SI2935331T1 - Proteini, ki vežejo receptor prolaktina in njihove uporabe - Google Patents

Proteini, ki vežejo receptor prolaktina in njihove uporabe Download PDF

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SI2935331T1
SI2935331T1 SI201331042T SI201331042T SI2935331T1 SI 2935331 T1 SI2935331 T1 SI 2935331T1 SI 201331042 T SI201331042 T SI 201331042T SI 201331042 T SI201331042 T SI 201331042T SI 2935331 T1 SI2935331 T1 SI 2935331T1
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seq
sequence
amino acids
chain
antibody
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SI201331042T
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Mark Anderson
Jieyi Wang
Archana Thakur
Debra Chao
Chung-Ming Hsieh
Qian Zhang
Edward B. Reilly
Enrico L. Digiammarino
Kenton L. Longenecker
Russell A. Judge
David A. Egan
Charles W. Hutchins
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Abbvie Inc.
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Publication of SI2935331T1 publication Critical patent/SI2935331T1/sl

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    • 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
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
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Claims (34)

  1. Proteini, ki vežejo receptor prolaktina in njihove uporabe Patentni zahtevki
    1. Protitelo ali njegov delec, ki veže antigen, ki je zmožen vezati receptor prolaktina (PRLR), ki vsebuje domeno, ki veže antigen z vsaj dvema setoma variabilne domene CDR, ki sta izbrana iz skupine, ki sestoji: (1) bodisi iz težke verige setov variabilne domene CDR, zaporedij SEQ ID NO:40,41 in 42 ali SEQ ID NO:46,47 in 42 in lahke verige seta variabilne domene CDR, zaporedij SEQ ID NO:49, 50 in 51; (2) bodisi iz težke verige setov variabilne domene CDR, zaporedij SEQ ID NO:56, 57 in 58 ali SEQ ID NO: 62, 63 in 58 in lahke verige seta variabilne domene CDR, zaporedij SEQ ID NO 65, 66 in 67; (3) bodisi iz težke verige setov variabilne domene CDR, zaporedij SEQ ID NO: 71, 72 in 73 ali SEQ ID NO: 71, 77 in 73 in lahke verige seta variabilne domene CDR, zaporedij SEQ ID NO: 79, 80 in 81; in (4) bodisi iz težke verige setov variabilne domene CDR, zaporedij SEQ ID NO:85, 86 in 87 ali SEQ ID NO: 149,150 in 87 in lahke verige seta variabilne domene CDR, zaporedij SEQ ID NO: 92, 93 in 94.
  2. 2. Protitelo ali njegov delec, ki veže antigen po zahtevku 1, ki nadalje vsebuje okvir humanega akceptorja.
  3. 3. Protitelo ali njegov delec, ki veže antigen po zahtevku 1, ki vsebuje vsaj eno variabilno domeno, ki ima zaporedje aminokislin izbrano iz skupine, ki vsebuje SEQ ID NO: 44; SEQ ID NO: 39; SEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO: 55; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 70; SEQ ID NO: 74; SEQ ID NO: 75; SEQ ID NO: 76; SEQ ID NO: 84; SEQ ID «·· · · »* W-- NO: 88; SEQ ID NO: 89; SEQ ID NO: 90; SEQ ID NO: 121; SEQ ID NO: 122 in SEQ ID NO: 123; ali, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje dve variabilni domeni, ki imata zaporedja aminokislin izbrana iz skupine, ki vsebuje: (1) eno izmed SEQ ID NO: 39; SEQ ID NO: 43; SEQ ID NO: 44 ali SEQ ID NO: 45; in eno izmed SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO: 53 ali SEQ ID NO:54; (2) eno izmed SEQ ID NO: 55; SEQ ID NO: 59; SEQ ID NO: 60 ali SEQ ID NO: 61; in eno izmed SEQ ID NO:64, SEQ ID NO:68 ali SEQ ID NO: 69; (3) eno izmed SEQ ID NO: 70; SEQ ID NO: 74; SEQ ID NO: 75 ali SEQ ID NO: 76; in eno izmed SEQ ID NO:78, SEQ ID NO:82 ali SEQ ID NO: 83; in (4) eno izmed SEQ ID NO: 84; SEQ ID NO: 88; SEQ ID NO: 89; SEQ ID NO: 90; SEQ ID NO: 121; SEQ ID NO: 122 ali SEQ ID NO: 123; in eno izmed SEQ ID NO:91, SEQ ID NO:95 ali SEQ ID NO:96.
  4. 4. Protitelo ali delec, ki veže antigen po kateremkoli izmed predhodnih zahtevkov, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje vsaj eno variabilno domeno, ki ima zaporedje aminokislin izbrano iz skupine, ki sestoji iz SEQ ID NO: 48; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 64; SEQ ID NO: 68; SEQ ID NO: 69; SEQ ID NO: 78; SEQ ID NO: 82; SEQ ID NO: 83; SEQ ID NO: 91; SEQ ID NO: 95; in SEQ ID NO: 96.
  5. 5. Protitelo ali delec, ki veže antigen po kateremkoli zahtevku od 1 do 4, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje zaporedje zaporedje težke verige in zaporedje lahke verige izbrano iz skupine, ki sestoji iz: (a) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 129; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 126; (b) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 124; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 125; (c) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 124; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 126; (d) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 124; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 127; (e) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 124; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 128; (f) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 129; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 125; (g) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 129; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 127; (h) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 129; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 128; (i) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 130; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 125; (j) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 130; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 126; (k) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 130; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 127; in (l) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 130; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 128.
  6. 6. Protitelo ali delec, ki veže antigen po kateremkoli zahtevku od 1 do 4, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje zaporedje težke verige in zaporedje lahke verige izbrano iz skupine, ki sestoji iz: (a) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 131; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 132; (b) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 131; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 133; (c) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 131; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 134; (d) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 135; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 132; (e) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 135; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 133; (f) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 135; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 134; (g) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 136; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 132; (h) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 136; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 133; in (i) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 136; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 134.
  7. 7. Protitelo ali delec, ki veže antigen po kateremkoli zahtevku od 1 do 4, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje zaporedje težke verige in zaporedje lahke verige izbrano iz skupine, ki sestoji iz: (a) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 143; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 144; (b) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 143; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 145; (c) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 143; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 146; (d) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 147; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 144; (e) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 147; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 145; (f) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 147; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 146; (g) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 148; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 144; (h) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 148; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 145; in (i) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 148; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 146.
  8. 8. Protitelo ali delec, ki veže antigen po kateremkoli zahtevku od 1 do 4, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje zaporedje težke verige in zaporedje lahke verige izbrano iz skupine, ki sestoji iz: (a) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 137; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 138; (b) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 137; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139; (c) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 137; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 140; (d) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 141; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 138; (e) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 141; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139; (f) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 141; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 140; (g) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 142; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 138; (h) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 142; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139; (i) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 142; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 140; (j) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 153; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139; (k) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 154; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139; in (l) težko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 155; in lahko verigo, ki ima zaporedje aminokislin zaporedja SEQ ID NO: 139.
  9. 9. Protitelo ali delec, ki veže antigen po kateremkoli izmed predhodnih zahtevkov, kjer ima protitelo ali delec, ki veže antigen lastnost izbrano iz skupine, ki sestoji iz: a) veže ligand, ki veže domeno Dl PRLR; b) zavira vezavo prolaktina na PRLR; c) je zmožen modulirati biološko funkcijo PRLR; d) je zmožen nevtralizirati PRLR; e) ima konstanto vezave (Kon) z PRLR izbrano iz skupine, ki sestoji iz: vsaj približno 102M_1s_1; vsaj približno 103M'1s‘1; vsaj približno 104M"1s"1; vsaj približno 105M'1s'1; in vsaj približno 106M'1s'1; merjeno s površinsko plazmonsko resonanco; f) ima konstanto ločevanja (Koff) z PRLR izbrano iz skupine, ki sestoji iz: največ približno 10'V1; največ približno 10'V1; največ približno 10'V1; in največ približno 10‘V1, merjeno s površinsko plazmonsko resonanco; in g) ima konstanto disociacije (KD) z PRLR izbrano iz skupine, ki sestoji iz: največ približno 10' M; največ približno 10 M; največ približno 10 M; največ približno 10'10 M; največ približno 10'11 M; največ približno 10'12 M; in največ 10'13 M.
  10. 10. Konstrukt protitelesa, ki vsebuje protitelo ali delec, ki veže antigen po kateremkoli izmed predhodnih zahtevkov, kjer omenjeni konstrukt protitelesa nadalje vsebuje polipeptidni linker ali konstantno domeno imunoglobulina.
  11. 11. Konstrukt protitelesa po zahtevku 10, kjer je omenjeno protitelo ali delec, ki veže antigen is izbrano iz skupine, ki vsebuje iz: molekulo imunoglobulina, monoklonskego protitelo, himerino protitelo, CDR-cepljeno protitelo, humanizirano protitelo, Fab, Fab', F(ab')2, Fv, z disulfidom povezan Fv, scFv, bispecifično rekombinantno protitelo, multispečno protitelo, dualno specifično protitelo in bispecifično protitelo.
  12. 12. Konstrukt protitelesa po zahtevku 10 ali 11, kjer omenjeno protitelo ali delec, ki veže antigen vsebuje konstantno domeno težke verige imunoglobulina, izbrano iz skupine, ki vsebuje: konstantno domeno humanega IgM, konstantno domeno humanega IgGl, konstantno domeno humanega IgG2, konstantno domeno humanega IgG3, konstantno domeno humanega IgG4, konstantno domeno humanega IgE in konstantno domeno humanega IgA.
  13. 13. Konstrukt protitelesa po kateremkoli zahtevku od 10 do 12, ki vsebuje konstantno domeno imunoglobulina, ki ima zaporedje aminokislin izbrano iz skupine, ki sestoji iz SEQ ED NO: 10-13.
  14. 14. Konjugat protitelesa, ki vsebuje konstrukt protitelesa po zahtevkih od 10 do 13, kjer omenjeni konjugat protitelesa nadalje vsebuje sredstvo izbrano iz skupine, ki vsebuje: imunoadhezijsko molekulo, kontrastno sredstvo, terapevtsko sredstvo in citotoksično sredstvo; neobvezno, kjer je sredstvo kontrastno sredstvo izbrano iz skupine, ki vsebuje iz radijsko oznako, encim, fluorescentno oznake, luminescentno oznako, bioluminescentno oznako, magnetno oznako in biotin.
  15. 15. Konjugat protitelesa po zahtevku 14, kjer je omenjeno sredstvo terapevtsko ali citotoksično sredstvo in je izbrano iz skupine, ki vsebuje: anti-metabolit, alkilimosredstvo, antibiotik, rastni faktor, citokin, anti-angiogensko sredstvo, anti-mitotično sredstvo, antraciklin, toksin in apoptotično sredstvo; neobvezno, kjer je anti-mitotično sredstvo izbrano iz skupine, ki vsebuje dolastatin, avristatin, majtansinoid, rastlinski alkaloid, taksan in alkaloid vinka.
  16. 16. Izolirana nukleinska kislina, ki kodira zaporedje aminokislin protitelesa ali delca, ki veže antigen po kateremkoli zahtevku od 1 do 9.
  17. 17. Izolirana nukleinska kislina, ki kodira zaporedje aminokislin konstrukta protitelesa po kateremkoli zahtevku od 10 do 15.
  18. 18. Vektor, ki vsebuje izolirano nukleinsko kislino po zahtevku 17.
  19. 19. Vektor, ki vsebuje izolirano nukleinsko kislino po zahtevku 18, kjer je omenjeni vektor izbran iz skupine, ki sestoji iz pcDNA, pTT, pTT3, pEFBOS, pBV, pJV inpBJ.
  20. 20. Gostiteljska celica, ki vsebuje vektor po zahtevku 18 ali 19.
  21. 21. Gostiteljska celica, ki vsebuje vektor po zahtevku 20, kjer je gostiteljska celica prokariotska celica ali evkariontska celica.
  22. 22. Gostiteljska celica po zahtevku 21, kjer je omenjena gostiteljska celica izbrana iz skupine, ki vsebuje celico CHO, celico COS, celico kvasovko in celico insektov S£9.
  23. 23. Postopek izdelave proteina, kije zmožen vezati PRLR, ki obsega kultiviranje gostiteljske celice po zahtevku 20 ali 21 v mediju za kultiviranje pri zadostnih pogojih za proizvodnjo vezavnega proteina, kije zmožen vezave PRLR.
  24. 24. Farmacevtski sestavek, ki vsebuje protitelo ali delec, ki veže antigen po kateremkoli izmed zahtevkov od 1 do 9 in farmacevtsko sprejemljiv nosilec.
  25. 25. Protitelo ali delec, ki veže antigen po kateremkoli izmed zahtevkov od 1 do 9, za uporabo v postopku zniževanja aktivnosti humanega PRLR.
  26. 26. Protitelo ali delec, ki veže antigen po kateremkoli izmed zahtevkov od 1 do 9, za uporabo v zniževanju aktivnosti humanega PRLR v človeku, ki trpi za motnjo v kateri je aktivnost PRLR škodljiva ali v zdravljenju subjekta, ki ima motnjo,v kateri je aktivnost PRLR škodljiva.
  27. 27. Protitelo ali delec, ki veže antigen, za uporabo po zahtevku 26, kjer je motnja rak,, nadalje neobvezno melanom, rak endometrija, limfom, rak dojke, rak jajčnika, ledvični karcinom, gastrointestinalni rak, rak debelega črevesa, pljučni rak, rak trebušne slinavke in rak prostate.
  28. 28. Konjugat protitelo anti-PRLR zdravilo (ADC), ki vsebuje protitelo anti-PRLR ali njegov delec, ki veže antigen, po kateremkoli zahtevku od 4 do 9, konjugiran na vsaj eno zdravilo.
  29. 29. Konjugat protitelo anti-PRLR zdravilo (ADC) po zahtevku 28, kjer protitelo ali njegov delec, ki veže antigen, vsebuje vsaj 3 CDR-je izbrane izmed težke verige seta variabilne domene CDR, zaporedij (CDR1, CDR2 in CDR3), ki sestojijo iz zaporedij SEQ ID NO: 40,41 in 42; SEQ ID NO: 46,47 in 42; SEQ ID NO: 56, 57 in 58; SEQ ID NO: 62,63 in 58; SEQ ID NO: 71,72 in 73; SEQ ID NO: 71, 77 in 73; SEQ ID NO: 85, 86 in 87; SEQ ID NO: 149,150 in 87.
  30. 30. Konjugat protitelo anti-PRLR zdravilo (ADC) po zahtevkih 28 ali 29, kjer protitelo ali njegov delec, ki veže antigen, vsebuje vsaj 3 CDR-je izbrane izmed lahke verige seta variabilne domene CDR, zaporedij (CDR1, CDR2 in CDR3), ki sestojijo iz zaporedij SEQ ID NO: 49,50 in 51; SEQ ID NO: 65,66 in 67; SEQ ID NO: 79, 80 in 81; in SEQ ID NO: 92, 93 in 94.
  31. 31. ADC po kateremkoli izmed zahtevkov od 28 do 30, kjer je zdravilo izbrano iz skupine, ki vsebuje mitotični inhibitor, antitumorski antibiotik, imunomodulacijsko sredstvo, vektor za gensko terapijo, alkilimo sredstvo, antiangiogensko sredstvo, antimetabolit, sredstvo, ki vsebuje bor, kemozaščitno sredstvo, hormon, antihormonsko sredstvo, kortikosteroid, fotoaktivno terapevtsko sredstvo, oligonukleotid, radionuklidno sredstvo, inhibitor topoizomeraze, inhibitor tirozin kinaze in radiosenzibilizator.
  32. 32. ADC po kateremkoli izmed zahtevkov od 28 do 31, kjer je zdravilo izbrano iz skupine, ki jo sestavljajo Ixempra, dolastatin 10, dolatstin 15, auristatin E, auristatin PE, monometil auristatin D (MMAD ali derivat auristatina D), monometil auristatin E (MMAE ali derivat auristatina E), monometil auristatin F (MMAF ali derivat auristatina F), auristatin F fenilendiamin (AFP), auristatin EB (AEB), auristatin EFP (AEFP), 5-benzoilvalerenska kislina-AE ester (AEVB), metotreksat, daunorubicin, vinkristin, majtanzin, majtanzinol, C-3 estre majtanzinola, ansamitocin Pl, ansamitocin P2, ansamitocin P3, ansamitocin P4, docetaksel, paklitaksel, nanodelce paklitaksela, vindezin sulfat, vinkristin, vinblastin, vinorelbin, aktinomicine, pirolo[2,l- c][l,4]benzodiazepine, dimer pirolobenzodiazepina (PBD), aktinomicin D, antramicin, chicamicin A, DC-18, mazetramicin, neotramicin A, neotramicin B, porotramicin, protracarcin B, SG2285, sibanomicin, sibiromicin, tomaimicin, antracikline, daunorubicin, doksorubicin, epirubicin, idarubicin, kaliheamicine, γι1, a.2, 0131, N-acetil-γι1, PSAG, θ!ι, duokarmicine, adozelesin, bizelesin in karzelesin, bleomicin, mitomicin, plicamicin, bacil calmette-guerin (BCG), levamisol, cepiva proti raku, cepiva, ki vsebujejo rekombinantni bivalentni humani papilomavirus (HPV), tip cepiv 16 in 18, cepiva, ki vsebujejo rekombinantni štirivalentni humani papilomavirus (HPV) tipe 6,11,16 in 18, sipuleucel-T, citokine, paratiroidni hormon; tiroksine; insulin; proinsulin; relaksin; prorelaksin; glikoproteinske hormone, kot je hormon, ki stimulira folikel (FSH), hormon, ki stimuliran ščitnico (TSH) in luteinizirajoči hormon (LH), jetrni rastni faktor; fibroblastni rastni faktor, prolaktin, placentalni laktogen, faktor tumorske nekroze, substanco, ki zavira mullerianov hormon, peptid povezan z mišjim gonadotropinom, inhibin, aktivin, vaskulami endotelijski rastni faktor, integrin, trombopoetin (TPO), živčni rastni faktorji, kot je NGF, rastni faktor platelet, transformirajoči rastni faktorji (TGFs), insulinu podoben rastni faktor -I in -II, ertropoetin (EPO), osteoinduktivni faktorji, interferoni, kot je interferon α, β, in γ, faktoiji, ki stimulirajo kolonijo (CSFs), granulocit-makrofag-C-SF (GM-CSF) in granulocit-CSF (G-CSF), interlevkini (ILs), kot na primer IL-1, IL-Ια, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, faktor tumorske nekroze in drugi faktorji, vključno z LIF in kit ligandom (KL), faktorji, ki stimulirajo kolonijo, eritropoetin (epoetin), filgrastim, sargramostim, promegapoetin, Oprelvekin, imunomodulacijski genski terapevtiki, nukleinska kislina, ki kodira funkcionalni, terapevtski gen, ki je uporabljen za zamenjavo mutiranega ali drugače nefunkcionalnega (npr. okrnjen) gena, povezanega z rakom, nukleinska kislina, ki kodira ali drugače zagotavlja proizvodnjo terapevtskega proteina za zdravljenje raka, alkil sulfonate, busulfan, dušikovi iperiti, klorambucil, ciklofosfamid, estramustin, ifosfamid, mekloretamin in melfalan, nitrozourea, karmustin, fotemustin, lomustin, nimustin, streptozocin, triazine in hidrazine, dakarbazin, prokarbazin, temozolomid, etilenimime, tiopental, diazikon, mitomicin C, derivat metilamina, epokside, altretamin, dianhidrogalaktitol, dibromodulcitol, angiostatin, cepivo ΑΒΧ EFG, Cl-1033, PKI-166, EGF, EKB-569, GW2016, ICR-62, EMD 55900, CP358, PD153035, AG1478, IMC-C225, OSI-774, erlotinib, angiostatin, arestin, endostatin, ΒΑΥ 12-9566 in s fluorouracilom ali doksorubicinom, kanstatinom, karboksiamidotriozolom in s paklitakselom, EMD121974, S-24, vitaksin, dimetilksantenon ocetno kislino, IM862, interlevkin-12, interlevkin-2, NM-3, HuMV833, PTK787, RhuMab, angiozim, IMC-1C11, Neovastat, marimstat, prinomastat, BMS-275291,COL-3, MM1270, SU101, SU6668, SU11248, SU5416, s paklitakselom, z gemcitabinom in cisplatinom in z irinotekanom in cisplatinom in z obsevanjem, tecogalan, temozolomid in PEG interferon a2b, tetratiomolibdat, TNP-470, talidomid, CC-5013 in s taksoterom, tumstatin, 2-metoksiestradiol, VEGF past, mTOR inhibitorje (deforolimus, everolimus in temsirolimus), inhibotiije tirozin kinaze (npr. imatinib, gefitinib, dasatinib, sunitinib, nilotinib, lapatinib, sorafenib, fosfoinositid 3-kinaze (PI3K), antagonisti folne kisline, metotreksat, 4-amino-folna kislina, lometreksol, pemetreksed, trimetreksat, antagonisti pirimidina, azacitidin, kapecitabin, citarabin, decitabin, 5-fluorouracil, 5-fluoro-2'-deoksiuridin 5'-fosfat, 5-fluorouridin trifosfat, gemcitabin, foksuridin, antagonist purina azatioprin, kladribin, merkaptopurin, fludarabin, pentostatin, 6-tioguanin, inhibitorji adenozin deaminaze, kladribin, fludarabin, nelarabin, pentostatin, boroficin, bortezomib, kemozaščitna sredstva, amifostin, deksrazoksane, mesna, androgeni, estrogeni, medroksiprogesteron acetat, progestini, aminoglutetimid, anastrozol, bikalutamid, klorotrianizi, ciproteron acetat, degareliks, eksemestan, flutamid, fulvestrant, goserelin, letrozol, leuprolid, lupron, medroksiprogesteron acetat, megestrol acetat, tamoxifen, triptorelin, asparaginaza, dakarbazin, hidroksiurea, levamisol, mitotan, prokarbazan, tretinoin, glukokortikoidi, prednizon, kromageni, barvila, protismiselni oligonukleotidi bodosi naravni ali sintetizirani z uporabo standardnih in/ali ne-standardnih nukleotidov (vključno z interferenco RNA (RNAi)), dvovijačna RNA (dsRNA), majhna moteča RNA (siRNA), microRNA (miRNA), aptameri, CpG oligonukleotidi, ribozimi, angiozim, "‘in, 177Lu, 212Bi, 213Bi, 21lAt, 62Cu, «Cu, 67Cu, »V '2SI, l3lI, 32P, 33P, 47Sc, "'Ag, 670a, 142Pr, l53Sm, 161Tb, '“Dy, ‘«Ho, ‘«Re, 1!8Re, lg,Re, 2,2Pb, ^Ra, 223Ac, 59Fe, 75Se, 77As, '»Sr, «Mo 10!Rh, ,09Pd, 143Pr, 149Pm, l69Er, l94Ir, 198 Au, 199Au, 211Pb, Co-58, Ga-67, Br-80m, Tc-99m, Rh-103m, Pt-109, In-111 1, Sb-119,1-125, Ho-161, Os-189m, Ir-192, Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-21 1, Ac-225, Fr-221, At-217, Bi-213, Fm-255, UC, 13N, 150, 75Br,198Au, 224Ac, 1261, 1331, 77Br, 113mIn, 95Ru, 97Ru, I03R., 105Ru, 107Hg, 203Hg, 125«^ 165^ 167^ 168^ 197^ 109pd 105^ U2?^ 143^ 161Tb, !66Ho, 199Au 57Co, 58Co, 51Cr, 59Fe, 75Se, 201T1, 225Ac, 76Br, 169Yb, taksan, cisplatin, metronidazol, misonidazol, desmetilmisonidazol, pimonidazol, etanidazol, nimorazol, mitomicin C, RSU 1069, SR 4233, E09, RB 6145, nikotinamid, 5-bromodeoksiuridin (BUdR), 5-iododeoksiuridin (IUdR), bromodeoksicitidine, fluorodeoksiuridin (FUdR), hidroksiurea, derivati hematoporfirina, fotofrin(r), derivati benzoporfirina, NPe6, kositrov etioporfirin (SnET2), feoborbid a, bakterioklorofil a, naftalocianini, ftalocianini, cinkov ftalocianin, kamptotecini, irinotekan, topotekan, amsakrin, daunorubicin, doksotrubicin, epipodofilotoksini, elipticine, epirubicin, etopozid, razoksan, tenipozid, aksitinib, Bosutinib, Cediranib, Dasatinib, Eriotinib, Gefitinib, Imatinib, Lapatinib, Lestaurtinib, Nilotinib, Semaksanib, Sunitinib, Vandetanib, abrin, veriga abrin A, alfa toksin, proteini Aleurites fordii, amatoksin, crotin, curcin, proteini diantin, davični toksin, davična veriga A, nevezni aktivni delci davičnega toksina, deoksiribonukleaze (Dnaza), gelonin, mitogelin, veriga A modecina, inhibitor momordica charantia, neomicin, onkonaza, fenomicin, proteini Phytolaca americana (PAPI, PAPII in PAP-S), antivirusni protein barvilnice, Pseudomonas endotoksin, Pseudomonas eksotoksin, eksotoksinova veriga A iz Pseudomonas aeruginosa, restriktocin, ricin, ricinova veriga A, ribonukleaza (Rnaza), inhibitor navadne milnice, saporin, alfa-sarcin, Stafilokokni enterotoksin-A, tetanusov toksin, cisplatin, karboplatin in oksaliplatin (Eloxatin, Sanofi Aventis), proteasomni inhibitorji, PS-341, inhibitorji HDAC, vorinostat, belinostat, entinostat, mocetinostat, panobinostat, inhibitorji COX-2, substituirane uree, inhibitorji proteina toplotnega šoka, Geldanamicin, adrenokortikalni supresorji, trikoteceni, Al 2,19D12, Cp751-871, H7C10, alfaIR3, ScFV/FC, EM/164, Matuzumab, Erbituks, Vectibiks, mAb 806, Nimotuksumab, AVEO, AMG102, 5D5 (OA-5d5), H244G11, Ab #14 (MM 121-14), Herceptin, 1B4C3; 2D1D12, NVP-AEW541-A, BMS-536,924 (lH-benzoimidazol-2-il)-lH-piridin-2-on), BMS-554,417, Cikloligan, TAE226, PQ401, Iressa, CI-1033 (PD 183805), Lapatinib (GW-572016), Tykerb, Tarceva, PKI-166, PD-158780, EKB-569, Tirfostin AG 1478 (4-(3-Jdoroanillino)-6,7-dimetoksikinazolin), PHA665752, ARQ 197, kapecitabin, 5-trifluorometil-2'-deoksiuridin, natrijev metotreksat, Raltitrexed, Pemetrexed, Tegafur, citozin arabinozid (Citarabin), 5-azacitidin, 6-merkaptopurin (Mercaptopurin, 6-MP), Azatioprin, 6-tiogvanin, Pentostatin, Fludarabin fosfat, kladribin (2-CdA, 2-klorodeoksiadenozin), inhibitor ribonukleotidne reduktaze, ciklofosfamid, neosar, ifosfamid, tiotepa, BCNU—* l,3-bis(2-kloroetil)-l-nitosourea, CCNU—> 1, -(2-kloroetil)-3-cikloheksil-l-nitrosourea (metil CCNU), heksametilmelamin, busulfan, prokarbazin HCL, dakarbazin (DTIC), klorambucil, melfalan, karboplatin, oksaliplatin, doksorubicin HCL, daunorubicin citrat, mitoksantron HCL, aktinomicin D, etopozid, topotekan HCL, tenipozid, irinotekan HCL(CPT-ll), vinkristin, vinblastin sulfat, vinorelbin tartrat, vindesin sulfat, paklitaksel, docetaksel, abraksan, iksabepilon, imatinib mesilat, sunitinib malat, sorafenib toslat, nilotinib hidroklorid monohidrat, L-asparaginaza, alfa interferon, avastin, IL-2, aldeslevkin, prolevkin, IL-12, toremifen citrat, Fulvestrant, raloksifen HCL, anastrazol, letrozol, Fadrozol (CGS 16949A), eksemestan, leuprolid acetat, Lupron, goserelin acetat, triptorelin pamoat, buserelin, nafarelin, cetroreliks, bikalutamid, nilutamid, megestrol acetat, analogi somatostatina, prendinzolon, deksametazon, ketokonazol, sirolim, temsirolim (CCI-779), deforolim (AP23573) in everolim (RAD00I).
  33. 33. Farmacevtski sestavek, ki vsebuje ADC po kateremkoli izmed zahtevkov od 28 do 32.
  34. 34. ADC po kateremkoli izmed zahtevkov od 28 do 33, za uporabi v zdravljenju raka v subjektu, ki tako zdravljenje potrebuje, neobvezno, kjer je rak izbran iz skupine, ki vsebuje melanom, rak endometrija, limfom, rak dojke, rak jajčnika, ledvični karcinom, gastrointestinalni rak, rak debelega črevesa, pljučni rak, rak trebušne slinavke in rak prostate.
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