TR201802088T4 - Polipeptidlerin rekombinan üretimi esnasında disülfür bağlarındaki indirgenmenin önlenmesi. - Google Patents

Polipeptidlerin rekombinan üretimi esnasında disülfür bağlarındaki indirgenmenin önlenmesi. Download PDF

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TR201802088T4
TR201802088T4 TR2018/02088T TR201802088T TR201802088T4 TR 201802088 T4 TR201802088 T4 TR 201802088T4 TR 2018/02088 T TR2018/02088 T TR 2018/02088T TR 201802088 T TR201802088 T TR 201802088T TR 201802088 T4 TR201802088 T4 TR 201802088T4
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antibodies
antibody
factor
human
tgf
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TR2018/02088T
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Kao Yung-Hsiang
Trexher Schmidt Melody
w laird Michael
L Wong Rita
p hewitt Daniel
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Genentech Inc
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Application filed by Genentech Inc filed Critical Genentech Inc
Publication of TR201802088T4 publication Critical patent/TR201802088T4/tr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/38—Chemical stimulation of growth or activity by addition of chemical compounds which are not essential growth factors; Stimulation of growth by removal of a chemical compound
    • 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
    • A61K39/39591—Stabilisation, fragmentation
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0018—Culture media for cell or tissue culture
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Abstract

Bu buluş, disülfür içeren polipeptidlerin rekombinan üretimi esnasında disülfür bağlarının indirgenmesini önlemeyi sağlayan yöntemler ve uygulamalar ile ilgilidir. Somutlaştırmak gerekirse, bu buluş, rekombinan konakçı hücre kültürlerinden antikorları da içine alan bir anlamda disülfür içeren polipeptidler hasat edildiği sırada disülfür bağlarında meydana gelebilecek indirgenmenin önlenmesi ile ilgilidir.

Description

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B = Merdiven D = Diyaliz Deneyi: Bioanalyzer analizi ile elde edilen ve medyana gelen intakt antikor (yaklasik kaybi ve antikor fragmanlarinin olusumu üzerinden kanitlanmis oldugu gibi diyaliz torbasinin disindaki okrelizumabin inkübasyon periyodu esiiasinda indirgendigini gösteren (her seridin bir zaman noktasini temsil ettigi) dijital jel benzeri görüntüleme. 48. saat zaman noktasinda (Serit 7), indirgenmis antikorun muhtemelen HCCF'deki indirgeme aktivitesinin yitirilmesinin bir sonucu olarak yeniden oksitlendigi görüldü. 28 kDa isaretinin hemen üzerinde uzanan bandin kaynagi antikorun hafif zinciridir. Inkübasyona baslanmadan önce HCCF'de halihazirda istatistiksel açidan anlamli miktarda serbest hafif zincir vardi. HCCF'de serbest hafif zincir ve hafif zincir dimeri fazlasinin bulunmasi, okrelizumab üreten hücre hatti içiii normaldir. E = Diyaliz Deneyiiiden Elde Edilen Serbest Tiol Seviyeleri: Diyaliz torbasinin içindeki (I) ve disindaki (0) serbest tioller birkaç saat içerisinde denk ve karsilastirilabilir seviyelere ulasarak, HCCF'deki küçük moleküllü bilesenlerin diyaliz torbasinin içi ile disi arasinda iyi bir düzeyde degis tokus edildiklerini gösterdi. F = Diyaliz Torbasinin Disi G : Diyaliz Torbasinin Içi H : Zaman (Saat) J : Tioredoksin Sistemi ve Antikor Indirgemesinde Rol Oynayan Diger Reaksiyonlar: Tioredoksin (Trx), tioredoksin redüktaz (Ter) ile NADPH'den olusan tioredoksin sistemi, proteinlerdeki disülfur baglarinin indirgenmesinde bir hidrojen donör sistemi islevi görür. Trx, tiol-disülfür degisimi araciligiyla birçok redoks reaksiyonunu katalize eden bir CXXC aktif yer motifinin bulundugu bir küçük monomerik proteindir. Oksidize Trx, Ter araciligiyla NADPH tarafindan indirgenebilir. Indirgenmis Trx, proteinlerdeki disülfurleri indirgeme reaksiyonunu katalize eder. Tioredoksin sistemi için gereken NADPH, pentoz fosfat yolagindaki reaksiyonlar ve glikoliz araciligiyla saglanir. K = Tioredoksin Sistemi L = Pentoz Fosfat Yolagindaki Ilk Reaksiyon M =6-Fosfoglukonolakton N : Glukoz-6-fosfat dehidrogenaz O = Glukoz-6-fosfat P = Heksokinaz S : Glukoz T = Tioredoksin Sisteminin In Vitro Aktivitesi: Bioanalyzer analizi ile elde edilen ve intakt okrelizumab (1 mg/mL) PBS içerisinde yer alan ve 1 mM NADPH ile birlikte inkübe edildiginde okrelizumabin tamamen indirgendigini gösteren (21 saatten daha kisa bir süre içerisinde tamamen indirgenmistir) gösteren dijital jel benzeri görüntü. U = Aurotioglukoz ile Inhibe Edilen Tioredoksin Sistemi In Vitro Aktivitesi: Yukarida Sekil 5'e dair yapilan açiklamada belirtildigi gibi olan reaksiyon karisimina l mM konsantrasyonunda aurotioglukoz eklenmesi sonucunda, Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntüde gösterildigi gibi okrelizuinabdaki indirgenine etkili ölçüde inhibe olmaktadir. V : Aurotiomalat ile Inhibe Edilen Tioredoksin Sisteini In Vitro Aktivitesi: Yukarida Sekil 5'e dair yapilan açiklamada belirtildigi gibi olan reaksiyon karisimina 1 niM konsantrasyonunda aurotiomalat eklenmesi sonucunda, Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntüde gösterildigi gibi okrelizuinabdaki indirgenme etkili ölçüde inhibe olmaktadir. Y = Tioredoksin Sisteminin In Vitro Aktivitesi: Bioanalyzer analizi ile elde edilen ve intakt okrelizuinab (l mg/mL) 10 mM histidin sülfat tamponu içerisinde yer alan , 5 "M Trx (insan) ve 1 mM NADPH ile birlikte ink'ube edildiginde Okrelizumabm 1 saatten daha kisa bir süre içerisinde indirgendigini gösteren dijital jel benzeri görüntü. Z = CuSO4 ile Inhibe Edilen Tioredoksin Sistemi In Vitro Aktivitesi: Yukarida Sekil 8'e dair yapilan açiklamada belirtildigi gibi olan reaksiyon karisimma 50 uM konsantrasyonunda CuSO4 eklenmesi sonucunda, Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntüde gösterildigi gibi Okrelizumabdaki indirgenme etkili Ölçüde inhibe olmaktadir. A1 = Okrelizumab Indirgenmesi: 3 L hacimli bir fermentörde elde edilen bir homojenize HCCF ile gerçeklestirilen bir ink'ubasyon deneyinde Okrelizumabda indirgenme meydana geldigini gösteren ve Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntü. 81 = HCCF'deki Okrelizumab Indirgeninesinin Aurotioglukoz ile Inhibisyonu: Sekil lO'da gösterildigi gibi olan inkübasyon deneyinde kullanilan HCCF 'ye 1 mM aurotioglukoz eklendiginde Okrelizumabdaki indirgenmenin etkili ölçüde inhibe oldugunu gösteren ve Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntü. C1: HCCF'deki Okrelizumab Indirgenmesinin Aurotiomalat ile Inhibisyonu: Sekil 10'da gösterildigi gibi olan inkübasyon deneyiiide kullanilan HCCF'ye 1 mM aurotiomalat eklendiginde okrelizumabdaki indirgeninenin etkili ölçüde inhibe oldugunu gösteren ve Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntü. D] = HCCF'deki Indirgeme Aktivitesiriin Yitirilmesi: Okrelizumaba yönelik 12 kL ölçekli üretim çevrimlerinden birindeki (Çevrim 8) bir dizi dondurma/çözme döngüsüne tâbi tutulmus olan HCCF bir inkübasyon deneyinde kullanilmistir. Ayni fermantasyondan alinan taze çözülinüs HCCF'de daha önceden görülmüs olan antikor indirgenmesine ragmen bu HCCF'de Bioanalyzer ile yapilan analizde sasirtici bir sekilde okrelizumabda hiç indirgenme gözlemlenmemistir. El: NADPH Takviyesinin HCCF'deki Yitirilmis Indirgeme Aktivitesini Eski Haline Getirmesi: Indirgeme aktivitesinin yitirilmis oldugu (bkz: Sekil 13) HCCF'ye 5 mM konsantrasyonunda NADPH eklendikten sonra gerçeklestirilen Bioanalyzer analizinde okrelizumabdaki indirgenine tekrar gözlemlenmistir. F1 = Glukoz-6-Fosfat Takviyesinin HCCF'deki Yitirilmis Indirgeme Aktivitesini Eski Haline Getirmesi: Indirgeme aktivitesinin yitirilmis oldugu (bkz: Sekil 13) HCCF'ye 10 mM konsantrasyonunda G6P eklendikten sonra gerçeklestirilen Bioanalyzer analizinde okrelizumabdaki indirgenine tekrar gözlemlenmistir. Gl = Okrelizumab Indirgemesi: Bioanalyzer analiz ile elde edilen ve 12 kL büyüklügündeki Çevrim 9'dan elde edilen bir HCCF kullanilarak gerçeklestirilen bir inkübasyon deneyinde okrelizumabda indirgenme meydana geldigini gösteren bir dijital jel benzeri görüntü. H] = EDTA'nin Okrelizumabdaki Indirgenmeyi Inhibe Etmesi: 12 kL büyüklügündeki Çevrim 9'dan elde edilen bir HCCF kullanilarak gerçeklestirilen bir inkübasyon deneyinde 20 mM konsantrasyonunda EDTA eklendiginde okrelizumabdaki indirgenmenin inhibe oldugunu gösteren ve Bioanalyzer analizi ile elde edilen dijital jel benzeri görüntü. ll = Indirgeme aktivitesi yitirilmis olan (bkz: Sekil 13) HCCF'ye 5 mM konsantrasyonunda G6P ve 20 mM EDTA eklendikten sonra gerçeklestirilen Bioanalyzer analizinde okrelizumabin indirgendigi gözlemlenmistir. Sekil l7'de gösterilen sonuçlardan farkli olarak, EDTA varligi, okrelizumabdaki indirgenmeyi bloke etmemistir. J 1 = Okrelizumabdaki Indirgenmenin Inhibe Edilmesi: Protein A elüsyon havuzlarinda intakt antikorun hemen hemen %100 ( oraninda varligini sürdürdügünü gösteren kantitatif Bioanalyzer sonuçlari ile kanitlaninis oldugu gibi, üç farkli yöntemin (EDTA eklenmesi, CuSO4 eklenmesi ve pH seviyesinin 5,5'e ayarlanmasi) hepsi okrelizumabdaki indirgenmeyi inhibe etme konusunda etkilidir. Diger yandan, koiitrol HCCF'sinde HCCF'de 20 saat bekletme yapildiktan sonra okrelizumabin tamainen indirgenmis oldugu görüldü. Kl = asetik asit Ll = Ekleme yapilmayan durum Nl :Bekleme süresi 01 = Hava ile kabarciklandirina Pl : Nitro jen ile kabarciklandirma R1 : Okrelizumab Indirgeninesinin Iiihibe Edilmesi: Protein A elüsyon havuzlarinda intakt aiitikorun hemen hemen %100 ( oraninda varligini sürdürdügünü gösteren kantitatif Bioanalyzer sonuçlari ile kanitlaninis oldugu gibi, HCCF'yi hava ile kabarciklandirma uygulamasi da okrelizumab disülfür baglarindaki indirgenmenin inhibe edilmesi konusunda etkilidir. Diger yandan, kontrol HCCF'sinde 5 saat boyunca nitrojen ile kabarciklandirma uygulamasi yürütüldükten sonra okrelizumabin hemen hemen tamamen indirgenmis oldugu görülmüstür. si = Hafif Zincir Tl = Agir Zincir Ul = Tipik Kesikli veya Kesikli Beslemeli Kültür Prosesi Vl = Ekim Dizisi Yl = Inokulum Dizisi Zl : Uretim A2 = Seçici Vasatta Birden Çok Pasaj B2 = Seçici Olmayan Vasatta Birden Çok Pasaj C2=SwßüMmwmühdMüßmn D2 : Sicaklik E2 : Ekim yogunlugu F2 = Kültürleme süresi G2 = Parametre kaymalari & zamanlama H2=Cßnwhhw 12:K%mhb%hmdh±hme .[ TR

Claims (1)

1.ISTEMLER Bir rekombinan konakçi hücrede eksprese olan bir polipeptiddeki bir disülfür baginin fermantasyonu takip eden proseste indirgenmesini önleineye yönelik olan ve fermantasyonu müteakiben söz konusu rekombinan konakçi hücrenin hasat edilmis hücre kültürü sivisinin pH degerinin düsürülmesine dayanan ve bahsi geçen rekombinan konakçi hücrenin bir Çin hamsteri yuinurtalik (CHO) hücresi oldugu bir yöntem. Bahsi geçen polipeptidin asagida belirtilen unsurlardan birini teskil ettigi, istein l'e uygun yöntem: (a) bir antikor ya da bir antikorun bir biyolojik açidan fonksiyonel fragmani; veya (b) istege bagli olarak, insan büyüme hormonu ve bovin büyüme hormonunu içine alan bir anlamda bir büyüme hormonu; büyüme hormonu salici faktör; paratiroid hormonu; tiroid stimüle edici hormon; lipoproteinler; alfa-l-antitripsin; insülin A-zinciri; insülin B-Zinciri; proinsülin; folikül stiinüle edici hormon; kalsitonin; lüteinleyici hormon; glukagon; faktör VIIIC, faktör IX, doku faktörü ve von Willebrands faktörü gibi pihtilasma faktörleri; Protein C gibi anti-pihtilasma faktörleri; atrial natriüretik faktör; akciger yüzey aktif maddesi; ürokinaz ya da insan ürin veya doku-tipi plazminojen aktivatörü (t- PA) gibi bir plazminojen aktivatörü; bombesin; trombin; hemopoetik büyüme faktörü; tümör nekroz faktörü-alfa ve -beta; enkefalinaz; RANTES (aktivasyon ile regüle olan ve normal T hücrelerinde eksprese olup salgilanan); insan inakrofaj inflamatuar proteini (MIP-l-alfa); insan serum albümini gibi bir serum albümini; müllerian-inhibe edici madde; relaksin A-zinciri; relaksin B-Zinciri; prorelaksin; fare gonadotropiniyle baglantili peptid; bir mikrobiyal protein, örnegin beta-laktamaz; DNaz; IgE; bir sitotoksik T-lenfosidiyle baglantili antijen (CTLA), örnegin CTLA-4; inhibin; aktivin; vasküler endotel büyüme faktörü (VEGF); hormonlara ya da büyüme faktörlerine iliskin reseptörler; Protein A veya D; roniatoid faktörleri; kemik kaynakli nörotrofik faktör (BDNF), nörotrofin-3, -4, -5 ya da -6 (NT-3, NT-4, NT-5 ya da NT-6) gibi bir nörotrofik faktör ya da NGF-ß gibi bir sinir büyüme faktörü; troinbosit kaynakli büyüme faktörü (PDGF); fibroblast büyüme faktörü, örnegin aFGF ve bFGF; epidermal büyüme faktörü (EGF); transforme edici büyüme faktörü (TGF), örnegin TGF-ß l, TGF-ßZ, TGF-ß3, TGF-ß4 ve TGF-ß5'i de içine alan bir anlamda TGF-beta ve TGF-alfa; insülin benzeri büyüme faktörü-l ve -II (IGF-I ve lGF-Il); des(l-3)-IGF-I (beyin proteinleri; CD proteinleri, örnegin CD3, CD4, CD8, CD19, CDZO, CD34 ve CD40; eritropoietin; osteoindüktif faktörler; immünotoksinler; bir kemik morfogenetik proteini (BMP); interferon-alfa, -beta ve -gamma gibi bir interferon; koloni stimüle edici faktörler (CSF'ler), Örnegin M-CSF, GM-CSF ve G-CSF; interlökinler (IL'ler), örnegin IL-1 ilâ IL-lO; süperoksit dismutaz; T hücresi reseptörleri; yüzey membran proteinleri; parçalanmayi hizlandiran faktör; Viral antijen, örnegin AIDS zarfinin bir parçasi; tasima proteinleri; homing reseptörleri; adressinler; regüle edici proteinler; integrinler, örnegin CDlla, CDllb, CDllC, CD18, bir örnegin HER2, HER3 veya HER4 reseptörü ve bu polipeptidlerin fragmanlari arasindan seçilen bir terapötik polipeptid. (i) Bahsi geçen antikor fragmaninin Fab, Fab', F(ab')2, scFV, (SCFV)2, dAb, tamamlayicilik belirleme bölgesi (CDR) fragmanlari, lineer antikorlar, tek Zincirli antikor molekülleri, minikorlar, diinerik antikor fragmanlari ve antikor fragmanlarindan olusturulan multiSpesifik antikorlar arasindan seçildigi ya da (ii) bahsi geçen antikor veya antikor fragmaninin bir terapötik antikor veya böyle bir antikorun bir biyolojik açidan fonksiyonel fragmani oldugu ve bahsi geçen terapötik antikorun istege bagli olarak okrelizumab, trastuzumab, rituksimab ve efalizumab arasindan seçildigi ya da bahsi geçen antikorun anti-HER2 antikorlari; anti-CDZO antikorlari; anti-IL- 8 antikorlari; anti-VEGF antikorlari; anti-CD40 antikorlari; anti-CDlla antikorlari; anti-CD18 antikorlari; anti-IgE antikorlari; anti-Apo-2 reseptörü antikorlari; anti-Doku Faktörü (TF) antikorlari; anti-insan (x4ß7 integrini antikorlari; anti-EGFR antikorlari; anti-CD3 antikorlari; anti-CD25 antikorlari; anti- CD4 antikorlari; anti-CD52 antikorlari; anti-FC reseptörü antikorlari; anti-karsinoembriyonik anti jen (CEA) antikorlari; meme epitelyum hücrelerini hedef alan antikorlar; kolon karsinomu hücrelerine baglanan antikorlar; anti-CD38 antikorlari; anti-CD33 antikorlari; anti-CD22 antikorlari; anti- EpCAM antikorlari; anti-GpIIb/Illa antikorlari; anti-RSV aiitikorlari; anti-CMV antikorlari; anti-HIV antikorlari; anti- hepatit antikorlari; anti-CA 125 antikorlari; anti-avß3 antikorlari; anti-insan renal hücre karsiiioinu antikorlari; anti- insan 17-1A antikorlari; anti-insan kolorektal tümör antikorlari; GD3 gangliosidini hedef alan anti-insan melanom antikoru R24; anti-insan skuamöz hücre karsinomu; ve anti-insan lökosit antijeni (HLA) aiitikorlari ve anti-HLA DR antikorlari arasindan seçildigi ya da bahsi geçen terapötik antikorun asagida belirtilen unsurlardan birine baglanan bir antikor oldugu, istem 2(a)'ya uygun yöntem: (a) istege bagli olarak HER2 olinak üzere ve söz konusu terapötik antikor SEKANS KOD NO.: 16, 17, 18 ve 19 arasindan seçilen bir agir ve/Veya hafif zincir degisken domain sekansi ihtiva etmek üzere, bir HER reseptörü; (b) istege bagli olarak söz konusu terapötik antikor SEKANS KOD NO.: 20 ilâ 25 arasindan seçilen bir agir ve/Veya hafif zincir degisken domain sekansi ihtiva etmek üzere, VEGF; (d) istege bagli olarak söz konusu terapötik antikor SEKANS KOD NO.: 1 ilâ 15 arasindan seçilen bir agir ve/veya hafif zincir degisken domain sekansi ihtiva etmek (e) istege bagli olarak söz konusu antikor SEKANS KOD NO.: 26 ilâ 29 arasindan seçilen bir agir ve/veya hafif zincir degisken domain sekansi ihtiva etmek üzere, (f) CD40; veya (g) istege bagli olarak söz konusu terapötik antikor Bahsi geçen polipeptidin hasat edilmis hücre kültürü sivisindan (HCCF) geri kazanilmasina yönelik bir basamak da ihtiva eden, istemler l ilâ 3'ten herhangi birine uygun yöntem. Bahsi geçen polipeptidin hasat edilmis hücre kültürü sivisindan (HCCF) saflastirilmasina yönelik bir basamak da ihtiva eden, istemler 1 ilâ 4'ten herhangi birine uygun yöntem. TR
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