HUE030150T2 - CD33 kötõágensek - Google Patents

CD33 kötõágensek Download PDF

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Publication number
HUE030150T2
HUE030150T2 HUE11764553A HUE11764553A HUE030150T2 HU E030150 T2 HUE030150 T2 HU E030150T2 HU E11764553 A HUE11764553 A HU E11764553A HU E11764553 A HUE11764553 A HU E11764553A HU E030150 T2 HUE030150 T2 HU E030150T2
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ser
val
thr
gly
leu
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HUE11764553A
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Renate Konopitzky
Eric Borges
Paul Adam
Karl-Heinz Heider
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Boehringer Ingelheim Int
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Claims (2)

  1. 6gabeöaimi igénypontok 1< 0033 kélöágeoa. aaei y hgmsn Cp33>C:os köfeéőik,: a 0033 kfe-i.cágens spy sós1 teat vagy egy onfeiteét; 3izás:paiék*i 3.¾ ázsal öef; oiáit:,· hogy a hámig 0033 ΓΗ3;Γ· iYiDKihPViíiYi CSihiP Co? I3U ksfeinösae asihveaciájában léyö yalisSíály episáphoz speel I: ikonén höfeéélk» 2y h s 1, :: genypnns ssslltifei CDi 3 kötőágnn.s,. a®z&amp;2 yeXlasnsssasa., hegy héhdilieaiki egy nehéz Céhe var Lábi s.is reorCsi, a:ae i.y sax t* Irma z CDRl-ex, 0PP2--1 is CDR3~at .· ék könnyő laoö: váz kákái áe szépiával, amely sarts Xmáz CO 34 -ex, CDRn-'OS is ODRé-eS, ekei a CDR'l .ami n*ss v szekvencias a a SeglD Pgj I ^ 1 i ke a öl, a ODR2 aminessv szekvenciáin a Cegli) 22:2: 15 « 23 Miül, a CDP: 3 asrlBeasv azekvanfeiála a Se-q'i D Heg 29 ~ 42 kö sül, a Ü0R4 siCihiiii azekyeneiája a Seglp No; 43 - 50 kozni, a CDP2 annex: sav asakvanci-l;>a a 3eq.I D Do; 57 ~ 70 kosai: a ODRI sjfeibgl&amp;V s zokszóin:: iia a SeqlP hal Cl ~ 84 kosiI vázíszto2t .
    2, Rz I. vagy 2, 1 fénypont. ηζρηΐϊήζΐ 0033:: köt oágen.S; qkqi as apitdp a iarcúénk iof gréléeé# t ömeqspek2zpeZköpi iva ·. meghat Irozc·:k , Ív Bármely papelőző igényzon:: ázepfenfeí: CP33 köt őspens, #0*1 á 0P33 kőSőágénaek ios ssrnai .s záxk ős kló# fel hál* éiyaü, hogy * 0033 későágensek kezqáfei moony i s*gé;a; a iepaiakká 4 Ok-a a aej t: fals cinen ma rsa se i oz.ssiác.i ét köReSŐ ··: irány i. i siókén .
    3, Bércei y megöl öze igelryponfe eásrlnfei. 0038 káhöégeos, ekei a nehéz Xans: feárléblils régié1 * Seal0 Mse 03 e 33 kosul válzszsot:. saineaav azekveneiát sart.a lesz és a könnyűiánc variáizilié Ráf ié a Sex? ID 3k>:; 13 ~ 112 közül feálaaztöfei: aminrsav asékvsnsiát aarfeaimasn
    3, Bármely rangéi őzé Igén ypont. szerinti 0033: kos öugen.s. ahol a 0033 két dkg essz olyan nehéz láncra i keoPellozik, arvtílynek ámlnozaé ssekvnnci 1 j s; a OegID 0*? 113 - 126 közül válás siet 2- ás * 1 van könnye lánccá i, *vse lyonk ss: · noaav aza·: vnnciája a Sag! D Hé: 127 - 140 közül vái.assiois . Ά Bárnál y neqoiáro igányböát sserimd CD33 kátö&amp;qnns:, «hol s CL· 3 3 15·:Olgons éi£;nsi rákénak Kdjo 10 «10 vagy ksvasobb aainb .a hallá RD3 l-boa., óihö a cynonís) gos? Cbal-hor ,
    6, Ré mos ·,·· mogölátő s.gósxypoi;;: ssarinti CD33 kct.áágensh ano! a Í1Í333 kokoágeiss. Ipásáni áálí: >, S v Mtín&amp;iy angol óvá i.gbnypssa·: soorint 1 ¢3)33 xokéáynsn?, ahol a Ri>33: k 5 rá ág erő. éaljisan komán, lö, Béronly angol ns:o iqányppát s;:%ri;3: .1 Cb33 xOtöáosnéy ahol g CD33 nőroágerss: ra rS a ina· a tavibbá a:;: sokUn: íöbSöábk'..,
    11, A lg, igénypont sf Irtát 1 CDi! kböőágtnáí: Ahol át af faktor főnbeiát egy ft domáá sys a iáXgö,
    13 , A Mc .Igénypont áötrtáöi CD 3 3 kátöégons, Ahol á CL· 3 3 tote ág a; a; ás; p xkaöénbon ás Γ, ííosaéá fan ke lói át ssobn 1 sió agy vagy több ísöiáenőt ar ηά&amp;3 r , 13. S 12, igénypont ttltrlnti 0033 kCröágansp öböl at fi torsén funkciójának sroös; lés: 15/ a öt ADCC áböbxlblaa IpgsaAbb 1 0 b - ka i , AlőnyÖssiA Sől-kAl·, ár még A iöIyöIIbfeö®: ) 06%··· kai- > 14 v A 12: . - 13* sgénynon cs>k némes yllo rrerlra.x 0D33 kööáágsns, ahol as: R, űöálbbia léyö morációk a Kamat 13) snianaása. Inda a aasr inti. 333 éa/vagy 333 éö/vaay Ifi pesti óiéiban lévő .sasion·.a a vak kásái válté r;: ott agy vagy több notlólábán vannak< 13, A 13, — 11 . iöénynötöok noraalyika r::ssr i sa. x CL·33 kör. hágó πa.· aba:l as: RC loaánnen levő ónkén 1 ák ss 232 és 332 pos: io l árban lövő sao:bIst;it:ös:idk éonos néc Iái a, oiőssyáaan a a 32230/13120, fő, A xtvaoks; aők Ιοα.αΐ viiasákott CB33 Ráirö ágens; sn.t.i.best# ásás: 1 y töiisiimtsr Rngsb Ma: 1: CbRlmöy SéglD Bői IS CbR2--1, Reg rigó: 2 2 CÖR3 -a*·, Rsgip ön: 13 CDR4~nt, SsqXD Böí S3 CDES-öt át 3 no Iá Sic: 71 C0RS~ox. ,· antitosíL· «::;«! y lark a 1 na a Roqli) Do: 2 C0R1 ··*:, RnqiO bői 16 ÖDEt-íp RagTD Rpy 3ö CDk3-vn, Sfálb Do: 4 4 CDR4 - vs, Sag: C Boa S3 őDRá-őt Ös Snqlü Hss: 72 g;DEb:«-őÍí a InÖitISt, sbööy tasstlllisat Sas::)'C ?R:; 3 CI331 -ot. Sag) 7 Dos 1,7 CCAv ··tt SlspL· öo: 31 C&amp;Rl-ét.; Rögbi bo; 4S Cl?24-ss , SvqfD Dn: :33 RbbS^ölt és SoglL· öo: 73 CDRö-os, test :i test , aos s y 5 a rtslLma s; RáqTO Mo; 4 C8R). -a 5, SáqéD Mo; 18 €012--1 ; OeqiP 80; 38 €083 - an, 3eqlí> MO; 4 3 CÜR4 -000 SeqTo 7145 80 2083-55: 8« SeqXD 04: 34 201 8 --o 5.. satitset, ísgsslq t.*;: 11 :·;*;·: Osealp No* S 8031---:0., OsqlO Mo: 13 2:)82-1, 5eqX:) Mq: 33 €03:3--:¾¾. OqqXX; €05 43 COli-at, OsgtO 8:5; «1 €01.0-:¾¾ ás 8%qXü Os; 35 - 3)88-01 , ont 1?:os- , ant) y 5 art a X:ts;;s leqXD On: 6 2081-44, Sag 10 Mo; 2Ö 8:002--1., leal D No: 34 C011--:5: , leqlD Mo; 43 CD84 -at, MaqIO NO; 62 CORS-os 5 s; real 0 Oss 35 20R0>-e5, anti test, amely to -q:a.i mat SoqlO Me; 7 €011-051 RaqlO Mo; 11 c:Dll- :, S-qXO Me: 35 €:.:13---at, ioqlO No: 43 COM4-at, RaqOD Mo: 13 CDR§~4:t 4a 8-qID €0: 77 300 8--ol., ant ?. r., a:;;ely ts ?: r a i nasr loqJO Mo:; 3 CDRl-s; ·:, OoqlD Miss 22 €012--1, 3oql0 80s 38 CORS-sr, Reg ID Mos 30 €014--5-:, Moqll No; 84 CURS-05 to Oes€ 0 8:5: 31 €018-05. Silsitoat, ss:*a ;.y tas:RnqIO Mo:; 2 €113:--0¾. iaqll :Mo: 23 CDR2 - 5, SaglO Me; 37 €083---05,, Roq.Ul Mq; 51 2084--05., leq-D Mo: 85 €013-35 00 SoqlD Mo: 72 €080-:15. any;.;: as; ·:, amely 1 or 5:,1 a;*;; SoqXD Mo; 10 €:811-0:5. leqlO MO; 24 2083-5:. leg ID Nos 32 2083-45, SeqXD Mo: 33: 2084-55:. SeqlO On; 66 2083-05 ie leqlO- Mq; 30 2214-·::·5, setitest, amely tattaisSaa 2 eg 12 -1,: 11 2085-55. Sqqlp Mo; 25 2082-5. 2sq: 2 Mo: 30 €013-55. SnqlD No: S3 €014-45, slsqXD No; 07 €€83-45: és OáqlO No; 11 2080-:55, siti 5445. smeiy 5ax- a lean Sag IP Me; .12: 2781 - at, SaqIO Mq.; 36 €012-5, SaqIO Mo: 4 0 €283-a-:, Sag 18 No; 34 €014-45. SRqlO: Ms: 01 €023-:5:. 5a Sag 18 Me: 32 €016-45. ant:.::eat. amely tart* inna SsqXO MO: 13 €011-45. Ra-q10 MR: 37 €082-5, SaqIO :84: 41 €083-54, SeglO Me: SS 2DR4 -* ·:, laqlO. lies 60 €010--45 ns Deq.XC Me: 83 €080-45. sat: :1 tens., astaly yssrtalm;::;. SaqIO No : 1.4 2281 ··«·:, 8::-::10 Not 28 2082---5 , geqlO Me: 42 €013-45, SaqIO Mo; 36 €21.4-45, SeqXD Mo: 70 CCR3-Ö-: és SéqlO Me; 14 5886-01 17, 1 kora::Snack k.0581 v* las: 5 tota C03.1 :<o::c>4ge:;s; a?:li·: a s; a, amely t o .r 5 e 1 maa a faqlO Mo: 30 r-eláa line vsriiOllie rtq :..5: 4a a SeqlO 80,: 31 konnyo iáié varián: 1. i s ráq 145, as-it l yeass i amyly tsar a.i.esrr.a a 3aqJ2 Ne; 36 eeiás line var i4q 1.- :. s 5ági45 át a SátpO Mq;: 100 tonrsyu liras eariiMlio régi,45, 5::)57.kast, aool.y tartsimsesa a ieqXP Mq: 67 n%hé;s iénq yarlioilrs rág lot ta a SeqlO Mo: lOlOonnysl láee oaréééllla ráqlét, soritesrt sgeiy: tartainasys a Deg II) bőr §S ft* hé a láng voriiollift régié·: és ft Cégit to: 1 02 könnyű lánc vaxr ólé 11¾ régiét, ant: 1!:ort, *;«« 1 y tartelaorta * CsqlD Do; óé neéér 1 áno vaxkláMIls re*lót és •5 often; Mer töo könnyű Iára:: variábilis: régiót, anciéésé, seely t3riál;raraá a Se*lé Mo; 9{) n.ahéa lácxc var lato k Is régiós é# a Cégi Dóba; bűé könnyé Mae vsriáOx;.!. s régiét·,· anéifeéét:, sas ly ;· áttolná;;·;·.:· a Sík; ID So; SÍ neSés lére vosoábil; r régiét ér: a ikqtt Hs; lét kénnyn: lánc varlsbiS Is régiét, áólikest,: áyely r arts: siess a á SeglD bé·; él: π akár 1 arc tét iábilié régiót ét a i/sgi D Mér 106 Könnyű Iá a··:: áaritaóilis; régiót,· .Sétáiéit; ana.i.y taxi a Lear;; a &amp; SégiD Mér M3 ftfttéft Iá na va ·: xáb.L I. xrégiós, óé a CbaiD Do; ió? könnyé iáné var iáéi.;. L« régiét:, not i , érnély tártá.ló;grsa a DealD box S4 nehés lére taróábiiié .régxér és á SenlD bo; lóé könnyű lano varian.; : rs .régiét,. entitás;:, are Ív I a-oséna;;.;·, a a ésgl D Mé; Ól nehor táró váriéba l:;,e régiét és é tog s D to; 1 ft? i-Oftnyb lánc wx .i.abi 1 Ír régiét:, sniitéslv aygiy taxi a Írás ar a g tag.: t bor át note;: lőné cáriahiitá régiét és g Sealé b;: iiö könnyű line verj.so; tiíj régiét, ggSltgsS.» aoely tajrtglísaóéé e SeqlC Sor ói sebét lése tar iáéi Irt régiét és é Ságié Mér Ili: kéggyű látó variábilis régiét, sbiibéat, áSíély tarraisr-rfta a SágiD bt; SS: ne nor lánc variábilis régiét és « Cog ID box L12 könnyű lánc vardébiiia régiét, Ιό, é kovát korok. körül váiesatott CD 11 k été ág vas ; aftii test:, areiy tartaléaft égy OaqkC to; Í13 soké;; lékóéi és égy Séglb Mg; 121 kóenyé láncok: aátitast, gyely tartgi-taá égy tag IC to; Ili nones Iár;gqt és égy Ságié Mer 120 kénnyé láncot, gtstitéét, artéiy tartályát ágy ósqlD Mg; itn no boa 1 ér:col ás agy Ságié Mo; 12 a ténnyé Iágáét, afttisort, assoly tarsalSíSt- agy Ságié Me; 1 lé a a hex láncét és agy óagiM Mo; Íré könnyű iássoot, áíítitást, arai y tso airaa egy SsqlO ég ; 111 nőnék lángét és égy iéglű Mt ; iűl irányé láncot, rnt xtasr, ssíieiy kártgigaé égy SéqXb 'Mm. Hű nébés iábóót és égy Sóqlb Mn; léi könnyű: láncot, áftti testi a ser 1 y tárta Igar egy Oeglb tksx 11S éenéé iábqot és agy Sggio to; 131 könnyé iáncgr, sifttisésto ástéiy: tartáláiaá egy tog ID Do; ÍŰ0 neher lánoc;; és agy Segít Mg; 134 konnyá iéncat. an·: itext, analy r aria 1¾¾¾ ogy éaglö So: XXI on hie láncol és egy degll Ig: lés kénnyé 1 s:v;x;·: ané s L iqér gésln nr, antléiisk, aroly tortáXéos égy élgfé éo; 222 nadir Idádét és égy Ságié éíg; XXI kéOdyd lángot and a ligát chain of, snoites/y áhády r: aria loar any Sag ID Dos 123 n ana a I áno-ot Is eqy SngXI la.; 137 kénnyé isaoot and s light· ohalo a|f: antitank, ansiy tns:rajasr agy éaglö l:>: X23 nahls láncol: as agy Ságié hon : 1¾ kénnyé lángok and a .Light oésin of., arc: r can·:. anni.y tortaXmas agy Son lé da:; 125 nahés, láncai ad égy Ságié do/ I3f könnyé .; áooot, or·: : mat, sdaly tártéInát agy Ságié én; 121 a ódé a Xádaat ág agy éoqlé do; ltd Lénnyé Láncol . Iá. ,á 11. - XX.s l.glnyronrok éássisXylka aaarXnti Céhé kétdágsnn, ah<; 1 a 3d33 kor oé gona rartaXnas toaádfeá a ff akt or: ran fői gr . 2é, A 1 d. iolgypont sosrinti Sédé kotéágoos, adod a a ősieké os lankaiét agy XX dósain jsadtáXja. ál. á lg, Igénypont sserinki dö:33 kéndloano, ahol a éD|3 Idtéágana as Fv donénoah aa XX dósain í as: rolójal saodöilió agy vagy í éné nar Sailá ::arts Ina .?:. 32. k 21, :. gánypon?: rrsr.i nr ;. XXXIX kétdaganáí a no L aa id non orr tüske Ló;: ána k andniáaXéja or AéCC non akadó;? a Isgalnho 1 ΟΧ - fai, előnyéi an X 02····: a 1, ás iáig aldnyésaopan löét-ikal. 23. X? XI. 22. tgányynritok :aá:nraXyi:ka soayXati 1333 tér élő ear t anal go donorén? n iáid aatéállók 3? Mfeaf: lé sranoréa.;. indád stsirintl 33X él/yagy 3 SS is/vagy XXó ?:,o;A c Lókban lévé an.lndáaysk kösdl 'volasdtorX ágy vagy kdéé por: e;.óban verőnk .. 23 . A 21, ~ iXS. ; gén yor-n:: ok bonod yi ke no tan ti ép33 korda cans., légi a a sb ooaanoon Ily# ssgtágidk e 232 ék 332 oor Inhr n lévé s fnéllr ftűd fők k ossbXoá.ggdgI, aidnyéllé á?. 3X33B /X132X.· 2 X. öld aiilokitXa. abd'lv e: feáltgly elérd igényéénr ógeilnii éö33 köéőágehs nadir láng ysriáéills ségié:jás kidőld régiét is:; ta Inat. 26, ölé kolakólá, a na 1 y or 1 . ~ 23. iglnypnnlck Xnltaaiyika átlrlrti CD33 kétdágans kddnyn ián! várlIbLIir régiégsk kódol X régiét ::oa la lose.. XX. Eapressrida vaktor, steal a a 2S. vagy 36, igénypont .sserinr 1 DNS svalekalót: tar iaissarss, M, kbsszéaseytí ape 1 y a 2?,. IgéhypöM: aS&amp;fiöti. >593# ysyy kébb yekbgzrb kerítesz* «$.,
  2. 2. Asz 1 . ~ 24, bgénypggyyk bs rraí: 1 y.: kg ezzerir·: x Clb33 rotbagers el b ad,2 1SY sirs sz ¢51 gálb sbys rá*, áss ál y t s.í: 2 a bea ág a ga kgá a aj:t 2:7 < ige o y p se k srsgrxintb agy Vagy több eéktbsra.I körtéíte -zranazzi'Steal kei, a yasdaszejk kabbéateéseb ®b ab se izéi ess esd, ékéi a via.·; zzsnye rését és btezteltésáb , 33 a Ovéqyzs:erisast.:. zspaposiogéi ezzel y Séri·él'éüsS htezlsnyag sete az l, * 22 . ábépybePteík bérseivé kz: eaériSSi egy vagy abbé fíbSa Mtbégeset ? és: begeiább egy fi.:s|slégiásag élfogeílbsbe ikorbssbr, 2:1, b. 3b, Igényper: ? Assteintb eybgvyszex éere·;.1. >zox?;oozz leié, apery Saietelsae ízzvAbtei «így sísgy ·: :>sb éceábbi beztepiés azse/t , 32 , A 3b, a 31 . x.gézzyoxas'.ck bárPíiiviazs srezrinti iyybgysaezzbsszabi korsyoa: ex Λ böld-ar a lei salaikba kzyfsjasb sebisak kiser x x éeere , 33 , A 30, - 3:i, x génypyrrck bánnal yj kp seériπti gyes yssze · és. zz szí .1 ksr^oaial.é észlelőié. sejt rísasrzlssteXabbség és zgiiiísíblsígjjiaisbkikbé szksxterbéa ybbS) kar® lés ebes t ér rise a ; ka iszap?ás re, 3:4 , <3y egye gores re ti keApíkSiPbb a 33 , xzteeypor.t szzsebzLbti a 1 ke testei ara, ebei neeeszett s telexé pgssriplkslatibsg asz akut teteteié teok<tex zs ss * ktgnzbkuS: séizid teakézíxzs kékéi váLaszxUzte . 3a, A, 3ó, " 3 b, Igénypers ok báxzzs: Lyike sgetixezd. gyégyg kérié kéííi texaposizz.i.é pabolégzil jgkssxr síelőid szed keket kaateteizteb: exibexlteaxg és g y is a la bá xz 0 a z-sext-e r a g ebes ok keo le x ében térréné a 1 kai xte zzasre,
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