AU2015201676A1

AU2015201676A1 - Anti-C5a antibodies and methods for using the antibodies

Info

Publication number: AU2015201676A1
Application number: AU2015201676A
Authority: AU
Inventors: Russell P. Rother; Douglas L. Sheridan; Paul P. Tamburini; Yuchun Zhang
Original assignee: Alexion Pharmaceuticals Inc
Current assignee: Alexion Pharmaceuticals Inc
Priority date: 2010-04-30
Filing date: 2015-04-01
Publication date: 2015-04-23
Anticipated expiration: 2031-04-29
Also published as: AU2015201676B2

Abstract

The present disclosure relates to, inter alia, antibodies, or antigen-binding fragments thereof, that bind to C5a and to use of the antibodies in methods for treating or preventing complement associated disorders such as, but not limited to, atypical hemolytic uremic syndrome, age related macular degeneration, rheumatoid arthritis, sepsis, severe burn, antiphospho lipid syndrome, asthma, lupus nephritis, Goodpasture's syndrome, and chronic obstructive pulmonary disease.

Description

ANTI-C5A ANTIBODIES AND METHODS FOR USING THE ANTIBODIES Cross-Reference to Related Applications This application claims priority to and the benefit of U.S. provisional patent application serial nos.: 611330,260, filed on April 30, 2010, and 61/471,465, filed on 5 April 4, 2011, the disclosures of which are incorporated herein by reference in its entirety. The present application is a divisional application of Australian Application No. 2011245117, which is incorporated in its entirety herein by reference. Technical Field 10 The field of the invention is medicine, immunology, molecular biology, and protein chemistry. Background The complement system acts in conjunction with other immunological 15 systems of the body to defend against intrusion of cellular and viral pathogens. There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. The plasma proteins make up about 10% of the globulins in vertebrate serum. Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic 20 cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonic, imrnunoregulatory, and lytic functions. A concise summary of the biologic activities associated with complement activation is provided, for example, in The Merck Manual, 16 th Edition. The complement cascade progresses via the classical pathway, the alternative 25 pathway, or the lectin pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same "terminal complement" components (C5 through C9) responsible for the activation and destruction of target cells. The classical pathway (CP) is typically initiated by antibody recognition of, 30 and binding to, an antigenic site on a target cell. The alternative pathway (AP) can be antibody independent, and can be initiated by certain molecules on pathogen smfaces. Additionally, the lectin pathway is typically initiated with binding of mannose- binding lectin (MBL) to high mannose substrates. These pathways converge at the point where complement component C3 is cleaved by an active protease to yield C3a 1 and C~b. Other palbtw av actiating complement attack can act hiter mn the sepience ot'ev ents leadmtz to \ anriu aspects rfteutnrlenment funceton, I. Ca15a apriyiatoxia. C b binds to bacterial and other celhs, as wett as to cerain l'irases and iunme conplexes and tas themlor remo\al t0am the S circlain. (CAb m thi role iK know n as opsmnin) The opsome function of Cb is generally considered to be the most important autnfcnm e act'ont fthe complemem sy stem, Patients with genetie lens that blocl. COb (tn'tion dot pm(bouttetmofin h\ a broad ariety of pathogenic organisms. u w h le patents w Nith lemons aiter in the complement0 cascade sequnenec, , pants01 \ wt lesions thait block, CS trinetns are 1 Iund to be more prone only t0 ho inf 'is'rteetion, and then only somewhat mot prane. bT alo tra cotmpde widi other ctfontdietitsunkqne tO cact pathavg hmu cassical o alteratie CS ce ise. which eaves ino CSaan d 0 . (2 thus regdrded as the central protein in the comaplememr reactuou sequence since a is eS .ential to bothi the alternative e and ciasir al pathways. T his property of L3b is regulated b-v the scramt proteaise Factor I, winc ac11dts ott C3b to prodaee 10Thb While -til! frnctionai as opsoum, 'C3 I>annot form an acive 05 coerts e-, CS is a 10 1SFd Ira ''lobulin ourtd in nofrmal scram at a cenetrdflion ot appros\ultateds 75 tg ml 10>4 p>l CS is tlvco~svlated, with1 about I15 to A pcrcetti of 20 its assx atiued to carh bvhdrate. Mature CS is a heterodimer of a 999 amino acid F1 .Da alpha chain tha 5isulfade hnked to a n55 amno acid 75 kDa beta chain. C) :is sthesi ed as a single &bain precursor protein product of a.snl copy gene tHar iland et at!. I19) hnmumo 146:363-6hh The eDN \ sequence et e transcript o this gene predicts a secreted pros ptecurse o' 65$. amo acisalon Swith dan I ammo acid leader seunee (s<:d dg., (S. Patent No ON, 55 T ) S he pro- 2 precursor i s aca aft amo aetna 0)n and 659. to yield the beta chain as an ami a terminal aln t 'rml"nd residues +-i to 655f the abv e seq0enet ad the alpha chain as a cabosyl ternmia fragment t amino acid cidnes ( 1.63 of M ch aoe ststtneel, AM t Skour ano acids dam actd residues 56 o O5 of the aboe sequenlec) dclctcd betw een the tn o c^sa is eaved fronm the alpha chan of C b- either aterate or clas al 'S con-ertse as an Vtmno terminal frament c1npiising the first 74 apmno acids of the alpha amn i t, amno i d .i aidues son ' v, the Pario sqbuen1e) approximately y 20 Perent of the II kfa ss ot ('Sn isn othatcd to carbohy drAte, Th c led\ age she f0r 001 vertase action 15 dt, or immed biet\ cdtplernl tO amio :acid rendune 7' &f the above sequenceA compoundd that nould hnd at or idlae, to j;. ha ~ ~ 0A Ila a;it ud have al I etenral o No ck acesofteCS omen e o te cau he cated teyo oCle zhans75 mcahibuer trvupSm Jigestion (a e z \lita and \ian (1 )i0 htoun 1 j - 4%02 a \eisel and lob (100 nMWu 1mmTeN 2240 'l rhronin. and acid treatrmei ( 2aud@010 313t tien h? 1 l s >N) '202i anid Uaterau v! at ( AR1Mi M hHM0041 i 142) cau also cleas h CS >sd produce actnve C05 10 0'( ap' ot'CS releases ( x. a Potent MuaphViutoaun and1chimotic fuCter, and 05 5 hi'h through a sencs ot protem iteoracons wcads to lhe carnation of the a tie terminal cormplemntt complex, (2$bt (i3d dat i Nh) also havdi ciotrop000c cell ativatng prpemes~ by amph%>na the grease of downstream miammtorv tbctors such as h drolytic eurwims, reactive sy :en species echidnme acid metabolic IS and varous cyAokine 5U combines utth (6, Q,7 and C t'o fom the Cb- complex at she srnt'ce of the arget cel T. Q oming of seval P9 mwlecdet die membrane atck complex i, \AP, C5&9, terminal emneplern wonwavxfC) i ltrmed. \Vbel suftiecint stusbet of \LA\s insert Nt tao et cl inembtaues the t pettus they 20 create :M AC poreS) medZat" r3pld osmetic lysis of the taet 0elI,. K 2e noni vtic concentraflosM of \ can produce other effects In partendar, mmbrane mnsertion ot'sniti .numbhrs 00 the t 'Tb complexes into endottl cells and plidsleis Can eneiSe dtetis04 ci at al ~u, in some cases acd\vatdon max' prec~de ec1I la si, As muenuoed above, 3 la dadO (ia are aUaphnvliains. These acivated complement v'mpnents can trig:er mast ell degnmulatiom, w hich releases histamme frn basophils and mast celLa and other mediators of inlammtio. Se~tii sm sithl musek consracthol increased vascentat pernicdhiiitv. lculkove e atni o and other 1n iamataior Pheiena incladin 'e n ar roeifeisnion rsUliins uinh5 percellularity (fa also itctons as a cllemoractic pepude dhi ser\ves 3to alttract prA, nflarmatorv giidilcy)tcs to the sitc otcoiiipbtnent actx iatront (^ a receptors are found on the suAces of hbronhial nd alveolar episheil ceis and bronchial smooth muscle ells tSa reep tot have aks been found on usmnoph wiA mast cells manocytes. neurohils. and actvated (vaphotes.

srmmary ftc ent (sckour2 rlAes te, 'a WON the genera1n b1 4 he maeitot' 0a a erm Qsf humanized xmcakroal anvibodie mth speci iul bind to oee Oa protein hat N Ga thtat has been prntol ealta eleaed from yt parotem> butS na to par along 5 proin fragenM free C 0r treCia Qte anubdiO arc ilven, referred to herein as th "5 sumibdie or <mti-G0a nepatope anb drej ' desenthed herein and evemphtid in the Workme examples. the gecrned t4'1 amihodie exhih a high afINt for free t'Sa Ppr e\Jmpte, alt e the .unImnnd o&nC i-a atitibodies desertsed heretaiptod to fiee { Sa eith a K that i' esh han 12 nanonmir. \any O 0 the antibde bimd to Pee (75a ( eg , free hsman Sul oh a K 0 tht s les than 300 picomolar, sev eral ofthe abodes bind tree (?a sh a , that is less than 100 picomolar. l addion, theb hmamized soil--GSa antibodie,> described beremn also inibit CSua-mediated signalin. Further s truentsd and fuuirnal ropere the antihibes described heremn ar e elabomated on below and exemphified in the w orima an examples Ate mnifltmr hav e also demonstrated, nsa in armal model of rhetuntaod a thmv (R A nd a vusrte nt i mouse CS a "ntiaodv with r operates siniu r to the hunmeed anubd x onunmeparts effiacyv l unmi4 53 anbodes o' tre4m' RA \lso show n a m thewor im examples are experiments demonstIami the posii ve. 20 therapeutic etteds of a h)umai zd antid S antbods in an animal ntodel of humarn G>a AduLd inu 'pena ecrdingly the teentoix believe e diat the ant' atibdies or amin binding famnents thereot descetied herein are useidi in a host of diag:nostiW and tberapeutie methods meted to dtordems in w ich Ca-mediated ignahincontributes to pathogeness For example, the imwentorN aser' that the hanmized amtica antibodies deserted herein are useful fSr treatma or L re ening RiA and other complement- associated disorders includinng but not limited to: atypical hemnoh tuc uretmi synhme allU S agec-rlated muculam deeuerato (AM wL sepVAsW oun te-.. severe burnt imop hosphohpid sndrome A\PSx acute respirator ditess 30 syndrome (\ R£DS), inthunomaion-tbavd pain, asthma, topus nephmti, irauterne gzrouib res tricPn S 5R H fill P kOd rome iemOlticmmia. Elevated iiser entl) rnes and o Platelet count' Goodpaature's syndrome, and chrom h scive puhnonalury disease (COPDI. Additiona dIisorer that ar e nansieuariv amenable to '4 eatient enn a w"i- bly saae Mrnb" nd fragtmrth Ste IUOnl t the artand rndherein ZTe I mmi d tt antib desd d es e t3 Cfe ian I ur ads aaes e~z pc wr ingent, that bind to. andinmhibit cleavage ot, ful-iength Or mat Cur 11. 4euh agetv the anti a antibodies (and antgeioing fwramcms theteofi described here are capable of mhibitmg O4e unaphy lnoie dowwremn offecvts; of (' t ti ath lou as mediated thrtnb gh Irfraet k \ 'bar V the anPtV/ a amibodies described heemn can inhibit the c mated mfanmmatory IrpO which is koeu n 1 o ,ma an tep al part mu he patthogenesos 0tcmh1etaeb disorders sush us but rit ,imiteJ to, sepn R and asIha Hm o C r e M the ConwntranoU of 0 i thiimian srum' 1 ppr'Aael P C e~t Rarml " and Pan burn (.0)Jrh nm I 661265-0442 the use of bUh concentrations ando t frequtut administration r anti-CS antibodies is oennecessary to e e A MX d , and hereby ihibit he aM edited maramatory esperse, in a hu1an Unhe 7. C {i 5 preset in ood a much lower concetraons and i often restnted w; specite reas of local wnorplement aetnai such as, eg, the lun. i asthma aa"ems the Aomia of RA parents, or the drusen in the ees of pants w ith. A MD. Tims, the anti Ca antibodies described herein cam be administered (ci, local administered to sites oe'omlaemen aetiatius to a human at a much low er dose WAdor ess IN regnenmiv than, e g. , an antie antibody, and effectively provide (he sanme or greater tdubmoRn of C i a human, T he Adbiby to admm t E a h wr dose oF the at-nCas tibody as compared to the reqaed dose Wf anuti'S antibd, also Asbw tW. additional deliver\ nues such as . y neutaneos admnstratian. itraunscular admnstration, ttinaty det'ver and d rt p Wa h 41 o f biWlogi A degradable nlcrospheres A lower coetmraiona of atigen 05a versus 5 alo tinoIs a longer half-e of the ati- a anybody as compared to, cit. tt1chalfhti of a therapeutne :mtnbdy that targes termriad comtidemremt due to a reduced contribution 01 an agn-rediettd anti clear ece hii addit ion, the ant!-Ci3a antibodies described herein can also be dts ingmished 30fom therapeutic agents that inhibit thermal complement (such as (CS inhibitors)i by their safety protik A noable conseqance of mhibiting terminal conmpleme components such as . A, (r C7. Ck r M is decreased potection by the host mme system aaist the e nupsuhed bacteria that terminal comnpleent ordinarilv oaenev e at (198) Con Sp in su I: !I -24 and Brodsky2009)Bood 1 ?26:65224527 A> the anti-C5a antibodies inhibit the Soa-mediat.ed inflammatory response. bu do nruot prr ue te ormation of the. termnal comrpcncm cmpe that lyss the 0 encapsiaed b e recving a Cherapeuic anti C5a dtnibody described herein woeld not require a proteCtive vacmatint C- a vaccination against d.Qisseria meningif des and Neseria gtonorrhowc. Accordingly, in one aspect, the didOSure features an timated antibody, or aUen bi in fagnmen therent that bindis to free CVa. in some embodiments, the 10 antibdy or antigen-binding fragnent thereof bind\ to free human Ca (hCa: eg, a human GNa protein comnpising e asn or os tr-< he amino acidt sequence depicted in SEQ if NO'l it nso L Ie embodjmtlt thG anibody can bind to a desarnmnid iorm of frce Ga, e, the desarsmated mni of human Sa compimng. o consistig of the amno acid sequence depleted in SEQ ID NO). The anniody can hAnd to a is neoepitpe of ree CS, uhich eMtope is not present on tuneced CS or s presem n nly a tmlet fracion Of total uneleatved CS5 While the dckosure i in no wt limited to an, particular thery or mrechamisn of'action, in sonte enoedments the amtilG5a antttbedy er aigen>Thti0an ra eit there'budt to he Sa (o S it. Re CSa) and ay also bnd to a 20 subpopulatin of uxnledn ad proceed '0 Pg.lssma CS) eonstituting hss than 10 ea, less thn 9 8 ~', 6 4 %5,,4S 4 A T3. 2, 1. i0.. 5, 04. 03 (2.' or lew tha 0 i l' total ppidtnen of $ul1 length ( in a samnde \ e g a Nood t 0Lasma sample or a sample compusmg recOmbinant full length Co5t whicb subpouiarion is A whole or in part, Ja tured such hat an otherwise occludeJ GSa J neoeptpe, to a hich the ant-S a antibods or aragment inds is elposed u an san Sa atibody or anogenbodit trng nien thereof decrined bei m can in rme etbodiems bind to fiee G Sa, but not to the unclear ed CS proteim of the 400 r greater ulnclea sAed, native C'5popuiaton in mote em.boiduusents the abo e-dewcribed oadriiy or fully denatured aihopuliatin of CS is inacive er has reduced activity le than 90, 8M 7 .5, 7$. i0., 55, 5A 45, 40.5, 30 2, 2.4, 15, 10, 5t af the acntny ofullvfunecinat full-lenth CS proentu in any number of soitah always useful for iestin; CS activity eg , a hemohyti asay or a c,'l:o9 away see Mob . table methods lbs tAtin g the ati0iyo f the mnor subpopulawlin to which the at an dA desmed herein In some :mbcdiments. au of the anit'Sa ntiodies r nte.mbiudjg finmemns there deswrnbed herein do not inhibit 'S anviy in an in too ,heml s assay or an ia nn' H eq away eiena to the prnsencef at e<v4 eqal to Or gre-ter dta a 5 i e v 5, 7. 8. 9. 10. Ai 20, 25, 3 35, 4145 50, 55. t65. 7 1' 5 S Th9. 9), 100, A 10 20 i1 1 40, 150- 1 1 1 0, 1 00 or 200) 4old exew ' the anti a aanhdy or angemti-hdov tratnent tr o to uncleaved '5 te g. umcleav ed, native (.53. in sme embodiments ann ut the ann C~a antibodies or 0 ateen-binm fragaments thereof described herein di n it inhibit C5 acti mw in an me iRo iemnolyss assay or an in Sa CI 0eaq ay even m the presence of' be een abJut a 5 o-ld to 200- Rid te ,g: bet "een abotl 5 ld and 100 lolds betWeen about 104VAd and 100 fOld, between about 20-idd and 100, fold, o between about 10-d and 1 50fodd exces of the anti 1u an tibdy or anmigen-hiding fi men t their eof to m relea ed, native t'5 1thubimone s, as it pertains to ('5 aetavut, includes at least a 5 eg at leat a A . 10, 15, 2A 25, 0 35 40, 45 5,R 55, or 60 " decrease in Te actmvy of uneleav ed. native C in, e g . a hemolytie away or '5e9 aMsay as compared to the effect of a control antibody I or antgn-binin A ' mn there under similar conditions and at an equivolar actra t Own ubstantial mtubhio. a 20 used heron ros to WhibtMn of a pr n aevity (e.g , 5f wa' tsus 0ft teast 40 at lesi 4 55, o0t 65o'r SO X T0 a r :re D te A ina some rnbdimnts the tI ns obtained frorat plasmIa t .pnfied toan to present m penm~nun',am In samne 'mbod imers the anmibeJv wt aangn-nbmnding rrgmemr thereof' binds to a i s a (e, a human na rin ) wih a K that i less than 2 n&I in wme embodienr tO antibod or >ntio n bnihong fragment thereof binds to a ('a protein with a Kr that iS le thanI M (also telerred to herem a subuatotir ant"tvi hr sonme "imbodimeno~ts the amti-c.a antihody or an tngenribotm fna ragment thereof' bo'ds la tree' (. '53 u ith a subdn'omaa aliinio [e y , ii N of kten than tr equal 30 ~ ~ ~ n to 93)YO toI)'uLs1AO0 pu Q\ 1066" a 0 ' U t \ttS 0 46 TO N 1 W0 tMa n t equA N 9 x 10 , \ 15 O ) 0 n \ 10 5x 10 '-a 10 40 1 0 t' 4 0 r tfl lat 5 ')r a> 1a 'doon eo",ss rA undleavxed, tatisve CS I. a. n irih'd and jor revoinoani (x n\l some emabodirents. am1) oa the ati-liSa aibol dies or antigen bid1 ianiet\ thelet desieted herein have at least a 100 (eg at least i10, 120, 130, 140. 150, 160 170, 180 190 200, 225, 250. 275> 300, 40th 500, 600. 700, 800, 900, 1000,0, 3000, 4000. 5000, 6000, 7000, 8000, 9000. or 10000 1fol 1 heater affity (ex.. represented by its Kn) f free C NSa thoan for Qnleaved, nntve C5 promin 5 f Ts in another aspect the disclosure features an antibody o rantigen-bmding fragment~. ~ thereof that (a) binds to free CL (cNg hCSa) with a subn'aniomusar a f'irnity and ( inds to free CSa with an affinity tA s I at least 100 e. g.. at least 110, 1.20, 130, 140, 150, 160 10, 1, 100 . 200, 225 250 275, ;o 400, 500,600, 700. 800, 900, 1000> 2000, 304 .4100, 000. 6000, 7f) 8000. 9000, or I0000) -fAid greater 10 than i corresponding afiniy lEr utncleavedx natve CS proin, For example, an anti Cia antiody or antigen-bi g fragmem thereof described herein can, in somen emnbodiems, bind to tree hCa with a K of 100 r W anqd to at least a subpopulation of uncekayd human C5 protein with a K that is at least 100-fod higher (g. at east 15 in anoner aspect, the diselosare feaures an sated antbady or anyn hindit irnei thereof that binds to a free human C5a polypeptrde having the aimno acid sequence depicted in SEQ 1D N): 1, wh h.rin t xnt diod) o antigen binding fragmem there~obimd toWtIh hutan d^ jmoa pptK 'ohe wiih a that is less tan 13 x 10 M m the pesene of a mola. exeCes e. a 2, 4 5, o, ~ 9, 10, 20 13. 20 25, 3N T4 40, t NM W0 , 10.l 150,70.0t0 motar excess Of unceuxedv, nam we hunmn t' over n m a C5. Al some etodintens, the Amtibld) or antgen bidity fragment there bids to a free l&Sa Prolpertide with a subuanomelat alf my te. g., uny of the subnanumolar h'S reited hernr) i the presence dl at least, or greater than a Mid moa eces but no 5 geate or Wlew than a 500 eg. 500, 450, 400, 30 300. 250 200. 10 M 100 0 80, 70 60, 30 40 0 25 20, or 15) --ld molar acess of uncleaed, nive CS oer free sa n saore enbodient the atbodo or a indm e. facngent theirof vinds to a tree h'5a rotehPtrde with a subaanomeoiar aftinity tiep, anty of the suOnanomoiar Kn reined hereOim the nresencf between 2-fold and 20 fold 30 molar exces of unea ed, ntive C5 oere 1ree hC5a tn some embodiments, an un tbodv or antien -binding fr agment thereof binds to a free bC~a poly peptide with a anbnanomnolar affinit)- e. es, an> of the snbnanomaolar 17-'s recited herein) in the pr esence of'between 10--fold and 20--fold mtolas excess of leaved, namive CS over free hC50 a tnome imbdmemts, an untliodv or antigen.bodng1 freagment thereot' Uk"W(n 5- ol and of th bindsK tO a tree hO~s polypeptide w ith a subtns omolar dfiinuyiegam fth subu molar K 13 4 teeited hlerent int the Presence ot betw en 5-10ld .nd I - ld molar exce5 0f uncleared, nine CS over free 605. In some embodiments an anrtbodv or a ien-obgn fragmemt thereof binds to :a Tree h<O5h polyp~eptide with a 5 ubnanon'ar aminitye any Mte o subnanomlar LQ's recited heren in t presence oF at leat told but M we greater tian a 20MJ mli exces of'unlts ed, tatrme. C> ov err hCea Such mneasuremems im" be in r ni-easmeimns nsm e. standard d d inir p d ntrminatilon technquermanw of xicb. are re Wed mnd or described hereim 0 ~in another aspect the disclosure feutures an isolated antibody or aiminen binding 'rmemn thereof that binds t a hWon; Sa poh peptide hang the amino acid sequence dtei(ed i 0 10 NO: L whJem the antibody or angen-bnding fragment thereof bnds to Whe human ('S pohrpepide wih a Kn tQ a i is es than L25 x 0 'l and \ herein the anlbod ;e aunigen-bindi it taramen there does not I ustantialh ibit, as compared to an egmmolar arntit oF a control antibod 03 antigen indmI fagntm thnreof, Cj5 actv een in The pr ce of le ihu or equal to a 10 ld iat e' cn 0W the antsC atdbd\ ot antMAne-bodlug ragment in somO "mbodiment> of an of the an i va anbodres or anigen-bidgn g20 mew r thereof described herein, the anubody or autien-bmdi. fragment thereof binds to free human (C and is crosweatre ith tree Ma from at Least one non Inman maniaan species or example, o nsme enbodtientso an amt,- Sa SMAodY t(r antgen-bxidwg tratient thereof) binds to fc Shoai bunion it:, wih sboanotmoar af1imiit und alsobhids to ree Sa rm a non-human prhnate 5 t eg, cmhuan s tniCauquo rhesus macaque ae. baboon, chmnipaa-ee, orangutn. ort gornlha, a rodent teg., mouse. rat hamster, Guinea pig, or rabbit), cow . out. donkey, pig, de, cot, or horse. In sorie einbodnik3nt an anl- ba anIlbody or nugen bindituigfragienti thereof descTibed hereju binds to Pvce h0a winh a 4 of less tt o w q , to x i. 10 e.s thMu or equad to 9 T ; x W N N 1 6 N 10 30 0 k 4 x0 3 1 n 10 , x 10 " x 10 \\ 1 71 x 10 ii0 0 P~ , : t A"xl 50 a 0 , 10 orO 3 0 "1 \ and ak I bimd to tree vzs irsun evnotrltus nmacotue (or another nonwhnan imate species, ' herei the affnity uxg.. represenlted by its 1n) (0r humtan (2:a is no more thni $0l0 (e~g no imofre tha3, ,100,3 0 7 0 0 125, 150,200, 20, 300, 30, 400. 450, or 4'

Q

-Ad greater than the affTy for emotpous mark p (or other non human pimae speees 0'Sa. For :exmple, m some emboimums. tou-C53 antibody hinds to fce h1a nith an afnimt tiaA is no Pnore than 50,-old greater than the eorresponduna ati"nit ot the antbodv ie non-human primam C5a too, a Kp :'r free t'c a MO 100 5 M and I K 'or non-human prmate ('5n of no more than 5 M In some emibodimets an anu-Jat aanbody or thtentbmda fragment there described heein b tic hCd wh a Ko ot lenothan a equal to n x 10 4e g, les than or eqpual to O K 10~ 8 x10 ^' Tx l0'74ox lO ',5x 10t 4 x10t3 x 10 '~ ' t in 'x t 8 2 K 10 iKY 0 , ''0 :x 10 O N M K 10' 50 x 10", 4 x 10 0 l \10 3) \0 >.d N l s binuds to Cfa rsom a oeu tm g, use, rat, or tabit wherein to aTit e I A repesemned by it Ko 'o human ca Sno more dhn 1000 ,. no more than 5", t2,. 30 -. 50 60, , (h 100, 125. 15 . 240. 25A 300, 0, 400, 450. 4750 500 550, 0A 650 ~00, ( 0 50, 900. 50 or 975 <old aeaer than the affniy f'r toe CSa i some emiboems. ,m o'the a:ta a S antuaia or antuen-m hng tragments thereof Jewnhed hrei bind w ith \ubmaN >moha aftinhm to bot human Cja and to C3 fwm a non- human mammal p g edent or A nonupman primate such as evynMolus macaquo n :mbody or ' bi-enrndTm frtagmp thereof can, inl onic tidIm&XTents, bind tos human ( Ua and uen -mman (rin n a N ith equa fitity (e.g, an eguivalem K) 20 1k r estrtlj eit the disclosure features an anubodV or antgen-admi tiagam thereof that Nnd to free ba man (a th nanomtlar afFosi 'e a , a K" of We\ than or equal t ' a0 ' teg , iess than or equal to 9a 1W 10 , '7 x 10 6 10 5 ,S 10 4 l 3 x 10 15 x 10 72x 10 V 10 to 10

T

K 10 ", a . 10.0 a 108. 4 0 a 10. ",or 3.0 a. 10 "N\l and is crossreactie with 5 ree Ca from cynomolgus maeague f(or other non-human primates the anibody or antigen-bindingA fragment thereof hnin to cynonolgus nacaque (or other non human riNmate) C'a with a K of less than 10 x 9 x to 8 x 10. 7 x 1 6 a 10 5 10 4' x 10 3 x 1 V, (2 x 10" 0 99 10<(e., less than 9 x 10 8 x 1 7x 10"*.6 N 10V 5 1 110 4 x 10O 3 x jjot 2 5 x 10W 2 x 10% I x 10 or 10 " M wheremin the Afi ty huNan C50 is no more (han 00 eg in more than , 0 3 40 50 60, 70, 1A 9 00 12, 150 151, 30(0, 3 50 400, 454 or 475) -fold greater than the affinity for cynomolus mnacagne (or non human primate)0ma (e.g. K for htuman Ca of 100 rtM and a KS fAr non-human priiare (Ua of no more thun 5O nM-l. Stuitable methods for determrining the affinity 10 Ora antibodUh er ani dRa no thUee fAna ang n ai menar knonin the art and exelified herein In 50one entodinment the cross-reaCtive aniiti-C' a 3iOdy Or aittie-fling fragtment thereof timetionaliy inhibits both &ere hC~a atnd the. non-human manmaalian Ca to which it binds For exatmpe, an antiy iibis t leasi 7 t a v5s st:5, WK01 orS9 or nreote %~ humain CndavdeN nn pfl ottophi WActi loil at a molar ratio of 1:1 nigmen-binding site:Ca an ih by atn !east 7 (e. at least 75,. 80, 85, 90, or 95 or greater) % non-human mnammnaan C<-depYendemn neutrophil activation the neutrtuphis being f A i s name npcws a tho non-huma 0 amialian (3a 1 W hih So anithd Mnd\ at a no!a r rad of 1: 1 iant gen-oinding site:tdai 41 another aspct, the disefosare feamrnes an isolated antibttd at ant gen Lindin t rament itheref that binds tou a fee hIC~e pvispertide hav ing' the aitmio acid sequence depted i SQ ID NO T where the umihuded or ane .ragm there bimdM to the un fPOlvpeYtid Cuth a lV ia t 3 less than 1 '5 !tS1 and wheem the anybody oriatlgen bmimg togmem there'bmds to both hC 5a and to C( 5f rom ai non-hutmaat mammalian species. The nan~matna mmnmalian piOW5 can be, ce2. a non-humarim Mate such as nlo~gu§ imaaapx rheans iacnque or baboona in some embodiments, the non-human mamrumahim see eis a 20 rdda ucht as a muse, rat rdb it, 'a~e pitt gefil, Or h3as. In so01e embodnents the ami bo O antign-hmdma fragment there binds to bCSa with an afiniy rio greater than 1(0-olM hhr thaum the correspondent attiny for (2a f rom the non3t-human~ 3Yammitialihan 5teex la-I -nine JnibodinemPZ dhe anmibody Ot atrSC3, binding lrzmenwihn by at lbas S0"> huran (Seendent human etrnophid a, aciain at a molar ratio of to g v.nnnmi apse te: (5aV In some embody hments the antibody or unte m dinUmlg fragmenm thereof binds to free CSa u4 lit t3n31-humuu~ irte 3i e t. .,. a cyiui-iolguis mnacague or rhesus Smaquc, the free Oa protein hong an amino add sequence Comptrisim or consisims of, the amino acid sequence depicted in SEQ ID \ Or SEQ ID As desernbed im the w orking examples the inventors have also discovered a bivalent aahkffa antibody, BN3383 that binds to free £5 in im nis eh humanm ifal Wth high fiTim) and, W it a much Woer attimt. onevead human C5 1iC 5 where, i a copo 00 te., an aqueous ounen inder physiolomical conditios at equilibri n and in the presetiee Of a molar exess of Unlicaled human t1 5 as *ompmred to the oldar omst of the antiget w1iding sitfe of thV nifiitdtes at least 950 of the pluralitv of antbodies each bind no more than one hCs moleule. The second antigembde she ofthe at least Q9 of the plurality of amiboies ramains avuhAbe teg, ,nbstantially ava dable to bind o tire C. hiI the dise tiMre in no wa bound by any particular theory or mtechaiism o action, the inventors beneve that the hi\vatent anrti-Cia antiod) S otisuneleaved CS irl such a Wa\ (tfat sucet an etutoe I that site ilfdanee prelmde\ Ot at le st sabstanvat\ ib'tds the bmndhtg of the second antigenay bdiu ste of the an -5i antbods to second 0 ) uncleaved C pr otein. although the anubodv can easily accommodate the bndig to iwo hCa molecules. hus the antibody" i 'nna molar escees of unckeV d 'S retains the abilty to bind to free M 5 w ith hih affinity and thereby ttdns. e c ion that molar exss, the aiit\ to inhibit the pRY WiromoatN ry aci vity of C5i One of ordinary skill in the art wouid easily md read dv appreite the myrid themieumie benefit of such an anti-Sa anibd. amla n P vbo, 0coutraton of cheul-ag it' 5in human seu ant Ver ho h Thua whben inroduned ito a mammal, un an-i Ca anbodv that iH a uable of suuitancously binng to two tuielenx'ed CS mrokeedes woudd be rapidlR in'iivated in the molar excess o f CO and uld then no loner be capabz of bmndin to free C5a in the event et'ccmplement 20 actiationu And, uai a d ati-C atibodies use of high concetrtions and /at frequent unninitration fthis type of anti-C a tibody woul be necessary to effretiv ely ;nhibit V'si, in th- Cven that it is produced In contrast the anti-Ci annody described vre that retains the ability to bind to free Cia, eve in a molar excess otuneleaed ( can thus he adnistered to a human at a much loenr dose 25 and or lesw liecquetnth' than, etg ,an anti 7: amtibody and . leta tiel prove ide the same or create rbition f C i the hun S Aceordmnl, in U e another aspect the disclosure teatures an -ioated aanbody cermprising tnwo antiebmdin- snes nherein ech *nt'ige ibmdong site ndependenitly can bmd to free human t u (hC ui or Mcleaved human C5 hC5, 3 herein, in an aqueous soluton comnpii g: i) a ptlurahtty oi said antibode and ii) a muobr eess ofh as compared to the mon0 amoum of the angenbding sitsn at equilibri and under pirvsiological conditins, at least e 95 g , at least ., W , 965, 97 975, or 9'7 ' of said pluralty of antnbodies bind no more than one hC( 5 troloeakt. W.. nol more tWDa 5"v of teantioe bar jK41Comtepe ~fv te nit nm.hai b 10ih1n hielO4 a In anot WNer apect, the dislestre featues an isolated anIbRdT compusma tWO anngeR.-brnduta sites, w herinl each anteesbindkuhy site independerulv tan bind to (free Aimmn or b5 tcead umman Ct =h5 n Whe n at olbm and under ph yltoogicali condationei m an aqtucous slution comph singg: 0) a ptmahty od sal d Antihodies sad d ilA a tl a excess otibCS 0 as cmpaed to the molar aMount of the ani iding sites (or aniliuies iit least 0% <said pifo dit\ u o f antibodtes retain at least ne antagen bomtn sec avaiable to bind aiY' b7 '55 10 In another aspect the disclosure features an isolated aritibodt conprintg tWrO antrgen-bmndmrw sites wherein each umtig:n-bind my site indepn deanN th binhd to free humtan (2 5{ihCS'I or uncleaved human tS ( hCSV wuherem i at eqtmhbriun anid under physiological eondiIon. m an aqueous soamiu compelisig' ti'\ a pr ality 01 said antalxdies and (i a molay excess of 6C as compared to V "e molar amoUit ot the ISantigesn-.bitng sites (or antrbodleSL each art:igebdhse of no more thatn % of sAid plual h of antibodies is bound to a r05 mticie, in some emabodiments of any of the isolated antibodies described heiun. t4e miOlaYt S t'i t a t a.WodIM to at last a NWtoM, M Tld, 4- Md, 5tel, Af010d 7 flid. 8-fold. 9-ld or eien 10 Al) mam excesN 20 i soe embodiment of any of the vioated anbodies described herein, the physiologva oaduton is ' rAM NalNQ A tm Naz.z0 and 50 mM \aCL at p717. In some enmbodiments of ant of the isolated antibodies described herein. each antigen-bindim sie iAdependenvI can bind o fee h'a w ith a .K that is less 5 than 1 .3 1 }0' M in some embodimts each antgen -bmdig site can Wdependenth bid to ret imC5a with a Sdhbanomalr alfmny see abov e) I w-: embodimeMs ot ay of tie olated antbodies described herei. the K antibody comOflwn. it AgM chinp iselated...l.d.. pn...,gh temre p~ptide comptisinig the ammno acid depleted i SEQ M0 NOW and a heavy chain p0lypepnde MOprisrm the. amno ned sequence depicted in St'Q D vhn:42t i sone endidhew< of anv at he: slated anmibodies described herein the isolated antibody conimises: o a light ebain Q'3R I compising the ihmmiat acid sequence deputed in SQ l) NO 20: i a b h t chaim DR coMRpisig the amiin acid sequence depicted in SEQ ID) NO2 2: (iin a Jat chain DR3 comprmg the arnino acid sequence depiered in 53Q 10 N 0: ii a heany chain CDR I comprising the ammio acid sequence depicted in SEQ .D k10: an heavy y eham CDR2 compr ising the amino acid sequence depicted in Sf'Q ID NO:4d and [v is a hey chai CDRA comprising the ammo acid sequence depicted in SFI) D 0:47. S ina some embodiments, the isolated antibody can comprise any el the light chai CDR sets described herei, any of the light chan variable regions described herein {e ixg. any of th' human red hghIt cham "thl rm mhms r i a the heavu chain CUR sets descWrbed heem n tthme heavy chain a aribe remains desCribed herein (cg , any of the humamzed he'av c habt v amiable rev ott or any' suitable I0 combation thcevof Sow. e, eg ,Ta i t . in another aspect, hdslOsmie l'eatutes a melhed fo r treuing a human affhlcted wah a complemcen asso ciated disorder es a C5a asmted complemeM disorder) svuhereina the method includes adiminstering to the human any of the isolated antibodies described herein in an amount sullicient to treat thbe comrplemenaot ariat 15 disorder In another as pect, the disclosure featurey a mertod for treating a human aflheted iith a. CS a:associated comuplemtent disorder, wherein the mathud compr iseS admiitermng to the humm at least ph (t., t least 0. I, 0 or n i mg of any of the isolated atibode described hrmern t 4 body eight of the uma to thereby :20 partialy or completely bind and sequester nanogam levels of fnre CSa fomrpeater than, egal to, or at least 12 e g, 1. 14. i ' 1 P l K A 1 ? L 22, 23. 24, or M in another aspect the disclosure features a. method fr treaty a. human atfbeited with ar CSa.associated compnlenment disorder, wherein the method cwomprie J5 adnmstemn itn the humat at Kast 10 mng ofmy of tbe isoted atibodes desrnbed heren per g body wght of the humin to thereby partly Er ownpleey bind and sequester nanoutrm levels of free Cia for at least 24 day In atolher aspec, the disclosure features a method for treni a himan affliced with a Ca- a waatd compenmt disrder, where the method comprises 1 adnisiermeg to the human ayoodcs described here n or "io example a pharaeutical cemposituon comuprisnig any ot the isolated antibodies described herein) in an amount suffient to a. achieve mlar Cmax values equal to or law than the phytOge nlareoneewmra tion of uncleaved hCs and N parulo comptetety bind and sequester pathophy sioioocgever ls of free C a,.

n some em bodmets of any oft themethods desciheJ hem., an atibd i adnB iistered to a. Wubet te t , hu in in n Amou int 03ym e d"c a mola Omans vale thut is sustanntahlylomer than the physogie moaru oncenttratinu of unclexv j (di e 0g.. h'S) S i~nme t mbodinreits Of any of the. methtods dseraied herein, the (mas value s. 0qt, no greater than 80 aM mor aprimately ( m og k In some embodimem ma\ le ame no Preatrb ' to N ,, 0 or 20) t N in some tlhodninesin, Cle 1M W Ka e w no doneatr thanappro\'madelv .10 nv in some emodirnenthOe Cta\ \Jhiei no Cru0 g10 oi0 JaVl ' nM D Inb some embodiments ot 1 n0 & f the methods deseiibed hereiui, the t V'ma I iue e g no greater than 400 nM t or approxumately mg' k In some embo imrnt t (max value is no greater than 400 MeRg 350 M0, 250 200, 50 100 90,1 08 ' t 5o, 40, 30,'0 or 10) tnt ls another aspect, the discosre fatura a method tot teaung a human afflicted w ith a CSaw ssreiatedl coinnee isorder, w\herein the mhedk eio Ciprises adiuisterng to the hun an\ of the aidd antibodies described herein (or irm example a pharmadeauixl *00m[coupot c 1mp My 01 iolaed antilodies deribed heeo) in an amount sutiiciet to a achieve mular mn values equal to, less than, or substanpally low er than the motar invsiologie eoneemrratin e.l uneleaved V'S nd (b) prrallv or coetcly btld and sequester nngam levels of 20 ee CSn O at least 12 days tog at least 24 days. SitaNe v mn vlues are descrilhed above. in som emodimets ofuany of the methods described herein, the cs'a associated complemnent dioder cart be, e ; . one selected t'rom the tgroupt cerustnn of sepsis, acute respiratory dire\ \v ndrome iAI) Ri 0\sepne shock, anti 2 ph osphohpid syndrorte, cadtastroptue ann-phoaph ohipi ssd idme' disseminated miniysnlar coagulatinn, iupu\ nephrit\n ioudpasu e 5 Syndrome, burn or severe '-a~ibee' ka'I iv'r" h'rw' up bumtatla, I-I LLip syndrome <dHnmol tc anemia. Ie<vated . a. ei en. a ou ad Low Platelet count) mdlainmatiom-induc ed pain, CGa-mediated neutopeniu, age related maeular degeneration ( t0tI chronic obstructive puimonar) disease, and 3 rheunmatod arthritis> In yeat another aspect, the dislosure keatres a conposion cormpris a pltraht\ by f isolated antibodies, each antibod of the p1lurahnt coimprising two anttigeim binding sites. wherein each antigen btintihng sie indepetndently can ind to free human Ci e hCe) or uneleav ed human C S rh(S),and whberein in the presence of'human CS it. ~ RIC MY m uder lhysiiocai rndzns no ao han OofnTx antibdis h of S: &urhay at ep Iibriumcompri tw anthen-inding sites nsutaneiuse bifomd to indeed K'5. in woe 'modimnents *if ans it the comiposmtons descrnheJ her ein, the pecetage et the p ntylk n :ny parucular hiding contigumton cam be evaluted usmg0high pei frmanee liquid chtmtatog raphy i iCiU . In some embhodm0ent ta physiological condnins In sw hih the anmibodies are evabuated e npnses the khlowing conditnn, inceban in elihCS en.g a m~Atar exess i g a 'Tfold moear exces y of hC with thVe phahty otanubodie at 4''t t (b4 hors 04 :" aqueous 0 solution conmptismg9 uM' Nal P 4 , .1 iaM NAHPO and 1 n M naCI at pm 0. For the purposes of this disclosure, the solution obttined at 84 hours at 4 0 'C is considered to be a equibrum Sn some embodment of any of the compositions desenbed herei no more tha 5% of the antibodies of the plurahty compnse oa men-hmdin sites musiiltaneonl bound to <ceaved hlIC under physopzia. conditons and in the presence of at east a 2 - 61d molar excess of h25 to antbody. in some enmbodinments of any of the compos rtons descenhed herein, no more than % olthe annbodles ofl the phui'y comapris two antige-brabiagnses smmtaneouslv bound to ncleaved 4IC molecules as ctdauaed using WP'C 20 tllowin incubanon of the piumaly of anibodies wn V 5 at 4 ' A 44 hours in ar, aqueous solutuon compnistni 3. Ci rM Nailt 4 6. 1 mM NadPiO h and 1530 mMt \a p i H ' 0. In another aspect the disclosure features a composting comparing a plurality oolaned antibodies ech arnibox n> the pluralliv mtprisin" reo amigatn-hindiog 25 sies, uwherein ecanugen hmndm sw' mndcrendeiul can hind to 'res hunan I S (hct or etcleaved huon C> 3' 4h5 and whieremn no more than & af it'he anubodies oli e pliitxh comprise two atigo-buing~n st s innultaneondh bound to uut'Car ed hVS as evaluated ta. using 1-121 C) fll~'Ow incumebatinn 'he plums ts 1t antibodies n ith ht. at 4 \' for $4 hours in an aqiueous whuion comprismna 3u mM 3 NallANO n. nmil NarHPO 4 and 150 mM NaCIl at rd-7,0. Ia t a nnher aspect, the disloure febamres a composion icomnprliig a plurair of iso laned antbodies, each aanbody of the piurahn t comtpriing a first antiaen--bimdmin e and a second anigen--hidmng site. wheremn each nmgen-bmdmng sie edoepcndentlv can1 bind to (tee hlumn t ibl1CSa orGi uCledved hunmat (S hCi40t 6.0 whee each agen-indmg sne indeendentiy can bind to the free hC pivpepttde Wuth a K 0 that i les than .5 x 10 A \i nd neemi mn the proee tf human C ShC51 and as ev aluated te, usig high perttmane hquiJ hrtvmatogsraphy 4 PLC)n under pui soloeida cmuitons the two anagemindmg tea ol at least u% of the piuraitv t anubods a-e 3ci a j i 5 the flikm lrig contigurationsty(i the firstatigen tidag site binds unceaved liCS and the second aniebsndm: u art fmnbound, Or (lit the fir angennding site is unboundnd d the second an tigen bmdmg ste hinds uncieaed .hS' In ) center aspect, hoe discosure features a com tion utasng a 10 pluraYity of iwoated antibodies each antabod ofthe plualitv eorpr ising twQ atuten binding sN n etie ng mdependemly can bind free humm VSa i ban or unceav ed humn. t h( A. and nl heroin n the presence 0 f human C ShC) 5 n as auhated e g o s bnty h pefat n10 e Quid oi Rnotoguphy ( HPL A undr pht siodogteal ondtions an leNt 'i% of tIe anube ies of the plualty IS comprse at ieast one antigen-indag sue capable of bwamtin "o free bC0a i some embodomens of arny 01 the cclroroions descered herein, the ihutatv of antibAdies is evaluated in the prewnce t at east a 2fold moau excess of hC 5am thod), la some emboodimnents oftany of the composttiona descrtned herein, the lurality of anibodies rs ev aluated hm the presence of at least a 2 Ibld nmdlar excess 0 20 hCS aanigentimdimg ste-s i yal nother apect the disclosure t'atures an nshlted antibodyc two a tinen- binding Mt wherein the atmbodv bmd& tw 1ee C a or inceacoe CS, and where one of the anhMen-bang ates of de anybody remins Vaitable to hd free (a im the presence of a mar eess ( k. n at leat or greater than a Ml, 25fold, 10-fold, 15 fold, or ev en a 204 old :molatr exces oftuneleawed CS. in aoe ebodinent o the antigen-bidmn sites have the same specekvty jeg, the CMDs Ef each oflte iu. autigtn-bid: stes share ideneai amino acd sequenceeK ln sonme enabodintents. tree (ba is huma C h somec embodimenta. the antibody is cro ns--eiwe bn en human C3 and(i 3 prn a nohuman mahan specie, The Antibmdy can in some ebodorentx, bid to free C5a with a subnanomaolar affinity b-sonic emiboduntus, the anmibody h-a an affinv fo tr C a tet , deanr than os eorrespontng afi for "Aea e In another aspect, die discloure features an isolatedt antibody cdoms tw o Aang bmdm Nts atr ch n-b site independemlv binds to free 3. / hilitan I sIn ihC's} or CueAaved 41n LKS and wherein, at an\ cowcenttion funclea\ed of' it. in a Dmolar ele of uceaved 11S er htot 3eaIt ot of The antennding sits of the anbod remains aa dable to hind to Kee hC05a (v under human phpiological enditons p. in hnanti blood or senmit n another aspect, the :disclnsnte teaures a iomnpositon conpriting a pluralt of isluted antibdttin h'et e each antibody 01 the riura lity e mp'e two atgn binding sies, herein each often anigen-hding sites independedy can bnd to fr?, human (, 5hCt otr Uncekteaed human C' r hC and herein, at a iu r'tio oU1 C 1 3mianodA)'hC> \. flo more than, Or le thte no more thian, or less tha I 45, I0 4 4 ., 4 4.3, 4.2. 4.1, 4.0, 3K. it3 3 A 5 3i,14, 3,2. 3.1 1 20 '22 2 . 14'1 2 112.0 1i , 13, W 0, 1 . 1.3 j , 1 t 1fl% of the otibeies of the rimah iomnnse m e 1ge btdog taas munaneouslI bound to uncleaved hS in some embodlments, each antipeu-bindig site ndependently can bind to free hM'a with a K, that is less than I .25 Y i) M (or, for ISexample, uith subnanoemalar altfitivr Inanother as pet, the dischosure feature\ a composuton comprisimg a plurality of isolated asmibodies uwhereiti each antibody of the' plualty comprises two antigen binding sites where each of theQ aien.btdin sites independently can bmd to tree human Ca Ma,5.i or unclear ed human '5 hCS ad wterein, i the presence of 20 phySiologi levo' e uncleaved C5. the antibedik of the Phurality partially or conmpeely bom and sequester nanogram les e o v free ('Sa far greater than, equal to, or t least I Ie u. I 3. 14 i1 , 19. 2 , 2 , 3,2I, or 25) daysW hen adlin crcd to a' human at does of ik o gu r gher ln another aspect, the disclosure teatures a compositin comprising a pharali J5 of sated antmbodies uherein eadc antobnd of h pluralit\ mprises to anigen bitiing ites wheren each OFiehrntmnen omding ues mdependently can bind to tree human CGa ihCai or uneleaced human Q5 "ho and xunweren in the presence e1 phsioleis. l'vsof uncleaved M. the antibodies l thce.I .in iI t rad or eonmpletel bmd 'md segnester rianog~ranm levl of ft ee GSa ibr greater than, equal to, rtatugar Jo"k ti how * n 4v gor Q aqaik. N t u; seton,12e oy, li s, 15 lW 7', M 19, Y". 21,2, 22,12 .r 20 dyv when adInmistered a human at does of 10 Mkg or higher .ln another aspect, (he isclosure features a compostion comprising a pluralis of isolated antibodies. Y hran each antibody of the plurali\ comprises two atigen bnding stes, whein each of the anioen -bmding s dependenti can bid to fiee human CY( .C b n or uneicavled iman V hit. and wherein, in Qhe presnce of phvidoic lewes of uncleMAed h5. the antibodies t' the pluran parnd or completedy beids and eqt n angrant levels of tree 'Ssa or greater tha, equal to, or at least 12 (e s' I 4 14, 16 1i ! I 19, 202. 2. N 14 or 25) days when 5 adiAnisted at doses acheong moar nta: \abnes subsi-mtiah lower h10 than te mlar phsisologic cfO Xentrou'n tl neleaved h . in another aspe, the disclosure ftetires a ceilipositon contprising a pluralit\ otisohdied n xdale w\herein each anrbod,\ ONO phuralh cnipnrss Ito atigen bImduty sies w he each of the antogen umdmn te mOidependemOv anbmd to ree 0I) humnnn COt hsaor uInctca ed hu man (35 ' W " tnd wherein t dh presence N phnioloe leeb ofuncleaed hr. the anibodie of the p lhty paa or cotmpletety ved and Sequester pathophyskOpie leel of free C5 when admimnt ed at doses aebievun molar Oas values substantially lkwer than the miolar phyinologee concentration ot utme leaved ht'S Sit Ao' asect the discloslre fetdures an sonated antibody conmplisvm a Iist anugen-bndm te nd a ' amigen bindmg tl, whh binding site r eti can Bid to As human On hC : or uncleared human 5 1,51. and wherein, whan heNh antien-ing Ste are fulloeeapicd tid, e. under human phgologlcal conditions eg. in human blood or Srnn the fliowing 20 binding coniigranons mre possible f W the first amWentndmn sie hmd fee hMa and the second aangen-bdi ite hdunleaxed b( : {ll the ntz ane indie sie binds free hO and the second antgenbndetne bir ree hOM: or ii the ist antgennmdm; site hm;dsuncieared ht'S and the Secund atuenuamdin site inds free h~ju. 115 n y et another aspect, the disclostre features an 1solatedJ antibhody comprising a lst atigeinbind ing ste and a second antigeri-hidine site, wherein each antigen binding sie sndependemtyeon hind to free hunian (lI3 t{hr'ai or unclestred hunian 0 ihi 5 wherein edeb> ami enemdmeii siue independeetly v ca bind to irech hta wb Ii a i(o that is Vw thim i 25 x I0 * l tor, for example, with suhnanomila dai ainiimt x and herntin a phn padogieal selurion containng a pirtahits oi the antibodies at leas t5' of the~ antibedies ar e :tu the tlfrt mcos niguations: m the firt anvien-hialins ngeb'hrnd itke hOha and the second antinent indinir sire hinds unclear ed 60'S <iil the fIrst anitgerwbbndin ste hinds firee htSa ad tle second antigewttdit site hinds fr ee hO~a,:< i) the tuin senindioc she hinds unleaaed ht S and the second jt %. l lt:a amigen-bibng site bmds free bCa: ( e the first atiertming site binds unele-aved hiCS and -the second .antien-bming site is unbound: (vi the first antieen bindng Nw it bids hCSa and the scnd antigendng site is unbound; m i the tiTh antigen-hinding Nite is -nbound and the eCond aniln-huna an se binds incleu ved 5 t e K ii the tCi5 antigen-hindng site i unbound and the second aiiten-binding Ste binds M' ne and (iiii the first antigen-binding sie is unbound and the second uidi 'iO a ~t ixauboin d in another aspect, the diseloslre featrues an oated antibXd composeig 4ou anuewen dii haod mes where each aSngc:nNd o ne tudoeendy wn bid to 0 free h auman C i nc ASa or ku Ved human ( 5 ,hkC and whercin. in a molr escess vf unkav ed Q5 'eer Ca, the anbody inbilii V ai least 5&h hCedpne human nteui'phil actiaatin at a moar mtino -of 1: a niagewbimNd sne: hCa I somF embodiment ians ofthe anbodes deseibed herem, the contigurations -are possible undertbunnan phy sioehgeal conditions wihitidilx'oldeJ, If alie, hnwn Ca and C5 pttKtei in stme embodiems oftant 0$ the aniei deeribed herei, the antbod binds to free b -a with a Q that is less than i 2$ s: 10 \O (or, Nm N!mpAe. ,ith subanomaioar an iity n yet another apeet the disclosure t'et res an antibody tha (a I ids to tie _0 0 a (es , hC at w Rh suban meiota affinty and lis tM t'ree ia with un affluit- that is at least 100 1e1 av t let 10, 1 20, 130. 40. 1 410 i 10. .180, 190, 20, '0 , 2 0 T 300 A00, 00, 00% 7 800 R 1000, Y00 3000, 400. 54000, 60R ~000. 8000, (S000T MiN Yow o )od g10 re than As correspindinn aitiniw i uncleued (3 protein. t a physiologic ;omn itOt CntiSmi a plural&ha y of the 5 atnode for -a least 65% of the antibodes. only one antige-nbndog s-e of the antibody bids to iunleared CS proeina whereas the second antgen-bmlg site re-imams aalable toid to Cree 1a. (he hCi ea have tie amno idn sequence depited in SEQi $ ID l A another sp0 et, the disclosure features a method co reatin a in 30 aflteed uwith a G~a-associated camplenment disordet, the method comprising adrnnmstcrng 1tohe human a compition onprismig a plurality of isolated antbodies w hen each antibody of the phial ita comprises o an igen-bindi stes u h r each of the tgenI<mdmg \t imd-pentlemn t can Lind to free human C (hC0a) or uieleated human S t45), vhnoe a least ip o thle 0 ntibodle ref 20 t,. qOdy Ktit 0f thW human is admisierd 0 to h tim and Mherin ad~nt Nin'tro c1Ol the anltbode\ is effective0 to pa'lyo opee)hdal on"haS s OWwisyAfly woiosyietly bind ando sequeser nunorarm level of free S Ior at leas 12 day hi aiothe asett the di slosunre features a method frp treathin i a huanu 5 afflicted w ith a eomsplcreetasweiafcd disorder teog. a (i 5-asoceiated 00tnpklement disorder), the nuettld cemptisinig admnrinte'iig to the human a comnpostion camprising a phnrbty of ioled anubodtes w herein each antbod of te plurality r0vrtpises two atntge. p-lnm \iii' w hein eh of'the antrgen-bmtdusysi tdelpettdeitft cart butd Y i un tV 5 t % ato unelea\ed. hunan (75 ,1hS, 10 wherein at least 10 mg of the antibodes per lo bod> wdebn of the human i dministered to the humain nid wneeinr dnuinlstration oi the dotihodies is fe etfve Wo pamally or completely bind and sequeter uansttim lese of free C5a ter at tos 24 dap. i another ae t, the' disco retan a met hod 1o treating a hunan ISafflicted w ith :a comuplemem n-oclated dbsorder i e g., a C'5:asweiatted compk~emn disorder), the ethod comprising a t0er0101 k; toh human a composito composing a ptuatity et isolated antibodie herei e ch antibdy the plurality compros two antigen-bmding stes herei uch the amign-bmdn stes dependently can bind to fre humn GOa (AN or 1nedeav3ed human C5 hO, K 20 w herein the antibo\a uKe dninistered at a dose sufficient to: ta) achieve e molair (max values substaiu lly 1 er than the molar PhISW lOec onenmraton ot umielceda hGS ad 6' oai tlly or corn le1els\ bid and SegttONter tnlgritri leveis 01 ree A ant leas0 d In another aspect, the di s.1os rc h'eatutes a method for treating a human 3ffadteted with0 a C0vtpiemnent-rss0eclated dibrde { %~g , a $-dSS0tittd -'otriplernet disorder the meth~od comapnisi adnimtering. to the human a composition comprising a pluralt) ofilidled antibodies w hern each amtbody OW piu'autn ceimprinses two antigen-binding sies, wherein each of the an tigeeindmg S stOS independently can bid to tiee human t 5u tht Si M ouneleaved human W 13(h ), 30 wherein the atibodies are admintered a doe sufficient to: at achieve tuor Gmax values substantially lower than the muolar physiologic concentration of' uncladved hG and (iA paralix lo completel\ bind and seqester nogram levels f fRee CID Ao at 4eas 24 dQys n anher aspect, the d eloure fatres a method or tretnig a human affected with a complement-asociatcd diordet (e g. a Ct- soeiated complement order, the method comprsing administering 10 the human a composition comprising a pluraitv isola n bin each amdsld of the plurality 5 -eoomprse tuo vin-mbg stes where each Q the amoni omding sies irdepemderdv can bNd to free human CSa IhCTa} &r wieleaved humn 5 (h'S1 whereim the anthoPe\ are admistered at a dose sfficient to. a achksc molar Cmrt A aines substantial lower than the noor plsiologie concentraon ot metlla Cnd a i pa ral or completely bid and sequester pathophysrologte e0 )eb of bee C~a. it is understand that any of the eonposhions (e coiprisinig a pumabl of aanbodies) or isolated antibodies te. dha itelm ine in esen'ne of C5S or molar escess of CS. a free Fe b arm carpable of bindinw to free CSa. described herein can be: (ali itrmu lated us pharnmaceutictal comnposmion\ in asedTatie e wth the disclosure. thb) is meided m therapeute kits (descrbed herem om r t inuded In the preilled 6y unes deseihbed herein described the working examples provided hei, the minrtors he, also diiseeved an anibod. WNHO (see beon that not only bmds with high affinity isabuantomotar afftity) to i ce hC.5abut a ecain exeseen neleawed CS 20 s iubibis tnnal comokement complex t CAM ttornnatio ain a dose dependent manner, Even at concentratins o the antCat anhlbodv in grea te than 0.5>9 tod excess f (75, however miribition of TO isa not complete. While the disclosure is bs no means limited by any particul thry or iechanr 'f non, the aanbody m: inhibit T1CC (ormnn by bihng to at least a fraction of unceaed C5 and pi latemnimg its cleave age and/o th erwise preventing the sucesse 'u asciation of CS with additional TC components. The oenors apporecatd that sNEh an antibody v useful tting eomrienvmssociated dsorders, peea ,sn Sa pay a sigticaint role and the C b-aoon g T C may pla a lew substantiale Such disorders can include, ent., sepsns acute respiraory disttess sy ndront (ARDS), septic 30 shoek anti -phospholhpid~ sndrxone, catastrophic anti-phospholipid syndrome, disnimiated intravauscular coagulation, hupus neobriislCe~asture's Syndrome, burn or severe burn, asthma, HIEILp syndrome (/Hemok ti anerma Elevated iver enfiCmeo and no laelet count iamain need pamn '5Oamediated nutropei. ag -einted macar erdegnein t A f) ehrneibraiyb diese, ad thenmatodi arthtis. z he inventor$ also appreciated that use of such an amilSa antibodyy to treat titese conditions amnong others. .ma provtde an even mnore benetilidi safety profile as S cotmpared to use of terminal complemnem inibitry drugs As noted ii)ab0 eOne etale osequence\2 etin ititmmal >Ucpemnt~ colmnm such as Ct. cx, Cd, (7 Ch*. or &9 is decreased protection by the host inirnne system agailst thle eneapsdate~d bacteri that termi nai complement erdi narity l sos - .for example. Ammiera an/arude and lvisweria aoarrhtuae As the anti- (75 antibodies 10 descr ibed in this section inut the ( a-mediiated in arnmuutry response, but do not completely inibit the formiatnen <t the te rnmal complement complete that lse those eeapsulated bhcteri a, patients ieeun therapeutics ami Su armibody descrnbed heremt may not require a protetiv e vaccimation,. e ge a vaccinaion against Nerrsr/ owciiy f/at and Skkssw/u ygoncrrhecm. Putat ihiin of the 'FCC wtuhile not IS wholly abroatrm terminal eomnplemnt' unti-tterctbial response, ma in huet reduce Tvcc-htduced ntftamation as tisue injry, iThe parties 'l CC inhibition, in combnation with inhibition uf Cau, is behieved to make the anti -GM antibody an even more po tent uni-inflammiator e omtpound, \ceodnulv. in another aspect. (he disclosure fdatures an antzbodv or annsenw :20 binding namen mereof that bimd\ to te 05. w herein the free C~a is human Cua hav ing the ammno acid sequence depicted in SFQ ID bN w hereim the antibody inhibits the hmndmig of G~a to G~a receptor, and. w herein the amtibody pairtia lA inhibits formationt of the terminal eOmp~flemfentt compe\ iTC' P Puia mhibinon bI un ant Cta utnbody' or ainten-birabug fragmemt ther-'of deser'bed herein can bce ga 25 onpleument activnit that is, in the presCe of ibe an~d , I p to. or no wtete than. 0 (e g. ~', '0,-~s 60 55. 5 45, 40, t5 . r '5 of the complemet actiny m the abwence of the' antibody et (nt enbintdhAip frame thref'n om enbodncnts rho antibody or antieu-bing fragment thereof hinds to 'free G Sa ie .. tree ht5a w ith a. robnanomtiara affinity In some embodiments the antibody or 30 antigen -binding franment thereof has an aftinity for free C ia that is at least 1 00-ibid cr eater than the corresponding aflimita of the antibody or atigen-bmnding fragment for uncle aved Si lnotu0e embodiments. he arnthbtby or anudgen-binding liacinent thereof! minhis b3 at lest 50% tormation of 'fCC at cuncentrations exceeding :w0 (o, 210, 220, 230, 240 250. 260. 270 2hP 20, 300.t 320. 340. 360d 390. or 4001 or It u more i pg/mt as measured usm a CI 0eq away in some mbedents the antibody Or atgeninding ragnent ther cof Lnibits by at least 50% clsical o n n nTWahv pathwny acti ntin a t conerntra tioin e n ( ne , 01, Yn, 130 330, 2.$0, 6 '. 270, u0. 300, d", e0 3 0, a or 400 or moeruN as. s ueaurued usi tie \\iesabI Classical Pathwa Completenm li as described n the woca ag 4eanrt es in another aspect, the dsclosure fearutes a Nethd for tratig a I unan alieted nwith a complemntitsissociated disordeT e a ( asoiated complement disorder ot a complemetit-asoeted imflammatory dier.det T ihe miethod incudes adtnistein to te bUrar att effetiy antrunt of In antibody o attiel dibid tiagment thereof that inbits the bindina, of CSa to Ctu tee'ptor. and w herein the anthodw paritalv itinbnt fortion K the teromna eny.ememt eotniple (OIK. See abe he order can be any those know n the art or derived here. in aotherI aecet, the diselosUi feature> an iol<ted antibody or an 1 bmditntrnem there f that bi,10t a human GSa pelveude hang the amino acid sequence depited im SEQ M0 NO , but dos uno bind t the apha shain o unclema~X na ivae C5,u flereco t the 3.uuhdv or aanen bmdum Iragment thereof binds to the human (a polvpeptide wuh a Kr' that a less rak; kw 1: 1I 'M In another aspect, the disclosure features a. wl iated sntibdy or antigon 2( bindiutYnrugeitt thereof that bnd& I10 a humanria f'3ipolypeptide hasing the amino acid sequene depicted in SE'Q 1D NO I, but dues net bind to the alpha chain of uncleav ed,natie CS. where the hunbody Abit by at least t huan ( dependent hrman nentropi anxauaon at a molar ratio ot I I a antien -hninmg sitetGatirt >ome embodiments the antibod inhibit> by ,at least 514% bumnan C5a3 .2 qdepeudent m rhnan neutroph'd mrigratismi n uaa n whch WA nN oftanihd is used tt inhibit the neutrhord emnion activity of : nW b ana CSa as described in K ample 5 in somn embodiments the antibOdy does not compnri exemplary CDR pir 3 depicted in Tabile 1. in ome embodoents te antibdy W I not N3371 in ttame Ctnbhdimeats, art isolhted anibody or aanpgea-bodme rityraert tereot desebed herein hinds to a human Ca poibpeptide huaig the ano acid 'Sieuec. depicted in SQ 11D NO:? In sormse embodiment "osod anhbod yor anteen-birMglfagmnem thereof descrhed heeing ise alghtchant polyptide contp g: a Chain 2>4 CDR I comprisifng dhe amnino acid sequence depicted in SEQ LD NO:20: a igaht chain CDR2 ctoprisning Weano acid sequence depicted in SEQ FD NO:2 I: and a light chain CDR3 comprising the amino acid sequence depicted in SEQ D NO:2 in sonme embodimts, an isdated antibody or antgmebind in fragment 5 thecreol described herein comprises a light chain polypeptide comprising: a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:24: a ightchain CDR2 comaprising the amno acid sequence depied i SEQ ID NO:3: and a beigt chain CUR3 comrising the amino acid sequence depicted in SEQ 1D NO: 22 hi some~ embodiments an isolated anthbodyo ntigen -bindng fragment 10 thereof described herein conpries a heavy chain polypeptdc comprising: a heavy chain CURl1 comprising the amino acid sequience depicted in SEQ H)D NO:2: a heavy chain CDR2 comprising the ano acid sequence depicted in SEQ ID NO:29: and a heavy chain CDR3 conpriing the amino acid sequence dpiced in SEQ 1D NO:30, In some enmbodiments, an isolated antibody or antigen-binding~ fnrae Sthereof described herein conprises a heavy chain poyipeptide conpriing: a heavy chain CDR I eomring the umino acid sequence depicted in SEQ ID NO0:28; a heavy chain CDR2 comprisin the amino acid sequence depicted in SEQ D NO:67; and a heavy chan CDR3 comnnsing the anino acid sequence depicd in SEQ D NO30. 4t somue embodument. an isolated antibody or antigen-bind ing fragment 20 thereof describd herein comprises a heavy chain pobypeptide comprising: a heavy chain CUR I conimsing the amino acid sequence depicted in SEQ ID NO:28: a heavy chain CDR2 conprisng the amino acid sequence depicted in SEQ IFD NO:4: and a heavy chain CDRI conrising the amino acid sequence depicted in SEQ ID NO:47. In some embodiments, an isdated antibody or anigcnindng hragment thereo described herein comprises a light chain polypeptide comprising the amino acid sequience depicted in SEQ ID NO:37 or SEQ iD) NO:36 In some embodimens an isolated antibody or antigenmbinding tfirem thereof desrcrib herein comprises a heavy chaip polypeptide conmpriIng the amino acid sequence. depicted in SEQ ID NO:27 or SEQ ID N:3. 3 A some embodimen, an isolated antibody or amtige-binding fragment thereof described herein comprises a light chain pokypeptide comprising the amino acid sequence depicted in SEQ iCD NO: 37 and a heavy chain pobypeptide compris ing the amino acid sequence depicted in SEQ ID NO:27.

n sone YmbabDiments, an iselled afnbodv or anthret-bindita frmnret therewf dutsibed herein eumpiM a lihht AhaiA p nptide cOprins. the a nlo acid sequence depleted in SEQ ID 11336 arid a hen\y chain polypeptide conprishig the amm acid sequence depied im SEQ ID 0;!. 5 hi oncme mblidimetit. in stated antibody or antigen-bndirg 'ragment thereof described heeim eenipurses a hght hain poly tpie.u otempng the ammto acid sequenice depicted in SIEQ ID N1'1 or SFQ I D N10:12' in some embdiments, an . ecdaed antibody or anusi -tndimg fragmeti there0f described hein c rupnrs a hea\vy chlaitlyp01 eptide eonmpr~si the alln1o 10 acid sequence depicted i SEQ ID W 2' of SEQ )D 'D. Ina ne embodiments an elated antibs at oraaienbmun hagment thereof described 7her compares a lght C h Vm polypepide composing the am1 acid sequence depicted SEQ D NO 1 and a eay chim poly veride compoing the amio acid sequence depicted m SEQ 1A) IS n some embednmlen.\ an ilk 4 e antibhody or neietr-binditnu fratasent therotf desriube~d Iteem CumllnseS a liht chaim poy pepide eirsnmg the amino acid sequence depiceed in SLQ ID NO ' and a heav c ham polypeptide comprsm the ammi acd itequenle epicii m SEQ ID 11:25, ht sme Cbodunenta an Wand antbodor attie -bidog lamsmt :20 there described heein enprises a hght coon polpenPu i c;mpmsing the mno acid sequence depicted n SF0 ID \0:42 r SFQ D NA 4 10 h1 some embodinmemns i an Slated anibodv -'r amigcn -hindnig frgatt thereof descried hereim prises a heare i< pepdde o" arprisg the aio acid sequence depicted in SEQ ID NAWS ar SEQ ID Nv 0:3. hn sme emrboditren zs an slated antibd or ansigen-bindimg fragment terageodecrbed herein catmpriiseS hu hin psolpeptde omprising th~e amino acid sequece demeted inSEQ CD NO0:42 nd a heavy etnan polpeptide comporig the amino acid sequence depleted in SEQ ID 110:27 in sonic embhodimiets an nsated aibody or amnti-nbindrag fragmreni 0 there desbed hereinos a lgh cnhai pol)ypetide compris inly the mino acid sequence depicted in SEQ I D NO:40 and a heavycr a polypeptide comiptsm the ammue aciad sequence diepicede in SEQ 1 I 11:3 In some enbodtnerni an isolated antibody or ange~tn mdg franmemt thei derived herin comnies a light chi polpeptide theen Eamino acid sequnde deriated in E DN:I ~l a e~Vcl.P ptie eCOtpS p flf theaminacideqae.Adepicted in SEQ ID WE, a".nbe ld100 oany Un 01ue aS ~ndan sn n some embodiments an nolated antibody or amiAenrbodmg fraocm thereoi described herei scores a heaht hain polpepde comprising the amino acid seqeuee depcd l SE 10 \ W19 try! a hem3"- ehAam o6 pouecop the5 in acid uence Nw depinca d in SEQ ID 140A5,S in some cmbo'dimtc an idated antibAY or waan-bm'uT tagmeni thereof desertbed herein~ imrngs :t bVh cham polvpeptde comprlmg the atmno aid requeonce depiewd in S0 ID N,1 7- and a heavy ciNtm noloepid compusnt 10he amino tai sequence e depwctd mn St Q 10) A 04 in some enT menn an oel ated antibody or antiget-i-bdg frawmeto teref described heem compnses a bght chain polypeptide comparing the ammno th acdquinc depted in SEQ ID NO i' and a hea, Shain poiyvieptrde p m samve d iquence depted m at ID i0: O in some em bo>dunent\ au wIited antibody oan ne mbondteg fianmenm teef described helrei Cmpusel & ~ hh ehni polyppode oepiing the amno acid sequence depcted n SlQ iDl \N:' er d a D hea c h1 Nome ermbodimem an eted] antibodv or amtigen -boi g frgment tiereof described hrein coumpries a liht t\ay p nchan 0p d No mpsing the aln acid sequence depicted in SEQ I NO57 a wQ IW NOA) i h swme cbodi ments an slated nubod er antien-bindmg r.mnut thereof described herein comprises a bght c ~ham poyppude c ompsemg the amino acid rnience depicted inSE ID 0:45 or SF0 d ) 40ye:49.lydral s InnsomegnbDe ans an a SEIDNO rr cred escrbed erein m rine ught can p perde .."rd asng t ino h n ci qen e soce ina SE D O th anoadaequence depiced i SEQ ID) 0:9 in me dimeas ano Mitchi amtbodv oramiginid framei theofderibe he ' rein com prses a light chaim poiypeptide coming the ambno acid sequence depicted inEQ SE) D 42 or SLQ 1 10:40. a woeC mbodiments, an isolated antibid( ordangershmg fragment thereof descnbed herein co n ses hea h ebain pehvpeptide compnsmg the amio acid sequence depicted in SEQ D NOM m SEQ ID Nll a hi mne cnshadmie' -i 'end andtbody ir antigatVb&d g f menpi thereof descrnhed terem camnses a eght chaim pci pepotd uopriing the aminW0 acid sequeuce depicted in SEQ0 '0 4OI and a heavy ehan polnpptide composmng 0 te aminei acId seuWCe depictd in SEQ ID 1A0:45 In sonmcenrmbdimeuts an i 1 al antibhdy or aangen-uir ldagmhent thete)Ot described bere bprses a 3 b cghaien polvoentide cepim h tn acid squencedepice m ctQ D10NO4 and athea:vy ciaqmpetidhLom' an oiated imitbaiy oranuen ddm foryragnnt thereof deribed heM ind to ht wu u a K that is less than ~ a 10' V in sonc Wmbodimets an isolated anhbodl or atrgerbodig agentt thereot desenibed herein >1mds to hC~a suth a~ \a that is less than fr a 10 M bl scome embodu netti an elated antibods or tint ii -tdng. fIdammi 20 thereof (desCenbed heremn binds to hC5a with -i n that is less thum 3 .x 1" > \L in some imbodmemts an slated antibod or anigeen -bondi fragment thereof descrbed herein hnds to h(Ba Woh a K tat is less than 2.5 x i 1 11 In sonme embdiments an isolated undl Jr ot anagend tragment theredotdesebned herein hinds to hCSa w nh a K ta is lA han L A x 10 N 2 ni some :mbodimc'r an related ntibeds or antigen-bindo myragent thereof described herein hinds to hC5a with Na ntht 35 leu man 1 0 a tf0 * M In somtie ebodime~ns an ated antibody eor iat gen-bdui tragmemt thereof' described herein binds to bhtsu with a in that is less than 5.0 a 10 " \. In snic emodinst an antibodn Ibibits by at least 70 0" at lest 75 0. 5, kor A5 or gretes % human CM.pe Yndent hunun . OPh acti as a ' rmotbr rato i I (aigen-inding sIeCSal ii some embodiments the anybody does not conjqris eyoiir CDRiV' does ot cmprie xeplara CDR paing ? depicted in T able 1. in some einbodtient heantibody is not If131 In Vet another aspect the di sre features an isohed antibody rmU gen hindi fagmer thereof thao ompses a light chain CD set a set torth in Tae 3 rTble 7 for example, the isolated antibody oF anngenfnndmg tragent thereof can eompnse a lght ehamn plpeptide comping: m a ih cab:I CDR I comprising the amma aid uen e depicted i an tD N: it ai:iu caIm CR comprnmg the ammo acd sequenee depicted in SEQ 1M N(:% and a igh chain CDR, comparing the anno acid serpience depteed in SEI Q ID N0,1 T ii) a Ught chan CDR I compring the amino acid sequence" depicted in SEQ ID NO: 1: a light chain (DR2 comrino th amins aci eedsequn de t in SEQ I) NO:157; nd a lighi 10 chain CUR3 comparing the aminu acid sequence depicted in SEQ D NO:158: (iii) a light chain CR c omprising the amio acid sequence depicted in SEQ ID) NO:l : a light chain CDR2 comprising the amino acid sequence depicted in SEQ IJ NO: 16: and a lit chain CDR3 coi:iOing rhe amino acid sequence depicted in SEQ ID NO:166; (i a light chain CDR) comprising the amino acid sequence deMctedin SEQ ID NO:172;a .liht Chain DUR2 comprising the amine acid sequence depicted in SEQ ID NO:73: and a lght chain CDR S crmprising the amino acid sequence depicted in SEQ D NO:174; q a light chain CDR i comprising the ainno acid sequence depicted in SEQ iD NO.4; a light chain CDR2 comprising the amine acid sequence depicted in SEQ ID NO:$5 and a light chain CDR comprising the amino 20 acid sequertoc depicted in SEQ ID NO0:86; (vi) a Iight chi> CDZRI comprising the amino acid sequence deputed in SEQ I) NO:92: a liHt c CUR2 comprising the amino acid sequence depicted in SEQ ID N0:80: and a high Cham CDR? comprising the amino acid sequence depic ed in SEQ ID NO v light chain C 0R1 comprising the amino acid sequence depicted in SEQ ID NO:8: a lit chain CDR2 m ii &Phe tin. acid ,equenc dete n SEQ ID N. and a lighta n CUR3 comprising the amino acid sequence depicted in SEQ ID NO:9: viii a lght chain CDR comprising the amino acid sequence depicted in SEQ ID N:95: a light chain DR2I comprising the amino acid sequence depicted in SEQ ID NO:%: and a light chain CDRt comprising the amino acid sequence depicted in SEQ 1D. NQ7 30 (in) a ight chain CDR comprising the amino acd sequence depicted on SEQ ' NO:99 a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO 100: and a hQ chain CUR3 comprisin the amino acid sequence depicted in SEQ I 111 a .ight cham CoR] eompnsmg the amino acid sequence dep-cted in SEQ.1D \NO:4, a ight chan iR2 composing the ammo acid seuence depicted i SEQ IL \AM and a ligh chalu 'DR3 comutising the amino acid sequence depicted in SEQ ID '.N 10;0 a light cbain CDRI eqmnrsm the amme acid segeenc Jeidp d in 5 SPQ 1) NO105; a hhht chain (. 2 cempriing the ammo cid sequene depicted n sFQ ID MO 10; and a IQt chain D3 conprismn the amno acid sequence depicted in SE Q 10 N0 107 (ii a heht cbain CDR I. comprisinga the aumno acid serpuence depted in SEQ ID N4092; a hszht chain CDRl coempring the amino aid sequence dpeted in SEQ ID NOQ: and a ight chai Clo3 compiling the &uano 10 acid sequence depicted n SLQ I) 0,: ii a ight chain LDR ecumpising the ammno acid sequence depicted in SE Q ID NO:20; a light chain (.1DR ' coiprin~g the amo acid sequence depicted in SQ I0 NO: la and a hnht cham CDR3 cmprising the amunoaid sequence depcted in SEQ I) NO 1 o ixi a bicht chain CDR 1 comnriinsi the ano acd sequence depicted in SEQ I D NO:20: a light S chain C.L.R 2 mpnisg he ammn acid sequence depied in SE ID \ 1; and a 1mht chain 0DR3 *ommo the amno acid sequence depicted m SEQ D NO 113 In some embndinents the antibody or :antgennbindmig haxgent therckflcompnsimy Ghe light chan CuR set ao comlpnses a han chain pofypeptid compnimg any one of the hanv chain CDR set a set R in Table 8 :2.0 In another aspect the discleure feature an isolated antix dy o' antigew binding fraument theredn thai compares a heavy chain CUR sei as set fonth in Table 3 or lase 8 For example "D soine embodnmens an violated annh&dc or aange bindingimumnent therotf de bed herein comprises a Way cao povptpide comprisine: 0 a he'9 chain CUR I comprisig the amnni acid sequence depiteed in SI 10 NO: a hcax chan CURd rnpansmn the amio aid sequence depnited in SEQ ID NO:'44; and a heavy chain CDR 3 co uprising the amino acid sequence depicted in SEQ ID NO:1; (iil a heavy chain CDR 1 cmprising the aino acid sequence depicted in SEQ I) NO:28; a heavy chain CDRd comprising the amino acid sequence depicted in SEQ ID NOW:6 and a heavy chain CDR3 comprising the amino 30 acid sequence depicted in SEQ IDNO:; (iii:< a heavy chain CUR 1 comprising the amino acid sequence depicted in SEQ 1) NO: 160; a heavy chain CDR2 copNrising the amino acid sequence depicted in SEQ ID N0 :161: and a heavy chain CDR3 comprisun the amino acid sequence depicted in SEQ ID NO:162: (iv a heavy chain CDR 1 cmprsing the amino acid sequence depicted in SEQ ID NO:]168; a heavy chain CDR2 comprising the amino acid sequener. depicted in SEQ D NO:169; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ l) NO:70; (v) a heavy chain CDR comprTing the amino acid sece depictd in SEQ .1D NO:P?6; a heavy chain CDR! coming t h amino acid sepience depicted in SEQ 5 ID NO: Iy; and a heavy chain CDR3 compnNg the amn acid sequence depicted in SEQ IID No:8; ( vi a heavy chai CDR I conmsing the amino acid seqyune depicted in Si t) NO: 1I5: a heavy chain CDR2 comprising the aminc acid sequence depicted in SEQ 'D NO: i16 and a heavy chain CDR eumprising the amino acid sequence depicted in SEQ ID NO; 11 7; (vii) a heavy chain CDR I 10 comparing the amino acid sequce depicted in SEQ ID NO: I19: a heav y chain CDR2 cornprising thn amino acid sequence depicted in SEQ ID NO:120; and a heavy chain CDR3 comprising the amino acid scquec depicted in SEQ 0D9 N:121: (viii a heavy chain CDRI comprising the amiu acid sequence depicted in SEQ iD NO: 11: a heavy chain CDR2 cuoprising the amino acid sequence depicted in SEQ iD IS N I: 1 .an aheay chain MR3 3: an a h a cha R3 comprising the amnino acid sequence depicted in SEQ ID NO:i I?: (Ia) ai heavy chain CDR(1 coriing tihe amino acid sequence depicted in SEQ ID NO:) 15; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 124 and a heavy chain CDR3 conmising the amno acid sequence depicted in SEQ ID NO: 117:; x) a heavy chain CR I 20 comprising the ainkno aci ep SEQ ID NO119 a heav cin R2 coming the a cid sequence depicted in SE Q 1 6 a heavy a KDR 3 comprising the amino acid sequence depicted i SQ ID NO: 1 W an0 a heay hea chai n CDR comriing the amnno d sequel nc depictdned in SEQ) ?D NO:1 1 heavy chain ODR 2 comprising the amino acid sequence depicted in SEQ IDN: NO '19; and a heavy hamN C DR3 comprising the auno acid sequence depicted in SEQ ID NC:11; (x a h ha cha in CDR comprising the amino acid sequence depicted in SEQ ID NO i 13 a heavy chain CDR2 coqmprisita the amino acid sequence depicted in SEQ ID NO:132; and a heavy chain CDR3 compryiing the amino acid sequence depicted in SEQ IL) NO: 133; (xiii) a heavy xcain C DR I 30 comprising tie c amino acid sequence depicted in SEQ ID NO:2 a hea chain CDR comprising the amino acid sequence depicted in SEQ ID NO:4 and a heavy chan WKYR enotsim; he amino aen sequence depled inSEQID N O F c a havy dan OR om ping the ano acid sequence depicted in SEQ IDNO 134 heavy chain CDR2 compo ing the anio acideuence decteddi SEQ 1 NO:137: and a heavy chain CDR3 comprising the arniO acid sequence depicted in SEQ 1D N: 13 In some embodiments, the antibody or antigen-binding fragment thereof comprising the heavy chain CDR set also comprses a light chain polypeptide comprising any one ofthe light chain CDR sets as set forth in abl 5 N anther aspect. the :disclu$Ore features an isolated antibwdy or attgen binding fragment thereof comprising a lighn chain CDR set rom Tal 7 and ins cognate heavy chain CDR set as set fArh in Table 8 hn another apect, the disclosure features an isolated anvibody or antinbinding fragnent thereof comprising a paired fght chain and heavy chain CRP set as set fwuth in Table 3 or Table 9. For cxamplc 10ain some embodiments an isolated antibody, or amgen-bnding fragment thereof eSribed herein comn t i a light chain CDR 1 coming the aino acid sequence depicted in SEQ ID NO:140. a light chain CDR2 compriing the amino aWid sequence depicted in SEQ ID NO:W: a i ght chain CDR3 comnprdi the anino acid sequnce depicted in E M N 142; a heavy c hain CDRI comprisi the amino Id acid sequence deted in SE Q ID NO:I ; a heavy chain CDRP cnmprising the anino acid sequence depicted in SEQ ID NO:144; and a heavy chin CDR3 comprising the amino acid sequence depicted in SEQ ID NO:17; (ii) a light chain CR 1 comiprising the amino acid sequence depicted in SEQ D NO)2; a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:: an a hght 20 chain CDR 3 comprising the amino acid sequence depicted in SEQ ID NO:22: aheavy chain CDR I comprising the amino acid sequence depicted in SEQ ID NO:2: a heavy chain CDR2 nomprising he amino acid sequence depicted in SEQ ID NO67 and a. heavy chain CDR comprising the amno acid sequence depicted in SEQ ID N:3Q0; (iii) a light chain CDR comprising the amino acid sequence depicted in SEQ iD NO; 156: a light chain CR2 comprising the amino acid sequence depicted in SEQ ID NO; 157: a ilgh chain CDR3 conprsing the amino acid seuenec depicted in SEQ iD NO:I 58: a heavy chain COR I comprising the amino acid sequence depicted in SEQ H) NO: 60 a heavy chain CDR2 comparing 6he amino acid sequence depicted in SEQ ID N: 161; and a heavy chain CDR3 conmriing the amino acid sequence 1 depicted in SEQ ID NO:l62; tv a iht Chain cDR i coprising the amino acid sequence depicted in SEQ ID N 0:164; a lt Chain CDR2 conprising the amno acid sequence depicted in SEQ ID NO: 165 a Ig chan CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 166 a heavy cain CDR comprising the amino acid sequence depicted in SEQ ID NO;168 a heavy chain CDR2 comprising the amno acid sequence depicted in SEQ 1D NO: 169); and ai hea±vy chin CDR3. compOsing the amino acid sequence depicted in SEQ UD NO:170; (v) a igt chain CR1 comprising the amino acid sequence depicted in SEQ D N) :172; a light chain CDR2 cornprising the anino acid sequence depicted in SEQ ID NO ?3 a ligh chain 5 CDR3 comrising the amino acid sequence depicted in SEQ VI MO:7 a heavy cain tD A 1 comprising the amino acid sequence depicted in SEQ) 1D NO:6: a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ 1D NO: 177; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ .1D NO:17& ( gh aCRI cmpriliw the aamln aci sequence depiced in 4 SEQ JD NO a ligh chain CD2 comprising the amino acid sequence depicted in SEQ I) NO:9: a igh chain C oR3 cosn the amino acid seqpence depicted in SEQ WD NO:90; a heavy chain CDR comprising the amino acid sequence depicted in SEQ ID NO: 119; a heavy chain CDR2 cwmrising the amino acid sequence depicted in SEQ ID NO:120; and a ha nychain CR) comprising the ano acid sentence 15 depicted in S [ AD NO 2; (vii a hight chain CDR 1 compnsing the ammn acid sequence depicted in SEQ 1D NO' :10 a ligt chan CDR2 comprising the amino acid sequence depicted in SEQ HD NO: 106 a 1ihr chain CDR3 comprising the ano acid sequence depicted in SEQ ID N(O:i M a heavy chaim CDRi cojmising the aiuno acid sequence depicted in SEQ ID NO:115: a hevy chain (2A. comprising the 20 amino acid sequence depicted in SEQ .1D NO; 124; and a hetv chain CDR3 comnprisin~g the amino acid sequence depicted in SEQ ID NO' 17; (viii a light chain CDR I comprsing the amino acid sequence depicted in SEQ ID .NO:84 a ligh. chain CDR2 comprising the amno acid sequence depicted in Q) I.D NO:85; a light chain COR3 comprising the amino acid sequence depicted in SEQ MD NO:86: a heavy chain : CDRc 1 comprising the amino acid sequence depictd in SEQ WD Ni:115: a heavy chain CDR2 comprising the aiino acid sequence depicted in SEQ 1D NO:116: and a heavy chain CDW3 comprise ng the amine acid sequence depicted in SEQ 10 NO. 117: (ix) a 1igh chain CDR 1 comprising the amino acid sequence depicted in SEQ ID NO:20; a ihthi in (2DR2 comprising the amino acid sequence depicted in SEQ 1D 30 NO:s 1:) a iht chain CDR3 comprising the amino acid sequence depicted in SEQ TD NO: i ii: a heavy chain CR I comprising the aminw acid quence depicted sn SEQ ID NO:16; a heavy chain CR2 comprising the amino acid sequence depicted in SEQ NO; 1 37; and a heavy chain CDR3 comprising the amino acid sequence depicted i SEQ 10 NO:118, (o a light chain CR 1 comrising the amino acid sequence depicted in SEQ ID NO:no: a lit chain CDR2 comprising the amino ad. sequence depicted in SEQ ID No:2 i: a ight chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 113; a heavy chain CDRi compriing the amino acid sequence depicted in SEQ iD NO:28: a heavy cAtin C DR2 comprising he amino acid sequence depicted in SEQ ID) NO:46: and a heav chain CDtR 3 comprising the amino acid sequence depicted in SEQ 0 N0:47: xi a ig t chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:99 a igh chain CDR2 comprisaig the amino acid sequence depicted in SEQ ID NO:M1R0 a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 10l1; a heavy chain CDR I ) comopring the amino acid sequence depicted in SEQ ID NO:1 a heay chain DR2 conmprising the amino acid sequence depicted in SEQ ID NO:126; and a heavy chain COR3 nmprising the amino acid sequence depicted in SEQ D Nt:127: (xii) a ight chain CDR oh mprisirg the amino acid sequence depicted in SEQ ID NO:93; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:96: a I iht chain CD R comprisIng the amino acid sequence depicted m SEQ D N:97: a heavy chai CR1 comprising the anu no acid sequence depicted in SEQ iL) NO: 115; a heavy chain CDR2 cmprising th ano acid sequence depicted in SEQ ID NO;144: and a heavy chain CD) R comprising the amino acid sequence depicted in 0 UaDSEQ IDNO _0 xJii4 a light chain D1 comprising the amino acid sequence depicted in SEQ ID NO:140; a Nigt chain CDR2 comprising the amino acid sequence depicted in SEQ ID WN% a Klh chai CDR coprsig the amiaci euec depicted in SQf D NO142: a heavy chain CDR i comprising the amino acid sequence depicted in SEQ D NO 113: a heavy chain CDR2 o mtprising the amino acid sequence depicted in SEQ ID NO:123 and a heavy chain CDRcl cmrising dhe amino acid equence depicted in SEQ ID N:1 7; (xiv) a light chin CDR) comprisin the amina acid sequence depicted in SEQ ID N:105: a ligh t thin CDR2) compisingP the amino acid sequence depicted in SEQ ID NO:106; a ight chain CDR3 compr ing the amino acid sequence depicted in SEQ ID NO;107; a heavy Chain CDRI cuprising the amino 0 acid sequence depictd in SEQ 1D No:11 V;a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ D NO: 123, and a heavy chain CDRI3 comaprising the amino acid sequence depicted in SEQ It) NO: 1 i7: (xv) a light chain 2DR 1 comprising the amino acid sequence depicted in SEQ ID NO:92: a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:89: a light chain ;4 CDR3 copim the amvinti acid sequence depicted in SEQ ID NO: 108; ai heavy chain CDRI comtpri ing the amine acid Sequenttce depicted in SEQ ID NO: 11: a heavy chain CDR2 conirising the amino acid sequence depicted in SEQ ID NO: 44; and a heavy chain CDR3 comprising the anino acid sequence depicted in SEQ 10 5 \NO:.7: (vil a ig t ain CDR coming he amine acd sequence depice o in SEQ !D NO:92:a lih chain CDR2 comprising the amine acid sequence depicted in SEQ ID NO:89 a it cAn CDR3 compising the amino acid sequence depied in SEQ ID NO:93; a heavy chain C')R I comiing the mnu acd sequence depicted in SEQ ID NO: 11: a heavy chain CDR2 compivmg the amine acid sequence depicted 10 it SEQ D NO:123;:and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 1 7;A (xvii) a tan C DR1 comprising the amino acid sequence depicted in SEQ ) ID:92: a lighi chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:89: a light chain CDR3 cumNiing the amino acid sequence depicted in SEQ D 40:93; a havy chain O DRI compising 'he amino acid I5 sequence depicted in SEQ ID NO: 11 5; a heavy (in CDR2 Comrisng the amino acid sequ.ee depicted in SEQ ID NU:144; and a heavy chain CDR3 Comprising the amuno acid sequence depicted in SEQ ID NO:1 7, (xviib a light chain CDRI cQmtpriSIng the amin acid sequence depicted in SE ID NO:84: a light chain CT2 cumprishi theano acid sequence dicd in SEQ D NO:85; a ight chain CDR3 20 comprising the anno acid sequence depicted in SEQ ID o:103, a heavy chain CDR comprising the amino acid sequence depicted in SEQ ID NO:115; a heavy chain CDR2 comnrisng the amine acid sequence depicted in SIQ ID NO: 129: and a heavy chain CDR3 conrising the amino acid sequence depicted in SEQ ?D NO:1 ;17 (xix a 1ight chain CDRI comprising the amin; acid sequence depited in SEQ D N 5 a light chain CIDR2 compising the amino acid euencc depictedn NO:96; a i h CDR3 coprising the amno ci s td in SEQ iDP3 NO97; a heavy chain CDR 1 compising the amino acid sequence depicted in SEQ ID NO: 1 a heavy chain CDR2 comprising the amino acid sequence depted in SEQ a hey chan C 3 comn the amino acid s equence depicted in EQ 01SEQ hea y :1 Q; xx Da eigh phitnCa depNOed2n SEQ id NA: a cit chain R2 comprisi ng the a cid sequence pt i depicted in SEQ ID NO:85: a ligti chain CDt3 comprising the amin acid sequc depicted in SEQ TD NO: 103; a heavy chain CDT 1 comprising the amine acid sequence depicted in SEQ ID 'NO:i 5; a heavy chain CDR2 conprising the amine .35 aidenieqe de Pe ID N: I O an avy Cnh coon EOin ov omprising eamino acid sequence depicted i n SEQ ID NO:0; a light cha n CDR2 comprising the amino acid sequence depicted in SEQ ID NO:>20: a light chain CDR3 comprising the amino acid sequence depicted in SEQ FD NO' ; a havy cn CR 1 conpi ngh ho acin aidenc e dep i cte in N'O: 1: a ai havy chai CDR2 omprniing e o amio acid sluene dict in EQ ID NO : 132 and heavychan CDR3 comprising the amino acid equencc depicted in SEQ JD NM 133 Ssome embodi ments. an antibody or mign-binding fragmenm tI ereof 1 ( com-prises a Paired ight chain CDR set and heavy chain CDR act as sat furth in Table 3 !n sonme embodnents, an anRbody or antigen-bindin fragment thereofcompises a pared 1lgh cbain CAR act and heavy chain CDR set as set forth in Table 2 For example, the disclosure features an anybody compriaing. i) a light cain CDR comprising the amino acid sequence depicted in SEQ ID NO:20: ni a li. chain S CDR2 comlprinig the amino acid sequence depicted in SEQ ID NO:21: and (iii) a light chain COR3 comprising the amino acid sequece depicted in SEQ ID NO:2: (iv ) a heavy chain CDR. I comprising the amino acid sequtenae depicted in SEQ ID NO:28; Al a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ i NO:4:, and via hcav chain DR3 comprising the amino acid sequence 20 depicted in SEQ ID NO:47, In sonic emibodinments, 'he anib ody or antigen-hinding fragmient thereof i a hig chain variable region st forth in Table 2, which light chain is paired with any one of the heavy chain variable regions set fhuh in Tabla 2. For example, the disclosure features an antibody (or an amigen-binding fragment thero 5 comprising: a) a eight chain variable region having an amino acid sequence comprsing the amino acid sequence depieled in SEQ ID NO:2 and b) a heavy chain variable region having an amino acid seqncc comprising the amino acid sequence depicted in SEQ ID NO:4. In some enmbodimnts an antibody or an 1 tigen-bninding fragment thereof 3 described herein cumrniscs: (i a heavy chain variable reion rework reion I comprising the amino acid sequence depicted in SEQID N:W or SEQ i) NO:T69 1ii) a heavy chain variable region framework region 2 conriing tIe amino acid sequence depicted in SEQ ID NO:70 or SEQ ID NO 7: and a heavy chain variabi reiotramework region 3 comptising the amino acid >euceft~lC depicted ini any one OfdSQ ID) NON:72 to 74. in some emb~odimentN, the anibodv or ant tgen-bindinga agentt teeotcomprise a heavy choun variable region franwurk region 4 comprising the amino acid sequtence depicted inSE ID NO:75, hn some embdime'nts, ihe anibdy or antigen-binding fragment thereofcmprises a heavy C hain V arable region Compvisoig thc amino acid quence depicted in any one o it) No:76 to SO The antbody heavy chain can comprise any of the heavy chain CDR sets ibed hrei. The hCavy chai variable region can be. in soa 'mbimns paird wih the variable region polypepide comprising ano ac--'id ieunce depicted in SEQ ID NO:16. 10 In some embodiments, an antibody or antigen-binding fragment thereof binds to a non-human Ca protein, For example, the antibody or amigen-inding fr em thareof can bind to mouse C0a and/or desarginated mouse C3a protein. In some d ts anisted anybody or aigen binding fragmet the can bind to mouse CSa (and/or desarginated mon uSCseCal and c mnrise:'fi a hght chain CDR{1 I cmprisng the amino acid sequence depicted SE ID) NO:54: JAM (i)ai chain (DR2 comprising the amino acid sequence depicted in SEQ ID NO: lii) a ligtt chain CDR3 compzri ing am ino acid sequence depicted in SEQ TD NO:56; (iv) a heavy chain CDR coming the amino acid seqNence depicted in SEQ MD NO:W, Cv) a heavy chain CDR2 comprising the amino acid sequcnce depicted in SEQ 10 20 NO:63; and (vi) a heavy ein CDR3 comprising the amino acid sequence depicted in SEQ ID NO:64, in some embodiments th anti-mouse CSa antibdy can comprise a ight chain polypepnide comprising the anno acid sequence depicted in SEQ iD NO:59 anod heavy chain popeptide comprisin the amino acid sequence depicted in SEQ ID NO:66. In some mbodiaent, an isolated antibedv orn amigeinding runent there described herein inhibits the ieraction between GO and a GSu receptor. the ina reeptor can be, e, c aR or C5L2 In somec emibodimnents an isolated antibody or atinen -bodi:ng'frame thereof decribed herein does not substantially inhibit comniemien mediated 30 hemolvis of red blood cells in vitro and or iinvw. tn soe enddimems, an isohaed antibody (und accordingly any amigem binding fragment thereof is a monoclonal antibody a hutmiamred antibody or a fuly human anmibody In somne yrobdimen>ts an neliated antibody or atgen-htndtog fragmemt thereof decribed htrein is seleceed fro9m the group eens rinn of a. tecombnant antibody, a smulje chaim antibody a diabody an intrabody a elemenzed or chimne anitobodty a demmned human aitth od' af FX +flrment an E d trhitment, an PFab t ragment, an PFab' fragmenm, and an W ab' h htmgment. hn some erbodimnts an ielated antbodx or antigen4inde frm thereof dcscrnbedk herein is iitispec~it e *),btpeci in Mhat the antibdy or frame bmids to a tet two different epit\pts the twoe different epitpes can be, c to differeem eintopes trom the same preiem e Ca' or the antibd can bind 1f to a fir st cpitpe trom a AiN protemn 1e g , a anJ a second cpitoe f'romn a. KeOnd in wme embodimtenta an iecated antibody r antisenbind g fra gment thereof described heremn eomprtses a heterologous moiety The hetet'olo'aus meehwty canbeeg asugar, For example. the umihady.o andgen-hedmisisx fr.gmen thereof can beO 4000 on a"NO inaoa m wwr Uad 15 at be giycosyilated. I he betere zous moety can be, e gt, a detectable label such as but nt knuired to. a thresent label, a lmineaen latbel, a heay metal label, a Krdioactic labet or An en:ymatic label. In some emibod imen 4 t5 an isohated amti42ai antibody Or triien-bmdinig fragment thbereof descrnbed herein is modified wiat a metye that imirov e\ the 20 stbibitatkm and/or retertion of the antibdv im chn'culatin For example, the nuohificanion can be P di>Wlatl orb hiatiu In .othe mhdbmenm the anu&5a antibody can contai n mialter ed constant regen that has .edeed. . no) etfeet timnetnon, as comprcf to the Ctltetor fiton of is correondm; unaltered constant reio, i some emboimrents, the ani a antibdy chains an ateed constant ?5rgon that has betweetn anoat 0 to abent 20{Y, of the ett(cctor iunletion of'the unalterd cnntm region hNetnpiarv embed intet ofuch dereased -ctheetor himenon antbodieoare decribe hein n terspe th ssure adature a i d anhbdyr aten bidngfagemnttef thatcroshiock the binding o aiw ne of theforegoe annthdes in y tnceraunpee the dsclsre iatures a. phradeutica etrtpositkan compisine one ormreo anyof the islate aanbodie orantigeinbinding fr'acmes tueol described heei and a pharmncertial -acceptabe carred iuent and/o excrrent in another aspet, the diselonire features' (il a n~ieieic ueid efleodili? onle or mor e of ans of the antibodies or antigenwbinding fragmremts thereof descibeJ herein, (I) a i etr of r1prising the niucleic acid,; ( iiil an ex ressiOn \ eetos cofiriring the seid and r (iv Ia cell comiprisig th li o v r no 5 another aspect the d l cNOsure teaIure a .nhod for pro iema a pol Ieptide (sbch as tuir of the aniode rn nigenbom fragments theret'dueibed hereiha The method ISmpses euhn a nnte. at'renrmAne bl " n iemm the depression \ ector) under conditotis antmr Oa ditie s tlhrent to alhvw 'wpression b We el of the antibds or amiigen binding fragment ieuRmded the ed udci d in die vector I The method can also include donated the ant ib amecn-binds fraeen ruom whn cell or from the medu n which the cl is cuitur d in mather aect the dislse aturan isoate rwkie aciencdingan cath anmo acid seqneamos described hereine oa.plpeptidc havingean amino acid seq ue c p r condiAinu ofang of the aninousequencee forth. herein. The nclec acdcan lee ndd in aIecte asn vpnett aanrilor can be pesenti t a el tn veat aniotbet aspect, the discelosure fea tures a therapeutic it coimprisini (il one or more of the isolated antibodies or a4tgnbidgfagmem> ~s wn herdaN Mgm one or more of anW e the hunaied nibodics or tuiembbmdin frat ments 20 thereof described heremn r ad (il means tei debc e 1 tfee anybody or ruiven, binding fragnment to a \ubjeet T he nruai un he suitable for eg., subcutaneous dvr mtmacular de ers Or mnraartic ular de.lix er of the aanbodv or amiens bnuding eagrueet thereet to the subtect 'The meains can be, erg a syringe, a double~ barreled syrumge. or two sep arate svrtges mecorporated for use in admimitering :a 25 therapeutIe smant eyo amijgenthmnm inia muen thereof, while draw mg cff knee tlEd t (e.. gfr analy ia tpsh-pull lashion, i some embodumentsC the means is t' ocular debierv and c nrses a trans-scseral patch or a coma lens, each of which coprises the auntbdy or amgndntig it 'gmem heJIe l emodmet, the means is s uitable for' iraputnmonary &ehverv. For e xample. the means can be an 30 inhaler or a nebubier I some enmboinmenms the ese is a pireluled syringe such as a pen d ee. The pretdbed syringe c~an cOniionl esg. at least one pharmtaceutical un dosage form of one or more of the antibodies at igen-bonding (ragents thereof pointethnr .n NStme emnbadjments3./00 $Ood ejrnnaaei~ least e additnal acive agent se treaia aomp enseno ed dio der in a viout The addional aive et a u ofheaddial aet decried herei 5in1 yet another aspect, the diselosure features a methed for treathng or ptmog a coinyndome oSeiated disorder The method indes adrnterng. to a jums, in heed dielret a thlrapeltlc nibhody or anden-Imdiyfracm cut thereof. described herei tin an amount sUfflet to teat a comROeme -asoetatcd disorder afftnug the human The method can alW inc lude idcnfSu the subject sa hainc a S eomplemtent-asoeiated disor der, The compemem associated disorder cn he, e g.a conplermentaeratedi mrtlumatorv dis rder, aty pical hem~olytie uremic synadroma' age-related macular d egcenratt. rhetttmatod mrthti\ Sepsis. or anuphosphoipid syndrome hn soncm l eindimmts, the complement-aseciated d ides a eomipie0iri0n-assocratd pUlca ar y disorder. For example, the cotpiernenF 15 Asocated PUtniODaty dsorder can be eg , aAthnma or chrANe 1bt0 etwe PU lmonlr disease, Other ermp enmem nassoeiated disorders amenable to treatment or ptev entieni as set forth in the method are deseried herein. The 1 <mode of adistation, which can vary depending on the ty p o eorplentent-associated disorder to se treated, ah be, ci., iravenous aimustation, i ntaputlm tuu)ni adtmaIOimrOt, ntttaouhd 20 admimitration, subcutaneous administration, or imuaartieula administration. in some emobodiments. the arntibody ot antigen-binding f'ragment thtereof is admilniered to the human in an amocit and wA ith a1 frdeee sut'heietto n a intamr a reduced lev el of sstermc CSa activ ity ler the duration of the treatent. i some embnotdhien2ts the rnehod~s can inelade atler thdlisterinn, monitoring the ii un0 2 for an improvement in one or more synmptnns of the comiplementbassgited disOrder' Inseemnodenuta the methods can incleadtnnistintnt eterman otn or nmore additional therapeutic agents hi vet another aspect, the disetosure t'eatnres an article of mautacture, which comprises: i}) a container with a label und iii} a composmton comprising an antibody 3 or ntiguen-binding fragment thereof described herein. The label can indicate that the composition is to he adtrinistered to a huran hatvingu suspected of anmg, or at ris ori dev elopng a copetn-uscae disorder. The'" 'ril e' omranlltfcCan also ncdete or more additinhlative agents bc. w lmwr40 As used throngbont the present diaeksure, the term 'attbdy" refers to i w hoe or iact antbody g, jM PG QA \ lgD, Or 1E) Moleul that I geneAted bv anlV One 0f a anetV 01 methods that are kutO~fnm the an and doetied herein. T he ter m "anhdy n " meluUdes a pyeln unantidn a mnonocktalJ umiho x, a 5 tum'med~ nr enerie anihod. *a U thumne antiodvs, a mmum-ed human antibody. and a fuly human amibdy. The antibody can be made in or demevd fAnn any ci's utvriewy e spceles e g , mammals webc~ a humnans, .nOtthman jNpoat Ie monkat baboons or himiancecs', horses cattle, pigs, sneep, noah. dogs cats. rabbits, cnics plt. g~rPt bdmthit, rati nre. The ant tuody canu be a purifiedd or a recoMboant Suabd \s tsed her'em, the term '"antib)Ody fr'agmeni "antigen-imding fragment,'' or >orna tenis01 refer to a gl i utt o Qann sinbody that retains the abi lit t bind to -i untigen {e. an eln tre present mi d but not in the alpha chai of mnelcanved, nati S protein ea a sngle cbaln antitodv I a.hy> an Fd trimetm an Fal 'agmem, an ta F agment or an ab' an t'agmcnt Ate sd t a a le podypeptide ain that includes both thc beay and tght chai \aate rliegto of the anybody t'iln hteh the seE \ i, demed in addition, diabedies trettak 1 194) STr r 11211 121 1123, HudsAn ci at 1199 m 1 Wa i? Ma d, I 21 ,Q ' 0' the dAdosures of both of which are incorporated herein dy rence in their entttet\ m ndidsa tiabodies :2.0 t Sehsoorighe et at. 00) 3th' ioteca Mo '0'\ domain untibedies tacs knonu as "heo'w chain immunogobuhn' or camehdk Ho et aO (003 I wraAlso.,' 1Q) 454490g and itrbodies ( husmon et aL '00 0.1 )zm A'0' t lett "U A1 I W herf et alj 293) Mb! Ter h Wh al Stocks (0i4 t"< I saie %2),4 %46Ai the disclosures of :ach of w hich are incorporated herein bv reference 25 i their enmretyi are mnehaded in the de finition of antibody tramrments and can be incorporated into the comaposmtns. and esed in the methods d"'cr'ben t"er' Unles oiterws e deflned, all tiema and scientiitean21s used hereint ha ae the oune meaunlo as acmonl understood i one ornar\ skil in the art to w hich this elasue pertinms In eatse of conflet. the present document, mecludimt delinitssa, w dl control Peferoled melhdsa and twieUr ale deseoed blo\, although methods and material smlar or esp\alent to those described herem can aso be used in the proeue or testng of the present d iNclosed methods and coinposittons. \ll tAlbheations patent applhcation antents,11 and other reerences mentiond herei a C nowrporated by Pernce in ther entety 41 otherature and adv tge te present die te e, ethedfr treat in e n ent-assoceedierders indn a L&Cwb apparent froxP the thlw descritin, te oanpks. ad froe the eamns. 5n of the Draings Fig. is a Aen diagram depleting the degree o oeriarp of te epiopes im human Et ound by a select set of murine unrihuman Canafbdie SantOi \MW San I80~M.E. SanO4X.M IF '' I MI i Sa ul~ \IME Fig a 2 s a Vine ph dettg the antagonism at Ca m-eiafmn dtabnn i S viro using a neutropla) au mun assay The Y mis represents the optical density D nmeasmrenrent of a chrongem \ubswate as a funttlin af onveioperoxidase reeuse iv freshly it daed inn ncnzrophls, I he >aais represents the eeneenrmon o antmtlody encubated wth the cellO Fwte iumameed ,itbtiehs tested BN Jh7 BN)39 NR , BN1ft' N4 i, E. and a hmnaed antibC I ~anmibod ar identified mn the mins legend, Fig. 3 i a line graph deretr the efet of several therapeutic anibodies on joint inlarnmathin a tnouse nede heunuatoid arthitis. The yaxis represeMs the thucknews of the initially inilamted tnee ju i tfl citt The Pauis represents the day a fiet disease onset. The therapeutde antibodies tested - Stnt 5\JE, (a mouse 2.0 antimouse Sa anybody) and a cotAro antibody wth the sMe Fe region as ih anti Qia antibody -are identied hn the nset leend fit 4 i a ne graph depwinm the etlet of several theraptiN antbodies on er all disease sev en ty in a mousw model of rhteumnatoid ar thr itis T he Ytaxis repruems the arthrntis mde The auis represents the day ate disease onet The therapeuti o antibohes tested - AI MS (a mMuw antimouse L a anybody ) and a control antibody with the sine e region as the ani a anybody o are ideniled i the inset lcnt Fig. 5 sets fCrth a series of humniazed heavy chain variable region seqpences In order rnm uppermst to lowermost: the heavy chain variable rnion of the BNJ34 S) humnanizedantiM5a antibody (SEQ MD NO: ; L t heavy ehain variable tegon of the B5NJ346 humanized ami-Ca anibody (SQ ID NO: 77 ! > the heavy chain variab region of the &B47 humanized anti-Ai5a antibody (SEQ UD NO:78h the heavy chain variable region of the BNJ354 humnanized anti-CGa antibody (SEQ UD NO:79); and the heavy chain variable region of the B3N1350 humanized anti -C5a antibody (SEQ 11D N 0Ot The Wie aisan "i Appreciat e delmieueo ontw een heave camin Bramenwrk eons L, 2. and 4 and to bea chain CDRs I 2,h deliaions as defined by KatY at K i aOre swhwn in d e tfze 'T ic FRI' r~t ers to heavy cham anaN: rY* gn famewnork regian 1, HC' F RY rees to heavy 5 cham vanialne region framework regon 2. HIC l' reers to heauy chami arable region tiamew rLreg =n 3. and W Uti 4" reYbrs to hieav etuy i an viabe g ion traamen erecion 4. '11( DR> i' " 'er to heuavy chain mvariabe raloa ompeme.ntarv detertnimng region CDR 1 1, "1C DR.rr io heuv chain variable rgion (2DR2, and "11' CDR e e hb n 0 Ig 6 i a line graph dating the eeentae of cidn ' rhi m the bood of mke tiAox admimsratin A' KC~a to the.mihe On the Y - i neutrophij counts are evpressed t openmaoge ot "vbain" which i the nutrphl ceitnt astidme I) (or 100 > ne'trophil The \i 8pree'Wti inne ti rmnates \l ouse cohorts w ere mitalinioadmmistred a cajtrol anitboh anianthrax proets e q antuen ul. [gt0" /l t 1 Na n l onm r Nc nced C 3 the mi- ilhuma tn On yrhd'b 10,1343 at one et the tellowo ma duta 24 m'kg (ive. islex 2ts kg five niuce mhg (ie mie e and 3 rn/e (n ieo and the tic ,ee adminitated h'O a. See 'anple I Six mice, "samn w 'ce act adumimtered imsan 'SaC Fig.7 3 a bar giph depreimn the myi lfpetoidase NPO) level i the plasma 20 of mie beoa and fonIos adminiration hthuman C"a to the oice, The Yas is represents the coneeniatoni ognd) of MP> in mouse plasma The ax re presents tmte in Imnte .Mouse echot s eravrefnnsl aitimmstered a centrie anonbav [ano-al~nhra police e agnelh'0Cioye eontrf' ciaeht mie. i th at-hann WSa antibedo MP11 at one VA fhe tollown dows: 24 mgpQ WIe mie- rnn/gcg ne e: mg/kg ns mc ' *: mg k ifte mce nP and then t/itrerde adriinlsrded hr.NC'kuir mice '\am " wee not idinered hman Fig.8 isaline grupb depietm; the range t human C evel in plasrna1 of mice tadnmstered hrtumi ) in the presence Or asence f hierenm eonresitratons 30 of an uuti- hC~a anubod) ($N13R The Yani represent the coneraton (y m/mb of hCSa in mouse hiasma. The TXis represents time in mints Mouse eulhorts were iraveno namstered a control antibody arttiithax protectivesatigen C.' I(7 4 isotv pej (eontro' six ui'eli or lthe anti human Ca antibody B13 am one et the following doses 24 m'gykg three mieel: 12 ma~o (th dree imeexA6 my kg 4?.

three tmie) and3 nrcgs fihie inice amd (e later were dnirsred aui Fig 9 is a li ne graph depleting the coettior 0i bding to human tin eUmo 23( pM of .ruthemum-lbeied annCea amtihocl (1&I &3 was mnbated with 5 nt biovayLted hatS e ag w ith v aniose cncemiralnins ie g , 40(3 33 4 . 4,1K IA I 4) and iS a'M ei ore of the ibeownmg : a) humuun (7 u deslurg protein in phosphave-hiffered salme iv human plasma, <e i eynomoi nacutge plasma. IdI $aih C iouser} plasma. or tel 131 A Wi (monse plasma \\'tb respect to the plasma cotmporietrstnu (cid (4i and 2e the conecemrsmon refers to the approxionate final coneetatlion) of (75 anh non in thein uatUbtion mixture The YEaxisrepresents aritrary fluorescence units as a famnen of the amount orfu runabeled amtiah aanbodv detected. Dhe ' -as represents concetnuation (itMi of the antgen cempeor Fig 10i a IIle araph diepit ing the effct of several compolemt! inh~torv 15 pvtemos on the ahternainve path ay (Ar> of complement the axi represemts the peremane of A? eomplenmemt aetit a compared to bal me 03BL the lev el of activity in the absence of a eomprlemnent inhibit on file \-ri represents the ceecntranon Of a g5 VI en oplemen~t htlhnbitor' (pM) Phe &ttCe5 ofthe ann-hiCfa anubodv. B'\3Ki alone withh an unti-P5 untibodsv on ,\P aetaita w ere esen :r evaluated, Fig I I is a line sraph detecrina the effect of se'seral eomptlcmet: inhibiorv proete on the claicalrpathyav (CT ) of complement, The t axis represents the percentage ofi('P complement aetiins as compared to baselie R I., the lev el of: activity in the absence of a complermernt iwhibber T he Y axi repr esenms the concentration or9 an ien complement itllhrtco- aM Al. The efflets of the ant-hC 53 annbtody ISiMil along, ith an anmi45 antibods on CP1 activity w ere each Fins. 1 I 2 12 7. and I I0f are a Neies of chrn autographs depictng the retention imes of the mni-Ga antihody (BklN1) and an a atis-hC5 antibody in the 30 presence otr absene of h protein. F or i o f the panels the Nan is represents retention ime in mirtrtes and the y axk represents the absorbance units at 2 1-4 Ut wax) elentt In each panel, the itlayedi subpatnei depicts an enhanced \viewl of the feared pe 4 P4 12 A depi teetaten i 3 in. thettsence of h5 ' 12B3 depicts the retention time or the a iA'S antiobdy in the absence o hCS protein, hin 20 depis the retention time: for RN J 3 in the presence of hOS t.2, I fZeld molar excess 0f hti over D3N3 U Fretin to left, the cenirted peaks represent: tai uncomplexed RN!343 or hIT: ab) RsNJ3& wth one antiger-lendog s Ow bond to nea\ R b anmmdr fhaetion consistent wrth dual occupancy of Bi123 w ith mecleav ed ItO5 10~F in. .12D depicts the retention time for the anti -C antibody uyee preh'Wce et afl etqtufmolh amoun thOf s F rnam right to left, the enumneratedJ peaks ccreet (au Q) unoetnipexcd anti -5 antibody or hCS (i the anftCS antibody w ith one antigen-hinding sie botind to uncleav ed hO5: and Cc') the an{s anmibody nod to to une. xJ C moles - e I4g. 13 is a le ;raph deptiao the bmdm4 ol the A.ti 5a antibody WN to daesarn m thep presence of hCo ueing an F 1SA ie \' aXs repre-sents the conecttttuttrn ongrmL3 ot the antibkd fe 'IJ ivepresents the optiead densty at 480 anm wav elength, Fig. 14 s a scater pot depiting the Concentration o free MCaTC~a darg :20 present in the pasnna of cynomsgns maucaqes as a union MA the ptsvm coneentratnon of anMUCMa wibdv i BN J The -usai depicts the concenMUat Spw mi ) 'Ct iab a d'rj Hectd in pl asma samdples twlr cA onvolus naedques at tne -0sts caugmllo tm I day to ?0 daa tWion ing a siale dose intravenous administration f PNJ)i3 at tndg kg, 10 mg/ kg, 100 mg/kg, 20 mn/g. or 400 25 ma/kg hoty W eght of te anmmals. the X axi represcms the concentration of the BN p0 yg ) in esib of the samples. Fig. 15A K a scatter jlot depitng the perecmage of emolt tc aem iy mn scrmm sampl relaie to baseline values is) initoated ia the classical axtthuav a a function of the concentration of anOan ittatbody13 1B Vh3) in cirenlation tX\' Fig, 1$B isa scatter plot depicting the percentage of terminal complement complex tormation initiated via the chissical pathway in sc rum'a samples measure by a CH50eq away relative to baseline values (Y axis) as a fWntion of the concentration oami-CHa antibody i1BN383 1 circulation tX -axis.

ig152 s a scante plot <kgieting th j)CCICtagC. 0f terminal cnigement compex ibrmaton m iea ait.te t adV$ I as eritn samples measured by a (IT assy ret aye to se n -ais) as a.ncn ofthe conentratont f and a mihdy t 23 in reinwAon (K-anvis Thbe ret cdschourO prides antibodies and autmienbim;in mrtytents thereof that bimd to tree YCa (en lvee hnmm hun. ad mp ttons containing hoe amibudie or their fragmeritk and method> ft u i an t e toreg0no fu teait or ( reent complement aouiatcd i soaders such a in but nt limied to sad W mdulai degeneration (e g. A. AID). R A sepsis antipbosphohpid aindrome, burn ogsecs burnt h O palstre'W s 5s3dam, Wi .neptri s or in e ;onepirnnt-.ssoetated pulmonary dioidCr such da dsthtild or chronic Oswtw pu nopiaryd d~seas (0GH) x The dislosure also man ideant i anibodies (mand frgmns thereofl ,Z0 that are rosshreacv between fTee G3 from human and ree (2d fronm a non-human rluaprnitm species such 3s a n01n--hunta1 primate (ea . cvytomoignts 10adque 'I (heus acaaguec While hi no way intended to be liming, cxemplatr amibodis (and fanmuate anh d rmentds0mpsithe coteaphare elar e onibelow and bam%|005 dMY Q a ethdno ur m g omho ank060 vi 1ib5i4, 0KH v,10 Nnd wd y eSnQpO aned in the worlime E ip"tes. Antid'Sa A\dibodies and A\ntien-binding Fruments Thereof' The dicbriure provides anmihcdies thai hind to complememd components (N'c 25As discnssed above, the prtonn~ of I ' 16 |'o amino acid residue precursor prtein, tsprocesed bt t ties of proteoh io el"invawe events T he fir:,t 1 2 peptides (numbered -I s t0- I constitute d siga'dl peptde thatis cl5eaedd t) orn the prcunsor protein. The remainumu I 0a tdano0 acid Preten is cleaved in tw o places to torim the alpha tma beta chain The furst cleanvage e\veut oceurs between ami no acid residues 30 5 dand 654. The second elca\adce ccurs between anamo acl residdes 45 and 0.6 The two c ledaae esvents result in the temiation of three distnct poly peptide fi'gnents (I a iragment comp..g amm acids I to ( 55u whichb i efer ted tO a the beta chain; { ti a firigmeznt comnprmg amitn aids 66 to 1052. whbli is raee'ed to as the alpha chaint and ( ii a tetrdpeptide lI dgment c0nsisting of ainho da ds r56 tol 659 he alhachainand the e caon pipmetde anJ ets -a n t e l.i t ia disulfide bond and conttte the atue Q oten he P or AP (4 Onertae activates matre ; by leaving the eaba cnh een ~cmsi 'ri~'nd 73. hich results in the leati nt o s 60 3 heT reraaid 6 5 Paonof ma ure CS i frament CA whih conyamn nthe reues -3 so I 658 te apha chain disulfide bonded to V be chain, hr uno (?Sa is rapidly m.nab'outn-d by a serumon -ne c.arbos peptidase B. to a ' amnmo add fam termed 'T5a desarg svwhieh has lst te arboxtomal argimne residue. Accord 'nnv, it6 somC embodimts. an atit bod) that bids t ee 0 Ca aSO blds to desk"inaled CSa i some embodiments an amibody that bmds to (SAU does not hrd to deSaragiraed Vc a i'n suine embodi-metsthe alC nti- l~ ad tttbodv btnbs to 5. nco0no0e. present ut Cu V an epitope tht becomes exposed upon the liberation of CSa from the alpha chaw fnment l' manue CS. >fht i in Pomeemnbodimnnm 4 an anit-Tca antibody 5 deserbed hereh bids to tQSa aOdk r (7a dsru but riot to ucudcaved, natmne hi Pided i C . As c, m some embodiments the ant i<a antibody t amien bitidm) fragmellt ther~e~o can bd to1 a' . subpcpaiation of inc-lea ved, proeCssed (' Kog, &sn CA Canttutittg less tha n 10 -e-, lesw tian U. .'8 '5, 7, (0 S 20 .5. 5-. 4. A 5 3. N 5 .15 .(5 .. A 2 rW a 1 Wko 5 i4 A? i -i l I t L 0.50Q4 0 0.2. or less than 0.1 i 4\ of th total popLool of lull length C t in a a, A od or plasmna sample or a sample emprtne recnrbutnrtn dl iength C -win sibpoptitiR; t Vi A Sl holer - Wail Sed such that an t e occluded CSu moepoe isi expoed Thus an an am antiubody o amien-biudig fragmem them-mo deser'bcd herem can, n some-t embodtents bhn -to free le bt n to M n Of A 4'( o 5 gter unce d\ 5 Atie: i p"pnltion. in some etnbodmnets the pamal - eror liv denatured swvbp 1 puhtln , mailn 0 ints reduced toit te g , les t GO S 80 7i 70 S. t 251 5d 40A l 25i20,15, 10, $ of the acCl5 o filXfuAtioial filleengt ( protemt) m >a\y11umber of sutable a3s a ase fu fur testing (2 ac tiv ity e g.. a 30 lemoalytic asa or a Ci 150eq assay Suitable i-ethods Ibi tcmng thle aet itv of the rutnor subpopulation to wuthle atn anti-'a antibody decribed herein m-ay in some emwbmients hid are known n the ar and deribed herein -47 tfn some embodiments the antiC~a antibody bindN tu a mammaaian (eg. humar CSa proteini. For examine, thC anti-C5a antibody can bind to a humn Ci protein ha min (tie olMOwng amino acid sequence: TL*QKKIEE 1.AAKYKHSVV KKCCYDSACVNNDETCEQ AARSSLOPRCIKAFTE 5 CCVVASQL RA.NISIK DMQE L R (SEQ ID) NO; I I. in iwme emlbodimt~~S, an anti CS antibody can bind to a esargiated human CTa protein having the following ino id sequence: T LQKUKIEEIA AKYK [HSVVKKCCYDOA CV \N NDETCE:IQRAA RISLPRCiIKA.FTE CCVVASQ RAN 1SHKDNQL (SEQ ID NO An iANi ua mby cb S herein can bind to both folIength human Cla u desarginated oma CSa, in some embodimems, the amibody can bind to human CA at an epirope withS vr ovhipig with a structural fragment of the proti his te amno acid setwence: T bLQKKI EVAAKYK ( ) NO:3}; HSVVKKCCYDGAC (SEQ ID NO:4&; VNNDE (SEQ ID NO:5 TCEQRAAR (SEQ !D NO:6Y MSLG (SEQ ID IS NO't R RAI.KAFTECCVV.ASQLRANIS (SEQ ID N:); HKDMQLO iSEQ UD NO:9 or HKDMQLR (SEQ iD NO:!T Se , e.g Cook . ( Q010)Ac C D6 190-197. Vn some tmbdiments the antibody can ai ' to Ca. aan epitope within or overpping with the' amino acid seq.nce of a peptide t'rgmenn otC5a comprisig -at least two ofth paire N.y..ciac rezidues For ex ample, an anti-Ua :20 antibody can bind to fr-agmntn comprising, or consisting of~ the amino acid sequence; C-CYDGiACVNNDET C(SEQ ID NO:W CYDOA CV.NNDETCEQRAARISLOP 5 RiKAFTEC SEQ 1D-NO: 12;.and CEQR AAISLGPRCIKAFTECC (SEQ ID NO: D) wherein, in each of the peptide fr-agments, the first-an final cysteine residuen-are paired hy disudlde bonds. In somec -5 vmN cbodimemnsn ni- antibody -esc-ribd herein can bind to a human C-a promain at an epitope within, or overlapping with, (he amino acid sequence:; YDGACVNNDETCEQRAAR (SEQ ID) NO: 14) or CYDGACVNNDETCEQRAA (SEQ D NC:1), hu some embodiments. an aibody can bind to a human CSa protein or fragment thereofecuntain$ing an amino acid \equence thai contains, or 30 consists of at least four (et.. at least fouir, five, si:<, . even, eighi, nine, 10, I 1, 12, 1 3, 14, 15, 16 or l or more) consecutive smno acids depicted in aTy one of SE 10 NOs: Ito 1 In some embodiments ann-a anybody described herein binds to a tcn-ur epitopeeonprisnoiw or mored (eg. at leas two, tree or ur diseomi nuous peptml regions of C Sa proten. tg., tuo or more dseonnumnus C pepude regns joined together b way <f a disulide ikag Mhods for ertivtnug the epitope to which a partiendalan tbody , an anti -<Ca antihody U binds are also known n the art. For cauople the binding eptiope 5 nwthin a or Jearnmated (a5 to which an antia antbdy its can be identified by measure the hdin of the antibody to ser al , Phm 1tur, 1y e, Seven. eih nine 0, 1, or 30 or ; more Overlapping peptide fragnre1n of a complement component COa protein (e. , seven overlapping fragments of a hunmn CVa protein having the amino .acd sequence depicted in SEQ ID NO:c or SEQ ID 10 NO:2k Each of the different overlapping peptides is then bound to a unique address on a s&id support, e.g. separate wells ofa muti-we assay Plate. Next, the am4i-CSa antibody is interrogated by contacting it to each of he eptides in the assay plate fAr an amount of tine and under conditions tat aluw for the antibody to bind to its epitope, Unbnn antiCK a aNMibody is removed by washing each of the wes, Next. a detectablylabeled secondary antibody that binds to the antiCSa antibody. it present in a well of the plate, iS contacted t each of the wells, and unbound secondary antibody is removed by washing steps Th pronoAce or amount of the detectable signal produced by the detectably-labeled secondary antibody in a well is an indication that the anti-CSa antib'd b nW to th p cular peptide fragment 20 associated with the well See, ea, HArlow and Lane ( n-pa) Benny K, C. Lo (supra), and U Paten. Application Publication No. 200601636 the disclosure of which is incorporated by reference in its entirely, A particular epitne to which an amibody binds can also be identified using BttAcore ehromatographi- techniques (see, et Pharmuacia BtAtechnology Handbook, IEpitope Manping,' Section 6.3.2 (May I1994): J and Johne e at (993) J i fnnl Methods 160:2M.91,8). In sore embodiment. an anti-CGa antibody described herein contains a spcitic 5et o iht chain comroementaritv determ'iniv regions (CDRs) and/or a specIiC ic et fd hay chain CDRn. Fot example, in some embnodiments an ani-C a antibody or antien-binding fragment thereof described hertn can compare a hght 3 chain CDR set btined fron a light chain polypeptide cumpnsing the amino acid sequence depied in arty one of SEQ ID NOs:19, 37, ur 42 n some embodiments, an ami-Cna antibody or angen-binding fragment thereof described herein can comprise a heavy chain CDR set obtained from a heavy chain polypeptide compriAng the amino acid sequence depicted in SEQ ID NW:27 or 41 Exemplary light chain and 49i, hleaa ch un CDR Nets obined rm the aterenentioned ligho chan variable .regons and heavy cham variable recious are described beho in more dtail ee T able 1 he exact boundales of ARs, and framework k rins. iave been defined differentV aceording to different method& in some eanbodanents the positious or the 5 CDs or framework regions wl nm ,a light or heavy' cnm n variable domamn can bx as defined by Kait er al. | 141 U' Squences orf imu oek al interest" -i Pablieti o. 4Ki, A Deparnmemt of 1lcshb and Ubuman Services. ehena M DI in such cases the CRs van be .referred 1 as Kabat CURS' . g., tuabat CDR'^ or 'Abat HCUR 1'r in somne emidaeuts the poisons of'the 10 CRs of a liht or heavy chain variable region can be as defined by Chothia et ali I 989) Nwre 32:87 7-83. Accordingly these region\ can be referred to as 'Chuhia CUR)"(.g, Chothia LCDR2" or "Chothia MUT CR" In some embodiments, the postons of the CURs of the ih an heavy chain variable regions can be as defined by a kabat-Choiha coined definnion, In such embodiments, IS these .regitons can he referred to as "comb ire Ka~ant-Cho bha CDRs."~ in some embo di ments, the poitonN of the (CDRs and/or framework reg ins within a hlh or hav chaiin varialeI domain can be as defined by Honnegger and P lckthu 2001) M B 109: 65770 ldentigation of the CDRs within a light chaI or heavy chain xvriable region usin the aforementioned definitions is wel knon in the art of 20 arntiboyengineering. For example, Thomas et at. [; 9961 Aki ffmmua MANL7NA;l891401] exemplifies the identification of ight chain and beasy chain CDPR boundaries according to Kabat and Chorht definitions. Accordingly, in some embodiments an anti-C5a antibody or antige-nbidng fragment thereof described herein can comprise a Kahat-deined a Chothia-defineSd yr a combined Kabt-Coia-efined light chain CfDR set obtained from a light chain polypepido comprising the amino acid sequence depicted in any one N SEQ D N-:9 37, or 41. in some emboduiments, an crni-Caa amiody or anlltigen-bfltding fragment thereof described herein can cumpris a Kabat-defined, a Chothia-defined, or a combmned Kabat-Chuthia--defined hieavy chain CUR set obtained from a heavy 30chain pciypcptide comprising the amtino acid sequence depicted in SEQ I D NO:27 ur 45, in some embodiments, an antiC5a anibody described herein comprises a ight chain variablereion comaming one or more o; a igh? chain CURI comprising or consting of the folowiing amino acid sequence: RASESVDSIN H (SEQ ID N:~2(); a light chain CDRx2compmring c nsitng of the following amino acid sequence: RASNL ES (SEQ JD >1:21) and a ligt chain CDR3 comprising or *consting ofthe flowing amino acid sequence: QQSNEDPYT (SEQ D >1:22)n in someemblodiments, an anti-C a antibody described herein composes a l chain 5 variable region containing each & a iht chain DR 1 comprising or consisting of the slowing amino acid sequence: RASESVDSYONSEMH (SEQ DNO:20); a light Cha hi CDR2 con sin or consi Sing of thec fow aino aci sequece:L RAS ES (SEQ iD N0:21 ; and a light chain CR3 comprisng or conssting of the folong aitno acid equence: QQSNEDPYi T SEQ I) NO:2 Exempliary n 1 C a anUtib)odis~ comprising such a. light chain vaiablek domain sichide, esg the N36 BNJ 36, BNJ37K BNJ366, BNJ36L and B383 antiC~a antihdies dues hcen (vdetngh abic h hi sone emrbodntv an anti-Cha antibody described herein comprises a light chain variable region containgone or more of a light chain CDR I comprising 5 or consistig of the fo lw amnao acid sequence: R ASLSVDSYGNSFM ( SEQ WD N 20): a igt chain CDR2 comprising or consisting of the following amino acid sequence: W\ST RES (SEQ ID NO:3): and a iht chain CDR3 comprising or counting of the Mlowing amno acid sequence: QQSNEDPYT (SEQ ID N:22) In sonme embodied, an amtiCa aminody described herein comprises a ight chain 20 variabic region containing each of a light chain CDR1 comprising or cosisting of the flowing amno acid sequence: .RA SESVDSYGNSFMH (SEQ A D N :2YT a light chain CDR2 conrisng or cnsi sing of the fuiowing amino acid seqowce: WASTRES (SEQ AD NM:x and a light chain CDR3 comprising or consisting of the fbuIiwing amino acid sequence: OSNEDPYT (SE D NO:23) Exmpar a C5 Pa antiodies comprising such a gh chain varable domain iud, di e ANKJ371 and BNJ81 ant i-CY a antibodies described herein (Wh&t Mnr: Table T 2 In some emlbodimpenti an amti-C~a antibody described herein comprises a heavy chain variable region countaing Oc or mote of: a heavy chain C1DR1. comprising or consismg of te foo&wing amino acid sequence: DYSMD iSEQ ID 30 NO:8 a heavy chain CDR2 c0prisin or consistig of eodownig amino acid sequence: AfNPNSGsTN YNOK KD (SEQ D NO:29): and a heavy chain CDR3 comprising or consisting of the following aimno acid sequence: SGSYDOYY AMDY (SEQ ID NO:30). in somn emodhitos, an anti-&a antibody described hereia comprises a heavy chain variable g containing each of a heavy chain CDR1 51i" com uprising or icusisng of the fouwing amino acid sequence: DYSMD &SFQ if NO:2Y naevy ehin CDR2 comprising or consitingK of the flowig arino acid sequence: AINPNSGGTNYNQKFKD (SEQ ID NO.29); and a heavy chain CDR3 comnprising or consisting of the following aino acid sequence: SGSY DQYYA.MDY SEQ ID NO:30).E wlarv antCa antibodies coming SOc a heavy Chain variable doman include e the BNJ364, BNJ367. BN 371. and BN13 antiCQa antibodiecs described herein (vide ig'o Table 21, In somet~ emodimehnts. an anti-Ct' atibdy described .herein comprises a heavy chain variable region ct aining un or murew of: a heavy chain CDRi compriina or consisting of the flow ing ai no aci sequence: DYSMD (SEQ 1 D NO:28): a heavy chain CDR2 comprisng ur coniting of the flowing amino acid sequence: AIHILNTGYTNYNOKFKGQ (SEQ ID NO:4t4: and a heavy chain CDR3 comprising or conssig of the following amino acid Sequence: GFYDGYSPIDY (SEQ iD NO:47, in sne emnbodiments, an amiCa anybody described herein comprises a heavy chain variable region containing each of a heavy chain CDR comprising Ur consisti of the following amino acid equnci ' DYSMD (SEQ "D NO:2 x a heavy chain CDR2 comprising or consisting f he followinag amino acid sequence: AIH LNTOYTNYNQKFKG (SEQ ID NO:4 ad a heavy chain CDR3 comnprisinig or consitgof the fotlowting amino acid seqluene: GJFYDGYSPMDY 20 (SEQ ID NO:47). Eempanry anti CSa aiodis comNprising such a heavy chain variable doma include n4g the BN T BN BNJ351 and BN38153 ami-CSa anwo AMs desertd herin id MN: ORk 2) In sone embodnt, an MCAt antibody or antigen-bindinA fragment thiereot'described herein can comain a heavy Chain CDR2 region comprising J5 amino acid sequence: AENPNSGOTNYSQK FKD (SEQ LD NO:67 . Eor example, an anti-Ca antibdy described herein ca comprise a heavy chain variable region containing one or more of: a heavv chain CDR I comnpsng or consisting of the Oblowing amino acid sequene: DYSID SEQ ID NO:2' a a C R2 comprising ur consistmg of the following amino ncid equence: 30 AiNPNSOGGTNYSQKFKD CSEQ iD NO: 67 and a heavy chain CUR3 comprising or conitgi of the following amino acid sequence: SGYDOY MI D (SEQo iD NO:0), in some embodimenrs, an anti-Ca an body described herein comprises a heavy chain variable region containing each of a heavy chain CUR1 comprising or consisting of the fbluwingi amino acid sequence: D YSMD (S EQ ID) NO:28); a heavy cha m D,2 COPnfms rtconsit ef the fol w ing amino acid Seqence AINPNSO(TNY SQKlFKD i SEQ ID NO :7 and a ieavy chOn CDR3 co nsmn or consisting ofdte follow in amino acid sequence SOSYDYY A\DY (SEQ ID N0:3 An efnple t' an i aitw amihady denh euein, uh coins auch a han chain poypendc and binds to hfmm Ma gthk a K a le thAn i nAT n the San1 bM ,tbdv deseIbed bclo w in ne anhbdrn ean a abody or an bindaW g tragnp tereof descoed APi taio of aplarv i chan D et andheai hain st paiiu I to d t la Exenplary L ! Chain 1Hat% h ( an Exemplary CDR CDR CDR2 CDR3 C DRi CDR2 CDR3 AntibAdies Par ings with such SMN:20 SlN:2~ SIN 225N SI N:29 SMN:30 B~N64, s~o S SIN:20 SIN:2 IN:2 S[N:28 SN:46 SN:4~ BN6 BNJ6 BNI83 3 ISIN I N s ShN:2 SI2 SIN IN:29 i SN:3 BN 7 4 SIN: 0 S4N StiN:22SIN:28 1N14 SIN:4 RNLB SIN~ refers uo "SEQ ILD NO. The amino acid sequence~s represented by the SEQ ID NOs in Table are set frth in hn some embodhmnts the ants'Sa aannhodv does not comprise enemphary C DR pairm:~ 3 nne emibodiimeuts dhe ami-Ea Su niihdx is not BWN)1 i hn some embodiments the light chain polypeptid rf Pn an min anflihtly described heremn can be ' ih chan polylepude se u a hhu imn er humanized 20 t lighi eha pi4lvpertde}. in eome embodimems the hgh Inas p ioiv peptidc of an anmiK a antibody dceribcd herein i> a : hgi ehwam polypeptide cenu. atulVy human or humaminsi ied C IigtsiC hai in 4 olinpeptide'i lih' 'mino aeid SequienceZis of ra~menmUS lugit chalua polypeptides i t , numerous immuv~n'ht chain polv pepndewt ire w etl knoun inm the art and se tofrth in, erg ,Kabat etai J 1 Ix rpra Lxemnplrv izlitht 2 chain yoiypeptide inuim acid sequences :are set tbrfh in Table 2.

n sme entbodliments, an antritmA nibd desenbed hereit ca conpse a hcht chin constant regioth For campei the ight chaK entant reWpon al be a ijght chain pa peq ptade constant region or a ic light chain constami regtoni The amino acid sceuekc for a number of human k and n hght chmin conan region arce known, W the art and described in, e gs, Robot et al. ( . Yvjukr hempfoty i: light chan p o pre amino acid sequences are set (orth in Table 2. nhe heur chain poivpeptide can comprise a conistant region { e g., a heavy cIi c wh~lvo I IO ftK heavy cain ca mt- Q2W hhw h chameensmt rgle 1 f H 1hecoeba tnm re-mon t2 f K hea\. vyhain instant rc n 3 ('01C3 an heay chain instant region 4 CHO or a combinanon o 10an of he ureoia'g The hieav c hain polypeptide canl compr se on~ e potlon of an umnmunoglin mnoiccc, TYhe Fe reAk a can be, e, an F rgic fiom an igtbL ibrC hily hgC4, hgA, igrt, ).gf or i tmunioclobubu mle&ukl o0' a COmbmiiation of pirtiii of each of theae To he clear the auti-'Sa amthodies esarbed herein cian b e.g , 1 ofit;UL g QW igOu g 4. 1gA, MY to 10i) isoy pe The amno acid 15 seea tor a number of human heav cham instant rcnons are knou in the arn and descnbed K e.g. Kabat et al 19911 >pa, i so me embodvents, the heavy chain po-peptide can eomprse a hybrid eonastant regi. or a rrion thereof' such as 4 02/04 hybrid c0Ytau region se eg ouren et al. i 199) .th ?nMn jk 1 0i Cintid W! al IVP i / c d ON i49 3 10 1491 and Mucer et A ,1997 -L td RmNoi 310111 -45' or sample dn in accoroance wih K abat manun rmgi i he! : 1 and 1904 consann fchmh compus UywUMN resaducs whereas the Ig eieni32 legion does not comprise resid- 249 bt des comprtise Onu in a (0 -04 l rl Consiar;t regiim, es here fre )4A2 t egen come from the 01 sequence, ble Cenistarkt region cmi be birther madtfied to introduce 25a tdeine residue at postion 24 to1 produce a 02/G4 tfusion har og Ma COo Other constant domano stvbrids that ctompise 0 t / Orc can also be pau of engmeed antbod'in accordance with the disclosure. s semplary beau~ chi in poh fppide amno acid seenences >arc \ct ftrth in T able The ani -'Sa anybody can be, e g. one of the spec Lie antibbdres esemiied 3 i the wo king examples, BNJ i , B3NJ6? F 7 B 6 BBJ36, BANJ83, RN127 1, or ISNJI I. The amino acid segqeences fIr these exemnphfied anti-'Sa nmtbodles w hich cati be used in cenjluthetion with kany of the nhethiads deserved her ein arc set foth Tab2 I y itn AD e s ~ 'N (4 A -' * CaN,'N 2 n 0 r '.~ S ix '. uA > QS A' '. -- 'fe h e h ~x x - ~ I' 7u > 2 o - - -- '- - O 'N isZ Z c '' 1- '. t- ' a- ' 0'0' S Ag C H NW - ' '-5' > < - 7'. x Q $ t ~ -' '>' .&.4 3 ,'8/ Nt' . 'S '-- ' 'S - N 'u"' -' ''A z-' ' &< ~.r~j >..N < -~ '-~'.'5< '-"''4 1 -4 C)'' H ~4 ' 4 h'4 ""4 .'U' [ C) r '"= 4 '> '- 4 '4 " '4 =4 >

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3 t3..,~ ~ V ,.'L..-~3 .3"'. /3-" 3' 'N Vtr~Q.~ '~ 33' ''"' ~ K-~ .'.~ N 'N' Sn >'t; ' K2 6 3s3~ 3K'* -t 22 H 'N" SE' '0.3 '.4 3 'N -" 7 '? -t Cs'> in ne embodimems a anu-tia amtbody deribed beein compne a t homturdefined lhta chain 'DR tet Or £ combed kanathnoduia-dehmed hi tham CDR set obtained from an> of the light chain viable rcgions described in Tabes 2 or 3, In some cmboddmint. an ani'5 antibody Or antigen nmtrarnm itrteot described hern comprises a othia-detned heavy chai 'o R set or a combined aat Chothia-deined hen hin ( DR set obtained fAm any of the heay chm variable regm ns described in Tall 's 2 or 3. in preferred embodiments an ani-Csa anuhbodi desenhed ngirim hinsb to (ISa, but not to nave. fuHllennh CS. In some embodimenms, an ant- a anuhodv bid to 10 (50. ut doA not bind to the alpha chan of uncleaCd natse A ued herein nitdea ed CS" Mtes to a Q protein that has not been cleared in f'aagnents ita ad C5b, by an AP or C? PC convertase. An exemplary amino acid 6e6uence for a human CS alpha hain is set onh in Hauund et i L . , .or- the seguetee otubich i inicorporate~d herein hy reernc m ~ tsmietv. hn min d described berein ckl o bimd to paatogs of human (75 such as human C9 or human CdA. The disclosure also features antibodies that crosbtock ending of an ua4'5 antibody described herein e g, crossbiocks any one of 1NJ304, RNJW36 I3NJ373 BN36n BNJ3369 $NJ33 L BNF 1. or BN3 As used herin, the tern 20 tuxsblocking amibody " referisto an antibody that lowers the anmot of hinainig for prvent luc QN &)d'w&, - 10~ ' na <'Ii"-6" pro fmdg o an 5anti-'a antd t n on a complement component Ca protein relainve to the around of binding of the anti-C~a antibody to the epuope in the Nacee of tlle erossbtoel anotody Sutable methods tr dctertiimn a he ia a irst antibodv crosbocks bindg of a second m an epitope are know ihe an, 25 For exanacrossblockmni untodie s ea be identified bn comnparm the bmdin of the BN334 monochmai aO-C'n amibody in the presence and absence ofa test aribody, De creased bondm of the BNJInd antibod in the presence of te test snthody as compared to bindn of the SN334 antibod in the absence of the test antbodv dictates he te aboi K a romblsk ntbdy 30 In som noodintes the .indin of Antibod to C niniibt thioog at o ( .. Mthods o adrg Gwtva acvy Anchue g. chemotasi assays, 78 radioimmnunoassays (R 1.Ask or enzymnedIinked immnunospecific asisays (E LISA) (se, eQg Ward and Zvnifler (11971)0 7Clinhn;et R 0o 366P-16 and Wuraner et al (1991) Coplemelunt Jntlamm:328n40). In soe mbodiments, the binding of an antibody or atigenbinding fragment thereof to Ca can inhibit Ca-nediated neutrophil activaion in eVaO Suitable methods for determining whether an ami-CSa antibody inhibits C~as miediated neutrophil activation o intra, or the extent to which the antibody inhibits actiation. ar known in the art and exemplified in the working examples below, For example, humran acutrophils obtained from heahhuy donors can be isolated and contacted with isolated human Ct in the presence or absence of a test anti-*Ca antibody. Ci 0 dependent activation of human in t t s can be measured as a function of' myeloperoxidase (MPO) release from the cells in the presence of Ca, An inhibition of the amount of MPO released from the cells in the presence of C5a and the test antibody, as compared to the amount of NO release from cells in the presence of Cia and a control antibody, indicates that the test antibody inhibits Cia-mediated neutrophil 1S activation. In som emodiments, an anti4a antibody or antigen-binding fragrent thereof does not inhibit (or does not substantially inhiboi the t complement component C5, as compared to the level of inhibition (if any) observed by a corresponding control antibody or antigenbinding augmentt thereof' i. an antibody that does not bind to free 20 Cia or C5 x C5 activity can be bneasured as a functin of its eellxysng ability in a subject's body fluids. Th cel-lysing ability, or a reduction thereof, of CS can be measured y nethods weil known in the art s as, for ot example, b' conventional hemolytic assay such as the hemolysis assay described by Kabat and Mayer teds' 'Experimental immunocheiistry, 2" Edition 135-240, Springfel, l I CC Thomas $ (1961. pages 135- 13t or a eonventional variation of that assay such as the chicken erythrrocjyte hemolysis method as desired in, e.g. Hoilmen et al. (20044 b EngJ Med In soni embodiments, CS activity, or inhibition thereof, is quantified using a CH50eqassay. The (H50eq assay is a method for measuring the total classical 30 complement activity in scrm. This test is a lytic assay.vhich uses antibody-sensitized erythroe\vt as thc 'e 'ai ato' of the classical complex niet pathu and varioUs dil hons of the test seiiT to determine the amouVn reclird to give 50% ly Ks (1501) The peent bemnolysis can be determined, tor' example, using a spectrophotometer. The C'Hweg assay provides a indirect measure ofiternial complement comnpiea (TF'C' > formanon. snen the 'C themselves are dioetly responsible l'r the hemolysis that is measured. The assy is ell known and common practiced b those of skill N the art Brieflh to actnyate the daweial coorpiemet pathuwax uudi utedi aenm sampks eeg., human serum samples) arc Aded to mierosamA wells conmainng the amibodyensitied 1 erythro.vtes to thereby generate RC Ne, the activated scra are dilated m mieossay wells, which are coated ith a capture reagent (eg. an antibod that hinds to one or more components of'the TCC) The RT present in the acinated samples bnd to the monoclonal antibodies coating the surface of the mictoassur nwells The w els are w ashed and, to each wel is added a detection reagent that is detestably labeled and recoties 15 the bound it C The de ab can be. e ,aumesenm label or an enynatic lae L The assa results are expressed in CH) umt equivaens per illiliter (CH0 L forth and cxemplied in the working examples, n some enbodminents, the binding of an antibody to C ~a can inhibit the interaction between C5a and CaR . Suitable methods for detecting and/or measuring the interaction between C5a and C5aRl (in the presence and absence if an antibody) are known in the art and described in. eg. Mary and Boula (1993) Eur Hamuti S l(Y1:287: K.aeko et al. (1995) thmmoogy1 :):149- 54: Giannini et at ( J995)] 2.5 Biot CThem 27(32):196619172; and U.S. Patent Application Publation No 20060160726. For example, the binding of detectab ly labeled (e, radioactivelIy labeled) C5a to C.aR 1 pressing J peripheral blood mononuclear cells can be evaluated in the presence and absence of an antibody. A decrease in the amount of detectably labeled (Sa that bimds to COaR I in the presence of the antibody, as compared to the 30 amount of binding in the absence of the antibodv, is an indication that the antibody inhibms the intaton beween Ca and CaR I in .somet embodtiments, the bin of an antibody to Ca can inhibit th neraction between Cla and (5L2 Methods ior detecting and/or measuing the imeraction between Cla and C5L2 are known in the art and described in, e Ward (2009) J A! Aed 84':37$378 and (hen et at (2007) xNure 46(01 3 203-207. Additional methods for evaluating the biological effect ofan anti-Ca antibody described here n are exemplified in the working exampriles below, in some enmbodiments, the anti-Ca antibody specificalLy binds to a human complement component Ca protein (e.g. the human C5a p i haisn the amino cid sequence depicted in SEQ ID) NO: or SEQ ID) NO:2), The teens "specific binding) a "speeiteally binds) and ike gmmiatical trms, as used herein, refer to two molecules %erming a complex (eyg a complex between an antiody and a corplement component C~a protein) that is relatively stable under physiologic conditions Typically, binding is considered spee when the association constant (lQ) is higher than HP M 's Tu n antibody can specifically bind to a CJa protein with a k. of at least for gr'nae than) 106 !(e.g at least or greater than 10 10% 101. 10" 0 1, 0 0" 10t or 0&or hgr M! In some embodiments, an antM-Ca antibody described herein has a dissociation constant (kQ of less than or equal to 10 (e.g. 8 x 10 5 x 10^' 2 x 10 10 or 10 s in some embodiments, an anti-Ca antibody described herein has a K 0 of less than 10n 10 10t 10K or 1 M. The equilibrium constam Rn is the ratio of the 0 kinetic rate constants - kjk. in some embodiments an anti-$a amibody described herein has a Kn of less than L25 x 10 At Eamples ofanti-Ca antibodies that hmd to tna with a K. that is less than 125 x L0 M includes. egthe BNJ364, BNJ367, N371 B 378, BNJ366. BNJ369, UNJ381. and BN J383 anti-Ca antibodies. In som. embodiments, ar anti-C~a antibody described herein has a K of less 25 tha 1 rt I 10 MA ExIaMpies of anti-Sa antibodies that bind to Ca with a Ko that is less than 10 aNI include, e EM the BN64 BN367, BN078, BN M NJ66. BNJ369 BN31. an BtNJ 383 anti&C5a antibodies, In soe enbodinments, an anti-CSa antibody described herein has a K of Less than 5 x 10 M, ExampLes of anti-C a antibodies that bind to C~a with a K 0 that is Less than a 104 M include,.g., the BNJ367/ BNJ37$ BNJ366, BN1369, BNJ381, and N1 nati.Cta antibodie 8IA n some embodriments, an a a ani body described ein has a K i of ess than 2 x 10V * M, Examples of anti-C5a antibodies that hind to Ca with a K hat is ess than 2 10 M inchde, e.g. the BN,369, NJ38 J B and N nnibodaes In some embodiments, an aniC a antibody described herein has a KaNof e than 5 x0 MI Examples of anti-Ca antibodies that bind to Ca with a Kthat isl ess than 7,5 x 10 M include, eg, the BNIJ6 9 and BN3 3 anti(-Ca amibodie. Methods for deternmining the affinity of an Wntibody for a protin antigen arc known in the an, [or example, the ainity of an antibody fo a protein antigen can be quanifiedu i a iety of tecniqs &u ch as, but not lniited to Western blot, dot blot Biolayer interterometry. Surace Phismon Resonance (SPR) method (e.g, BlAcore 15 system: Pharmacia Biosensor A B, UHppsala. Sweden and Piseataway, N ), or enzyme~ linked imnmnosNci fc assays (EL ISA ) See, eg, Harlow and Lane (1988) "Antibodies: A Laboratory Manual" Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. BUnny K. C. Lo (2004) "Antibody Engineering: Methods and Protocols, Uumana Press (ISBN: i58 29092I); Borre-bak (1992 "Antibody Enginering A Practical Guid," 20 0W. Freeman and Co, NY; Borreback (1995) "Antibodv Engneering, 2< Edition, OxfIo University Press, NY, Oxfrd; Johne c-t al. (1993)! ihnwmo Mehh 1(0:191-198: Jonsson et a( 11993) Am d Cio! Cin 5:19-26; and Jonsson et al 1991) Boecnmwe, 11:620-627Y. Any o thelight chain CDR. sets or light chain variable regions described herein s) can be paired with any of the heavy chain CDRI sets or heavy chain variable regions describe hern It is well within the purview of the ordinarily skilled artisan to, e., confirm (sn) that an anti-Ca antibody generaed by such a pairing possesses the desired affinity or activity SuSitable methods fAr confirming the activity and/or affinity ofan atnti-C5a antibody are described herein, 30 In some embodiments, the anti-C5a antibodies described heroin bind to both human C(a (hCa, and C75a from a nonInman iamunmal such as a non-iuan primate 92 (eAgy eynonogus maaque Y in some zmodimems, an anThCa antibody or atigaten binding fragmen thereof described herein does not bind to paralogs of human Cy such as C3a or C4a from the same non-human mnam matian species. in some embodimets an ani-C5a antibody or anti en-binding framenct thereof 5 described herein binds to ire. ihCa and a cyinwogus macaque CS protein comprising or consisting of, the foilowinga amino acid sequence MLQEKIEEIAAKYKHLVVKK CCYDGVRNH1 DE EQRAAR ISVOPRCVKA FTECCVVA SQLRANNSHKDLQLGRt (S EQ iD) NO:1 79). in sonme emboduimens, an ant i-CS5a antibodyv or antigen-binding Fragment thereof described herein binds to free 10 hCOa and a rhosus macaque CSa protein comprising, or consisting of the amino acid seqne c depicted in SEQ iD NO:179. in some embodiment, an anybody, or an antigen-binding fragment thereof, can bind to a desargnatcd form of Cia protein from a non-human maammaLan s' pecies (.a non-human primate species). Fr example, the anibody or anti-en-inding fragment 5 thereof can bind to a free Sa-desarg protein from eynornolgus macaque or rhesus nmaeaque, the protein Comprising, or consisting of, the following amimo acid sequence: MLQEKiEtAAKYKHVVKK CCYDG VRIh DETCIEQRA.AR ISVGPR(V'? KA FTECCVVASQLRANNSHKD LQLG (SEQ iD NO:I80, in some cmb odiments, the anti-C>a antibodies described herein bind to mouse CSa {ime. The free Ca fron mouse in som embodiments, the anti-Cia antibodies described herein bind to mouse Ca, but not to human Ca. In some enmbodiment, an anti-C5a antibody described herein does not bind to uncleaved, native (fully-foded} mouse C. in some embodiments, an anTi-Ca antibody described herein does not bind to paxaiogs of mouse C5 such as mouse C3a or mouse C4a. An ami-mouse Cia antibody, or an amigen-binding fragment thereof, can hind to a mouse Ca protein comprising, or consisting of, the folowing amino acid 5sequentce: LR9QiKI EIEQAAKYKHS VPIKKCCYDGARVNFYETCE ERVA RVTIGPLCIR ANECCT IANKIRKESPHKPVQLGR (SEQ ID N:51 See also, eug, Wetsei et al. (1987) BWchem >6:737-743. In some embodiments, an ant-mousc Cia antibody, or an antigen 30 binding fragment thereof, can bid to a desarginated tbrm of mouse Ca protein c i c ting the flowi amino acid sequence: LRQIKJEEQAAKYIKYSVPK KCCYO XARVN BE TOERYAR VTGPt (uAFNE{CT 1ANKURKIBSKPVQ) (SEQ Dn sonic erboimns te anti-aouse CA nibody Ads to both the fiengh muse C protein ang he esAr ated 00u of Mhe mose (Ia protAn 5 An anti-mnouse. CUa antibody described herein can. e., contain a Kght chain CDR set obtained trom a light chain variable reg inn poilypeptd comprising the following amino acid sequence: EUVLTQSPA I MSASL BKVTMSCRASSSVN Y lYWYQQKSDA SPKL W YYTSN LAP V PARFSCSCSONSYSL T ISSMEGEDAATYYCOQFTSSPLTFGVGT KEL KR 10 (SEQ ID NO:53). For example, an anti-mouse CSa ami bod ctan contain: () a Kahat defined light chain CDR 1 comprising, or conssting o te flolowing amino acid sequence: RASSSVNYY (SEQ ID NO:54) (ii) a Kabat-defined lght chain CDR2 conprsing, or COcaiin of, the folowmg amino acid sequence: YTSNLAP (SEQ ID NO:55 ) and/br (iii) a Kabat-defined light chain CR3 comprising, or consisting of, the 15 fol lowig amino acid sequence: QQFTSSPLT (SEQ ID NO:564 The ati-mouse C5a antibody can contain a light chain constant region, ezg the mouse kappa light chain constanvmgn comnprisng, or consisting oh the folkowing anuno acid sequienece AA APT SI PESSB QLTSGASVVCFLN N'BY NNFYK D VR IK DOSER MN L ENSW 2 ATDDSKDUS $MS$ Sli iIDEY KlTNSYgTCEl'IKTST SP $KSNRMN SEQ in some embodiments, an anti-mouse C5a anibody described herein can contain an amino-terminal signal peptide, g a signal peptide comprising or consisting of, the lowing amino acid sequence: MGWSCIL FL.VATAC TVHS (SEQ 1I NO:584 in some eMbodiments, an anti-nousc Ca antibody described herein can conain a light chain polypeptide comprising, or consisting of the flowing amio acid sequence: RE lVLQSPAIMSAS LGEKVWTMSCRASSS VNY YWY QQKSDASPKL WIYYTSN LA PVPARF SGSGSGNSYSLT1SSMEEDAATYYCQQFTSSPLTFGVGTK LE KR N AD AAPTVSI FPPSSEQL SGGASV VCIFL NN FY PKDINVKWK I GSERQNG VNSWTD s) QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATH KTSTSP VKSENRNC (SEQ 1. NO:$59 { MGWSCILFL VATAGWVHSREIVLTQSPAIMSASLGEKVTMSCRASSSVNYIYWY QQ KSDASPKLWYYT'SNLAPVARFSG SGSG NS YS LTISSMEGEDAATYY CQQF TSSP LTFG VGTK LELK RADAAPVTVSIFPPSSEQ L TSGGA SV VCPLNN FY PKDINV\K WKIDGSERQNGV LN SW TDQDSKDSTY SMSST L TL TKDEV ERHN SYTCEA TUK TS TSPIVKSFNRNEC (S EQ ID NO40 Y~Oin sonic embodiments, an ant-mouse C~a antboy dscibe hrei cntansa light chain Ipolpide compriig amino acids D o 214 of SEQ ID NO:59. In some embodiments. an ant&- mouse C~a antibody desc ribed 1V .4- 'kC H)IAM herein contains a light chain polyvpepride compr.Uiin amiuno acids 1 to 19 and. 21 o23Af SEQ ID NO:60 . 0 An antimse Ca antibody described herein can. c.. conain a heavy chain (DR set obtained from a heavy chain variable region poly'pcptide comprising the toli ng~n amino acid sequetnce: L EVQLQQSGPEL LV KPGA SV KISCKASYVTETDY YY I NWV KQSGKS LE WIGY Y P NDGLDTN YNQKF KGKRAT LYTV DK SSSTA Y ME LRSLTSEDSAW W Y CARRY YSD)YGM ISDY WG QGTS VTV SS (SEQ 1D NO:61 1.For example, anz ati-mouse CSa antibody can contain: () a Kabat-efined heavy chain C R MR cOmprising, or consisting of, the following amino3 acid scqenc: DYVY IN (SEQ ID NO:62 (ii a Kabat-defined hcavy chain CDR2 compnsmg, or consisting of he flowing amino aciSd sequence: V IYPNDGDTNYNQKFKG (SEQ ID NO:63v and/or (iii a Kabatind heavy chain 2C(DR3 comprising, or comnstng of, the following amino acid sequence: PYSDYVM DY (S EQ 1D NO0:641. The antaimouse CA amibody can contain a heavy chain constant region, In some embodiments. an anti- mouse Ca antibody described herein can contain an iOno terminal signal peptide, eg., a signal pepide compnsing. or consivtng of the foiowing 25 amino acid sequence: MG WSCiLFtLV ATATGVHUS (SEQ 0D NO:65}. in some embodiments, an anti-mouse C5a antibody described herein can comain a heavy chain polypeptide comprising, or consisting of,he following amino acid sequence: L EVQLQQSCPEL VKPGASVK I SCKASCY TFT DYY IN WVKQS lGKSLET:WIGC VY P NDCDTNYNQKFKGKATLTVDKSSST A YME LRS ITS EDSA VY YCARPYY SDVCM 30 DYVWGQCT WVS (SEQ ID NO A6 or MWCIULO FVATATG t. VQIQQSCEIKPCASKISCIKAS3 Y NWVKQSIHG KSLEWGY YPNDG DTNYNQKF K :TVDKSSSTAYMEL RSU Sf&DSA VV YC.ARPYY SDY G Nil) YW GQTSVTVSS (SEQ ) NO7. In somc embodiments an anti-mouse CSa antibody described herein contains a hWavy cAkn polypeptide Comprsing aino acd 2 to 21 of SEQ H) NO:66 In some embodimetnt anp ami-tmouse C>a antibody described herein contains a heavy chain piolypepitido comprising anino acids! to 19 nad 21 to 140 of SEQ ) NO:6 In SOme embodiments. an anti-mouse CS:a antibody described herein contains a heavy chain constant region pot ,a.6, ypehd ionni oeori iore amino acidsubstitions from the above described 10 In some enmbodimtents, an ant-mouse Cdia anmibody described herein contains a lighl chain potypeptide comprising (i) a light chain CDR 1 comprising, or consisting ot, the amino acid sequence depicted in SEQ ID NO:54: (ii) a light chain CDR2 comprising or consisting of the amino acid sequence depicted in SEQ ID NO:5 and (iii) ai chain CDR3 compriinHg. or consisting o the amino acid sequence depicted in SEQ ID 15 NO:56; (iv) a heavy chain CUR I comprising, or consisting of, the amino acid sequence depicted in SEQ ID NO:2: (vI a heavy chain CDR2 comprising, or consisting of, the amino acid sequence depicted in SEQ 1D NO:63, and/or (vi, a heavy cin CDR) compOsing. or conisting of, the amino acid sequence depicted in SEQ 1D NO:64, In some embodiments, an an-wnouse Ca anybody described herein contains a 20 lght chain poypeptide comprismg, or consisting of, the amino acid sequence depicted in SEQ ID NO:59 and a heavy chain polypeptide comprising, or consisting of, the amino acid sequence depicted in SEQ ID NO:6A in somc embodiments, an ani-C5a anibody described herein can hind to hunma C Metho Pdig nt a tidead ig ldgFragments hercof The disclosure also features methods for producing any of the antCa antnbodies or antigen-binding~ fragmoents thereof described herein, in some embodiments, methods for preparing an antibody described herein can include inmmnizing a subject (e,- a non 30 human mammal) with an appropriate immunogen. Stable imunnogens for generating any of the. antibodies diescribed herein are set forth herein. For example, to generaic an antibod) Mhat bindq to C a a sanidld aristan can imunize a suiale suie {y a uwo human mammwni such as a t at, a mIouse, a ger bit, a hatiste.t dOLX a eat 3. pgt~ t goat a horse, or a non-human. primate) ith a floength CA a polypepiec such as a fuMl-length t5n pot pepudce ompntsig ibe amino acid seuence depicted in SQ ID NO: I or the Cegmated trm of t, tegI the human a desagt eompristing the amino acid SequencC dpicted mn SEQ ID NO2}, In some embodimerts the no~nmuan mammal i. Q ditcien ei a C5-deficient mouse described in, eg.. Le y and Laddh I ) A A ;0g 00905 1-5, Cro kher v at ( 1974) 1 O ah J 27G AP122-124V \\is et a al (1990)1 ; Ch4 - > I 24-244o, and Jungi nd Pepys 14 mun 4 7 1 27 Human cQa cnn be puntied ron human serum an described m, e g \ tbtrti and I enson ('9)/ /mnumo1-2517 and Mandenno et i 2 J nusrel ATRhads 15314 -50 ee also the working examples Human C s a alo be geneated i rs as desrhbed in, ay. \allota and \NIAlerdherbard (19) J F. ted f7 11 09 Punfied human Ka is aso comnmereialv axilable timreg. Comrpl ement Tcehnology Ine (catalog mimnber A 144; T>1er T exs Kcomindant CA can also be generated by one of ordinary skill in the art as descnbed in, e g. lAthe et at (1994) /W >c 01159 116W \ stCtable subiet (ag. a non-human mammal)han e inanied with the appropr iate antigen adong sith subsequent booster imnatnurauions a number oh'imes utficent to ebei the productou of an autibody by the man l'he mun gen can he admimstered to a subieOe g. a non-human mamma an adjuran A useful i producing an mob'dy inaubjac include but are not hted to. protein ad juans bacterid aduunts, eg p, n hoic hactertia I M < 'nct rat n pcmnn or .seumnn la ItsmIa?.ra) and bacterial coinponxeits mebiuing tcel We all skti o.ii ealose 5 dimycoiate, inonophosphoryl ihid A, methanol exactable residue (IkW ) of tuberele /a.J/utx. complete or inplete [reunds adjtwan iral adjv ans; chemcal adjuvan, e. alumim in droxide and iodoaaetate and choiestervl hemisuenate Other adiuv ants that can be used in the methods t'or mdluem g ani imnettt response include, e g, cholet a tOun and paroxa as protest 'See also Bicg at al. i 1990) AunsnosMnr 30 Nit MA- See alo, eg. Lod eli et al (2000h 1 e j: 510In: Johnson et al 1999 d 464464 :adidge t A Q C99 ) MAh 10 310 and in some embohmerts the methods include prepanng a bindona cell lne tha sere es a monclonal antibdy that Winds to the imunoyge For a suitable mmal such as a labmator mouse is imnmumzed with a Ci polypeptide as deribed above. Antubodyproducing ell eth . 13 ells of the spleen) of'the munumed mammal can be seated tvo to for day alr at lest one booster immunizatmo of the imn n~ogen int thenl g anow briely in hte before uin wth cel of' a stable rmvel omran cel lin 1hIIe cells can be fused in the presencee of a fuson promoter such as 0O g., vacinWm ur or polyetlt a gly col The hybrd eS obtamed in thm i are elMed, and cell lone's seetin; the deMed antibodies are selected For example spleen cs of PaibT mice immuniAed with a suitable immnnogn can be fised with cells of the myeloma cell line P Al or the rnyelotma cell line Sp2/0-Ag 14. After the vision, the cells are expanded in suitable culture medium. which is supplemented with a selection 5 medium. for example I A T medium, at regular intervals in order to prevent nrmal yeloma cels from overgrowing the desired hybridoma cels. the obtained hybrid cells aire then screenedt for secretion of the desired antiboies cyg an ani ody that binds to O5n and inhbits ithe interaction between (ia ard a Chu receptor e C a S ). In some embodiments, a skilled artisan can identify an ani-Ca antibody &om a 0 non-immune biaed l"Irar as described in, eg IU.S. p[ a e no, 6300,064 (to Knappik e at: .Morphosys A) ad Schoonbroodt et al(2005) ANuclei Acids R (A 3:1eX I. in some embodirnents, the methods described herein can involve, or be used in conjunction with, e~g phage display techniologies, bacterial display, yeast surtface display, eikaryotic viral dspa, mamnmailian ecll display, and c cie (e.g, ribosomal 5 d isp lay) antibody screening techniques (see. cdg. Etz et at. (2001) 3 hBacterioi 183:6924 6935; Comelis (200 CurrOin Biotehm>/ 11:450-454: Klemr et at (2000) irnbdoy J46:3025.-3032; Kieke et ad. (1997) Proen Eag J:1303-13: Y cg a at (2002) Binawhcno Prog 1 0:212220: Boder et al (2000) M Utod& Enmoe 328:430-444; Graherr et al (200) Comb Chem High Thughpui Screen 4:185-192: 30 Michael a) (995) (4a Ther 2:160-668: Pereboev et at (2001)J7 Vi! 757107- 13: 8i Sh ai ea i9 9J laJ m W AM 231 1 9 15 and es 4 at (200O) A, 40110(1 for uleynt ,m amliodies uoini varous phaiz disp~q aswohods are know; in the at I phag a isplavnithovS, tmrietronai antody d anae yed 5 othe surface of Mhee pancle4which arry the polyn eotide sequences encoding them, Such phage can i utied to play antigenbnding domains of anti bodies, such as Fab. v or diN fide- ond stilliz-d Fv antibody framet expressed fronm a rperTirrcoinatorial antibody library (e. han or murna) Page usd n i hse rmthods ar typically hinmenious phage such as fd and M I3 The antigens domains ar expressed as a reconinantty fused protein to any of the phage coat proteins pill, pVI L or pIX. See, eg, Shi c at (2A010) JMB 3%385& Exaimples of phage display methods that can be ued to make the immunolobulins. or fragments thereof, described herein mclude those disclosed in Brinknma et at (1995) JInualn Alehods 82:4-5W; Ames et at (199) Jhnunuolethods 1 77-186; Kettieborough et At 15 (19941 Eur hnmuno/n4:99 Persi e at (1997 Gene 187:908; Buton et At (1994) Advance in n l A196280: and PCT publnaion nos WTO P()09, WO 91 /1073 7, W) 92/ 0104 WO 92/9 619, WVO 9311236, WO 9515982 and WVO 95/24% r . SaIb nmthods ar also described in, e . U.S patent nos, 5,698A26; 522 Q3,09 ; 5 ,7 , ,7 75; 5882'2047; ,57 5 , ' 4273908 In sone ombodimets, the phae display antibody hbraries can be generated usi nmRINA colected from B1 cells from the immumnized rmamals. For example, a splenic cell sample comprising B3 cellIs can be isolated from nice imsmunized with C~a polypeptide as described above. imRNA can be isolated from the cels and converted to 25 cDN~A using standard molecular biology techniques, See, eig. Sambrook et at (1 99) "Mcula C loning: A Laboratory Manuad. 2' Edition (Told Spring Harbor Laboratory Press C.old Spring H arbor, N~c [Harlow and Lane (119881. supra; Beanny K. (C. Lo (2004% aupra; and Borrebacek (1995), spa. T he cDNA coding for the variable regions or the heavychaad lihtg haine polvedes of inninglo ns ar used to construt 30 the phage diplay I ibar Methods t generating such a ibrary arhe bribed la in . n-;R59 Mer Ct at (ITS ) A y 'J AlNS j 1:21.4% Di 'Nro e al. (2005" Bwem MEF 9 604 and Fagbcr g at (1995) ARod MOI N/o! 51355-7 in some embodiment a comtnation of m.lction and ccan be employed to idetn't n anybody of interest ironu, . a popua Of hybridomadenived 5 antibodies or i phae dispta antibody ibbran. Suitable methods are known in the art and ar dlescribhed m, e v I, loognboom ( %'') in /iotlw g 15:62-0: rnkrman etk (19915)m unro, Ames t a (1 N0 5 ), pra Kettleborough e at i 4) up' Pese c it ( 1997 k r and anton et al. (19V4), .sun. For example, a pluraity of phaermd vectors each encoding a fusion protein of a bacteriophage coat potim t -g It) pl ill, or pIN of \ 113 phage) and a d"trent amtten-combumap region aepre deed wim standard molecular biology techniques and then inroduced into a popuolaOn of bacteria (t g . , v/i) Expresson of the bactenrbhage in bacteria can, in some eihodiments, require use of a bdper phage In some emlodient, no helper phage is required (see e , Chasteen et a. (2006) AN &/ Ic/J Rev 34A'11i 4). Phage 15 produced hon the but era an recovered and then comacted to e g., a target anign bound to a solid support immobilize) Phge way also be contacted to antigen i solution. and the complex is subsequenty bownd to a sohd suppon. In some enmbodunents, the mnbiedpae are the page& of mret Accordingly the unbound phage are removed b h support. 'oowi the 2v wash step, hound vhe are then elated from the solid support. ea vnum a tow pI I buffe or a free target antgen competitr, and reeoered by iecung bacteria. in some erahoduents, te plth that ar t' not inmobibled aR the phage of met l an embodimenus the opattion of phae can be contacted to the antigen two or more times to deplete from the population any of the hate that bind to the support bound phige z are then collected and toed tor subsequent screening steps. To enrich the phage population fr phage particles that contain antibodies having a higher affitv tor the e antigen (white reducing the proportion of phage that may bind to the antigen non-speciicallyt the chLd phagne (described above) can be used to re-infect a population of bacterial host ceis. The expressed phage are then isolated from 30 the bacteria and agiun contacted to a target antien. The concentration of antigen. pH, temperature and inclusion o detergents and adjuvants during contact can be modulated to enrich or higher affiimt anuhiod fragments. The Unhond phagp ar removed by washing the solid support The number or eYee duratuon, pH. temperature and inclusion of detergents and adJuvwts duing wshng can also be modulated to nich to' higher affinit tragent. antibodam Fl'ow i the nash step bound phe are then duted fron the soid support, Anywnere m n one to six neravri e evVees of pannig may be used to emric h for phage contaimtng anmibosdles haxng hig~her affiniy or the target ani en. in some embodimems a deseleeon step can also be performed in coniuncon wuth aniv of the panning approaches desce heein,9 ndix idua hgeo eopuion Canb so d by[ nfetig bateti adtna 10 latniat a densit to allow tbnwion otooo niois For example) to identify using phage display techniques an antibody that binds to Ca, but not to (1. the flowing panning approach ca be employed The population can first be contacted to a surface containing bound ntive ftull-ebngt human C5. The process can be repeated two or more times, each tin col cting the unbound phage, The 15 populatio can also be contacted to a solid support cornaining surfacc-bound C4 and/or contairni ng bound CJa or desarginated Ca. Phage that bind to Ca are eluded front the surface and recovered by infecting bacteria, iterative rounds of phage selection may be performed. After one to six rounds of selecuon, individual recovered phagemid can be 20 screened for expression of antibody fragmnts with the desired specifcty and affinity, A subpopulation of antibodies screened usn the above methods can be characterized for their specificity and binding a tinity for a particular invrnunogen (e.g, Cai using any immuntological or biochemical based method known in the art. For eampl of an anti.y to C5, as compared to native, full-lngth Ci. 25 nmay be determined for example using inmuMologieal or biochemical based methods such as, but not limited to, an EUSA assay. SPR assas, imunopreipitation assay, NAnity chromatography. and equibrium dialysis as described above. lmmunoassays which can be used to anayze immnuinospeciic binding and c4ssreactv of the antibodies include, but are not tinbitd to, *c and , uIean but ae no imted ornopetitive an on-conmpetitive assay systems using technique 30 such as Western bots, RIA, EUSA (enzymn linked immnosorbent assay. htsand wich" uimmunoassays, immunoprec ipitation assas. im unodiffusion assays, aggiutinaion assays, oin enewhationsssuitnitt orauetric assays tore~cn mtass and -otin A Smmmassavs uch assaysareiutine and welt nownin Antibodies can also bo asaed u0 arsy SPR-1ased assas know n m tho it tor 5characterizing the kinetic parameters of the imteraction of dhe antibody with ( Sn Any SPk instrument comnretll v aidble ndhuding. but not limited o, RAeol Instrumons (Biacore AM lppsala dimn L sy instruments (fnity Sensors Fraktn, \MassaculsseiK USN moh mindsor ScieOn limited; Rrk K K SPR (I LIA .s steins Nippon L ase and Eliroomes Lab; hokkaido, Japani, and SPK 0 Detector Spreta (Text lnsituments Dallas, Texa can be used in the methods described herein, See, eg, m\ullet et al (2000) AhocL 2 'O L Dong et l. (2002) RNon s i lAM; RWmv 42.; 303,13 Fivash al ( 1991) WT OrV t chnol: 97 101 and Rich et al (2000) (C (Ar iechmo j 54-6 1 it is understood that the aboe rnethods can also bc used to determine if. cq., an 1 Manti-L'5 antibody does not bant to len't, native PS, C3, and/or CA proteins The abo e methods can also be used to determine i an antibody that bmds to U5 also mibus the intraction between Cg and a ( Sa receptor 1he abe mehod can also be used to determine if an antibod that biIds to t'5a also inhibits the activity of (a As desrtbed in the above references, sler phage seetin, the antibody codm 0 regions nom the phage can be isolated and used to generate w hole antbodies including human antibodies, or any desired fragmes, and exprened i any desired hosi, including inamduni-n cells i ct ells plant cells yeast, and hatrA, e g as described in detail beow F or example techniques to reonbinamly produce ab. Fab' and F(lb' rauguents am also be epnoyed usm0.0 methods know Ai the art such as those discllsed in PT publication no. "O 9212231 Muhlina. e; a i KAM ( BToer hivn- Ii62-1 diQ' and Sawai ci (A 5 M ) AY0 3 R r um/ 3:234, and Ektter et a! (195 ~&lenn 240041-1043. Eanpies of ehoques which can he used to produce sigle chan W and antibodies include thoe inl'S pant nos 43116.701 and 52549 1 (usion et aL 190 1) lethods inEnniog 20A4M; Shu et a. (199 3) w Wa A, d MA: L%) 9:09A799: and Skerra ei a!. 1980 Spnas l 4:030- 1040. 1)r>' Phage display technology can also be used o, et. increase the affinity of an a' cm6 h. o-cencI antibody fr its cognate antigen. The technology,. reered to as affinit maturatin can employ muttagjenesis or CDR wa1 king and reosel action to identify antibodies that bind with higher affinity to an aetign as compared to the int or p a See, 5Chg Gaser et at. (1I992) I /mu ndu 149:3903913, Liraries can be constucted cons isting of a pool of variant clones. each differing by one or tmore amn acid substitutions, Mutants wsith in cased binding affinity fru the antige~n can be seleted for by contacting the immnobilizd mutants with labeled antigen or any comibmation of methods described above, Anyv creening t method known in the art can be used to identify 10 mutant antibodies with inercased affinity to the antigen (xCg SPRI or ELISA techmueittts), In some em~bodrments, epitope mapping can be used to identify, e.g. the region of Cfla that interacts with an antibody, etg, a region of CSa that hinds to C~aR L Methods for identifyirng the epitope to which a particular antibody binds are also known iP the art and are described above, T 'he antibodies andlt frgmenits threofj~ ietfid herei cnt heo a e madve "chirnerie: Chimneric antibodies and antigen-binding fragments thereof compri ye port ions tromi two or more d ifferent species (e g * mo use and human. Ci meric antibodies can be produced with mouse variable regions of desired specilfiyusd to humnan constant domains (fort example, U S Ptent No, 4,216,5 674 in this mnne~ r, non huani anibdisa be modified to make them more suitable for human clinical app.lica tion (ei. mnetbods for' treatig or prevanting a complement-mediate~d disorder in a subject). The monoclonal iatibodties of the present disclosure include Thunmanized" forms of the non~hurman (e.g. mouse) antibodies. Hutmanized otr CDR.-grafted muAbs are 25 particularly useful as therapeutic agents for humans because they are not cleared from the circulation as rapidly as mouse antibodies and do not typicalty provoke an adverse immune reaction, Generally, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-hunan amino acid residues are often referred to as "imnpor" residues, which are typical taken from an "nmort" 0 variable domain. Methods of preparing humanized antibodies are generally well known in the art. For example, huzation can be essential performed flowing the. method C50001Ano" Wh a anbod, ofQnW, of Wnter anJC v ae , Jons ai d - \ 3 et ak (1988' \:% 33a232 3 022: and VeThoCpeon ei al {1:S< &Wn.c 2v391534-1 by substuting rodent trameWors or CDR sequences for the corresponding sequences of a human anibod. Als see, eA, Stalens ct at (2006) Ald hna o 4: 2431257. In 5 some cmbodiments. hum am zeid t'raq of non-hunan (eg.. mouse) antibodies are human antibodies ( recent antibody in which the CDR regton ammo acid reidues m'the non human antbody (gy, monue rat rabbit or non-human prmate aidy u hmns the desrdl speedic c natMY and bindmig caePNy are grated onto the framework scaffold of a hmn a nuodN AAdIon humanizaton methods are descbd below n the 'Mthods for gDR sequences from a donor antibody (eg. a nonuman amibody)f to the framework. regions of an acetratbd (., ahuman antibody) are well known in the art and are described ii, eag. Jones et at (1986) atre 321:522525; Verhoeyen et at (1988 Scec 239(4847h 534-536; Riecmann et at (1988) Nature 15 332:323-327; Queen ct at (1989) Proc Nad Acad Sci USA 86:10029~1033; PCT publication nto. WO) 93/0 1 1237: Kettleborough cet at (1991) Protein Lngineerrings Desgzn tand Se/action 4:773-783; Benny 1K. C,. Lo (20041 "Antibody Entgirneering: Methods and Protocols Hlumana Press (ISBN: 158829092 1): Borreback (1992) "Antibody Engineering. A Practical Guide..' WH. Freeman and Co., N Y: and Borrebaek (1995) 2 Antibody Enginnerngn" 2ff Edition, Oxford University Press, NY, Oxtord. For example. CDRs from a donor antibody cant be grafted onto framework regions of an acceptor antibody using overlap extension polymerase chain reaction (PC) techniques as described in, e.g . Daugherty etuat (1991I) Nucict Acids Re: 19(9):2471-476;' Rogska et at (3996) Protei Engineeng~ (10):895-904: and Yazaki et at (2004) Protein Engineerig. Doigs~n & Selection 17(5):481-489, in emibodim'nts where the selected CD aK mino acid sequences arc short sequences (e.g fe t wer than 10-15 antino acid' in lengthxa nucleic acids encoding the CDR s can he chemically synthesized as described in. ecg Siraishi et at. (20(17) ?vudet Acciis SmoiuSri esC'5 11:12 9,1.30 and U.S5. Patent No, 6995,259. For a given 34) nucleic acid sequence encoding an acceptor antibody, the region of the nucleic acid sequence encoding the CDRs can be replaced with the. chemic >alby synthesized nucleic n~d~h' '94 acis Wno itg Stardd a iiUl Ida oigsdy tchogs Tl, be and T ends in,hA Ae Icatiy synthesied ucicd acis hesiedto comps sticky end estrniien enzym sMen t use in. cloninreg uleccd it the nucleic ac ,i encdin dtevarabl reti a oo niody.hnennadad eeenia a a a I some instances, one or more framework r amino aeid resides of the human immunoglobulin are also replaced by corresponding amno acid residues of the non-tuman amibody (so called "back nutiions" in addition, phae display libraries can be used to vary amino acids at chosen positions within the antibody sequence. The properties of a humanized anybody are also affeted by the cHOice of the human 10 framework, Furthenmore, humanized and chimorized antibods can be modified to compose residues that are not fond in the recipient antibody or in the donor antibody in order to fuher mov, such as for example, affinity or efftctor tunetion. Fully human <mbodies are also provided in the dielosure. Th term "humam 1 S atibody nehle antbodies hvin s Ibe and constant begins I prewt deMved from human mtogh butin sequenes, preferable human permhnc sequences. Iurnan antibodte can mnclde amno ad residues not encoded b hamuigunlme immunoglohuliti sequenese~t nutatons introduced by random or Af sp eIei mutagenessn tnro r b somatic utaionn it ) However, the term "'human 20 antibody" does not include anOtibdies n whth UOR sequences derived n)m another mammntahan species, such an a mouse, have been graned onto human framework sequenes ue.. humnandzed antibodhI) Full human or hulman antibodie mUay tie dernred tiom transgenc mice array y ig human ntibody genes earrymng the variable fl). in erw (mcing (Jndmstant (C) exons or horn lman cell For example, it is 5 now pos1 to produce transgenic animals (eq mie) that are capable, upon imnmuahon, of produnmg a ±uI repertoire of human antibodies n the absence or endoueiunoun aunoglobuhin production. See,e p.. Jakobovuts et al L199N ) Pto \att Ad S ! 1 90251, <jakobovits ct A (193 Nuae 3MSh225 Bruggemann t al (193) Wer in mland. 733; and Duchosal et al. 1992) nare 11125& Trangenc 30 mouse straws can be engineered to domain gene sequenwcs from unrearranged human immtmnoglobulm genea One eampie of si h a mose is the HuMAb )iouse (ledarex, Ine. , hich contains human rnm noglotdhn trausgene mniloi ti encode unmearraneed human p heavy and sc light chain imflmmfOglObuhlm xequenceet together with iarghet'd miutadons that mneetiate th Iendm.ogenous pn and K chain 1et. %ee, e < . Lonbere et A (I4 4 Na 31904'4,836 'V he preparation and use of HuMah tice, and 5 the gelorme moiOctionh armed l: unh mice. arc father deserved in Tavor a at (o 192) \wldc lads ON 2 2874i5, (hen. J et at i 1993) hitranmi la imnology 53 6656 Thuiion et A I9t3) Poe AW Aed &d SAO 90~32047, ( hoi e; A * I03) Man ( n *s 4 i 7123,lu lKon et it (19mM)d hnmuul 5241-020, Taylfor et al. (1'WA i nr;r'nu /estod hgn 6:'9t§I, and Fishw ild ciel i 99%) .10 ;Uy B& anwhs h 14 4515 An alternate transgem mousc sytem for 'xprcssins human imnogouhm gtene is referred to a the Xnomiouse (\bgenm hto) and is desehied i, e g . IS. patent nosW U071, i ISM 6.1 50.54 and i, 2InKn like te hiuM Mous svsein, The Xcnomous sytem nnvohves dirupton of the endogenous mouse heav y and hht chain genes and insertion iNo the genome of the I15 oun tNag'e c tYy lg Wari'ainnged huinan heav and light chain mnmmnuogtlohln loCI that contain human vriNable and consent regam sequences Other systems know n in O art 'u O xpressing human nonunoLohthu genes mnlude the KM \ouseu 5'vsiem, desched in doti1 in P hiPubeation WO 02 4M78 and tile T mouse sy stem described inrommka et I (2000) Pcw\alAcaS U 1i 7.722427 2'he human sequences may code for both the heavy and light Shams of human antiboies ard would fRunction correcdy in the mice, undergoing rearrangement to provide a wide antibody repertoire similar o that in humans, The transgenic mice can be immrunized with th~e target protein immnunogen to create a diverse array of specific antibodies and their encoding RNA. Nucleic acids encoding the antibody chain 25 components of such antibodies may then be cloned from the animal inmo a display vector Ty pically, separate populations of nucleic acids encoding heavy and light chain sequences are cloned, and the separate populations then recombined on insertion into tile vector, such that any given copy ofthe vector receives a random combination of a heavy and a 1igt chain. The vector is designed to earess antibody chains so that they can be 3 assembled and displayed on the outer uace of a display package containing the vector. For example. antibody chains can be expresseN as tusion proteas with a phage coat 106 PnOo n ion thet"." oeU tee of the Flage r paaes can he Abeitrd and screed fr display of antibodies binding to a target, bi addition, the phagct-dispiay libraries screened above can include human attibodies (Hooenbo.o et al. (1992) :o/ Bi! 22:381: Mart at A. (1991) AL/I 8 222:514597; and Vaunhan at al (1996) Ntwre Blotch 1:309i Symhetic phage libraries can be rated which use randomized combinations of synthetic human antibody V-regions By selection on mign, WlY human antibodies can be made in which the V regions arc very huriamik e in nature, See, e.g, U.S. Patent No. 6,94 32: 6,680209; 4,634,666; and Ostberg at al (1983) Hvbri na ;2:36367, the contents of each of which 10 are incorporated herein by reference in their entirety. For the generation oftuhuma n antbodies, also see Mendez ct al. ( 998)i lAn/ure Genras 1:146-1.56 and Green and Jakobovits (1 99 8) J Er te J848345 th disclosures of which are hereby icorporated by reference in their entirety, H uma antibodies are father discussed and delineated in US Patem No.: 5,93998 6,673,986; 15 6i 1498 6,075,14 :6J62,967: 6,150,584: 6,713, T and 6W657O03 as Wel a U d , Patent Publication Nos. 20030229905 A L 20040010810 A 1, 20040093622 A , 20060040 363 A 1, 20050054055 A 1. 20050076395 A L. and 20050287630 A 1 Sc also imematonai Publicaion Nos W 9402602, WO 96/34096, and WVO 98/A483 and Eurpean Paten No, EP O 463 15 1 B1 The disclosures of each of the above-ested 20 patents, applicatons and refrences are hereby incorporated by reference in their In an alternatine approach. others including GcnPhaum Intern atwinut Ic., hav e utilzed a "molocu< approach, In the nunoux approinah, an exogenous lig oau is imkced through the vision of pie s ndiVial gencs) born the ig locus. I hus. one 5 or nt ore Vel gene or or ne or nore ll genes a Ou constant remon, and a second constant region (preferahh a zamna const regim re ormed into a construct for inertion amon anima Thi approach i described in, eg. U. Paten Nom ",54807: 545806. 512515: . 26, W O 33 5t SAW 56I0: 5370,29' 73o5d 1.3i As L K6; 5612,205, ?ZnLm, imAs 5 3 30 i56901:i 57t3 30129: 5.47409; 25558, and A01W71. the dislosures of Which arc h'brev mpomtad by refr ence in their entet Sae ao European Patent 97 No, 0 546 073 B, international Patent Publicaion Nos, WO 92/03918, WO 92122645, WO 92/22647, WO 92/22670, WI 9/12227, WO 94/00569, WO 8 WVO 96/14434 WQ 97/I3852, and WO 9824884, the disclosures of each of which are hereby incorparated by reference in their entirety. See frther Taylor et aL (1992) Nuc Als R( 20: 6287; Chen et at (1993)1nr /i un : 647; Tuaiiion e at (19931 ProI Narl AMc Sc USA 9: 3720-4. Choi et at (1993) Nure17; Lobrg e a (1994) Atmure 36$: 856-859: Taylor em aL (1994 n namahu /mmunl Q: 579-91 Tuation et at (0 995)9 A nunol m 4: 6453-5: Fishwild t At (1996) Nature Biotech rn JA' 845: and TMailon ct At (2000) Eur JmWmnl. 10: 299 000 the 0 isclosures of eac .of wich arc hereby incorporated by reference mi their entrety in certain embhodients, de-immnnized foms of the antibodies, or annigen binding fragments described herein are provided. Dc-irnmitnized antibodies or antigten binding fragments thereof are antibodies that have been mod ified so as to render the antibody or antigen -indring fhrment thereof non-ismmunogenic. or less imniunogenic. to I§ a given spces.e-immuanization cani be achieved by rmodifying the antibody or amigen binding fragment thereof uttilizin any of a variety of techniques known to those skilled in the art (tee, e~g,. PCT Publication Nos. W() 04/10815 8 and WO 0054317). For example, an antibody or antigen-binding fragnment thereof may be de-iunized by identifying prntial T call epitopes and/or B ell epitopes wirhmn the amino acid eque ofth nbore antagen-bhmdmg fi ient thereof and rencto og one or more of the potemiral I ellB epit pesnd/or R3 eel epitfopes from the antibody or antgen binding fragment thereof for euample. usmg recombmnant techniges The nmdfied antibody or antigen -binding fihiment thereof mayv then optionally he produced and tested to ident fy antibodies or antugen-b inding. tragments thereot that hav e retained one or more tolomeal- acivtis suc adore 25 desired beoiclatin suha afrcmple, bimdms amminty, but ha e reduced tinumogemecsty. Methods for utentinm poteriral F cell epitopes and r cl p0 o may be camed out osng techniques know inv the art. such as fo example, computatonal methods (see e.g. PT Pubbiaion No. WO 02/ JI3"A m rro or /aT technique Sad bological asag or physicn methods buch as for example Sdeterminaon of the binding of peptides to MR molecules determination of the bidmg ot popde:MLi ' complexes to the W cell rceptors rion the species to receive te 08 ej psk datiood) 0r a194tenlindina ir na ent thereol tkStlio te protein or peptde N'Wrts itereof ain transient amals with the MHC molecules of the speces to recede the atibod or anogen-idig fragmem thereof or testmg t tammgeme ammal, reconstated nit mimzune sysem edl tio the speeds to ree n U the nindy o antogenlyedg impment thereof, etc In rious embhodiments th d Kmmuied .untibodes desried heemi niude demmintied awigen-bodnmyng fi fm ents, hl' s20 , Fai' and .ahl , monoelonal antbode inne a0tibodeS fung human anti bodie nneertd aniduies cutec aS Mr emp e, ebauerie igle chain, d W'OR tirafted, humanmzed, and arti lI ly selected untibodieCs; syntheite antibodi es and set IP sntheti andbtoies" hn the therapeuc embodments of the present disclosure, bispecitic antibodies are eontempated. Bcispertie antibodie are monochmat preferably human or hminianized, antibod that have bmding speeieties or at least two ddl'lent ante n the 11946,~ ~ ~ ~ ~ ist in mthe~g 2P1 tJ pr esent ease, one of the binding specificities is for CU~a the other one is for any other 1 U 1 antreci'S .S M 5 m. IU' 99 ], 17.-,5 J Me thods for making bispecific antibodies are within the purview of those skided in the art. T raditionaily, thte recombinarn production oftbispecific antibodies is based on the co-expression of two immunoglobuti in heavychain/ight-chain pairs, where the two heavy chain ligh9chain pairs have different speciiciies (Mi stein and Cuello ( 1 3) 20 Arwev M0: 37-539), Ant ibody variable domains with the desired binding speeificties (antibody-antigen combining sites) can be fused to immunnoglobulin constant domain sequ~ences, The fusion of the heavy chain variable region is preferably is with an immunoglobuhin heazvy-clhain constant domait, ineluin at lest part of the hinge, Cn2. and C03 regions. DNtAs encoding the immunnoglobuhia heavy-chain lesions and. if 25 desired, the immuntnoglobuhin light chain, are inserted into separate expression vectors, and are co-tansfected into a suitable host organisam. [or further details ot' illustrative currently known methods for generating bispecifie antibodies see, e.g., Suresh et at. (1986) MAhhdst in Ea nQ 21:2 0; PCT Publication No. WO? 96/270i1; Brennan et at {1 985) Science 22:81; Shalaby et at, a Eap Med (1992P) 171:21 742$5; Kten eta 30 (1992)] JImmunol 148(5):1547' )553; Hollinger et al. 1993) Pmec Nat/ A4cadS&i USA 90:64444448; Grutber et' al t1994) J mmmo! I52:5368; and Ttutt et at(1991)1 mlflna"l 14n>0. ipecaie Tibodies aNo mIde crs-inked or heeerocongeate -mtiodies HIeeroconjugae anulodie, may be made usmn an convenient eroodhro method\ Suitale ess-linking g sae w elt known m the an, and are disclosed m 11 S Patenu No. 4.rn6NO. along with a nmnther of edsne chqes. 5 X ~armaos teennmques for making and isolaing bispecedic antibody tragmems direcdy fromY recombinant cet l rtre hav e ahnQ been desenibed. For example,~ bispeeda antibodieS hae a been produceudum e apper. See, eg, Kostelny eta i lo99) J Jonos I485 i 1547 553 The eueme opper peptides from the 'os and m protems ma\ he hked to the Fab' portons of two different anbodies by gone fusion ,ene antid homodimerS nmy be reduced at the hinge regon to form mononers and then re oxidid it fatrmi the anybody heterodirners '[his method can also be utilized fir the production of amtibody homodumers T[he "ibabody> technology descenbed by Illhnger et ad I 19931 Pro< \Ar4/ Adc Set L/S 9 0:444+6441 has provided an alternam ve miechanmam for making btspecifie amtibody' fragments. The fragments eomnpnsc a heavy 15chamin ar-mble domain (V\'1) connec ted to a hight-chuin variable domuin (\' 1 by a tmker nwbich is too short to ailon pairmng between the two domains on the same ehant Accordingly, the V'U and \'l domam is ofone fragmentI ar e forced to peua with the counpieen'tary V and V |t dorinus of another franment, therelb\ for~m in to antitgen binding sites. Another strategy for making bispecifie antibody f'ragments by the use of 20 snde-chim F> (Qf\ ' diners has als been reported. See, e g , Giruber et al. (In94) ? Pammuo l 'G *3th Altematis ety, the antibodies can be 'limear antibodies'" as desenhbed mn. e g- 7a pata ret 9 9 @5 Prort; l'az 8(t0)' I05-1062 Brily, these ant ibodies comnprat a nair of tandem F d emnt 4 u I -V \(I4 1) w hich t orm a pair of antigen bimdig regions inmear antibodies can be btspeci le or ronospecie contemplated and deSernhed in, en. Tat eat ad a{ 1991)JIlmun a 1^':60. The disclosure abso embraces viant rorms of rnrdin-specitie antibodies such as the deaO v5s a' i3 doma inmmnogklobunti (D\>ig) molecules described in Wu et al (2007) \br /itct no! 25 lj 1200-197 The D\YD-Ig molecules are designed suc that 30 two different light chain variable domains K\'l.) fom two different parent antibodies are hinked in tandem directly or via a short linker by recotibiriat DNM techniques followed A (199, 1o00 by the lght chain constant domain. Simiarty, the heavy chin comprises two different heavy cham variable domains (V) Iliked in nandem, tollowed by the constant domain C41 and Fe region. Methods oW making; DVWD- moleucle fron two parent antibodies are further described in ~eg PCT1 PblicPCation Nb. WO (W24IS8 and WO 07/024715. The disclosure also provideS camelid or dromedary aniiodies (e. antibodies derived from Camelus bceC muw. Cauis Iomaderfu or Am pccos Such antibodies, unlike the ty pical two cha in (fragment) or tour-chin (whole antibody) antibodies from most mammals. generally lack light chains. See U S. patent no, 575938; Stijlemans et at (2004) JBid Chem 2791 256-1261; Dumoulin e a. (003) 10 Ntre 42:478-78; and PIeschberger et at (200( "oconjugate Chem 4:440-448 Engineered libraries of armed antibows and antiody hfrugments are commercially available, for example, from AbNYx (heat, Belgium. As with other antibodies of nm human orign, an aMino acid sequence of a camelid antibody can be altered reombinant to obtain a squence that more closely resembles a human sequence, i,c, 1 the uanobody can be Alrumnirzed" to thereby further reduce the potential immunogenicty tthe arditbodv in some embodiments. the anti-Ca antibodies described herein comprise an alterd heavy cain constam tegon that has reduced (or no) effector function relative to its correspond~ntin altered cnstant regi. Efibetar functions involving the constant region F th anti-Ca antibody may be modulated by alterig properties of the constant or Fe reion. Altered effec.tor funeions include, tor example ai m6odation in on or mo of the fhllowmg activities: antibodv-depndenit totxity comuplenment-ependent cytotoxicity (CC. apoptosis. binding to one or more Fe receptors. and pro-ifl aniatory responses. Modulation refers to an increase, decrease, 5 or elimination of am efteWtor function activity exhibited by a subject antibody containing an AWlered constant reior as compared to the activiy of the unaltered form of the consrtnt region, in panicular emhodiments, modulation includes situations in which an activity is abolished or completely absent. An altered constant reion with altered FR binding affinity and/or ADCC 30 actiivy and/or altered CDC activity is a polyOeptide which has either an enhanced or dimnished FR binding activity and/or AIX activity and/or CDC activity compared to 1.01 the unaltered arm of the wontamt regm An ahered consant region whicb display mteiarsd hiding to an IcR bINds at least one il RYn great . aftimv than the unaltered polyppbtde An altered constant rich JItplays decreased bndng to an cR binds at least one eR <th lower atink thn10 the unatered fora of the constant 5 region. Such iants w hi display decreased biniAng to an FcR may posses litle or no apprenabie binding to an F'R. ag, 0 to O0N Mg , less than WR 49 4W 47, 4, 45, 44, 4. 42,41. 40, 39, 34 7 36. 31 A4 33, 31, 3, 9. 24, 210 25 ;' 4, 23, 22, 2. 20, 9 , 1 3 6 14. ,, 1, 0, N, 7, , 4, 3 2,or o n the bIdmg to IN eR Yq comped to the leOl of bindny of a natie sequence immtglobulin constant or '1 F'e region to the PeR. Simnai dy an altered conitant region that displays modulated A1X mnd/or tD amut 'may crbap bi eith er eased or reduced AD(t and/or (DC ACitt WCOmparWd to the unaltered constant region. Fornecample, mi some enmbodtmemt the anti(I'Sa anybody compnsng an altered onant region can exhibit approumateh 0 to 50% (e y leUs thon 50, 49, 48, 47,46,43,44, 43, 42, 41, 40, 39 34 37, 3A 35 34, 33 15 32. 3 30, 2. , 26. 25, 24, 22 21. 20, 19, 1S. 17, 16. 15. 14, 11.3 12, 11, 10.9 , , A 5 4 3, 2, or 1%) of the AJDC( and or CO D( active 0f th unaltere forrn of the consta ore "~i An anti Sa anybody described herein comprismg an altered constant ion diplay ing reduced ADC ( and ('DC may exhibit reduced or no ADOC andr C&t DCct'YitV as exemphiied herein .0 In certain cMbodnents the alted a onst t egion a t l one amino acid substitution, insertion, and/or deletion compared to a nauty sequence constant region or to the unaltered constatt region, eg. Prom about one to sbout one huh'ed amino acid subsittions nserions and/or deletions in a native sequence constant reaon or in the consat region of the part polypepde. In some eiubodines. the al tered constam region herei ill possess at leat about 70% homology (similarity or idenuty wn the unaltered constant region and in some distances at least about A and m other instances at le'st abooi WON homology or idanttt1 her\ ith ad in other' embodiments at least about 8% 904; or 95% honologx or idemi therewith The aUered consat region may also contain one or more aimno aid deLoon W or nseronos Additonall the 30 altered constant egon may contun on" or more ammo acid substitions detions. or insenttons that resuis m altered post-t.ransonal nmodaons, including, t'r examine tl altered giveosylation patr (e g. the addiroon of one or nore sugar components the loss of one or uore sugar Conponents, or a hange n composmon of one or more 1suIlr coupon cos relative to the unalitered tonut mt region) A\ntibodhes u ith altered or no eetor tuimeuous nmuy be generated by engmneermr 5 or producing antibodies with variant constant, Fec or heavy chain regions; recombinant DNA technology and/or ceil culture and expression conditluns may be used to produce anibodies with altered function and/or activity, For example, recombinant DNA technology ,ty be used to engineer one or more amino acid subsitutions, deletions. or insertions in regions u:ch as, for example. Fe or constant regions) that affect antibody 10 function including etkctor functions Alternatively, changes in posytislational mrodications, such as, e. g, glycosylation patterns, may be achieved by maniipulatinlg the cell culture and expression conditions by which the antibody iS produced. Suitable methods Fr introducing one or more substitutions, additions or deletions into an Fe region of an antibody are we known in the art and include, e sndard DNA Smutagoness techMques as described in. eg, Sambrook et ai. (1989"Molecuiar Cloning: Aab\ratory Manual, 2" Editiot," Cold Spring Harbor Laboratory Pess, Cold Spritng Harbor, N.Y.; H arlow and Lane (1981 supra; Borreback (I992), supnxr Johne et atL (1993), supr: PCT publication no. W(06) /53301: and U.S. patent no. 7,704,497, In some enbodiments, an anti-Sa antibody described herein exhibis reduced or 20 no effetor ftimtion. In some embodimets, an anti-OSa antibody comprises a hy brid constant region, or a portion thereof, such as a C2/G4 hybrid constant region (see e.g, Burton et aL (1992 Adr ttmn 51:1-18; Canfied et aL (1991) Exp Mtd_7% 1483 1491 and Mueller c a. (1 997) its Anmus/ 34(6#44 -452, See above. In addition to using a 62/04 counstruct as described above, at ant-CSa antibody 25 described herein having reduced effcectotr fu itioeay be produced by introducing other types ot changes in the amino acid sequence of certain regions of the antibody. Such ainmo acid sequence changes .nlude but are not hmited to the Ala-la mutan described in, e"g., POT Publication nos ?1) 2 207 and iO) 4 17531, and Xu ct a (000) (111 mmund j 1-6. 1's, in some embodiments an aniUsa anybody with 30 one or more mutatins withm the comsan region mrludng the Ala-Ala mutation ha Seduced or no etteetor fnction Accordig to these embodiment the constant region of 1.03 the antibody can comprise a substiuRion to an ahmine at poIsiti 234 or a mutation to an alanine at positon 23i Addionaly the altered co-stant region may econi a double mtaltto: a mutation to an alanrijn at position 234 and a second mutation to an alanineat position 23 Yn oneentodiment, an aitinT5a aOtieody compares an igsI hrameWork. 5 wherein the Ala-A Ia mutation would descrbe a mutationias) from phenylanine to arane an posiion 234 and/or a mutation fom eine to alanine at position 25 In another embodiment, the anti-Ca aibody comptries an 1gG1 framework wherein the Ala-Ala mutation wouid describe a muttation(s) from letucine to aanine at position .234 and/or a mutation from leucine to alanine at position 235, An anti-C5a antibody may atemNativeiY or additionally carry other mutations, including the oint mutation K322A in the CH2 domain (Hezare ce al 001) wo '5:12161- 216$), An antibody with said .mutationts) in the constant region may furthermore be a blocking or non-blocking Addinonal subatitutins that when Introduced io a heav chain constm region, rcsnt in decased effector timeton are Sct (bath in, eg , Shield et aL (2001)1 /o/ Coa'n w 2( o591r 404 See particularly' ;able I ("idding of human I4il variants to human FRn anJ FeyR) of Shields et at, the disclosure oeu is incorporated herei by reference i Wis entirety BV screnng a hbrary of ani-IF anbodies each anybody of te library diferng b oe or nlres ubstluutons in the heavy etain constant region, for 20 bmdig to panel of Fr receptois(meladog FeRn. FeyLi. eyR IIA FeyR I1B. and FeyR 11IlA1, the authors identited a number or substitutions that mod ulate speedic 'eFee r ecitol interactions. For example, a v ariant laCDa berrvv chain constant region in whichh the U 12 domain ctains a D26K A sub ttution (heavy chain amo acid nutenuc according to Kabiat t ( iwvga)) results in a complete loss ot interaction between the ariant constat reown and JgG Fe reeptors Fes'R!!i H1ii, FeS nd Shteld, et at 001 ) at page 595, Table I .ee alo Baudino a aL (200) j hmwo Changes wiin the bins region also adibct efketor lunchors For example. deheton of the he region may reduce affimt for F receptors and may reduce complemem armatn (Kle i et at Y1 Prm \r dead LI , S~ 524-:28). Ihe esemdisclosure theretore also relates to antibody ith alteration i the hinge region. I104 In some enmbodiments, an anti-C>a antibody mayk contain an at tered constanm region exhibiing enhanced or reduced complement dependent cytotoxicity (CDC). Modulated CDC activity may be achieved by introducing one or more amino acid substinions, insertions, or deletions in an F" region of the antibody. See, eg U.S. patent no, 6,194,551, Aleavl radiinlyysteine residue(s) may be introduced in the Fc region, therebyallowing interchai inside bond formation in tis region, The homodimeric antibody thus generated may have improved or reduced internatlation capability and/or increased or decreased compiement-mediated cell king . S ,g Cain e at ( 1992) J &p Aed 176:119 1 195 and ShOpes (1992) bmwwno! 143:2918 it 2922: PCT publication nos, W) 99/516 W42 and W 942935 Duncan and Winter (1983) NaUre 22:7 38-40; and U.S. Patem Nos. 5,648,260 and 5624,821 Another potential means of moduating effector function of antibodies includes changes in ycoslation, which is summarized in, e.g. Raju i200) Biofroces rnational 1j44:44-51. According to Wrigh: and Morrison: the microheterogencity of 1 5 manigG oigosacchardes can affhet biological timions such as CDC and ADCC, binding to various Fe receptors, and binding to CQ protein(. 1997) 7TECW JI:2632. Glyvosylation patterns of antibodies can dier depending on the producing cell and the cell culture conditions {Raju. srai. Such diferences can lead to changes in both effector function and pharmacokinetic. Sec, egn lsrael et at (996) Thmum:lo 20 57(4-573-578; Newkirk et at (1996) (7li Ex byaiul U6.' :259-264, Differencesn effector function may be related to the tgG's ability to bind to the Fey receptors (Feyks) on the effect t cetls. Shields at at have shown that Ig , with alterations in amino acid sequence that have improved binding to FeyR, can exhibit up to 100% enhanced AUDCC using human effetor cells. (2001!) 1 Bio! Chem .?K):59.6. Wile I these . alterations include changes in anino anids not found at the binding interface, both the nature of the sugar component as wel as its structural pattern may an contribute to the differences observed, In addition, the presence or absence of fucose in the otigosaccharide component of n ig can improve binding and ADCC. See, e.g Shield et at (2002) JBlo! (hew 2(30t26733-26740. An IgG that lacked a fucosylated 30 carbohydrate linked to Awn" exhibited normal receptor binding to the FyRI receptor. 1.05 in contrast, binding 1o the EcyR ILA receptor was improved 50-old and accompanied by enhanced AD(C especially at lower antiody couenue ns. Shinkawa ev at demonstrated that an antibody to the humanm L-5 receptor produced in a rat hybridoa showed more than 50% higher ADCC when compared to the 5 antibody produced in Chinese hamster ovary cells (CHO) (Shinkawa eA al (2003) /Bi (Cm 2701:3466-73 Monosaccharde composition and oliosaccharde ofiling showed that the rat hybridoma-produced 1Ig had a lower content of fucose than the CHO-produced protein. The authors concluded that the lack of fucosylation of an 1gG has at~ iu. role in enhancement of ADCC acivty A diffrnapproach wa aken by ! m ac a w banged the A hosvion patom of cCE7, a chineric 11G 1 antineuroblastma antibody. (1999) Ar Biomern" I 7:0I180). Using tetracycline, they regulated the activity of a glycosyliransfe~rase ernzye GnH)D which bisects ligosacchaideS that have been implicated in ADCC acivi. The 1 ADCC aetivity of the parent antibody was barely above background level Measurement of ADCP activity of the chCE7 produced at different tetracycline levels showed an optimal rang of (n Fill expression for maximal chCE Q t iro ADCC activ. This activity corr.elat with the level of constant region-assoc.ited,hbisected complex oligosaccharide, VNey optinizd variants exhibited substan ial ADCC activity. Simnilari y, Wright and Mlorrison produced antibodicas it a CHO0 cell inme decien in glycosylation and showed that antibodies produced in this cell line were incapable of cop mnt-mediated cytolysis (i994) J Ex Med 18:3087-1096. Thus, as known alerations that affect effector function include modi fications i die glycosylation pattern or a change in the noniber of glvcosylated rescues, the present disclosurenreates to an ant-Cla antibody wheri glycosylation is alered to either enhance or decrease effector functions) including A\CC and CDC, Ahered glycosvlation includes a decrease or increase m the number of glycosylated residues as wed as a change in the pattern or location of glyosylated residaes. Still other approaches exist for altering heoeffector fnmtion ot antibodies. For example, antibody-producing cells can be hypermutagenic, thereby generating antibodies with randomly atered polypepide residues throughout an entire antibody molecule. See 1(.. PCT publication no, WO 05/01 1735. Hyprmutagenic host cells include cels 10 defcient in DNA mismatch repair Antibodies produced in This manner may b less antigen ic and/or have beneficial pharmaeokinetic ppi Additionally, such a hibde aybei d amibodis may esected for properties such as enhanced or decreased efietor functions. Additional detail of molecular biology techniques useful fo preparing a 5 antibody or antigen-inding fragment hereof described herein are set l h be low. Recombinant Antibody Expression and Purification The antibodies or an'stinding fragmCtrnts threat described herein can be produced using a variety of techniques known in the art of molecular biology and ptotein cheisty. or exarnpte, a nucetic acid encoding one or both of the heavy and light chain polypeptides of an antibody can be insferd into an expression vector that contains tscriptionalI and ennslational regulatory sequences which include, e~g.. promoter sequence rbosomai binding sites, transcriptional start and stop sequences, translational start and stop sequences, transcription termainsatot signals polyadenylation signals, and enhancer or activator sequences, The regulatory sequences iWNlde a promoter and transcriptional start and stop sequences. in addition, the expression vector can include more than one replication system such that it can be maintained in two different organism tor example in mammalian or insect cells for expression and in a prokaryotic host for cloning and amplification, 20 Several possible vector systems are available for the expression of cloned heavy chain and light chain polypeptides from nucleic acids in mammalin cells. One class of vectors relies upon the integratior of the desired gene sequences into the boat cell genome. CeJls which have stably integrated DNA can be selected by simultaneously introduci ngs drug resistance genes such as 6 colb gpt (Mulligan and Berg (198 I )P N5Aat/ '(cad Se UiSA 7S:2072) or Tn5 ne~o ( Souhern and Bewrg 1982 ) Hac App (Genet 1327 The selectable marker gwen can be either linked to the DNA \ee sequences to be expressed, or introdced into the same cell by cotranstection (Wigler et at (1979) CeN Q:77), A second ciass of vectors utilizes DNA elements which confe autonomously replicating capabilities to an extrachromosomal plasmid. These vtors can be derived from animal viruses, such as bovine papillomavirus (t carver er at 1982) Proc Nar A cad c USA, 79:7147). cytomegalovirus, pol orma viruS (Deans et at (94) Pro: Am/ Awnad W?,US 81:2 q o q V4 gius (LisiKy and Moth ant 19 W)Ntr l expression ctors can be irroduced in cels in a ntner suitable fo spent epresW IN of the nucleic acid. The method of inoducton is largly dictated 1the targeted cell Pipe, dcuwed belon. Eemplar method include arO preci p ation, iposme suic catnoni lipos . eIetropornon, ural mfco dextrn-mediated transfecioen, puvbreWne-mcdeed transfeetion protoplast u.nU,<m diect minj ection, Aprpa host cells he eOr resion o ibodi or an inoC, I tagmentsteref includefyeast. baeten isect, plantand mammalan ells Of pardcuar interest are bade such as E. cW funA i such ans uccbar s acrcawx and Pich.o pasiaris, insect cells such as SF9, mammalian cell lines (eg. human cell lnes) as wel as prirnary cell ines. n some embodiments, an antibody or fragment thereof can be expressed in, and 15purmfed from, transgenic amimats (ecg, transgecn ic mammals ), For example, an antibody can be produced in transgenic non--human mammals (erg, rodents) and isolated frorn milk as described i, cig. Hloudebine (2002) Cw7 (pin Biarechnoi 13(6#25-629;xvan Kuik-Rorneijn et at. (2000) :TransgenicRe AY92{:155-159; and Pollock et at. (1999) J krmnmn Aethode' 1(1 47- 57, 20The antdes andi fragments theeo can be produced ftrm the cells by culturing a host cell zransforme'd with the expressionr vector containing nucleic acid encoding the antibodies or~ fragmcn\tshunde conditions, and for an amount of time, sufficient to allow expression of the prortins, Such conditions for protein expression will vary with the choice of the expression vector and the host ell, and will be easily ascertained by one 25 skilled in the art through routine experimentation. For examrpl e, antibodies expressed in E coll can be refolded from irclusion bodies (se, cig. Hou cet at (1998) Cyhoine dl: 319 -30). Bacterial expression systems and methods for their use are well known in the art (see Corrent Protocols in Molecular Bio logy, Wiley & Sons, and Molecular (Ilonin-AN Laboratory Manual -rd Ed., (Cold Spring Harbor Laboratory Press, New 30 York (201)). The choice of codons, suitable expression vectors and suitable host cells willI vary depending on a number of factors. and nay be easily optimized as needed An fw'n'MKOW oi- ~n-1.0'a ainoody (or rgmenindereof) escribd heen eepressed tirnannalia ells or n e expression osems ineuding but not tnoie to yeast. hac dovin and in i'% cyN'~j.1 SYS~n me,~" '" w.." '" S n!nl (2000(Prtey PwgicalI )C: I 220Y Foiowing expresion, the antibodies and fagmenn thereof can be isolated. The term "purifie" orF "isoated" as~ appled 1o any a f the proteins (antibodies or fragmtents) described herein refers to a polypeptide that has been separated or purified fRom components (e.. proteins or other naturral ytccurring biological or orgniC mnoecuiles) which naturally accompany it e~g., other proteins. lipids, Od nucleic acid in a prokaryoe expressing the proteins. Typically, a polypeptide is puritied when it constitutes at least 60 (eg. at least 65, 70. 75, 80. 8, 90, 92, 95, .7 or 99) %, l weight. of the total protein soo~ a sample.fkn \n antihody or fraumemt Ihereof cun be usolated or purified in a va nety of w a known to those skilled in the art depending on what other components are present in the 15 sample Standard pun tiention methods irelade eletrophoretic, molecular, imnunolojeal, and ehrontographic techmiues, including ion exchange, hydrophobic, aimy, ad .reers>phae HPL C chromBography For example. I an tibOdy cn be purified using a standard ati-anthody coum n e g. a protem-A or protein column) lkrafuilItration and di aflittradton techniques, ni com unetion w ith protein concentration, are 0 aiso useh al See. eg. Scopnes (I 9 W IN lag, Nw \ort City. New York The degree of puriiation necessary uill va depending on the desired use, In some inances, no purfication of the expressed antibody or fraunemts thereof will be necessary. \Metods lir determining the yield or purty of a puiied anibody or rameolt thereof are know n i the art and include, eg., Bradford ansay t V spectroscopy luret prote in assay. assrypoti ay aa e p aseaya hirh presur hm chromaatog raphv (iTLC\ mas speetronery MS), aid gel elc r methods e g using a protein stain such s Coomassie Blue or colloidIa sil er stain }. in some erbodinents endotoxin can be removed from the antdbOdes or 30 fragments Methods for removing endAtoxin fron a protein sample are known in the an and exemopliiedt in the working examples. For example, endtoim can be remo ed om a1 prtotem .swepe usmng a uarit of .conrnereiadI va ble reauents mehiuling, w thOmi imiation, the Protcospin* I adotoun Removal Kis tNorgen bIoNck Corporaton . DetoudCel Fndtalan Remnoval (e]. (Thermo Scienu fie, Pierce Protein Research Products> WiraCLElA>K Lndotmmi R emomal Rn (irus)t or Aerodiecf- Mustang® L p membrane. (Pail Corporation). Methods for detecting and/or measuring the amount of endotoxin present in a sample (both before and a fer purification) are known in the art and commercial kits are available. For examtfple, the concentration of erdotoxin in a protein sample can be determed using t QCL-1000) (Chromogenic ki t(BioWhittaker the limlus anmebocy nysate ( A L) hased kits such as the Pyrotel. Pysroteh T Pyrochrme% Chromo LAL. and (SE kits avilablc from the Assocae\ ofMCpe Cod incorpord. While in no way intended to be limiting, exemplary methods tOr g a the antibodies descrbed herein arc set forth in the working Examples, \ldheatigo o te Antibodjes or Antigen-Enl dinga Frag~ments Thereot The antibodies or atugen-hinding fragments thereof can be modified following thei r expresion and purification. 'T modifations can be covalent or non-covalent modificationsa. Such modifications can be tiroduced No the aibodies or fragments by, e. g racing targeted amino acid resuos of the polypepide w ith an organ derivatizna agtuent that is capable of reating with selected side chains or terminal residue Suitable sites for modification can be chosen using any of a variety of criteria including. e. structural analysis or amino acid sequence ana&lysis of the antibodies or fragmentis, In some embodiments, the antibodies or antigen -binding fragments thereof can be cougated to a heterologous moicty. The heterologous moiet can be, eg 25 heterologous polypeptide, a therapeutic agem (e.. a toxin or a drug) or a detectable label such as, but not uited to. a radioactive NaeI, an enzymatic label, a fluorescent labelM a heavy mtal label, a luminescent label or an affinity tag such a biotin or strepta vidin. Su itabhle heterolognus polypeptides include, e.g. an antigenic tag (e~g.. FLAG (DYKDDDDK (SEQ ID NO:50)), poihistidine (THis; HEH H (SEQ ID 30 NOt].). hermagglutinin ([IA: YPYDVPDY A (SEQ ID NO:82)x glutathione-S transferase (GST or ma]ose-.biinding protein (MBPly for use in purifying the antibodic 1i 11t) oISupuV'nN t.siktnsoum polypcerides~d ml e nlude~ poly peptides (e yn.05ms)ta arce useful a diagenost e or detectable markers 'or exumuple, hicif'erase, a fluoresent protein (e g. green fluorescent protein (OF P or cbioramphemkoi acety transferase (CAT) Suinable radioaive labels inclde, e " P, "P, L , S, and 1t n suitable fl uorcacent labels include, wv thous timtation, lr'eeei luoresceem iothiocynate (IC'M green fluorescent protein ((f:Pl) D I sr'M 4. 0hyeoer thrmi (P ) propidm iodide P Perm PFAleau Hunr>' , C(v allophvcncvamn and Cv?7 Tunnesced labes mehCe, eay, Ans ofa anety oF lurmnesenm lanhaide (eg,. eurOpm or terbnn) chelates. For ample. suitable europium chelates iMlude the europium chelave of dietenetnammne penta e acid (DTPA) or tetreaazuevelododecane- , lVtetraacettcid VDf \ nainatic label included e DO alkahine phosphatase,. CAT, hietrase, and horseradish perosidase Iwo protems (e . an antibody and a heterologous moity) can be cosInked uing any of a number of known chemical cross hikera Examples of such cross nkers 5 a those wh ich lmk no amino acid residues via a Hnkage that includes a hmdered diubide bond In hese linkages. a disulfide bond iAthm tbe crosslinkingumt is proteetci (<by hderi groups wn either side of the dhside bond) trom reduce. by the action. fr example, of reduced glutathione or the enzyme diuMtide reductase. One suiable reagent 4\ccinintdlvlox3-veuilon l-u-ithyv I -2py ridyldvbio) oluene 20 (SMPIF fo ms sucb a linkage betseoen two protest uting a terminal IsMe on one of the proteins and a teinal aine on the other Heterobitimenonal recent, that crss link by a dii'eren con plmg moiety on each protein can also be used Other usetid cross inkers inceidwithoutlimiatin reageta which lnk two am inn groupste 'fN 5 azido-2-nitrdbenzoyloxysucininidet two sulfbydryi go ups (eg. I A-is m5aleimidobuane, an amino group and a sulfhydryl group (e g-malimidobenzoyb hydroxysuccinimilde ester), an amino group and a carboxyv gop (eg 4-p aziosalicy amidoj butyan inet and an amino group and'i a gudinium group that is present in the side chain or Urgnine (e g p-azidophenyl glyoxal monhydrate). In some emnbodieta radioative label can. be directly conjugated to the amino 30 acid backbone of the aintidy Aiternativel y, the radioactive label cart be included as part o"a larger molecule (cV ' in mneta-{mliodophnylNhydroxysuccinimide ' I5mPNI ) which binds to Wiee amno gomu n to born a-odopheng l unli) dematives or elesant proteins (see, . Runers et al. (1V7) jtW !1d ! -22 1-122v) or ehelate (eag., to DOTA or DTPA} nwhih is in turn boud to the protein backbone. Methods of eoiigatong the radioative labels or tye moleculch(bie co ng 5 them to the anTbodics or atigen-bmdog fragMoent desnbed herein are known in the artn. Sc methods mwhle inenhanng the proteins wub the radioative la under coniditions (e., 11, salt conentrattoit and.or temperature that Oeditae bidinu of the radioactive libel or ehelate to the protein e, e'. g ,t Patent No. A 213 \Methods for conjugaing a fluorescent 1abel (sometimes refer red to as a tluorophote'i to a protem (e.< antibodX are known in the art of protein chemisny 'or e ample. fuorophores can be conugated to free amno groups (ejg. of lysines or sulRdr groups te , eysteines) of protein um g succimidvl LNHS) ester or tetrutoiphem (T'ITP) ester inities attached to the iluorophores la some nbodimet, ibe ftoroiphores can be comugatcd to a h.aAbiettano l Cross-inkel 5 oiety arch ah -S lI C Sliable cotilion ineuiods nsoluc ineubating atn potem or Icrmnt thereof with the luotophore under condtLon that faci bute bmdn b of the tluoropiaoe to the protein. See, e,g , Welch and Redvanlv (2003) "H andnook of Raiophainacentieas: Radiochemistry and AppOeatins' John M dey and Sons (ISBN 04 714940 ;n some emibodment, the: antbodi or fragens can be oifno ed, e g with a moiety that improves rhe S Nion and/nr reteintm of the antibodies m circulaom, eg ,im blood, serum, or other tisues For ampie, the antibody or fragnem can be PRI\lared as described in. e.,g Lee t al a OWh rhon/ug (hem 0 bY ~ 1 istle et al (2002) Uvned org/ ries Rem' er s ' 14~ h'; and R(bents ct & C002) 25 dAd d DaIag fle erRevinw 3:459'at H hSxhtted (frtsenims Iabi. Germany; see, gPai et al( 2010 hit Pha' tLI) i10-119) The stibibzation moety can unprove the stabilty or retention of, the aardxdo (or fragment by at least 6 (et at es' , 10, 15 2.0 5. 30., 4, or $0 or more) ftolJ In some embodrments, the antibodies or antgen-hndmg frnaument thereof 30 desnibed herein can be glyosyated i some embodiments. an artOody or antgen bindig ragnen their eof described herei can be subjected to enzynatic or eeuIal 112oc 'n" treatment, or prodhied rwn a Cell 01 that the antibody or traecnt has educed or absent gi yeosy lukron. Methods for prodnems .atbdies w ith reduced ,glv osylauon are known in the art and desAbed in, e g. U.S patent no, f033836: Mright t al 199 D W 10(J1027 l >2723: and Co et al (1903) A/ nwm / 3: 13 1. ihrmacet ica Tompositns opos itons eontirn An a ooAdl or n an aeU-ttnd1 p n 3agmnt thereof' d bercd hereui can be nmated a a pharmaceuucal compositioet got adronstration to a subiect for the treatment or preenmion of a complementoacated. I disorder, The phtarmaentiedl cnmositions vill general include a pharmaceutically acceptable cnnir As used erein a pharmaceuticall acceptabe carter" refers to and includes, any and all solvents dispersion nmedila, coatings antibacterial and antifungal agents isotomc nd absorptin deay mg agens awl the lke that are physiological comnpatible T he compositions can include a. pharnmcecuticallyI acceeptabe salt e. gs an v aid auddition salt or a base additon salt msee~ ca. , eroe et al. (19~7).] Pharm 80 66. I he comnposiins can be 10rr0nulatedarerding to standtard mnethods. Pharmunrceutical tbiirnitlaueni is a w eilestabiisbed aut, and is further desenhedc m, e c, Gentnuo (2000) lRenmington The Science and Practice of Pharmacy," 20* Fdiio 20 ippTot iams & Wilkins ISBN: 063306472) Anscl dt al (1991 Parmaceutcal Dosage Forms and Drug Dea crv Systems) 7 Edition, I ppi nt W iam s & Wikins PubhlAisers (I SB> MY 3 305727 ) and Kibbe (200) 11 andbook of Pharmacutical xopients A meric an Pharmaeutical Association Idion !SBN 091 330A n In some ernboirhment. a conposiIon can be tnnulatd for ample. as a bufferd solution at suitable concentration and suitable for storage at 2KC eg 4C:() In soie embodimens a composmon can be fbra ated fib storage at a temperature below 'C' (e. v.2{'C or 40t6 hn sone embodmet, the composition can he formulated for storage tor up to 2 years e g, one month, tno months three months tour monlts fIle months, six months, seven month%. eight nolhs nine Onus, 30 llmnth I mon, yedr ears o yarsit I 4V Ths in son 241 WeC 4,17., The pharmaeutieal compositions can be in a variety of forms. These forms include, etg, liquid, semvsolid and solid dosage forms such as liquid solutions (e.g. injectable andin fusible solutions) dispersions or suspensions. tablets, pils, powders iposnmes and suppositories The preferred form depends, in part. on he intended mode of administration and therapeutic application. For exampe, compositions containing an antibody or framnt intended for systemic or local delivery can be in the form of injectable or intusible solutions Acordingly, the compositions can be formulated for IP administration by a pareteral mode (etg. intra venous, subcutaneous, intraperitoneat. or intramuscular injection. T"arenteral administration 'administered parenterally and other grammniatically equivalent phrases, as usedI herein refer to modes of administration other than eneral and topicat administration, usually by injection, and include. without limiation, intravenous, innranasal, intraocular, intramuscular, intraarterial, intrathecal. tracapsular. in traorbital intracardiac, intradermat, itraperitoneal transtracheat subheutaneous subeuticular, itn trticultar, subeapsutar, subarachnoi d, intraspinal, epidura, intraccre bral intracrnan, inracarotid and intrasterna injecton and infusion, The compositions can be formulated as a soutiorn, microemuision, d ispersion, Ii posome. or other ordered structure sui table for stable sto rage at highl concentration. Sterile injectable soluions can be prepared by incorporating an anibody (i a fragment of the antibody) described herein in the required amount in an appropria sovem with one or a combination of ingredients enumerated above, as required, tolow y iltered sterilization Generally, dispersions are prepared by incorporating an anuiody or frament descrbed herein io aterie vehwle that contains a baic Adspero medhin and the required other inrdiems [um those enumerated abov . In the eae of sterile ponders for the prepare action of sterile inJectable solutions, nethods for preparation include vacuum dayn and freee-dying ihat ield a powder of an anubdy or no angen-bndig tragnmet thereof, described herem plus any additional desired mgredien (see belowi fwm a previously steriefilered sohmon thereof. The roper flmdia of a 30 solution can be maminted, r temple, by the ose of a coating such as eenhon by the nmitenance of the rq umred partel sie i the ease of'disperson and by the use O 11 J, faian r loedaorption necn eeormndsons can be brouht about by iac ldingin the e Moosion a reagent t aeaas absorpo, for exape. onostearate SAWs and. 2&aatn The anti.5a antdies, or amtgenimdmg fragments their eof, described herem can also be 'onnulated m immunoliposoneonpostons Liposomes contmmg the tnbioJ) can be prepared by methods knon mn the art such a eg, the methods descrnbed in hpstein et al. i $Si Prv \ad led 5 l' WA S&68 Hvug at al. (IPS0t Pro \r,),tcdA .a $ 2~k40aU, tAd X.U2 S Pa.1 tent No, 4Mt S 'mdt,5 5 Liposmes with enhanced circulAion time are disclosed m, eg I Patent No. In certain embodiments, an ad ing fragment thereof can be prepared with a carrier that will. protect the compound against rapid release. such as a eontrolled release fornmulation, including mupiants and tic roencapsulated delivery systems. Biodegradable, bioonpatibe polymers can be used. such as ethylene viny acetate, polyanhydrides, polyglycolic aci L pohyorthoesiers, and pohyactic acid. Many methods for the preparation of such formulations are known in the art. See, e.. J R Robinson 1978 Sustained and Controlled Release Drug Delivery Sstems," Mar2e1 Dekker. Inc., New York, i sonc embodien ts, an antid or antigen-binding fragment described herein 20 can be formulated i a composition suitable fo ntr apulmonary administration ( for administration via nebbUzer; see, below) to a mmnal such as a human. Methods for preparing such compositions are well known in th 'rt and described in, eg, US, patent application publicaon no, 20080202513; U.S. -aintis. 7I 1234 1and 6.01 9968: and PUT application publication nos, WO 00/06 I 178 and WO 06/1257 t disclosures of each of which are incorporated herein by reference in their entirety. Dry powder inhaler forniuiations and suitable systems for administration of the tonrmu ltion are described in, egc U.S. patent application publication no, .20070235029, PCT Pulicaion No. WO 00/69T7; and U.S, patent no, 5997"4U in some embodiments an antiC5a antibody or antigen-bindingfagment thereof 30 described herein can be formulated in a composition suitable for delivery to the eye. In some emnbodients, one or more of the anti-Ca antibodies (or antigen-binding fragment thereoil deserited here in cini he admnistered he'ullv, for xasnpke, b's'uwa of topieul dI~3Ppl~t~Ofl oW lt4 itrCi clfleti n or ec inpl e. i emi'entS ahe U ia antibodies can be tormnulated for administration Lv way of an ey e dropY fhe ther apeuimc prepairation thortreatimye the e e can eCtltum)O o lmOe of the c anti.-Ca anbodies mn a Concentration from about (Y I to about I % bv uweighlt prefierably Irrtm about 0t to aborit {b% m a pharaeeiwalt) aceptabte sohuiton, bsspetm or ointment 6 he preparation ni preferably be in the form of a sten e aqueous soltion contamy. e , admona miuedi cents suh aN but not tmited to., preservam es tters tonicitV agets, andtiodAnts and stawitrer, rnotiote welt1ntg or clarifyIng agents and i vscosity Increasing agents. Suitable preservsatives for use in suceh a solution elude bentzalkoniumn chloride, bcethoni~umr cloridkchlorobhtot th imerosal and the lke Suitabe buffers ieude, ca ,O acd sodtm and potassim breAbonate. sodum and potauin horates, sodium and potssumm carbonate, sdiom acetate, and sodinm biphosphate, in amounts I S satlecri t maintain the. pQ- at betwen about rd! 6 and pH- ,adpeerby ewe about pH 7 and pHi 75. Stable tonicity aemrs are dextran 40, dextran 70, dextrose, Iyce m vp'amm eIderid, ro b lycW iot and odo chorada hidutable antoidants and stan ili irs hi celtide sodiuml bisuhIfte sodium nmembia bllte, sodium th iosulf0ite, and th io urea Suitable uweting and c bani) mg agents 2 minlude poivsorbate 30. polsorhate 20. poloxamuer 3T2 and tyloxapol. So tble u.osity mere ggn gelatin, gl eWt , hydroxvethv lcellulose. by-droxmnetln Ipr op leilhdose, iamohn, mneths Keeltulose, netroiatum, poivethy Vn-' gy col pofuvin> alcohol pomuvmy ipy mlidone, and caboymetbyteelluose The pi eparation can be admimstrd topically to the eve of the bject m ned of trentmem {e g, a sbjet afieed with AMD) by eov ennnon methodWO c. 4,i the form of drops or by bathing te ev in a therapeuic. sobution, eontaining one or mortnt111Sa anllboilles. In addion, a v-nctv of devices have been deTeloped or itrodumcin drugs ino the vtreai eat of th eve, For example. S patent applia1ion pubbeatin no 2002(0266 deacres a phanmtcedA -containing plug that can be inserted trough the 30 seca suAch t prgedno thetrous eat to de t pharmac tagen nto he eous cav i anothereample tent t'o 44p M0N describes an 116 impuiaalez deQvic for introdutctioni in tos a r upacoroidal space or an aivascuilair reion for sustained release of drug into the interior of the eye, U.S. patemt nos, 52773, 019 arid 6001,3X6 each disclose an implantable drug delivery device attachable to the scleral surface of an eve. T he device comprises an inner core containng an effective aount of 5 a low solhity agent covered by a nonioerodible polymer that is permeabL to te low solubity agent, During operation, agent ermeates the iorodibl polymer cover for sustained release out of the device. Additional methods and devices (e.g. a transseeral patch and delivery via contact lenses) for delivery ofta therapeutic agent to the eye arc described in, e.g. Anbti and Adamis (2002; Prog Reri &e Res I 20 21(Y l45-151 Ranta and Ur.t (2006) Adv Drug Delivery Rev S"JI) I x 6I48; Bamcas and ialachandran (500 .&per (pin Dru Dei;er N: 'I0(10 Gulsen and Cha uhan (2004) Linvst OpThahmo/ is S0 4:23412-234 Kim oat( 7) OphMwhalmc' Res 3 -:244-254; and PCT publication no, WO 04/073551, the disclosures of which are incorporated herein by refrence. in their entirety. Nucleic acids encoding an antibody (or an angen-bining &agment thereof can he incorporated into a gene construct to he used as a par of a gene therapy protocol to deliver nucleic acids that can be used to express and Nroduce aets with in cels (see below . Expression constructs of' such compcnens may be administered in any therapeuticallys eftctiv e carrier, e~g. any fbomulation or composition capable of' 20 efectvel delivering the component gene to cells in oivn Approaches include insertion of the subject ace in virali vectors inciudi ng recombinant retroviruses, adenovirus, adeno-asociated virus, lentivirus, and herpes simplex vius-1 (HSV 1), orrecombinant bacterial or eukaryotic plasids, V iralvectors can transfect cells directly: plasmid DN A can be delivered with the help of, for example,.catonic liposomres (lipofectin) or derivatized (e.g antibody conjugated) polytysine conjugates, gramicidin S. artificial viral envelopes or other such intraceilular carriW as well as direct injection ofthe gene consmict or CPO4 precipitation (see, e Vg. 4004 074) carried out in viro. (Sec also, Ex vu Approaches;' below.) Examples of suitable retroviruses include pUL 5 pZIP, pWE and pEM which are known to those skilled in the art (see, e., Eglitis et at (1985) 30 Scence 230:1395 19: Danos and vtulligan (1988 Proc Natl AdcAn ScK (SA 1 6460 6464; Wilson et at i1988) Poc a Acad SW USA 85:3014-3018: Armentano et a 117 .1990 )N Prc a W. Actad. Se?. USJA !2:6 41-6145: rxuberie alB -~ ( 9 ) Proc NatduAcad Sci USA !I:803948043; Ferry et al (1991 Proc Nar Acad Sc USA 88 7783 8: Chowdhury et at I19 91 ScienxC A.4-: 1802-1805: vaaesce t at (1992 Pro> Nat? A ad ci USA fj2:7640^644; Kay et at (1992) man GOne Therpoy 1641647: Dai W t aA(1992} Proc Na Acad Sci USA :10892-0185; Tw at W. (1993) Jimuno . 150:410441 iS; U.S. PatenNos, 4,868, 16 and 4,98{X286; PT' Publication Nos. W08'O ? 07136, WO89/02468. WO89405345, and WO92)07573). Another via gne deliv sysem ii zmes adenov nas-drived vectors (see " ' ierkner et al. J188 iochniues :6i6: R -osenfed t al (1991) Sci nce ! 52 .3-434; an Rod . dt at 10 P (1992) C/H 6:143155 . S uitabe adenoviral vectors derived from the adenovirs strain Ad ype 5 dl 24 or other straps of adenovirs (e. Ad2,A d3, Ad7, etc. are known wo those sklled in the art. Yet another virid vector system useful for delivery of the subject gone is the adeno-associated virus (A AV , Se, e.g.. [lotte at a (1992) A? .1 Rphir Cel to/Blt 7:349-356: Samulki a al. (1989) iro! 3:3822-3828; and Mcaughlin et alt 15 (989) Viol 62:1963-1973. in some embodiments, an antibody, or antigen-binding frament thereof, described herein carn be formlatd with one or more additional active agents useful for ng or tin comp nt-assoiatd diworder in a subject, Additional agents for treating a cornpieme~nt-aocite disorde in a subject will vary depending on the 0 paticular disorder being treated, ut can include, without limitation, an antihvpertensive (e.g, an an gotensinconverting enzyme inhbitor), a anticoaglant, a cortieosteid (zog. prednisone), or an imnunosuppressive agent xe.. vincristina or cyclosporie A), Examples of anticoaguants include. eg. warfain (Coumadin 1 heparin phenindiona, fondaparinux. idraparinux, and thromnbin inhibitors (a. g. argtatroban, lapirudin, bivairudin or dabigaran i An antibody or frament thereof described herein can also ha frmulated with a fibrinolytic agent (emg. ancrod, c-amnocaproie acid, antiplasmin-a prostacycihn. and deirtide) for the treatment of a complement-mediated disorder, in sone enbodiments, an antdy can he formulated with a lpidIowarng agent such as an nibitor of lydroxvmethylglutaryl CoA reductase. In some embodiment. an antibody Scan be formulated with, or fo use :ih anti-CD20 agent such as rituxnmah (Rituxan% Btiogen ec Cambtidge. V ). In some embodiments, e. for the treatment 11> ort'RA the antibody or antigenljbmdmg liaiment thereourcan be tbrnnulatcd wuh one or both of inib Anat (Remieade® (lentocors Inc and metlore eate (Rheumatrxd Trevil lIn some <mbodiment, n aIbnody or an anunbidig fralmem thereot denied her eim can be tormuated with a nonateroidaI anib imnator dh n 5 SAID)Many \ tlrent NA IS are avmulable, some over the counter inluding ibuprofen ( Adul n , mtreix Nupnri wl and nnproen (\llevek ) and manvy others ar avanilable by prenpon inclu~ding mxelou cama (Mobie n)t etodohie (I odimert nabornetone flW datri, sutindiue (Ckmontk t tulemeti r -lcmeAcon magnesium sali. Uate. ('lrpasatec% dielotenae (CataaR \ oliarenPW Arthrotec') Difisimn (Doloba indomethe ic boci nA Reoprof en Orudiws , Ormvad Wha oxaproAm Day po ' and prowcam (Feldenee fn some embodimnts an anybody or a lament thereof can be formauld for use with an antihy perensae, an antiseizure ageMn te magnn sidfate), or an aM tbiYhombotic agent \th Mynes m de, et glabetaloL invdralazine, nifedirpine, ealci um chian nel antagonmst, mirogyerit. or 5 sodium nitroprnisate. See, cag , v hu et nil (20~) J (Iio mtrmintr f D/s I 6o41:44 9 424 Anti-dhrombotne agents include, ea. heparin, amtithrombin, prstacychin, or low ih some eunbodmnents.an antibody oratigen.binding fragnmenthereot an be formuhated for administration to a subject along with intra venous gamma globulin therapy (IVGA plasmapheresis or plasma exchange. in somn embodiments, an anti-C~a antibody or antigen-binding fragment thereof can be formulated for use before. deung, or afSenr, a k idney k transplant, When an antibody or antigen-binding fragment thereof' is to be used in combination wit a second active agent, th a s can bc formnulated separatly or 25 together. For example, the respective pharmaceutical compositions can be mixed, eg just prior to admirstration, and administered together or can be adnministered separately, etg. at the same or different times ( see below> As described above, a com-position can he formulated such that it includes a therapeuticaliy effective amount of an apntC antody or arigen-inding fragment 30) thereof described herein. in some embodiments a composition can be formduate~d to include a sabdtherapeutic amount of the antibodyx (or fragmnent) and a sub.-therapeutic and a uid ltt O'une or more adtitai active agents vcdhal the coripon-s ni total ar ther apeutreall Vffrem we trc atmng or preventmng a eomlememn tasoctated disor dei. Methods for deterring a dherapeticay etbeniV dose of an agent. such as a therapeutic antthody are knokn in he art and descrhed herein., The: antibodies antigen-binding fragments thereof, conjuagates and compositons t Man of the lormtns can be used in a anber of iagnstIc and therapehu 0appheatnons For example, detecembN--Iabeled anti-Ca atntibodies e cs., ant --human C Sa antibodies or anti-mouse C a antbodiesl can be used in assays to detect the presence or amont ofi .a prenwt in a bir U cal "anpie. Dctermiing the amount of Ca in a sample, e,g a patient blood sample can be useful to em alunae the level of'complement acttvatt0n hthe sailed Suitable Nethods tor usine the anng t bdes in diagnostle assalys 1 are kn on i the art and include, without brmtation FISA. tluorescence reson'nce eerry transttr applicatins. Western blot, and dot bot tehuns. SeC e , sambrook et aL. segt- and Austubei et at. Sy~n in some emwbodnents, the antibodes and antigenbmdmg fragments desnhed e-rem can he used as postve controls in assays desred to identfy addtuonal novel 20 compounds for treammg conmp tment-medied disorders l'or euampke, an amti4C5a antbodv that inhibvis Ca actiiy can be asd as a pot we control in an asy to Nidenufy additional comounds (e y ,a nolecules atamers or antibodies) tha ihibi C or na dependentGcaireceptor signaling in som embodinents, the cross-reactive ami-a antibodies or antigen-binding 21 tragrments thereof (cg cross-reactive with humnm Csa and, e. cynornolgus macaque Cia) described herein can be used for pre-clinical testing in non-human mamas, em. ph armiacokinetic or ph armacodynamtic stud ies in non-human primates. A ccordingly, a researcher wishing to evaluate the efficacy of an anti-t antibody in treating a comiplement-associate disorder of interest (e., RA or sepsis) can use a cross-reactive 30 anti-Ct antibody described herein tn an appropriate non-human primate model of the disease. Sif th researcher, for exa mple. establishes efficacy of the antibody in the non human primate model. these results rmay provide anuffcien t prooftf-concept support fr regulatory approval for use~ of te antibody in treatinig hu mans, Al ernati vely, or in addition, a researcher may administer the cross-reactive antibody to a non-humn primate to study, e~. antbody clearance and/or pharmacodynamics properties. Based on such studies using the cross-reactive antibody, the researcher can better approximate the dose > required to treat hiunman disease, in soni embodiment, the anti-mouse CSa antibodies or antigen-binding fragments thereof described in, as wel as antibodies that crossreaet with human and mnouse C.Na. can~ beO used ats a surrogiate antibody in mfouset models ofm hurman dsease. This can be especially useftt where a humanized anti-human Ca antibody does nor cross 10 c a nd/b..'.r is in 10 react with mouse Cia an/o liely to cause an anti-humann antbod rsponse in a mouse to which the humanizcd antibody is administered. According, a researcher wishing to study the efect of an anti-C a antihody in treating a disW. (e0g., ischemia reperfusion injury) can use an anti-mouise Ca antibody described herein in an appropriate mouse Nodel of the disease, if the researcher can establi officacy in the j mouse molof disease using the antI-nouse (5 antbody. the0 restn may establish proof-o F-concept for use o f an anti -human CUa antibody in treating the dlieas Iin humans. The working examples disclose an exemplary study usngm an antimnouse Csa antibody surrogate in a mouse model of RA establishing proof -ofconcept the use of an and-human ia antibody to treat RA in man, 20 The anti-CSa antibodies described herein can also be used in methods for purifying CSa from a sample (e g, a biologicalsample}. in some embodimenta an anti tla antibody can be imnaobilied on a solid phase support using methods wel known in the art. A sanpe containing the an n to be purfidc is contacted to the antibody on the solid support under conditions and for a time sufficient to allow the amigen to bind to the antibody. The solid support is then w asked one or more times with a suitable buffer to remove unbound material The solid support can be then contacted with a second buffer that results in the release of the antigaen from the antibody, The released antigen is then collected and characterized fe. for purity and activity) using w~ell known methods in the art 30 The anti-C a antibodies and antigen-binding fragments thereof described herein can also be ised in therapeutic methods as elaboiated on below. 121i Methods for Treatmenm The above-described compositins arc useful in imer aia. methods Or treating or prevention a variety of campiement-associated disorders in aubject The c compositions can be administered to a subject, et. a human subject using a variety of methods that depend, in part, on the rouem of administration. The route can be. C, intravenous injection or infusion UVL subcutancous injection (SC), intraperitonea (I i njection, or intramuscua r in jection (iMvl. Adrministaion can be achieved by. eg local infusion, injectio or by means of 0 an implant. THe inplan can be of a porous non- porous, or gelanous material inl udin membranes, such as sialastic membranes, or fibers. The implant can be configured for sustained or periodic release of the conposin to tohe subject, See, e, US, Patent A plication Pubication No U. Patent Nos, 530i,56: 4,863,57 and 7,0:"9: 1,.5P4884; and EP 430539, the disclosures of each of which are incorporated 1 herein by .reference in their entirety. The composition cia be delivered to thie subject by way of an imipamable device based on, e~g.. diffusive. erodible, o~r convective systems. e.g,. osmotic pumps, biodegradable inmplan ts, electrodiffusion systems, electroosmos s stems, vapor pressure pumps, electrolytic pnmps. effervescent pumps, piezoelectric purn ps, erosion-based systems, or elceetronmechan ical systems. In some embodiment, an anti-W5a amoy or antigen-binding fragment thereot is herapeuticaly delivered to a subject byway of local administration. As used herein, 'local adminamtration or "local dehetry. rtr te o deer that does not rely upon transport of the composion or agent to is inteded target isue or ste v the vascular Sem uFo examipl the composton may be dehv ered by injection ot implamation of 25 the composton or agent or by ictnon or imp antion of a doce comn mng the opposition or agent Follong local admmiitranon m the icity of a target iusu or sue, the compositou or aget, or one or more comnponeun thet eot may di fiuse to the inded taget tiuose In some embody meatsan anti -ta antbody or antd en.bindin fgamnent thert 30 can be locally amnsedtoaJoint",~. anariutejot) reame n embdirnnt wer te cmpemntasocatdbw diore isathiis he opeie idubnt can be adinistered i t jt space) or n the init or'a jont, Eanmples of imnaarninar FJoins to whh an anIC5a antKodS to ant uen bindin igment thereof can be oaly admiistered m rd ow. the hilp. knee. elbow, wrnst sternoclau Iar tenmperomandibular, carpal, rarsal ankle, and any other loin 5 subject to arthr itic conditions An aon4tita antibody or anmigen-inding fragment theic eo can ako be admintered to bursa such as, eg, aerotrual. breapuradt cubiioradial doid, orpatelar, ischiad, arid any other burna known in the an of medeme. in some embodiments, an antin a anybody or antrae-bidn trament therco t can be locally adminstered to the eye. As used herem, the term "ee refers to any and 10 al anaonuical tissues <rd structures aseiated with an ey e T he eve has a uwail composed of thire dinct laves the outer sciera, the middle choroid laye, and the inner retina. 'he chamber beh d the lens is ild with a gelatious fluid referred to as the uRreois humor, ,\t the back of the ele is the retina, which detects light. The cornea is an optically transparent tissue, w htch conveys images to the back of the ev e, T he cornea 15 ha lrdes one pathway for the pernranon of pru Am into e Othr anatomical tissue structures associated wih the eye include the laerimal drainage svsteni which mcludes a ecreory oy stem, a disrbuit e sstem and an ewcretory system The seretory satem comprises secretors that are stunxutated by blinkiog and tempera'in exchange due to tear e\vaporaton and retle\ Secretors that have an efrfeent parasympathetic ner\v supply and 20j seer etc tear in response to physical or enotamal stimulation. The ditributv e y stem includes the eyelids andthe tear ninscus around thc lid edges of an open ey.. WhiCh spread tears over the ocular surface by blinking thus reducing dry areas from developing, in some embodiments, an ani-Ca antibody or antien-inding fragment thereof is administered tO the posterior chamber of the eve, In some embodiments, an anti-CS 25 antibody or anutn-bindiing fragment thereof is administeted intravitreally, in some embodimlents an anti-C.a antibody or antigen-binding fragment there is administered trans-sclerally In some enbodiments e.gt in embodiments for treatment or prevention of a complinment-associated pulmonary disorder such as COPD1 or asthma, an anti-C~a 30 amibody or antigen-inding fragment thereof described herein can also be administered to a subject by way of the lung Pulmonary drug delivery may he achieved by inhalation, 12S arnd administration by ihalaon here may be oral and/or nasa Examples of pharmaeetutica devices for pulmnary delivery include metered dose inhalers, dry powder inhalers (DPls x and nebulizers. For example, an anti-C~a antibody or an autigentbinding frngent thereof can be administered to the lungs of a subject by way of - 5 a dry powder inhaler. These inhalers are propellIam-fee devices that deliver dispersible and stable dry powder frmulations to the lungs. Dry powder inhalers are well known Ui the art of medicine and include, without limitaton: the TurboH al er (AstraZeneca: London, England) the A1Rot inhaler (AikermaesfhCabridge," Massachu setts); Rotahalem (GlaxotmithKline; London, England); anod EcipserT (Sanoi-Aventis: Pars 0 France d See also, e Fg PCT Publication Nos. W) 04/02638Y WO 04/024 156, and WO Olf7869. DI devicmes have been used for nulmonary 'amimsratio~n of polypeptides such as insulin and growth hormone. In some embodiments, an ami.-Ca anybody or an antign-binding fragmem thereof can be initrapulronariy administered by way of a mtetered dose inhaler, These ihalers rely on a propellant to deliver a discrete dose of a 15 compound to the lungs. Examples of compounds administered by metered dose inhaler inchude, e., Astovent® (Bioehringer-.Ingeiheim: Ridgefi eld, (Connecticut) and FloventY (C0axoSnithKline). See also, e.g. U.S. Patent Nos, 6170,17: 544T150; and 6,09514 1 in some emhodiments, an ani-Ca antibody or antigen-binding fragment thereof 20 can be administered to the lungs of a subject by w ay of a nebulizer. Nebulizers use compressed air to deliver a compound as a liquefied aerosol or mist . A nebolizer can be. eg. a jet nebulizer Ie~g. air or i quid-jet nebulizers) or an ultrasonic nebulizer, Additional devices and intrapulmonary admninistration methods are set forth in, e~g, .S. Patent Application Publicaion Nos, 20050271660 and 200901 1067, the disclosures of 25 each ofwhichancorsporated herein by referencein theirentirety. in some e.mbodbments. the antbodies or anigen-bing rmgamemt, theri provIded herein ar preset in unit d .sa.e hrm, hich can be partularly smiable for seladministrabion, A formulated product oflde present disclosure can be included within a con r, qrpicahy, fr examplea val. eartue. pra odlied syrmge or disposabL 30 Pen A dowr sch as the doser device described in U.S Patent No 00 55 may als be used, [or example, h an imjecton system of the preset disclosure 14 An inieetnon sysem 01 he present disclosurre may emnpky d LdliS'erv peuS as desnbed in US. Patent No. 5.303.4 1. Pen devcs, most commonly used 'or self delivery of msulin to patients sn th diabetes, are wel known in the art. Such deces can compns at least one imjeeton needl (eg a 31 Atwe needle of about 5 to X mmo in length) are typical pre-iiled ith one or more therapeui unit doses of a therapeutic sohom, and are uld1 for rapidly d t uion to a subject with as lile pai as pONie. One medication delivery pen naiudes a vi hioldier ito which a vial of iuhin or other medication may be received. The vial holder as an elongate general tubular structure with p imad and distal ends The distal end of'he ual holder mekldes munuing means for engauina a double-ended needle cannula, lhe prinual end also mi~des mourning means for engaging a pen body whi. includes a drver and dose etnmg apparatus A diposable medicaton eg a high IncentraionM solution of an ant Sa antibody or antig-hmdmgu fiAgmem thereof) contninmn ia m or use w ith the prnor 5 art vial holder meludes a distal cnd hWinr a piecaMe elastomeneseptum that can be pierced by one end ot a double-ended needle canmua The proxinal end of this vial iudes a stopper slhdably pdiosed m luid tght engea en w it the cyl undrcal w al of the Oial. This mdeaton deicvry pen is used b nserting, the ual of medicatin ito the vial holder A p body then is connected to the proximal end of the vial holder, 'he 20 pen body neiudes a dose setting apparatus f'or designate; a dose of medieaton to be delivered by te pen and a driving apparatus for ming the stopper of the vial ditally for a dWance corresponding to the selected dose. The user of the pen mouts a double ended needle earmula to the distal nd of the vial holder such that the prosimtd poit of the needle cannula pires the septum on the nal. The parent then selects a dose and -. operate the pen to urge the stopper dtally to deliver the seected dose. The dose seeting apparatus returns to ero upon mlec tion or'the selected dose fie pantm then renov es and discards the needle. canuda, and keeps the medicaton delivery on in a convenient location for the next requredt medicauion administraion The medication in the ual will become exhausted afer several such admmnrations of medicatin i'e 30 patient then separates the vial holder from the pen body. The empty vial may then be removed and discarded Aew v A can be inmed it the ai holder and the vial 125 hoide nd pen bodygcan her serabled ard used sC.pil d ab)V>ACeCOfdtlJV a medicatio deiery pengenerally achsanism fo arate osing ad case of \ dosage mechanism such as a rotatble knob allows the user to accurately adjust 5 the amou of mendicarliona oilU be. injewl by the pen, in a pt'epachititd via! of med nation, To inect the dose of mdeadiAon, th user mserts the eedle uuder the skin and denresses the kTB once as for as At a dt depr i The pen Ma be an entU'el\ ech m ea d e u c or m ay be con d ml dc n at t el i u cir u m to N rrat el.R ) se and or mdicate the dosage of medication that i injeted io the user, See S Patem in some emboduentw VtIe needle of the pen devce i disposable and the kits meclude one or more dipsible replacement needles. Pen devices suitable for de hivery of the any one of the nresend\ teautred antibodies or ani'erlogunldng tagnents thereof are also described mi g. e . peont nos, 6N04 6NOO29 and h 4636 the S disclosure of ean . wnich tarc incorporated her by reerenEc in their entirety A nrsouedlc-basexd pen de-ice is desenbed in, e , S pent no. 7 5 5 the. disclosure otwhineb is mn orrorated herein by referece o its~ ntirety' Sec also the Precision Pt'n injeeor (PPIl device. Molly mauiaetured by Scandinavian Health id. The present disclosure aio presents controledrelease or extendedrelease 20 [oIulations utae for chrome and/or self-adminration of a medicaton sw h as an antiCS a antibody Oran aigen-mdin fm thereof described herein The various formlatins can be adminimstered to a parent in need of treatment w ith the medicatio w, a. bols or b coninuous infusion over a period of toe. in some embodiments, a hig concentraon anti-CS. antibody (or amiggn-binding fragment thereof) described herein is formulated for sustained -release, extended-release, timed-.release, comitrolled-reease, or continuous-release admmistration, In some ermbodiment depot formulations are used to administer the anibody to the subjetin need thereof, In this metho, the antibody is formulated with one or more carriers providing a gradual release of active agent over a period of a number of hours or days, 30 Such ormulations are oen based upon a degrading matrix which. graduly disperses in the body torkasthe actie agent.

In ome e odiments, a C5a-binding fragment te. a smigl chain ambody, a diabody, ora Fab' fragmen of an anti-Ca antibod described here is administered by way ot intrapultnonary administration to a subject in need thereof. For example, a single chain anibody form of any of the anti-C~a antibodies described herein can be delivered bY way of a nebulz:er or an inhaler to a subject (e~g, a human) afflicted with a .compemnt-associated pulmonary disorder such as asthma or COPD, A suitable dose of an amtibody or fragment thereof described herein, which dose is capable of treating o reventn a compIemet-associted disorder mn a subject, can depend on a variety of factors including, e.. the age sex, and weight of a subject to be 10 tread aid the prticular inhibits compound used. For example, a different dose of a wwo anti anreq uired to treat asubjec with RA as compared to the dose of a Ca-binding Fab' antibody fragment required to treat the same subject. Other factors affecting the dose admnistered to the subject include eg.. the type or Severity of the compilement-.mediated disorder, f or example, a subject having R A may require 15 administration of a different dosage of an anti-C5a antibody than a subject with AMD. Other factors can include, ejg. other medical disorders concurrently or previously a.ecingthsubject, the general health of the su bject, the gene tic disposition of the subject, diet, time of administration, rate of excretion, drug combination, and any other additional therapeutics t hat are administredto the subject. Pt should also be understood 20 tha a specific dosage and treatment regimen for any particular subject w il aiso depend upon the judgment of the treating medical practitioner (e~g.. doctor or nurse). An antibody described herein can be administered as a fixed dose. or in a milligram per kilogram (mgikg) dose, in some embodiments, the dose can alo be chosen to reduce or avoid production of antibudies or other host immune responses against one 5 or more of the active antibodies in the composition, While in no wa intended to be limiting, exeimlary dosages of an antibody, such as~ an anti-C~a antibody iclhide, e.g.. 1-1000 pg/kg. 1100 pgkg 0.50 pg/g, 0,100 g/kg, 0,5-25 pg/kg, I20 pg and -10 Pg/kg, 1-100 mg/kg, 05-50 mg/kg, 0,1-100 mg/kg 0,5-25 mg/kg, k)20 mg/kg, 0,100 mg/kg to 1 mg/kg, and 1 -10 mg/kg. Exemplary dosages of an antibody or a binding fragmnent thereof described herein include, without imitation, 0.1 pg/kg, 1 Pg'k 1 h jgigk t pz 4 gtg. and k 0. kg O kg. O ) kg 21 rtg.g 4 ra Vg, 8 nikgc ad 2 rl~dm A pharmnaceuteica composition can include a therapeuticalyN effective amount of an ami-CSa antibody or antigen-bndin fragment thereof described herein, Such $ effective amount can be readily determined by one of ordinary skill io the art based, in part, on the effect of the administered antibody, or he comnbinatoral effect of the antibody and one or more additional at sive agen, tifore tnvd one agem is used. A therapeNincaliy effective amount of an antibodV or franent thereof described herein can also vary according to factors such as the disease state age, sea, and weight of' the 0 ( individual, and the ability of the antibody (and one or more additional active agents) to eicit a desired response in the individual eag, amelioration of at least one condition parameter, cig. amelioration of' at least one symptom of the complemnent-mediated disorder For example e a therapeuticaly effectve amount of an anti-C~a antibody can inhibit (essen the severity of or eliminae the occurrence of) and/or prevent a particular disorder, and/or any one of the s p o f the particular disorder known in the art or described herein A theatrical y effective armotnt is also one in whieb any toxic or detrimental effects of the composition ar outweige bh eravpeutical ly beneficial effects. &uitrdfe human doses of any of the antibodies or fragments thereof' described .20 herein can furter be cvluated m, e g. Phase dose escahmin studies See, eg., van Carp et at. i 008) Am/ fbaspUrtato hLhJ: 711-171 8; H anouska ei al. (007) C/b; Cancer Per 32, 15 31, and Hetherington et al. 2001 Atmuhal 4o dAvcwr rwAp t mo 10): m499S.00 tib:: terms "therapeuicaih effeetihe amount or "thempeuteall effective or similar terms used herein are headed to mean an amount of an agent (eg, an anti C a antibody or an antigen-inding fragment thereof) that wil elicit the desired biological or medical response (e.g. an ipnovement in one or more symptoms of a compeemn-associated disorder) In some embodiments, a composition described herein contains a thera peuticaily effective amount of' an antibody, or antigten-bindinga fragment 0 thereof, which especially binds to a neo-epttope present in na 1n some embodiments, the composition contains any of the antibodies or antigen-binding fragments thereof descrhed harei and one or mor e ( g., two, three. four, fhve, six seven eight, noe, 10. or 1 or more addhtonal therapeutic aents such that the composmton as a whlole & therapeuticallV effeetine For example, a composinon can conua an anttt5a antibody desenbed herein and an imOsupprsi e agent whee the anibody and agent are each at a concentration that wen combined ar peutily effete tbr 1eding or prcventmnug a coemplement-assoenaed diarder (e g co emplement- carted inlanatory disorder such as COP). asthma, sepum, or RA in a subject Toxity and thempeuce fficacy of sch compostons can be determmed by known pharmaceutiwal procedures m ceO cultures or experimental annds (e.g., animal mode of any of the complement-mediated disorders desenbed herei I e of'an ami (faa antibody in an aimal model of R A is exempined in the working examples. lhse procedures can be used, e g, for determining the I. (the dose keal to 50% of the population) and the E. Ova dohs theapzuttcuth effective i 30% of the population). The dose ratio between toui and therapeuticefl'ces i the therapeutic mdex and it can tbe 1 y pressed as thc ratco 11 D M o. An anybody or antigenbnng fragment their eof that eWbits a hUh therapeutic idex is preferred. While compostions that eahbit toxic side etfects may be used, cam should be taken to desg t debvery sytem that mrets such compounds to the ste of affectd tissa and to mnnoe potential damage to noimal cel and, thereby re duce side efftezs. Fhdata obtained froa the cell cuirTe asays and anmal studies ean be used i formulatig a range of dosage fbr use in humans. T he dosage of such antibodies or antigen-binding fragmnents thereof lies gene all' ti a rgeof' circulating coneentratons of the antibodies or fragments that include the EDY with little or no toxicity. The dosage may vary within this range den upon thed sagefo 3 employed and the rute of administration utilized, For an ami-Cn antibody described herein, the therapeutically effective dose can be estimated initial ly nom celi culture assays, A dose can be formulated in animal models to achieve a circulating plasma corncentrnuion range that includes the 1C's (i.e. the concentration of' the antibody which achieves a halfnmaximal inhibition of symptoms) as determined in cell culture, Such 3(1 in tormation can be used to more accurately determine. useful doses in humans. Levels in plama ay e masuedforexaple byhigh performance liquid chrromatography, In SomeWhee local administration (VIA- ao the eye or a jOnit) is dejrecd cel culture or animal modeling can he used to determine a dose required to achieve a therapeutically effective concentration with in the local site. in some embodiments, the methods can be performed in conjunction with other therapies for complement-associatcd disorders, For example, the composition can be administered to a subject at the same time o r after, plasmapheresis, IVIG therapy, or plasma exchange, See. eu, Appel ct at (2005) .S Am So NePhrai K-:1392 1404. In flom embodiments the comvpositon can be administered to a subject at the same tie pi on fe a dMny IaNpnt. 0 A "suhicti as used herem can be any nummaL For example, a subject canbe a huntam a noinnhumai pmate (e. monty or chnupan~e a tors, a cow a pi, a he g a a at a rabbit a gumca pi a gerbi, a hantter, a rat, or a mouse. In soe emrbodimnents the subiect isma mftat ie g. a human iutn. As used heren a. subject 'in need of preention. "in need of treatment or "in 5 need there? refers to one, who by the judgment of an appropriae medical practitioner toy. a docor, a nueo a nurse rotimer in the ease of humans, a utermar in n the case of uno-hrumla manmak would reasonably heriebt 6rom a grven treatunt " Sich as tr eatmnt w ith a composition en msing an antbC~a an tbod< The term 'preventin' is aworecogmnd, and nhen used in relaon toa condition, 20 is ell understood in tha. and mecldes administration of a composition which reduee the frequency o or delay s the onset of, symptoms of' a medical condion in a subject relin ye to a stihject \\h ih does teceive the composition. Tius pre\vention of a eomnplmenaMsocited diorder such as asthma inludes For example reduce the exten or frequency o cOuhing , hl gne or chet in aof patients 2 receiving a prophyact treatment rehtve to an untreated control popation, and'or delayinge the oceur renc e of cougihmg or w beeim& m a rreated pope lation sversus an unitreated control portilation. C g. ,by' a stattitldlv addr licaelly significdait aunt. As described above, the antibodies and biological-vact iefagmemns dsc red herein can be used to treat a \ariety of conplnent associated disordes such as, hut not 30 bmited to: rheumatoid arthntis I R %upus nephriis ischemtareprtsonnjury; atypwal hemolytie uicimtesy ndrome (alltSi US p, or mt'eenous heinolytte arrnie 131 SCYdomeC (( il); dense de posit disease t DD} paus smral nocturnal hemnoguobuuria (PHi; n uitipic sclerosis (htS mucular devneranon (eg arerelated macular dezenerationi tA\MDP hemoivis elev ated liv er enzy mes, and lou phayel ets (HELLPI syndrome; sepis dennatomy osots; dabetnc retmnopathy tlthroton th~hihOyegtOJ3emet 5 purpura (fT Pl rpomaneous feral loss; Paucilnmmune asculius, epidermolysis builosa, recurrent Rt los, mutuple sclerosis (\l): and trmmatic braim iniur. See, et e. llle (20018 Jmomcdetal &a kvion 223 ;000 1 and Moltrs and T hurman (2(004) iAhcdcnar Jwnwwuwe 41 ii 152. hi sonme embhoduments, the comnpieent -th~dated isordert a a eomptemcnt-mediated vascular disorder such as~ hut not lmited to, a cardiovascular 1 i dioder.myocarditis a cerebros ascular disorder, a peripheral tog , museuhoskeieta}h vascular disorder, a renov aseular order, a anrrsentenec entene v ascular disor det., revascualarization to trnpat nd/or replants. vasculitis, Henoch- Schdnlemn purpura rethatti stsenuc lupuis cry thematosus-associated v aseu i vascuis associted with rheumatmid arthritis immune complex v aseubis Taka asu's dik'as capillary leak Is ymboYmlt.C lakted eardhmioratb\ dubt tie auwionath dihorasiec.abdom mal anirti aneurism, KawasaM? disease (ancttis enous gras embolus (\VGt), and restenosis t'odkwimg stet placemtem, rotatuonal JJbicetonAy, and percutaneons traistunmial coronary angioplasty (PICA). (See, e g' 1t N flatent apphtwiton pubhetation ncr 200%0 7483 i lni soe embodiments the complememvassoceted disorder is 20my dsthema grayt, coldagglJutimi disease (CA\D)L paroxvsmnai col bemogiobinuria (Pt IX dernutomysli is seinidermn, w arm amtohmnun* hemolyric anema Grav e)^ disase i'ahitnoto ~ ty)oiditi,. type I dii'tie 'olat pemLiiu uonm hemnolyue inemia (AlA, idiopathic thromoocuopensc purpuro I fP). (ioodpature sydm.auntiphospholipid syndrome L APS). Degos disease, and ci atastroph tecAPS 2 (CA PS). in some embiodi ments, ain arti-C~a antibody or antigen-binding fragm'ent thereof described herein, alone or in conmbination with a second anti inflammtatory agent, can be used to treat an inflammatory disorder such as, but not l imited to, RA abovev el infiammrnatory bowel disease, sepsis (above), septic shlock, acute hung injury disseLminated d Ao 3 inraVasCular COagt~ltion (D IC), or CTohn' Ssase. In Some embodiment. the seCOnd atiinflammlatoriy agent can be one selected fromt the group consisting of N SALDs, I M T M3 coricosteroids, methotrexate, hydroxychtloroquine. anti-TNF ats sueh as etancreept and infainab, a B cell deplering agent such as rituxinab, an rwerlukin antagonist, or a T ed costmulatory bocking agent such as abatacept. In some embodim ts the com plement-associated disorder is a complement associated neurorogica disorder such as, but not mited to, anytrophic lateral sclerosis (ALS), brain inAr., Alzheimer's disease and chronic inflammatory demyelinating nieuropaithyp Comnplemcnntssociated disorders also include complemnt-iassociated pulImonaray disorders such as but nodelmited to, asthma. bronchitis, a chronic obstructive pulmonary 10 disease (COPD an imeistial lun disease, ot l anti-rypsin deficcy, emphysema, bronchiectasis bronchiol itis obliterans, alveolIitis, sacoidosis. pulmron ary fibrosis, and collageno vascular disorders, in the case of compiementassociated hemolyt disorders such as PN H, CAD, and PCII. a medicaid pr acumaner uwi appreciate that ('S tiament ('Slu by way of h e terminal mp element complex) contributes "siicamd to the pathognesis of these disorders. e, eg.. Kaplan (200:) CYnj A Iv Drug 317y 1017-23 W01h (2005\ t' *in Thv f matoi KMaN 3fl4849.- and Roth et a A 000) Na Rgotnuoge 251256- 14 A ,cordingly. a medical prachtioner may elect to adinister one or mor of w amitfA anhodes described herein n conjunction w ith one or more 20 addition terapies im the hemriolytie disorder such a a complement inhibitor that presents donation of t i e '5-0 terminal comntem complex In some embodiCmnts ot the rieiods deTribod herem, the complememissocited deorder is not a crimrpliem-awsoe iatcd heumo lne dsor der. la some cnmbodimrents an an4'Sa antibody ofr an le mm iagmntn thereot c, admanistered to a suibject to tredt .. e .nt or 25 ane te at'. i least one >' pto ena complIceem-assonuad mdana tory response t: g. th.ecomrpiemnenit-assoeaaed inflammatory response aspect of a comlplement awsouiated djooer l in a subject [or example, ar anoi-CSa anatbod v described herema can he used to tr eat, prevem,. and br amichorate onec ogr mnoresyifptomxt associated uwth a compieriem taei ated ilammriatorv response such as graft regection graftaersuis-bost 30 disease (U\ fth reper'tiwn mLJies te, f ollowing earchoptdhnouarv by pass or a issue transptantt and tisue damage following other om"s of uramaie iury suc a a burn ea, a Serea r). blunt trnaa. pl njury, or trostbho F Par 9 Anets) 045148 0i nt af. (1998)]nr artm u 060. SIN8 Sebmids 01 a. (1997) SAOck%2 119 4 n.Bese al. (9%AuJhs 5 hi some embodiments, ain ani-C~a anti body or an antigen-binding fragment thereof descrbed herein can be adrnisrered to a subject as a monotherapv Ahemtive as described above, the antibody or fragment thereof can be administered to a : ubect as a combination therapy with another treatment toy a compkemnit-asocated disordCer or a compierment-associated inflammatn ory response, Pot' example, the cobmi int therapy can include administenA to . a hum patient) wne or more addtional agents ecg art iwcoagulants antihypertensives or anti in flammatory drugs (e. g. steroids)) that provide a therapeutic benefit to a subject who has, or is at rsk of developing. sepsis. it another example, the combination therapy can include admiistering to the suiect one or more additional agents (eag, an anti-igEi 15 antibody, an an- L-4 antibody. an anti-iL5 antibody, or an ami-histamine) that provide therapeutic benefit to a subject who has, is at risk of d o ,,oAi suspected of havin a complement-associated puhnonary disorder such as COPD or asthma. In some embodiments, an anti4CSa antibody and the one or more additional active agents are administered at the same time. In other embodiments, the anti-Csa antibody is 20 administered first in time and the one or more additional active ages are administered second in time. In some embodiments, the one or more additional active agents are administered firs in time and the anti-Ca antibody is administered second in tne, An anti-C5a antibody or an anmigen-inding fragment thereof described herein can replace or augment a pro-vously to cunenly admuustered their apy F'or example upon treating wth an ant-Oa antibody or aninbnAding fragment thereof administmion 0 the one or more additiora ,actie agents can eeaSe or dionmnan e g., be adnmimstered at tower leih Ii some embodiments amstraim of the preous therapy can be maintained .in somembodnents a previous therapy wil he mailed until the level o the anti caSa anybody reaches a levul sufficient to provide a therapeutc effect. The 30 to therapies can be admuinistered in combinanon \omitowmg ai uteet S Clte. attumar aiet) thr Or improve ment m a comnplenentissowieti' disoroler ( e g.. seps se\vere bti RA I lupus 11eph11vis& odopastuire sndroe or athmal, as detMed haremn, mea e\.atuating the Subiect foi a change in a cd disease parameter, e g, an hiprolknt in one or more si- ptoN of a gl en 5 dider, The symptorma of cnmplemiem-associated dirder s are wel known nm the art ot medhe in sowre emodhwns. the evtluauon is perfTrned at least one d bor a' C at least 1 4 , & 1, 24, r 4N hours or at least I day. 2 days 4 da 10 dV\ 3 20 days or more, or at least I Week~ . ud o, 4 w eeks 10 weeks 13 w eeks 20 ueeks or -afi an idinsrradtni. ho subject can be eaCmed i one or more of'the fokogn periods prior to beginning ot treatment; dhtrmgihe treatment, or Aller one or more elements of the reatent hase been adnumsteced laataon can ielude evatluatinme the need for further treatment, eg i, e\a aamn whether a dosagze, frequency of? admnnminratiotn or duration of trealmhmt houAld be altered I can also inlude eh "anad the need to add or dop a elected therapeun modah, eg. adding or dropping any ot I he reatmnens for a *complemenfs ciated disorder deserbed herein The disclosure also fletures therapeutie arid diiagnOte kits conaunmg amio other igs one or more of the antb'i antbodies, and/or antigen-bmdmg fragment 20 thereof described herein The therapeutre kn\ can contain, e t. a suitable mns tom' dZI\VtrV of the aunibodty or anugen-bdnn gn fragmiem to a subject. in some embodimients the means iS suite Mr subcutaneous delirery of the anAbody or antitwerpbindiog framemt thereof to the subet. 1 he means ca be e a syringe or an osmotic pump, That is, a therapetie .kt descerthed betein can contain a syrmnge pre-iled with rn ani a antiboy or antken.indink I'aWment therol Tay, a pen device conta0n;0 1 the anybody or hiagmentuM described herein or the kit can contain a pump (e.g, an osmout pmp and one or nore disposable casosttes contIgured fo rune w it the pump, the cassettes pmtrted wh an antiCa antibody or antgenihmdmg fragment terrof described bhern teg , prefilled uith an ucuuous sotNlon contammr the antlCa 30 anybody or anugen bding fragment therect) in :mother example the ki can contain a tranwscleral or implntnable deliver devce <e .g. a plug) thai is prttiled wih (or 134o oyerwisecetain 5i titO~oniimnng an atif anoody O titgenbdha ragmenth ileeof derbed. herein" to some embodiment the means for delivering an anu<ja anthody or Mne binding f'ragment thereof is a pen devcee for drug delivery 5 ~~In some enmbodinment the means is suitable f'or intrapulmionary deliver) of' the ant ibody or antgenin ding i'ragment thereof to a ubje, eg., for use i treannem or prevention of' a complement-ansociuted iumormary disorder such as but not limited to, COPD or asthma. Accordmgv the means can be. e g. an orad or nasal mbaer se abou~>) ITb i nihler can be, eMg. anie~trrd dose' inhler ilMlD dry poWder inhaler U DPI or a nobulizer. Swuh a kit can also. opionalyv, incude instructions f'or adnriiaistering (e~g.. sOfadrimitration of) the anmi&5 a antibody ci anti etniinding gen threofto as The therapeutic kits can include, eg. one or more additional active agents tot t or preenting acornplement-ssocaited disorder and/or aneiorating a sympon t5drm&n or areventin an' ption- " 1 IS thereof, For exanmple, therapeuatie kits designed for use in treatirig or preventing a compiemem-associated pulmonary disorder can include one or more additional active agents including, but not limited to, another amnibody therapeutic (e.g. an antigE antibody, an anti-l-4 antibody. or ar anti l165 antibody), a small molecule anti-igE ihibitfor (e.g, momelukast sodium a synm pathomimetic (e.g abuterol, an antibiotic 20 (cg tobramycin, a deoxyribomiclease ie . pulmozymet an anticholineraic dru eg ipratmupiuam bromide), a corticosteroid (e~gg, dexarmethasone}, a p-adrenoreceptor agonist, a leukorieo inhibitor (e.g. zi letont .a 3-ipoxygenase inhibitor, a phosphodiesterase (PI) inhibitor, a 1D23 antagonist, an IL 13 antagonist, a cytokine release inhibitor, a histamine Hl receptor ana tnst an anti-histamine. an anti-inflammatory agent (g cromoiyn sodium or any other anti-inflammatory agent known in the art or described herein), or a histamine release inhibitor, In some emrbodiments, the means can be suitable for intraocular administration of an anti-C5a antibody, or an antigen-bmding fargment thereof, described herein to a subject in need thereof, eg. asbjct afflicted with A MD or any other conplemen associated ocular disorder, The rcans can be e. a syrnge, a trans-seeral patch or even a contact lens containing the antibody or fragment, The means can, in some 135 emrbodimnents, be an eye dropper, wherein- the antil-Ca amib)ody or antigen-bindting frag ment thereof is tormoulated (or such administration. Such therapeutic kits can also include, cx. one or more additional therapeutic agents for use- in treating eomplement associated disorder of the eye. The therapeutic agents can be, eg.- bevaeizunmb or the Fab fragment of bevacizumab, ranibizimab. both sold by Roche Pharmaceutcals, inc. or pegapsjtan ib sodhim (Mucogn&- Ptizer, inc.) Such a kit can also, optialy,- include instruction& for administering the anti-C a antibody or igen-hinditg fragment thereof in some enmbodimtents, the means can be suitable f'or intraarticular administration 10 of an anti-Ca antibody, or antien-bindin fagment thereof, described here to a subject in need thereof, e~g., a subject afflicted with RA,. The means carn be .g---a syringe or a double--barreled ryringe. See.g. U.S Patent Nos. 6,065,645 and 6P698k22K A double-barreled syrine is usefutl tor admtinistering to a joint two different compositions with only one inject on. T wo epaiate syringes may be incorporated for use I S in adrunsteing the thrpetc ykin ann otIne-c li i'h anl isappn1i ma push -pull fashion, Additional therapeutic agents tha t can he administered with the anti C>a antibodies or iragments i conjunction ii Ih dotble-barreled yri- o i can otherwise be gTeneraly included in the therapeutic kits described herein, include, e.g. NSA IDs, corticosteroids, methotrexate, thdovxychioroquine, anti-TNF ag ents such as canercept and inflixiab, a i cClU depleting agent such as rituximah, an interleukin-1 antaconist, or a T cell costimulatory blocking agent such as abatacept Stch a kit can a-lso, optionally,. incitude instructions for ad ministering the antiC~a antibody or anmigeni bindinedic orgrssbce. N biningframen thereof to a sbct it wil be appreciated that the disclosure embraces kits comprising one or more of the anti-CSa antibodies described herein and one or more 25 anti-infmmatory aents selected front the group consisting of NSAIDs, corticosteroid, mnethotrexate, hydroxyhl-orocqune, ani-TNF agent uc as tanrcept and infixiab , B cell depleting agent such as rituximab, an interletkin- antagonist, or a T cell costinndautory blocking a-gent such as abatacept. The antibodies and agents can be.e is formulated separately or together. The kits can be used to treat an inflammatory 30 condition uch as RA, Coho's disease, inflammatory bowel disease, or any other inflammatory disorder known in the art or recited herein, -l R% Alsotfeatured are ditastic kits containing the ati-Ca antibodies or atigen binding fragments there described herin. For example, the kican comain a dhcab eled brn of an anti-C a anybody (e. an anti-Ca antibody or an ani mouse Ca antibodv) described herein fOr use in detecting or quantitating the amount of CMa in a biological sample, In some embodimenis, the kis can contain isolated C~a protein (e.g. one or both of human and mouse Ca protein " inor a control sample composing one or both of human and mouse CQa protein. in some embodiments, the kit contains a multi-well plate coated with a first anti-Canibhaiga first spec dficity. The kit also contains a second anti-Csa antibody (eg. a deteetably-labeled second anti 0 Ca antibody} having a second specificity. Such a kit is designed for use in capturing, with the first antibody bound to the plate, C5a prAtein (e.g, human Cia protein) in a sample (etg. a biological sanmle) contacted to the plate and then detecting the cpue Cia protein uisingt the second antibody, in some embodiments, diagnostic kits include both an anti-mouse Cia antibody and an anti-human Ca antibody described herein. In 15 some embodiments. the diagnostic kits include an anti-Cia antibody that binds to boh mouse (Nn and human (Sa. The fa o-ing emnlhs are .ntended to iilutste noton iteetin. hxrnmLe L rm miiziti i metha!ds T e presently described ami-C3a antbadiews are humanized forms of nmurino 25 antibodie generated under the following immunization protocol. Immunizations to raise antiodies against human desarginated Cta were performed on four mice incliuding two mic of the Mrain DBA/23 and two mice ofthe strain A/. These strains were selected because they carry the allele He. which makes them deficient in endogenous C5. Alt inunnzations were repeated at 4 day intervals for a tota of three immnizations. All 0 animals reeciaved a subcutaneous booster immunization of approximnatdy 50 pg of purnfed Cta in 200 ql ofadjuvant emulsion approximately 14 days after the last immunization and 5 to 7 days before harvesting. Titering of serum from immunized ToIni UIsag an Hi$A assa, Showedodit the a ce Mhitnod n sing antitbody n agtainstthe human desanated (a Anm noaen. >MA " trnngAN gtecificityof hmogs antibodisotf hiorn ( 5 A subset of five mouse antiunman C7a Fabs that were representa\ ve o nccepitope SeltAivC Fabs were converted to fl length mouse iguia antiabi desigMnated as - SanO48ME, Sani0IME, 5an78ME, San179ME, and San SlE. These antibodies were evaluate om r specificiy usin Bioaycr interferometry n n Octet (Fortetto incd (The amio acd sequences of the ight chain and heavy chain CDR sets 10 of each antibody. as defined by Kabat, are set Ioth in Table 3. Briefly, human CMa, human Ca des Arg, human fulLlength C5. or Csa paralogs human (3a and human C0a were conijugated to bioti a t a toichimey ofC 1(b iotin ): I (antibodys) through anine grps and imoizd on a strpavidin rip, Loaded ti were then exposed to a solution containing 20 nM of anti's PgQ anybody, Each of the antibodies bound to Ca and desarginated Ca, No5 o the at-a lgG antibodies bound to Ca or to Cia. However, San 178ME and an179ME each bound to fuilength human C5. A sma amount of binding was observed between SanO48ME and fM!engeth human Ci, However, the binding of 5anO4NE to C5 was much less han the binding observed to C a 20 These results cofimed that mouse ant-human C a antibodies SanOCA-, ni1\ME, and tin 80\ME bound to a nepenop on (In that was occluded in nativ fu ngd C of generated ater the ceaage of CS mto fr'ogenis ( 5 and ('5b. The results also ndiaed that the three antibodies wre selectie for human Ga as compared oparatoas ON or (Ma. Trable 3. AminoAXe'] ive ........ e Ani.u....Atiode Ab jSIlN Description A iwAcidSeuec SanO48 151 V\ Amino Acid E VlTQSPAIMSASPGEKVTMTCRASSSVSSS ME Sequence YL.HWYQQKSGASPKL.WIYSTSNILASGVPAR SSSST SY ST ISSVE AEDA ATYYC Q(s G V P LTFGGGTKL E IKR 14 0 | ih Chain C DR 1 RASSSVSSSY LH 10 14. Lh Cn dR QQSGPiaKG G HNQR KGKK (KLTVDKSSSTAT E2RLUS 15 HeavyI ChanCDRI DYYYMN 44 Heav Chai CD LR2 YIF PK TKGTHYNQ RFKG Heavy Chi C.I~ DR3 GiPFAY nnl~ 5 \ Amno cidDIRMTQSP AXSVSQRAHS$CR $ESN\VD' vHS ~ Scqgcne GN&N \\ YQQK CQPPKL . FRA$N 1.i$ iRFSOSOSRT[TINPV £ADA )X S C iQQY P L 1 2.A C ) t JSSGSYY DW 22 j~j~hiiyDRj QU\\MD HSaCqunaCDR YMAN QOSWCMNPNSGGTNYQKFK 3K \Vavy'nkCDR3SSGCFDG YAMDY WQST aalw, LO. ' 6 San 0 i5 n - D--- - - t \ S Y F SE N vIE ~ Scucnce DYWNWQKQRKPQLEMNATEDPSR Ni'KFKISST1QPEQLSSYtSED __________ S GE TPART D.D£AKR WD QGE a17 1 deCain N QSNP SRE 54 W Anoo;\cid EQQQAUR(SKL"A(I IT-) YM QQKK 0.QLIII A PSPN IG 2 I Cl~n(DRIN Nafli 7 S~~~~~ ,6 V mn Ai N S 1 Q. XSI 1VLQAICXEVX NIL Sqaenc: GTNI NIN\ NQt PxGQPPKL---Y-------t NIXINNSTNSNIEEDA\1( -- --- ------ ----- ---- ------ ----- ------ ------- ------ - _________________QQSRKW'PWTFGGGTK.UJR Flight CaiT D1iR SASESVEYPGTSLIiQ I>4Can (ILR AASNVLS5 sA~ Seqn TAG NWNVRQA\PdKG N AFSSGS\N YAYIKG}n sRDNPKNLLM% SLs Xii191 Amnoa Acid DWVMTQTPSLPY SWGDQAS SCRSSQ\S ME ~Sequee SNGONTYLi IWY LQK PGQS PKhL YKVS\NRFS cv RnFSCSCSOIIT LmtUSR E~A E~N u CQSTHYPVdGACTLLLR qcp'>ce S I NWVKQKPGQGLFWR VYPENULG KN N[NKGKM TTSSSS MY i P. SSLSF \ AR \S IGPHYGGSYG DE)~ Q MV ~ ~ ~ ~ ~ ~ , V1 Ir soertr o"~M)N FAY as o Y-,-yv s (no ad se ene de d t . rding ( ata et A. series of sandwich assay were perR..med by Octet on the selected subset o mouse ant ihmaun Cia igGla antibodies to determine the degree of overlap of the Ct~n epitopies for each of the five representative lgG2a antibodies, Britly, a first antibody wasM biotinytated and imoiie Nstreptavidin coated tip on the Octet ptatform. Next homan C>a w'as captured froim a 201 n MI solution on the immobilized antibody. The tip carrying th:niod- n oplex was thenr exposed to a sotlution containing 20 nM 10of an untabeled second anti-CSa IgGO antibody. The citation of an additonal association prone hot he sn'asrnm would idicae that he two anibodies bonnd ciSa simultaneousty in a ternary comnpiex and that the bindiog epitopes tor the nwo antibodies MIS 171niio Aid MYTULS SCRS 140v were non-overlapping. A failure to obtain a second associtton oi u pon addition of the second antibody would indicate that the two antibodies bound Ca in a compete manner. i.e the epitope oil Ca to which the second antibody bound was occluded alter binding by the first antibody, In contrast to nonncomi petitive binding, cttive binding does not neccssarilv indicate that the irst and second antidies recognized the a ,re overapping, pit on human Cia. Using this p a tbidiw sites of the five representative anti-4na antibodies were assigned to 4 distinct epitopcs on human a Fig. 1. Antibodies SanO48ME. San INME, and 5anl0 w competed with each other. While 5AN04Y and 5an1 I also competed with the nonoepitope selective 10 San 179ME. San1 01 E did not, which indicated that San048ME and an I80IME recognize a neoepitope that is different than the epitope recognized by an 101 M In addition, while the non-neoepitope seeciv atbod ' anI78ME competed with non neocpitope selective San179ME, only the matter competed with San180ME and 5anO48M E. showing that San 79ME and San I 78ME bind different epitopes that are accessible both in C5 and Ca, The results also indicate that some conbiations of the anMibodies culd be used in sandwich-based assays to detect and/or quantify the mount of Gsa in a sample. a hI n 1 iz m fslc oueatlunn Iaatbde an1 01 ME andi San185>ME - were selected for humnanization as hilt lengtdih i a~otho~I IimOlawn-4ion of light and heavy chai-n vaiabl-e rtt~swAs ae i ulemnu it'adi, Hia framewor regions Avon ua ~tbdes(ihapeeec jven to gnermine 'genes with a high degree of sequence identity to the oiginai murine Parent anmbdy, Methods fr identifying suitable candidate framework regions are described in U.S. patent no. 7,393648 to Rkother and Wu,. Definitions of framewok (FW) and complementarity determing regions (CDRs) were performed according to methods described by Kabat, Chothia and IMGTo (ternational tmunnieneti cs Information System. fance). Briefly, database queries were periimed independenty 30 tfor both the light and heavy chain vaiable regions with a variety of antibody framents including: intact murine variable region from F'W through FW4, intact minne variable 14 regiOUS ewsudhig ('D s and All possihie fragments o mura arabe rewon mekdm one. two of thre trgaeworks Oth or witout their flanking (.Rs Unan frameworks ere selected from this candidate pool based on their overall sequence identify to the WYKat in ne atibodieand ran met teef.Ruin icua niolonic lotods w ere employed to assemble small CombMatom libraries of les than i members in Which each set of mHisn (DMs were flanked by Ad possible combinons of selewed human frameworks rThse huminzed antibodies were e pressed as soluble Fbs and evahted bOr bndng to desargmated Ca unsg FLIS'\ Fabs that bound to sa. w ere then subjected to DNA sequene analyst 10Fro these hinders a swbset of si humanized Fabs were reooatted as fll length g Wnimunt lgG2 or human Jg(I2V G additional l humanization was performed n two antibodPe~ B3NJ3' I and BNj38 I hr repilaciog matrine residues in (DR 2 of the light eba i a h their orrespondnm human ge'rmh amino acids The aino acid sequences of tb humnized annCoa antibodi\ 4 BNJ36?,BNJ7 L BNJ378 BNJBnA 15 RNJ3, FNJI33, and 1M33 -ar set tAth in Table 2 aboe The humanized antibodies w ere subjected to Bd Acore analvsis to quantify their respect e affinties for human (a See, og. Karlson and Larwon (2004 i dAkhud Vt' Blot 283 36A43 BrAiy, each of rhe humanized amibodies were screened w h 3-A concentrations of human M a angcn) uimg a capture technique. i he anibodies wnere captured by an Antibc (human) directly immobilized on a CMS sensor chip wih various coucentratls in the range omn .6 Wti to 5'9 PM of human a passed over the ensor 25 chip surface. The surface was regenerated w ith 20 mWl M101 0.02% P20 at each cycle to remove bound antibod and amigen. The dsata was evauated usgn Bacore WAev valuation soft are using a 1J Lanmir Model 'it (Rma global Fit R local Fit inetics information such as (k: Association R ate constant ( association R ate constant and K a(Equilibrium Dissociation constant) os obtained fAm the fit. The rests of the analyses are st forth inm able A. These exNernients wre for screening 14 'puposs robam ~iud number of (Ali cuei toon A' tr 04 w t dicae 'INerefore the approximnate kinec ivsalnes are reported in 'Iable 4. Table 4, A~firiity Measurements for Select Humanized AntieC5a Antibodies An dbody kZ I MS) Iisny k (1/ (x10) Ko (MI) (d1 ) 0 Dengaatio (10") BNJ364 0.991 6.33 644 0 819 B1h367 3,9 '7.78 1%804 B3NJ371 2.38 282 1180 9.52 BN3 L 9 d ,7 298 3.63

B

4 NJ366I 05 ~ '58 150 123 BNJ369 4. 19 , 53,1 0.642 BN381 J 157 .,09 56 25 L93 N j 12 5 70A 2,52 Al of the humanized anuibodies specifically bound to human C~a with a K 1 ) les than L1 20 nanomoiar. All of the amibodies with the exception of BN 3371 bound to human (CBa with a Kco less than I nanomolar, Three of the antibodies, BN3369, B3NJ38 L and BNJ38{3 bound to human C~a with a Kon less than 100) picoomolar, Ekxamplie 5.. AniCa antfibod ies inhibi C5a-mediated sienahna /n v/tro An in vitro neutrophil activation ass wvas used to evaluate the activity of the humanized antibodies. The assay s general described in. e-- Paczkowski et a., 1999) Br! JPharmac~o/ 12): 1461 ~! 466, and serves to quamtaic the amount of ISmyeioperoxidase (MIPO) produced by neutropbils as a measure of neutroph i activation, Briefly, polymorphonudlear cells, the majority of which being netrophils, were isolated using deneity centri fugation (nmono -poly resoving medium catalogue number: 91698049; MIP Biochemicais; Solon. Ohio) fromt whole blood &omn a healthy donor. 'The cells were washed once with phsospht-ufrdsatine (PBS) and the red blood cells (RB(C) 20removed from the cell popuihuion by Iysis in a hypotonic solution (ACt lysis buffer catalogue number 10->548E; Lonza). A lr two more washes with PB'S, the R\BC-ftree I j ~143 36W.

cilS were resuspended at a cone ntratio~n of 4 x 1) cells/rL in 1ank's Balaned Sa Sol utton (11SS; Mediatech, catalogue nmber 21-023-CV which was suppienented with calcium adiV magnuml and further supplemented with 0.1% gelatin (Signa ch' St, Louis 4 issour [eainaer the assay huork Cytochalasin B (Sigma Aldrich) was added to the su'spension in an amount suticient to reach a concentration of 10 pg/nL The \uspension was then incubated for 0 minutes at 37"C. 100 pt of cells was added to weis of Uboumed 96-on well plates, The wel no the plate were grouped into several dferent sets, Each of several of the derent ses of wells contained an anti&Ca anbody: each well of set 1 contained a 0 hurmani antibody that binds to Unleaved, native CS, but not to free C5a; cach well of set 2 contained the BNJ367 humanized anti- Ci atibody: eh wel of set 3 contained the BNJ369 humamized anti-CSa antibody; cach well of et 4 contained the BN137 huanized anti-C5a antibody; each well of set 5 contained the BNJ378 humanized anti Cna antiboy: each well of set 6 contained the BN381 humanized anti-5a antibody; 1 s and each well of set 7 contained the INJ383 humanized ant!5a antibody, Each well of an eighth set of welIs contained no mibody, A range of antibody concentrations was evaluated in each set of wells 4 the range including f,08 nM, 0.4 nM 2 nM and 10 nM anybody, ia(obtaied f C>niseneehnoiogi n was evaluated at a 20 onenration f 2 ON A OX ork i conetaion of 20 oer was pmpard in te areenoned asay utf and 20 p deto e d Alte addition nf to e pate asinbated 10 es tt 3C .[ol n t inc baion 60 oh fP15wsde to each well of the plate fhe plates were sutecwd to eentr nation at2 rp n (approstnatlv 335 x g) for 1mimtes ai room temperature 25 100 L of the supemaan im each w was tansfrd to te corponding Wl o a second phow 25 o btrate (Sitna Aldr atalue nner T440)I s added oi aed a a Of the second plat amd th peroneactio was slowed to deveop fo aperoxmativ woto five nunotes he reaction was termiated by the additon of 25 o, o IN C bh ) at450 n s e 30OA show in F 2. aln of the hitnani d UCa antbodi inhited netrophi ac on . ese resultsindicat he maninetS antibodi described herein an po i nhi dCors of {C edated gtdig in r, and pporte conelusion by tne nventors tha the atibodies arc usefif for re ain a vardt of in C,In ma is. 5 Emple iK Caratenaion agtte moue ant-moe Saatibody A series of sand wich assays were performed on a selected mouse anti-mouse Cia Ig antibody - Sarl 95M E- to determine the specificity of the a o fr5 Brief, the weis of an assay plate were coated with the San 195M anybody. The plate was washed hooughly to remove unbound antibody. Next. wels containing San 95 M were contacted with mouse COa for a time and under conditions sufficient to alow the antig-n to bind to t ib Unon p was r with washin. Flowing the wash step, the wells were further contacted with a so]hution containing a second, biotnylated anti-aSn anybody, The wels were again washed to remove any unbound second antibody. le amount ofbin of the second antibody to the we I was quanted using streptavidin-conjugated horseradish peroxidase (AR P). Th am ount of bidig of the second antibody was a finiction of' the binding of C"a to Satu]95ME, in a para] exsperirnent, a set of San195M Ecoated wels were inubaed with fuidength mmoseC5 protein, rather than Ca. Following a wash step, the wells were contacted with a solution containing a second anybody: a botiylated anti-mouse C5 antibody The amount of' binding of the second nbody, as function of the amount of CS bound by Sa195NE, was quantified using the treptavidit-conuated HRP construct A lack of binding of the second antibody indicate that San 195M E does not bnd i -ength muse C $ While SaC5MEbound to C in adosedenden nrno bindine between th Santibody and tlennth muase CS was detected using usg assa bl'ase results indicate that San 5ME ids t a neoephope present in S The atve ding afnty oanl9SM to mus Ka was f er quanmid The antibody was captured by anAt (mous drect rnrobzed ona C sensor chip with vaious concentrations between anId iclusive of 0.4 IM and 25 NiM o mouse Cta passed over the sensor chip surtace. Dupheates of each concentration were also run, The surface of the chip was rgenora ted with. 10 mM glycine HCI pH 1)7 after each cycle to remove bound antibody and antigen. The data were evaluated using B macore 5 ilA Ovaluakon sottwre sing a 1: umgnuur Model Fit (nRax:Global Fit; RI:Local Fit) Kinets informaton such as , (Association Rate constant ka (Dissociation Rate constan and K O (Equilibirium Diociation constant) was obtained from the fit. The - - - - - - - - - ----- --- ---- -- --- ---- -- --- ---- - ----- -- -------- ---- - ----- --- -- --- -- L - - - - - - ---- -- --- --- ---- --- Paranwter; k IMs) k. (Is) hp(I 5an495ME 8A7 x 10 L27 0 L5 x 10 Thnto result indi' IN n heouse aol rromte (A as'ntiody is not only specific tor C~a as compared to fnul u t dinause QR has ssovhi tn' antibody binds wth hitg afhnity to mouse as hvample . eOf th s"-ogate ana mqs 19n5bod anl ME inR a :at The San 5NIL arttornouse G'a antibody nas elated m a tOuSe model of' collagen-nduced ar thr itis. \Male DBIM L ac mice V) to 12 neeks old) woere imounid . irraderial jAuon at 0he base of the tad vth 300 pg of bovimv' type 11 colagten eniutsnecd with ::qua volues of Feud's complete adjuumt The procedure was repeated tUo weks afer the tirst trmunaton \Th; w ere epected daly to identiy inflamation at an initial knee uoit Once the initidl inilanmmation was identified, mice were mitapentonaally adianstered three timeweek t}he San I9OME' anti -mouse ('5~a .5 antibody (40mg ;kg or a control antibody anus g) The thickness of the initially inmianmed joint i mi) w as measured daily to day 12, As shown in fig. 3. San 105lOME reduced oll t thlektick s eornpai'ed to the control amtibody SaiIO1%\11 appeared to provide the benefit of masintammgn a knee ioint thAknes belon 4,5 na, 14 t" addition to 1 evaluatmgt the abii of the Aman15\i antibody to reduce setng of the initaUy in flamed knee joint, the abihty oi the SanMt E ni a anibods to pvnt nrurlan of intlamiaon to new jints in alsO evaated, Lhe niubr of newly recmued joins was measured dakly from day 1 to day 2. The rauhs of the Tab cacy San n odel I-ireahnent, Ntumberi " \ mr o f Numbeir of Xsege tibrf of Moce jonts iflmed newly inflamed newly inflamed joints on day I joints on day 12 per momie ComroAtl AbE 6 0 5n195 6 | 7 2 c 3 14 As shown in Tal , . ie treated With San19M E had markedly fewer newly inflamed joints as eompeid wit co hrol A treated animals bY day 1 5an 95Mb reae.d mice a so had on average markedgey fewer newly inflamed joint the arthenis in the mice was also monitored and deicned usin a clinical score/arthritis index. Each imb waS graded dy according to an estabished scoring system (0 normal joint; K mil/moderate visible erthena and swing; 2, severe eyrncrma and swelling a affecting an entire paw or joint; 3. deformed paw or joint with ankyiosAs with a maximum score of tweary-four per animal See, eg, Wang ct al (2000)J hnuan4 164:434-4347 As shown in Fig, 4. mice treated with the anti-mouse C !a antibody Sani. 19 5%ME exhihitd a maked reduction tn clinical score (average score o .0 less tItan l as compared to mice treated with the control antibody (average score above 6 over the course of the study. In umnar, tes reuh inicae hatth suro ate slmouse (7$a is effev intreatig RA both a an tiial joha and thetngatin ofnamation to seondary S joints n themose modlfdisease he resua o strgy suggeah a therapeu~ n -hi taC~a ibtiod.sc a ygOfN h a? rind ant .ani bodes described hereis usefulfor treatiucg humans wit A. 5 Ahuman naients dentifid bQ u medical pwatonear ms luiing rheurnatoi arthnits in a single articulated joimt The patient is shor tly there administered intraartieuiarv or Iiranerltoneali a vonvosition continuing a himurna cd ami- 5a aanbtody ,esenbhed berein in an amonot silleicnt to reduce (75a n dimtd C~aR I gnaling localy within the lomt space. he patent and medical practitioner observe a subtantial improveent im at least two known symptoms of rheumatoid arthritis fbllowbma the tr eatment, The patient rceives inravenously administer ed 'lmamntenanrce doses' of' the antibody everv month to prervemn reoccurrence of the symptoms to prevent the progrewion of R\ at the single omnt, o to prev et the migraton of RA\ symptonm to a. second joint. isan im Example 9. se of an anOMIa antibdy to treat sepsis \. bumain pattert is identtied by a edicalpseps T patent is shortlv thereater adminisdrd a composition contining a humant/ed anti- a antibody described heremn at adose of approumatel 600 to 900 mg by way of aitaenou ifusioni Phe patient and M 0edica[ prAitioner observe a substanti improvement in at leas two known rsymnptos of septs during the treatment. The patient receives miraenously addmstere ''tamtenane. doses' of the antidy evivo two n weeks until the patient leaves the hopita 5 Exampe. 10. Use of an anti-0ta antibody to treat corptement-associated pulmonary A human patiem is idenified by a medical practitioner as having a severe form of COPD. Once every two weeks for four weeks the patient is administered a composition containing a humanized anti-C5a antibody at a dose of approximatey 600 mg to 900 mg 30 by inmravenous infusion. The patient and medical practitioner observe a substantial improvement in at least two known syntons of CORD during the initial treatment, For 14 xt example, the patient r eceivimg the antidlSa aut body has a teduced i'requencv amd or Seerty of ('OPD-eiated e xacerbatons The patient contnw> to recei airaraenousx administered 'maintermee dosn of the antibody ev er y tw weeks to mamam the redaed freqmency and/or severe of(OPD-related exaeations. 'A human patim i identied by j mudcal practioner as having a sevre torm of asthma. 'he patitt is presenb~ed a thenapeuuic huamed em4 >a anbod t be admnistered by way of an Ah.lci Dwing the next attack of brochospasms the patient H-.adom~stets h anks amonbody in mtnoum suftieent to reduce th C medted imlamatory response in the lungs of the patient The patient conm ues to uW the inhiae needed to Pre em o lesen the se rity of asthma attacks .Egja gLL .Aiditioniti-is~anihteis iegnti fontagth m inro stniac ne Several additional antibodies were obtained from the immunized miuce (see Example 1) and further idemified by E LISA as caable of binding to human CWa. The aditionat antibodies include 15 iiue liht chain CDR sets (et forth in Table 7) and 14 unique heavy chain CDR sets (as set frtb in Table 4 -l----A----c---e--Seera-iq-- adKiabvdejg- jtt- haig CDR A-- -ron 1Additionat i urinP. ina ia Antibodies 5M 110 83 V Ammo Acid D'MTQ5QKFMSTSVGDRVSVTCKASQNV.[ Sequence NVAWYQQK PGQS PKAL YEAS YRY SOV PDRF GMSGSG IDFT L SNVQE DL AEY FCQQY NSY P FTFGSGTKL IJKR $4 | Liht Chain CDR I K KSQNVGTNVA 85 |. vLth Chain CDR2 SSYR YS "anim 87 V\ Amino Acid E IV LTQSPA IMSASPGEUKVTMvTCSASSSVSY MH Sequence W YQQKSCTS PK P WA IYDTSKL ASG VPA R FSGS GSGKTSYSLT ISSM EA EDAA ATYYCQQWSSNPLT FG OAGTKL.ELKR 88 1 hhi CDR1 SASSSVSYM iPDTSK _____90 L. A,tChi Q T "l "U QWSPIT 149 A A 0 Q QSPMSASP J KVTN CSASSSIlSYM4h SWqunce WY QKPTS PKRW DSKLA SV PAR SGS CSCT SYS LISSMNI EADAA VYCHQRSSY PWT P'GGCTKt EIKR 92 hI ha Ci I sA sSM v 1nOS2 94 V Amino Acid QI VLTQSPAIMSASPGEKT LTCSASSSVSSSY L Scquence Y WY QQK PGSSPK LWIY STSNL ASGV PARFSGS GSGTSYSTISTV EA EDVAASYFCHQVWSSYPPTF (JGCTK L E21KR % U hs Chain CDR2 STSNL AS ______________ 97 L __han DR IQWSSY PPT__ _ ] 07 9& Ammio Ae. d DIQMTQSPAPMLVSVCET VTITCRGSENIYVSNL Sequenice A WYXQQKQOKSPQLL VY A ATNLA )XVPSRF< SG SGSGTQYVSLKINSLQSEDFGSYYCQORFWGTPR TFGCCTK L[EIKR 99L hi Cha ni CDR 1 R(SENtVSNLtA 100 Li ht Chain CDR3 \HFWGTPR San11102VLmi no \Aid DUVMTSQRMSTVGDRVSV TCNKASQNVGT~ Sequetnce X X VAWQQ )KPGQSPKAL YSASYR YSCVPDRF TGSOSGTDFT L TISNVQSETDLAEYFCQQYNSY P WTFVOGTK L EUKR 84 wkChan CP1 LKiiQ TO C' + ou hi Chain CDR2 Y SASYRYs 103V LighChain C(g tQQYNSYPW T San054 104 N Amino Acid QIVLTQSPVIMISASPCGEKVTMTCSASSSVSYMN Sequence Y WYQQKPCGSSPR L LIY DTS NLASG VPVRFSG S GSGTSYS LTBSR MEA EDAXAT YYCQQWVSSYPP>T FYAGTKLELCKR i0~1.ihi(ai l RISG S SY EAAR --- ' ---- ----- -O -- ------- ------ ------------------------------------------- 1Q~ i4it 1) M' k )R AK(Q\SVT -- --------------------------------------- ---- -4 ---- '-- ----------

----------------------------------------------------------------------------

Scq( c X OKCVPR YTKSVAFG ---------------- TI- SSM I2h L) AT ----- Q---RS----- 99 U I CCMK YNKN 9 D. i ChainaCDR HQP S1YM 20 Lph Chain CDR D RSESSNFM iO L ht Chain CD R2 LARSYWE Sanj185 V' Amino VAi DI VLTrQSPASLAVSUGQRATISCRASESVDSVG Se.quence \SF MHWYQQKPOQPPKL L IYR ASNL ESGVPA R FSGSGRTDFTLINPVEJADDV)ATYCQQSNE DPLFGAGiTKLLKR 20 Lih ha n Cu~.DR RAK SESVDSYGiNSFMH 1101 Liuh .Chain CDR2 I RASNLIES ________________________ L____l~tilaDPLCDRCASNED LIIK 7N1T1w I 5"", nn [hif -hI ..... SN...I "S W in~ the' Tw aberfr to "SEQ ID NO * CD imino acid seq uences are defined accordingm to Kua] (ulupra Tke 5. Amingo Ak cI Segguecs of~'' Sa aniti eand KabaectHevyChain CDR sceences flm Additional Mu'rine Anti-humana Antibodies \b SIN Descrition Amino Acid Semsence* anI 10 4 V Amino Acid EVQLQQSGPLIVKPGASVKSCKASiYFSDY Sequence YYM NWVKKSHQKSLEW ICY FPKTGGTNYS QRF KGKATLTVDKSSST'AYME.LRSLTISDSA VYYCASCPFAY WGQGTLVTVSA ______ i V N (ImiSRR (PLAY%0i San1 77 12 no d Acid G NYTRP YEU M DVWCQCS YSS HeI ChxjSER ID NYPDNYKC _________ 12 1-iavvaw C a(lrc YED MD -- - -- --- ----- ----- 1- -- --- -- A iO52 AioAd EQQQSGPFLKVASKSCKASGTFSDY Seq uecrc 'VY MNWV KKSHOWKSL ENV KA FTV VPTOCN QRF KCKATLTYDKSSSTA'VMELLS SDSA VYYCASCPFAY WGQCTLVTV SA Heavy Chan (ORI GYYEA C "'v Chain CDR2 CYTGYNRK ~' 05414> v. pAmin Acid F.VQ.QQOPELVKFCA'SVKJ SCKSYFD Sequence Y M N WVKSTPKRLS E WVA IS S PNGYTY Y QDNVKGRFI'LSRDNKSTLYMLMSSLYSEDTA VYYCTRGYFEDY PMDCY TSVVS 9 s s fv n CDR SY YMAN ________ 1.1Heav Chain CDR ke IGPGY Y YRDN K MnnnM 12 A sAmmo Acid EVOLVESGPGKPCASLK ASGYTFSY eqttenec 'Y M WRQT'DK RPLW TSUSYY scNn VKCwyKQlSHGN KNTLG LMrGGKETA QRFKDKAY TLVDKSSSTAY OQLSLTSEDS 110. Was"h M (R I S A YWbGLV V I2~H'-Cha Vn( DR DYYIf YMY Ran1I 12> VV Anizno AKid lv N; QIZ [QAPllKPGAn SLSCK ASFTS Sz Seqene WHWKOSHPGQGLEwYi~iFSi>NYT NK NC \> V NW AE""'SSSTAY MELN" -: Q GFLK TLTLTSSST YV SLTSEDSA NcA RGuPAmaY wGQG i'YTs.ss 115 Wasivy Chain CORCL) V AII N, Sequen OWNM WAKQRK -- EWG NFTG Y- Q FKKAT LT1DSSTA YMRSS ITS DSA 0" V fCARCOUR ROY A MDY "&CQCTVTV SS S3 lia CI di 1i (O itS v~ buV DRTFI ELLRC R SLl\ KUOKATN DRYSMSAY"11 MERST SL1 --- -- --- -- -- --- -- --- -- -- --- -- -- -- --- --- --- --- --- --- --- --- --- --- ----- --- N-- ------------- - - -- - - - - - - - - - - - - - --- ------- QC T S V--V S 15?C I K QRChain CUR IsDYSM 46 tyAT CI)R AITYNNQKFKG6 4 H {h i DR OftDG\WPD L~~ K~e L 9E35th an~~ :I0 'I tmn 1 a. 'S I, (A QK"i I N&CSKS ASYES D nciddg erice N Xned acUn t WVKQR 1>0 EYfURSSHY tYC RXSI U V \MD WO(VVSNTV"ISS ~IN a d pskrf& ta kID aNO ign4 ~ 137 .... an ME and .. n . .aniode .e c .iden on T l.. 7.and 5 U seOn ar. Sn 1 1 F. ut Onk? 9o bckw la o a9. Amin Aid Sccucns ofr Q d hea ch in o Ant-lntCiAdods A Se 4 SIT N A o St *, LUYQKSGASPK SS SGYPAR i4 nsehitnU RAwSSVSSSsYIAeeT 96 1 14Cha CDR3 SGS A 43 A0R QOVSrft Aino Acid E MA-QQ ',:'SK J 1'S S Q z C XTLTVDSSSTA FEER!YYSE P4 Gkv Fhi~ M ,t N' QI PU TQR K .............. 117 Tm' hnCA WA;N On 1 ~ ~ ~ ~ p 1k 1i ---- VI TQ IPIMSASPOEKVF\ - TN C ,AS-SV-S-S S -Y- .............. ...... .... NQ.........TNLA CV >A IE I11.s 14 LhtChan (DRI RASSSVSSSYLH %6 vghcChan.CDR2 STSN..AS 12 AsnA 5G ELQO VPCVKSCKAd 3TS Seqene KSHQKS. Y$FKCN QRYKCKAIIJFDKSSS'AYMEDLSLTSEDSA ____ ____________ YY \C ASOPE AY WGQ.OTY SAk 42 t sensa hrna I PwYsN 1~ ~~~~~~~~a L~ Uch CI n CDR 711K'C SASSS MTYQRK____________ 6 L ~k (. Cha n CDR2 DTS NLA S K CK AGT SD TEDSAA YYASP L GITTS Chn CDR2 Y T I G(TNYNORF Sequenice HMYQQNY KGSP KSLW Y IFKTCSG PATRFS WR FFGGGTKT VKSTMMLSTES 9 I Chain CDR SASIYMK j.jcl\ (han CDR2 DTSLA 1I 7 j4a sChainsCUssDyS tAS 4oN RYKGSA DPdS KED AMCA\SGPFAYNCQCLV.SA 5 Chi CDR DYWMN I I H"p ~( I n I XI I \N .. .... ...... ....... .. ..... .... .......... ....... ... .......... .......... .......... ......... .. .. .. . -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - --- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - -- -- - - - - - - - - Sqmxc WYQQKPAJTS PK R W TS 'K ASS PARFSPS T '2S188S2S1 ~M EAEDAATWCHOR0 SSY PWT [GGCGK KR ~ 0 ~ \n d e QM\QQSGP.VKPG ASYK SCKASGTFS NSNN W VVKKSHIGKSLF I AFPKThCTN NQKFGKATL TK$SSAN MELRSiLTES O VY IASGPi G(QG 5 HeavI ~y Chain CDR1 D YYY MIN i23 Hovy Chain CDR2 Yl FPIKTGGTNYNQRFKG 7i Heasvy Chain CDR3 GPFAY 5anG 22 91 \ .Amino Acid QI V LTQSPAIMSASPGEKVT MTCSASSSISYM Sequence HWVYQQK PGTSPKR WIY DTSKLASGVPA RFSC SGSOTSYSLT I SSMELAEDA ATYY CHIQRSSY PW TFGGGTKLUEKR 92 1wht Chain CDRI SASSSISY'MH 89 htns CN6OCD0R DTSKI \S 93 UtChai DOR HQRW4YPWT A N C ASOPPA WCGT $VN'A 51 HeavL y Chain CDR1( DYYKY YMN __ _ 4 Heav Chain CDR2 N' FPKTJGOTHYNQRFKG _______17 Heavy Chain CDR3 GIPFAY 'SanS2 94 V Amino Acid QIVLTQSPAIM 'SASPGEKVTLTCSASSSVSSSY Sequence L YWYQQKPGSS P1KLWIN'STISNLFASOV PARFS GSGSGTSYS LTISTVEAELDAASYFPCHQWSSYP PTEGGGTKLE KR 93 1mhzChain ODR2 STASSSL 97 ~ I Chan) CDR3 HQWSSY PPT .. . .. .... ... ... .... .... \ W K S C K L W C N W K G ~ > ANdQ [KOPEI VDSSAY'R S. LSU SND j__ _________ A13 ANmNno GSPA W(QOLVSA,',SY s K Kv.A, I F Kst s ) R______I $ AYHewvy $hain COR /NNY 6 Y an1ui9 An no Acid D~MQSQKFiSSMRS YTyCKASQNJ Sc ence NV VQQK PCQSPK ACY$ASYRYWPD RF TOGSGSG~TFT1 SNVQSED) AEYFCQQVNSY 8$ Lvg h ain CDRP SAS RY ' 3V IiLha CDR3 QQYNVYPWT I> ~AmioAci FNf SPELGKPGASOKISCKASOUT DY Scece YMNW\\VKQSHCKSLEWICYPNTOCTSYN QNI DK \KTVDKSSTAY MEERSL'SEDS.A VY CSPFAY WOQCTIJTVSA 5i Heavyt Chain CDR D EYY YMN _________________ 29 HevjhanCR Y IFPNTC(TSYNQRFKD ,OH 7 teav Chain CDR3 GPFAY San055 I 50 \ Amino A cid EIV LTQSP A i MSASPGFEKVT LTCSASSSVSSSY Sequence LYWYQQKPCSSPKLfl\'YSTSNLASCVPARFS GSGSGiTSYS LT1NIMAEDAASY FCHQ WSSYPI PTEGGT.K EIKR 95 Luht (I'bain CDRI SASSSVSSSYLY 96 ht ChainC(DR2 STSN LAS q1 T"-As o A 11S ly ;v 971 h'bah n CDR3 HQWSSYPPT 12 N Amino Acid 2VOLOQQSQPELVKPGASVK SCKASCYTFSDY Sequence Y YM NWV KKSHGKSL5 E WIGYIFPKTGGT'NYN QRFKQKATT iVDKSS ST AY Milk RSTS EDSA VYYCASG PFA YWG~QGiTLVTVS A 5> Havy Cham CDVRI DYMN __ 123~Io i Heav hain CDR2 V FPKTGGTNYNQRFKG 117 U eavv ChanCDRI 3BF AY San E I I 10 | Amo Acid DIVMTIQSQKFEMSTSVGDR VSVTCKA SQ NTVT Soeence NV AWY QQKP(GQSPKAL IYSASYVRYSG VPDRF TOSG3SOTDFTLTISNVQSEDLM A EY FCQQYNSY 85 L h~ (ha n CDR2 SASYRYS 03 I Lu'h Chain CDOR> QQYN SYPWT\ 14 v Amino Acid EVOLQQSGPELVKPGASVR SCKASGYTFSDY 6 N S T NYMNWV>KKSH GKS LE W N G TIYN QFKCKA TIVDKSSSTA A ELRSUSEDSA \ v YCAsO PFAYY -[L, vr'Ms 5 I I H TAW N D .i ... R. DY..MN AR f S SG S"D N EN I QQS ~ani 3 II \'e knd E VUQQSPASLVSRGQRTKSCRASESDS 'NUPLMACRPO LE. R G H I ittt ChaiTS(2S3k QQ$NEEDt 30 V! Amino",~ QBSPJkVLCA~EVS Heav Ch WMDR E ITSWKNYN3)EKKG UVSHNYL FKKOA TLTDTS$TAYVDISULSEDSAVY Y I) I J , t io C "'2 1 SW I s

-------------------

"N'in the( T able refer\ to "SEQ ND OC * CDR amino acid sequecs are definedaccording to Kabat et at (supr) Eamml e'K Additimai tm nive aitbu nao Chaauhien Sveal additional humaied anti-C5a anbody heavy chain variable regions were generated. all of which when paired with a cornmon igaht chain variable region (the light chain having the aNino acid sequence depieed in SEQ ID NO:16) bound to human C'a with a K~ of essthant I nMf as determined by iacore analysis (see above for methodology \I AI of these additional humanizedt antibodies hound spci ficaily to human i0 a, but did not bind to native, fdly-folded human C5, C4Am or C3a as determined by ctt analysis (see above for Iethodology) The additional humnized antibodies conad: i a hev chain variable region framework region 1 conaining one oft contained: (i tu following amino acid sequences: QVQL VQSGA EVKKPGA SV'KVSCK ASGYIT (SEQ ID NO:68) or QVQLVQSGS EL KKPCASVK VSCKASGYTET (SEQ D NO:69): 5 (ii) a heav chain variable region framework region containing oneofthe following amino acid sequences: WV RQAPGQGL EWMG (SEQ HD NO:70) or WVRQASGKGL EWVG (SEQ ID NO:7) (iii) a heavy chain viable region framework region 3 con tainn one of the following atmino acid sequences: R VTIRDTSAS-TAY MESS LRS EDT AVYYCAR (SEQ ID NO:72h RVT1TA DESTST AY MELSS RSEDTAVYYCA R (SEQ 1D NO:73); or RVTITR DRSMS' 'AYMELSSLRSEDTAMYYCAR (SE Q ID NO:74); arid a heavy chain variable region framework region 4 containing the tollowing amino acid sequence: WGQGTTVTVSS (SEQ ID NO :75) Exemplar addiiona humanized heavy chain variable regions comprising one or more of the additional humanized framework sets 10 described in tisectionnare set thri in hip 5 Smurine model of CUa1nuropenia w as uied to muate the efti of an ant-human fre Cju anybody in Prv To mduec neurropnA, punfled, natia human to Ca (hC a n as admmistered by way of inravonous tad mi e to BnoT e m ame Then n er o& eating neuwophils was evaluted up to ftoe mutes atie addinirain ohC~A Adnmwsration of 300 pnk of ha was consisent found to induce neuophi actuation as nmeasured by the mn oeri iPIO release assay (see Eumple 5 fio 20 use with serum as compared to cef cuhure supernatumt, pr and neuropemna (a reductn in the number of irulatng neumophd) in addition. plasma levOs of bCtz and the human antbC~a anuibody 1N\ 3 (when administered to the mee, rm were Also measured to establsh the pharnacmodynanue response see bom) Peripheral blood neumphil coums were eumied before challenge with hCS or 25 vehicle control Compred to shau-t eated contol ime 137- 0.09 x7 m' 1Tl neutrophdl coumts in mice treated with anti-human free Coa antibody (13 ± 0. 1 3 10(' per o, at 24 mg kg; P 05, or isotype conto mA i.1 1 ± 0. 10 x 10" per mL at 24 ny kg, P>0.05 remained the same, thesee results indkated that anibody alone did not induce changes in irculating neutrophil conms 30 ToI er aluate the eflicacy of an ani.05a antibody to inhibit hC~a-imduced neutropemia im mrue, ifferen t dosages (24 imyLg, 1 2 mg/hg, 0 mip/ pkand 3 mg/kg) of ofan 578 the anti-human Ca antibody BNJ383 were administered to Balb/c mic 24 hours prior to hCla injection, Adminiiistration of the anti-C~a antibody 2.4 hours ahead of hC Sa al lowedi for 11he pharmacodynacs properties of antibody to bdurint antibody elimiian i on frm the ice, 5As show i m 6. neuropbn counts atei treatment a axpreed as peeentage o "baseline (where the count at time 0 equals W00. In shamuemed control n0 c\e. te neuUpbdl coonts werei O 71% 67'42 ' ,.. and 59.A 2 1% of baseine at L 3 and 5 mutes post hC5a adnmistraton, respectively The isoty pe control antibodvtrcated mie demnonstra ted a sisntiaam reductanm (, (11 m i the neuophil cont to . ". 0.81" at 1 inute, s I u 134 at 3 tomine H ndP S.29 a 0.79 r at n m suts aner intnrvelnous neuei jn of h 5a, The anuC5a anuhody exh Wiited a dose-dependent effect on aC5amduced neutropema At the highest dose 24 m/kg. the antiCia ntibody completely blocked the neutropena \etrophil counts Qere 735 a 84% at minute, 635 5 608 at 3 ni ute and 59.t5 6 6 3<; at 5 minutes. which 15 was Compaabtle to the neutrophil. els in shann-reated control 1mnals ai the same ime pomins. The tower doses of 12 mg kg or 6 og kg of the anti&Sa antibody also sngtfiamti inhabited neutrophil depletion (12 mg kg: 42.61 ± 5. 1234 at 1 minute, 45.33 :' N. ' at 3 mntes. and 41 02 ± 7.08% at 5 minutes P: 0,01, 6 myonkg I 00 a 3.8 at I immute 1240 4 ow at 3 minutes, and 2b.03 :5 451% at minutes PAOR,05) follow 20 administration of hc<a as compared to the Watype eontml antibody group . n :l at I inute, 6 6 t 0 1 % at n Binutes, and 4.29 . 0 7~A at 5 mates T'he isoly pe control antibody Sn ian body 'hat hiandmthrax protective anign 63 and contains a human yG .norp R region Admimnsration of the low est dose of the antC a antibody (3 m/ kg) did not sigmiicantly reduce neutrmpenia (6. 5 0.88" at n1 mute, 5 6.71- 2.14% A 3 m~ iwNe and . 'o 21~' Latz rnuunat PATS v RC :g Ainftaa (3a antilbody nhibit hCa~inducned NiPO reese in vo As discussed abov e, human '5a acvaas neutrophils through elireactne binding of the mnose a receptor. \yeloperoxidase IMPO) release a consequence of 30 neutrophl scuivank thr ouh (ladon to CS R See Darren et at (2004) AM lLPrm 65(4t8Sk o, Intravenous nection tlrecortbinant human GSa mio the mouse can iduce nitropniai and activte ne tiop has in circa ton he abiity of geananwumn e a antibody to inii M( ease ic to neutropi activation l41 dvoas eltedsnghlaniCa antibodytidfe hC~wand prent bidin to tG marine C5aR 5 An in mv experiment In which human Sa was administered to mce) as pr Jrmed as desCribed abo e, The ' e1el of plasma MoPI at time 0 w as 79 2± : 22 nS mi the shamntreated cool group. Five ruun As after m iraSn mjecuion of i. uic e buller, 4 ivwu ieves were not AinuucantLy enarnged (i .- 'T:t. 2 l Ugl, Pm0,0x Prior to itravenous ictton of hCia, \1.PG leel in tsotype comMi atibodv 0itreated (5.17 14/to ng miL or antd4 a antibody rated anms (.' r i Lk ag'ml )weren compuarable w ith the levelh obsers ed in the shan-treated eonuel~ amimali. After iravenous infection of hCia. MPG levels at all doses of Ca were raised and remained at sanoticandy higher levels at minutes (Fi 7) ahen compared to isonypl control anibodvireated animals (22 1 00 ± 51 02 5 ngn the arn'hCia anbod heated animals showed dos-dependen reduchou of NIPO leSANls ( 1 3 23e Wg. mn, P, 0, i k" cohort 104 80 ± 29Y3 ni nL, P 0.5 i 12 ig k cohorL and 260 = : 34.40 nmd.. P:::0i mn Omg/L cohot he NIPO lesek of low dose Nmg kg)20ti'5a anihody-reated aimal (17653 23.05 ng nL) w ere not signify ili dterent 1rn s .pe comro antibodytreated anmak 20 (P >0 55). An anti-05a ainibodt reduce s tcirculating bC~a neel in mike AN woted aboe USa is a potet ilua atory pepuide with several bioloical hutons These above stade demonstrated tit human Cvu crossreats wth murin MSR on neUtrophils siCe intravenous infection of recombinant human ( Iaaecn iduce neutmpena While this losis m o Oay hued by say particular theory or eetuism of action, the an2t4'5 anybody may be ihibitng human (a-nduced neutropenia by forming complexes wuh hUM and prev entog hM a from binding to the nrine M'a exposed on dhe cell surface. h"a levelswere measured in dhe plasma oz 30 mice beiNre and 1, V and 5 minute after minraenous administration of bCa to confirm 160 rathe leeS ofe le in lh5a aNtiody Ii 4 e e o t ingdepCd ~ nhiioan of hCia. \n experiment a prormed as descrbed above usmg the mouse-ht'lndueed ne;utropena modeL hC aw not detected n plasma i any group of mice pnio to adminstraton of hM'a at time A using an ennie-i inked immunosorbent assay ( LSA) The levl or hCa m plasma. h ever, increased to a peak at mmue {7783 50 - 3277 nz ml ', then reduced to 474S3 8 260.51 niniL at 3 minutes, and then to 3t 575 : P2 ) 9Oasml at 5 mflnuw fO.1Oirim intrav enous inlecto of hC~a (in istvpe control mAhnueated mouse) omp iced to control antibodyt'iam ice, the e eOI of ha in 10 ice tented wth 24 mng kg of the anti-Ci anNbody ehibited a 43 30, and 23-fold dMein af 1 nniute (I 7M4 s .14 uMi ), 3 minutes (1554 Ii 10 ng/mL v and 5 mmun eI - 1 .2 i 5I i ng mL 1 respect' ly. The level of hC(a in plasma nom the 12 nwkg and 6 mngk cohorts w0ere A35 01 2233 and 601920 + ^S "5 ng/mL at I nn-te, 2105>0 P 1534 and 52740 ! 512'5 tg at 3 minutes .'20 d ?40 and 505.00 4 15 45 96 nmL s 5 imnutes. raspeAi The antafa-arcated nueexhbited signitcantA rNeduced hC5a levels in a dose-dependem manier um ntropea Roong intavencos auecuon of h'Sa (PA 0) 1 l\hough the mice the lones dose of atniC$a anybody 3me/kg) nere not spared forn hC' -mduced neutropenia, the mice nonethels had a sig ticam reducion in plasma hCa (313040 n 20 433 Q rMnmL at 1 minute, 19010 t 268.2 ngml. at 3 minutes 159100 ± TO ng m. at 5 minutes) as com pared to plasma h'Sa le " s found in iotype comrol body W tecdmice W O Se g. . These data indicated that dnistratiof anti( St Ubody to mice signcanly decreasede oncenration o fe $ ien ad auing beatly a lioratedaCanduc neuopen Taken together, these results presented in this section indicated that an amti-humnan na antiboady described herein can inhibit the biological efhet of human CUa in an in viw> disease setting and rvi s trong evidence that the antibodies (and antigeninding fragments thereof) are useful in, among other things, treating or preventing complement, 3( associated disorders such as any of those recited herein.

Several humanized antibiC~a anilbodies were tested tor their abiha to erowreac Wth (E a from one or more non-human mainaban species. As noted abmx, the benedtsi of such an uandi 5a antibody arc nmerous e e the abibty of a research or medical pratltioner to mood the efficacy of a therapeute anti-GSa tibodv in a nonhuman disease model prior to ahmstermg the antiody to humans 1estna in on-,uman mammals can also alow for detenmnaten or approximation of the appropriate dosage of an antK a Libod. r i t ficnay in huans Bie~ BNti9 BN6A B3N 4, a RNJ3 described b cR) w ere altiated todetermine w hether they could eo-imnmunoprecipitate CSa protein in the activated serum from seeral non-human or mites mehidog n baboon, i bes aau and nomotu s maaque The srum w as acti vated by addition of nosan. Following an oserIAht mcubaton of each amibody uwith actn ated serm, the antibodies w ere separated from the solunon phase using protein A- -coniogated agarose beads. The heads w ere washed thoroAghly and then boid i sodt dodecyl suh'atc-polvaervlanide gct cctrophoeei (SDS-PAGlE)ample bter containing -mercap~toe taol. The bolted samples nere then subeted to N5 PAGE: Non-human pnmate C1 u as detected by western blot tsmn the commercialIy -avui lbleair-GSa neoepuopre aunbody 422 ( A beam. C2ambrdge. MA)4 Each of'the antibodies tested as apab e of 20 imiiopcitaing G 53(or GCa des) from baboon, rhesus macaque., and cviomolgeus macatue mdicatng that the anybody i crosreactive with (iSa from these species as wel as with human Sa. The determination of binding affinity parameters to cynomiogus macaque CSa was determined as described above, Briefly, the MNB83 antibody was screened against 2 -4 concenrations of recombinant cvnomolus macaque C~a faie)ua capture technique as described above, The antibody was captured by an Anti-Fc human) directly immobilhed on a CM5 sensor chin with various concentrations m the range from 0,6 aM toS9 nM of eynomolgus CGa passed over th sonasr chip surface, The surfae was regenerated with 20) mM HRl, 02% surthetantr P20) (Biacore) after each cy le o emove 3 bound antibody and antigen. The data was evacuated using Biacore BlAevaluation software using a 1:1 Langanir Model Fit (Rmax:Global Fit; R:Local Fin These\ 162 nunaer.oenn urpossxvt a nna nmber oa nyte *oiirnici were toy sIrect nFgI cOnmemtradioins (3 to 4 wih ep ica e approiate o ie anibod for cyombas acakque (ai is M.jr 'UtZ 10. 5 Table 10.A\flinity Determination for non-Humnan CBa Proteins SpecMes k, 1NIS) | ki | KN Hurma 07 327 108 1.23 Cyonoorgs I.28 42.3 3300 1A 5 nmacaque Mouse 2A 106 3 7 9* 238 * This lonldy an approxination of thC K baed On the punaliy Of the Crve fitA The BN383 antibody was also screened against 3-4 concentration of recombiant mouse CUa (anigeni using a cpture technique as described above to 0 determine is affinity for mouse protein, The antibody was captured, as deserved above, by an anti-C (hunan) direct inumobilized on a ('M5 sensor chip with varios concentratons in the range from O n M to 59 nM of mouse CBa passed over the sensor Chip surface, The surface was regenerated with 20 mM HCL 0,02% P20 after each cycle to remove bound antibody and antigen, The data were evaluated using B5acore B S IlAevaiuation software usig a 1: 1 Langmnuir Model Fit (R max:G0lobal F it; RI :Local Pit), I he above resultsicatedl that several of the humanmred anui-hC fa <mtibodics described heren are emossreactie w ith ('5a. frum sev eral non-h'uman prmate species including cynomtgus maagu . rhesus naae. and baboon The BNRT amibody 20 etau erossreacts u th iOuSC (Sa Furthermore the r results described this sectn indicate that an. amthuman 0, antubdy, such a B\J3N1 is usefhl not only in ebncal applhations for teatog eomplement-assoesaed diorders, but aso in a varet of pie clnical applications in non-human mammals, which are necessry for, or supportive of, appri ad ot ce mlse in h6umam An experiment w as pediormed to ev aluate the euimg ot'an anmu-isa asubody deribed herein. B\MW3, m ho prosene of pel ycompetie antgens Briefly, otheniu-Labeded BN3 ( 050 p04 wn iMubated fR twou hours at mom temperature wuh I nMl bot'tnliited tS'a aglot ng vtrious conlcetlrfluunS {eg ,~t ii0, i. L 4 Km 4., 1 . aund 0.5 nN) of'one o'the 0'1leng (a human C desae gproim in phosphate buffered saline (by human piansa, e c nomohtus macague plasmu, td) Bab/C (mouse plasma, or (ei DBA2J imu Psh pt to the p"a C c ponets (bIt) (d and (et the concentradn refers o the appronutei final concenration of ( 5 antigen 10 i he icetan miture Following 'the mncubation period, the samples were cotcetorpciv individual wells of a streptavidin.-coatd assay p late under condins that attowed fo the binding of bonyMated U5a to the streptavidin in the wels ofthe plate. The wells were washed thoroughly to remove unbound material , The amount of binding of BN3383 to 15 Ca in the presence of competitorwas determined b derecrng the amount of signa! produced on the detectable ruthenium labeL. The results are shown in Eg. 9. Whereas human C(a desam was an efective competitor, there was virmally no competition observed in the presence of mouse serum ( 17% reduction in detectable ia observed at approx imateily a 400:I ratio of Batb/C mouse plasma-derived C5 to 20 biotinylated human a and 25% reduction in detectable signal observed at approximatelya 4t01 ratio of DBA2/t plasma-derived C5 to biotuiated human CSat No change in the 1ee of binding of BND3 to bioti nylated human C was observed at up to approximately' a 15:1 ratio of human or cynomoigus mlaiuue plasma-derived (5 to biolinviated human (75a1 As noted above, white the disclosure is in no way limited to any particular theory or mechanisn of action, the inventors hypothesize that the ani-Ca antibody nav bid to a subpopulation of unleaved, processed C5 (eg. plasma CS) constituting less than 10% of the total population of fut length C5 in a sample (e. a plasma sample. which subpopulation is in whole or in part denatured such that an otherwise occluded CIa 30 neoepitopc to which. the anti-Sa antibody or fAgmont bids, is exposed. Thus, it is believed that the antibody does not bind to a fully fumctional and/or fully functional 104 SPedieed C> tid thu d10s ni b sind Una d, alve I pnn !Hasman is at eastan appixmatev$0t Ilibi weker compa to' rm otoninyated Ca than human Ca desarg. Anothstunimtg these constderations. these wetb further indicate that anti 5 human C )a antibodie de.senbed h>rei, such as BN18 3, presidential bind to free homan CSa even in the presoce of up to approonnaty 20-tld exces of 'imelea ed. but not neceary entirely native, plman derived human f protem Example 6, Effet of anti-Ca ( anybody on AP and CR activity tr An experiment was peformed to evaluate the ef'eet of an n-Cva antibody described herein (BNJ383)l on aIernative pathway (AP) colement activity n rum using pooled normal human serm I PNHSj Tb expeimn uiz the Wiesab? Alernative Pathway Complement Kit Wielab® COMPL AP330. Euro-Diagnosica, Swedcn) and the associated protocol was followed with only routine optimization well 5 itin the purvlew of one of ordinary skill in the art. Briefly ahiqots of the PN I-S were incubated in wels of a lipopiolysaccharide-coated plate for one hour (at 37*C along with various concetrattiotis (0,778, 0389, 0.194, 0.097, 0,049. 0,24, 0.012, 0.006, 0 003, and 0,002 pM) of an anti-hC5 antibody or an anti-hCa antibody (BNJ383) The anti-C5 antibody inhibit th- cleavage of human C5 into fragments CIn and COb As a negAtive 20 control, several wel were incubated with PHS under th same condiuons. bet in the absence of ant itC5 aitbody or anti-htCa antibody, Follow ing the incubhation, the weIN were washed thoroughly with kitssuppiied IX wash buffer, h 0l of alternative pathway complement activation was measiued by absorhance at 405 tnm, following. contact of each well with ai kit-supplied enzyme conjugate (an anti-C5b-9 anybody conjuted to alkaine phosphatise) and fluorogenic substrate (which is operated upon by the enzyme) and incubation for 30 minutes at room temperature. The results arc shown in Fig. 10. While the anti-C5 antibody inhibited alternative pathway complement activity completely at concentrations greater than 0, 1 ift 4 the anti-hClu antibody did not 39 signuficantiy inhibit eomrdement activity even at the highest concentration tested.

An experiment was performed to evaluate the efect of an antil'Sa anybody described hert in (BN838 on classical pathway (CP) complemem activity in VioR usin PN-IS, The expertiment tuized the Wieslab@ Classical Pathway Complement Kit Wieslab COMPL CP310, Euro-iagnostica, Sweden) and the associated protocol was followed wiT only ro tiae optiaiatioRi wel wohin the purview of the ordinar!l-skilled artisan,1 Briefy aliquots of the PNHS were incubated in wells of a human igM antibody coateo plate for one hour (ar 37T I akong with various conXctrations (7,2. 3,6. 1 0,. 0, 0.2, 0,1, 0.05, 0.02, or OA01 g M 01 ofl anti-hC5. antibody or an anti-hC5a antibody 10 (B3NB3l The anti-C5 antibody inhbi the cleavage of human C5 into fragmeins Q5n and COb, As a control, several wen Iere incubated with PNHS under the same conditions. but in the absence of anWth(5 antibody or anthC a anybody. Following the incubation, the wets were washed thoroughly with kivsupplied IX wash buffer, The level of alternative pathway complement activtio wa s measured by absorbance at 405 nm, flowing contact of each well with a kituppld enzyme conjugate i{an anti-Cab-9 antibody conjugated to alkaline phosphatas&) and fluorogeic substrate (wh ich is operated upon by the enzy me and incubation for 30 minutes at room temperature. The results are shown in Fig. 11. While the anti-C5 antibody inhibted claussi pathway complement activity 0 completely at concentrations greater than 0. j p4M the ant-hC5a antibody did not sit'ieantiy inhibit complement activit) even at the highest concenuratiou tested. Taken together, these reuls indicate that, in vivo. the anthC5a antibody, DNAUM3 did ot si rifieantlv afet CWAI generation (terminal complement activationc driven b either the classical or alemative pathw ay of complement thus gn m further evidence that the ant hCa antibodbs deribed herein spericaly target the free (5a ,maphyvhitoain arm of conmplenment acination, I(66 LxrpeI7 Antitiamtatodrlan unocen edse a~nt knindingzseliadale to bindjto_(Ia ven in the rcsnce of agotexss of f5, The antiC Ma anti body BN33 (set forth above) was incubated at 4 ? for 84 ours in the presence of a 2,1-fld molar exess of human C5 (hC5) to alow tbr complete antibody:CS complex formation. A xr t was performed sng an antibody that binds to human C5 at a :scie (hin antibody) Antibody:C5 complexes were resolved on a TSKM G4000 SW size exclusion column (Tosoh. Tokyo) using a Watersru 2690/5 HPLC system wu 49 Waters rM W2487 dual wvaveienth detector to determine the occupiancy of binding site s. Peaks were I0monitored at a wavelengtn of 214 nnm. The mnobile phase for the H PL a nalysis contained the allowing buffer compostion: 39 oM NaHTPOst nM Na HPN t and 150 mM NaCL at U7A. The flow rate was 1.0 nil per minute and the run rime was 20 minutes, Data were acquired and analVzed w it Waters Epowerr. 2 chromto aphy softae As doptcd in Riu, 12, 'R NiS3 alone (Fig !2.\ and hC alone ig, 13) :[ch resch es a amogle peak entered around 10.2 mines and ' 9% of the anti-5a antib)Odshlit5 compl1exe resolve a a single peak centered around 9. n mines (iniure 12C) n cotrast. complexes of hC$ and the antVS antibodyv resolve in tw o peuks cemered at 46 nun (mm vand 92 min to1 (Fig M13D) Thus, even in a molar excen 20 of h 952% ofte BNUM3 has a free [ib ann that ma be capable of hindong to hmoan cit. Those samrplea were t'urther examined to determine if' thle B\JJS3 antibody retaeind the abihtY to bind (Sa in the presence of saturating concentratons of CS ree anioJy or aanbody C75 conloplexcs w ere tutnatedi from Silt) to 0 '5 ngrmd on a streptavdmn .5 coated plate to Which hiotin conrhgated h05a was immobilize, Captured anybody was detecten uih an antvhuman Re antibody coingated to horse radsh peroxidase The results depicted in i s demonstrte that ev en UN 383 complexed wth hC5 L capable ot binding C5a and that the concentration of anybody available to hmd Ca is not detectably diiinushed in the presence of saturatng CO. hbus, the results described hevrem 30 indicate tha theantibody, even in the presence of a molar ewes o uncveed CS retains 16 7 hI al y to nd tee C50 wi hgh tny antheneb s eein that -noolai exces, the abihty to in"hit he a ctivity i nCt 2 atacomst ottenninal comment complexrifumation <nm (Pynormigis itac aques tvrea:dninsteredi itrav enously a single dose of the

BN

1 33 antii&a anmody at 1 mg/kg. 1 nog/kg, l00 nko:50 mg/kg ot 00mkw Plasma samples w ere colkecedo ron the racarines at tne ptots ranging hm da y to 0 days fo lowng the admmtrtaion of the antIody. Ie els of C ja '5n dsar In IplAasma were determined by an electrochei ninescent (FCL assay m x bich a tree (Ka toa desar ynas capped on a mierouter plate coated with an antibody speedic fra neceitop onC'a 'a d"ar and detectedo with ai non ceompe-titiv e Ca atibod y coniugated to a rthenate chaining FCh moiety and read on a S:FCTOR M00P" lamte reader (Mesocecale Diseov ery. (ircu lati ng antibody concenitaenonn were dietermin ed by and cozy me liked immunosrbent assay (L.LA \I in which free antibody (RNJ w-%as captured on a microtitersplate coated nith human C. desarg and detected with a mouse aniuhanman antibody conjugated to borseradish pe rovidase (iRP). \s shown n 'ig 14, hka the results desenbed in Example 13 eculatn concenUations of BN33 as low as 10 pgm deplete plama Oa/Sa desarg levels to below detectable limit, in eornobus monkeys. these results ao underscore that the antibody, even in the presence of a molar exesms of uinlaed CS, retail the ability to bind to free CGa wth high affinity and they retams, even i that molarxcest Abiliy iib the pro inflammao acvityofCa To determine whether BNJ383 had an effct on hemoitic activity of macque serum, the antibody was evaluated in an in vr red blood cell hemolysis assay, The red blood cel hcmoiysis assay is generally described in detail in, e g. Grinder et al (1995) Clin Hnest 6:1564-1572. Briefly, serum samples obtained from macaques administered BN3823 (as described above) were added to muliple wells of a Swell assay plate such that the concentration of the serum in each well was 3!) approximately 10%. The serum samples. by virtue of the time points in which they were obtainedi, contained various concentrations of the BN383 antibody. The bemolytie iy erolmancajngse noreconing BN 3sre as a nOgae control andl as the base henta iocs1 a it t Ch icken eryth eoytes (Lampire iological Laboratores, Piperville, PA) were washed and resuspended in bufer at a final concentranton of 5 x W cells/mL The ry throcytes were sensszed to iysis by incbaung the cells with an anti-cicken red blood cell poiyclonal antibody composition, The sensitized erythrocytes were added to the wells of the 96 well plate and the plate was incubated at 37 C for 30 minutes, Henolothin release was measured by apparent abr at 415 nm using a micrpeat reader.

As shown in i. VAeven high centratnof 13N133 did not subtanhallg WI ht crthoevt hemto is under these hemolyn mc ay expeinental conditions. ihe NJ antibody ewa also ewluated to determine if it had an effect on IS complement aem aton of maempa srum nsmg an a mo C191$O assay The Cl150eq aWay is a method for measuring the total classical complement activtv in serun f hi test is an ewyme linked imnmosntb assay. which uses human gammatdobulin, and mousAe rnonocdnadl antibodies a the mctidaor ofthe cldsseal i0mpierient pt way and captures the termitl uomplemeni complex (TCC) geneated on a mirotiter well coated ith a 7CC net'pitope specific antbody, CaJptued I Ci s deteced wih a undt 41ti5 TC' antbody conjugated to horse radish peroudase The clhoeq away prondes a diirect measure of terminal comnpiemet complex ClCC) formation. As shown in 0ig. 35 high concentranons of BN3 present in the nmcaque serum were capable of Mbstamtall: adulbtin 7CC fonnaon tmider these mso conditios, T}~e reulr t indicate that the 5J38 antibody is not only eanable of bnding to and sequestenng ee cSa but is aNo capable of, as a fiction of concentration, pariral f oubatatl inhibitg ICC formation0 An w o exerirnent vas Am puformed to evduate theeffet of' IN on 30 sa pathway complete active ing themaaque senm sample desded a hbe e experimet atiedte isb as Pathway(oppment Kit 169 (Wislab@n (0MPL CP3, EXuro-Diagnostia. Sweden) and Mhe associated protocol was followed with only route optimization wel within the purview of the ordinariskiled tisan. Brictly aliquots f the macaque scrum samples were incubated in wells of a hunman 1gM antibodyvoated plate for une bour. As a cotrol, several weils were incubated under the same conditions with serum tirm macspiues not administered the BND8t3 antibody. Following the incubation, the weUs were washed thoroughly with kit-supplied IX wash butlbr. The level o f alternative path way complement activation was mteasured by absorbance at 405 nm. folowing contact of each well with a kit-upplied enzme 0conjugate (an ami-CSb-9 antibody conjugtated to alkaline phosphatase) and fluorogen ic substrate (which is operated upon by the enzyme) and incubation for 30 minutes at room e tenmerature The resuks arc shown in Fig. 15SC. The ani-hC5a antibody did sigmficantly, though not completely, inhibit complement activity in a dose-dependent manner, Taken together, the results described I5 herein indicate that BNJ3 is not only a potent antagonist of C5a, but is also an incomtpetc/parta antagonist of terminal comp element mplex formation 0n vo, Thus the antibody and antibodies sharing its properties are usetid for treauti a varity of cornplement-associated disorders in which C5a-medated tnflanmation is the primary contributor to deleterious pathological effects and TCC maysi play a tess signiftiam or 20 even heneficiai role in the pathology, While the presnt disclosure has been described with re'rence to the specific embodiments thereof it should be understood by those skied in the art that various changes mas Oe made and quv ienms miay be substnned without departing romn the true spirit and scope of the disclosure, in addiuon mans modifications may be made to adapt a parneuliar si tuation,. material, comnpo51tion of matter, proces process step or stes to the objective, spit t and scope of the present disclose, \. such modifications are intended to be within the cope of the. disc losre. 17t)

Claims

7. The isolated antibody or antigen-binding agmen thereof of any one of elaimsI to 6, wherein (he antibody or antigen-binding fragtnqnt thereof binds to free C5a from a non-hunan marahan species 8 An isolated antibody or atigen-biding fragment thereof that binds to a free CSa polypeptide, wherein the free C~a polypeptide is a human polypeptide (hGWa) or a non human manmmaian spies Ga polypeptide; and wherein the antibody or antigen -binding fragment thereof binds to the free hCSa polypeptide with a K 0 that is less than 1,25 x 1W' 9, The isolated antibody or antigen ending fragment thereof of claim 7 or 8t wherein the non-hnnm mamman species is a non-hurnan prIIate M0 T isolated antibody or antigen-bindng fraginemn thereof of daim 9 wherein the non-humnan primate is a cynonOgus nacaque. rhesus inacaque. or baboon. TL The isolated antibody or antigen-binding fragment thereof of any one of claims 7 to 10, wherein the antibody or anligen-binding fragment thereof'binds to free hCa with an affiity no greater than i 00-fbd its corresponding affinity for free (5a from the non human mammalian species, 12 The isolated antibody or antigen-binding fragment thereof of any one of claims 7 to 11h, wherein the antibody or antiaenbiing fragment thereof unds to human C5 with an affrity no greater than 50-fold its corresponding affinity for C~a frm the non-human mammaian species. 172 S iThesolated antibody or aniggebinding fragmen. thereof of any one of claims I to 5 or 8 to 12, wherein the antibody inhibits by at least 50% hCa-dependent human neutrophil activation at a molar rado of 1:1 (antigen-binding site: hCa) 14, The isoated antibody or antigen-bindng fragment thereof of any one of claims I to 13. wherein the antibody or antige-dig fragment thereof binds to a free hC5a polypeptide having the amino acid sequence depicted in SEQ ID N0:2' 15, The isolted antibody or antigen-binding fragment thereof of any one of cnns I to 14, w herein the antibody or antigen-binding fragment thereof comprises a light hain polypeptile comprising:a light chain CDRA] comprisire the amino acid sequence depicted in SEQ ID N0:20; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:2l; and a light chain CDR3 eomprising the amino aeid sequence depicted in SEQ ID NO-22 0 The isolated antibod or anten-biiding fragment thereof of any one of claims I to .14'herein the antibody or aei-bi ding fragment thereof comprises a light chin poypeptide comprising a light chain CDR I. comprising the amino acid sequence dected n SEQ UD 4.20 a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID N; a n aaI light chii -DR3 comprising the amino acid sequence depicted in SEQ ID NO:22 I The isolated antibody or antigen-binding fragment thereof of any one of claims I to 1.6. wherein the isolated antibody or antigen-binding iegent thereof comprises a heavy chain polypeptide comprising: a heavy chain CDR] comprising the amino acid serience depicted in SEQ ID NO:28; a beavy chain CDR2 homprisingbe amino aci sequence depicted in SEQ ID NO:29; and a heavy chain CDR3 comprising the amino acid seqence depicted in SEQ ID N0:30.
18. The isolated antibody or antigen-binding fragment thereof of any one of claims I to 16, wherein the isolated antibmy or antiger-binding fragment thereof comprises a 173 heavy chain polypeptide comprising: a heavy chai CIR cArprising the amino acid sequence depicted in SEQ ID NO 2; a heavy chain CDR2 comprising the amino acid sequence depicted n SEQ ID NOAh and a heavy chain CDR3 comprising the ainno amid sequence depicted in SEQ ID NO:47 19; The isolated antibody or antigen-idig fragmeni thereof of any one of claims to 5, 14.or wherein the isolated antibody or antigenbinding fragment thereof comprises a ighbt chain polypeptide comprtng the anino acid sequence depictedi SEQ ID NOs37 or SEQ 1D NO:36,
20. The isolated antibody or antigenvbnieng fragment thereof of any one of claims I to 5, 14, 16, or 19, wherein the isolated antibody or antigen finding fragment thereof comprises a heavy chain polypeptde comprising the amino acid sequence depicted in SEQ ID N0 27 or SEQ ID N0 33, 21 The isolated antibody or antigenmbinding fragment thereof of claim 19 or 20, wherein the isolated antibody or antigenaindinig fragment thereof comprises a light chain polypeptide comprisirg the amino acid sequence depicted in SEQ 1D NO7 and a heavy chain polypeptide compiling the amino acid sequence depicted in SEQ ID NO:27,
22. The isolated anybody or antigen-binding fragment thereof of claim 19 or 20t wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain polypeptide comprising the amino acid sequence depeted in SEQ ID N0:36 and a heavy chtiin polypeptideomprsing the amino acid sequence depicted in SEQ I) NO33, 23, The isolated antibody orantigen-binding fraunent thereof of any one ofdcaims I to .1 5 whereins the isolated antibody or antigenbinding fragment thereof comprises a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 19 or SEQ I) NO:17, 174
24. The isolated antibody or anigenwbinding fagmen thereof of any one of eiairns I to 15 or 23, wherein the isolated antibody or antigentnding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ tD NO:27 or SEQ ID NO:25. 25, The isolated antibody or ani gen-inding fragment thereof of clain 23 or 24. wherein the isolated antibody or antigen-hinding fragment thereof comprises a light chain polypeptide comprising the amino acid sequence depicted in SEQ [D NO:19amd a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:27, 26 The isolated antibody or antigen-imiiiig fragment thereof of claim 23 or 24, wherein the isolated anibody or antigentbinding fragmentthereof comprises a light chain polypeptide comparing the amino acid sequence depicted in S EQ 11) NCO:17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:25, 27 The isolated antibody or antiuen-binding fragment thereof of any one of claims I to 15, wherein the isolated antibody or antigernbindig fragmen thereot comprises a light chain polyneptide conprising the amino acid sequence depic,-ted ir S EQ ID NO. 42 or SEQ ID NO:40 28 The isoated antibody or antigenbindinga fragmen thereof ofany one of aims I to 15 or 27, Wherein the isolated antibody orntigenbinding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence depicted in S EQ ID NO:27 or SEQ I) NO:33. 29, T!he isolated antibody or antigen-bnding fragment thereof of dain 27 or 28. wherein the isolated antibody or antigeninding fragment thereof comprises a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO42 and a heavy chali poypeptide eomnrpsing the anminio acid sequence depicted in SEQ 1D NO:27. 175 30 The isolated antibody or anigendbinding fragment thereof of claiM 27or28 wherein the isolated antibody or antigen-hini fragment thereof comprises a ght chain poypeptide comprising the amino acid sequence depicted in. SEQD E)NO:40 and a heavy chain polypeptide comprisig the amino acid sequence depicted in SEQ ID NO:3,
31. The isolated antibody or anigen-binding fragment thereof of any one of claims I to 15 wherein the isolated antibody or antigendilng fragment thereof comprises a light chain polypeptde comprising the ammo acid sequence depicted in SEQ ID NO:17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:33. 32 The isolated antibody or antigen-binding fragment thereof of any one of claims I to 15 % wherein the isoIated antibody or antigenbinding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence depicted in any one of SEQ ID NO:45, SEQ D NO:44. or SEQ ID NO:49, 33 T!h isola teld antibody or afntgenbindg raginent thereof of ciaim 32 wherein the isolated antibody or an-tigen-binding fragment thereof comprises a eight chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 19 and a heavy chain poypeptide comprising the amino acid sequence depicted in SEQ )ID NO:45. 34 The isolated antibody or antigen-binding fragment thereof of claim 32. whcee the isolated antibody or antigen-binding fragment thereof comprises a light chain polypeptide compsing the amino acid sequence depicted in SEQ ID NOi 7 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:44, 35 The isolated antibody or antigen-binding fragment thereof of claim 32 wherein the isolated antibody or antigenbinding fr thereof comprises a light chain polypeptidle comprng the anmino acid sequence depicted in SEQ ID NO: 7 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO49. 176 36, Th isolated antibody or atigen-binding ragnmieeof of any one of ciarns 1 to 14 or 16, wherenthe isolated antibody or antigeninding tragmcnt thereof comprises a ligit Chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:37 or SEQ ID NO:63 37 The isolated antibody or anigennding fragmein thereof of any One of caims 1 to 14 16, or 36, wherein the isolated antibody or antigen-bindig fagment thereof comprises a heavy chain polpeptide composing the aimino acid sequence depicted in SEQ ID NO: 45 or SEQ ID NO49, 3 The isolated antibody or antigen inning fragment thereof of clain36 or 37, wherein the isolated antibody or antigentbinding fragment thereof comprises a light chain polypeptide comprising the amino acid sequence depicted in S EQ 11) NO37 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:4, 39; The isolated antibody or antigen binding fragment thereoof f claim 36 or 37, wherein the isolated antibody or antigen-inding fragment there comprises a light chain polypeptide comprsine the amino acid sequence depicted in SEQ ID NO:36 and a heavy chain polypeptide comparing the amino acid sequence depicted A SEQ ID NO:49,
40. The isolated antibody or antigen-binding fragment thereof of any one of eaiIs I to 1 5 wherein the isolated antibody or antigenbiding fragment thereof comprises a light chain polypeptide comprising the amino acid. sequence depicted in SEQ ID NO:42 or SEQ ID NO:40, 41, The isolated antibody or antugen-indng fragment thereof of any one of daims I to 15, or 40, wherein the isolated antibody or antigentinding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:45 or SEQ ID NO:49. 177 42, he isolated antibody or anigen-inding fragment thereof of claim 40 or 41 wherein the isolated antibody or antigen-bini fragment there comprises a iight chain poypeptide comprising the amino acid sequence depicted in SEQ I) NO:42 and a heavy chain polpeptide comprisng the anino acid sequence depicted in SEQ ID NO:45. 43 The isolated anoibody or anige-bi nding fragment thereof of claim 40 or 41 wherein the isolated antibody or antigen-inding fragment thereof comprises a light chain poypeptde comprising the amno acid seqnc depicted i' SEQ D NO:40and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:49,
44. Thelsolated antibody or antigen Winding fragment thereof any one of claims I to 18 or 23 to 43, wherein the antibody or antigen Winding fragment thereof binds to hC5a with a Kj that is less than 7 x 1 )' >"N4 45, The isolated anybody or anti gen-Wning fragment thereof of any one of clairns I to 18 or 27 to 43, herein the antibody or antigen Winding fragment thereof binds to hC~a with a K that is less than 5 x I0^' M. 46 The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 18 or 31 to 43 . wherein the antibody or antigen-inding fragment thereof binds to hC5a with a K8 tat is less than 2.5 x 10 M1. t 6 2 ar 6 o 3 werinth anid r antienbnigfamn hro id to hC~a with a Kn that is less than l10 bNI 48, The isolated antibody or antigen-binding fragment thereof of any one of claims I to 16. 2, 33 35. or 40 to 43, wherein the antibody or antigensbinding fragment thereof binds to hC~a with a Kp that is less than 8.0 x I0'i M. 178 49 Theisolated antibody or antgen-bxnig fragm thereof of any one of cairns I to 1632k 33 or 35 to 43, vherein the antibody ihibits by at least % haman C5a& dependent human neutrophil activation at a molar ratio of 1:1 (antigen-binding siteC (a 50, The isolated antibody or antigethbinding fragment thereof of any one of claims I to 16, 32,33, or 35 to 39, wherein the antibody inhibits by at least 9% human C5a~ dependent human neutrophil activation at a. molar ratio of 1: (antigen-binding site:(ax 51 The isolated antibody or antigen-binding fragment thereof of any one of claims I to 50t w herein the antibody or antigenbinding fragment thereof inhibits the interaction between U~a and a CI5a receptor. 51 The isolated antibody or anttgen-bnding fragment thereof of claiin 51. wherein the Ca receptor is 5aR 1. 53 The isolated antibody or antigen-binding fragment thereof of claim 51, wherein the C~a receptor is (51.2 54 The isolated antibody or antigentbnding fragment thereof of any one of claims 1 to 53, wherein the antibody or antigenbinding fragment thereof does not substantially inhibit eonpiemenn-mediated henolysis of red blood cells initro. 51 The isolated antibody or antigen-binding fragment of any one of claims I to 54. wherein the antibody is a monoclonal anfibody. 56, The isolated antibody or anttgen-btnding fragment of any owe of claims I to whereinthe antibody is a nmanized antibody. 57 The isolated antibody or antigen,-bin.ding frarnment of any one of clairns 1 to 56 wherein the antibody is a ful ly human antibody. 179 58, 'The isolated antibody or antigen-binding fragment of any one of claims I to 57/ wherein the antibody or .anti-geninding fragment is selected gmm the group consisting of a reconbwinant antibody, a single chain antibody a diabody. an intrabody, a ci merized or chimeric antibody, a deinminnized human antibody, an. v fragment, aa Fa ffrag'ment, an Fab fragment an Fab' fragment, and an F(ab) fragment. 5 The isolated antibody or antigen .binding fragment ofoany one of clais I to 57, wherein the antibody is a bispecific antibody, 60, The isolated antibody or antigen-binding fragment of any one of claims I to 59. wherein the antibody orfragment eompses a hetlogous moiety, 61, The isolated anybody or anti gen-bnding fragment of claim 60, wherein the heterologous motety is a siena"" 62 The isolated antibody or antigen-binding fragment of elai n 6, wherein te antibody or fragment is glycosylated, 63, The isolated antibody or antigen-binding fragment of claim 60, wherein the heterologous moiety is a detectable label. 64, The isolated antibody or antigen-binding fragnoent of clain 63,wherein the detectable label is a fluoresent label, a luninescent label, a heavy metal label, a radioactive label, or an enzymatic label,
65. The isolated antibody or antigen-binding frag.ment thereof of any one of claims i to 64, wherein the antibody oianuien-nding tagment thereof is rnified with a o iety that improves one or both of: (a) the stab.lization of the antibody or antigen binding fragment th ereot in circulation and (b the retention of the antibody or antgen binding. fragment thereof in circulation. 180 66, The isolated antibody or ntigennding fragrnent thereof of claim 65, where. the modfieation is PEG ylation,
67. The isolated antibody or antign-inding iagment thereof of any one of claims I to 66, wherein the antibody cornprises an altered heavy chain constant region that has reduced effector function as compared to the effedtor function of the unaltered form of the heavy chain constant region. 68, The antibody or antigeenbinding fraginent thereof of claim 67 wherein the effector function is selected from the grotp consistin. of, (a) antibody-dependcnt col imdiated cytotoxicity (ADCCV (b) complement dependent ytotoxicity (CDC); and (c binding to one or more iecep- t. 69 The anybody or antigenabinding fragment thereof of claim 67 or 68, wherein the altered constant region is an altered form of a constant region selected from the group consisting ofIgG, IgG2g igG41 Ig6 gM, igAt, IgA2, igA, igD, and IgE, 70 The antibody or antigen-binding fragment thereof any one of claims 67 to 69, wherein the alered constant region comprises at least one amino acid substituton. insertion or deletion relative to the unaltered constant region., 71i The anttbody or antigen-binding fragment thereof any one of claims 67 to 70. wherein the akered constant region composes altered glycosylation comprising one or more of the following: (0 a change in one or more sugar components; (ii) presence af one or more additonal sugar components; or dii.absence of one or more sugar components. 72 An antibody or antigen-binding fragment thereof that crossblocks the binding of the antibody or antign.ddig frangmient thereof of any one of claims I to 71. 73, A pharmaceutical composition comprising the antibody or antigeninding fragment thereof of any one of claims I to 72 and a pharmaceutia lly-auceptable carrier. 181 74, A nucleic acid encoding thfantibody or antigen binding fragment thereof of any one of claims I to 2 7?5. A Vector comprising the nucleic ad of claim 74, 76, An expression vector comprising te nucleic acid of claim 74, 7T A cell compising the expression vector of claim 76. 78, A mthnod fbr producing an aniibody or antigen-binding fragment thereof, the method comprising eulturing the cell of claim 77 under conditions and for a time sufficient to allow expression by the cclI of the anibody or antigen-binding fraginent enodoed by the incleic acid. 79 fTe method of claim 78, further comprising isolating the antibody or antigen1 binding fragment thereof 80, A therapeutic kit comprising (i) the antibody or antigenbinding fragment of any one of chms I to 721 and (ii means for delvery of the antibody or atnigen-binding fragment to a subject. 81 The therapeutic kit of claim 80 whe.rein the means is suitable for subcutaneous delivery of the antibody or antigenbinding fragment tlereof to the subject
82. The therapeutic kit of claim 80. wherein the means is suitable for intraocular delivery of the antibody or antlgendbndingframient thereoftio the subject
83. The therapeutic kit of clain 80, wherein the neans is suitable fbr intraarticular delivery of the antibody of antigen-binding fragment thereof to the subject., 182 84, The therapeutic kit of any one of claims 80 to 83, wherein the means is a synge. 85 The therapeutic kit of claim 84, wherein the syringe is a double barreled syringe 8$6 The therapeutic kit of claim 82; wherein the means is a trams-sceral patch or a contact lens cotnprising the antibody or antigen-bning fragmenth ereof;
87. The therapeutic kit of claim 80 wherein the means is suitable for intrapuhmonary delivery of the antibody or antigennding fragment to the subject, 88 The therapeutic it of claims 87, wherein the neans is an inhaler or a nebuhzer. $9 The therapeutic kit of any one of claims 80 to $8, further comprising at least one additional active agent for use in treating a complerent-alssoiated disorder in a subject,
90. A method fortrtng a cmpl emen tassociated disorder, the method comprising administering to a human in need thereof an antibody or antigenbinding fragment thereof of any one of claims 1 to 72 in an amount sufficient to treat a complenent-associated disorder afficting the human,
91. The method of claim 90 -wherein the complement-associatcd disorder is a coimplement-associated inflammatory disorder: 9. The method of clzain 9, wherei the c noplementassociated. inflammatory disorder is selected from the group consisting of atypical hemol tie uremic syndrome age-related macular degeneration., severe bum rheumatoid artritissepsis lupus neph.rtis and antiphospholipid syndrome 93, The Tethod of claim 90 wherein the complement-associated disorder is a eonplementassociated pulmonary disorder. 183 94, The method of claim 93 wherein the complementassociated pulmonary disorder is asthma or chronic obstructive pulmonary disease,
95. Thennethod of any one of claims 90 to 94, wherein the antibody or anti.gen binding fragment thereof is administered to the human in an amount and with a frequency effective to maintain a reduced level of systennc C5a activity For the duration ofthe treatment, 96, The method of any one of claims 90 to 95 further comprising, after the administering, monitoring the human for an improvenent in one or more symptoms of the conplemenassociated disorder. 97 The method of any one of claims 90 to 96, further comprising admnisterng to the human one or more additional therapeutic agents,
98. The method of claim 90. wherein the antibody or antigenbinding fragment thereof is delivered to the suhect by way of intravenous administration, intrapuimonary administration., intraocular adnistraton subcutaneous adriinistraion, or itraaricular administration.,
99. An article of manufacture comprsng a container conprisig a labe; and a compositioncm the antibody orantigen dining frament thereof ofany one of claims I to 72 wherein the labelindicates that the composition is to be admUistcred to a m haig or at risk for developing a conmpinent-associated disorder. 00, The article of manufacture of claim 99, further comprising one or more additional active agents. 184 101 An isolated anybody or antigen-binding figment thereof that binds to us C5a, the anybody comprising: (I) a hight chain CDRI comprisinghe amino acid sequence depicted in SEQ ID NO:54; (ii) a li ght chain (DR2 comprising the amino acid sequence depicted in SEQD ID NO0:55; and iii) a liht chain CD)R3 compnrising dbe taino acid sequence depicted in SEQ ID N0:56; (iv) a heavy chain CDR comprising the amno .acd sequence depicted in SEQ ID NO:6-2:v) a heay chain CDR2 conripriing the amino acid sequence depictedin SEQ 1D NO:63: and (N) a heavy chain CDR3 comprising the amino acid sequence depicted in. SEQ ID N0:64 102, The isolated antibody or antigen-binding fragment thereof of claim 101, wherein the antibody comnprises: a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:59: and a heavy chain polypeptide comprising the amino acid sequence depiced in SEQ ID NO66, 10. The isolated antibody or antigen binding fragment thereof of claim 100 or 101, wherein the antibody binds to the desargina ted form f mouse CS a. 104, The antibody or antigenabinding fragment of any one of claims 100 to 103, wheren the antigen-ibinding fragment is selected from the group consisting of a diabody, a single chain antibody anFvfragment, an Ed fragment, an ib frag men an Fab fragment and an F(ab' u fragment. 05, An isolated antibody or an.tigenbinding fragment thereof, comprising a light chain polypeptide comprising (i) a light chain CDR comprising the anino acid sequence depicted in SEQ ID NO: 140; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:96; nd a iight chain QDR3 comprising the amino acid sequence depicted in SEQ ID NO: 142 185 (ii) a light chain CDRI cornprising the amino acid sequence depicted in SEQ ID NO: 156; a eight chain CDR2 comprsing the amino acid sequence depicted in S EQ ID NO: 157 and a Iight chain CDR comprising the amino acid sequence depicted in SEQ ID NO158; (iii. light chain CDR I comprising the armino acid sequence depicted in SEQ MD NO:.164; a l ight chain (CDR2: comprising the amino actd sequence depidted in S EQ IfD NO:65; and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO 166 (iv) a iight chain CDR I comprising the amnino acid sequence depicted in SEQ ID NOl7; a light chain CDR2 comprising the amino acid sequence depicted in S EQ ID NO Il?3;ud a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO.7'4; (v) a light chain CDR1 conprisinthe aino acid sequence depicctd inSEQ I) NO:84; a eight chain (DR2? comprising the amio acid sequence depicted in SEQ ID NO:85; and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:86: (vi) a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:92; a light chain. CDR2 comprising the amino acid sequence depicted. in SEQ ID NO:89; and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:93 (vii) a lightchain CDR I comprising the amiao acid sequence depicted in SEQ ID NOI8 a tight chai n CDR2 comprising the amino acid sequence depicted in SEQ ID NO89: anid a light chain CDRS comprising the amino acid sequence depicted in SEQ ID NO:90; (viii) a light chain CDRJ comprsing the amino acid sequence depicted in SEQ I) NO:95; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:96:and a light chain CDR3 comprising the amino acid sequence depicted in S EQ ID NO:9' (ix) a light chain CDR.I conprising the amino acid sequence depicted in SEQ ID NO:99; a light chain CDR2 comprising the amino acid sequence depicted. in SEQ .D 186 NO: 100; and a light chain CDR3 comprising the amino acid. sequence depicted in SEQ Ii) NO:101; (x) a ightk chain CDR! comprising the amino acid sequence depicted in SEQ ID NO84; a light chai-n. CD1R2 coanising the anmino acid sequence depicted in SFEQ I) NO:85 and a light chain ()R3 comprising the amino acid sequence depicted in SEQ ID NO:103; (i a light chain CDR1 composing the amino acid sequence depicted in SEQ I.D NO:1 05; a light chain. C)R2 comprising the amino acid sequence depicted in SEQ ID NO: 106; and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO107; (xii) a light chain CDRI omprising te amino acid sequence depicted in SEQ) NO92; a light chain CIR2 comprising the amino acid sequence depicted in SEQ I0 NO89 ard a. light cha in CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 108; (xiD) a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:20: a light chain CDR2 comprising the amino acid sequence depicted in SEQID NO: I10; and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:11; or (xiv) a light chain CDR I coniprising the amino acid sequence depicted inSEQ ID NO,20 a light chain C the no acid sequence depicted in SF0 ID NO: .1 and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO]I 13. 106 An isolated antibodyor antigenbinding fragment thereof comprising a heavy chain polypeptide comprising: (i) a heavy chain CDR I comprising theamnino acid sequence depicted in SEQ ID NO:5; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 144; and a heavy chain COR3 comprising the amino acid sequence depicted in SEQ ID NO] 17; (ii) a heavy chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:28; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID 18.7 NO:67; and a heavy chain CDR3 comprising the ano acd sequence depicted in SEQ 11D NO:30; (iii)a heavy chain CDRI comprising the amiino acid sequence depicted in SEQ ID NO: 160; a heavy chain CDRi2 comprising the amino acid sequence depicted in S EQ ID NO: 161; and a heavy chain CDR3 comprising the amnino acid sequence depicted in SEQ I) NO: 162; (iv) a heavy chain CDR I comprising the amino acid sequence depicted in SEQ ID NO:168; a heavy chain CDR 2 comprising the amino acid sequence depicted in SEQ ID NO: 169; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ I) NO:170; (v) a heavy chain CDR I comprising the amino acid sequence depicied inSEQ) NO: 176; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ 11D NO: 177 and a heavy chain CDR3 comprising the aTino acid sequence depicted in SEQ ID NO,178; (vi) a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO: .15; a heavy ohain CDR2 comprsingthe amino acid sequence depicted in SEQ I)D NO: 16; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:! 17; (vii) a heavy Chain COR I comprising the amino acid sequence depicted in SEQ ID NO: H 9; a heavy chain CDR2 coTaprsing ihe amino acid sequece depicted in SEQ ID) N0:20; and a heavy chain CR3 comprising the amino acid sequence depicted in SEQ ID NO:121; (viii) a heavy chain. CR comprising the amino acid sequence depicted in SEQ ID NO: 1 5; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID N :123; and a heavy chain (DR3 comprising the amino acid sequence dcpied in SEQ ID NOi 17; (ix) a heavy chain CDR I composing the amino acid sequence depicted in S EI 1) NO: 115; a heavy chain CD012 comprising the amino acid sequence depicted in SEQ ID NO:124; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:!17; 188 (x) a heavy chain CDR I contrisini the amino acid sequence depicted in SEQ II) NO; 119; a heavy chain CDR2 composing the amino acid sequence depicted in SEQ ID NO:126; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ 1D NO; 127; (xi) a heavy chain CDR] comprising the amino acid sequence depicted in SEQ D NO; 15; a heavy chain CDR2 comprisirg the amino acid sequence depicted in SEQ ID NO;29; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:1 17; (xii) a heavy Chain CDR I compsing the aniino acid sequence depicted in SEQ ID NO:131 a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:1 32; and a heavy chain CDR comprising the amino acid sequence depicted in SEQ ID NO;133; (xiii) a heavy chain. CDR 1 comprising the anino acid sequence depicted in SEQ ID N028; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:46; and a heavy chain CDR3 comprising the anino acid sequence depicted in SEQ ID NO47; or (xi) a heavy chain CDR I comprising the amino acidseqkuence depicted in SEQ ID NO: 136; a heavy chain CDR2 comprising the amino acid sequence depiced in SEQ ID NO; 137 and a heavy chain CDR3 composing the amino acid sequence depiced in SEQ ID NO:138 107 An isolated antibody, or antigen-binding tagment thereof coinpising a paired set of iight chain CDR sequences and heavy chain CDR sequences as paired in Table 3 or Table 9. 08. An isolated antibodyor antigen-binding agentt thereof. comprising. (i) a light chain CDR I comprising the amino acid sequence depicted in SEQ ID NO: 140; a light chain CR2 comprising the amino acid sequence depicted in SEQ ID NO:96; a light chain CDR3 composing the anino acid sequence depicted in SEQ 11 NO; 142; a heavy chain. CDR1 comprising the amino acid sequence depicted in SEQ ID NOH 15; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID 189 epicte n E NO:.144; and a heavy chain CDR3 comprising the amino acid sequence deitdi E I) NO:1 17; (ii) a light chain CDR I comprising the amino acid sequence depicted in SEQ ID N020; a light chain CDr2 compnsing the amino acid sequence depicted iSIQ ID NO,21, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:22; a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:8; a heavy chain CDR2 comprising the amio acid sequence depicted in SEQ ) N0:67; anda heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO30; (iii) a light chain CDR I comprising the amino acid sequence depicted in SEQ [D NO: 156; a light chain CDR2 comprising the amino acid sequence depicted in S EQ ID NO:157; a. light chain (DR3 comprising the amino acid sequence depicted in SEQ ID NO: 158; a heavy chain (DR-comprsing the amino acid sequence depicted in SEQ ID NO:160; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 161; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID N 0:162; (iv) a light chain CDR compiising the amino acid sequence. depicted in SEQ ID NO:164; a light chain. CDR2 comnprising the amino acid sequence depicted in SEQ ID NO: 165; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:166; a heavy chain C'DR1 compising the amino acid sequence depicted in SEQ ID NO: 168; a heavy chain EDR2 comprising the amino acid sequence depicted in SEQ ID NO:169; and a heavy chain CDR3 comprising the aiino acid sequence depicted in SEQ HI)NO: 170; (v) a light chain CDR1 comprising the amino aeid sequence depicted in SEQ ID NO:372; a light chain CDR2 comprising the amio acid sequence depicted in SEQ [D NO:173; a light chain CDR3 comprising the amino acid sequencedepicted in SEQ ID NO:I74; a hey ih in CDR comprising the amino acid sequence depicted in S EQ ID NO: 176 a heavy chain (DR2comprsing the amino acid sequence depicted in SEQ ID NO:177 and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 178; 190 (vi) a light chain CMR] c1 omprising the amino acid sequence depicted in SEQ ID NO:S8; a eight chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:89;a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:90: a heavy chain CDRI comprising the amino acid sequence depicted in. SEQ) ID NO, 11 a wy chain CDR2 composing the amino acid sequence depicted in SEQ ID NO: 1 20; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ I) NO:21; (vii) a light chain CDRI comprising the anino acid sequence depicted in SEQ iD NO:105; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 106; a light chain CDR3 comprising the amino acid sequence depicted in S'EQ ID NOM; a heavy chain CDRI comprising the amino acid sequence depicted in SEQ ID NO: 115; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID) NO:124 ad a. heavy chain CUR3 comprng the amino acid sequence depicted in SEQ ID NO 117; ii) a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:84' a light chain CR.2 comprising the amino acid sequence depicted in SEQiD NO:85; a light chain CDRJ comprising the amino acid sequence depicted in SEQ ID NOI86; a heavy chain CDRI comprising the amino acid sequence depicted in SEQ ID NO: 115: a heavy chain CDR2 composing the amino acid sequence depicted in SEQ ID NO: 16; and a heavy chain CDR- comprising the anino acid sequence depicted in SEQ ID NO17; (ix) a light chain. CDR! comparing the amino acid sequence depiced in SEQ ID NO:20k a light chain. CDR2 comprising the amino acid sequence depicted in SEQ I) NO: 110; a light chain DR 3 comprising the amino acid sequence depicted in S EQ ID NO I11; a heavy chain CDR I comprising the amino acid sequence depicted in SEQ ID NO: 136 a heavy chain CDR 2 comprising the amino acid sequence depicted in S EQ ID NO, L3 aid a heavy chain CD)R3 comprising the amino acid sequence depicted in SEQ 1D NO 38; N) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:20; a light chain CDR2 comprising the amino acid sequence depicted. in SEQ ID NO:; I., a light chain CDR 3 comprising the amino acid sequence depicted in SEQ ID 191 NO: 1 .1 3; a heavy chain. CDR cominsing the amio acid sequence depicted in SEQ ID NO:28; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ D NO:46: and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ 1D NO:47 (xi) a light chain CDR I comprising the amino acid sequence depicted in S EQ ID NO:99, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO; 100; alight chain CDR3 comprising the amino acid sequence depicted in SEQ [D NO:101; a heavy chain CDR comprising the amino acid sequence depicted in SEQ ID NOI: 19; a heavy chain CDR2 comprsig the amino acid sequence depicted in SEQ ID NO: 126; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID No:127; (xii) a light chain CUR comnprising the amino acid sequence depicted in SEQ IfD NO 95 a light chain. CDR2 comprising the amino acid sequence depicted in SEQ H) NO 96 a light chain CDR3 compising th amhio acid sequence depicted in SEQ ID NO97 a hea ivy chain CDR) comprising the anino acid sequence depicted in SEQ ID NO1 5; a heavy ohain EDR2 conprningthe amino acid sequence depicted in SEQ 1D NO:44; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 17; (xiiiba light chain CDRI comprising the amino acid sequence depicted in SEQ ID NO:A40 a light chain CDR.2 comprising the amino acid sequence depicted in S EQ ID NO:96: a light chain CDUR3 comprising the amino acid sequence depicted in SEQ ID NO:42; a heavy chain CDR composing the amino acid sequence depicted in SEQ ID NOIl:5; a heavy cain CDR.2 comprising the amino acid sequence depicted in SEQ [D NO: 123; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ I) NQ 1I7; (iv) a light chain CDRI conposing the amino acid sequence depicted in SEQ ID NO05; a light chain CDR2 comprising the anino acid sequence depicted in SEQ I) NO:106; a light chain CDR3 comprising the amino acil sequence depicted in SEQ I) NOd 107; a heavy chain CDR coIgsing the amio acid sequence depicted ipSEQ ID NO: 115; a heavy chain CURicomprising the amino acid sequence depicted in SEQ ID 192 NO: 123; and a heavy chain CDR3 comprising the amino acid sequence SEQ H) NO :1.17; (XV) a light Chain CD.Wcomprising the. mino acid sequence depicted in SEQ ID NO 9 a licghtchain CDRI compising the amino acid sequence depicd in SEQ ) NO89; a light chain CDR3 comprising the amino acid sequence depicted in SEQ I) NO: 108; a heavy chain CDR1 compising the amino acid sequence depicted in SEQ ID NOA 5; a heavy chain CDR comprising the amimo acid sequcene depicted in SEQ ID NO:144; and a heavy chain DR3 comprising the amino acid sequence depicted in SEQ ID NO: 117; (xviy a light chain DR 1 comprising the amino acid sequence depicted in SEQ ID N0:92; a light chain CDR2 comprising the amno acid sequence depicted in SEQ ID N;4089; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:93; a heavy chain CDRI comprislnZ the amino acid sequence depicted in. SEQ ID NO: 15; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:1 23; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO117; (xvii) a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NOS2 a light chain CDR2 cmprieig the amino acid sequence depicted in SEQ ID NO:89; a light chain CDR3 comprising the amio acid sequence depicted in SEQ ID NO:93; a heavy chain CDRI comprising the amino acid sequence depicted in SEQ ID NOA 15; a heavy chain CR2 comprising the amino acid sequence depicted in SEQ ID NO:144; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ 1) NO. 17; (xviii) a light chain CDRl comprising the amino acid sequence depicted in SEQ ID NO'84; a light chain CD.R2 composng the amino acid sequence depicted in SEQ ID NO:85; a light chain CUR3 comprising the amino acid sequence depicted in SEQ ID NO: 103; a heavy chain CDRA comprising the amino acid sequence depicted in SEQ ID NO: 115; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NOI29; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO; 117; 193 (xi.x a light chain. CDR1 coniprising the amino acid sequence depicted in SEQ ID NO:95; alight chain CDR2 comptstng the ammo aci sequence depicted in SEQ ID NO:96; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID-) NO97 a heavy chain CDR-I comprising the amio acid sequence depicted in. SEQ ID NO 115; a heay chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 123; and a heavy chain CDR3 comprising dhe amino acid sequence depicted in SEQ ID NO:1 !7; (xx) a light chain CDRI comprising the amino acid sequence depicted in SEQ ID NOI84; a light chain (DR2 comprising the anino acid sequence depicted in SEQ ID NO:85, a light chain CDR3 comprising the amino acid sequence depicted in SEQ I) NO:103; a heavy chain CDRI comprising the amiio acid sequence depicted in SEQ ID NO 115; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO 144: and a heavy chain CDR3 comprsng the amino acid sequence depicted in SEQ ID NO 1i7;or (xxi) a i chain CDRI comprising the amino acid sequence depicted in SEQ ID NOW0 a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:21; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO113; a heavy chain CDRI comprising the amino acidsequence depicted in SEQ ID NO: 13 1; a heavy chain CDR2 composing the amino acid sequence depicted in SEQ ID NO:132; and a heavy chain CDR comprising the amino acid sequence depicted in SEQ ID NO133.
109. An isolated antibody, or ainigen-bndifragrent thereof>comprsing: a heavy chain variable region framework region I comprising the aino acid sequence depicted in SEQ ID NO;68 or SEQ IDND:69; (ii) a heavy chain variable region framework region 2 comprising the amino acid sequence depicted in SEQ ID NO70 or SEQ ID NO:7 ;and a heavy chain variable region framework reion 3 coinrjisng the amino acid sequence depicted in any one of SEQ 11 NOs:72 to 74 194 10. The isolated antibody or antigen binding fragment thereof of claim 109; wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region framwork region 4 comprising th amino acid sequence depicted in 5QID$ [ NDO75 I11 The isolated antibody or antigen-binding fragment thereof of claim 109 or 110, wherein the antibody or antige-binding fragment thereof comprises a heavy chaia variable region comprising the amino acid sequence depicted in any one of SEQ ii) NOs: 76 to 80.
112. A prefilled syrnge comprising the antibody or antigeibinding fragment thereof according to any one of claims 1 to 72.
113. The pretilled syringe of daim 112, wherein the antibody or antigenbinding fraginent thereof is formiAtd lor intraocular intravitreal orminarucuar administration,
114. The pre-filed syringe of claimi 12 wherein the antibody or nigentding fragment thereof is formulated for intrarnuscular or subcutaneous administration. 115 The predilied syringe of claim 112, wherein the syringe comprises at least one pharmaceutical unit dosage foPm of the antibody or antigen-binding fragment thereof
116. The pre-illed syringe according to any one of claims 112 to 115. wherein the syringe comprises between 0,05 mg to 10 mg of the antibody or antigen-binding fragment thereof
117. The prelfilled syringe according to any one of clanns 112 to 115 wherein the syringe comprises between about I mg and 100 mg of the antibody or antigentinding fragment thereof. 88 The preilled synge according to any one of laims 1.15 to 11,wh erein each pharmaceutical unit dosage form has a volne of between 0.02 mi Uo I rmL indl.sive.
119. The pre-illed syrine according to any' one of claims 115 to 117, wherein the pharmaceutical unit dosage form has a volume of no more than 0.05 mL.
120. An isolated antibody comprising two antigen-binding sites, wherein each antigen binding size independently can bind to free human Ca (hCa) or uneleaved human C5 (hCS. and wherein, in an aqueous solution comprising; (i) a plurality of said antibodies and (iila molar excess of IC5 as compared to the molar amount of the antigenbinding sites, at equibbhurn and under physiological conditions, at least 95% of sad plurahy of antibodies bind no more than one hC5 molecule.
121. An isolated antibody comprising two antienanding siteswherein each antigen binding site independently can bind to free nuan. C5a (hC5a) or uncleaved hum an C5 (hC5), and wherein, in an aqueous solution comprising (i) a plurality of said antibodies and (ii) a molar excess of hCS as compared to the molar amount of the antigen-binding sites at quilibrium an under phy siological conditions,at leasi 95% of said plurality of antibodies at last one n site vailabkto bind free hC a, 2 An violated antibody comprising two antigen-indig sites wherein each antIgen bidig dependent can bind to free human (5a (hC5a) or uncleaved human C5 (bC5).and wherein, in an aqueous solution comprising:(i) a purality of said antibodies and (ii) a molar excess of hC5 as compared to the molar amont of the antige-binding si es, at equilibrinm and under physioioical conditions, the two antigenbndin i sites of no more than 5% of said. Plurality of antibodies are Mily occupied by hC molecules,
123. The isolated antibody of any one of claims 120 to 122 wherein the molar excess is a twofdid molar excess, 196 124 The isolated antibody of any one of claims 120 to 123, wherein said physoiogicai condition is 3,9 nM INa O 6- mM Na*1PO 4 and 150 rmM NaC at pHI?.0 125 The isolated antibody of any one of claims 120 to .124. wherein each antigen binir site independenty can bind to free hCa with a K 0 that is less than 1,25 x 10 ML
126. The isolated antibody of any one of claims 120 to 125 wherein each antigen binding site independenty can bind to free hCa ith a subnanomolar afinity. 27, The isolated antibody ofany oneof claims 120 to 126, wherein the isolated antibody compises(i) a light chain (IDR1 comprising the amino acid sequence depicted in SEQ ID NO:20; (ii) a light chain CDR2 comprising the amino acid sequence depicted in SEQ 1D NO:2 1 and (iii a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:22; (iv) a iavy chain CDRl comprising the amino acid sequence depicted in SEQ ID NO:28; (v) a heavy chain CDR2 cotnprising the amino acid sequence depicted in SEQ ID NO46; and (vi) a heavy chain C DR3 comprising the amino acid sequence depicted in SEQ ID NO:4T
128. The isolated anybody otany one of claims 120 to 127, wherein the isolated antibody comprises a ight chain polypeptide comnprising the amino acid sequence depicted in SEQ ID NO:42 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:45. 129 A method for treating a hman afflicted with a comlementassociated disorder the method comprising administering to the human the isolated antibody or antigen binding fragment of any one of cIans I to 72 or the isolated antibody of any one of claims 120 to 128 in an amountsufficiento great the compenentassoci ateddisorder
130. The nethod of clahi 129, wherein the complement-associaled disorder is a Gta associated complement disorder; 197 131, A method or treating a human afflicted with a C5aassociated complement disorder. the method conrtrising ad'mtistering to te human at least 1. rmg of the antibody of any one of claims 120 to 128 per kg body weight of the human to thereby partially or completely bind and sequester nanogram levels offree (5a fior at least 12 days. 132 A method fbr treating a human affected with a C5a-associated complement disorder; the method comprising administering to the human at least 10 mg of the anybody of any one of claims 120 to 12 pr kg body weight of the human to thereby partially or completely bind and sequester nanogram levels of free C5a fo at least 24 days, 13 3. A method for treating a human afflicted with a C5a-associated complement disorder; the method comprising administering to the human theiantibody of any one of cldims 120 to 128 in an amount sufficient to (a) achieve molar Cmax valIes substUntially lower than the molar physiologic concentration of uncleaved hCs and (b) parialuy or completely bind and sequester pathophysiologic levels of free CGSa 134 A. method for treating a human afflicted with. a CSa-associated complenient disorder, the method comprising administering to the human the antibody of any one of cdaimrs .120 to 128in an amount suffidient to (a) achieve a molar Cmax value substantially lower than the molar physiologic concentration of uncleaved hC5 and (b) partially or completely bind and sequester nanogram levels of free C5a for at least 12 days. 135 The method of claim 134, wherein the Cmax value for the antibody is no greater than 100 nM 13i The method of claim 34, wherein the Cmax value for the antibody is no greater tha 80 nM
137. The method of any one of claims 130 to 136, wherein the CSasassociated rpiunent disorder is selected from the gioup consisting of e a 198 distress syndrome (ARDS), septic shock, atit ihosphopid syndrome. catasrophic anti phospholipid syndrome. h di sseminated intraasculfar coaguation, hipunephritig Goodpasturfs Syndrome, burn or severe burn, asthma, H ELLP syndrome (femolytic anemia, lev acd Liver enzymes nd Low Platelet count), inflammation-induced pain, GSa-mediated neutropenia, age-related macular degeneration (AMP.chronic obstructed pulrnwary disease and rheunatoid arthritis
138. A prefilled syringe comprising the antibody of any one of claims 120 to 128. 139 A pharmacutical composition conmprising the anybody ofany one of claims 120 to 128 and a pharmaceutcaiiacceptaube carrier.
140. A herapeutic kit comprising the antibody of any one of claims 1 20 to 128 and a means for delivery the antibody to a subject afflicted wii a complementassociated disorder. 199