain c pem a amino acid sequence as seorth in SEQ MD NO: 4 or af ent tereof I43n certain embodiments, he invention provides fra anybody compring a heavy chain and a liht cain, Wherein the heavy comprises a variabe region,. compriing an amioid seuneasse forth i SEQ ID N0 : 13 or a fragment thereo and wherein th igh-tchicmpsea variabe region comparing an amino aRcid sequencew: as set foth in SE UD NO 14 Or a fragment therof j)11 ~ in cetn ebdmns h neninpvcsfra antiody comprising a. heavy chain ada light chain, whri he lra?vy chain, compoises an amino ad equence as set forth in SECA M NC: Z or a fragment [011] In certain embhod"iments, th~e ineto rvdsfor an anioy copriig to heavy chain and a ih hiwe eintehav hi compoises avariable region comprising an amino acdsqec sstforth fn SEQ4 ID O:13 or a frgn ttheireof [012] in certain ebdmnsPhinetnprvesfran antiody omprsinga hvychainr and a l iain, w~herein- thelihchn coprD n m cinE 4 or a fragment thereof. [0131 In ceai mbodens he nventin oes an antibody comprising a heavy chain and a eight chan(a wheren e htcain comiss a Variable region c p s w nga heqe NEQ I) O 14 or a famn hro [014m in certAn emboades, the n t poe r "a antbody, comprising a he'avy chiain and a- lghft c.hai.n, (av hereinthhav chai copries fisvriabegion, and wilherein the first eaqalergon compise a equncethat has A least 00% ide ntity to ,he amino acdSequence set forth in SEQ 0 NO 3and (b wherein e iight chaincomprsessecon varab regionnd wherein the second vaiable region comprises a sequence tNhat has at, least 905 iden to the amio aid sequenc e set forth i SEQ NO; 14Q and ( wheind the anibody v tacts wdih an epre eqinceiganD OPGL) [015] rn ertain embodiments, the first varied region comprises a sequence that has at least 9%ideiy to the an acd sequeneset ftin SEQ D NO, and the second variable regn compares a sequence that has atleast 99%identity to the amino acsequence setorth n SEQ D : 14 [01T in certain embodiments, tefirst vralreincoumprises, a sequence that has at least 9% AMetiY to teaioaci."d sequence -set forth in SEQ ID) NO;,D itan teecon-.d vAR regicmpie a sqec a a atlest99 dentity to h mn dsqee 1se1frth i S EQ E,, . :4, acJseqa nS (017] in certain embodiments, the invention provides for a heavy chain, comprising an amino acid sequence as set forth in SEQ iD NO:2 or a fragment thereof, in certain embodiments, the invention provides for a heavy chain comprising a variable region and a constant region, wherein the variable region comprises an amino acid sequence as set forth En SQ ID NO: 13 or a fragment thereof to18] in certain embe rthe inventon provides for light chai comprisig an amno acid sequence as set forth SEQ D NO4 or a ragmenthereofi certain enbodiments, the invention provides fora gh hain comprising an amino -aid sequence as set forth in EiD N 14or a fragnt thereof 1S In certain embodiments of he~ invention, sigl hain antibodies are provided, n ceain embodiments f the mention, single chain Fv antibodies are provided. in certain embodiments of the invention, Feb antibodies a provided n ceran embodiments of The invenion Fab' antibodies are provided. In cetan bodime of the nvenaion (Fa&)2 antibodies ae provided. [020] - In certain embodiments, a pharmaceutical composition comprising an antibody of the invention is provided, In certain embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anibodyto OOs provided [021) Ir ceain enodimentsa pharmaceutalomposition comnprses an antibody to OPGL andat leaat onetherapeutic agentseeted from a bone morphogenic factor, transforming gowth factor GTC ), an interieukin 1 (Il) nhibtor LI rKierf

T

, a Th~u inhbito, a soluble TVIA receptor, an NF ant bo Rem cade, a D2E7 anybod y 1 a parathyroid hormone 1 ' an analom~g of a. paahri omnaprtyod roerltd pti, an anatg nthtr horm e s n prosse adtnr a bishophnaean alendrnate, flord% clm 1 norseoa ni infamatrydrug (NAWa ~?ihiibitor,, Celetbre*x"- Vi-oxxh aen imnunosuo premssatmtorxtfuoi, an, siprtse initr a secetoy euk ooyta rae hbor(L inn ILSe inhbitr, nVtiody to. IL 1 an -$ iniior antibody to [Us,; an lLi niioa L-f inding protein, an 1I1! 8n antodyan Inierleukin1 c ronveing enzyme CE) moduato, a brobast growth factor (FGF), an FGF moduator a PAP antagon a keratinocyt,,,e grwhfco REaKOFrelate_-,d moec , F md~tr trix mtaiproteinase (MMP) modulao, a nitri oxcde synthas NO oduatr a m odulao of gcocorticoid receptor aoddlato of guamater reepor amdulto o pplysaccharide (LS)lvds no adrenaie a u.02] in cean emodiments of the venVCon, p method of rat n oteeni disorder is proded comprsng admnstering an pharaceuicay os teopeniac dis order omprisng adnister iapam ula cmoion is provide [024J in certain embodiments ethod treating an inmmatory condition with attendantbone osin a patient compriig adniniteriga p harraceuticalcomposition is rd ed [024] in certan embodinent, a method of treetl~ang a un s on n an ant one o ptent comprising amnistering pharmaceutial compositin iprovded. the invenon is provded, 02} i certain ebdments of he vent a method of detecting the leel of OPOL in a biologicalsam-ple is rvdd;cmrsn conact the nan anbody. SRI E DECRITIONO HE FIGz'URES 0 Figure ' shows a -DNA sequence encoding th P atbody havy can. (EQ ID NO:I Figure 2 shows the aino acd Sequence of the aRGYil ntychain (S0 D NO: 2). [029i Figure 3sosa r DNA seuneencoding th-e cP antibo~dy Hhh han(SQI NO:, 3") [0301 Fiur 4 sho-,ws- the amino acdsqec of the aOPGL-I antibody Iigr hin (S EQ ID NO:0 -4> 1Fg 5 shw ascheti diagom f the QOPGL-1 ka pp light chain expression plasrnid oOPGLJ1-KappalpDSRa195. [032] Figure 6 shows a schematic diagram of the OPGL-1 1gG2 heavy chain expression plasmid, aOPGL-NgG2!pDSKa19, [033] Figure 7 shows dose-dependent binding of aOPGL- to OPGLcoted LA plates. (034] Figure 8 hows specific biWding of OPG L-1 to membrane bound OPGC 0gure 9 shows inhibkion of uOPG 1 bi d ing to OPGL c-oatd E,"A pate b y Sol1u-,bl QPGL, [035}Figure 10sowzpecdhc biding of aCG-1 to OPOLcoated EJA plates ure 1 shows dependent nhiiton o osteodlat [0381 Figure 12 shows dosedependent nhbion o OPL bing oDAR by oOPGL-1. Figure 13 shows thd ensrmcnetrto iepoie aft Zte a single dose of oOPGL-1 to Cynomogu monkeys. {040] Figure 14 shows the mean percent change i serum N-T concentation after .dm stenasinge dose of Oa onomo Monkeys.

[041] Figure 15 shows the mean percent change in urine N-Tx concentration after administering a single dose of aCOPGL1 to Cynomolgus Monkeys -,D4 2- Figure '16 shows antibo.,dy poiiv nd ne-gative srm conOentr n time p eofles after adinsen a single dose of AOPGL-1 to 043 Figure shows the amino acid sequence ofhe aOPGL antibod hev hanvrable rein(E D NO: 13), [044I Qur sfl show the amino a equenceo of tne ciPCL antibody ght ceegion (SE I NO 4 Figure 19 shows a c cure process for productin Of aOPGQ& [06] Figure 2G show",s t'lhe ser akiu percent hag aftr adminsterng a single dose of OPGLi to Cynomolgus monkeys 047Fgure 2 shows the maa eru Alkaline Phosphatase perenchang anfo admInIStering a sil e doseo O to Coous DETAILED DESCRIPTION OF CE TAN PREFERRED EMBODMENTS 041 The section heading used herin re frognz~r puroses only and arenot to be construed as ling the subject m er describe references cited in this appcation are express imcporaed by refeenc heeinfor any proe f049j Standard techniques may be used for recombi-ant DNA, oligonucleoide syteiadtsu culture and transformation (a,g, electroporation, protection). Enzymatic reactions and purification techniques may be performed according to manufacturers specifications or as cornmory accomplished in the art or as described herein. The foregoing techniques and procedures may be generaIl performed according to conventional methods weil known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See eg, Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor NY (1989)), which is incorporated herein by reference for any purpose, Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, ard treatment of patents, (OS0j As utilized inacordance withthe present disclosure, the following terms, unless otherwise dicated, shall beunderstood ave te following meanings; I05T The term Isolated plynucleotide* as used herein shall men a polynucstede of genami, DNA or synthet origin or some 11 combea hathereof whih by rA of is orig n he oated pdyfudeotide ( it not associated wh all or a POrWo of a polYnUceotide in which. the solated polynudeodde" is found in natne (2) lnked t apone de ct is not ned to in nature, t does not ocr i nature as part f a lageequence [052] The term isolated prote referred to hren means a pr ec oded by oNA ina A o nthetic orn o s conaton thereof which (1) is free of at ea soe it wuioral be, found, (2) is essentally free of oter proteins torn the same Sorc. ri, fr the same speCies (I 3) expressed by a cell from a different s pieces, or P4) does not ocur In nature. [0531 The term polypeptid& i used h~erein ?as ageic term to refeto natitepts or fencess that have deletions, additions, andlor subsutios o one ornmre amio acids of the netTsequenceThe tern paoypeptide also encompasses OGL-1 (as described belw, SEQ NO and SEQ ID N40: 4), or sequences that,' ha-ve deletions, additions, and/Or substitutions of one or more no acd of aOPG Accordin to certain emboimens, he invnton orses the humnan haych~ain mungobi molecue represented by FiguLre 2 (SEQ MD NO: 2) ari d the lhum nan light chain imniunoglobulin molecule represented b Figure 4 ( or frame s or analogs theref, [0541 The term 'atur|yoccurg as used here in as applied to an objetrefers to the fac that an object be fo nd iature Forxamp polypeptidede e ence hat is present in norgaismirding 12 virses tat anbe ioadfrmasource in nau , a" nd hich has, not been v inenti namodied by man in Me laborato r otheise is naturAlyccnTngo 055 term opera nked' a used herein refers to components that wec in a reonship manner, For example, a control ) sequenrce "o -per-ably linked to acdn sequence is igatd i such a way that ex s the n sequence achie ved ude condi tions comipatible witvfh tecnrlsqec ~056 Theterm, "contrlsqune as usdherein reesto poynuceotde sequence which may effet the epression and processing of coding sequences towhich they are gated The nature ofsuch control sequences may differ depending upon the host organisms Accord to certa embodiments crol sequences for prokaoes may nclude promoter, ibosorne binding site and transcription ternation sequence According to certain embodiment control sequences for eukaryotes may include promoters sequences" can include leader seqece ad0 ofusio p f sequences. [057I The term "polynuceotide as referred to hereinmeans a o erfom ofnucieotdes of eas bases en n certain emboiments, the bases ay e erionuceotides or deo bonueotdes or a omdifnid form of ether tpe of neem includes s nmd de stranded forms of DNA, [05 The term "ignceid reerdtohrincudes aausl ccurring,@" anwd modified nuloie ikdtg they natural 13 ocourrrilend/o onnatral ocrringogcanucide liages. O~qoucletids ar a olyncletidesubet gnerfly ompisin a ength of 200 bases o fewer n ean embodiments, igonueoes e to0 bases i length. In certain embodiments lonueotides are 12, 3, 14, 15461 17, 18, 19, or 20 to 40 bAte s in egh Ognceoie a be sigestr.anded. or double stranded e fo e in ens rt of a gene .mtant oucudeotdes of te invenaon may be sense or anisense ogonuceotides [0$9] The term aturaly occu ring nudeofde& inctdes deoxyribonucdeotides and ribonudeotides The tern Todified rnucleotides" inlue ncoidswith Mdiie or susiue ua rusan d telk.The terno Wnageiu o linages uc as popoWo stme, phosphoodo aeposphorsenoae, p hosphorod iseienoate, phosphoroanioth io-ate, phoshorsniadate, osphormidae, and the le See, g, LaPianohe et Nud Acds Res 14:9081 (1986); Stec et al J, Am Chem So )06:6077 ; Sein et i. Nu A s Res. 16:3209 (1988); Zon et aL Anti-Cancer Drug Design 6:539 (1991) 2on et aL onudodes and Anaogues Practica Approach, pp. F0 (K Ecsti, E., OtdUies~ Press, Oxtord England (1@31)); Stec et at. U.S, No. 151 510 Uhrann and Payman Chemica Reviews 90:543 (1990) the dislsures of which are hereby incorporated by refeenceor any pupose. An ognueG de can include abe r detecion. 0) dentiy a similarity of related and polypepides a be reail clclaedby known methods?- -Such me 'thods' inld, ure no"0t liied 14 .

to tsedescbed in Conputationl o a Boog e, d o UnierstyPreas, Newv York K(1' 9884; Biooew ng:ifrac n eon Pret. S D 18 Academic RSS. Newor (193; alsis of Seqnce Data G A adGr G ds Press, Nw Jerey (1994) Sequenceas in Molecular Bioloy, von Heinje, GuAcaemic Plress;(1987);Sqec Analysi.s Primner, Grbs 0v"M and fDevereux, J,, eds, MPSoko ress, Newy York (1 091); an'd Cafli&at SIAM ' 1,~~~~~~~ Apl8 Ms/,4103( 8), fO~iJ Peferedmetodsto deemn dentity are desinedto iv te arest ac between the sequences tesed. Methods to determine identiY are described in pubi avaiale computer progam refeed comut proram< methods to determine identity btenwosequences include, but are toG program package ncdin GAP(Devereux ci at c s 1387 (1984) Gen CompAer up Univers o Wiso Madison VI, BLASTP, BLASTN, and PAT ~tcu ia,,, J',o! Blt,, 2154 10 (1 90) The BLASTX program ub y aa e frnom t NatinalCener or BotehnoogyInformation (.NCD-l' and other ouce (S'LA Mana4 liehu "ta CJL/I Bethies'da, MD284:Atc taat supura 990n tie woW-known Smith Waterman siortm may Na be used to 6 C schems or alignnq tw ano acd sequences may resl in the catching of oly o ie d sequences, and this small aligned region may, have ver-y hg uneiett even though there is no signIficant relationship between the two fuR-iength sequences, Acco'rdingly, in certain embodiments the selected aigiment method (GAP program) will result in an alignment that spans at least 50 contiguous amino acids of the target polypeptide' 063] For example, using the computer algorithm GAP (Genetics Computer Group, University of WisconsinMadison, WI), two polypeptides for which the percent sequence identity is to be determined are aligned for optimal matching of their respective amino acids (the matched span", as determined by The algorithm). in certain embodiments, a gap opening penalty (which is calculated as 3X the average diagonat the "average diagona" is the average af the diagonal of the comparison matrix being used: the "diagonal" is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (wich is usually 1/10 tmes the gap opening penalty, as wed as a comparison matrix such as PAM 250 or BLOSUM 62 are used in conjunction with the algorithm, in certain embodiments, a standard com prison matrix (see Dayhoff Pt at, AMes of Protein Sequence and Structure, 5(3)(1978) for the PAM 250 comparison matrix; Henikoff et al, Proc, Natf. Acad, So USA, 89:10915-10919 (1992) for the BLOSUM 62 comparison matrix) is also used by the algorith. in certain embodiments, the parameters tot a polypeptide sequence comparison include the following: Algorithm: Needleman at at, J. Mo. Bioh.. 4&:443-453 (1970); Comparison mastrix BLOSUM 62 from Henikoff aL supra (1992); Gap Penalty: 12 Gap Length Penalty: 4 Threshold of Simiarrty: S [065J The GAP program may be useful with the above parameters In certain embodiments, the aforementioned parameters are the default parameters for polypeptide comparIsons (along with no penalty for end gaps) usng the GAP algorithm. As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See immunology A Synthesis (2nd Edition. E. S, Golub and D, R. Gren, Eds, Sinauer Associates, Sunderland, Mass, (1991)), which is incorporated herein by reference for any purpose. (e.g. D-amino acds) of the twenty conventional amino acids, unnatural amino acids such as a-. adisubstituted amino acids, N-aikyi amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention, Examples of unconventional amino acids include: 4-hydroxyproline, Tarboxyglulamate, a N, N, N-trimethyl lysine, e-N-acetyllysine, O-phosphosertne, N-acetylserine, N formyimnethionine. 3-methylhistidine, 5-hydroxylysine, c-N-mnethylarginine, and other sirnhar amino acids and inino acids (e.g. 4-hydroxyproline) In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention. [067] Similarly, unless specified otherwise, the left-hand end of single-stranded polynucdeotide sequences is the 5' end: the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5' direction, The 17 direction of 5 to 3- addition of nascent RNA transcriptsds referred ts the transcriion direction; sequence regions on the DNA tand having he same sequence as the RNA and which are 5 to the 8' end o te RNA tanscript are refeed to as upstrear sequenee:sequence regions on the A strand having the same sequence as the NA and whih are 3 to the 3 and of the RNA transcipt are referred to as "downstream sequencs 6Conservative arrino acid substituhons may enompass non naturall ccuring amino acid residues which are typically incorporated by cemica peptide synthesis rather than by synthesia in biological systems These include peptidomim~tics and otherreversed or inverted forms of amino acid moieties. [069J Naturally occurring residues may be divided into clas based on common side chain properties: 1) hydrophobic: norieucine, Met, Ala, Va, Leu, lle 2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; 3) acidic: Asp, Glu; 4) basic: His, Lys, Arg; 5) residues that influence chain orientation: Gly, Pro; and 5) aromatic: Trp, Tyr, Phe, [0)701' For example, nonconservative substitutions may involve the exchange of a member of one of these classes for a member from another class. Such substituted residues may be introduced into regions of the human antibody that are hotologous wih non-hurnan antibodies, or into the non-homologous regions of the molecule.

[0711 In making such changes, according to certain embodiments, the hydropathic index of amIno acids may be considered. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics, They are; isoleucine (+4.5): valine (+4.2}; leucine (+3,); phenylalanine (+2.8); cysteine/cystine (+2,5); methionine (+1,); alanine (+1.8); glycine (~4.4): threonine (C?7) serine (-0.8); tryptophan (-0.9); tyrosine (-1,3); proline (-18); histidine (432); glutarmate (-3,5); gPutamine (-35); aspartate (23.5); asparagine (-?5); lysine (-3.9); and arginine (-4.5), [072] The importance of the hydropathic amino acid index in conferring interactive b ological function a protein is understood in the srt Kyte etal, 'jI. M BiaL, 157:105-131 (1982), it is known that certain amino acids may be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity, in making changes based upon the hydropathic index, in certain embodiments, the subStitution of amino acids whose hydropathic indices are within t2 is included, in certain embodiment, those which are within iW are included, and in certain embodinents, those within ±&, are inclded. [0731 t is also understood in the art that the substitution of le amino acds can be made effectively on the basis of hydrophiicity, particularly where the biologically functional protein or peptide thereby created s intended for use in imrunigicalambodiments as in the present case. in cain embodiments the greatest vcal aetrage hydrophlicity of a prtein, as governed by the hydrophcity of its adjaent anno acids, createsiits mmunogenicity and antigenityv e with a bioloica property of the protein. [0741 The itBowing yydrophiiy ues have been assigned to these amino add residues: argine (+3 lysire 30)asparta(+3 1 glutamate (+30 ± 1) serine (+0); asparagine (40.2): glutamine (+0.2); glycine (0 hreonine(4 prone 0,5 ± 1 atanie (5);istidine-0); cysteine 1.0% niethionine ( );vane (15); eucne (8);so cine (1 rosine 2.3 phenylalanine (-. end tryptophan (-3,4. in making changes based upon similar hydrophiicity vales, in certain embodimentse substui of am acds whose hydrophlicity values are within 2 isi in cedain embodihcents those which are wikin ±1 are included and cerain embodiments, those within±05 are induded. Onemay also identify epiope tram primary aino acid sequences on the basic of hydrophilici These regIons are also referredto asepitopic core regions 075Exeniry amino acidsubstitatons are set forthi ablei Table 1: Amino Acid Subtitutions Original Exemplary IPrefre Resdue Substitutions Substitutions ASiVal, Leuj, 'Je Va Arkg Lys, GIn, Asn Lys _____Asp __n___ Glin G in Asp Gir GIn Cys f____Ser, Ala Set GIn Asn Asn Giu.__ Aspj Asp ____ G__ v Pro, Ala } Ala -His Asn, Gin, Lys, Arg Arg lie f Leu, Val, Met, Ala, Leu -_____ ~Phe, Nordeucine ___ I~~---- -_____ --------- ____ ------ beu Norleucine, Ue, ile Met Vat M Ala Phe Ly I u Arg, 1,4 Diamiho- Ag ______ butyric Acid, Gin, Asn I _______ K._Met ILew, P'te, lie )-Leu f Phe Leu, Vat lie, Ala, iLea OAla -- - -(-- Thr, Ala, Cys I Thr Thr I _____ Ser i___ Se____ 5r Tp Tyr, P- - I Tyr Tyr Trp, Phe, Thr, er I Phe Vilie, Met, Leu, 4 Phe, Lea _____________ Ala, Norleucine i _____ 0O6 A skiled artsan wiln be abiceto determine suitable vadants of the polypeptide as set ort herein using wellknown techniquesn certai ambodinments, one skilled in the art may identify unable areas of the molecue that may be changedithout destroying activy by tageting regions not believed to be important for activty. In certainembodments one can dentify resdues and portions of the molecules that are conserved among similar polypeptidles.n certain embodiments, even areas that may be important for biologicaal activiy or for structure may be subject conservative amino acd substitutiorns witout destroyin the biological activity or without adversely efecting the polypeptide structure. la Additionally, one skilled in ,the art can review structure function studies identifying residues in simnlar poypeptides that are important fo activiy or structure in viewe of such a com parison, one can edict the importance ofamino acid residues i a protein that correspond to amno aci residues which are important for activity or structure in similar proteins. One 21T skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues, [07a) One skiled in the art can also analyze the threem-densional structure and amino acid sequence in relation to that structure in similar polypeptides. in view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with respect to ts three dimensional structure. In certain embodiments, one skiled in the art may choose not to make radical changes to amino acid residues predicted to b& on the surface of the protein, since such residues may be involved in important interactions with other molecules, Moreover, one skilled in the art may generate test VWriants containing a single amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skied in the art Such variants could be used to gather information about suitable variants, For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, oF unsuitable activity, variants with such a change may be avoided, In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations. [079] A number of scientific publications have been devoted to the prediction of secondary structure, See Moult J, Curr Op. in Biotedt 7(4):422 427 (199), Chou et at, Biochemisty, 13(2):222-245 (1974); Chou at at, i chemistry, 1 C3(2)211-222 (1974); Ohou et at Adv. EnzyrnoL ReaL Aeas Mao bot 47:45-148 (1978) Chou et et n evoBioohern 4725-276 and Chou Ot at B/ophys. , 26:a7384(19. Morover computer programs arme currently available to assist with predictng secondary stucture. One method of prdcng secondary srcreis based upon homology modeiing. FRea two poiypeptides or proteins which have a sequence identiofgreter an 3 or simrdiy greater than 40% often have simiar stuctural topogie he recent growth of the protein structurlatabase DB has provided hensrced predictabiity osecondary st em ncdng e potanumber offods within apoypepties strce e i a N c e 271 :244247 (1 09 It has bee ggested e et cacw O s B/ot, 3 6e a ( h.A thereae amied m o ldsi ag en polypeptide or protin ardat once ectical numberosrtures have been resoled structuraprediction welcome drmatcly moea ate [080] AdditdOl methods of pred cn seco ndary strue inld "treadino (onesW O 0p stot,7S7 (1997Y Spl et at, (1996, ple nlysis ( eai, 253164 170 (199; Crbko Mh & 133146-159 (19901 Gbskov At al, PRoc. N Aced. So, 84(1 34356-43$8 (1987)) and evoutiorary g (See H m, supra (1999, and Brenner, supra (1997)) [0811 n certain emnbodimentsantibody varints incude been altered compared to te amino acid sequences of the parent plpeptde In certain embodiments, protein vagrants comprise a greater or a esser number 23 of N-nked glycosylation sites than the atve oie -inked glycosyeto sit ischaactriari y th.e s-equence: Asn--er or--As n-X-Thr, wherei whe amino acid residue desigated as Xt may be aniy amno acdrsidue except t The substi of amina create Ths sequence pvd potenta new site for the addion of an Nnked carbohydrate chain Alenatvy subst Sors wi eiminate this seq ence wil remove an exisng Nlinked carbohydrate chain, Ato provided is areamrnement of nked cohydratechains whereia or more Tned osyationsesyal those that are natural ou nare mn and moree N-inke sites are ceae Addtional preferred antibody vaants Incde cysteine vaants wheren one or more n residues aredleedfom orsubstitd f her amin ac(g serene) as compared tohe part amno acid sequence Cystee varints may be useful when antbodies must be refolded inO a ici~ogic ay clycofrainSuKh as Ate the isoiuton of inoubl e inclsion bodies Cyeine vaints generally ave fewer csteine residue than the nae rot and typically havn an even number to mininie interactins resutin from unpaired cystines, [082) According to cerin embodimentsamino acid substtutor are tose which: (1) d suscepbly to ( reduce b o oxidaton, () a-ter bndingafniy form mplexes ( aie binding afiniies and/r (4)onfer or modify other physiocochernial or functions properties on such polypeptdes. According to cerain mbodiments sige or mAtiple amino acid sEubAutions netanemodints conservative ami ad ubstitutions) mayb sae tuarady-oceunn sequence (iertain embodiaents, in the poton of the poypeptide nutsidete domain(s forming itermoleuar wntacs In cerin embodimenta conservatve amino acid gabsttutinntypicaey may not sunt ane testructra catss of the parent sequence (ga replacement mino acid hould not tend io break a hex that occurs i the parent sequence, o disrupt other types secondary structurethat chaacteriesthe parent sequence).xampesftecoged poypeptide secondary and tertiary struoturs are described inProteins, Sutures and oecula Prnciples (reghon Er . eeman a zeE ed Gran usn 99 nd harnto et ct easno sefei -, eee Natur'e 3 54:,105DS (I191), whih are e-ach in corpiorate-d h- erein.- ibyefrece ay The temoypeptdefagment asedereinres o a polypepUde that has an amino-terminaland/or carboxytemna deletion n certain embodiments) fragments are at least 5 o457 amino acis t be appreciated that in certain embodiments fragments are least 5 10, 14 20 50 70 100,50, 200. 250, 300 350, 400, o 40 armno acidslong [084] Peptide anaogs are common used in te pharmaceutical industry a non-ppde dugswit propertiesanoous to those ofth tepae peptide, These types of non peptide compound are termed apeptide mimetics o pi , Adv DL"rug Res 5:9 (1926) Veber and Freidinqer TINS p292 (1985); and Evane at al Med Cha 30rd229 (987 which are incorported herein by reference for a purpose Such compound 25 are often developed with the aid of computerized moecu ar modeling. Peptide mimetics that are struturaly similar to therapeutically useful peptides may be used to produce a similar therapeutic or prophylactic effect. Generally, peptidorimetics are structurally similar to a paradigm polypeptide (iep, a poiypeptide that has a biochemical property or pharmacological activity), such as human antibody, but have one or more peptide linkages optionally replaced by a linkage selected from: -CH 2 NH -H 2 0 ~CHa -C , -CH=OH-(cis and trans), -GOCH 2 , -CH(OH)0H 2 , and -OH 2 SO- by methods well known in the art Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., Dysine in piace of L yshne) may be used inc certain embodiments to generate more stable peptide In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods know in the art (Rizo and Gierasch Ann. Rev, Biochem. 81:387 (1992) incorporated herein by reference for any purpose); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide. [085] - "Antibody" or "antibody peptidess' refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding. In certain embodiments, binding fragments are produced by recombinant DNA techniques, In certain embodiments, binding fragments are produced by enzymatic or chemical cleavage of intact antibodies, Einding 28, fragments include, but are not mded to, Fab, Fab F(ab)2, F, and singte-chain antibodies The tern "heavy chain" ncudes any, '. ypetlde hav sufficient variable region sequence to confer for ansPGL The term !qight chain includes any polypeptide havingsufcetvralrgineune Sconfeseci y an n he nudes a region domain, and three constan egon domains, C12, and COH2 h H domain is at the ainoerminus of thep t and the 3 domai is at udIength heavy hain and ragments thereof A full-length light a e vaialereio dmanVL. andf a cnttreindomain. 0 L;, .Lik- e hay chain he variabe region domain of the light cain is, at thea th polpide T t t c as sed here, eco asses length' light chain and fragments Teef A :Feb- fragmentm is cmp-rised o n giht chain and the CHi and variahe regions Of one heavy chain. The heavy Ai of a Fab molecuteacannot for a disulide bond another heavy cha olecule A Fab' fragment contains one eight hai and one heavy chain that contain m e th constant region betw een tr I and C domais suc that an bterchain disuide bond can be f e b o eg cns to form a F(ab')2 mecl.The $ ego cmrie the vral ein rmbt the heavy and light chains, but lAsks the constant regio ns. ige-hi antbodesnre Fvmoeus in wihthe hav and light Chain v rialergion-s haebeen cnetdby a flexible liner to form a singl,,e polypeptida chain which forms an antigen-binding region. Single chain antibodies are discussed in deai in 'WO 88/01649 and US. Patent Nos. 4,94,778 and 5,260 2013 [087) A bivalent antibody other than a "mulispecifi or "muitifunctionaf antibody, in certain embodiments, typicaly is understood to have each of its binding sites dental lAn antibody sUbstantia y adhesion of a ligand to a receptor when an excess ofantibody reduces' the quantity of ecep'tor bonzo COUnterr0cpt0r by at leat ab 20%, 40%, 50%, 80%, 85%, or mor measued in an I vifo onpet bi ding say). loss! The= teM W 'eioencludes a ny poly peptide d*neerm, inatt capable of specific bindig to an iamm ogbobun -c eeptor i certain embodtments, epiope deteian de chally ateua o mokoeues such as amio as suga de n pspr and i crtain. embodiments, may have specific thre'eimesoa structural chrateisicand/of specifc chargesh cersis An epitope is region o f an ani ge tha is bound by an antibody. In certain sAd to specally bind an ang en ni embodim ents, nds said to ec bind a a dissociation constant isY certaen embodients, when thedissoi onstant is 100 oMt and in cerainemoietwnthdsocaonosat is 510nb. 28 f09O] The term "agent" is used heri t denote a chemical compound, a mixture of chemicaompounds, a biobgica rcomor e n exta made from biogima terias 09 As used herem, the teams abe or labeled" refers to corpo, of a detectable mar e Opoan a radiolabeled amnno a~cid or atcmn to a potypeptide Of boimieesthat can het detected by maked aWiin (emg., steptavidln ontann lorsetmre or enzymatic actity that can be detected by opt r coormetric meth n cerin e omes the lel or a r can ao theapu ethOdsf label Wg polypeptides and glcoprote n are knoWn in the art and may be used examples of labels fr polypeptides n e but are not cited he w radiolsotopas orradionucdides (e g) H14 C 15 N. 35 S, 90 Y,92Th, 11 In 125 1$ 11 !1 florescernlabels ley, g T rhodamned anthanide pho s enzmaiclaels(e>,hoseradish peroxidase, -gaactidese, uciferase, lknephosphte) cemilumiescen bitngops predetermined poypeptide epiopes recognize by a secondary reporter (eg euciezippe pai sequences, binding sites for secondary antibodies metal binding domains epiope tagsp in certain embodents abei are attached by spacr arms of arious legh oreduce;otnia i hinrace fC92] The tem "bilog as ued herei nudes but is not l eto, any quanti of a substance fom a d t ang or fAmery l g thig.uchlivngthingsnlue but are not Umited tohumrans ,nmice, monkeys, rWt, rabbis, and other an 5as.Suh sbtneiclude bt are no i i o, blood, serum urine cefl orans tissues, boe, bone marrow, m ds and skin The tern "osteopenic disorder includes, but is not limited to, osteoporosis, osteopenia, Paget's disease, ytic bone metastases, periodontitis, rheumatoid arthritis, and bone ioss due to immobilization. In addition to these bone disorders, certain cancers are known to increase osteoclast activity and induce bone resorption, such as breast, prostate, and multiple myeloma, These cancers are now known to produce factors that result in the over-expression of OPGL in the bone, and lead to increased osteoclast numbers and activity. [094] The term "pharmaceutical agent or drug" as used herein refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient [f95) The term "modulator as used herein, is a compound that changes or alters the activity or function of a molecule. For example, a modulator ray cause an increase or decrease in the magnitude of a certain activity or fun action of a molecule compared to the magnitude of the activity or function observed in the absence of the modulatorW In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of at least one activity or function of a molecule, Certain exemplary activities and funcdons of a molecule include, but are not limited to, binding affinity, enzymatic activity, and signal transduction, Certain exemplary inhibitors include, but are not limited to, proteins, peptides, antibodies, peptibodies, carbohydrates or small organic molecules. Peptibodies are described, e18 in WO01/83525, (f067 As used herein, "substantiay pure" means an object species is the predominant species present (Le, on a molar basis it is more abundant than any other individual species in the composition), In certain embodiments, a substntially purified fraton is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of a macromoiecular species present, In certain embodiments, a substantial pure composiwon will comprise more than about 80%, 85%, 90%, 95%, or 99% of at macromolar species present in the composition, In certain ernbodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentialy of a single macromolecular species, (007] The term patient includes human and animal subjects. (09 Ihi aipcti the use of the singular includes the plua unlssS speciicll staed othmWise. I this applicatin, the use of"r means and/or unless stad oerise, Furthermore. the use of the terq "ncldi as Wl As othr forms, such as 'incudas n "nde- s o imtn. lo terms such as element" or o nentencompass both elements and componentss comprising one untand emntadcopetshtcmrie more an one subunit guess speciftcalysated otherwise 099] Osteoprotegeri Ligand (O a member of The tumor necrosis factor ([NP) famy of cytokine is iwoled the formation o ostecclasts. increased osteacast ctiiy correlates with a number oiosteopenic disorders including post-menopausa osteoporis Faget'sdisease lyik bne metastases, and rheumatoid arthritis. Therefore, ~reduction in OPGL acty may resultin a decrease in osteoclast actvty and may reduce the sevety of osteopenic disorders cording to certain embodiments of the iventon antibodies Rected to OPGL may he used teat osteopenic disorders incuding by not lnmted t those mentioned above [O100] certain embodiments of the present ivetionhere is provided a fully human monoclonal antibody against human osteoprotegerin ligand (OPGL In certain embodiments, nucdeotide sequences encoding, and amino acid sequences comprising heavy endlightchain inmunogobli molecules, particularly sequences coesponding to the variable region are proved In cerin embodiments sequences corresponding to complmenta deterining regions (DRs) specfically from DRI through ODR3, are provided According to certain embodiments, hybrdoma cell ine expressin such arniunoglobuin molecul and onodonal antibody is also provided, In certain embodients, purfied human monoclonal antibody against human OPGL is provided [01011 The ability to clone and reconstruct rnegabase-sed human ioci n yas artfca homosomes eY~s and to itoduce te nto the mous germilne provdes. an approach to elucidating.q thefctoa components, of very large orcudelymapped oc as wel as generating use odelf human disease, Furiermore, the utizatiOn of such tecnoy or substiutin of mouse Alovwih their human equivalent could, provided unique nigt nt h expression and regulation of human gene products during development, their ommunicatonwith other systems, and their inovement in dieaseinduion and progression. [0102] An important practical application of such a strategy is the "hunmanizati" of the mouse humorel immune system, introduction of human mimunoglobulin (g) loci into mice in which the endogenous ig genes have been inactivated offers the opportunity to study the mechanisms underlying programmed expression and assembly of antibodies as well as their role in B-cell development. Furthermore, such a strategy could provide a source for production of fully human monoclonal antibodies (MAb) In certain embodiments, fully human antibodies are expected to minimize the immunogenic and allergic responses intrinsic to mouse or mousederivatized Mabs, and thus, n certain embodiments, increase the efficacy and safety of the administered antibodies. In certain embodiments, fully human antibodies may be used in the treatment of chronic and recurring human diseases, such as osteoporosis, inflammation, autoimmunity, and cancer, which may involve repeated antibody administrations. {103 One can engineer mouse strains deficient in mouse antibody production with large fragments of the human kg Joci in anticiation that such mice would produce human antibodies in the absence of mouse antibodies, Large human Ig fragments may preserve the large variable gene diversity as well as the proper regulation of antibody production and expressions By exploiting the mouse machinery for antibody diversification and selection and the lack of 3 3 imunologcal tolerance to hmnan proteins, the reproduced human antibody repertoire i these mause straws may yield high affinity antibodies against any anigen of interest, including human antigens, Using the hybddoma technology aniger-specific human MAbs with the desired specificity may be produced and selected. 04J n certain embodment ne may use constant mens fo wpecies otAher than human wklong wviththhunvaabergns) aturahy Occurring Antibody Structure 0 Naturaly occurring antibody structure nits typically comnpise a tern~.Each such fermrtpclyi opsdo w lnial pais f pofyp,-,eptide chains, each. pair having one f-llngh htk(ncrti embodiments, a t25 kDa and one fuiie ngt e"avf chain (in certain embodments, aout 55070 Ma) The anoatrnal p on of, e a yicaly includes a vabe region of about 10c0 to 0 o"r more amino ads tat typcaly is responsible for antigen recognition. The carboxyterminl portn of each chain typicahy defines a constantregion that may beresponsible for affecter function. Humanligh chains are ypicaly cassified as kappaand lambda eight chains Heavy chains are typical cassfied as m dtaara alha, or epsilo:nn dfn the anioY'S iSotype as 1gM% bRgt3, IgA, And g respectivy IgG has several subclasses incudin but not mied to g ig02 gGZ, ad 1g04. 1gM has subclasses icldi b not li'med tog and lgM42. IgAk is sirnlaiysbdivided ito suasses inluinbut not limited: to, 34 FA andigA2WMn fu!Nenoth ght and heaychains bpica the vadable and constant regions are jaed b Tegn ou ore ai acids, w01h the heavy chain al i n a rio about 0 'more aino acids. , g. Fundamentaim nology O 7 (Paun W, ed, 2nd ed. Raven press NY( 1989) incorporatedd by referencein is entirety for adumposes>The arbe regions of each light/heavy chan pair iciOy fOrm th aigen hiding [010} Th vardb reins tyially xhii tesame general structure of elave conserved frameworkregios ( onedbhree hyper varabe rginsalo alld ompemntrit dterinngregions or CDRs& The CDRS fOm the No chains of each pair tpcary ar signed by the framewrk egiorswhih ay enable binding to a specific epitope Fron-terminalo terminal bot ighit nd heavy han varabe egions typical comprise the domin F, 0 -DM, PPt 00RP2, FRS., CDRS and FR4. The assthmntwof amin-o acids toch oani-yial in acodnc ihedfntoso Kabat Sequences Proten of immunolgicalnteest (Nat a tes of Health ethesda 987 and 19 Chotha & Lesk .Bo 196:90M917 (18) Chohi e al. Na4,-ture 32723(8) SBisp cific- or Bl-iunctioina ntiode 010 A bispecfic or bifunctional antibody typically is an artial hybrid antibody having two different heavy/lightnhi pairs andtwo different ending sites. lBispecdfic antibodies may be produced by a variety of methods 35 indtsding, but not lirnted to, fusion of hybridomas or linking of Fb fragments. See, e .g, Song&slai & Laohmann Cin. Exp. Immunol 79: 315321 (1990), Kostelny et-t ,i 3 immuno 148 1547-1553 (1992), Preparation of Ant bodies (0100 WK codngt eti embodimoen'ts, eti atbde specicady binding to OP ae encompasses the ne in,n cetai embodiments, the antibodies may beprduced b m aon with auMength OPGL souble foms of OPG or a fragmegnt ereof n cein mbo t a tibodies of the invenion may be ponl ormno na, aodror may be recombinant antibodies. Inertarnembodimentantibodes o te inventonar human anidis prepared for example imunatonotrangenic animals capable of producing human antiboes (ee or exaplePOT Pulshed Application No WO 3/1227' [0091 In certain embodments, the cormplementarity determining regionsj(Ds) of the eight and heavy chain variable regions of rOPGL may be grafted to framework regions (ERs) fom the same, or anther special cerai ebodmetsthe CORs of the light and hav chain varia ble regions fI oSPOL I may b e grfe t osensu hmanEas, To createconsnu han FRs, in certain embodments Rafom severthuman heavy chain or ligt chain amino acid equences are aligne toentiya consensus amno aci seqene.In ceti modmns he m~se of the cOPGL-1 he avy cor light chain are replaced with te FRs from-r a differe-nt hevy ChAiN or light cAin in certain embodiments, rare amino acids in the FRs of the heavy and light chains of aOPGW are not replaced, while the rest or the FR amino acids are replaced, Rare amino acids are specific arino acids that are in positions in which they are not usuahy found in Fs. In certain embodiments, the grafted variable regions from cOPGL- may be used with a constant region that is different from the constant region of aOPOLA In certain embodiments, the grafted variable regions are part of a single chain Fv antibody, CDR grafting is described, e, in U.S. Patent Nos, O,180,370, 5,893,762, 5,693,761, 555,09, and 5,530,101, which are hereby incorporated by reference for any purpose, [C1o! According to certain embodiments, antibodies of the invention are prepared through the utilization of a transgenic mouse that has a substantial portion of the human antibody producing genome inserted but that is rendered deficient in the production of endogenous, urine, antibodies, Such mce, then, are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies., Technologies utilized for achieving this result are disclosed in the patents, appLcations, and references disclosed in the specification, herein, in certain embodiments, one may employ methods such as those disclosed In POT Published Application No, WO 98/24893, which is hereby incorporated by reference for any purpose. See also Mendez et at Nature Genetics 15:146-156 (1997), which is hereby incorporated by reference for any purpose.

CI According to certain embodiments, fully human rnonoclona anibdisspecific for GPGIL are Produced-. as,_. folvows. T-an~synic ic OWNen human inuncoungeearim nidwththe atgno inters.Lmpaocll sc as R-eil ro hemce that express antibodie are obta ied. Such recovered celHs are fused with a myeloidtype cel line to prepare fimortal hybridoma ce lines, and such hybridnia cenes are screened and s ted t idefy hybridoma ce lines that produce anibodies specitc to the antigen of interest, in certain embodiments, the roducton hybridoma cel lne that produces antbdes specific to OPGL is provided 01121 ceain embodiments nbodeof the neno are produced by bybridma nes AMG 6 AMO 6A, AMG 6-52 AMG . and AMG 7.2. In certai emodmnt, nibodies of the iwnvenion ar rdcdby hybrdorra ins AMO , AMG 64, and AMG I ceran embodets the antibodies of the invention bind to OPGL ith a disocatio constant (Kd) of between apprmatee 0.23 nd 0.2 nM in certain embodiments A H inventorthe anibodies bind to OPGL wth a Kd ofless than 023 nM. (01 131 In Certain emocens heatboiso the ivnonare of the lg(32 isotype, In certain emo iets o-ftheinetoheaibds comprise a human kappa lght chai and a human gG2 heavy cha In ceain embodiments, th anibo."dies of the invention hav be-en clndfor xpesio in; mammlia cels certain embodiments, the variable egons of he antibodies are oa constant region oer than thle constant region for the ir O isotype 36 0'14J In Certan embodimentsoseatie modifications to the heavy and Ught chans of oOPGLA (and cOrresponding modifications to the encoding n ucleotides) will produce antibodies to OPGL having functional and chernical characteristics similar to those of aOPGLI. In contrast, substantial modifications in the functional and/or chemical characteristic of aOPGL-1 may be accomplished by adeecting substitutions in the amirno acid sequence of the heavy and light chains that differ significantly in their effect on maintaining (a) the structure of the iolecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobioity of the moiecule at the target site, or (c) the bulk of the side chain. {0116] For example, a "conservative amino acid substitution" may ~nvoive a substitution of a native amino acid residue with a nonnative residue such that there is ittle or no effect on the polarity or charge of the amina acid residue at that position. Furthermore, any native residue in the polypeptide may also be substituted with ahnine, as has been previously described for "alanine scanning g mutageness [011 &J Desired amino acid substitutions (hether conservative or non-conseative) can be determined byhose siled n heart at therne suc substitutions are desiedc In certain embodiments amio acid substitutionsca be used to identify important sidues of aOPG or torease or decrease the affinity of the antibodies to OPGL described here. 017 In certanmbodimens ntibodiesofte present invention can be presed in cellnes other than hyridomace ines I certain $9 emnbodimnens, sequences encoding particular antibodies can be used for transfimatnOf a suitable main inhstcl codiqt eti modments tsformation ca be b aoi poynueoIdes Iio a host ce, id o exampeae poynucleoide in a virus (or ito a iral Veco and tansduing a ho cel wh the vius (or vetor) or by transfection procedures knowi th art, as exempNfed by UAS Pat Nos 4,399,21. 9 4 740 and 4,59A55 (w h patens are hereby incorporated heren by referencefor an purpein emb metsthe tansfrmation proe dre used may depend upn th notto be trnfre.Mtosfor inrdcinof heterologous polynueotides intoan ce e wl known In the ar and include, but are not iited to. detrnmediate0d transfectio, calium jphosph ate precipittin, cpolybrenem mediated transfctio, protoplast fuioeecooro, e--.capsuilation ofA the: . po udectide(S) n lposomnes, and diretmcronetonof the DNA into p113] Maxmalan cell lines aaiable as hosts for exrsinar;e wll k the ar and ebut are nli t t e cell lines available frm the American Type UdClt (A TC), including but not lied to Chinese hamster ova Co el He cels ab hamster kidney (21-1K) cells, mnykieycepls (003S! hum nheaocluarcrcnm c (e, Hep 0), and a number of re a exresinlevels and produce ant ibodies wit cosiuieOO ~dng propertes. 40 [011l9J According to certain moietanioiso h ,,vnton are usefu fordetecting QPGL inbiloic amplesl. I et embodiments, this allows the identi n s or tissues which produce the proten. In CertaK embodiments, antibodies wic bind.- to POL an d block Interaction wI ofer ending compound m have herapetic useI o n se di ation and bone resrption n ca embodimentsantibodies t OPL may block OPGL M tOA h may result in a block tinhe signal transducnascade ndNF-k mdatead tran~scriptoaciainAsysfrrasrngN tieiad transcription acct on usng e a uferasae reporter assay aret those skiled in the ait 101201 n certain embodiments, method are proved of tratng bone disorder copmriing adminsering a therapeuically! effective aoun of en bone disorder comparing adrnnistring a hrpuialyefoviaon fa -nioy to OPLand another therapeutic agent in certain suc ebodim-ents: Te addtina therapeutic, ag-ent i administered in a theapeutically effedctiv in ceran errooments, the bone s a n tbone oss, including buSo r nlted to, osteopeia and oste oss In cerain embodiments, tretmet ith n.antibody toOPSL is used to: supp-res the rate o)f bnreopinThefein cranebdmns ramn a be used to reuetert fbn eopinweethe, resoriokn raeis abo;ve normal, or to reduce bone resoirption to elo nrml evl in oret 41 compensate for below normal Ieves of bone formation, in certain embodiments, antibodies can be tested for binding to OPGL in the absence or presence of OPG and examined for their ability to inhibit OPGL-mediated ostecastogenesis and/or bone resin. [0121} Condicns which may be treaedacording t cert embodiments include. but are nolimted to, the following Osteoporosis, icudirg, but not tedto imary endocrIne ostenoorosis (including, but notlmited to hyperthyroidism hyperparathroidism Cushin's syndrome and acromegaly). hereditary and congenial forms of osteoporosis (including, but nomited to, osteogeneSis imperfecta, haiocystinuia Menkes syndrome Riey-Day syndrome> and osteoporosis due to immobiliation of extremities; Paga dIseas& of bone (csteitis deformans)in adunts and Osteomyehs, kan infectius lesion bone adding to bone loss; Hypercaicenia, including, but not lmiedto, hypercalcemia resultng from solid tumors (ncludng, but not limited tog breast, lung and Mdne) and hematologicrdignacies Onodin, but not mited to, mUtiple myeloma, lymphoma and leukemia), idiopathic hyperca&cemia, and hypercalcemia associated with hyperthyroidism and renal function disorders 42 Qsteopenincluding but not limited to, osteoperia foowing surgery, eCopeiDanhduced by steroid adraion osteopenia associaed with diodrso he, sm.rall and lare ntstine. n osieopenia associated with chronc hepatic and renal diseases; Q sOO ei, eones Ce dh dna Wied to, woteorms ssoeaed w W mithta tiyione with0Gaucher seaseO steonechrosi acitd th sice cOl anma osteonect si nassai e ad wihsemic hi psoedwthaothrusna osencoss oan d onnassociated with rheumatoidah dosencoi nd Loss of arte ad vonv eoknhsoiae it humti 1Q1221 in ceitair embodiments an anti body to OPOL mybe used alone or with at least one aditona therapeutic 'gns o he traten f bonem disorder n ceran embodients, a aantbody to OPGL i used n conjunction wit h a, therapeuically eff'ectiveaon f an addtoayheaetcaent. Exemplary therapeti aetthtmybadiserdwhanntiibo to OPGL nde, are nt liied tbne morphogencfatrs desnated Stgrowth fctor (GF and TGF-P fardily members; ntedleukin- ( lb-) inhibitors, incuding, but ntimted to Lia and deriaties teofand Kinere'?A TFo nbios include ing, butO not limited to 431 soule TeNFa receptors, EnbreV antLTNFa antibodies, Remicadaytad 32E7 atibodies parathyroid homione and nlogs theeo parathyr-d elated rotin and anaogs thereof sere rostagandns; bsphosphnates (such as eando e and ohersbonenhcne r a s flord and now4eoialaninkflarrmatoni drug (N$AiEs), inldnbut noCt limited to, CX-2ch s Cebrx nd V o i unuppressants su methotrexate or etunonide serene proteasenbors including bunot l ed to, secetory leukocye potee inhibitors (ncdig but inted to, antibodies to los) IL- inhibitors (incldig but not cited to, anibodfes to I- ib ( udi but not limited to IS binding ooen and a-Santiodies);anerleuin-i onveng enzymeOF) mdulaors fbro bast growth factors FOE-I to FGF-I 0 and FGF moduators PAF antgonsts keatinocyte growth factor"- ) G-eatdmlcls and 14SF modulators; matrix metaoprotnase(MMeP) modulate Niri oxide aynthse (NOS) modulates, including, but not mited to moduator ofinducible NOS; modulators of gcuocorticoid receptor; modulators of glutamate receptor modulators of lipopolyachaides ad adrenalined moduators and mimetics thereof, [0123 Inceain embodimens an antibody to OPGL is used wdh parular therapeAtic ages to treat various immator conditions autoimmune conditions, or other condos with attendant bone ls. I cedaan embodiments, in Viw of the condition and the desired evelofteatment wo treeor more agenmay beaminsteredn ern embodiments such agents may be provided together by iclusion 1 the same fomuulation, certain embodimens, Ach agents and an atibody to OPGL may be provided together by inclusior i the same formulation certain embodiments uh agents may be provided together by inclusion in a treat in cain embodients such agents and an antibody to OPGL may be proved together byidusion ir a treamen dtIncranebim tS uch agnsmay epoieeaaey ncerta embodiments whe admi d by gene therapy the genes encding proein agents and/of an1l antibody to SP':G may Le includedA i the same vecto in cetan embodiments, hegenes- ericodinig protein agentsado an antibody to OPGL may be under the Conto of the same promoter region n e n ebdientse genesecoding protein agents r a nb to OPGL may be separate vectors (01241 in Can embodent he present rnenton i rested to therapies omprising in atibody to POtG and at east one iteru -1 (an!) irdbtor and methods of treatment using such therapies eta embodmens, a therapy comprisesanan dy to Stand an IL- bor and at least one additional mecule descibed herei n ceain embodiments methods o treatment use L inhibitors and/or TNP inhibitors in con notion with an antibody to OP Ln cedan embodiments an antibody to O n combination with L-1 inhibitors and/or TNP-q inhibitors may be used for treament of condtoOns such as asthma, reumatoid arhritis and multiple sce"osis 3r 5 I $ erieukin4 (I)i an antiinaammatory cytokine in tL is a medator in many diseases-: and india certain instances, L- manufaced by e f the copa oc nege n cean instances, [L1 is produced ino forms 1 01261 A disease or medical cod 0o isonsidered to be an intriuki-Imediated viseas&4 if the spontaneo,..us oreprmna iese or edal condo i associated th elevated eve of n d s tsue andr I cs tissues taken tm the body produce el e levels of IL byso d by pthe folloing ddi l X c condition; ( d) fidings associated wt the diss or mdia conditioDn c anre iice exermetalyin a nimals by adiitainof Ul o prglto fepeso of 1W; and (2)~ a pathology induced in experiental anim al mrodels of the disease or medical condition can be inhibited or abolished by treatment wih agentsthat nhibit the ation o I In certain embe sone or more of the above conditi are met in an medaed disase ertin emodimenfts al hree of the conditions are met in an IL-Imediated disease. 01211 Acute and chronic r nedeukn- -medated diseases Include, but are not liM to, the fol lowin~g: acue pancreatiis emyotrophic lateral scersi ALS, or, Lou Ghi' ies) lhiresdsae acdhxi/anorexia, including, -ut note os Autmmuceda a sthma fatigue syndrome; Qiostrjdiunm associated illnesses, including, but not limited to, Clostridium-associated diarrhea; coronary conditions and indications, including, but not limited to, congestive heart failure, coronary restenosis, rayocardia infarction, myocardial dysfunction (.g, related to sepsis), and coronary artery bypass graft; cancer, including, but not limited to, leukemia, including, but not limited to, multiple myeloma leukemia and myelogenous (eag, AML and CML), and tumor metastasis; diabetes (including, but not limited to. insuln-dependent diabetes; endometriosis; fever; fibromyalgia; glomerulonephritis: graft verus host disease and/or transplant rejection; hemnohorragic shock; hyperalgesia; inflammatory bowel disease; inflammatory conditions of a ot, including, but not limited to, osteoarthritis, psoriatic arthritis, and rheumatoid arthritis; inflammatory eye disease, including, but not limited to, those associated with, for example, cornea transplant; ischernia, including, but not limited to cerebral ischemia (including, but not limited to, brain injury as a result of, e,g , trauma, epilepsy, hemorrhage or stroke, each of which may iad to neurodegeneration); Kawasakis disease; leading impairment; lung diseases including , but not limited to, acute respiratory distress syndrome, or ARDS); multiple sclerosis: myopathies (e.g, muscle protein metabolism, including, but not limited to, muscle protein metabolism in sepsis) neurotoxicity (including, but notilimited to, such condition induced by HV); osteoporosis; pain, including, but not limited to, cancer-related pain; Parkinson's disease; periodontal disease; preterm labor; psoriasis; reper-fusion injury; septic shock; side effects from radiation therapy; temporal mandibuMar joint disease; sleep disturbance; uveitis; and an 47 iflrniIator condton resuting from, g. strain spram, cartilage damage, ma, ortopedic surgery, inetin or oher disae processes. 012j n cerain embodiments, an L- inhibitor may be amy protein or morecue capable of specficaly prevening activation of celuaa receptors to V!, whiho may esufrm any umber of change empia mechanisms include, but are not lite to: oneuaigI- rdcin binding fee , nterferng with 16 binding toitseceptorenerferng wh foratonofthe 10l reetrcm leLe, associaton of MLA receptorwith IL-1 receptor accessory protein), d inte fering with modulation of 0,1 ignaling after bindg to ts receptor. [0129 9ertain intereukin-nhiitors incde, but are not lirnted to: ILA receptor antagonists, including, but not limited t e IL-Ira? iL-ira vagrants, and rde es ich are coliIvey termed a pOteins;" anti- receptor monoona antibodies (see, e.g_ EP 623674 with ishereby incorporated by reference for any purpose); It-l bindingprotein including, but not imed to, soluble L receptors (see, eg, U. S. Pat No 549268 u S Pat No 5,488:032, and Ut S. Pat. 5464,937A U , Pat No, 5:319,071, and U.S, Pat. ' No, 5,180,812, whi are hereYinoprtdbrerncfr any puroOe; ani- mo1n97 tibodie seC 9402627, 9006371 usPat No. 4o 935,343, EP 3478, E P 26761 and EP 220063, whih are hereby icorporated by reference for ani purpose);L receptor acessory proteins an antodi Dtheretosee e w 96/237 and V/CNOf3773 which are hereby incorporated by referencefor any purpose) 48 inhibitorso intedeuki1 beta converting enzyme(CE)or caspase I (see, e, wo 4624 WO 9474 n WO 99/4714 whh are hrebincopoed erence any ae used to beta production and secrei 'beta protease s and ompunds and proteins that block nA v/, sylnthes a or extraceluaelase of L-I. [0o Exemplary IL-I inhibitors are s daeg in US NPat. o, 1.74T,444; 5!3542 ; 5608035; 5843,35: $"39,032 -5566,576': 5,89,60; 5869 15; 58705; SABS 5,s965,564; e non (WO) patent applications 98121957, 9/09323, 91117154, 94 907, 332733. 8435 98/44940, 98/47892, M 3, 99/037, 9 42 9 042 91/7249z 9 /327 33, 98/1768, 9 708174, 953432ez 9/3642 93 415 E uopean R, ) pae applations 534978 and 894795; and French patent applicaton FR 276214.The discosures of all of the afrmnindrfrnc,es are-, hereby incorporated%- "by reeeneFor anly purpose. [0131 tee rece ptorntagon ra) is a humanproten that aqcts as6 a natr inhibi tor oiniiterleuki-.] nd isamme of teI- aiy Wich n des iand iL- . aIn receptor n and variants and dervatves there as ell as methods of making and using the, redzerifbed in UES, Paet o ,07422 'VVO 91/0285 WO 91/"71 84; AU 9173536 Wa 92/16221; WO 93/2194; WO 94/0,67; WO 94121275; FR 2706772; WO 94121235; DE 421962, V/C 94/20517; WO 9S622793wO 3712828 and WOD 99/36541, wich ;-,eaicroa herein by reeeneFor aSny purposeIcertain embodiments n l receptor antagonist may be 49 ycosylate n cerain embodiment an Repto antagonist may be non 22forms of IeIra and var!an described in U.S. at. N. 5175222 (the 222 patanQ The fis omcle L'i~' inth'22 patent is characterzed as a 22-23 KD moledce on SDPAGE with a approxi mate iselecthc point of 4, which Ms frm a Mono Q FPLC o at td2 S ,NaC ind o L is chaacterzed as a 22-23 kD protin, whih fetesfom a Mono 0 o m at 43 ir I i MaC I B-3oth Il -ua aan d GL- 1raP are glyoyae Th t,, hird frIiei as 20 kD p s a Mono na Naci and is nonl-ricsltepTe'22ptn as ecibscrai ehd for sotnggenes that code for the inhibiors, cMoing Thosmgnsin!ial vecor, rasfrmnganld trWSWe-i ths enes- ito certai3"n celtPsndl expressing those gene--,s t.o produce the ihbitors. icea emboments, eensiseins andi substitutons (indidualy or cectively referred to as arantaf) ae made Wtite amn cdsqecsof IL-ra. In cetinebdiet,an IL-Ir~a vaiat i d yoiogically a cti v e (eg,, po s sesses- te ai l ft to inhi ;b it IL - ) (0134] In certain emoiettepres ent invention is directed to terapies compisig an anybody to OPGL and a least one TNa to and methods of treatment usng such thrapies Cedain embodiments atherpy antibody to OPGL and aNa nbtor and at least one addition molecule described herein 50 S ertain diseases andmedicaconditions are mediated by TNFf and sybe catgoried aS inlamaor oniton. Asue herein, a 7NFamedited disease" includes. but is not iimted to, a disease or edica condition that asocated with elevated eveis of T11 in body fs or tisse and/o i hich ey or tissues taken frm te body prode ee ated eve TNF in culture, In cedain embodiments; diseases a TN mediateddiease (1)patolgicl fndngsasscitedwit te dseae r medicl coditio'n can be n d ein aias by the admiitrto or Upreg nation of expression of TNFf and/or ()apa~thology ind"Juned ineprmna nmlmdl of the diease ror edca condition can b inhibi'ted or aboliished by treairnenti wth agents that ihibit thea of TN CertainR aAe and croni e d dseases incude but are not liitd ochexia and anorexia; cancericdng bu.tct liitet,, !eukemi" a; chronic faiu snrme oonary conditons andor indication-s, inciudng, bu not lmitedtoNcogestiv hear faiure crnry- retn s mnyocardi infarction, yocardial dysfunction including but not lmted to, such condition related to sepsis and oronaryate ss aft depression dabet, udng, but notimitedto jvnie onset ype dabete diabetes e'us aid insul resistance (includg, but n d to, su resistance associated OW bst) noeroiedrerts n eae odto fibromaa and analesi; graft ersus os per inammatory bowe diseases including but not rimted to, Cohns disease and clostridim dificiiassciAed diarra; se inlui t nid to., cerebral ischemia, which inc~Ludes, but is not limited to, brain injury as a result of trauma, epiepsy, hemorrhage, and/or stroke; lung disease, including, but not limited to, adult respiratory distress syndrome, asthma, and pulmonary fibrosis; multiple sole rosis; neuroinflammatory diseases; ocular diseases and conditions, including, but not limited to, corneal transplant, ocular degeneration and uveitis; pain, including, but not limited to, cancer-related pain; pancreatitis: periodontal diseases; Ptyriasis rubra pilaris (PRP); prostatitis, including bacterial end non bacterial prostatitis, and related conditions; psoriasis and related conditions: pulmonary fibrosis; reperfusion injury; rheumatic diseases, including, but not limited to, rheumatoid arthritis, ostearthritis, juvenile arthritis (inciudig, but not limited to, juvenile rheumatoid arthritis), seronegative polyathritis, ankylosing spondyliNs Reer syndrome and reactive arthritis, Sts dhease, psoriatic arthritis, enteropathic arthritis, polymyositis, dermatomnyositis, sdieroderma, systemic erosis, vacuitis eg Kawasskrs d erebra is yeg. disease), vasotiliti, Lyme disease, staphoccaindue(sepic) arNi, Sjgrensyndome rheumatic fever, po dras and pajmyaigla rheumatiand giant e! artertis) septi shock; sde effectsfrom radiation therapy;ystem lupus erythematosus (SLE;tempora mandibur joint disease;hyroidiis and tissue transpantaton and/or an inflammatory ndiion, esulting fromstral sprain,: Cartilage damage, traumae, orthpedicsrerifcto e'. V Clostrdiun dffi and related species)or other disease process, on 1 $73 r tin certain enbdimen, TNF irdibitodn ma acy ateast oneof owre~iainqor nhbitngTNF production, bindingqre TINE, inteferig 52$ with NF nding tosecptor d erfeongit ndustion of TNF signing after ending to t receptor. The rTN inhibto incdes, but is not li to, obliged TN rceptos i ancudin9g but not liied to, solubetm neosi factrrcepor yp (shR I 510Called the p55 rece9ptor), st obluo necrosis facto recepor type HI (also called the p75 b&et4 end Inre antibodies to TN incudingb omted , Re-icade and D2E7 see U.S. Patent eo cs382 ad 6 56; anbde TNF ANF ('e a ~. WO 98!2463 etanarcept (Enbel) Avaine inhibitors of TNFo en enzym rA and othroecesa ae TEty ~0438) xerrplary TNF~oinibiors are desed e g, an Eopen patent apcationsP 305 3 P422 339 EP 393 ;E 398 32 P 412 F P418 -014, E 417 563, ER 433 900 EP 464 533; EP 5125 K P 526 905; ER 568 928; EP 607 776we efluomde o inh n of TNF-; ER 683 210; P 542 795 E $1 439; EP 664 128- EP 542 795; ER 741 707; EP 874 819 ER 882 71 EP $80 070; ER 848 783 EP 73 701; EP 8 988; EP 550 376; ER 802 74 ER 853 06 EP 550 376; E 943 61 P 939 121; EP 614 984 ;P 0 U.S Patent o 536 02 92917 594838 " 280716Z 5Sa95§53' 5834435 S 1 2;5830a7s42; 5834 435 851 56; 5 5,077; 5359037; 5A1244; 5695953; 5811261 "631145; 5C86312;566 616; 5641673; "8 §77; 569511; 5872146 51854,00; 58 64 5577222; 1877200; 5877151; $886 10; 5869,660 515127; 5,89183; 1877j 80; 5,95548O 5955476; 59554351 9$945 1090119; 52,320: 5, 924 1 terraina patent appiatiuns WO 901i 55 53 WO 91/03553 WO 92/01002. WO 92/13096, W/ 92/15221 WO 93/0o83, WO 93/21946, WO 9/19777, V eC5/34326, WO 96/28546, VO 98/27298, w 9W30541.WO 96/381507 VVC 95638150, N 97C 820 VC 97/1551 WO 97/129, VV/ 98/W258b1, WOC 95/12735, INC 96P11209, V/VC 98/3ME& VA-C' 9/39316 WO N8/A85 WC 98b9315, W 98/42659, WO MG3329, We 98/43959, WO 98/45268 Y 98763, W 9633172, /O 620926, VA .7137974, Vo 97/s 27. o/ 97/479, We Y371 , VC 9 851 65 Vv s C 98/4 3946, VVC) 95004,V/C 2-8156377, WO 97/l2244, ,/ 90C0364,V/ 99100363, ~ ~ ~ ~ VV V/ 653#,')9/14,499/01139, VVC) 28/56788, We'O 8(6 7565, VV/C 98/ 5383-42, WO 35 2 948B, VV/0 9 8/52 9 37, VV/0 99 / 02 510, OVC ) 9/43250V/C 99/06410, V/C 0 O N W 99/09022, WO 99M0688, VOC 99/07679 W 09965, 907704, w M0604 VO 99/3781 8 V 99/37625, WOC 97/11868, WOC 9523,v/C 99'/476'72. /)9/89 Japanese patent applcatns 1014 023128 1025940 and 0130149 10316570, 11001481, and 127800199i; Woman appliati no 19731521; and British application no.2 21 8 101. 2 326 881, 2 24$ 5W9 The dicosus of all of the afoxernentioned references are hereby inoprtdby reeenefr y purpose. [0EP9 S 33 438 and ER' 422 339 describe the amn o acid and eic acd sequencs of a soluble rN Feceptor type I (also known a sTNFRI or 3OkOa TNF ihibtor) and a solble TNF rceptor type iao known as crNFR ~Ti Wnn~mr/ wrh ecrecv.yhtiu ~ 393 438 and EP 422 339 a&-', -esacribe mdfe forms of TNRland aTNK-l, 4 including. but not limited to fragments, functional derivatives, and variants, Furthermore, EP 393 436 and EP 422 339 describe methods for isolating genes that code for the inhibitors, cloning the genes into suitable vectors, transforming or transfecting the genes into certain cell types, and expressing the genes to produce the inhibitors i "A0 TNFR and ANFR are members of the nerve growt factorTN receptor superfamy of reactors which ncludes the ne growth factor receptor (NGF), the B cAl antgen OD40, 4- B8, the rat ce antigen MPC 0X40, e fas antge,and- the 00,27 an-d 0030 atgn Siha l 1990) iene 2481019 0523 A conserved feature of that group o ce r o i a cysteinerich extracelular igand ending ain which canbe ivied ntofour- repea--ted motifs ofabout, forjinoy acis tatontain & cystene residues at positions that ae weconerved mih t al, 1 ) [01411 EP 93 43 teaches a 4kDa TNF ihNor AS and a 40kDa TNF inhibitor ASS which are truncated versions of the fullengtb recombinant 4OkDa T nhibior protein. A5I and $53 have 51 or 53 ano acids, respectvely deleted from the carboxy terminus of the mature protein. [0142] Published PCT Appiataon Nc WO , 6015 describes truncated forms of sTNFR and sTNFR4I that do not contain the fourth domain (anno acid residues Thr 7 AsnA of ATN9FR and amino acd resduesPro Thr 7 of AN ; a portion of the third domain( W46 12 of ANhFRA and, ano acid, residue Prol 2 &Lys 4 -O of sTNFR-Il); and, 55 ptonaly, do not contain a portion of the ist doman (amno acid residues Ap% 0ys 19 of sTmER and amio acid residues eucysSof erta embodients he trncated sTNF s idudethe proteins represented by the formula R 1 fy~~sO> 2 and R4052-yl6~,These proteins are truncated os TNFR and sTNFRM, resecely, 01431 As used herein, -ys y ne or more prtis[een(13-LCysiOni is reide 1 th roughn I Qi,3 of sTNFRl h sequence of which is provided in Figure 1 of!0 98/01 555; w re represents a methionylated or nonmethionylated amie group of Cys 1 9 or one or more amno-terminaiainno aid rescues selected fnom yslM to Asp'; an presenacaroxy gup ys or one or mor ecaboxy terminal amino a7cd residues selected fronm Phe 1 to Le 1 l 144) Exempiary truncated sTNFRs of the present invention inclu bu are n cNFm ed2 o t s TNNF2P-1 26D105 1TrR12D60/0106, sTNFR 2,6/N 105, sTNFR .Dd8 sTNFR 3D/diS, sTNF 2 1d 15, either metbonyate ornnethionylatd nd vardants and derivatIVes thereof. Ceram exempary truncated sTNFR-l a are deswrbed e i pushed Application No. WO 981 55 f0145 As used herein, R(0ysGysl1JR& represets one or more proteinS wherein tcys is residues OysSethrough ybof sTNER The sequence of which providedrnFiure B of WO 98/15 5 wherein P presents a rethion ted or nonmethionyted ame gop o 0ys 3 or one or more SamIo erminal aino acid esidues seieted from Cys 1 t Leut and wherein R4 represents a carboxy group of Cys' 1 or one or more carboxy-terminal amino acid residues selected from Aiaa 1 io Arg 222 [01461 in certain embodiments, the present invention is directed to therapies comprising an antibody to OPGL and at ieast one serine protease inhibitor and methods of teatmantsing suchtherapies n certain embodirents a therapy comprises an anybody toQPG ansaserine protease inhibitor and latest ne additional moleue described here [0147] Endogenous proteoiytic enzymes may degrade invading organism2, antigen-antibody complexes, and certain tissue proteins that are no longer necessary or useful. nfective agents may introduce additional proteolytic enzymes into the organism, Protease inhibitors nay regulate both endogenous and invading proteolytic enzymes. (0148 In ceranembodiments aturay occurng protease inhibitors serve to controindogenous protease by limidigtheirreactions loca and temporary in certain embodiment protease inbitors mayihibit proteases introduced ino the body bynfecve agents carain instances tissues that are particularly pronto proteoyattack and infection inlding but not lmited those o the respiratory tract re i n protease hibitors. [0149] rtese nhibitos comprise approimately '% of the human nasma proteins Ateast eight inhibors have been isoiatedfom this source and characteredin the iierature. ese include, but are not mitedto apha 2-macrogobun aphaS 2), pha protease inhiitor (alpha lPipha 57 1antichymotrypsin (alpha 1Achy), alpha tanticoliagenase (alpha lAC), and ~nter-alpha-trypsin inhibitor ([alpha-I), O050 10 ertain instances, a dstubance of teproteaselprotease inhibitor balance can lead to proteaseediatedissue deduction cluding, but not Botdtepyea rhiiglornerulo-nephdhis, periodontitis, muscular dystrophy tumor nvason, ad vaious oer pathoogca ondions i et sitaton, eg. severe atogil prcse suh as se--psis o ct ekma the amount of free proeolytc enzymes present ay crease e o e ase 10151 Furthermore I an stances a danihed regultng nhibitorcapacity of the organismay aso cause aeration i the protease/protease inhibitor balance. A onmiting example of such tarnished regating ibior capaciy is an apha otese inhbito deficencyw is correlated With the deveopme of pulmonary emphysema. [01521 in certain instances, serous damage to the oragni can occr he schaberant conditions are present unes"esue"an be taken to c0otrohe prtoyi nye.Themrefre prta nhiioshv been sought that cAn be administered to an organism ocontd potolytezymes [0153] Lukocyte elastase, rypsin cabepsin G and pancreatic eastse pre i exampes of a clas protease known as sein proteases. 0i 543 In certain stances, leukcyte elstase when released extraceiuarly degsdes cannotive tissue and other valuable protein Whila 58 normawy functioning organism degrades a certain amount of connective tissue and other proteins, the presence of an excessive amount of heukocyte alastase may be associated with various pathological states, mnluding, but not limited to, emphysenm and rheumatoid arhrit In certain embodiments, to counteract the effects ofJ u easse when tA is preset an greater than normal a protease inhibitor hs been sought wich is serifor r e easase. Suc a protease WINhiio may be use ful if it were capable. o.f bigioae rpeae vi a purified form andi siufticint quarititea to. be bamce calyuefl [01 5$~ Cert~n leutocyteelastase inhib,,itor.saedscide. n Schiessier et a"., rcdtbeInbiosof GauoyeNurlPoessI Huma Mucus Screio-.ns: B-iochemity and Possibl Diogial Furction, iM Neutral Proteases of Human Polvmorhoneuear Leuccoves. Havemanm et a eds Urban and Schwarenberg n 9781 and in Tra and Savesen, Ann Rev 2iocGem. S~ 65)5J09 (98E3). [aa te trypsn initiates degradation o certain sof oran issesuch as pancreatic tsue, during a variety of acute;: conUons, Suding, but ri tedo ncreats A trypsn nhibiormay be useful f it coldbe isolated and prepredin apurfied form,- anid insufcin quantities t be pharmaceutical useful, [0157] Cathepsi G anoer proteaspresent in icukocytesIn ertain emodents, catin capable of derdi a varieof prOOeins w ncld hose other complement pSA Y Pancreao eatse iner 59 protease thatmay have a role n pancreatits Thus ihbitors frhese proteasesmay alsobe ofpc,,etia"vle 1~ 58 In CeaArtjai em1b od im")ent, the su bsre seictyad sensitivity to different inhibtos of sh-cpoeesar'e believed to reutfrom changes in only a few amino acid residues 3y anagy, i may be possible to conceive o cas f sedne protease inhibios i wh changes i a relatively few amino acids wl result in nhibition of different proeases In certa embodiments, a member of th ass inhibits everyseine potease 0e1501 An exemplr sine protease inh sseetory eukocyte protease inhibitor (SLP) and fragments and analios thereof Exemplary series Sto eaede ib aa ut re n imied t protease ALP mucous pro -sse inhtor (MP), human semin asma bronchial mucus inhibitr (M and crcamusinbtr(Ut>in. cer tain bodimentsa seine protease ibitor aso may be LPS modulator. See, g in et at 49 8 n certain embodiments, tese e r wlsuted for Use in conditions leadi o boels bheyB aepr;eerent-niallirected to the criae U S. Pat, No. 4,76,13Q; US.. Fa-t a. 90O00 and US, Pat No. 5163j27, which are he ioroat references a any purpaorse Tah e ues discosed in the foregoinrefrne as wlAl asanvrinsoaalge th~ieeof are cc~ehecivl termed 'rieroasihiirs [alai!1 I-S is -a 0rfflmaoyct Idn at was fon oic e interferon-y and was reviousy named ierferon gamma ducng ao ) 18S induces production of a number of priianaor yoie,including IL -6 and MP-i, See, e,o7 , "'-a33' ata 19) ELekct Io 358-64.' mn certain instance. c'aspase I so mportantfor products x permitss als ggstta a p S production and that simul inhibiQi(n f TNri-o "-a nd iL 8 -proet agist --- e oxct ee, Fagi at al, 20CC, PNS907 23S7-72. de 1n2 WAS acs i WV' through a receptor systerof" the ExLK- sys t em. EL-Cr in wit an eh urfae recepto (yW SR> wiCh interacts Ni an accessory praten (PLand a at Snedrate an prcedsupn orato otht comrplx of RL, I l 1 SR, end ILAS:RAcP. A nature ihito for ILAI is L-Wl18bp. in certain emL-ens I 5bp acis ans a 2 d coy rceptor t by bidngt L-IS- monlecules and preven-tin g intracionwih UL r01 em In 'ertain mbdens the prese-rnt ivnonis dire!cted t therapies comprising a,n b aniboy to PLada ss neIlihbtr n methodsoftreatment usng such terapes n tn embo cents a hea comprises an antibody to PGL and mn IL-IS inhibitor and at least one ad dona to certain embodimentsce bt are no imied nutomune diseases5 L- mediated diseases an NFditd d isas Exeplary conditions that rnay be treated with an antibody to OPGL and at least one IL-18 inhibitor according to certain embodiments include, but are not limited to, arthritis, including, but not limited to rheumatoid arthdtis; systemic lupus erythematosus (SLE); graft versus host disease (GvHD); hepatitis; sepsis; and the loss of bone and cartilage accompanying these diseases, [0164j Exemplary L-18 inhibitors include, but are not limited to, antibodies that bind to IL-18; antibodies that bind to IL~18R; antibodies that bind to IL-18SRAcP; [L-18bp; IL-1SR fragments (e~, a sciubilized extracellular domain of the It-1 receptor); peptides that bind to !L-18 and reduce or prevent its interaction with iL-18R peptides that bind to IL-1 BR and reduce or prevent its interaction with IL-18 or with IL-1SRAcP; peptides that bind to IL-18RcP and reduce or prevent its interaction with iL-1 SR; and small molecules that reduce or prevent IL-18 production or the interaction between any of IL-1, ll-1R, and IL I RAcP [0165} Certain Wt-18 inhibitors are described, e.g., in US Pat No, 5,912324, is sued July 14,1994; EP 0962 531 published De, 8, 1999; EP 712 931, published Nov. 15, 1994; U-S Pt, No, 5,914,253j issued July 14, 1994; WO 97/24441, published July 10, 1997; US Pat No, 6,060,283, issued May 9,2000; EP 850 952, published Dec. 26, 1996; EP 364 585, published Sep. 16, 1995; WO 98/41232, published Sep. 24, 1995; US Pat, No. 6:0S4,4S7, issued April 25, 2000; WO 99/09063, published Aug 14, 1997; WO 99122760, published Nov. 3, 1997; VD 99/37772, published Jan. 23, 1998; WO 99/37773, published March 20,1908; EP 0 974 600, published Jan. 26 200;:W 00/12555, published Mar. 62, V, 2000; Japanese patent applicaton JP 111399/94, pubUshedct 31, 197 Israel patent appliCatio iL 1215'-54 A, pubise0Fb. 8 ; h are ncorte Rh by rF*CiSrence frr ny pudpsed [0166] in cetiM moetan antibody ; to OF L. m 1ay be se with at lAst" one therapeu tic agent for nfamtoin ceqtan embodimnts, an antibodyv to- OPOL may be used with at estonethraeui agen-t for an immune isorder Exemplry therpeuticagents forlnamtonndi un disordersclude but are not liied to, couotris nldnbut not limited to, prednisolone; nonsteroidal anflnflamnmatory drugs (tMDsa noudng but not Unmited to cycioxygenase type 1 (COX-1 2"n cyloygns i'ype X(0 2 ) inihibitors; dise-ase mdfignire atcdrugs (DAbicldn, but not limied tomtorxchdoxolrqie hooqie ylsoie gold compounds (such as ranauo aed o c and leflnoride tye I phsopodisteaseihbiorsicdn, b'ut'- niitedto Rolipram and Pentoxe aoinus S irousaparyin mop henoi at; poxygenase ibiors, iud butnotimitedto ZIleutn; modulo of nl - ); s a m c mdulators ci 3 )a ntraceuar eues nolved in lammaton pathways where sh intaceluar moleues nclde, but are notiid to, jnkTK, NF-S, ZAP7 Cerai exemplary therapeuftc agets fo inflammatin re descbed e 3 Amgen Inc. Thousand Oaks, CA, Certain exemplary therapeutic agents for infammaton and autoimmune diseases include, but are not limited to, interferon gamma (FN) modulators; modulators of 0X40/0X40L (including soluble forms of x40); modulators of 4-18/4-1BE ligand (including soluble forms of 4-18$); aid modulators of B ceT cell costimulory pathways, including, but not limited to, modulators of the receptor ligand pairs CD28/P7, C40/C40L, ICOS/B7RP1, and AGP-3JACiBAFFR (AGP-3 binds to both TACl and SAFFR receptors), Certain exemplary modulators of B ceIV- cell costimulatory pathways include, but are not 4mited to, inhibitors of CD28, 37,1, and 7,2 (including soluble forms of F7,1 or 87.2 and double forms of CTLA4, both of which may be fused to a heterologous peptide or protein which reduces or prevents degradation and/or increases half-ife, reduces toxicity, reduces immunogenicity, or increases biological activity of a therapeutic protein by increasing solubilty or irculating half-life); inhibitors of CD40 and CD40L (including soluble forms of 0D40 which rnaiy be fused to a h eterologous peptide or proteiri) inhibitors of ICOS and B7RPI (including soluble forms of 100$ which may be fused to a heterologous peptide or protein) and inhibitors of AGP-3, TACI and BAFFR (including soluble fonms of TACI and SAFFR). 1CO$, B7RP1 and inhibitors thereof are described, e , in WOO/46240, AGP-3, TAC and BAFER and inhibitors thereof are described, e.g, in WO00/47740, WOO1/86872, WVO2/1$273, WAO98/39361, and von ulow and Brain (1997) jScience 27S:138j n 67 certin embodiments an antibody to OPGL is used to treat bone osincluding, but notlimited to bone loss resultingfom osteolytic destruction of bone caused by medgntor nmet tictumors I certain embodimnts, a antibody tc OPO' 'L "ma y be usdCotra boneC ioss ascae with cancer. Exemplar-y cacr nclude, but ar o imite to, breast, prostate, thyroid, kidney. ung, esophages retaW, bladder ceica ovaian and iver cancers, as wel as cancerof the gaatrointestiord track n ertai embodients an antibody to OPGL may be used to teat bone oss associated with eqg certin hmatooqic maignacies incudin, Ai not kille t, multiple 01 tin e mbodim , an antIboy to OPOL is adnitered alone n certain embodimers, an arnibody to OPGL is ad ministered with at least one other therapeutic agentincluding, bt ntimted to. at least one other 0ane therapy agentE xe ycanCer tea s icde, but are not lmted to radaton therapy and chemotherapy n certain embodmentscheotherapy may involve rametwthoeormr of the followng: antiir oies, talF aoifndoouiin -luruacl n other drug-s know, n i-n the ar in certain em,-bodime3ints, a cancer therapy age ,nt is ,a Jutenizng ormoe-rleainghormn (HH) an'tagoit n eti embodimentsa LHRH antagonist is a peptide antagonis (0159) in certain embodiments, arn LHHatgns comnpris es the- , peptide: A hd aN s~ ydrae As NH2 (SEQ ID NO 2, where Nat is 3d2rnapthyl)alaninyi4; ha is 4 615 chibrophenyv~ataniyl Pa is 3py an a ys(iP propyllysinyl ['01 70] in certain embodiments, an LHRH antagonist is an LHRH antagonist decapepUde. Certain exemplary decapeptides are described, eg, in US. Patent No. ,843,901. which is herein incorporated by reference for any purpose. [ 171] Exemplary therapeutic antibodies according to certain embodiments include, ut are not iirnited to, rnouse, mouse-human chimeric, CDR-grafted, humanized and fully human antibodies, and synthetic antibodies, including, but not limited to, those selected by screening antibody libraries, Exemplary antibodies include, but are not limited to, those which bind to cell surface proteins Her2, CDC20, CDC33, m ucin-like glycoprotein, and epidermal growth factor receptor (FR) present on tumor cells, and optionally induce a cytostatic and/or cyttoxic effect on tumor cels displaying these proteins. Exemplary antibodies also include HE*RCEPTIN

T

" (trastuzumab), which may be used to treat breast cancer and other tor- of cancer, and RITUXANT (rituximab), ZEVALINT" (ibritumomab tiuxetan), and LYMPHOCIDEh (epratuzurnab) which may be used to treat non-Hodgkirts lymphoma and other forns of cancer. Certain examplaryantiodies also include ERBITUXTM (IM C225), SEXXARh iodine 131 tositumomab) and Campath, 10172] in certain embodiments, cancer therapy agents are polypeptides which selectively induce apoptosis in tumor cells: including, but niot limited to, the TNF-related polypeptide TRAIL in certain embodiments, an 6aN antibody to OPL may be administered aast e e prio to, concurrent with and susqun o treatmentith a c:anc-er therapy agent In cerain emod ants, an antibody to OPGL may be administered prophyiatjaiy to prevent or mitgate the onse of bone Loss bymetastatc cancn cerain embodimenks an antibody to OPGL ma-,y be adiitrdfor the teatment of an exisingcondtio ofbone ioss du'e to met ass [01711 in cetan embodiment, an atibody to OPG3L may be used peventandor teat bone los assocated wth multiple myomaandr to prevent andor teat the dlseasitse tpe myeloma is a c eldeied tat su senmant r t a rmotaitny certn dances a cinical '-ifestaton of mu#tpe mny is foca bone oss hch may be due to incrased osteoclast actvation in Loalied regions Many iyIomm pab ns present ith bone lesions vise by adioogic anys and suffer fromskelta pai. in certain ntances patents wih myeoma are susceptible to patholgicaactures of iwoved bone, which may occ eithe nta uto injur in eai stane aS tat occur during rnyeloma not only lead to bonefrcurs but @lsodeomtan ccasionay v cossi h vertera s h some patients a thogical increase ln serum calcium (hyperaicemia occurs, and may cause sigifcant problems during disease treatment In certain 'bn nersor an and ro ePeL may be amwhiiyte ed to patients toked bok boeeortion and release of calcium, whiNch ma rce-tL, the ris c fr' Iatures ar.i spinldefriy O 174 In cri stances moyema ceAs o not diretpai pate nbone destrucpnunstead roduce extreelua signais That lead to ostocas. iferntatonand aciaioI certain instancesoseolet produce high leve of the cytokine L-. particulary when they become activated. IGS is a Sei 9rowih factor, and contrbutes0 tohe growh of both mune and human myeloma cells l viro. Myeiorna cells may aiso either directly or indectly produce OPGL, which may result in loca bone lysis surrounding the myeloma cals embedded in bone marrow spaces. ertaininsances, thenora osteoclasts adjacent to temyclma celi turn produce IL, hich may lad to Aocalexpansion of the tumor cells Myarlia cells expand a cona fashion and may occupy bone space that a rated by ppopriateoneresorpton 01 751 t has been obered tot OPG adminsaion rodets tuces rapid deith ofhe o seodast ppulaton (see, eq.. Lecey et AI (2000) gi I. P j.5:4362448),A reduction in the number of osteoclasts may counteract the effect ofncreased lL production by those cels arid may therefore affect the growth and survival of myeloma s whi trabecular bone us in cert embOdiments administration f n antbody to OPGL to a y apte my not ony block the ype sorpton o bone but may yalso affect the expansion and survival of the tumor itself (0175] 8hceils express the receptor orOPL ODAR. Ml omn cel aso express OCAR and in additin may produce OPGL. in certain mnsacesate expresin ot both OPaL ant sOAR in the same mell pcpuiTon m--ay create an autoc: rie stmlsthat affects survWai of the m'yelma cel.; P~us, 65 Certain embodiments, administration of an ttibody to OP mayirndue tumor ce survivaltereby daueasing or elmiatng the tumor burden seen in myeloma patents, f0177J In certain embodiments, the invenn proves for pharnceuticaaompostons comprising atherapuicay efectvemount of an antibody to OPGt together wi pharmacetcally acceptable diuent carrie sober eamulse reservav andor adjant [0 1 73) In c ent , the invention s fr pharmace ial composans comps atherapeua e ece mount of sma endbody to OPGL and a thepeuticay effective amount o a east one additionamterapeutic agents, tgethe with a pharmaceuticaly accept diluentarrer solubier emdsiier preservative andor adjuvantin certain mboden h a east one add therapauO a t is selct dfromb orphoganicactor designated BIP-1 through BMP-1 2; transfo g growth factOr- (TGFj3 -and T1.GP- ' f^ailymebr;TtluknI(i)ihbtos nluding, utnot Wmited to Lna and derivatives thereof and Kineet TNF inhbior, icldigbut notlmie to, a soluble 'TNFIrcpor-nra~,at TNo ntboi~, emcaeTand 02E7 anttcdy; prt-yodhmneand anaogs theeof parathyroid related protei and analogs thereot E series prostagand nsi bisphosphonates(such as Mendonate and others) bones enha3ncing m-inerals such afloide adclim o-tria nifamtr drug 4 st nlAuding CX- inhitors, such as Cee ad Voxt immunosuppressants suchaetore orlenoneseineroteas (39 inhibitors such as secretory euk ct potease haibitr LI) be nios (esg antibodies to IL-C) I8 ihibitors (a.;g antibodies to IL-8) ILI inhibitors (e 8 S binding protein or IL antibodies [ntereukinI con ting nzyme (E) modulators' fbroblast grwirt factors FIto FGF Cand dulators; PAF antagonistseratinocyte growth ftor (KGF), KF-related molcuesmo KGF odltr;matr'mx metaloprote inas'e (MMP) mod ulatort ' Nitric oxide synthese (NOS) modulators, incuding moduators of inducenOS; moduistors of giucoco rticoid recepton moduator of glutaateceptor; modulators of liooyacaia(LPS) lvs;an~d noarn~eand modulators and miesthere [017 I cerain embodiments acceptable formation materials preferably are nontoxic to recipients at the dosages and concentrations employed. n150 m cetian embodiments thepharmaceuinca composite may contain formulaion materis for mrodiyn maintaining or preservngnfor exanplethe pH, oSmoNty, viscosity rarity color sotonicit odor sterility, stabilty, rate of dissoution or release, adsorption or penetration of te conposiin, In ceain em bodimnents, suitablWe fom tr materials include, butA are not led t no acids (such as gy , y utnnine, sagne, n or lysne); antimcrobials; atioxidant (s uch aasobccisodiu.m slft or sodium hydrogensat buyers (such as borate iarbonaterisHC, states psphatesor oher ra acids); bukng agents (such as maaor gycne); cheatng agents (u e eniam atersaciaid (ETA); coming 7G agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxyp ropy-betacyclodextrin); fibers; mnosaccharides: disacchaides; and other carbohydrates (such as glucose, mannose or dextrins);-proteins (such as serum alburnin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinyipyrroldone); low molecular weight polypeptides; saltdorming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimierosal, phen ethyl alcohol, mnethylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or weting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, rnannitol sorbito!); delivery vehicles; diluenits: excipients and/or pharmaceutical adjuvants. (Remington's Phanmaceutica/ Sciences, IS* Edition, AR. Gennaro, edt Mack Publishing Company (1990). [01811 in certain embodiments, an antibody to OPGL and/or a therapeutic molecure is linked to a half-ife extending vehicle known in the art Such vehicles include, but are not limited to, the Fc domain, polyethylene glycol, and dextran. Such vehicles are described, eg, in U Application Serial No. 09/428,082 and published POT Application No. WO 99/26044, which are hereby incorporated by reference for any purpose, 71 L01821 in certain embodiments, the optimal pharmaceutical composition will be determined by one ski ed in the art depending upon, for example, the intended route of administration, deivery formt and desired dosage. See, for example, Remington's Pharmaceulcal Sciences, supre In certain embodiments, such compositions may influence the physical state, stability rate of in viro release and rate of in vivo clearance of the antibodies of the invention. [Ol831 in certain embodiments, the primary vehicle or cater in a pharmaceutical composItion may be either aqueous or non-aqueous in nature, For example, in certain embodiments, a suitable vehicle or cater may be water for function, physiological saline solution or artificial cerebrospinal fluid, possibly suppemented with other materials common in compostons for parenteral administration, In certain embodirents, neUral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain embodiments, pharmaceutical compositions comprise Ths buffer of about pH 7085, or acetate buffer of about pH 4,0-6,5, which may further include sorbitol or a suitable substitute therefor, In certain emnbodimnens, a composition comprising an antibody to OPGL. with or without at least one additional therapeutic agents, may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (Remington's Phamaceutical Sciences, supra) in the form of a !yophitized cake or an aqueous solution, Further, in certain embodiments, a composition comprising an antibody to OPG1 72, with orwlthotr at least one adiinlteaeicgtsmybfouatdsa LU181in certain entodimens, he pharmnaceu',ticaN copstin f the invention ca be sAeeced for parentera ee in certain embodiments the compositions may be selected for inhalation or for delve through the destiVe tract, suc h a ry Te preparatao o sudh pharaceuica acceptable compositis is within the skdof the art [015 Incerta embodimen theformation components are present in concentration, that are acceptable to the site o)f adiitainn certain embodiments offers re used to maintain the cmposion at physologiclpH or at sight lower pH paa th a ph range of from about S to about 8. [01 a] In CI enhodirnentshe par-enter-,;l adiitainis contemplateda trapeutompos n may be in e om y ogen 'parenterally accptbl aueous soluton comprising the, esred aniboy t PGL. wiho ihu ddJiioal therapeutcaeti hrncuial accep-,-tabl'4e vehicle. in certa~n !emrbodmnt, a vehicle fo etrlijcinis seledistilled' water inih th de antbody to OPGL, witnrwtota es n addiona herapeut agens fonmdated as a steri e, isotonic solution properly preserved In certain embodimentste preparation can involve the fomlaton of the desired molecule with an agent such as injectable microspheres bio roible polymedc compounds( as pol.ic acid or polyglycoic ac, bead or iose, at, m-ay provide for the controlled d or sustaned 73 relase of the product whichmay then be delivered dvia a epot inecto n certain embodiment hyauronic acid ma also be used, and may have th e of promoting sustained durator in the cuiatbn certain embodiments, mplantable drug delivery devices may be sed to introduce the dewrd [01871 in certain embodiments, a pharmaceutical composition may be formulated for inhalation. In certain embodiments, an antibody to OPGL, with or without at least one additional therapeutic agent, may be formulated as a dry powder for inhalation, In certain embodiments, an inhalation solution comprising an antibody to OPGL, with or without at least ore additional therapeutic agent, may be formulated with a propellant for aerosol delivery, in certain embodiments, solutions may be nebulized. Pulmonary administration is further described in PCT application no. PCTU$94/01875, which describes pulmonary delivery of chemically modified proteins. [OI88 in certain embodiments, it is contemplated that formulations may be administered orally, In certain embodiments, an antibody to OPGL, with or without at least one additional therapeutic agents, that is administered in this fashion may be formulated with or without those capers customarily used in the compounding of solid dosage forms such as tablets and capsules. In certain embodiments) a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized, in certain embodiments, at least one additional agent can be included to facilitate absorption of the antod ad an addItiona therapetc agens i c Jubricants, suspending agents, tablet disintegrati aents and bders may diso be employed 1019l In certain embodiment apharmaceuta composition may nvole an effective quantity of antilbodies to OPGL, wth or without t least one additional therapeutic agents in a mixture withnon-toxic excipieats whih are suitablefor the manufatue of tablets. In certain embodiments by dissoing the tablets i sterile water or another appropriateveh le solutions may be prepared Sunitdose orm n certa embodiments, suitableacipients inlde but are not limited , inr iunsauh sclimcroatsdu abnt or bicarbonate ate, , o alcium phosphate; or binding agents, such as tarch, gelatin, or acacia" or lubricatng agents such as magnesim stearnto-d 11ojAdditional, pharmaceutical compomsitions wMil be eviden to those skilled in the artt including fomulationiolving antibodies to PGLwth or without latest one addnal therapeutic agentsin sustained orcntroled delivery fomiulatiOn n er embodied teChni qus for formating a variety of other sustained o contrleddevery means such as iposome carriers, bio-erodb microparticles or porous beads an depot ijtions are aiso known to those asked irn he art, See for examp P T Applation No PCTUS3 s wch describes the controlled release of porCus poteic microparticies fore -he delivery ofpharmaceutical compositions n cerain 75 embodiments. sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e. films, or microcapsuies, Sustained release matrices may include polyesters, hydrogels, polylaotides (U.S, 3,773,19 and EP 058,481), copolyners of L-glutamic acid and gamma eihy glutamate (Sidman et aL, Biopoiytmers, 22:547-55 (1983)), poly (2-hydroxyethy mnethaoryate) (Langer et at, I Biome. Mater, Res, 15:167277 (1981) and Langer, Ghem., Techt, 12:98-1 05 (1982)), ethylene vinyl acetate (Langer et atL supra) or poIy-(--3-hydroxybutyrio acid (EP 133,988), In certain embodiments, sustained release compositions may also include liposomes, which can be prepared by any of several methods known in the art, See ag., Eppstein at at Proc, NatL Acad. Sc i USA. 82:3688-3692 (1985): EP 036,676; EP 088,046 and EP W494 [019011 he pharmaceutcal composition t0a based for iVVQ administraion typicaly s sterie in ctan embodiments this ma e accomplished by filtration though stele flration membranes n certain embodiments, where the composition is yaphlizedr sterilzatin usng ths method may be conducted either prior to or folhing yophilization and reconstitutionr. In certain embodiments, he composing fruparenteal administration may be stored in lophilized form or in a olution. n certain enoodhmntns, parenteral cooiionIOs generaly are placed into a continer having a sterile access port, forexamplean intravenous solution bag or viaa having a stopper pierceable by a hypodermic injection needle -m. in ,, -7.e i 2 in ce inemboments o the pharmaceudea composition has been fbmuaitedi may e oed in sterie viaas as a soutin, suspension, get emulsion, solid, or as a dehydrated or lyophilized powder in certain embodiments, such formuations may be stored either in a readyto-use form or in a form (e.g. lyophilized) that is reconstituted prior to administration. [01g3] In certain embodiments, the present invention is directed to kits for producing a single-dose administration unit, In certain embodiments, the kits may each contain both a first container having a dried protein and a second container having an aqueous formulation, In certain embodiments of this invention, kits containing single and multi-chambered pre-filed syringes (cag, liquid syringes and lyosyringes) are included, [0194 In certain embodfrments, the effective amount of a pharmaceutical composition comprising an antibody to OPGL, with or without at least one additional therapeutic agent, to be employed therapeutically will depend, for example, upon the therapeutic context and objectves, One sIled in the art will appreciate that the appropriate dosage levels for treatment according to certain erbodiments, will thus vary depending, in part, upon the molecule delivered, the indication for which the antibody to OPGL, with or without at least one additional therapeutic agent is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient, In certain embodiments, the clinician may tier the dosage and modify the route of administration to obtain the optimal therapeutic effect, in certain embodiments, a typical dosage may range from about (.1 pg/kg T77 to up to about100 mig or moredepending on the factors medioned above a certain embodnt, the dosage may range fmrn 0.4gg up to about 00 gtg or gup to about 100 g ; or 5 4gikg up to about 100 @gog. [1 gan icentaon embodiment, e frequency of dosing wilake into account the pharr et paree of the anti bo addfiona therapeutic agents in the formulaton used certain erboen a clincianwld tre m in ' a dosage is reached that achieves the desired effect. n certain emnodiment the compost ma therefore be admiistredas a single dJose, o.r astOor mo-re dose th a or may nt ccnAaat the sam am of tolecue) over time, or as a coin uou infusion A an implantaon devie or cater Further refinmen of the appropriate dosage is routinely made by those ofordinary s n theat and is wti the ambit of tasks routney performed by tem n certain embodnents appropriate dosaqes may be ascertained through use of appropriate dose response data 0196] cedtain ernbodiments, the'route of admInistration of the iection by intrvenous intraperitnea, ntracerebral (rtapaenchvnm orcntinroventry u ly , inCra m la nta rv e i oa intaleina routes by sustained release systems or by imlnato evcs n ceain emoiettec*Opsitions m-',ay be adinnistered bybolusineto or ontinuously b~y inuincr 'by ipatt eie [0I97 In certain embodiments, the composition may be administered locally via implantation of a membrane sponge or another ap ate material onto w he desired molecule has been abused or encapsumte in eain embodmerts, wherein mpan device is used, the device may be impanted into any suitable tissue Of organ, and de.ver of the desired mouecue may be viad sionmerease bosor cnnuous administration [08s! i certain embodiment, R may be desirable to use a pharmaceutica composition corprising an ntbadgy to OPGL with or without at lestoe additional hrpui agent, in an ex v/ Anrn such intace, ces, isues and/r organs that have been removed fr patient are exposed to a pharmaceutia composition comprising an antibody to OPGL, with orth.t st o addona therapec agent, te Which the Ceils, tissues and/or organs are ausun implanted back into tatet 9n 1certa n embodment, an antibody to OPOL and/Ar any additional therapeutic agents can be delivered by impanting certain cels that have been geneicly engineered, using methods such as those described herein, to epes and secrete the pOiypeptides. In certain embodiments, such cells ma,,,y beanimal or hnum-an cell, and miay be atlguhtrlguo xenogeneicIn certain embodments the elsm e immalzed n cean enbodinents n order to decrease thechance of anino ogica response, the cells may be encapsulted to avoid ifiltratini ofsurounding issuesIn certain embodiments, the encapsulation-materials are typically biocompatible semi-permetbe polymeric enclosures or membranes that agow the release of the protn produog) but prevent the destructior of theels bythe patient .mmune system or by other detrimentat factors from the surounding issues EXAMPLES 020 The folelawg eampis, including th experiment conducted and results achieved are provided for iustratie purposes ony and arenot tow be constued as lim.iing the prese-nt inve-ntion, Cloning the oOPG Heavy and Ught Chains [0201 HO cells expressing the length hunan OPGL cDNA are used to i tsgenf ied counting uma imuno nenes Lymph nodes from the immnized mice are fused to murineinyera els to generate hybdomas. Supernatant from the hybridona lnes ar tested n an E~iS asay OMoiS that react wit human OPGL nPPLepesn hybridom ines AMG 6 AMG 64 and AMG are found to express antibodies w ith high afiiyfor OPGL (Kds of OZ28 nMll 0. nM, and 0,".23 rM respectvdy> and AMG 6,5 s selected for cloning Heavy and light chain cONA Clones om AMG 6.and AMG4 areidentic and AMG 6is usd to cdone the aOght Chain MA, wile AMG6.4 is used to cone the aCPGF heavy chain cNA. $0 Ckonn fthe aOGL-1it chain [0202] The aOPGL-1 kappa hqht chain variable region is obtained using PCR aminplication methods from first strand cDNA prepared from AMG 6.5 total RNA. First strand eDNA is prepared from AMG &5 total RNA using a random primer with en extended 5'~adapter (S' GGCCGGATAGGCCTQACNNNNNNT-.3' (SEQ D NO: 15)) and the materials and methods provided by the Gibco SuperScript Preanplificaiion System for First Strand DNA Synthesis kit (cat no, 18089-011) The o0gonucleotides below are used for the FOR: 5$ kappa RACE ~rimer: CAT GAO OCA GTG TOG AGO CAC CCT 0 3 (SEQ ID NO: 5) 'a p RACF primer SAAG GT AG AGG COA AAG GAT O-?G (SEQ D NO: ) [02031 The ampfhed DNAs re cloned into pCRIOPO (Invitrogen) arid th esulting pasmids are sequenced The kappa chain consensus sequence is used to design primersfo PCR ampfcadon othe fui-ength aOPGL-i kappa chain. The 5' OPGL-1kappa primer corporate a Xbal site (TCAGA) or coning and a UOCACC" Kozak sequence beforethe initiator Met codon.-- The 3'oPL1Kappa pieinrpatsa Sail sh e ,C(GIOGAC) fbflowin0,g the ,stop cdon for lnig 5-CAA C TAG A 00AC ATG GAA AGO A GCG 5EODNO; ) -b4 Site Kozak I E P A (S0E t NOD: 6) a"OOPGLIkappa primer: &-77A 'TO T", TTATA A CA, OTC dO COT GTTGAA C -3, ($80 ION Cc B) Sal C G FZ N F (SEO1D NO l7) [02-04. The fukengt aOPGL kapp chain eDNA clone is obtained usirn the AMG 53 firsttrand cDNA describedabove y PC ampfiad, n with he 6 and 3' aOPGL4 kappa prmers The PC reaction generates a 738 bp 2agment encoding h amino acid rsdues (iud the 20 amino :cdkpacansga eune)o h.a0PGL-1 kappan Chain (igure 4, 8C D NO: 4). Fo owing pur using a O qu c k PCR Puridfica""tion kit Qiencat no2810), h fragment ',s us ed tocnsrc the kappa light chain expression vector. [0205] The 738 bp fuiaength kappa agent generated aboveis cut with Xbal and SA, is purifed using the Promega Wizard DNA Cleanup System (Promea cat, no A7100) and s cloned into pDSRi 19 to generate plasmidQPCu9kappalpD$Ra19 (Figure 5). pDSR 9as been described pieviously (see VVO "'N 433 which is herein incorporate byrerence for any purpOS (Se Figure 12)) ef to mae pDSRcdS, pDSR2 i{ modified i the fowing w the FSH poiyA sshotened by agpoximately 400 base pairs, to 85 base parks and now ends t the dei ste; the dihydrofolate reductase (DHFR) Promoter now contains 209 base prs, h ng been snortened from the 5-nd by approximately I koase; and an approximately 580 base pair Bgl1i fragmentfom the OHFR polyA sequence is deslted, 82 T he o0PG kappa light hbiexpressindoneis sequenced to confirm that it coded for the same peptide thatis identified in the AMO 65 hybidoma he ina exprkssi vector, aOPGL-tkappa/pD$Rrrih is 5476 bp and contains the 7 functional regions shown ab 2, Table 2: Features of aOPGL-I kappapOSR-i S !asmid Base Pa/r Number 2 to 881 A transcrdption termination/polyadenylation signal from the acsubunit of the bovine pituitary glycoprotein hormone (I-FH) (Goodwin, eat iNucleic A cids Res. 1983 11: 6873-82; Genbank Accession Number X00004) 882 to 027 A mouse dihydrokiate reductasa (DHFR) minigene corftaining the endogenous mouse DHFR promoter, the cDNA coding sequences, and the DHFR transorption termination/poiyadenylaion signals (Gasser et a[ Proc NAelAcad Sci U S A 1982 79:6522-6. Nunberg et aQ Ce! 1980 19:35564; Setzer at at J BlAI Chem, 1982 257: 5143-7; MGrogan e t J Blot Cham 1985 260: 2307-14) 2031 to pBR322 sequences containing the ampicilln resistance marker 3947 gene and the origin for replication of the plasmid in E, col (Genbank Accession Number JO1740) 3949 to An SV40 early promoter, enhancer and origin of replcation 4202 (Takebe et at Mo? Cell Blot 1988 8: 466-72., Genbank Accession Number J02400) 4299 to A translational enhancer element from the H TLV-i TR domaln 4565 (Seiki et al, Pm, Nail Aced Sc U S A, 1983 80: 3618-22 Genbank Accession Number JD2029) 4574 to An intron from the SV40 168, 198 splice dono/acceptor signals 4730 (Qkayama and Berg, Moi Cell Blot 1983 3: 280-9 Genbank Accession Number J02400) 4750 to beaOPGL Kappa light hai n cONA between the Xbaand S 5476 sites [0207 A circuar plasmid map of the vector is shown ngure 5.

Clornng of the aOPOL1heavy chain j028}The- aO'PGL-1 k1,-02 haybinis clo0ned trn AMG 6A4 hybdoma doube-stranded DA produced with the Clontech MarathonlA cDNA Anma Kit (cat. n a02 Arn an oAO eavy chn oNA is sccompished by 5' and T rapid amplification of cDNA ends RACE) echniques perforned wih human gemine 1G2 heavy chain .onstant region specific prmers (shown beow) and RACE prmers and othermaterat and methods povided in the Marathon VDNA amplation kit ' G2 RACE primer 6- OCT GA OQAAG GCC CAYCG TOGsT - SE 10 10)i 0209 The 600 bp 5 RACE roduct and 1200 bp $RACE p duct iNOrumin is used to design, aQ ,CPGL-1' he a-vy c 'han specifi primers fo the ckning of the full-length seuec.The hev han: pie (5' kO -iGQ Priner reted against eene a stadand has a Hindi N ste and consensus Kozak sequence before the natura start site, The heavy chan primer (3a0PGL gG2 P r s an antisense prmerhat conain a Sag sie a' stop :odon after the last amino acid of the av chain G2 sequence 34 (SEQ) 10 MC% 1$ 3? aOPGLI G2 Primer G C 5 A (SEQ 0 NO; 19) [02101 The dDNAd above i used to generate the fun-eagg heavy chain oDNA by R hefag nith 5'- ad e- cPrL f0 prAmers, Th Pn R generaes a 1433 bp Aqigmen encoing thie 46i7 am--no a'cid resies ncldn the '19 amino acid IgS signal sequel ance) wf ma. cxOPGL1 lgGZ heavy chaoin protein (igr 2, SE, ID NO; 2. Folio > ing u eio u a quk cant on),ti agent I used o conuct the heavy chain expSSi n vecr as elows P0211 ] DN AinA betwcon the akie Sa egth g he fraGt gene-rat ed above' is c ut wiJth Hniland Sipurifled using a f qukSl Exrct-io kit Oge'n cat, no&8704) and ths fragmet I cloed 010o PDSWc 9, Th rsutig exrsinpi-asriid is named aPL1IGJD~d Fgr ) A;vctrcmpnnt r identical to OPLi-papDRd9vetr aOPGL-1 kappa light c hain 01NA bewxeec-n the ta and ,SM sites, TIhe ctOPGL I IgG2 heavy chain expression clone is sequenced to confirm that it coded for the same polypeptide that is identified in the AMG 6.4 hybridoma, Example 2 aCPGL-1 expression in CHO cells (0212 Stable expression of aOPGL-1 antibody is achieved by co transfection of aOPGL-i-kappa/pDSRaI9 and aOPGL-1 -IgG2/pDSRu.19 plasmids into dihydrofolate reductase deficient (DHFR-) Chinese hamster ovary cells (CHO AM-1ID, U.S. Patent No. 6,210,924) followed by isolation and testing of individual clones. [0213 A 100 rnm tissue culture dish is plated with 1.5x1 06 AM-1/D cells grown in CHO d- medium (DMEM-high glucose, 10% fetal bovine serum, 1% penicillin/ streptomycin/glutamine, 1X NaPyruvate, 1% nonessential amino acids (NEAA))(Gibco®) and 1% ht supplement (Gibco@)) the day before transfections (Day 0), On day one, 400 pi of serum-free RPMI 1640 medium (Giboo@) is aliquoted into a 12x75 mm polypropylene tube. Twenty four microliters of TransIT®-LTI reagent (Mirus Corporation) is added dropwise to the medium and the mixture is allowed to incubate at room temperature for 10 minutes. A total of 15 pg of linearized plasmid DNA (7.5 pg of aOPGL 1-kappa/pDSRa19 and 7.5 pg of aOPGL-1 -lgG2/pDSRai9, digested with Pvui) is then added dropwise to the mixture and is incubated at room temperature for 10 minutes. 10214] The CHO d- medium is removed from the cells, which are washed with 10 ml of Dulbecco's phosphate buffered saline (Gibco@). Six 86 miliiersofseum-re M~ mdim supplemented with Ti Lgk± NEAA, and Na pyruvate (Obo@) is added t the cells, TheDN complex is added dropwise to the plates, which are gently rocked back and forth to distrute the DNA evenly over the cai After 6 hours in a tissue ulturencubatote medum is replaced h fresh CHO -medum Forty eght hours ater the ces are split to ted 100 mmoure;dshes in QUC slet edum(DE igh glucose, 10% dialyzed fetal bvne serum (PBS 1% pencn !streptomyoin /gutaNine, % nonsseni no acids and IX Na pym vate) ibc®) Medum is changed ee uti coodies appeared. [02151 After1014 days closes re picked using 5 mm cloning discs (Labore) soaked in 1 ypsin-DTA(Gibo®) and are cultured in 24 welltissue culture plates with CRC select medium. When the celis become confluent, serum free media (Q1O select medium mnus FBS) is added and is thn coected 48 hours later These conditioned media are analyzd for blotteoxidase HP) conjugated goat atihuman IgG F antibody (Pierce, Rokford L to detect the GOPOLI heavy chain, and goat anthumankappa chain antibody (Pierce, Rockord, L) followed by HRP-conjugated abbit anti-goat lgG(H+L) antibody (Pfrce Re~od, L)to detect the riORG- Ight chaW, in. he hgetexpressin-g cones are expanded and stored in lqud nitrogen 87 Excam pie$ Production o GPGL Preparaton and Creation of Cell Lne '2r0 [02161 CHO cells producing a0POLi' aecloned by Iworoudso citing dlton in 90 we patesnder semrfree condins The clones are selected based on producton and growh chaaterstis in vaous suspension vessels. EIAs ae peomed to setite clone that produces the highest level of P cOG GI, rowth chrcesis nk dingdubling timnes nd dtensities are then measured by growing the ein 100 ml, 250 ml500 a, - L: and 3 L spinnr~er fla'sks, as well as in KL Aplikon bioreactors. The clne whhT the fastes-at doublrng ime that reacees the highest dene ty n culture s selected and i designated Cel ine 1250. hentIecoeasepndtoyldufiet c ells to free350 ampules at aprxmtlyligels/rnL cels are resuspended n a ryopresavee med % V Soy Medium (see Table $frdet .ail) supplemented with 10D mIL nonesseni amino acids and 10 milL Gutrne(bcLi/niog),and 10% dirneth -sulfoxidJe (JT Bkr)adfrozen. Amnpules are storeF d in a liie cesfaclliy and are submrge inlqud a get in liqid nitrgen dars. 10217] Based on growth and produ in Sman wsca winners and langer scale birectos, Cein 1250 .s chosen as the elln for manufacturing cA ofQPGL-t Sa [0218] a- oGL-1 is produced by expression in Cell Line 1250a, clonal line of CHO cels that expresses aOPGL- from plasmids aOPGL 1-kappalpDSRa19 and aOPGL4 -gG2ipDSRa19. The cell culture process for aOPGiL- is shown in Figure 19. For each produoIon run, cells from a vial of Cell Line 1250 are iniialy grown in $0 mL of VM-Soy BAtch Medium (see Tabe 3 for composition) supplemented with 10 mlL nonessential amino acids and 10 ml/L Lglutamine (GibcolLT /nvitrogen) (VM-Soy Supp) in 125 mi erlenmeyer shakers at 100 rpm for 5 days, The entire culture is then used to inoculate VM-Soy Supp a 500 ml spinner flask to 3x1 0 viable cels/mi (3E5 vc/ml), and is grown with 70 rpm spinning for 3-4 days, The entire culture from the 500 ml spinner flask is then used to inoculate VM-Soy Supp in a 3L spinner flask to 3E6 vo/mi, and is grown with 70 rpm spinning for 3-4 days. L021 91 The culture from the 3L spinner flask is then split to two 3 L spinner flasks at 3ES v/rni in VM-Soy Supp without phenol red and grown under the same conditions, These spinner flask cultures are then used to inoculate four additional spinner flasks at 3ES vC/ml in VW-Soy Supp without phenol red, and grown under the same conditions, Four liters of culture from the four 3L spinner flasks is used to inoculate 10 L of VM-Soy Supp without phenol red in a 20 L bioreactor, and the bioreactor is run in fed-batch mode for 7-10 days, in fed-batch mode, a nutrient feed containing concentrated media components ("Feed" as set forth below in Table 3) is added to maintain cell growth and culture viability, 0220] The entire cume rom the 20L biireacors then used to noclate 70 Lo V Soy Supp whout phenol redrn a IOL bioreactoer and the bioreactor in fed-batch de for 9-1 day Finaly, the entire culture from t-he t5DL biormaotor is used to inculat apprmately H8O L of VM-3Soy (ihu supplement or phenolred in a 20L bioreatorand the bioreactoris in 0fed Etch mode, The rate of feed during fed-batch nde ia determined such that the gAuCose leVe i teclre mataned at 06 for e reactor cef density and glucose concentration are measured di and the rate of feed adjuste-d accordingly. [021 Production rn th 2000L bloreactor lasts forapproxmatey two weksdring which tine QQL1is cosiuieyproduceid by thie ceus ad secreted into the cell culture medum. [02221 The production reactor is controlled at set pH, temperature and dissoled oxygen level: pH is, 7,C) and is contrIled by carbon doxide gas and sodium cront A dissove oxygen is '120 inngad icorolled by air nitrogen, and oxygen as fls ellS are mantained at $7C throughout the process A es are passed trough membrane terms of pore size. 022 pm or j022] At the end of production, th ecell broth is fed ito a dis k stack centrifuge antecutrespemr.atant is separ-ated frm the iceals- Thentrt is rther ed through a Cuno OSP depth r ollwed by a 2pm Posidyne fliter (Pail Co, The ACarfd conditoned Wedi is then concentraed by tangential low u-riltr (UP) usng SOkD NML memranes (Millipor 90 Thmoax 50 he doritioned media is concentrated 1 o 3 f The resultng concentrated conditioned medium (0CM) s hen either processed through puriicatin or rozen for purfication at a atedatehe producio process summaiedin Figurei9 CellCiuue Medium 0224] The cel future medium fo use hoghoutthe ente cell cure process is based on Dulbeccos Modied Eag e Medium /am N F12 (EM/F12, Mt and contains supplemental ves of amino acids, addition nutrients and salts, a soy hydrolysate and recombinant huaninsu N ucellin Zn EIi Lily> The components are isted in Table 3 meda i referred to as VIWSoy. Media solutns are itered roughmembrane fmers of 02 pmn poa size prior to use, Table 3. CeU Culture Media Components COMPONENTS FOR BASAL Media and FEEDS_ _ COMPONENT VM y Bath MediummgL' E (rn/L) DMEM/V12 COMPONENTS -------- Inorganic salts CaCM (anbyd,) 116.60 233.2 CuS045HcO 2.0026 0.0052 Fe(NO3)3 9R2'0 21000 0.2 FeSO4,7H20 O,8340 1I6 KCI 311-80, 623,6 MgcI (anhydt 57280 124.36 MgSO4 (anhyd) 976180 19536 NaCl N181L98 Na1T2P.H20 125,00 DO a2PO 42.040 284138 ZnSO47R2 0,8640 *328 Other Components D-lucose 3151.0 12302 Na Hypoxanthine 5,40 i0 Linoleic acid 0,090 0.18 Lipoic acid 0,2060 GA12 Phenol Red 810 162 Putescine 2H 01620 0324 Sodium ?yrnvate 110.00 220 Amino acds L-Adanine 26.70 53A L~Arginine H~l 295.00 590 L-Asparaginelk2Q 45,00 90 L-Aspartc acid [39,90 79,8 L- Cysteine-LH-2 35.120 70.24 L--Cystine,2HC1 62.580 125.16 L-Gumac44.10 88.2 L-Gut ai 657.00 1314 O-Vine52.50 105 L-Ristdine-HlH2O62.950 11 L-Isoleucin1e N217.88 L-eucine 118.10 2362 L-Lysine HC 182.50 365 L-Mthionn& 34.480 68,96 L-Phyanine 70.960 14192 LProline 57,50 115 L-Serie 73,50 147 L-Threooine 106.90 213,8 L-Typtophan 18 36,A8 L-yrosine.2Na2Hi20 11, 580 1 223.16 L-Valine 10570 214 vitamins Biotin 00073 0,0146 92 D-Ca Pntohenat 4,480 8.96 Choline Chloride J17 960 35.92 Foic Acid 530 10,6 l14noSitol 25.20 50.4 Niacinamnide 4,040 8.03 Pyridoxai TJCI 4,00 8 Pyridoxine HCI 0,0620 0,124 Ribojavia 0,4380 0.876 Thiamine HC 4,340 8,68 Thymnidine 0.3635 0.727 Vitamin B12 1260 2.72 AD)DITIONAL OMPWONrNTS 1 _ _ Nucellin Zn, (rhuilnsxlin) 5x00 '5 Selenous Acid 0,0050 0,015 Triiodothyronine 0,000040 0,00012 Hydrocortisone 0,020 0,06 Ferric Cifrate 1122,450 122,450 Piuronic F~68 1000.00 500 Soy Hydrolysate 6000.00 6000.00 NaHCC3 3000.00 3000.00 NaGI 3500,00 Pridfication Proces p25J aOPGC~4 expressedinCHIO ceil issecreted into the extaceluar edim 4 A se e of steps may be used to generate pure material The process uses hydropnobic charge inducton cationexchange) and h ydrophobic ineractiorn chromiatography alono with a ow pH step and viral filter 4 Thse procedures are descried beIow, 93 A, Hydrophoia Char IndutZon Chromatography iC (02261 This Thrometography step removes the majority of host cell proteinsa LCNA, The concentated condoned media CM is filtered ;rug a Cuo $Pter a enough a Cuno VR mhared celllosebased filter, and then oaded on to an MEP HypeCe esi, After oadno the colin is washed with equibration buffe(20 Mi da pH 72), The anybody is eluted from the resin using a low pH buffer (20 M SodiumAcetate pH 5,0). Ait is eluted from the column the product is cotected based on the absorbance at 280 nm of the column effluent [0227] ThelEP pool is titrated to pH 3. and is held for aproiatl 50mte to inactivat Pote ntillycotaintngrerirs Following the hod step, the pH is adjsted to approximately 0 C N ralFlrtion 0228 The pFbajusted pod is flexed through a Milpre Viesove NFR fiter or equiaen The antibody flows through the ler while potentialy contaminatng viruds on50 nim are, retained. Cation Exchange Chromatography (CEX) f0229] The antibody is further purified by caton a change chromatography usngE S Sepharose HP .Amersham Pharmci)o equivalent The cation exchange chromatography step reo'es additional e cel proteins DNA, lower molecar weight proteins, and aggregated forms of ,OPC'.. The virakl filtered pool is bloaed onto thie catoexchange resin After 94 loading, the column is washed with equilibration buffer (20 mM NaMES pH 52), The antibody is then slued with a linear gradient of increasing salt (20 mM NaMES pH 0,2, 0 M NaCi to?0 mM NaMES pH 5,2, 0.3 M NaCU, As it is eluted from the column, the product is collected based on the absorbance at 230 nm of the column affluent 5,Hdrophooi neraction Chromatography (a10 02301 The antibody is further putted by ydophobeintercton chromatography using Phery Toyopead 650$ (Toh Biosep) or euihen e hydrophobic neracton chrratography step ise as a polshng Sp and C" aetresoves addJiNai 01 proteins CNA, lecula weight proteins and agrgtdfrsof wOPG&1. The cat.ion exhnepo scniindbefore loading onto the colm by addition of ammonium sulfate to a conductMtfof 05 mS/cm at 15=5C Afterloading, the coluin is lashed with the equilbration buffer (1M Potassium Phosphate ph 8), The antibody s then eluted with a linear gdient of decreasing salt concenatn (1 M potassium hosphate PmM Trs H ' to OM Potassium Phosphate, 20 mM Tris pH ) As is elited from the column the product is oete based on th absorance at 280om or the column euent. Concentration and Diafiltration f0231 he HIC coumn poo s concentrated and dafered into formulation buffer by tangential fhow ultraton using 501D NMWL membranes (Mpore iomax 50). The formuatin bu ffr inCe 1 mM Acetate, 5i Sorbitol pH 5.2 and iOPGIs at 30 rmgirmlL ia] Fiaon and oage [02321 The purified bulk ispassed through a 022 rm PVDF fiter (Milliporeis sampled, arnd stored at appoimatey 3C in a secured feezer, Example 4 Binding Specificity of aOPGL& (02331 Antibodies that are oduced CHO efls that are ransfected with the two expression vectors as discussed in Examples I and 2 may be Med Ai the flowing examples 4, 5; and 6. C02341 Human OPC binds anid neutraizes OPGL in s mie and cynomoigus monkeys, as we as in humans. odPGL-1 binds human CPGL With Ih affniy but does not bind significantly to mune OPGL (Ta 4 Table 4: Affinity of aOPGLA to Cel Membrane Expressed OPGL of Human Cynomolgua Monkey, or Mouse Sequence, OPGL Species aCOGL1A ------------------- E- (n -- i Uumnan 1 6 Cynomiolgus 19 Mouse No Specific Binding OPGL of these species is expressed in CHO cels as the fullength, membrane-bound protein, Binding of coIGLi to the cel surf ace expressed OPGL is assessed by FACS analysis of cells incubated with OPGL- and a i-ibeled secondary antibody to human gG2, aQOPGtA- binds human and cynonolgus OPGL but there is no specific binding to mouse OPGL 235 In addition, human OPG has been report to show weak iding to (Tmor necosis faor;eadpoptosisinducng igand(R Truoeh at a, 2000 a related member of the TNF faUy, which shows DNA arid 96 amino aid sequence homology to OPGL (Lacey et aL, 19M), However: OWP does not detdab bind to other TtFE-ated proteins such as TNFa N, or -23C1 cONGL b r speicalo OPGL on EA pates (Figure 7)Recombinant soluble OPGL (2 pg/mf )is coated onto 96wel IA plates at room temperature for 16 to 24 house, Ater block with 1% BSA in PBS, varyin concentrations of CPQG (approxiaty 2 n Ito 1000 ng/i diluted * A BS A/PrnS are added to the wels ad the plates, are 'neubated for aot2, hours at rom temperature Bound antibodies detected oat antiHuman lgG (FaelORP using TMB-H202 (tatramethyhendine and hydrogenerox de) substrate cocktail. The absorbanc is read at 4Onm and 60Om j0237) oPGL binds spe ctaily PGL expressed on the surface of ransfe-cted cells (Fire 8), wOPGLI1 (1001 n/mI) dilte i FAC'S B-uffer (PBS, M i%BSA, .1$dimAie is piobadwthvar,,ying conentatinsof OPLTNFa, T,,NFt. TRAIL, or 0D40 ligad (approvim atel'y 0". St r aNded to approxim adty 200,000 CR 218-9 Weil, which are CHO ceAt stbY expressig iebaeb~n PLo the celsurface. After 1 hour at 268C, unound antbody I rencaed by cantrfugation and washing. Cels are then ncubatedfo 30 minutes at 2-8C e F(ab') 2 eoat ant=uman 1§(3 Ecy fagment spec) After cenrtrifuatoan was cel surface fluoescence Is mesured ung low yometry gure s shows that binding of oCPGLI to CHO REN 29 cells is :17 specific, and is competitively reduced by addition of soluble OPG 4 but not by addition of TNFa, TNFb, TRAiL or CD40 ligand, [0238} In competition experiments, aOPGL- binding to OPGL or ERA plates is inhibited by addition of exogenous OPG,, (Figure 9), but not by the addition of TNFz. TNFP, TRAIL, or CD40 ligand Figure 0 This procedure is performed in substanty the samenanner as above, For binding of tOPG o OPG on E1A plates, except a constan oncentation of cOPG- (rOng/nm) is preincubated with varying concentrations of soube OPGL or other igands (approximately I ng/i to 1000 ng/mi for each) before it s added to the OPOL. coated plates, Example 5 aOPGLi Neutrain Aciity Inhibition of Osteoclast Formation (0239] RAW 2647 (ATOC No TIR7, Manassas, VA) is a mudne nacrophage cell line that was derivedK om an Abeison munn leukemia virus induced tumor. RAW 2647 cels wll differentiate to steoclastike cells in the presence of OPGL. The basic assay for generation oosteoclasts in culture from RAW cels in the presence of OPG has been descdbed in detail in Simonet t a (997) Ce/S p. 309, and Lacey et al (1998) Cell3 p 4 155 which are herein .corported by reference for any purpose. [02401 RAW cells are stimulated by ligand to differentiate into osteoclast-like cells, and the differentiation can be measured by TRAP activity, a pronerty 01 Osteoadasts, Thus, the effectoaOPG on osteoclastgenesis a n be measured. 0241RAW cels are coubated for 4 day inthe presence oa constant amount of OPGL (40 ng nd yn amount of OPGL- (63 ngm to 200 ng/mI in ced culture medium (DMEM 0% FS 0,292 mg/mi L Gkt 100 urts/mi PeniCin 100 pgm Steptomycin suf At t end of 4 days, the cells are stained for tartrateereistant acid phosphatase (TA ac perme dat and acdicaionfo owed bytreatmen th p S ranitr phe F phos phot for Bdieflyt m di isa offof th'e ce-,, ls- an.d '1 -00 p1 of cirate buffer (410 mnl DAM cir, acid .5g% mi 0,1 m. citrate, trsodium salt, I u nitrlton 410CC) is added to ach wedl and the plas are irnubated for 3 to 5 nues a room temperature One hundred microAte Of PPP ' oi on s then added (167 mg acid phosphatase reaget (Sigmai04 00) 7.2 mrrate soluiIon (Sigma cat n. $ and 2Z18 m citrate aend pltsare incub"ate-d for 3- to 5 minutsS at roomtepeetre The reac tion is terrmiad by ad on of 50 o1 05 M Ne"Hs R2,12 TRAP wil convert pa-nrphyposht to ara nitropheno, which can be uantitated by optical densy measurement at 405 rim. Thei TARAP act, aa gat maker for osteolaste pme herefore correlates wi the optical deny at 405 n A plot of opal densiy vemus OPGW- concentaton is shown in Figue , and demenstrates that IOPGI Inhibits osteockst fo'maiionin this assay jnhlbftiorDfCPGL oinding to ts Receptr [0243] The potency of uOPGL- is demonstrated by its ability to block the binding of OPG hgand to its cognate receptor, the qteoclast differentiation and gtivating receptor (ODAR, also known as RANK). This assay uses homogeneous time resolved fluorescent resonance ($TRF) to detect binding of aOPGL-1 to Europium-conjugated osteoprotegerin igand (Eu-OPGL) if oPGL- inhibits Eu-QPGL binding to ODAR, fluorescent output wil decrease, and the amount of KOWPGL- present wil be inversely related to the amount of fluorescence. :0244] OPGL is labeled with europium, which emits light at 620 nm when excited with 337 nm light< ODAR is fused to FLAG and to Fo, and the FV ODAR-FLAG fusion protein is 4absiad with an anti-FLAG antibody 0nked to allophycocyanin (APC), a fluorophore which emits 665 nm light when excited by light at 620 nm. Therefore, when Eudabeled OPG igand binds to the Fc-CDAR FLAG/anti-FLAG-AFC complex, the tertiary complex wil emit 565 nm eight when excited with light at 337 nm. [0245i Eu-OPGL at 00 pg/ml is preincubated with various concentrations (01 to 150 ng/mi) of aOPGL-1 in assay buffer (50 mM Tris pH 8, 100 mM NACL 0>05% NaN, 01% B$A, and 005% Tween 20) at room temperature for approximately one hour (Preincubation mix), A mixture of Fe OJDAR-FLAG (I pg/m) and anti-FLAG-APC (2,5 pg/rni) is also prepared in assay buffer and incubated at room temperature for one hour (Fluorochrome mix> Equal volumes of Preincubation mix and Fiuorochrome mix are then combined n cubate a roma tperaare far 3 hours The rsene b ai plaes on ,e ackard Dsccvery HTR mpF rropiate analy7er excitation waveljength of 337 in- and an- eisowaenghf6$nS [024S) When aOPGL-1 is poreincubated tuP igand and then mixed with A A an o h e ene at 665 Onn decreases in a dose depedent manner, as shown in Figue 2 demnstatig tat cOPGLI62 can effectie& inhbi OFGL ubding to QAR Example S Ptarmacokinetics in Cynomolgus onkeys f02471 Si male and six female cynomolgus monkeys, not greater than 4.5 years of age and Weihing 2 to 4 kg are assigned to 4 dose groups Group consists of T males and 3 females Groups ard 4 each consists o 1 male and Ifae Anima's n Group are administered single C doe of mg/kg OPGL- ,while andmas in Groups 2, 3 and 4 are adistered singe iN doses of 0.1, a, r 10)0 eg/kg of oOP esgectvely [0248 Anma are dosed with aOPGLI expressed from transected Ahnese hmste ovary MHO)cl. Seu amlsa eefr eermnation of aoPGL-1 lee6, antibdy anali, and anlyi o he b-,one n er teopeptlde (serun, alkea~e phosphatase ,,AlP) and se calciu serum 04 Urine is alo colected for analysis of" e ropeptid (ure N rTx) r and $eatin$re [02491 The serum concentaion-4-irne profiles following 11V administraton are characterzed by a trphaskcdstiuio Fgue1) Initiplly, i O there is a rapid distribution phase, followed ny a significantly slower plateau phase, which appears to be concentration-dependent, The third observed phase is a rapi elimination phase t02501 Nonompartmental ana ysig of complete serum concentrationtime profiles using WinNonln Professiona (vI.5 and eponential analyst of the data up to 14 days after test artcle administration and above 101000 ng/msL unAg SAM (vi l12) are utilized o investigate the pharmacokinetics of oOPGLI in monkeys The initial volume of disibutIonfm all IV doses averages 229 mk similar to plasma vo'me. Steady state volume (V/, ) of distribution averages N mi/kg across alV doses xponent analysis indicates that aQPG1 has an average distribution ha life ('tof &02 hours, an extended secondary phase with a haSflife (ty0 that increases with dose from 86,9 hours at a dose of 0,1 mg/kg to a maximum of 444 hours at a dose of 10.0 mg/kg. Terminal elimination hfe (tZ) estimated non-compartmentaly averages 31 hours across all N, dose groups. Clearance (CL, CL/F) of aoCPGY is found to be non-iinear, with animals receiving N doses of 10 mg/kg having an average clearance (0,120 milhr/kg) that is 3,3~fold lower than those receiving 0,1 mg/kg (0.401 mlhr/kg). (0251 After administering subcutaneousyabsorption is slow, with average peak concentration (CQ) of 11600 ng/rrat 132 hr. There is high variablty in the range of exposure after SC administration resutin an average clearance of 0387 t 0 128 mIhrkg and mean ridence time of 202 801 hours Average biavaiablty is 89% C2$1 The presdjng data remmraried i b Table S: Mean (E *D NonGompartmental Pharmaoolknetic Parameter"n CynLus Monkeys A Administerin n Do f QPGL- IV ad SC Non-Cempartmiental Paramneter Estimates ___ mg/kg___0_ mg/in~kg LOwmglkg i mg/kg Pmtr Unit SC (n=6) IV (riF2) IV (ri2) IV (nn2 Tramehe 132 612 ?A0a 0vt Mea Cep I g/hI 11600 3410 43310 38200 3200 hr 34,9 f 11d 302 31A.ND AUy tghr/i 3520 1730 253 3950 9900 CL, CL/F mrnkcg 0.387 0.281 0A01 0256 0.120 MRT b 202 803i 84.8 124 1 519 vamd/kg N NA 33 ~/ 31.7 SS 9 teNt Datermined, PK Mrnpies eMdddgpaa 0 hs eme~nlcaei o bue *Not AppUmde f025) oOGL~1causea rpid decrease e t insumfT evel within 24 hours post dose (iure 14). The average time of maxirumr effect s observed tooccur between 12 hours and 7 days post dose as NVdoses increase from 0.1 to 10 mg/kg. and betven hours and 11days inanimals receivng SC dose of I 0 mg/k. Maxiumr effect increases with dose from approximately urther sup ressicn is observed with maximum inhibition of Si % Mean levels of serum Nb~ return to baseline by day 28 after administering GA mg/kg Vad by day 70 after adinistering rg/kg SC. Urine N-Tx shows similar tends tothose of eru Nx, xcet hatallgrUps return toS$ baein values by study day 105 (Figure 15) 10...........23-------- [0254] Siuppression, of seumCa increass vith dose to a3 mean ir of 3110% bWo the baene av erage seven days ater adm tA on of 0 m other dose groups have mean Ca ess than 26.4% fRom thI& bastine averages. ESy day 17 alsrmCa le vels !in trated animals rtur to within 10% of ther basekne averages (Figre 20). [025 As be resrptlon and formatin are inmate ike changes in bone formation markers (ALP) are alo observed wih a mch lwr decline in ALP lls and a more prolonged supression tharhe formatin arker rx (Fiue 2 Observing bone resorpion markers decrease pror to bone formatio markers (ALP) flowing dosing with OPGL1 confms thatthe ciOPOL-l is a bon e antresorptiv-e aga-nL [0256} The maorly of animals (9 of 12) developantibodies to aOPGL-1, The incidence of antibodies toOPGL s dose or route dependent ot poible to assess the effect of anibodies to CPGL-l on antoy ne v and posRite anim , mgg IV, the naority of MOPGL 1 i Maed pror to ant boddeve opmet andereore, effes o disposition ari not observed (Figure 16 104

Claims (16)

1. 4. The antibody of claim 3, which is a single-chain Fv antibody. $, The antibody of claim 2, which is a Fab antibody. 6, The antibody of claim 2, which is a Fab' antibody.
2. 7. The.antibody of claim 2, which is a (Fab)2 antibody 8, The antibody of claim 2, which is fully human. 9, The antibody of claim 2, wherein the antibody inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR).
3. 10. A heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 2 or a fragment thereof
4. 11. A heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 13 or a fragment thereof, i05
5. 12- A light chain comprising an amino acid sequence as set forth in SEQ ID NO: 4 or a fragment thereof 13, A light chain comprising an amino acid sequence as set forth in SEQ ID NO: 14 or a fragment thereof.
6. 14. An antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 2 or a fragment thereof, 16, An antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 13 or a fragment thereof,
7. 16. An antibody, comprising a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 4 or a fragment thereof.
8. 17. An antibody, comprising a heavy chain and a light chain, wherein the light chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 14 or a fragment thereof
9. 18. An antibody, comprising a heavy chain and a light chain, (a) wherein the heavy chain comprises a first variable region, and wherein the first variable region comprises a sequence that has at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 13, and (b) wherein the light chain comprises a second variable region, and wherein the second variable region comprises a sequence that has at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 14, and 106 (c) wherein the antibody interacts with an osteoprotegerin ligand (OPGL)
10. 19. The antibody of claim 18, wherein the first variable region comprises a sequence that has at least 95% idnetity to the amino acid sequence set forth in SEQ ID NO: 1 and wherein the second variable region comprises a sequence that has at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 14. 20 The antibody of claim 18, wherein the first variable region comprises a sequence that has at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 13, and wherein the second variable region comprises a sequence that has at least 99% identity to the amino acid sequence set forth in SEQ ID NO 14,
11. 21. A pharmaceutical composition comprising an antibody of any of claims I to 9 or 14 to 20. 22 The pharmaceutical composition of claim 21, further comprising at least one therapeutic agent selected from a bone morphogenic factor transforming growth factor-P (TGFp), an interieukin4 (i1) inhibitor, IL-ira, Kinerett a TNFa inhibitor, a soluble TNFa receptor, Enbrel T an anti-TNFa antibody, Remicade-M, a D2E7 antibody, a parathyroid hormone, an analog of a parathyroid hormone, a parathyroid hormone related protein, an analog of a parathyroid hormone related protein, a prostaglandin, a bisphosphonate. an aiendronate, fluoride, calcium, a non-steroidal anti-inflarnmatory drug (NSAD), a COX-2 inhibitor, Celebrex, Vioxx; an immunosuppressant, methotrexate, 107 leflunomide, a serine protease inhibitor, a secretary leukocyte protease inhibitor (SLPI), an IL-6 inhibitor, an antibody to IL-6, an (L-S inhibitor, an antibody to IL-8, an IL-18 inhibitor, an IL-18 binding protein, an IL-18 antibody, an lnterieukin-i converting enzyme (ICE) modulator, a fibroblast growth factor (FF), an FGF modulator, a PAF antagonist, a keratinocyte growth factor (KGF), a KGF-related molecule, a KGF modulator; a matrix metalloproteinase (MMP) modulator, a nitric oxide synthase (NOS) modulator, a modulator of glucocorticoid receptor, a modulator of glutamate receptor, a modulator of iipopolysaccharide (LPS) levels, a noradrenaline, a noradrenaline mimetic, and a noradrenaline modulator.
12. 23. The pharmaceutical composition of claim 22, wherein the at least one therapeutic agent is selected from Kineret% EnbrelM, Remicadew, D7E7 antibody, and methotrexate,
13. 24. A method of detecting the level of OPGL in a biological sample comprising contacting the sample with the antibody of claim 2.
14. 25. A method of treating an osteopenic disorder in a patient, comprising administering the pharmaceutical composition of claim 21. 26, A method of treating an osteopenic disorder in a patient, comprising administering the pharmaceutical composition of claim 22. 27, A method of treating an inflammatory condition with attendant bone loss in a patient comprising administering the pharmaceutical composition of claim 22. 108
15. 28. A method of treating an autoimMune condition with attendant bone loss in a patient, comprising administering the pharmaceutical composition of claim 22.
16. 29. A method of treating rheumatoid arthritis in a patient, comprising administering the pharmaceutical composition of claim 22. 109