TWI819458B - 雙特異性抗‐人類cd20/人類轉鐵蛋白受體抗體及使用方法 - Google Patents
雙特異性抗‐人類cd20/人類轉鐵蛋白受體抗體及使用方法 Download PDFInfo
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Abstract
本文提供抗-人類CD20/人類轉鐵蛋白受體之雙特異性抗體及使用其等之方法。
Description
本發明係關於抗人類CD20及人類轉鐵蛋白受體之雙特異性抗體、其等製備方法、含有此等抗體之醫藥組合物及其等之用途。
淋巴球係白血球之數種群體中之一者。淋巴球會特異性識別外源抗原並針對外源抗原回應。淋巴球之三種主要類別係B淋巴球(B細胞)、T淋巴球(T細胞)及自然殺手(NK)細胞。B淋巴球係負責抗體產生及提供體液免疫之細胞。B細胞於骨髓內成熟,及離開骨髓時在其細胞表面上表現抗原結合抗體。當初始B細胞首次與特異於其膜結合抗體之抗原相遇時,該細胞開始迅速分裂及其子代分化為記憶B細胞及稱為「漿細胞」之效應細胞。記憶B細胞具有較長壽命並繼續表現與原始親代細胞具有相同特異性之膜結合抗體。漿細胞不產生膜結合抗體但反而產生該抗體之分泌形式。分泌抗體係體液免疫之主要效應分子。
CD20抗原(亦稱為人類B淋巴球限制性分化抗原,Bp35)係位於前B及成熟B淋巴球上之具有約35 kDa分子量之疏水性跨膜蛋白(Valentine等人,J. Biol. Chem. 264 (1989) 11282-11287;及Einfeld等人,EMBO J. 7 (1988) 711-717)。該抗原亦表現於大於90%之B細胞非霍奇金氏淋巴瘤(NHL)上(Anderson等人,Blood 63 (1984) 1424-1433),但未於造血幹細胞、祖B細胞(pro-B-cells)、正常漿細胞或其他正常組織上發現(Tedder等人,J. Immunol. 135(1985)973-979)。CD20被認為可調節用於細胞週期起始及分化之活化過程之早期步驟(Tedder等人,同上)及可能充當鈣離子通道(Tedder等人,J. Cell. Biochem. 14D (1990) 195)。
鑒於CD20於B細胞淋巴瘤中之表現,此抗原已成為治療此類淋巴瘤之有用治療靶。鑒於CD20於B細胞淋巴瘤中之表現,此抗原可充當用於「靶向」此類淋巴瘤之候選者。本質上,此靶向可概括如下:向病患投與對B細胞之CD20表面抗原具有特異性之抗體。此等抗-CD20抗體特異性結合至(表面上)正常及惡性B細胞兩者之CD20抗原;結合至CD20表面抗原之抗體會導致腫瘤B細胞之破壞及去除(depletion)。另外,具有破壞腫瘤之潛力之化學劑或放射性標記可共軛至抗-CD20抗體,致使該化學劑特異性「遞送」至腫瘤B細胞。不考慮方法下,主要目標係破壞腫瘤;藉由所利用之特定抗-CD20抗體可決定特定方法,及因此,靶向CD20抗原之可用方法具有相當大之變化。例如,利妥昔單抗(rituximab) (RITUXAN®)抗體(其係針對人類CD20抗原之基因改造之嵌合鼠類/人類單株抗體(自Genentech, Inc., South San Francisco, California, USA購得))係用於治療患有復發性或難治性低惡性度或濾泡性、CD20陽性、B細胞非霍奇金氏淋巴瘤之病患。利妥昔單抗係於US 5,736,137及於US 5,776,456中稱為「C2B8」之抗體。活體外作用機制研究已證實RITUXAN®結合人類補體並透過補體依賴性細胞毒性(CDC)溶解類淋巴B細胞系(Reff等人,Blood 83 (1994)435-445)。另外,其在用於抗體依賴性細胞性細胞毒性(ADCC)之分析中具有顯著活性。活體內臨床前研究已顯示RITUXAN®可去除(depletes)食蟹猴之周邊血液、淋巴結及骨髓中之B細胞,推測是透過補體及細胞介導之方法(Reff等人,Blood 83 (1994)435-445)。經指示用於治療NHL之其他抗-CD20抗體包括鼠類抗體Zevalin™(其係連接至放射性同位素)、釔-90 (IDEC Pharmaceuticals, San Diego, CA, USA)、Bexxar™(其係結合至I-131之另一完全鼠類抗體(Corixa, WA, USA))。
CD20亦係用於治療自體免疫疾病之有用靶抗原。利妥昔單抗亦已於各種非惡性自體免疫失調症中加以研究,在這些失調症中B細胞及自體抗體似乎於疾病病理生理學中扮演了作用(參見例如,Edwards等人,Biochem. Soc. Trans. 30 (2002) 824-828)。利妥昔單抗業已報告可潛在緩解(例如)以下之徵兆及症狀:類風濕性關節炎(RA) (Leandro等人,Ann. Rheum. Dis. 61 (2002) 883-888;Edwards等人,Arthritis Rheum. 46 (增刊9) (2002) S46;Stahl等人,Ann. Rheum. Dis. 62 (增刊1) (2003) OP004;Emery等人,Arthritis Rheum. 48(2003) S439)、狼瘡(Eisenberg, Arthritis. Res. Ther. 5 (2003) 157-159;Leandro等人,Arthritis Rheum. 46 (2002) 2673-2677;Gorman等人,Lupus, 13 (2004) 312-316)、免疫血小板減少性紫瘢(D'Arena等人,Leuk. Lymphoma 44 (2003) 561-562;Stasi等人,Blood 98 (2001) 952-957;Saleh等人,Semin. Oncol.27 (增刊12) (2000) 99-103;Zaia等人,Haematologica 87 (2002) 189-195;Ratanatharathorn等人,Ann. Int. Med. 133 (2000) 275-279)、純紅細胞發育不全(Auner等人,Br. J. Hematol. 116 (2002) 725-728)、自體免疫貧血(Zaja等人,Haematologica 87 (2002) 189-195 (erratum appears in Haematologica 87 (2002) 336)、冷凝集素病(Layios等人,Leukemia 15 (2001) 187-188;Berentsen等人,Blood 103 (2004) 2925-2928;Berentsen等人,Br. J. Hematol. 115 (2001) 79-83;Bauduer, Br. J. Hematol. 112 (2001) 1083-1090;Damiani等人,Br. J. Hematol. 114 (2001) 229-234)、重度胰島素抵抗之B型症候群(Coll等人,N. Engl. J. Med. 350 (2004) 310-311)、混合冷凝球蛋白血症(De Vita等人,Arthritis Rheum. 46 增刊9 (2002) S206/S469)、重症肌無力(Zaja等人,Neurology 55 (2000) 1062-1063;Wylam等人,J. Pediatr. 143 (2003) 674-677)、華格納氏肉芽病(Specks等人,Arthritis & Rheumatism 44 (2001) 2836-2840)、難治性尋常性天疱瘡(Dupuy等人,Arch. Dermatol. 140 (2004) 91-96)、皮肌炎(Levine, Arthritis Rheum. 46 (增刊9) (2002) S1299)、鳩氏症候群(Somer等人,Arthritis & Rheumatism 49 (2003) 394-398)、活性II型混合冷凝球蛋白血症(Zaja等人,Blood 101 (2003) 3827-3834)、尋常性天疱瘡(Dupay等人,Arch. Dermatol. 140 (2004) 91-95)、自體免疫神經病變(Pestronk等人,J. Neurol. Neurosurg. Psychiatry 74 (2003) 485-489)、伴腫瘤性眼陣攣-肌陣攣症候群(Pranzatelli等人,Neurology 60(增刊1) (2003) PO5.128:A395)及復發緩解型多發性硬化症(RRMS) (Cross等人(摘要) 「Preliminary results from a phase II trial of Rituximab in MS」Eighth Annual Meeting of the Americas Committees for Research and Treatment in Multiple Sclerosis, (2003) 20-21)。
關於使用利妥昔單抗之療法之公開案包括:Perotta及Abuel, Blood 10 (l998)(part 1-2) 88B;Perotta等人,Blood 94 (1999) 49 (摘要);Matthews, R., Ann. Rheum. Di's,同上;Leandro等人,Arthritis and Rheumatism 44(9): S370 (2001);Leandro等人,Arthritis and Rheumatism 46 (2002) 2673-2677;Weide等人,Lupus 12 (2003) 779-782;Edwards及Cambridge, Rheumatology 40 (2001) 205-211;Cambridge等人,Arthritis Rheum. 46 (增刊9) (2002) S1350;Edwards等人,Arthritis and Rheumatism 46 (2002) S197;Levine及Pestronk, Neurology 52 (1999) 1701-1704;De Vita等人,Arthritis & Rheum. 46 (2002) 2029-2033;Hidashida等人,Annual Scientific Meeting of the American College of Rheumatology; Oct 24-29; New Orleans, LA 2002;Tuscano, J., Annual Scientific Meeting of the American College of Rheumatology; Oct 24-29; New Orleans, LA 2002;Martin及Chan, Immunity 20 (2004) 517-527;Silverman及Weisman, Arthritis and Rheumatism 48 (2003) 1484-1492;Kazkaz及Isenberg, Current opinion in pharmacology 4 (2004) 398-402;Virgolini及Vanda, Biomedicine & pharmacotherapy 58 (2004) 299-309;Klemmer等人,Arthritis and Rheumatism 48(2003) 9,S (SEP) S624-S624;Kneitz等人,Immunobiology 206 (2002) 519-527;Arzoo等人,Annals of the Rheumatic Diseases 61 (2002) p922-924; Comment in Ann. Rheum. Dis. 61 (2002) 863-866;Lake及Dionne之「Future Strategies in Immunotherapy」,於Burger's Medicinal Chemistry and Drug Discovery (2003 by John Wiley & Sons, Inc.)中;Liang及Tedder, Wiley Encyclopedia of Molecular Medicine, Section: CD20 as an Immunotherapy Target, 2002,標題為「CD20」;附錄4A,標題為「Monoclonal Antibodies to Human Cell Surface Antigens」,由Stockinger等人,編:Coligan等人,於Current Protocols in Immunology (2003 John Wiley & Sons, Inc.)中;Penichet及Morrison,「CD Antibodies/molecules: Definition; Antibody Engineering」於Wiley Encyclopedia of Molecular Medicine Section: Chimeric, Humanized and Human Antibodies;於2002年1月15日在線發佈中;Specks等人,Arthritis & Rheumatism 44 (2001) 2836-2840;Koegh等人,「Rituximab for Remission Induction in Severe ANCA-Associated Vasculitis: Report of a Prospective Open-Label Pilot Trial in 10 Patients」, American College of Rheumatology,會議編號:28-100,會議標題:血管炎,會議類型:ACR Concurrent Session, Primary Category: 28 Vasculitis, Session 10/18/2004 (http://www.abstractsonline.com/viewer/SearchResults.asp);Eriksson, Kidney and Blood Pressure Research 26 (2003) 294;Jayne等人,Kidney and Blood Pressure Research, 26 (2003) 294;Jayne, poster 88 (11th International Vasculitis and ANCA workshop), 2003 American Society of Nephrology;Stone及Specks於Clinical Trial Research Summary of the 2002-2003 Immune Tolerance Network,http://www.immunetolerance.org/reseaTclT/autoimmune/trial s/stone.html中;Leandro等人,Arthritis Rheum. 48 (增刊9) (2003) Sl 160。
涉及CD20抗體之專利案及專利公開案包括US 5,776,456、US 5,736,137、US 5,843,439、US 6,399,061、US 6,682,734、US 2002/0197255 A1、US 2003/0021781 A1、US 2003/0082172 Al、US 2003/0095963 Al、US 2003/0147885 A1、US 6,455,043、WO 00/09160、WO 00/27428、WO 00/27433、WO 00/44788、WO 01/10462、WO 01/10461、WO 01/10460、US 2001/0018041 A1、US 2003/0180292 A1、WO 01/34194、US 2002/0006404、WO 02/04021、US 2002/0012665 Al、WO 01/74388、US 2002/0058029 Al、US 2003/0103971 Al、US 2002/0009444 A1、WO 01/80884、WO 01/97858、US 2002/0128488 A1、WO 02/34790、WO 02/060955、WO 02/096948、WO 02/079255、US 6,171,586 B1、WO 98/56418、WO 98/58964、WO 99/22764、WO 99/51642、US 6,194,551 B1、US 6,242,195 B1、US 6,528,624 B1、US 6,538,124、WO 00/42072、WO 00/67796、WO 01/03734、US 2002/0004587 Al、WO 01/77342、US 2002/0197256、US 2003/0157108 Al、US 6,565,827 B1、US 6,090,365 B1、US 6,287,537 B1、US 6,015,542、US 5,843,398、US 5,595,721、US 5,500,362、US 5,677,180、US 5,721,108、US 6,120,767、US 6,652,852 B1、US 6,410,391 B1、US 6,224,866 B1、WO 00/20864、WO 01/13945、WO 00/67795、US 2003/0133930 Al、WO 00/74718、WO 00/76542、WO 01/72333、US 6,368,596 B1、US 6,306,393、US 2002/0041847 Al、US 2003/0026801 A1、WO 02/102312、US 2003/0068664、WO 03/002607、WO 03/049694、US 2002/0009427 A1、US 2003/0185796 Al、WO 03/061694、US 2003/0219818 Al、US 2003/0219433 Al、WO 03/068821、US 2002/0136719 A1、WO 2004/032828、WO 2004/035607、US 2004/0093621、US 5,849,898、EP 0,330,191、US 4,861,579、EP 0,332,865、WO 95/03770、US 2001/0056066、WO 2004/035607、WO 2004/056312、US 2004/0093621、WO 2004/103404。涉及CD20抗體之公開案包括:Teeling, J.等人,Blood 10 (2004) 1182。
WO 2014/033074係關於結合血腦障壁上之受體之血腦障壁穿梭體及其使用方法。WO 2012/075037報告低親和性血腦障壁受體抗體及其用途。WO 2014/189973係關於抗-轉鐵蛋白受體抗體及其等使用方法。WO 2015/101588報告包含腦效應實體、連接子及一個結合至血腦障壁受體之單價結合實體之血腦障壁穿梭體模組。WO 2010/033587涉及用於治療病患之漸進多發性硬化症之方法及製品以及其使用說明書。WO 2012/096924報告用於治療、阻止或預防患有對使用抗-CD20抗體之治療具有反應性之疾病之病患之方法,其包括向該病患投與至少一個低於去除劑量之抗CD20抗體。Hawker, K.等人(Ann. Neurol. 66 (2009) 460-471)報告關於利妥昔單抗於患有原發性漸進多發性硬化症之病患中之隨機雙盲安慰劑對照多中心試驗之結果。
如本文報告之一個態樣係雙特異性抗體,其包含
a)一種(全長)抗體,其包含兩對(全長)抗體輕鏈及(全長)抗體重鏈,其中由各對(全長)重鏈及(全長)輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至該(全長)抗體其中之一重鏈之任何C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各(全長)抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各(全長)抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至該第二抗原之另一Fab片段包含域交轉(crossover),致使該恆定輕鏈域(CL)及該恆定重鏈域1 (CH1)彼此置換,及
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
在一個實施例中,該另一Fab片段係藉由肽連接子融合至重鏈之C端。
在一個實施例中,該Fab片段之重鏈可變域之N端係融合至(全長)重鏈之C端或肽連接子之C端。
在一個實施例中,
a) 該融合至另一Fab片段之(全長)重鏈具有三肽LSP作為C端(重鏈)胺基酸殘基,其中其脯胺酸係經由肽鍵直接融合至另一Fab片段之第一胺基酸殘基或肽連接子之第一胺基酸殘基,及
b)非融合至另一Fab片段之(全長)重鏈具有三肽LSP或SPG或PGK作為C端(重鏈)胺基酸殘基。
在一個實施例中,該(全長)抗體係
a)人類亞類IgG1之全長抗體,
b)人類亞類IgG4之全長抗體,
c)具有突變L234A、L235A及P329G之人類亞類IgG1之全長抗體,
d)具有突變S228P、L235E及P329G之人類亞類IgG4之全長抗體,
e)在兩條重鏈中均具有突變L234A、L235A及P329G及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG1之全長抗體,
f)在兩條重鏈中均具有突變S228P、L235E及P329G及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG4之全長抗體,
g)在兩條重鏈中均具有突變L234A、L235A、P329G、I253A、H310A及H435A及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG1之全長抗體,或
h)在兩條重鏈中均具有突變L234A、L235A、P329G、M252Y、S254T及T256E及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG1之全長抗體,或
i)在兩條重鏈中均具有突變L234A、L235A、P329G、H310A、H433A及Y436A及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG1之全長抗體。
在一個實施例中,該另一Fab片段係融合至包含突變T366W之重鏈之C端或融合至包含突變T366S、L368A及Y407V之重鏈之C端。
在一個實施例中,
該(全長)抗體係具有在兩條重鏈中均具有突變L234A、L235A及P329G及在一條重鏈中具有突變T366W及S354C及在另一重鏈中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,及
該另一Fab片段係融合至包含突變T366W之重鏈之C端或融合至包含突變T366S、L368A及Y407V之重鏈之C端。
在一個實施例中,該雙特異性抗體包含
i)與SEQ ID NO: 01具有70%或以上之序列同一性之輕鏈,
ii)與SEQ ID NO: 02具有70%或以上之序列同一性之重鏈,
iii)與SEQ ID NO: 03具有70%或以上之序列同一性之輕鏈,及
iv)與SEQ ID NO: 04具有70%或以上之序列同一性之重鏈Fab片段,
其中
SEQ ID NO: 01具有胺基酸序列DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
SEQ ID NO: 02具有胺基酸序列QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG,
SEQ ID NO: 03具有胺基酸序列AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC,及
SEQ ID NO: 04具有胺基酸序列QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
如本文報告之一個態樣係包含具有SEQ ID NO: 01之胺基酸序列之(全長)輕鏈;具有SEQ ID NO: 02之胺基酸序列之(全長)重鏈;具有SEQ ID NO: 03之胺基酸序列之(全長)輕鏈;及包含SEQ ID NO: 04之胺基酸序列之抗體Fab片段之雙特異性抗體。
在一個實施例中,該雙特異性抗體係單株。
如本文報告之一個態樣係包含以下之雙特異性抗體:
a)第一及第二Fab片段,其中該第一及該第二Fab片段之各結合位點特異性結合至第一抗原,
b)第三Fab片段,其中該第三Fab片段之結合位點特異性結合至第二抗原,及其中該第三Fab片段包含域交轉,致使可變輕鏈域(VL)及可變重鏈域(VH)彼此置換,及
c)包含第一Fc區多肽及第二Fc區多肽之Fc區,
其中該第一及該第二Fab片段各包含重鏈片段及全長輕鏈,
其中該第一Fab片段之重鏈片段之C端係融合至該第一Fc區多肽之N端,
其中該第二Fab片段之重鏈片段之C端係融合至該第三Fab片段之可變輕鏈域之N端及該第三Fab片段之重鏈恆定域1之C端係融合至該第二Fc區多肽之N端,
其中該第一及該第二Fab片段之各全長輕抗體鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中該第一及該第二Fab片段之各重鏈片段包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
在一個實施例中,該第一及第二Fc區多肽係
a)屬於人類亞類IgG1,
b)屬於人類亞類IgG4,
c)屬於具有突變L234A、L235A及P329G之人類亞類IgG1,
d)屬於具有突變S228P、L235E及P329G之人類亞類IgG4,
e)屬於在兩條Fc區多肽中均具有突變L234A、L235A及P329G及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,
f)屬於在兩條Fc區多肽中均具有突變S228P、L235E及P329G及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG4,
g)屬於在兩條Fc區多肽中均具有突變L234A、L235A、P329G、I253A、H310A及H435A及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,或
h)屬於在兩條Fc區多肽中均具有突變L234A、L235A、P329G、M252Y、S254T及T256E及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,或
i)屬於在兩條Fc區多肽中均具有突變L234A、L235A、P329G、H310A、H433A及Y436A及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1。
在一個實施例中,該第三Fab片段之鏈中之一者係融合至包含突變T366W之Fc區多肽或融合至包含突變T366S、L368A及Y407V之Fc區多肽。
在一個實施例中,該雙特異性抗體包含
i)與SEQ ID NO: 14具有至少70%或至少80%或至少90%或95%或以上之序列同一性之輕鏈,
ii)與SEQ ID NO: 15具有至少70%或至少80%或至少90%或95%或以上之序列同一性之重鏈,
iii)與SEQ ID NO: 16具有至少70%或至少80%或至少90%或95%或以上之序列同一性之交叉抗體鏈,及
iv)與SEQ ID NO: 17具有至少70%或至少80%或至少90%或95%或以上之序列同一性之經修飾重鏈,
其中
SEQ ID NO: 14具有胺基酸序列DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
SEQ ID NO: 15具有胺基酸序列QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG,
SEQ ID NO: 16具有胺基酸序列QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,及
SEQ ID NO: 17具有胺基酸序列QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG。
如本文報告之一個態樣係包含各具有SEQ ID NO: 14之胺基酸序列之兩條全長輕鏈;具有SEQ ID NO: 15之胺基酸序列之全長重鏈;具有SEQ ID NO: 16之胺基酸序列之交叉抗體鏈;及具有SEQ ID NO: 17之胺基酸序列之經修飾重鏈之雙特異性抗體。
在一個實施例中,該雙特異性抗體係單株。
如本文報告之一個態樣係編碼如本文報告之雙特異性抗體之經分離核酸。
如本文報告之一個態樣係包含如本文報告之編碼如本文報告之雙特異性抗體之核酸之宿主細胞。
如本文報告之一個態樣係產生如本文報告之雙特異性抗體之方法,該方法包括下列步驟:
a)培養如本文報告之宿主細胞使得產生該雙特異性抗體,及
b)自細胞或培養基質中回收該雙特異性抗體及藉此產生如本文報告之雙特異性抗體。
如本文報告之一個態樣係包含如本文報告之雙特異性抗體及細胞毒性劑之免疫結合物。
如本文報告之一個態樣係包含如本文報告之雙特異性抗體及醫藥上可接受之載劑之醫藥調配物。
如本文報告之一個態樣係如本文報告之抗體,其用作藥劑。
如本文報告之一個態樣係如本文報告之抗體,其用於治療癌症。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於治療B細胞增生性疾病。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於抑制可表現CD20之腫瘤細胞之生長。在一個實施例中,該抑制作用係於腦中。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於治療惡性腫瘤。在一個較佳實施例中,該惡性腫瘤係腦之惡性腫瘤/腦中之惡性腫瘤。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於治療淋巴瘤。在一個較佳實施例中,該淋巴瘤係原發性中樞神經系統淋巴瘤(PCNSL)。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於治療自體免疫疾病。在一個實施例中,該自體免疫疾病係多發性硬化症。在一個較佳實施例中,該自體免疫疾病係繼發漸進多發性硬化症。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於去除可表現CD20之腫瘤細胞。在一個實施例中,該去除作用係於腦中。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於去除可表現CD20之循環B細胞。在一個實施例中,該去除作用係於腦中。
如本文報告之一個態樣係如本文報告之雙特異性抗體,其用於去除可表現CD20之經腦隔離B細胞。
如本文報告之一個態樣係如本文報告之雙特異性抗體於製造藥劑中之用途。
在一個實施例中,該藥劑係用於治療增生型疾病。在一個實施例中,該增生型疾病係B細胞增生性疾病。在一個實施例中,該增生型疾病係B細胞淋巴瘤。在一個較佳實施例中,該增生型疾病係原發性中樞神經系統淋巴瘤。
在一個實施例中,該藥劑係用於腫瘤。
在一個實施例中,該藥劑係用於治療人類惡性腫瘤。
在一個實施例中,該藥劑係用於治療自體免疫疾病。在一個實施例中,該自體免疫疾病係選自由以下組成之群:炎性反應,諸如炎性皮膚疾病,其等包括牛皮癬及皮膚炎(例如,異位性皮膚炎);全身性硬皮病及硬化症;與炎性腸疾相關聯之反應(諸如克羅恩氏病(Crohn's disease)及潰瘍性結腸炎);呼吸窘迫症候群(包括成人呼吸窘迫症候群;ARDS);皮膚炎;腦膜炎;腦炎;眼色素層炎;結腸炎;腎小球性腎炎;過敏性病症,諸如濕疹及氣喘及涉及T細胞之浸潤及慢性炎性反應之其他病症;動脈粥樣硬化症;白血球黏附缺陷症;類風濕性關節炎;全身性紅斑狼瘡(SLE);糖尿病(例如,I型糖尿病或胰島素依賴性糖尿病);多發性硬化症;雷諾症候群(Reynaud's syndrome);自體免疫甲狀腺炎;過敏性腦脊髓炎;鳩氏症候群;青少年發病型糖尿病;及通常於結核病、類肉瘤病、多發性肌炎、肉芽病及血管炎中發現之與細胞介素及T-淋巴球介導之急性及遲發性超敏反應相關聯之免疫反應;惡性貧血(艾迪生氏病(Addison's disease));涉及白血球滲出之疾病;中樞神經系統(CNS)炎性失調症;多器官損傷症候群;溶血性貧血(包括(但不限於)冷凝球蛋白血症或庫姆氏陽性貧血症(Coombs positive anemia));重症肌無力;抗原-抗體複合體介導之疾病;抗-腎小球基底膜疾病;抗-磷脂質症候群;過敏性神經炎;格雷夫斯氏病(Graves' disease);蘭伯特-伊頓(Lambert-Eaton)肌無力症候群;大皰性類天皰瘡;天皰瘡;自體免疫多內分泌病;萊特氏病(Reiter's disease);僵體症候群;白塞氏病(Bechet disease);巨大細胞動脈炎;免疫複合體腎炎;IgA腎病;IgM多發性神經病變;免疫血小板減少性紫瘢(ITP)或自體免疫血小板減少症。在一個實施例中,該藥劑係用於治療多發性硬化症。在一個較佳實施例中,該藥劑係用於治療繼發漸進多發性硬化症。
在一個實施例中,該藥劑係用於去除可表現CD20之腫瘤細胞。在一個實施例中,該去除作用係於腦中。
在一個實施例中,該藥劑係用於去除可表現CD20之循環B細胞。在一個實施例中,該去除作用係於腦中。
在一個實施例中,該藥劑係用於去除可表現CD20之經腦隔離B細胞。
如本文報告之一個態樣係治療患有增生型疾病之個體之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體。在一個實施例中,該增生型疾病係B細胞增生性疾病。
如本文報告之一個態樣係治療患有惡性腫瘤之個體之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體。在一個較佳實施例中,該惡性腫瘤係腦之惡性腫瘤/腦中之惡性腫瘤。
如本文報告之一個態樣係治療患有淋巴瘤之個體之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體。在一個較佳實施例中,該淋巴瘤係原發性中樞神經系統淋巴瘤(PCNSL)。
如本文報告之一個態樣係治療患有自體免疫疾病之個體之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體。在一個實施例中,該自體免疫疾病係多發性硬化症。在一個較佳實施例中,該自體免疫疾病係繼發漸進多發性硬化症。
如本文報告之一個態樣係用於抑制個體中可表現CD20之腫瘤細胞之生長之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體以抑制可表現CD20之腫瘤細胞之生長。在一個實施例中,該抑制係於腦中。
如本文報告之一個態樣係用於去除個體中可表現CD20之腫瘤細胞之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體以去除可表現CD20之腫瘤細胞。在一個實施例中,該抑制作用係於腦中。
如本文報告之一個態樣係用於去除個體中可表現CD20之循環B細胞之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體以去除可表現CD20之循環B細胞。在一個實施例中,該抑制作用係於腦中。
如本文報告之一個態樣係用於去除個體中可表現CD20之經腦隔離B細胞之方法,該方法包括向該個體投與有效量之如本文報告之雙特異性抗體以去除可表現CD20之經腦隔離B細胞。
如本文報告之一個態樣係治療人類之多發性硬化症之方法,該方法包括向該人類投與治療有效量之如本文報告之抗體,其結合至人類CD20並去除B細胞,及其中該抗體係不與細胞毒性劑結合。
節至孔中(knobs into holes)二聚化模組及其等於抗體改造中之用途係描述於Carter P.; Ridgway J.B.B.; Presta L.G.: Immunotechnology,第2卷,第1期,February 1996,第73至73頁中。CH3域中之額外雙硫鍵係報告於Merchant, A.M.等人,Nat. Biotechnol. 16 (1998) 677-681中。
關於人類免疫球蛋白輕鏈及重鏈之核苷酸序列之一般資訊係給定於:Kabat, E.A.等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)中。
如本文使用,重鏈及輕鏈之所有恆定區及域之胺基酸位置係根據描述於Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)中之Kabat編號系統編號及在本文中係稱為「根據Kabat編號」。具體言之,Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)之Kabat編號系統(參見第647至660頁)係用於κ及λ同型之輕鏈恆定域CL,及Kabat EU索引編號系統(參見第661至723頁)係用於恆定重鏈域(在此情況下,CH1、鉸鏈、CH2及CH3,其於本文中係藉由參考「根據Kabat EU索引編號」進行進一步闡述)。
I. 定義「血腦障壁」或「BBB」係指末梢循環與腦及脊髓之間之生理障壁,其係由腦毛細血管內皮漿膜內之緊密連接形成,其產生限制分子(甚至非常小分子諸如脲(60道爾頓))輸送至腦內之緊密障壁。腦內之BBB、脊髓內之血液脊髓障壁及視網膜內之血液視網膜障壁係CNS內之連續毛細血管障壁,及本文中統稱為血腦障壁或BBB。該BBB亦包含血液CSF障壁(脈絡叢),其中該障壁係由室管膜細胞而非毛細血管內皮細胞組成。
術語「抗-人類CD20抗體」及「特異性結合至人類CD20之抗體」係指可以足夠親和性結合人類CD20之抗體,使得該抗體適用作靶向CD20之診斷及/或治療劑。
因此,該術語亦包含結合至人類CD20之縮短片段之抗體。
結合CD20抗原之抗體之實例包括:現稱為「利妥昔單抗」之「C2B8」(「RITUXAN®」) (US 5,736,137);命名為「Y2B8」之經釔-[90]標記之2B8鼠類抗體(US 5,736,137);視需要經131I標記以產生「131I-B1」抗體(BEXXAR™)之鼠類IgG2a 「B1」(US 5,595,721);鼠類單株抗體「1F5」 (Press等人,Blood 69(1987)584-591);「嵌合2H7」抗體(US 5,677,180);自International Leukocyte Typing Workshop購得之單株抗體L27、G28-2、93-1B3、B-C1或NU-B2 (Valentine等人,In: Leukocyte Typing III (McMichael編),第440頁,Oxford University Press (1987));及描述於US 8,883,980中之單株抗體。
「CD20」抗原係約35 kDa之非醣化磷蛋白,其發現於來自周邊血液或類淋巴器官之大於90%之B細胞之表面上。CD20係在早期前B細胞發育期間經表現及保留直至漿細胞分化。CD20係存在於正常B細胞及惡性B細胞兩者上。參考文獻中用於CD20之其他名稱包括「B淋巴球限制性抗原」及「Bp35」。CD20抗原係(例如)描述於Clark等人,Proc. Natl. Acad. Sci USA 82 (1985) 1766中。亦參考SEQ ID NO: 05。
本文之「自體免疫疾病」係源自及針對個體自身組織之非惡性疾病或失調症。如本文使用之術語「自體免疫疾病」明確排除惡性或癌性疾病或病症,尤其排除B細胞淋巴瘤、急性淋巴母細胞白血病(ALL)、慢性淋巴球性白血病(CLL)、多毛細胞白血病及慢性骨髓胚細胞性白血病。自體免疫疾病或失調症之實例包括(但不限於)炎性反應,諸如炎性皮膚疾病,其等包括牛皮癬及皮膚炎(例如,異位性皮膚炎);全身性硬皮病及硬化症;與炎性腸疾相關聯之反應(諸如克羅恩氏病及潰瘍性結腸炎);呼吸窘迫症候群(包括成人呼吸窘迫症候群;ARDS);皮膚炎;腦膜炎;腦炎;眼色素層炎;結腸炎;腎小球性腎炎;過敏性病症,諸如濕疹及氣喘及涉及T細胞之浸潤及慢性炎性反應之其他病症;動脈粥樣硬化症;白血球黏附缺陷症;類風濕性關節炎;全身性紅斑狼瘡(SLE);糖尿病(例如,I型糖尿病或胰島素依賴性糖尿病);多發性硬化症;雷諾症候群;自體免疫甲狀腺炎;過敏性腦脊髓炎;鳩氏症候群;青少年發病型糖尿病;及通常於結核病、類肉瘤病、多發性肌炎、肉芽病及血管炎中發現之與細胞介素及T-淋巴球介導之急性及遲發性超敏反應相關聯之免疫反應;惡性貧血(艾迪生氏病);涉及白血球滲出之疾病;中樞神經系統(CNS)炎性失調症;多器官損傷症候群;溶血性貧血(包括(但不限於)冷凝球蛋白血症或庫姆氏陽性貧血症);重症肌無力;抗原-抗體複合體介導之疾病;抗-腎小球基底膜疾病;抗-磷脂質症候群;過敏性神經炎;格雷夫斯氏病;蘭伯特-伊頓肌無力症候群;大皰性類天皰瘡;天皰瘡;自體免疫多內分泌病;萊特氏病;僵體症候群;白塞氏病;巨大細胞動脈炎;免疫複合體腎炎;IgA腎病;IgM多發性神經病變;免疫血小板減少性紫瘢(ITP)或自體免疫血小板減少症等。
「拮抗劑」係結合至B-細胞表面標誌後(例如)藉由減少或預防由B細胞引起之體液反應來破壞、殺滅或去除哺乳動物中之B細胞及/或干擾一或更多種B細胞功能之分子。該拮抗劑可去除經該其治療之哺乳動物中之B細胞(即,減小循環B細胞濃度)。此去除可經由各種機制諸如抗體依賴性細胞介導之細胞毒性(ADCC)及/或補體依賴性細胞毒性(CDC);B細胞增生之抑制及/或B細胞死亡之誘導(例如,經由細胞凋亡)來達成。拮抗劑包括結合至B細胞標誌且視需要與細胞毒性劑結合或融合至細胞毒性劑之抗體、合成或天然序列肽及小分子。
「生長抑制」拮抗劑係彼等預防或減少表現該拮抗劑結合之抗原之細胞之增生。例如,該拮抗劑可預防或減少活體外及/或活體內B細胞之增生。
「誘導細胞凋亡」之拮抗劑係彼等誘導由標準細胞凋亡分析判定之(例如)B細胞之程序化細胞死亡(諸如結合膜聯蛋白V、DNA碎片化、細胞收縮、內質網擴張、細胞破裂及/或形成膜囊(稱為凋亡體))之拮抗劑。
「結合」受關注之抗原(例如,B-細胞表面標誌)之拮抗劑係可以足夠親和性及/或結合性結合該抗原之拮抗劑,因此該拮抗劑係適合作用於靶向表現該抗原之細胞之治療劑。
「中樞神經系統」或「CNS」係指控制身體功能之神經組織之複合體及包括腦及脊髓。
「血腦障壁受體」 (本文中縮寫為「BBBR」)係表現於腦內皮細胞上之細胞外膜連接受體蛋白,其可跨BBB輸送分子或用以輸送外源性投與分子。本文中BBBR之實例包括:轉鐵蛋白受體(TfR)、胰島素受體、類胰島素生長因子受體(IGF-R)、低密度脂蛋白受體(包括(但不限於)低密度脂蛋白受體相關蛋白質1 (LRP1)及低密度脂蛋白受體相關蛋白質8 (LRP8))及肝素結合表皮生長因子樣生長因子(HB-EGF)。一種較佳之BBBR係轉鐵蛋白受體(TfR)。
「轉鐵蛋白受體」 (「TfR」)係跨膜醣蛋白(具有約180,000 Da之分子量),其由兩個經雙硫鍵結合之子單元(各具有約90,000 Da之視分子量)組成且涉及脊椎動物中之鐵攝取。在一個實施例中,如本文提及之TfR係包含(例如)如於Schneider等人,(Nature 311 (1984) 675-678)中之胺基酸序列之人類TfR。
「多特異性抗體」表示對於相同抗原或兩個不同抗原上之至少兩個不同抗原決定基具有結合特異性之抗體。例示性多特異性抗體可結合BBBR及腦抗原兩者。多特異性抗體可製備成全長抗體或抗體片段(例如,F(ab')2雙特異性抗體)或其組合(例如,全長抗體加另一scFv或Fab片段)。亦已報告具有二、三或更多(例如,四)個功能抗原結合位點之經改造抗體(參見,例如,US 2002/0004587 Al)。
用於本文之目的之「受體人類框架」係包含衍生自人類免疫球蛋白框架或人類共同框架(如下文定義)之輕鏈可變域(VL)框架或重鏈可變域(VH)框架之胺基酸序列之框架。「衍生自」人類免疫球蛋白框架或人類共同框架之受體人類框架可包含其相同胺基酸序列,或其可含有胺基酸序列變化。在一些實施例中,胺基酸變化之數量係10或以下,9或以下,8或以下,7或以下,6或以下,5或以下,4或以下,3或以下或2或以下。在一些實施例中,該VL受體人類框架序列係與VL人類免疫球蛋白框架序列或人類共同框架序列相同。
「親和性」係指分子(例如,抗體)之單一結合位點與其結合配偶體(例如,抗原)間之非共價相互作用之強度之總和。除非另有指示,否則如本文使用,「結合親和性」係指反映結合對(例如,抗體及抗原)之成員間之1:1相互作用之固有結合親和性。分子X對其配偶體Y之親和性可通常由解離常數(kd)表示。親和性可藉由此項技術中已知的常用方法(諸如表面電漿子共振及包括彼等本文描述者)來量測。
「親和性成熟」抗體係指於一或更多個高度可變區(HVR)中具有一或更多個改變之抗體,相較於不具有此等改變之親代抗體,此等改變導致抗體對其抗原之親和性有所改善。
本文之術語「抗體」係以最廣義使用且包含各種抗體結構,其等包含(但不限於)單株抗體、多株抗體及多特異性抗體(例如,雙特異性抗體),只要其等顯示所需抗原結合活性即可。
術語「抗體依賴性細胞性細胞毒性(ADCC)」係由Fc受體結合介導之功能及係指藉由如本文報告之抗體在效應細胞之存在下溶解靶細胞。在一個實施例中,ADCC係藉由用如本文報告之抗體在效應細胞(諸如來自膚色血球層之經新鮮分離之PBMC (周邊血液單核細胞)或經純化之效應細胞(諸如單核球或NK (自然殺手)細胞))之存在下處理表現CD19之類紅血球(例如,表現重組人類CD19之K562細胞)之製劑來量測。靶細胞係用51Cr標記及接著用抗體培養。經標記之細胞係用效應細胞培養及分析上清液中的釋放之51Cr。對照包括用效應細胞而非抗體培養靶內皮細胞。該抗體誘導介導ADCC之初始步驟之能力係藉由量測其等對表現Fcγ受體之細胞,諸如重組表現FcγRI及/或FcγRIIA之細胞或NK細胞(基本上表現FcγRIIIA)之結合進行研究。在一個較佳實施例中,量測對NK細胞上之FcγR之結合。
「抗體片段」係指除完整抗體外之分子,其包含完整抗體之結合該完整抗體所結合之抗原之一部分。抗體片段之實例包括(但不限於)Fv、Fab、Fab'、Fab’-SH、F(ab')2;雙功能抗體;線性抗體;單鏈抗體分子(例如,scFv);及自抗體片段形成之多特異性抗體。
術語「嵌合」抗體係指其中重鏈及/或輕鏈之一部分係衍生自特定來源或物種,同時該重鏈及/或輕鏈之剩餘部分係衍生自不同來源或物種之抗體。
抗體之「類別」係指其重鏈所具有之恆定域或恆定區之類型。存在抗體之五種主要類別:IgA、IgD、IgE、IgG,及IgM,及此等類別中之數種可進一步分為亞類(同型),例如,IgG1、IgG2、IgG3、IgG4、IgA1,及IgA2。對應於免疫球蛋白之不同類別之重鏈恆定域係分別稱為α、δ、ε、γ及μ。
如本文使用之術語「細胞毒性劑」係指抑制或預防細胞功能及/或引起細胞死亡或破壞之物質。細胞毒性劑包括(但不限於)放射性同位素(例如,At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212及Lu之放射性同位素);化學治療劑或藥物(例如,胺甲喋呤、阿黴素(adriamicin)、長春花生物鹼(vinca alkaloid)(長春新鹼(vincristine)、長春花鹼(vinblastine)、依託泊苷(etoposide))、多柔比星(doxorubicin)、美法侖(melphalan)、絲裂黴素C(mitomycin C)、氯芥苯丁酸(chlorambucil)、道諾黴素(daunorubicin)或其他嵌入劑);生長抑制劑;酶及其片段,諸如核溶解酶;抗生素;毒素,諸如小分子毒素或細菌、真菌、植物或動物起源之酶活性毒素,其等包括其片段及/或變體;及下文揭示之各種抗腫瘤或抗癌劑。
術語「補體依賴性細胞毒性(CDC)」係指由如本文報告之抗體在補體之存在下誘導之細胞溶解。在一個實施例中,CDC係藉由用如本文報告之抗體在補體之存在下處理表現CD19之人類內皮細胞來量測。在一個實施例中,該等細胞係用鈣黃綠素標記。若該抗體在30 µg/ml之濃度下誘導20%或以上之靶細胞之溶解,則發現CDC。可於ELISA中量測對補體因子C1q的結合。在此分析中,原則上,ELISA板係經濃度範圍之該抗體塗覆,其中添加經純化之人類C1q或人類血清。C1q結合係藉由針對C1q之抗體,接著經過氧化酶標記之結合物進行偵測。結合(最大結合Bmax)之偵測係量測為在405 nm下針對過氧化酶受質ABTS® (2,2'-次偶氮基-二-[3-乙基苯并噻唑-6-磺酸鹽(6)])之光學密度(OD405)。
「效應子功能」係指彼等可歸因於抗體之Fc區之生物活性,其等隨抗體類別變化。抗體效應子功能之實例包括:C1q結合及補體依賴性細胞毒性(CDC);Fc受體結合;抗體依賴性細胞介導之細胞毒性(ADCC);吞噬作用;細胞表面受體(例如,B細胞受體)之下調;及B細胞活化作用。
Fc受體結合依賴性效應子功能可藉由抗體之Fc區與Fc受體(FcR)之相互作用介導,Fc受體係造血細胞上的特化細胞表面受體。Fc受體屬於免疫球蛋白超家族,及已顯示介導藉由免疫複合體之吞噬作用移除經抗體塗覆之病原體,及經由抗體依賴性細胞介導之細胞毒性(ADCC)細胞溶解紅血球及經對應抗體塗覆之各種其他細胞靶(例如,腫瘤細胞)兩者(參見例如,Van de Winkel, J.G.及Anderson, C.L., J. Leukoc. Biol. 49 (1991) 511-524)。FcR係藉由其等對免疫球蛋白同型之特異性來定義:IgG抗體之Fc受體係稱為FcγR。Fc受體結合係描述(例如)於Ravetch, J.V.及Kinet, J.P., Annu. Rev. Immunol. 9 (1991) 457-492;Capel, P.J.等人,Immunomethods 4 (1994) 25-34;de Haas, M.等人,J. Lab. Clin. Med. 126 (1995) 330-341;及Gessner, J.E.等人,Ann. Hematol. 76 (1998) 231-248中。
IgG抗體之Fc區之受體(FcγR)之交聯觸發各種效應子功能,包括吞噬作用;抗體依賴性細胞性細胞毒性;及炎性介質之釋放,及免疫複合體廓清及抗體產生之調節。在人類中,FcγR之三種類別已經特徵化,其等係:
-FcγRI (CD64)以高親和性結合單體IgG及係表現於巨噬細胞、單核球、嗜中性球及嗜伊紅細胞上。於Fc區IgG中胺基酸殘基E233-G236、P238、D265、N297、A327及P329 (根據Kabat之EU索引編號)中之至少一者之修飾會減少結合至FcγRI。位置233至236處之IgG2殘基(經取代為IgG1及IgG4)10³倍減少結合至FcγRI及消除對經抗體敏化之紅血球之人類單核球反應(Armour, K.L.等人,Eur. J. Immunol. 29 (1999) 2613-2624),
- FcγRII (CD32)以中等至低親和性結合複合IgG及係廣泛地表現。此受體可分為兩種亞類型(FcγRIIA及FcγRIIB)。FcγRIIA係發現於涉及殺滅之許多細胞(例如,巨噬細胞、單核球、嗜中性球)上及似乎可活化殺滅過程。FcγRIIB似乎在抑制過程中發揮作用及係發現於B細胞、巨噬細胞及肥胖細胞及嗜伊紅細胞上。於B細胞上,其似乎作用在於抑制其他免疫球蛋白產生及同型轉化為(例如)IgE類別。於巨噬細胞上,FcγRIIB作用在於抑制如透過FcγRIIA介導之吞噬作用。於嗜伊紅細胞及肥胖細胞上,B形式可有助於透過IgE結合至其不同受體而抑制活化此等細胞。(例如)對於包含具有胺基酸殘基E233-G236、P238、D265、N297、A327、P329、D270、Q295、A327、R292及K414 (根據Kabat之EU索引編號)中之至少一者之突變之IgG Fc區之抗體,發現對FcγRIIA的結合減少,
- FcγRIII (CD16)以中等至低親和性結合IgG及作為兩種類型存在。FcγRIIIA係發現於NK細胞、巨噬細胞、嗜伊紅細胞及一些單核球及T細胞上及介導ADCC。FcγRIIIB係高度地表現於嗜中性球上。(例如)對於包含具有胺基酸殘基E233-G236、P238、D265、N297、A327、P329、D270、Q295、A327、S239、E269、E293、Y296、V303、A327、K338及D376 (根據Kabat之EU索引編號)中之至少一者之突變之IgG Fc區之抗體,發現對FcγRIIIA的結合減少。
人類IgG1上的針對Fc受體的結合位點的繪圖、上文提及之突變位點及用於量測對FcγRI及FcγRIIA之結合之方法係描述於Shields, R.L.等人,J. Biol. Chem. 276 (2001) 6591-6604中。
藥劑(例如,醫藥調配物)之「有效量」係指以必要之劑量及時間週期有效達成所需治療或預防結果之量。
如本文使用之術語「Fc受體」係指藉由與受體相關聯之細胞質ITAM序列之存在進行表徵之活化受體(參見例如,Ravetch, J.V.及Bolland, S., Annu. Rev. Immunol. 19 (2001) 275-290)。此等受體係FcγRI、FcγRIIA及FcγRIIIA。術語「不結合FcγR」表示在10 µg/ml之抗體濃度下,如本文報告之抗體對NK細胞之結合係針對如報告於WO 2006/029879中之抗-OX40L抗體LC.001所發現之結合之10%或以下。
雖然IgG4顯示減少之FcR結合,但其他IgG亞類別之抗體顯示強結合。然而,Pro238、Asp265、Asp270、Asn297 (Fc碳水化合物之損失)、Pro329及234、235、236及237 Ile253、Ser254、Lys288、Thr307、Gln311、Asn434及His435係若以改變方式提供則亦減少FcR結合之殘基(Shields, R.L.等人,J. Biol. Chem. 276 (2001) 6591-6604;Lund, J.等人,FASEB J. 9 (1995) 115-119;Morgan, A.等人,Immunology 86 (1995) 319-324;及EP 0 307 434)。在一個實施例中,如本文報告之抗體係屬於IgG1或IgG2亞類及包含突變PVA236、GLPSS331及/或L234A/L235A。在一個實施例中,如本文報告之抗體係屬於IgG4亞類及包含突變L235E。在一個實施例中,該抗體進一步包含突變S228P。
本文之術語「Fc區」係用以定義免疫球蛋白重鏈之C端區,其含有恆定區之至少一部分。該術語包括天然序列Fc區及變體Fc區。在一個實施例中,人類IgG重鏈Fc區自Cys226或自Pro230延伸至該重鏈之羧基端。然而,該Fc區之C端離胺酸(Lys447)可存在或可不存在。
如本文報告之抗體包含諸如Fc區,在一個實施例中,衍生自人類起源之Fc區。在一個實施例中,該Fc區包含人類恆定區之所有部分。抗體之Fc區係直接涉及補體活化;C1q結合;C3活化及Fc受體結合。雖然抗體對補體系統之影響係取決於某些條件,但對C1q的結合係藉由Fc區中指定結合位點引起。此等結合位點係目前最佳技術中已知及(例如)由Lukas, T.J.等人,J. Immunol. 127 (1981) 2555-2560;Brunhouse, R.及Cebra, J.J., Mol. Immunol. 16 (1979) 907-917;Burton, D.R.等人,Nature 288 (1980) 338-344;Thommesen, J.E.等人,Mol. Immunol. 37 (2000) 995-1004;Idusogie, E.E.等人,J. Immunol. 164 (2000) 4178-4184;Hezareh, M.等人,J. Virol. 75 (2001) 12161-12168;Morgan, A.等人,Immunology 86 (1995) 319-324;及EP 0 307 434描述。此等結合位點係(例如)L234、L235、D270、N297、E318、K320、K322、P331及P329 (根據Kabat之EU索引編號)描述。亞類IgG1、IgG2及IgG3之抗體通常顯示補體活化;C1q結合及C3活化,然而IgG4不活化補體系統,不結合C1q及不活化C3。
「抗體之Fc區」係熟習技工已知的術語及基於木瓜蛋白酶裂解抗體來定義。在一個實施例中,該Fc區係人類Fc區。在一個實施例中,該Fc區係屬於包含突變S228P及/或L235E (根據Kabat之EU索引編號)之人類IgG4亞類。在一個實施例中,該Fc區係屬於包含突變L234A及L235A (根據Kabat之EU索引編號)之人類IgG1亞類。
「框架」或「FR」係指除高度可變區(HVR)殘基外之可變域殘基。可變域之FR通常由四個FR域組成:FR1、FR2、FR3及FR4。因此,HVR及FR序列通常呈現於VH (或VL)中之下列序列中:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
術語「全長抗體」、「完整抗體」及「全抗體」在本文中可交換使用以指具有大體上類似於天然抗體結構之結構或具有含有如本文定義之Fc區之重鏈之抗體。「全長抗體」係包含抗原結合可變區及輕鏈恆定域(CL)及重鏈恆定域(CH1、CH2及CH3)之抗體。該等恆定域可為天然序列恆定域(例如人類天然序列恆定域)或其胺基酸序列變體。更詳細言之,全長抗體包含兩條抗體輕鏈(各包含輕鏈可變域及輕鏈恆定域)及兩條抗體重鏈(各包含重鏈可變域、鉸鏈區及重鏈恆定域(CH1、CH2及CH3))。C端胺基酸殘基K或GK可彼此獨立地存在或不存在於全長抗體之兩條抗體重鏈中。
術語「宿主細胞」、「宿主細胞系」及「宿主細胞培養物」可交換使用及指其中已引入外源核酸之細胞,包括此等細胞之子代。宿主細胞包括「轉形體」及「轉形細胞」,其包括原代轉形細胞及其衍生之子代(不論傳代數)。子代在核酸含量上與親代細胞可不完全相同,但可含有突變。本文包括具有與初始轉形細胞中篩選或選擇之功能或生物活性相同之突變子代。
「人類共同框架」係表示在人類免疫球蛋白VL或VH框架序列之選擇中最常出現之胺基酸殘基之框架。通常,人類免疫球蛋白VL或VH序列之選擇係來自可變域序列之子群。通常,該序列之子群係如Kabat, E.A.等人,Sequences of Proteins of Immunological Interest,第5版,Bethesda MD (1991), NIH Publication 91-3242,第1至3卷中之子群。在一個實施例中,就VL而言,該子群係如Kabat等人(同上)中之子群κI。在一個實施例中,就VH而言,該子群係如Kabat等人(同上)中之子群III。
「人類化」抗體係指包含來自非人類HVRs之胺基酸殘基及來自人類FRs之胺基酸殘基之嵌合抗體。在某些實施例中,人類化抗體將包含大體上所有之至少一個及通常兩個可變域,其中所有或大體上所有之HVRs (例如CDRs)對應於非人類抗體之所有或大體上所有之HVRs,及所有或大體上所有之FRs對應於人類抗體之所有或大體上所有之FRs。人類化抗體視需要可包含衍生自人類抗體之抗體恆定區之至少一部分。抗體(例如非人類抗體)之「人類化形式」係指已經人類化之抗體。
如本文使用,術語「高度可變區」或「HVR」係指包含胺基酸殘基延伸物之抗體可變域之區之各者,其等於序列(「互補決定區」或「CDR」)中係高度可變的及/或形成結構上定義之環(「高度可變環」),及/或含有抗原接觸殘基(「抗原觸體」)。通常,抗體包含六個HVR;三個於VH中(H1、H2、H3)及三個於VL中(L1、L2、L3)。
HVR包括:
(a)於胺基酸殘基26至32 (L1)、50至52 (L2)、91至96 (L3)、26至32 (H1)、53至55 (H2)及96-101 (H3)處出現之高度可變環(Chothia, C.及Lesk, A.M., J. Mol. Biol. 196 (1987) 901-917);
(b)於胺基酸殘基24至34 (L1)、50至56 (L2)、89至97 (L3)、31至35b(H1)、50至65 (H2)及95至102 (H3)處出現之CDR (Kabat, E.A.等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD(1991), NIH Publication 91-3242.);
(c)於胺基酸殘基27c至36 (L1)、46至55 (L2)、89至96 (L3)、30至35b (H1)、47至58 (H2)及93至101 (H3)處出現之抗原觸體(MacCallum等人,J. Mol. Biol. 262 (1996) 732-745);及
(d)(a)、(b)及/或(c)之組合,其等包括胺基酸殘基46至56 (L2)、47至56 (L2)、48至56 (L2)、49至56 (L2)、26至35 (H1)、26至35b (H1)、49至65 (H2)、93至102 (H3)及94至102 (H3)。
除非另有指示,否則本文根據Kabat等人(同上)編號可變域中之HVR殘基及其他殘基(例如,FR殘基)。
「免疫結合物」係結合至一或更多個異源性分子(包括(但不限於)細胞毒性劑)之抗體。
「個體(individual或subject)」係哺乳動物。哺乳動物包括(但不限於)家養動物(例如,牛、綿羊、貓、狗及馬)、靈長類動物(例如,人類及非人類靈長類動物,諸如猴)、兔及嚙齒動物(例如,小鼠及大鼠)。在某些實施例中,該個體係人類。
「經分離」抗體係已從其天然環境之組分分離之抗體。在一些實施例中,抗體係經純化至大於95%或99%純度,如藉由(例如)電泳(例如,SDS-PAGE、等電聚焦(IEF)、毛細管電泳)或層析(例如,離子交換或逆相HPLC)測得。就回顧用於評估抗體純度之方法而言,參見,例如,Flatman, S.等人,J. Chromatogr. B 848 (2007) 79-87。
「經分離」核酸係指已自其天然環境之組分分離之核酸分子。經分離核酸包括通常含有該核酸分子之細胞內含有之核酸分子,但該核酸分子存在於染色體外或位於不同於其天然染色體位置之染色體位置處。
「編碼抗-人類CD20/人類轉鐵蛋白受體抗體之經分離核酸」係指一或更多個編碼抗體重鏈及輕鏈(或其片段)之核酸分子,包括單一載體或個別載體中之此(等)核酸分子,及存在於宿主細胞中之一或更多個位置處之此(等)核酸分子。
如本文使用之術語「單株抗體」係指獲自大體上均質抗體群體之抗體,即,組成該群體之個別抗體係相同的及/或結合相同抗原決定基,除可能之變體抗體(例如,含有天然生成之突變或於產生單株抗體製劑之期間產生)外,此等變體通常少量存在。與通常包括針對不同決定子(抗原決定基)之不同抗體之多株抗體製劑相比,單株抗體製劑之各單株抗體係針對抗原上之單一決定子。因此,修飾語「單株」係指如獲自抗體之大體上均質群體之抗體之特性,且不應視為需要以任何特定方法產生該抗體。例如,根據本發明待使用之單株抗體可藉由各種技術製得,包括(但不限於)融合瘤方法、重組DNA方法、噬菌體顯示方法及利用含有所有或部分之人類免疫球蛋白基因座之基因轉殖動物之方法,本文正描述用於製備單株抗體之此等方法及其他例示性方法。
「裸抗體」係指未結合至異源性部分(例如,細胞毒性部分)或放射性同位素標記之抗體。裸抗體可存在於醫藥調配物中。
「天然抗體」係指具有變化結構之天然生成之免疫球蛋白分子。例如,天然IgG抗體係約150,000道爾頓之異四聚醣蛋白,其係由以二硫化物鍵聯之兩條相同輕鏈及兩條相同重鏈組成。自N端至C端,各重鏈具有可變區(VH)(亦稱為可變重域或重鏈可變域),接著具有三個恆定域(CH1、CH2及CH3),藉此在第一與第二恆定域間放置鉸鏈區。同樣地,自N端至C端,各輕鏈具有可變區(VL)(亦稱為可變輕域或輕鏈可變域),接著具有恆定輕(CL)域。抗體之輕鏈基於其恆定域之胺基酸序列可分配兩種類型(稱為kappa (κ)及lambda (λ))中之一者。
術語「包裝插頁」用以係指通常包括於治療產品之商業包裝中之使用說明,其等含有關於適應症、使用方法、劑量、投與、組合療法、禁忌及/或涉及使用此等治療產品之警告之資訊。
相對於參考多肽序列之「百分率(%)胺基酸序列一致性」定義為在比對序列並引入間隔(若有必要)後得到最大百分率序列一致性,及未考慮任何保守取代為序列一致性之一部分時,候選者序列中胺基酸殘基與參考多肽序列中之胺基酸殘基相同之百分率。出於測定百分率胺基酸序列一致性之目的之比對可以熟悉此項技術者已知的各種方式達成,例如,使用公開可用之電腦軟體(諸如BLAST、BLAST-2、ALIGN或Megalign (DNASTAR)軟體)。熟習此項技術者可決定用於比對序列之適當參數,其等包括在比較中之序列之全長上達成最大比對所需之任何演算法。出於本文之目的,然而,使用序列比較電腦程式ALIGN-2產生%胺基酸序列一致性值。該ALIGN-2序列比較電腦程式由Genentech, Inc.授權,且源代碼已與用戶文檔一起於U.S. Copyright Office, Washington D.C., 20559提出申請,其中其以U.S. Copyright Registration No. TXU510087註冊。該ALIGN-2程式係公開獲得自Genentech, Inc., South San Francisco, California或可編譯自源代碼。該ALIGN-2程式應經編譯以於UNIX操作系統(包括數位UNIX V4.0D)上使用。所有序列比較參數由ALIGN-2程式設定且請勿變更。
在其中採用ALIGN-2以比較胺基酸序列之情況下,給定胺基酸序列A相對於給定胺基酸序列B之%胺基酸序列一致性(或者,可表述為相對於給定胺基酸序列B具有或包含一定%胺基酸序列一致性之給定胺基酸序列A)係如下計算:
100乘以分數X/Y
其中X係藉由序列比對程式ALIGN-2於A及B之程式之比對中評為相同匹配之胺基酸殘基之數量,且其中Y係B中之胺基酸殘基之總數。將瞭解在胺基酸序列A之長度不等於胺基酸序列B之長度時,A對B之%胺基酸序列一致性將不等於B對A之%胺基酸序列一致性。除非另有明確說明,否則本文使用之所有%胺基酸序列一致性值可如前一段落中描述使用ALIGN-2電腦程式獲得。
術語「醫藥調配物」係指一種製劑,此製劑所呈現的形式是使活性成分之生物活性具有效性的,且該製劑不含有對欲將該組合物投與之個體具有不可接受之毒性的額外組分。
「醫藥上可接受之載劑」係指醫藥調配物中除活性成分以外之對個體無毒的成分。醫藥上可接受之載劑包括(但不限於)緩衝劑、賦形劑、穩定劑或防腐劑。
如本文使用,「治療(treatment)」 (及其語法變化,諸如「治療(treat)」或「治療(treating)」)係指嘗試改變治療中之個體之自然病程之臨床干預,且可針對預防或在臨床病理病程期間進行。所需之治療效果包括(但不限於)防止疾病之發生或復發;緩解症狀;減小該疾病之任何直接或間接病理學後果;防止轉移;減小疾病進展之速率;改善或減輕疾病狀態;及緩和或提高預後。在一些實施例中,如本文報告之抗體係用以延遲疾病之發展或減緩疾病之進展。
術語「可變區」或「可變域」係指抗體重鏈或輕鏈中涉及將該抗體結合至抗原之結構域。天然抗體之重鏈及輕鏈之可變域(分別係VH及VL)通常具有相似結構,且各域包含四個保守框架區(FR)及三個高度可變區(HVR) (參見,例如,Kindt, T.J.等人,Kuby Immunology,第6版,W.H. Freeman and Co., N.Y. (2007),第91頁)。單一VH或VL域可足以賦予抗原結合特異性。此外,結合特定抗原之抗體可使用來自結合該抗原之VH或VL域以分別篩選互補VL或VH域之庫進行分離(參見,例如,Portolano, S.等人,J. Immunol. 150 (1993) 880-887;Clackson, T.等人,Nature 352 (1991) 624-628)。
如本文使用,術語「載體」係指核酸分子,該核酸分子可傳播連接至其之另一核酸。該術語包括呈自我複製核酸結構之載體及併入宿主細胞(該宿主細胞中已引入該載體)之基因體內之載體。某些載體可引導其等操作連接之核酸之表現。本文中亦將此等載體稱為「表現載體」。
如本文用於輔助治療之術語「免疫抑制劑」係指作用在於抑制或掩蔽本文之治療中之哺乳動物之免疫系統。此將包括抑制細胞介素產生;下調或抑制自體抗原表現或掩蔽MHC抗原之物質。此等免疫抑制劑之實例包括經2-胺基-6-芳基-5-取代之嘧啶(參見US 4,665,077);硫唑嘌呤;環磷醯胺;溴麥角隱亭(bromocryptine);達那唑(danazol);二胺苯碸(dapsone);戊二醛(其掩蔽MHC抗原,如描述於US 4,120,649中);用於MHC抗原及MHC片段之抗-遺傳抗體;環孢黴素A(cyclosporin A);類固醇,諸如糖皮質類固醇(glucocorticosteroid),例如,普賴鬆(prednisone)、甲基普賴蘇穠(methylprednisolone)及地塞米松(dexamethasone);細胞介素或細胞介素受體拮抗劑,其等包括抗-干擾素-γ、-β或-α抗體、抗-腫瘤壞死因子-α抗體、抗-腫瘤壞死因子-β抗體、抗-介白素-2抗體及抗-IL-2受體抗體;抗-LFA-1抗體,其等包括抗-CD11a及抗-CD18抗體;抗-L3T4抗體;異源性抗-淋巴球球蛋白;泛-T抗體,較佳抗-CD3或抗-CD4/CD4a抗體;含有LFA-3結合域之可溶性肽(WO 90/08187);鏈球菌激酶;TGF-β;鏈球菌去氧核糖核酸酶;來自宿主之RNA或DNA;FK506;RS-61443;去氧精胍菌素;雷帕黴素(rapamycin);T細胞受體(US 5,114,721);T細胞受體片段(Offner等人,Science 251 (1991) 430-432;WO 90/11294;Ianeway, Nature 341 (1989) 482及WO 91/01133);及諸如T10B9之T細胞受體抗體(EP 0,340,109)。
「化學治療劑」係用於治療癌症之化學化合物。化學治療劑之實例包括烷化劑,諸如塞替派(thiotepa)及環磷醯胺(CYTOXAN™);烷基磺酸鹽,諸如硫酸布他卡因(busulfan)、英丙舒凡(improsulfan)及呱泊舒凡(piposulfan);氮丙啶,諸如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替呱(meturedopa)及烏瑞替呱(uredopa);伸乙亞胺及甲基蜜胺,其等包括六甲蜜胺、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫磷醯胺及三羥甲基蜜胺;氮芥,諸如氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、鹽酸氮芥、氮芥鹽酸鹽、美法侖(melphalan)、新氮芥(novembichin)、氮芥膽甾醇(phenesterine)、潑尼莫司汀(prednimustine)、氯乙環磷醯胺、尿嘧啶氮芥;硝基脲,諸如卡莫司汀(carmustine)、氯脲黴素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,諸如阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安曲黴素(authramycin)、偶氮絲胺酸(azaserine)、博萊黴素(bleomycin)、放線菌素c (cactinomycin)、卡奇黴素(calicheamicin)、卡洛比星(carabicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycini)、放線菌素d (dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、蒽環類(marcellomycin)、絲裂黴素類(mitomycin)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、波非羅黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、新製癌菌素(zinostatin)、佐柔比星(zorubicin);抗代謝物,諸如胺甲喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如二甲葉酸(denopterin)、胺甲喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷(azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙脫氧尿苷(dideoxyuridine)、雙脫氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氮尿苷(floxuridine)、5-FU;雄激素,諸如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酪(testolactone);抗雄激素,諸如氨魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸顯影劑,諸如亞葉酸(frolinic acid);乙醯葡萄糖內酯;醛磷醯胺糖苷;胺基乙醯丙酸;安吖啶(amsacrine);貝塔布辛(bestrabucil);比生群(bisantrene);伊達曲仙(edatraxate);德弗法明(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);伊弗尼辛(elfornithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);洛尼達寧(lonidamine);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫吡丹莫(mopidamol);根瘤菌劑(nitracrine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙肼(ethylhydrazide);甲基苄肼(procarbazine);PSK®;雷佐生(razoxane);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);2,2',2''-三氯三乙胺;胺基酸乙酯(urethan);長春地辛(長春地辛(vindesine));達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);呱泊溴烷(pipobroman);瓜西託辛(gacytosine);阿拉伯糖苷(arabinoside) (「Ara-C」);環磷醯胺;塞替派(thiotepa);紫杉烷類化合物(taxoid),例如,紫杉醇(TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.)及多西他賽(doxetaxel) (TAXOTERE®, Rhône-Poulenc Rorer, Antony, France);氯芥苯丁酸(chlorambucil);吉西他濱(gemcitabine);6-硫鳥嘌呤(thioguanine);巰嘌呤;胺甲喋呤;鉑類似物,諸如順鉑(cisplatin)及卡鉑(carboplatin);長春花鹼(vinblastine);鉑;依託泊苷(etoposide) (VP-16);異環磷醯胺(ifosfamide);絲裂黴素C(mitomycin C);米托蒽醌(mitoxantrone);長春新鹼(vincristine);長春瑞濱(vinorelbine);長春瑞濱(navelbine);鹽酸米托蒽醌(novantrone);替尼泊苷(teniposide);柔紅黴素(daunomycin);胺基蝶呤(aminopterin);卡培他濱(xeloda);伊班膦酸鈉(ibandronate);CPT-11;拓撲異構酶(topoisomerase)抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);維甲酸;維甲酸類;卡培他濱(capecitabine);及上文中之任何一者之醫藥上可接受之鹽、酸或衍生物。此定義中亦包括抗激素藥劑,其等作用在於調節或抑制腫瘤上之激素作用,諸如抗雌激素劑,其等包括(例如)他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香酶抑制4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene) (Fareston);及抗雄激素,諸如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);及上文中之任何一者之醫藥上可接受之鹽、酸或衍生物。
II. 組合物及方法在一個態樣中,本發明係部分基於如本文報告之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體具有經改善之性質之發現。在某些實施例中,提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體。如本文報告之抗體係(例如)用於診斷或治療帕金森氏病(Parkinson’s disease)或多發性硬化症。
A.例示性雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體
在一個態樣中,本發明提供結合至人類CD20及人類轉鐵蛋白受體之經分離雙特異性抗體。該等抗體係由(全長)核抗體及其中某些域係經交錯交換之融合Fab片段組成之雙特異性抗體。因此,所得之雙特異性抗體係非對稱的。因此,該等雙特異性抗體係使用具有所謂之節突變(HC節)之第一重鏈及具有所謂之孔突變(HC孔)之第二重鏈使用稱為節至孔中(knob-into-hole)之異源二聚化技術產生。
抗體0039(其亦係本發明之一態樣)係由具有SEQ ID NO: 06至09之胺基酸序列之四個多肽組成。
抗體0039係雙特異性抗體,其包含
a)一種全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至該全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中該等全長抗體輕鏈之各者包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中該等全長抗體重鏈之各者包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使輕鏈可變域(VL)及重鏈可變域(VH)彼此置換,及
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
抗體0041(其亦係本發明之一態樣)係由具有SEQ ID NO: 01至03及SEQ ID NO: 10之胺基酸序列之四個多肽組成。
抗體0041係雙特異性抗體,其包含
a)一種全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各全長抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各全長抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,及
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
抗體0040(其亦係本發明之一態樣)係由具有SEQ ID NO: 11至13及SEQ ID NO: 22之胺基酸序列之三個多肽組成。
抗體0040係雙特異性抗體,其包含
a)一種之全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,及
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
抗體0042(其亦係本發明之一態樣)係由具有SEQ ID NO: 14至17之胺基酸序列之四個多肽組成。
抗體0042係雙特異性抗體,其包含
a)衍生自特異性結合至第一抗原之第一抗體之第一輕鏈及第一重鏈;及
b)衍生自特異性結合至第二抗原之第二抗體之第二輕鏈及第二重鏈,其中
在第二輕鏈中,恆定域CL係經第二重鏈之恆定域CH1置換;及
在第二重鏈中,恆定域CH1係經第二輕鏈之恆定域CL置換;及
i)其中在第一輕鏈之恆定域CL中,位置124及123 (根據Kabat編號)處之胺基酸係彼此獨立地經選自K、R及H之胺基酸取代;及其中在第一重鏈之恆定域CH1中,位置147及213 (根據Kabat之EU索引編號)處之胺基酸係彼此獨立地經選自E或D之胺基酸取代;或
ii)其中在第二重鏈之恆定域CL中,位置124及123 (根據Kabat編號)處之胺基酸係彼此獨立地經選自K、R及H之胺基酸取代;及其中在第二輕鏈之恆定域CH1中,位置147及213 (根據Kabat之EU索引編號)處之胺基酸係彼此獨立地經選自E或D之胺基酸取代。
如本文報告之雙特異性抗體已藉由於CHO細胞的瞬態表現獲得。產率係顯示於下表中。
個別多肽於不同表現質體上之不同分配/組合及所得質體之不同比率已用於雙特異性抗體之重組產生。HEK 293細胞中獲得之結果係呈現於下表中。
雙特異性抗體已小規模產生於CHO細胞中及副產物分佈已在使用蛋白A親和性層析術之第一純化步驟及在使用製備型粒徑排阻層析術之第二純化步驟後經分析。結果係呈現於下表中。
雙特異性抗體已產生於不同細胞系中。結果係顯示於下表中。
用於抗體0039、0040、0041及0042之聚集溫度經測定分別係約54至56℃;約50至53℃;約51至53℃及約55至57℃。
整體上,抗體0041顯示經改善之性質及因此係本發明之較佳態樣。該等經改善之性質尤其在於經改善之副產物概況。
如本文報告之一個態樣係雙特異性抗體,其包含
a)一種全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各全長抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各全長抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213處之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,及
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體。
如本文報告之一個態樣係雙特異性抗體,其包含
a)一種之全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各全長抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各全長抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體,
其中該人類CD20結合位點包含與SEQ ID NO: 18之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性之重鏈可變域(VH)序列及與EQ ID NO: 19之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性之輕鏈可變域(VL)序列,及
其中該人類轉鐵蛋白受體結合位點包含與SEQ ID NO: 20之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性之重鏈可變域(VH)序列及與SEQ ID NO: 21之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性之輕鏈可變域(VL)序列。
在某些實施例中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性之VH序列相對於參考序列含有取代(例如,保守取代)、嵌入或刪除,但包含該序列之結合位點保留結合至其抗原之能力。在某些實施例中,SEQ ID NO: 18或20中總計1至10個胺基酸已經取代、嵌入及/或刪除。在某些實施例中,取代、嵌入或刪除出現於HVR外之區域內(即,於FR中)。
在某些實施例中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性之VL序列相對於參考序列含有取代(例如,保守取代)、嵌入或刪除,但包含該序列之結合位點保留結合至其抗原之能力。在某些實施例中,SEQ ID NO: 19或21中總計1至10個胺基酸已經取代、嵌入及/或刪除。在某些實施例中,取代、嵌入或刪除出現於HVR外之區域內(即,於FR中)。
在一個實施例中,該人類CD20結合位點包含SEQ ID NO: 18中之VH序列(包括該序列之轉譯後修飾)及SEQ ID NO: 19中之VL序列(包括該序列之轉譯後修飾)。
在一個實施例中,該人類轉鐵蛋白受體結合位點包含SEQ ID NO: 20中之VH序列(包括該序列之轉譯後修飾)及SEQ ID NO: 21中之VL序列(包括該序列之轉譯後修飾)。
在一個實施例中,該雙特異性抗體包含
i)與SEQ ID NO: 01具有至少70%、至少80%、至少90%或95%或以上之序列同一性之輕鏈,
ii)與SEQ ID NO: 02具有至少70%、至少80%、至少90%或95%或以上之序列同一性之重鏈,
iii)與SEQ ID NO: 03具有至少70%、至少80%、至少90%或95%或以上之序列同一性之輕鏈,及
iv)與SEQ ID NO: 04具有至少70%、至少80%、至少90%或95%或以上之序列同一性之重鏈Fab片段,
其中
SEQ ID NO: 01具有胺基酸序列DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,
SEQ ID NO: 02具有胺基酸序列QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG,
SEQ ID NO: 03具有胺基酸序列AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC,及
SEQ ID NO: 04具有胺基酸序列QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
如本文報告之一個態樣係雙特異性抗體,其包含
a)一種之全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各全長抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及於位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各全長抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體,
其中該人類CD20結合位點包含具有SEQ ID NO: 18之胺基酸序列之重鏈可變域(VH)及具有SEQ ID NO: 19之胺基酸序列之輕鏈可變域(VL),及
其中該人類轉鐵蛋白受體結合位點包含具有SEQ ID NO: 20之胺基酸序列之重鏈可變域(VH)及具有SEQ ID NO: 21之胺基酸序列之輕鏈可變域(VL)。
如本文報告之一個態樣係雙特異性抗體,其包含
a)一種全長抗體,其包含兩對全長抗體輕鏈及全長抗體重鏈之,其中由各對全長重鏈及全長輕鏈所形成之結合位點特異性結合至第一抗原,其中該全長抗體包含由兩個全長重鏈之Fc區多肽形成之Fc區,各包含CH1、CH2及CH3域,及
b)另一Fab片段,其中該另一Fab片段係融合至全長抗體其中之一重鏈之C端,其中該另一Fab片段之結合位點特異性結合至第二抗原,
其中各全長抗體輕鏈包含在恆定輕鏈域(CL)中位置123之胺基酸殘基精胺酸(而非野生型麩胺酸殘基;E123R突變)及位置124之胺基酸殘基離胺酸(而非野生型麩醯胺酸殘基;Q124K突變) (根據Kabat編號),
其中各全長抗體重鏈包含在第一恆定重鏈域(CH1)中位置147之麩胺酸殘基(而非野生型離胺酸殘基;K147E突變)及位置213之麩胺酸殘基(而非野生型離胺酸胺基酸殘基;K213E突變) (根據Kabat EU索引編號),
其中特異性結合至第二抗原之另一Fab片段包含域交轉,致使恆定輕鏈域(CL)及恆定重鏈域1 (CH1)彼此置換,
其中該第一抗原係人類CD20及該第二抗原係人類轉鐵蛋白受體,
其中該人類CD20結合位點包含具有SEQ ID NO: 18之胺基酸序列之重鏈可變域(VH)及具有SEQ ID NO: 19之胺基酸序列之輕鏈可變域(VL),
其中該人類轉鐵蛋白受體結合位點包含具有SEQ ID NO: 20之胺基酸序列之重鏈可變域(VH)及具有SEQ ID NO: 21之胺基酸序列之輕鏈可變域(VL),及
其中該等Fc區多肽係
a)屬於人類亞類IgG1,
b)屬於人類亞類IgG4,
c)屬於具有突變L234A、L235A及P329G之人類亞類IgG1,
d)屬於具有突變S228P、L235E及P329G之人類亞類IgG4,
e)屬於在兩個Fc區多肽中均具有突變L234A、L235A及P329G及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,
f)屬於在兩個Fc區多肽中均具有突變S228P及P329G及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG4,
g)屬於在兩個Fc區多肽中均具有突變L234A、L235A、P329G、I253A、H310A及H435A及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,或
h)屬於在兩個Fc區多肽中均具有突變L234A、L235A、P329G、M252Y、S254T及T256E及在一個Fc區多肽中具有突變T366W及S354C及在各自另一Fc區多肽中具有突變T366S、L368A、Y407V及Y349C之人類亞類IgG1,或
i)在兩條重鏈中均具有突變L234A、L235A、P329G、H310A、H433A及Y436A及在一條重鏈中具有突變i) T366W及ii) S354C或Y349C及在另一重鏈中具有突變i) T366S、L368A及Y407V及ii) Y349C或S354C之人類亞類IgG1之全長抗體。
在另一態樣中,根據上文實施例中之任何一者之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體可單獨或組合合併如下文章節1至3中描述之特徵中之任何一者:
1.嵌合抗體及人類化抗體
在某些實施例中,本文提供之抗體係嵌合抗體。某些嵌合抗體描述(例如)於US 4,816,567;及Morrison, S.L.等人,Proc. Natl. Acad. Sci. USA 81 (1984) 6851-6855)中。在一個實例中,嵌合抗體包含非人類可變區(例如,衍生自小鼠、大鼠、倉鼠、兔或非人類靈長類動物(諸如猴)之可變區)及人類恆定區。在另一實例中,嵌合抗體係「類別轉換之」抗體,其中該類別或亞類已變化自親代抗體之類別或亞類。嵌合抗體包括其抗原結合片段。
在某些實施例中,嵌合抗體係人類化抗體。通常,非人類抗體係經人類化以減小對人類之免疫原性,同時保留親代非人類抗體之特異性及親和性。通常,人類化抗體包含一或更多個可變域,其中HVR(例如,CDR或其部分)係衍生自非人類抗體,且FR (或其部分)係衍生自人類抗體序列。人類化抗體視需要將亦包含人類恆定區之至少一部分。在一些實施例中,人類化抗體中之一些FR殘基係經來自非人類抗體(例如,其中衍生HVR殘基之抗體)之相應殘基取代以(例如)恢復或改善抗體特異性或親和性。
人類化抗體及其製法回顧(例如)於Almagro, J.C.及Fransson, J., Front. Biosci. 13 (2008) 1619-1633中,且進一步描述(例如)於Riechmann, I.等人,Nature 332 (1988) 323-329;Queen, C.等人,Proc. Natl. Acad. Sci. USA 86 (1989) 10029-10033;US 5,821,337、US 7,527,791、US 6,982,321及US 7,087,409;Kashmiri, S.V.等人,Methods 36 (2005) 25-34 (描述特異性決定區(SDR)移植);Padlan, E.A., Mol. Immunol. 28 (1991) 489-498 (描述「重整」);Dall’Acqua, W.F.等人,Methods 36 (2005) 43-60(描述「FR穿梭」);及Osbourn, J.等人,Methods 36 (2005) 61-68及Klimka, A.等人,Br. J. Cancer 83 (2000) 252-260 (描述以FR穿梭之「導向選擇」方法)中。
可用於人類化之人類框架區包括(但不限於):使用「最佳擬合」方法選擇之框架區(參見,例如,Sims, M.J.等人,J. Immunol. 151 (1993) 2296-2308;衍生自特定子組之人類抗體之輕鏈或重鏈可變區之共同序列之框架區(參見,例如,Carter, P.等人,Proc. Natl. Acad. Sci. USA 89 (1992) 4285-4289;及Presta, L.G.等人,J. Immunol. 151 (1993) 2623-2632);人類成熟(經體細胞突變)之框架區或人類生殖系列框架區(參見,例如,Almagro, J.C.及Fransson, J., Front. Biosci. 13 (2008) 1619-1633);及衍生自篩選FR庫之框架區(參見,例如,Baca, M.等人,J. Biol. Chem. 272 (1997) 10678-10684及Rosok, M.J.等人,J. Biol. Chem. 271 (19969 22611-22618)。
2.人類抗體
在某些實施例中,本文提供之抗體係人類抗體。人類抗體可使用此項技術中已知的各種技術產生。人類抗體係通常描述於van Dijk, M.A.及van de Winkel, J.G., Curr. Opin. Pharmacol. 5 (2001) 368-374及Lonberg, N., Curr. Opin. Immunol. 20 (2008) 450-459中。
人類抗體可藉由向已經修飾以對抗原激發作出反應而產生具有人類可變區之完整人類抗體或完整抗體之轉基因動物投與免疫原來製備。此等動物通常含有人類免疫球蛋白基因座之所有或部分,其等置換內源性免疫球蛋白基因座,或其等係染色體外存在或隨機整合至動物之染色體內。在此等轉基因小鼠中,該等內源性免疫球蛋白基因座已通常失活。為回顧用於自轉基因動物獲得人類抗體之方法,參見Lonberg, N., Nat. Biotech. 23 (2005) 1117-1125。亦參見例如描述XENOMOUSE
TM技術之US 6,075,181及US 6,150,584;描述HUMAB®技術之US 5,770,429;描述K-M MOUSE®技術之US 7,041,870;及描述VELOCIMOUSE®技術之US 2007/0061900。來自由此等動物產生之完整抗體之人類可變區可經進一步修飾,例如,藉由組合不同人類恆定區。
人類抗體亦可藉由基於融合瘤之方法來製造。已描述用於產生人類單株抗體之人類骨髓瘤及小鼠-人類異源骨髓瘤細胞系。(參見,例如,Kozbor, D.,J. Immunol. 133 (1984) 3001-3005;Brodeur, B.R.等人,Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York (1987),第51至63頁;及Boerner, P.等人,J. Immunol. 147 (1991) 86-95)。經由人類B細胞融合瘤技術所產生之人類抗體係亦描述於Li, J.等人, Proc. Natl. Acad. Sci. USA103 (2006) 3557-3562中。額外方法包括彼等描述(例如)於US 7,189,826 (描述自融合瘤細胞系產生單株人類IgM抗體)及Ni, J., Xiandai Mianyixue 26 (2006) 265-268 (描述人類-人類融合瘤)中者。人類融合瘤技術(Trioma技術)係亦描述於Vollmers, H.P.及Brandlein, S., Histology and Histopathology 20 (2005) 927-937及Vollmers, H.P.及Brandlein, S., Methods and Findings in Experimental and Clinical Pharmacology 27 (2005) 185-191中。
人類抗體亦可藉由分離選自人類衍生之噬菌體顯示庫之Fv純系可變域序列來產生。此等可變域序列可然後與所需人類恆定域組合。
3.抗體變體
在某些實施例中,預期如本文提供之雙特異性抗體之胺基酸序列變體。例如,可能需要改善抗體之結合親和性及/或其他生物性質。抗體之胺基酸序列變體可藉由將適當之修飾引入編碼該抗體之核苷酸序列內或藉由肽合成製得。此等修飾包括(例如)於該抗體之胺基酸序列內之殘基之刪除及/或嵌入及/或取代。可作出刪除、嵌入及取代之任何組合以達成最終構築體,只要該最終構築體具有所需之特性(例如,抗原結合特性)即可。
a)取代、嵌入及刪除變體
在某些實施例中,提供具有一或更多個胺基酸取代之抗體變體。用於取代突變形成之所感興趣位點包括HVR及FR。保守取代係以「較佳取代」之標題顯示於下表中。更實質性之變化係以「例示性取代」之標題提供於表1中,且如參考胺基酸側鏈類別進一步描述於下文中。可將胺基酸取代引入所感興趣抗體內並針對所需活性(例如,保留/改善之抗原結合、減小之免疫原性或改善之ADCC或CDC)篩選產物。
表
胺基酸可根據常見側鏈性質進行分組:
(1)疏水性:正白胺酸、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)鹼性:His、Lys、Arg;
(5)影響鏈位向之殘基:Gly、Pro;
(6)芳香性:Trp、Tyr、Phe。
非保守取代將涉及將此等類別中之一者之成員交換為另一類別。
取代變體之一種類型涉及取代親代抗體(例如,人類化或人類抗體)之一或更多個高度可變區殘基。通常,經選擇用於進一步研究之所得變體相對於親代抗體將於某些生物性質(例如,增強之親和性、減小之免疫原性)方面具有修飾(例如,改善)及/或將具有親代抗體之大體上經保留之某些生物性質。例示性取代變體係親和性成熟抗體,其可合宜地(例如)使用基於噬菌體顯示之親和性成熟技術(諸如彼等本文描述者)來產生。簡而言之,一或更多個HVR殘基係經突變且該等變體抗顯示於噬菌體上體並針對特定生物活性(例如,結合親和性)進行篩選。
可於HVR中作出改變(例如,取代)(例如)以改善抗體親和性。可於HVR 「熱點」(即,由在體細胞突變過程期間經受高頻突變之密碼子編碼之殘基(參見,例如,Chowdhury, P.S.,Methods Mol. Biol. 207 (2008) 179-196))及/或接觸抗原之殘基中作出此等改變,且測試所得變體VH或VL之殘基之結合親和性。藉由構築且再選擇自輔助庫(secondary library)之親和性成熟已描述(例如)於Hoogenboom, H.R.等人之 Methods in Molecular Biology 178 (2002) 1-37中。在親和性成熟之一些實施例中,藉由各種方法(例如,易錯PCR、鏈混組或寡核苷酸定向誘變)中之任何一者將多樣性引入針對成熟選擇之可變基因內。然後建立輔助庫。然後篩選該庫以識別具有所需親和性之任何抗體變體。引入多樣性之另一方法涉及由HVR定向之方法,其中隨機化若干HVR殘基(例如,每次4至6個殘基)。涉及抗原結合之HVR殘基可(例如)使用丙胺酸掃描誘變或建模來特定識別。特定言之,通常將CDR-H3及CDR-L3作為目標。
在某些實施例中,取代、嵌入或刪除可發生於一或更多個HVR內,只要此等改變不大體上減小抗體結合抗原之能力即可。例如,可於HVR中作出不大體上減小結合親和性之保守改變(例如,如本文提供之保守取代)。此等改變可(例如)在於HVR中接觸抗原之殘基之外部。在上文提供之變體VH及VL序列之某些實施例中,各HVR未經改變或含有不超過一、二或三個胺基酸取代。
適用於識別抗體之可經靶向以誘變之殘基或區域之方法稱為「丙胺酸掃描誘變」,如由Cunningham, B.C.及Wells, J.A.,Science 244 (1989) 1081-1085描述。在此方法中,殘基或目標殘基(例如,帶電殘基,諸如arg、asp、his、lys及glu)之群經識別且經中性或帶負電之胺基酸(例如,丙胺酸或聚丙胺酸)置換以判定抗體與抗原之相互作用是否受影響。可於該等胺基酸位置處引入證實對初始取代功能敏感之其他取代。或者或另外,抗原-抗體複合體之晶體結構識別抗體與抗原間之接觸點。可將此等接觸殘基及相鄰殘基作為目標或作為用於取代之候選者進行消除。變體可經篩選以判定其等是否含有所需之性質。
胺基酸序列嵌入包括長度介於一個殘基至含有一百或更多個殘基之多肽之範圍內之胺基端及/或羧基端融合,及單一或多個胺基酸殘基之序列內嵌入。端嵌入之實例包括具有N端甲硫胺醯基殘基之抗體。抗體分子之其他嵌入變體包括將抗體之N端或C端融合至酶(例如,針對ADEPT)或增加抗體之血清半衰期之多肽。
b)醣化變體
在某些實施例中,如本文提供之雙特異性抗體係經改變以增大或減小該抗體之醣化程度。藉由改變胺基酸序列使得建立或移除一或更多個醣化位點可便利地完成抗體之醣化位點之添加或刪除。
在抗體包含Fc區之情況下,連接至該抗體之碳水化合物可經改變。由哺乳動物細胞產生之天然抗體通常包含分支、雙觸寡醣,其通常藉由N鍵聯連接至Fc區之CH2域之Asn297。參見,例如,Wright, A.及Morrison, S.L.,TIBTECH 15 (1997) 26-32。該寡醣可包括各種碳水化合物,例如,甘露糖、N-乙醯基葡萄胺糖(GlcNAc)、半乳糖及唾液酸,及連接至雙觸寡醣結構之「主幹」中之GlcNAc之海藻糖。在一些實施例中,可對如本文報告之抗體中之寡醣作出修飾以產生具有某些經改善之性質之抗體變體。
在一個實施例中,提供具有缺乏(直接或間接)連接至Fc區之海藻糖之碳水化合物結構之抗體變體。例如,此抗體中海藻糖之量可為1%至80%,1%至65%,5%至65%,或20%至40%。例如,海藻糖之量係藉由計算相對於如MALDI-TOF質譜儀測得之連接至Asn 297之所有醣結構(例如複合體、雜合體及高甘露糖結構)之總數,在Asn297之糖鏈內海藻糖之平均量而測定,如WO 2008/077546中所描述。Asn297係指在Fc區中位於約位置297 (Fc區殘基之EU編號)之天冬醯胺酸殘基;然而,Asn297亦可因抗體中之微小序列變化而位於位置297之約± 3個胺基酸上游或下游,即在位置294與300間。此等海藻糖化變體可具有改善之ADCC功能。參見例如US 2003/ 0157108;US 2004/0093621。關於「去海藻糖化」或「海藻糖缺乏」抗體變體之公開案之實例包括:US 2003/0157108;WO 2000/61739;WO 2001/ 29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/ 0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO 2005/053742;WO 2002/031140;Okazaki, A.等人,J. Mol. Biol. 336 (2004) 1239-1249;Yamane-Ohnuki, N.等人,Biotech. Bioeng. 87 (2004) 614-622。可產生去海藻糖化抗體之細胞系之實例包括缺乏蛋白質海藻糖化之Lec13 CHO細胞(Ripka, J.等人,Arch. Biochem. Biophys.249 (1986) 533-545;US 2003/0157108;及WO 2004/056312,尤其於實例11),及基因剔除(knockout)細胞系,諸如α-1,6-海藻糖基轉移酶基因FUT8基因剔除CHO細胞(參見例如Yamane-Ohnuki, N.等人,Biotech. Bioeng. 87 (2004) 614-622;Kanda, Y.等人,Biotechnol. Bioeng. 94 (2006) 680-688;及WO 2003/085107)。
進一步提供具有平分型(bisected)寡醣之抗體變體,例如,其中連接至抗體之Fc區之雙觸(biantennary)寡醣係由GlcNAc平分。此等抗體變體可具有減少之海藻糖化及/或改善之ADCC功能。此等抗體變體之實例描述於例如WO 2003/011878;US 6,602,684;及US 2005/0123546中。亦提供具有至少一個半乳糖殘基在連接至Fc區之寡醣中之抗體變體。此等抗體變體可具有改善之CDC功能。此等抗體變體描述於例如WO 1997/30087;WO 1998/58964及WO 1999/22764中。
c) Fc區變體
在某些實施例中,可將一或更多種胺基酸修飾引入如本文提供之雙特異性抗體之Fc區內,藉此產生Fc區變體。該Fc區變體可包含人類Fc區序列(例如,人類IgG1、IgG2、IgG3或IgG4 Fc區),該序列在一或更多個胺基酸位置處包含胺基酸修飾(例如,取代)。
在某些實施例中,本文預期具有一些但非所有效應子功能之抗體變體,該等效應子功能使該抗體變體成為其中該抗體活體內之半衰期係重要的應用所需之候選者,然而某些效應子功能(諸如互補及ADCC)係非必要的或有害的。可進行活體外及/或活體內細胞毒性分析以證實CDC及/或ADCC活性之減小/損耗。例如,可進行Fc受體(FcR)結合分析以確保該抗體缺乏FcγR結合(因此,很可能缺乏ADCC活性),但保留FcRn結合能力。用於調節ADCC之原代細胞(NK細胞)僅表現Fc(RIII,而單核細胞表現FcγRI、FcγRII及FcγRIII。造血細胞上之FcR表現匯總於Ravetch, J.V.及Kinet, J.P., Annu. Rev. Immunol. 9 (1991) 457-492之第464頁上之表3中。活體外分析以評定所感興趣分子之ADCC活性之非限制性實例描述於US 5,500,362 (參見,例如,Hellstrom, I.等人,Proc. Natl. Acad. Sci. USA 83 (1986) 7059-7063;及Hellstrom, I.等人,Proc. Natl. Acad. Sci. USA 82 (1985) 1499-1502);US 5,821,337 (參見Bruggemann, M.等人,J. Exp. Med. 166 (1987) 1351-1361)中。或者,可採用非放射性分析方法,參見例如用於流動式細胞測量術之ACTI™非放射性細胞毒性分析(CellTechnology, Inc. Mountain View, CA);及CytoTox 96
®非放射性細胞毒性分析(Promega, Madison, WI)。適用於此等分析之效應子細胞包括周邊血液單核細胞(PBMC)及自然殺手(NK)細胞。或者或另外,所感興趣分子之ADCC活性可活體內例如於動物模型(諸如揭示於Clynes, R.等人,Proc. Natl. Acad. Sci. USA 95 (1998) 652-656中之動物模型)來評估。亦可進行C1q結合分析以證實抗體無法結合C1q且因此缺乏CDC活性。參見,例如,WO 2006/029879及WO 2005/100402中之C1q及C3c結合ELISA。為評定互補活化,可進行CDC分析(參見,例如,Gazzano-Santoro, H.等人,J. Immunol. Methods 202 (1996) 163-171;Cragg, M.S.等人,Blood 101 (2003) 1045-1052;及Cragg, M.S.及M.J. Glennie, Blood 103 (2004) 2738-2743)。FcRn結合及活體內廓清率/半衰期測定亦可使用此項技術中已知的方法來進行(參見,例如,Petkova, S.B.等人,Int. Immunol. 18 (2006: 1759-1769)。
具有減少之效應子功能之抗體包括彼等具有Fc區殘基238、265、269、270、297、327及329 (US 6,737,056)中之一或更多者之取代。此等Fc突變體包括在胺基酸位置265、269、270、297及327中之兩個或更多者處具有取代之Fc突變體,其等包括殘基265及297取代為丙胺酸之所謂之「DANA」 Fc突變體(US 7,332,581)。
描述某些具有改善或減少之結合至FcR之抗體變體(參見,例如,US 6,737,056;WO 2004/056312及Shields, R.L.等人,J. Biol. Chem. 276 (2001) 6591-6604)。
在某些實施例中,抗體變體包含具有一或更多個改善ADCC之胺基酸取代,例如,於Fc區之位置298、333及/或334處之取代(殘基之EU編號))之Fc區。
在一些實施例中,在Fc區中作出導致改變之(即,改善或減少之) C1q結合及/或互補依賴性細胞毒性(CDC)之改變,例如,如描述於US 6,194,551、WO 99/51642及Idusogie, E.E.等人,J. Immunol. 164 (2000) 4178-4184中。
具有增加之半衰期及改善之與負責將母體IgG轉移至胎兒之結合(Guyer, R.L.等人,J. Immunol. 117 (1976) 587-593及Kim, J.K.等人,J. Immunol. 24 (1994) 2429-2434)之新生Fc受體(FcRn)之抗體描述於US2005/0014934中。彼等抗體包含其中具有一或更多個取代之Fc區,該等取代改善Fc區對FcRn之結合。此等Fc變體包括彼等於Fc區殘基中之一或更多者處具有取代者:238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434,例如,Fc區殘基434之取代(US 7,371,826)。
亦參見涉及Fc區變體之其他實例之Duncan, A.R.及Winter, G., Nature 322 (1988) 738-740;US 5,648,260;US 5,624,821及WO 94/29351。
d)經半胱胺酸改造之抗體變體
在某些實施例中,可能需要產生經半胱胺酸改造之抗體例如「硫MAb (thioMAb)」,其中抗體之一或更多個殘基係經半胱胺酸殘基取代。在特定實施例中,該等經取代之殘基出現於該抗體之可接近位點。如本文進一步描述,藉由以半胱胺酸取代彼等殘基,反應性硫醇基藉此放置於該抗體之可接近位點且可用以將該抗體結合至其他部分諸如藥物部分或連接子-藥物部分,以產生免疫結合物。在某些實施例中,下列殘基中之任何一者或更多者可經半胱胺酸取代:輕鏈之V205 (Kabat編號);重鏈之A118 (EU編號);及重鏈Fc區之S400 (EU編號)。可產生經半胱胺酸改造之抗體,如描述(例如)於US 7,521,541中。
e)抗體衍生物
在某些實施例中,如本文提供之雙特異性抗體可經進一步修飾以含有此項技術中已知且易於獲得之額外非蛋白質部分。適用於抗體之衍生化之部分包括(但不限於)水溶性聚合物。水溶性聚合物之非限制性實例包括(但不限於)聚乙二醇(PEG)、乙二醇/丙二醇之共聚物、羧甲基纖維素、聚葡萄糖、聚乙烯醇、聚乙烯吡咯啶酮、聚-1,3-二氧戊環、聚-1,3,6-三噁烷、乙烯/順丁烯二酸酐共聚物、聚胺基酸(均聚物或無規共聚物)及聚葡萄糖或聚(n-乙烯基吡咯啶酮)聚乙二醇、聚丙二醇均聚物、聚環氧丙烷/環氧乙烷共聚物、聚氧乙基化多元醇(例如,甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛因其於水中之穩定性而在製造中可具有優勢。該聚合物可具有任何分子量,且可為分支鏈或非分支鏈。連接至抗體之聚合物之數量可變化,且若連接超過一個聚合物,則其等可為相同或不同分子。一般而言,用於衍生化之聚合物之數量及/或類型可基於包括(但不限於)以下之考量來決定:抗體欲改善之特定性質或功能;該抗體衍生物是否將在已定義之條件下用於療法中等。
在另一實施例中,提供抗體與可藉由曝露於放射下而經選擇性加熱之非蛋白質部分之結合物。在一個實施例中,該非蛋白質部分係碳奈米管(Kam, N.W.等人,Proc. Natl. Acad. Sci. USA 102 (2005) 11600-11605)。該放射可具有任何波長,且包括(但不限於)不傷害普通細胞但會將該非蛋白質部分加熱至殺死鄰近抗體-非蛋白質部分之細胞之溫度之波長。
B.重組方法及組合物
抗體可使用(例如)如描述於US 4,816,567中之重組方法及組合物產生。在一個實施例中,提供編碼本文描述之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體之經分離核酸。在另一實施例中,提供一或更多種包含此核酸之載體(例如,表現載體)。在另一實施例中,提供包含此核酸之宿主細胞。在一個實施例中,該宿主細胞係真核的,例如,中國倉鼠卵巢(CHO)細胞或類淋巴細胞(例如,Y0、NS0、Sp20細胞)。在一個實施例中,提供製造雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體之方法,其中該方法包括在適用於表現抗體之條件下培養包含編碼如上文提供之抗體之核酸之宿主細胞,及視需要自宿主細胞(或宿主細胞培養基)回收抗體。
就雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體之重組產生而言,分離編碼抗體(例如,如上文描述之抗體)之核酸並嵌入於一或更多個載體內以用於進一步選殖及/或於宿主細胞中表現。此核酸可使用習知程序(例如,藉由使用可特異性結合至編碼抗體之重鏈及輕鏈之基因之寡核苷酸探針)簡單分離及定序。
適用於抗體編碼載體之選殖或表現之宿主細胞包括本文描述之原核細胞或真核細胞。例如,抗體可於細菌中產生,特定言之,當無需醣化及Fc效應子功能時。就於細菌中表現抗體片段及多肽而言,參見,例如,US 5,648,237;US 5,789,199;及US 5,840,523。(亦參見Charlton, K.A., In: Methods in Molecular Biology,第248卷,Lo, B.K.C. (編), Humana Press, Totowa, NJ (2003),第245至254頁,其描述於大腸桿菌中表現抗體片段)。表現後,該抗體可以可溶性部分分離自細菌細胞糊狀物及可經進一步純化。
除原核生物外,真核微生物(諸如絲狀真菌或酵母菌)係適用於抗體編碼載體之選殖或表現宿主,其等包括真菌及酵母菌菌株,其等醣化路徑已經「人類化」,從而導致具有經部分或完全人類醣化模式之抗體之產生。參見Gerngross, T.U., Nat. Biotech. 22 (2004) 1409-1414;及Li, H.等人,Nat. Biotech. 24 (2006) 210-215。
適用於表現醣化抗體之宿主細胞亦衍生自多細胞生物(於脊椎動物及脊椎動物中)。脊椎動物細胞之實例包括植物及昆蟲細胞。許多桿狀病毒菌株已經識別,其等可與昆蟲細胞結合使用,特定言之,用於草地夜蛾細胞之轉染。
亦可使用植物細胞培養物作為宿主細胞。參見,例如,US 5,959,177、US 6,040,498、US 6,420,548、US 7,125,978及US 6,417,429 (其等描述用於在基因轉殖植物中產生抗體之PLANTBODIES
TM技術)。
亦可使用脊椎動物細胞作為宿主細胞。例如,適應於懸浮生長之哺乳動物細胞系可為有用的。有用之哺乳動物宿主細胞系之其他實例係經SV40轉形之猴腎CV1系(COS-7);人類胚胎腎系(如描述(例如)於Graham, F.L.等人,J. Gen Virol. 36 (1977) 59-74中之293或293細胞);幼倉鼠腎細胞(BHK);小鼠塞氏(sertoli)細胞 (如描述(例如)於Mather, J.P., Biol. Reprod. 23 (1980) 243-252中之TM4細胞);猴腎細胞(CV1);非洲綠猴腎細胞(VERO-76);人類宮頸癌細胞(HELA);犬腎細胞(MDCK;水牛大鼠肝細胞(BRL 3A);人類肺細胞(W138);人類肝細胞(Hep G2);小鼠乳房腫瘤(MMT 060562);TRI細胞,如描述(例如)於Mather, J.P.等人,Annals N.Y. Acad. Sci. 383 (1982) 44-68中;MRC 5細胞;及FS4細胞。其他有用之哺乳動物宿主細胞系包括中國倉鼠卵巢(CHO)細胞,其等包括DHFR
-CHO細胞(Urlaub, G.等人,Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220);及骨髓瘤細胞系,諸如Y0、NS0及Sp2/0。為回顧適用於抗體產生之某些哺乳動物宿主細胞系,參見,例如,Yazaki, P.及Wu, A.M., Methods in Molecular Biology,第248卷,Lo, B.K.C. (編),Humana Press, Totowa, NJ (2004),第255至268頁。
C.用於診斷及偵測之方法及組合物
在某些實施例中,本文提供之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體中之任何一者適用於偵測生物樣品中CD20之存在。如本文使用之術語「偵測」包含定量或定性偵測。在某些實施例中,生物樣品包含細胞或組織。
在一個實施例中,提供用於診斷或偵測之方法中之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體。在另一態樣中,提供偵測生物樣品中CD20之存在之方法。在某些實施例中,在某些實施例中,該方法包括使生物樣品與如本文描述之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體在允許該雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體結合至CD20之條件下接觸,及偵測是否於雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體與CD20間形成複合體。此方法可為活體外或活體內方法。
在某些實施例中,提供經標記之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體。標記包括(但不限於)直接偵測之標記或部分(諸如螢光、色基、電子緻密、化學發光及放射性標記)及間接偵測(例如,透過酶反應或分子相互作用)之部分(諸如酶或配位體)。例示性標記包括(但不限於)放射性同位素(
32P、
14C、
125I、
3H及
131I)、螢光團(諸如稀土螯合物或螢光素及其衍生物)、玫瑰紅及其衍生物、丹磺醯基、繖形酮、螢光素酶(例如,螢火蟲螢光素酶及細菌螢光素酶(US 4,737,456))、螢光素、2,3-二氫酞嗪二酮、山葵過氧化酶(HRP)、鹼性磷酸酶、β-半乳糖苷酶、葡萄糖澱粉酶、溶菌酶、醣氧化酶(例如,葡萄糖氧化酶、半乳糖氧化酶及葡萄糖-6-磷酸鹽脫氫酶)、雜環氧化酶(諸如尿酸酶及黃嘌呤氧化酶)與採用過氧化氫以氧化染料前驅物之酶(諸如HRP、乳過氧化酶或微過氧化酶)之偶合、生物素/抗生物素蛋白、自旋標記、細菌噬菌體標記、穩定自由基及類似物。
D.免疫結合物
本發明亦提供包含與一或更多種細胞毒性劑結合之如本文報告之抗-人類CD20/人類轉鐵蛋白受體抗體之免疫結合物,該等細胞毒性劑諸如化學治療劑或藥物、生長抑制劑、毒素(例如,蛋白毒素、細菌、真菌、植物或動物來源之酶活性毒素或其片段)或放射性同位素。
在一個實施例中,免疫結合物係抗體-藥物結合物(ADC),其中雙特異性抗體係與包括(但不限於)以下之一或更多種藥物結合:美登素(maytansinoid) (參見US 5,208,020、US 5,416,064及EP 0 425 235 B1);阿裡他汀(auristatin),諸如單甲基阿裡他汀藥物部分DE及DF (MMAE及MMAF) (參見US 5,635,483、US 5,780,588及US 7,498,298);海兔毒素(dolastatin);卡奇黴素(calicheamicin)或其衍生物(參見US 5,712,374、US 5,714,586、US 5,739,116、US 5,767,285、US 5,770,701、US 5,770,710、US 5,773,001及US 5,877,296;Hinman, L.M.等人,Cancer Res. 53 (1993) 3336-3342;及Lode, H.N.等人,Cancer Res. 58 (1998) 2925-2928);蒽環黴素(anthracycline),諸如道諾黴素(daunomycin)或多柔比星(doxorubicin) (參見Kratz, F.等人,Curr. Med. Chem. 13 (2006) 477-523;Jeffrey, S.C.等人,Bioorg. Med. Chem. Lett. 16 (2006) 358-362;Torgov, M.Y.等人,Bioconjug. Chem. 16 (2005) 717-721;Nagy, A.等人,Proc. Natl. Acad. Sci. USA 97 (2000) 829-834;Dubowchik, G.M.等人,Bioorg. & Med. Chem. Letters 12 (2002) 1529-1532;King, H.D.等人,J. Med. Chem. 45 (20029 4336-4343;及US 6,630,579);胺甲喋呤(methotrexate);長春地辛(vindesine);紫杉烷(taxane),諸如多西他賽(docetaxel)、紫杉烷(paclitaxel)、拉洛他賽(larotaxel)、特西他賽(tesetaxel)及奧他賽(ortataxel);單端孢黴烯(trichothecene);及CC1065。
在另一實施例中,免疫結合物包含與包括(但不限於)以下之酶活性毒素或其片段結合之如本文描述之雙特異性抗體:白喉A鏈、白喉毒素之非結合活性片段、外毒素A鏈(來自綠膿桿菌(Pseudomonas aeruginosa))、蓖麻毒蛋白A鏈、相思子素A鏈、蒴蓮根毒素A鏈、α-八疊球菌、油桐蛋白(Aleurites fordii protein)、香石竹毒蛋白(dianthin protein)、美洲商陸蛋白(Phytolaca americana protein) (PAPI、PAPII,及PAP-S)、苦瓜(momordica charantia)抑制劑、麻風樹毒蛋白(curcin)、巴豆毒蛋白(crotin)、肥皂草(sapaonaria officinalis)抑制劑、白樹毒蛋白(gelonin)、絲林黴素(mitogellin)、局限曲黴素(restrictocin)、酚黴素(phenomycin)、伊諾黴素(enomycin)及單端孢黴烯族化合物(tricothecenes)。參見,例如,1993年10月28日公開之WO 93/21232。
在另一實施例中,免疫結合物包含與放射性原子結合以形成放射性結合物之如本文描述之雙特異性抗體。可獲得各種放射性同位素以用於產生放射性結合物。實例包括At
211、I
131、I
125、Y
90、Re
186、Re
188、Sm
153、Bi
212、P
32、Pb
212及Lu之放射性同位素。當該放射性結合物係用於偵測時,其可包含用於閃爍研究之放射性原子(例如TC
99m或I
123),或用於核磁共振(NMR)成像(亦稱為磁共振成像,MRI)之自旋標記,諸如碘-123再次、碘-131、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。
雙特異性抗體及細胞毒性劑之結合物可使用諸如以下的各種雙官能偶合劑來製造:N-琥珀醯亞胺基-3-(2-吡啶基二硫)丙酸鹽(SPDP)、琥珀醯亞胺基-4-(N-馬來醯亞胺基甲基)環己烷-1-羧酸鹽(SMCC)、亞胺基硫烷(IT)、亞氨酸酯之雙官能衍生物(諸如二甲基己二亞醯胺化合物HC1)、活性酯(諸如辛二酸二琥珀醯亞胺酯)、醛(諸如戊二醛)、雙疊氮基化合物(諸如雙(對疊氮基苯甲醯基)己二胺)、雙重氮鎓衍生物(諸如雙(對重氮鎓苯甲醯基)-乙二胺)、二異氰酸酯(諸如甲苯2,6-二異氰酸酯)及雙活性氟化合物(諸如l,5-二氟-2,4-二硝基苯)。例如,蓖麻毒蛋白免疫毒素可如描述於Vitetta, E.S.等人,Science 238 (1987) 1098-1104中來製備。經碳-14-標記之1-異硫氰基苄基-3-甲基二伸乙基三胺五乙酸(MX-DTPA)係用於將放射性同位素結合至抗體之例示性螯合劑。參見WO 94/11026。該連接子可為「可裂解連接子」,其促進細胞毒性藥物釋放於細胞中。例如,可使用酸不穩定連接子、肽酶敏感連接子、光不穩定連接子、二甲基連接子或含雙硫鍵之連接子(Chari, R.V.等人,Cancer Res. 52 (1992) 127-131;US 5,208,020)。
本文之免疫結合物或ADC明確預期但不限於用包括(但不限於)以下之交聯試劑製得之此等結合物:BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、硫-EMCS、硫-GMBS、硫-KMUS、硫-MBS、硫-SIAB、硫-SMCC及硫-SMPB及SVSB (琥珀醯亞胺基-(4-乙烯基碸)苯甲酸鹽),其等係市售的(例如,來自Pierce Biotechnology, Inc., Rockford, IL., U.S.A)。
本文亦預期如本文報告之雙特異性抗體及一或更多種小分子毒素(諸如卡裡奇黴素(calicheamicin)、美登素(maytansine) (US5,208,020)、單端孢黴烯(trichothene)及CC1065)之結合物。在本發明之一個實施例中,該雙特異性抗體係與一或更多種美登素分子(例如,每拮抗劑分子約1至約10個美登素分子)結合。美登素可(例如)轉化為May-SS-Me,其可還原為May-SH3及與經修飾之拮抗劑反應(Chari等人,Cancer Research 52: 127-131 (1992))以產生美登醇-抗體結合物。
或者,如本文報告之雙特異性抗體係與一或更多個卡裡奇黴素分子結合。抗生素之卡裡奇黴素家族可產生子皮莫耳濃度之雙股DNA斷裂。可使用之卡裡奇黴素之結構類似物包括(但不限於)γ1 I、α2 I、α3 I、N-乙醯基-γ1 I、PSAG及θI 1 (Hinman等人,Cancer Research 53: 3336-3342 (1993)及Lode等人,Cancer Research 58: 2925-2928 (1998))。
本發明進一步預期與具有核分解活性之化合物(例如,核糖核酸酶或DNA核酸內切酶,諸如去氧核糖核酸酶;DNase)結合之如本文報告之雙特異性抗體。
或者,包含如本文報告之雙特異性抗體及細胞毒性劑之融合蛋白可(例如)藉由重組技術或肽合成來製造。
E.醫藥調配物
如本文描述之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體之醫藥調配物係藉由將具有所需純度之此抗體與一或更多種可選醫藥上可接受之載劑(Remington's Pharmaceutical Sciences,第16版,Osol, A. (編) (1980))混合成凍乾調配物或水溶液之形式來製備。醫藥上可接受之載劑通常在採用之劑量及濃度下對接受者無毒,且包括(但不限於):緩衝劑,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如十八烷基二甲基苄基氯化銨;氯化六甲雙銨;氯化苄二甲烴銨;氯化本索寧;苯酚;丁醇或苄醇;對羥苯甲酸烷基酯(諸如對羥苯甲酸甲酯或對羥苯甲酸丙酯);兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚(乙烯基吡咯啶酮);胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、二醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑(諸如EDTA);糖,諸如蔗糖、甘露糖醇、海藻糖或山梨糖醇;形成鹽之相對離子(諸如鈉);金屬錯合物(例如,Zn-蛋白質錯合物)及/或非離子表面活性劑(諸如聚乙二醇(PEG))。本文之例示性醫藥上可接受之載劑進一步包括間質性藥物分散劑,諸如可溶性中性-活性透明質酸酶醣蛋白(sHASEGP),例如,人類可溶性PH-20透明質酸酶醣蛋白,諸如rhuPH20 (HYLENEX
®,Baxter International, Inc.)。某些例示性sHASEGP(包括rhuPH20)及使用方法描述於US 2005/0260186及US 2006/0104968中。在一個態樣中,sHASEGP組合一或更多種額外醣胺聚醣酶(諸如軟骨素酶)。
例示性凍乾抗體調配物描述於US 6,267,958中。水性抗體調配物包括彼等描述於US 6,171,586及WO 2006/044908中者,該等後者調配物包括組胺酸-乙酸鹽緩衝劑。例示性抗-CD20抗體調配物係描述於WO98/56418中,其以引用之方式明確併入本文中。
適用於皮下投與之凍乾調配物係描述於WO 97/04801中。此等凍乾調配物可經合適稀釋劑復水至高蛋白濃度及經復水之調配物可向本文之待治療之哺乳動物皮下投與。
本文之調配物亦可含有超過一種針對治療中之特定適應症而言所必需之活性成分,較佳係彼等具有不會不利地影響彼此之互補活性者。此等活性成分適宜地以就預期目標而言有效之量存在於組合中。
活性成分可包埋於例如藉由凝聚技術或藉由界面聚合分別於膠狀藥物遞送系統(例如,脂質體、白蛋白微球、微乳液、奈米顆粒奈米膠囊)中或於巨乳液中所製備之微膠囊(例如,羥基甲基纖維素或明膠-微膠囊及聚-(甲基丙烯酸甲酯)微膠囊)中。此等技術揭示於Remington's Pharmaceutical Sciences,第16版,Osol, A. (編) (1980)中。
可製備緩釋製劑。緩釋製劑之合適實例包括含有該抗體之固體疏水性聚合物之半滲透性基質,其中基質係以成型物件之形式,例如,薄膜或微膠囊。緩釋基質之實例包括聚酯、水凝膠(例如,聚(2-羥乙基-甲基丙烯酸酯)或聚(乙烯基醇))、聚乳酸交酯(US3,773,919)、L-麩胺酸及γ乙基-L-麩胺酸鹽之共聚物、非可降解乙烯-乙酸乙烯酯、可降解乳酸-乙醇酸共聚物,諸如LUPRON DEPOT™ (由乳酸-乙醇酸共聚物及乙酸亮丙瑞林組成之可注射微球)及聚-D-(-)-3-羥基丁酸。
待用於活體內投與之調配物通常係無菌的。無菌可輕易地例如藉由透過無菌過濾膜過濾達成。在一個實施例中,該調配物係等張的。
F.治療方法及組合物
本文提供之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體中之任何一者可用於治療方法中。
在一個態樣中,提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用作藥劑。在其他態樣中,提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用於預防及/或治療B細胞增生性疾病。在某些實施例中,提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用於治療方法中。在某些實施例中,本文提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用於治療患有B細胞增生性疾病之個體之方法中,該方法包括向該個體投與有效量之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體。在一項此實施例中,該方法進一步包括向該個體投與有效量之至少一種諸如下文列舉之額外治療劑。在其他實施例中,本文提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用於去除可表現CD20之經腦隔離B細胞。在某些實施例中,本文提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體,其用於去除個體中可表現CD20之經腦隔離B細胞之方法中,該方法包括向該個體投與治療有效量之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體以去除可表現CD20之經腦隔離B細胞。根據上文實施例中任何一項之「個體」較佳係人類。
在另一態樣中,本文提供雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體於藥劑之製造或製備中之用途。在一個實施例中,該藥劑係用於治療B細胞增生性疾病。在另一實施例中,該藥劑係用於治療B細胞增生性疾病之方法中,該方法包括向患有與B細胞增生相關聯之疾病之個體投與有效量之該藥劑。在一個此實施例中,該方法進一步包括向該個體投與有效量之至少一種諸如下文列舉之額外治療劑。在另一實施例中,該藥劑係用於去除可表現CD20之經腦隔離B細胞。在另一實施例中,該藥劑係用於去除個體中可表現CD20之經腦隔離B細胞之方法中,該方法包括向該個體投與有效量之該藥劑以去除可表現CD20之經腦隔離B細胞。根據上文實施例中之任何一者之「個體」為人類。
在另一態樣中,本文提供用於治療B細胞增生性疾病之方法。在一個實施例中,該方法包括向患有B細胞增生性疾病之個體投與有效量之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體。在一項此實施例中,該方法進一步包括向該個體投與有效量之至少一種諸如下文給定之額外治療劑。根據上文實施例中之任何一者之「個體」為人類。
在另一態樣中,本文提供用於去除個體中可表現CD20之循環B細胞之方法。在一個實施例中,該方法包括向該個體投與有效量之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體以去除可表現CD20之循環B細胞。在一個實施例中,「個體」係人類。
在另一態樣中,本文提供包含本文提供之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體中之任何一者之醫藥調配物,例如,用於上文治療方法中之任何一者中。在一個實施例中,醫藥調配物包含本文提供之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體中之任何一者及醫藥上可接受之載劑。在另一實施例中,醫藥調配物包含本文提供之雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體中之任何一者及至少一種(例如)如下文給定之額外治療劑。
如本文報告之抗體可單獨使用或與其他藥劑組合用於治療中。例如,如本文報告之抗體可與至少一種額外治療劑共投與。在某些實施例中,額外治療劑係有效治療與正採用如本文報告之雙特異性抗體治療相同或不同B細胞增生性疾病之治療劑。
上文指示之此等組合療法涵蓋組合投與(其中兩種或更多種治療劑包括於相同或不同調配物中)及分開投與,在分開投與之情況下,如本文報告之抗體之投與可發生於額外治療劑或藥劑之投與之前、同時及/或之後。在一個實施例中,該雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體之投與及額外治療劑之投與可發生於彼此投與之約一個月內,或發生於約一、二或三週內,或發生於約一、二、三、四、五或六天內。如本文報告之抗體亦可與其他介入性療法(諸如(但不限於)放射療法、行為療法或此項技術中已知且適用於待治療或預防之神經失調症之其他療法)組合使用。
如本文報告之抗體(及任何額外治療劑)可藉由任何合適之方式投與,包括非經腸、肺內及鼻內及(若需要針對局部治療)病灶內投與。非經腸輸注包括肌內、靜脈內、動脈內、腹膜內或皮下投與。給藥可藉由任何合適之途徑,例如,藉由注射,諸如靜脈內或皮下注射,部分取決於該投與係短暫的抑或係長期的。本文預期各種給藥方案,包括(但不限於)經各種時間點之單一或多次投與、推注投與及脈衝輸注。
此外,該雙特異性抗體可適宜地藉由脈衝輸注投與,例如,以遞減劑量的雙特異性抗體投與。該給藥可藉由注射、靜脈內或皮下注射給定,其部分取決於該投與是否係短暫抑或慢性的。
如本文報告之抗體係以與良好之醫學實務一致之方式調配、給藥並投與。此內文中應考慮之因素包括治療中之特定失調症、治療中之特定哺乳動物、個別病患之臨床病症、失調症之病因、藥劑之遞送部位、投與方法、投與時間安排表及醫務人員已知的其他因素。該抗體不一定,但視需要需與目前用以預防或治療待討論之失調症之一或更多種藥劑一起調配。此等其他藥劑之有效量取決於存在於調配物中之抗體之量、失調症或治療之類型及上文討論之其他因素。此等通常以相同劑量及以如本文描述之投與途徑,或以本文描述之劑量之約1至99%,或以任何劑量及藉由經驗/臨床判定係適當之任何途徑來使用。
跨BBB輸送融合構築體或化合物之基於脂質之方法包括(但不限於)將該融合構築體或化合物囊封於脂質體中,將該脂質體偶合至結合至BBB之血管內皮細胞上之受體之單價結合實體(參見例如,US 2002/0025313),及於低密度脂蛋白顆粒中塗覆該單價結合實體(參見例如,US 2004/0204354)或載脂蛋白E (參見例如,US2004/0131692)。
就疾病之預防或治療而言,如本文報告之抗體之適當劑量(在單獨使用或與一或更多個其他額外治療劑組合使用時)將取決於待治療之疾病之類型、抗體之類型、疾病之嚴重性及病程、該抗體是否出於預防抑或治療目的投與、先前療法、病患之臨床歷史及對抗體之反應、及主治醫師之判斷。抗體適用於向病患一次性投與或經一系列治療投與。取決於該疾病之類型及嚴重性,約1 μg/kg至15 mg/kg(例如,0.5 mg/kg至10 mg/kg)之抗體可為用於向該病患投與之初始候選劑量,無論例如藉由一或更多次分開投與或藉由連續輸注。一個典型每日劑量可介於約1 μg/kg至100 mg/kg或以上之範圍內,取決於上文提及之因素。就經數日或更久之重複投與而言,取決於病症,該治療將通常持續直至出現對疾病症狀之所需抑制。抗體之例示性劑量係介於約0.05 mg/kg至約10 mg/kg之範圍內。因此,可向病患投與約0.5 mg/kg、2.0 mg/kg、4.0 mg/kg或10 mg/kg (或其任何組合)中之一或更多個劑量。此等劑量可間歇性投與,例如,每週或每三週(例如,使得病患接受抗體之自約二至約二十,或例如約六個劑量之抗體)。初始較高負荷劑量後,可接著投與一或更多個較低劑量。然而,其他劑量方案係為有用的。此療法之進展係可輕易地藉由習知技術及分析來監測。
應瞭解上文之調配物或治療方法中之任何一者可使用如本文報告之免疫結合物代替雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體或除雙特異性抗-人類CD20/人類轉鐵蛋白受體抗體外亦使用如本文報告之免疫結合物來進行。
包含結合至B-細胞表面抗原之如本文報告之雙特異性抗體之組合物係以與良好之醫學實務一致之方式調配、給藥並投與。此內文中應考慮之因素包括治療中之特定疾病或失調症、治療中之特定哺乳動物、個別病患之臨床病症、疾病或失調症之病因、藥劑之遞送部位、投與方法、投與時間安排表及醫務人員已知的其他因素。待投與之拮抗劑之治療有效量將藉由此等考慮因素控制。
除B細胞增生性疾病之治療外,如本文報告之雙特異性抗體可用於治療自體免疫疾病。自體免疫疾病或失調症之實例包括(但不限於)免疫介導之血小板減少症,諸如急性特發性血小板減少性紫癜及慢性特發性血小板減少性紫癜、皮肌炎、西德納姆氏氏舞蹈症(Sydenham's chorea)、狼瘡性腎炎、風濕熱、多腺性症候群、亨诺赫-舍恩莱因紫癜(Henoch-Schonlein purpura)、鏈球菌感染後腎炎、結節性紅斑、高安氏動脈炎(Takayasu's arteritis)、艾迪生氏病、多形性紅斑、多動脈炎結節、強直性脊柱炎、古德巴斯德氏症候群(Goodpasture's syndrome)、原發性膽汁性肝硬化、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、甲狀腺毒症、慢性活性肝炎、多發性肌炎/皮肌炎、多發性骨髓炎、尋常性天疱瘡、華格納氏肉芽病、膜性腎病、肌肉萎縮性脊髓側索硬化症、脊髓癆、多發性肌痛(polymyaglia)、惡性貧血、迅速漸進腎小球性腎炎及纖維性肺泡炎、炎性反應,諸如炎性皮膚疾病,其等包括牛皮癬及皮膚炎(例如,異位性皮膚炎);全身性硬皮病及硬化症;與炎性腸疾相關聯之反應(諸如克羅恩氏病及潰瘍性結腸炎);呼吸窘迫症候群(包括成人呼吸窘迫症候群;ARDS);皮膚炎;腦膜炎;腦炎;眼色素層炎;結腸炎;腎小球性腎炎;過敏性病症,諸如濕疹及氣喘及涉及T細胞之浸潤及慢性炎性反應之其他病症;動脈粥樣硬化症;白血球黏附缺陷症;類風濕性關節炎;全身性紅斑狼瘡(SLE);糖尿病(例如,1型糖尿病或胰島素依賴性糖尿病);多發性硬化症;雷諾症候群;自體免疫甲狀腺炎;過敏性腦脊髓炎;鳩氏症候群;青少年發病型糖尿病;及通常於結核病、類肉瘤病、多發性肌炎、肉芽病及血管炎中發現之與細胞介素及T-淋巴球介導之急性及遲發性超敏反應相關聯之免疫反應;惡性貧血(艾迪生氏病);涉及白血球滲出之疾病;中樞神經系統(CNS)炎性失調症;多器官損傷症候群;溶血性貧血(包括(但不限於)冷凝球蛋白血症或庫姆氏陽性貧血症);重症肌無力;抗原-抗體複合體介導之疾病;抗-腎小球基底膜疾病;抗-磷脂質症候群;過敏性神經炎;格雷夫斯氏病;蘭伯特-伊頓肌無力症候群;大皰性類天皰瘡;天皰瘡;自體免疫多內分泌病;萊特氏病;僵體症候群;白塞氏病;巨大細胞動脈炎;免疫複合體腎炎;IgA腎病;IgM多發性神經病變;免疫血小板減少性紫瘢(ITP)或自體免疫血小板減少症等。在本發明之此態樣中,本發明之ABM係用以在延長期去除具有正常B細胞之血液。
然而,如上文指示,雙特異性抗體之此等建議量係受到大量治療自由量裁權之處理。如上文指示,選擇適當之劑量及安排給藥時間之關鍵因素係獲得之結果。例如,可能初始需要相對較高之劑量以用於治療持續及急性疾病。為獲得最有效之結果,取決於疾病或失調症,該拮抗劑係當儘可能接近於第一徵兆、診斷、外觀時投與或在該疾病或失調症之緩解期間投與。
除向病患投與如本文報告之經分離雙特異性抗體之外,本申請案預期藉由基因療法投與雙特異性抗體。編碼雙特異性抗體之核酸之此投與係由表達「投與治療有效量之雙特異性抗體」涵蓋。參見,例如,WO96/07321,其涉及使用基因療法以產生細胞內抗體。
存在使核酸(視需要包含於載體中)進入病患之細胞內之兩種主要方法;活體內及活體外。就活體內遞送而言,該核酸係直接注射於病患內,通常注射於其中需要雙特異性抗體之部位。就活體外治療而言,該病患之細胞係經移除,將該核酸引入此等經分離細胞內及經修飾細胞係向病患直接投與或者(例如)囊封於植入病患種之多孔膜內(參見,例如,US4,892,538及US 5,283,187)。存在可用於將核酸引入活細胞內之各種技術。該等技術取決於是將該核酸轉移至活體外培養之細胞內還是轉移至目的宿主的活體內細胞中而變化。適用於將核酸活體外轉移至哺乳動物細胞內之技術包括使用脂質體、電穿孔、顯微注射、細胞融合、DEAE-聚葡萄糖、磷酸鈣沈澱方法等。用於活體外遞送基因之常用載體是逆轉錄病毒。
目前較佳活體內核酸轉移技術包括使用病毒載體(諸如腺病毒、單純皰疹I病毒或腺相關病毒)及基於脂質之系統(例如,適用於基因之脂質介導之轉移之脂質係DOTMA、DOPE及DC-Chol)轉染。在一些情況下,需提供具有靶向靶細胞之藥劑(諸如對細胞表面膜蛋白或靶細胞具有特異性之抗體;用於靶細胞上之受體之配體等)之核酸源。其中若採用脂質體,則可使用結合至與胞吞相關聯之細胞表面膜蛋白之蛋白質以靶向及/或促進攝取,例如,對特定細胞類型具有泛嗜性之衣殼蛋白或其片段、用於在循環中經內化之蛋白質之抗體、及靶向細胞內局部化及增強細胞內半衰期之蛋白質。受體介導之胞吞之技術係(例如)藉由Wu等人,J. Biol. Chem. 262:4429-4432 (1987);及Wagner等人,Proc. Natl. Acad. Sci. USA 87:3410-3414 (1990)描述。為回顧目前已知的基因標誌及基因療法方案,參見Anderson等人,Science 256:808-813 (1992)。亦參見WO 93/25673及其中引用之參考文獻。
熟知用於將額外治療劑結合至抗體之一般技術(參見,例如,Arnon等人,「Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy」,Monoclonal Antibodies and Cancer Therapy,Reisfeld等人(編),第243至56頁(Alan R. Liss, Inc. 1985);Hellstrom等人,「Antibodies For Drug Delivery」,Controlled Drug Delivery (第2版),Robinson等人,(編),第623至53頁(Marcel Dekker, Inc. 1987);Thorpe, 「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」,Monoclonal Antibodies '84: Biological And Clinical Applications,Pinchera等人(編),第475至506頁(1985);及Thorpe等人,「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」, Immunol. Rev., 62 (1982) 119-58)。
III. 製造物件在如本文報告之另一態樣中,提供含有適用於上文描述之失調症之治療、預防及/或診斷之材料之製造物件。該製造物件包含容器及貼於該容器上或與該容器相關聯之標籤或包裝插頁。合適之容器包括(例如)瓶子、小瓶、注射器、IV溶液袋等。該等容器可由各種材料諸如玻璃或塑膠製成。該容器裝載組合物本身或與對治療、預防及/或診斷病症有效之其他組合物之組合且可具有無菌入孔(例如,該容器可為靜脈內溶液袋或具有可藉由皮下注射針刺破之塞子之小瓶)。該組合物中之至少一種活性成分係本文報告之抗體。該標籤或包裝插頁指示用於治療所選病症之組合物。此外,該製造物件可包含(a)其中含有組合物之第一容器,其中該組合物包含如本文報告之抗體;及(b)其中含有組合物之第二容器,其中該組合物含有其他細胞毒性或其他治療劑。此實施例中之製造物件可進一步包含指示該等組合物可用以治療特定病症之包裝插頁。或者或另外,該製造物件可進一步包含第二(或第三)容器,該容器包含醫藥上可接收之緩衝劑,諸如注射用抑菌水(BWFI)、磷酸鹽緩衝生理鹽水、林格氏溶液(Ringer’s solution)及葡萄糖溶液。其可進一步包括商業及使用者立場所需之其他材料,其等包括其他緩衝劑、稀釋劑、過濾器、針及注射器。
應瞭解上文之製造物件中之任何一者可包括如本文報告之免疫結合物代替如本文報告之雙特異性抗體或除如本文報告之雙特異性抗體外亦包括本發明之免疫結合物。
IV. 實例以下係本發明之方法及組合物之實例。應瞭解,在給定上文提供之一般描述下,可實踐各種其他實施例。
材料及一般方法
關於人類免疫球蛋白輕鏈及重鏈之核苷酸序列之一般資訊係給定於:Kabat, E.A.等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)中。抗體鏈之胺基酸係根據Kabat (Kabat, E.A.等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991))編號及參考。
重組 DNA 技術標準方法係用以控制DNA,如Sambrook, J.等人,Molecular Cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989中所描述。分子生物試劑係根據製造商之說明書來使用。
基因合成所需基因區段係從藉由化學合成所製得之寡核苷酸加以製備。長基因區段(兩側有單一限制性核酸內切酶裂解位點)係藉由包括PCR擴增及接著經由指示之限制性位點選殖之寡核苷酸的緩冷配對反應(annealing)及接合反應組裝而成。經次選殖之基因片段之DNA序列藉由DNA定序證實。基因合成片段係藉由給定之說明書在Geneart (Regensburg, Germany)進行排序。
DNA 序列測定DNA序列係藉由於MediGenomix GmbH (Martinsried, Germany)或SequiServe GmbH (Vaterstetten, Germany)進行之雙股定序測定。
DNA 及蛋白序列分析及序列資料管理GCG (Genetics Computer Group, Madison, Wisconsin)之軟體套裝10.2版及Infomax's Vector NT1 Advance組件8.0版係用於序列建立、繪圖、分析、註釋及繪示。
表現載體就表現描述之雙特異性抗體而言,可應用針對基於有或無CMV-內含子A啟動子之cDNA組織或基於具有CMV啟動子之基因組組織之用於暫態表現序列盒(例如,於HEK293細胞中)之表現質體。
除抗體表現匣外,該等載體亦含有:
-容許此質體於大腸桿菌中複製之複製起點,及
-賦予大腸桿菌氨比西林抗性之β-內醯胺酶基因。
抗體基因之轉錄單元係由下列元素組成:
-於5’端之獨特限制性位點,
-來自巨細胞病毒人類之即時早期增強子及啟動子,
-在cDNA組織之情況下,內含子A序列,
-衍生自人類抗體基因之5’-未轉譯區,
-免疫球蛋白重鏈信號序列,
-編碼各自抗體鏈之核酸,呈cDNA形式或具有基因組外顯子-內含子組織,
-具有多腺核苷酸化信號序列之3’未轉譯區,
-終止子序列,及
-於3’端之獨特限制性位點。
編碼抗體鏈之融合基因係藉由PCR及/或基因合成產生及藉由已知重組方法及技術藉由連接相應核酸區段例如使用個別載體中之獨特限制性位點來組裝。經次轉殖之核酸序列係藉由DNA定序證實。就暫態轉染而言,較大量質體係藉由來自經轉形大腸桿菌培養物(Nucleobond AX, Macherey-Nagel)之質體製備物製得。
就所有構築體而言,節-至-孔中異源二聚化技術係與於第一CH3域之典型節(T366W)取代及於第二CH3域(及兩個額外引入之半胱胺酸殘基S354C/Y349’C)中之對應孔取代(T366S、L368A及Y407V)一起使用(包含於上文闡述之各自對應重鏈(HC)序列中)。
細胞培養技術使用如描述於Cell Biology (2000), Bonifacino, J.S., Dasso, M., Harford, J.B., Lippincott-Schwartz, J.及Yamada, K.M. (編), John Wiley & Sons, Inc.中之Current Protocols中之標準細胞培養技術。
於 HEK293 系統中之瞬態轉染雙特異性抗體係藉由瞬態表現產生。因此,以個別質體使用HEK293系統(Invitrogen)之轉染根據製造商之說明書完成。簡而言之,將於搖瓶中或於經攪拌之發酵器中於無血清FreeStyle™ 293表現培養基(Invitrogen)中懸浮生長之HEK293細胞(Invitrogen)用各自表現質體及293fectin™或fectin (Invitrogen)之混合物轉染。對於2 L搖瓶(Corning),以含於600 mL之1.0*10
6個細胞/mL之密度將HEK293細胞接種及在120 rpm,8% CO
2下培養。第二天,該等細胞係以約1.5*10
6個細胞/mL之細胞密度用約42 mL之A) 20 mL包含600 µg總質體DNA (1 µg/mL)之Opti-MEM培養基(Invitrogen)及B) 20 ml以1.2 mL 293 fectin或fectin (2 µl/mL)補充之Opti-MEM培養基之混合物轉染。根據葡萄糖消耗,在發酵過程期間添加葡萄糖溶液。在5至10天後獲得含有分泌抗體之上清液及自上清液或冷凍及儲存上清液直接純化抗體。
蛋白質測定經純化之抗體及衍生物之蛋白質濃度係使用基於胺基酸序列根據Pace等人,Protein Science 4 (1995) 2411-1423計算之莫耳消光係數藉由測定280 nm下之光學密度(OD)而測定。
上清液中之抗體濃度測定細胞培養上清液中之抗體及衍生物之濃度係藉由使用蛋白A瓊脂糖珠(Roche Diagnostics GmbH, Mannheim, Germany)之免疫沈澱反應評估。因此,60 µL蛋白A瓊脂糖珠係於TBS-NP40 (50 mM Tris緩衝劑,pH 7.5,以150 mM NaCl及1% Nonidet-P40補充)中清洗三次。接著,將1至15 mL細胞培養上清液施加至於TBS-NP40中經預平衡之蛋白A瓊脂糖珠。在室溫下培養1小時後,該等珠係於Ultrafree-MC-過濾器管柱(Amicon)上用0.5 mL TBS-NP40清洗一次,用0.5 mL 2x磷酸鹽緩衝生理鹽水(2xPBS, Roche Diagnostics GmbH, Mannheim, Germany)清洗兩次及用0.5 mL 100 mM Na-檸檬酸鹽緩衝劑(pH 5.0)短暫清洗四次。經結合之抗體係藉由添加35 µl NuPAGE® LDS樣品緩衝劑(Invitrogen)溶離。將一半樣品分別組合NuPAGE®樣品還原劑或保持未經還原,及在70℃下加熱10分鐘。因此,將5至30 µl施加至4-12% NuPAGE® Bis-Tris SDS-PAGE凝膠(Invitrogen) (針對非還原SDS-PAGE,使用MOPS緩衝劑,及針對還原SDS-PAGE ,使用具有NuPAGE®抗氧化電泳緩衝劑添加物(Invitrogen)之MES緩衝劑)及用考馬斯亮藍(Coomassie Blue)染色。
細胞培養上清液中之抗體之濃度係藉由親和性HPLC層析術定量量測。簡而言之,將含有結合至蛋白A之抗體之細胞培養上清液施加至於200 mM KH
2PO
4,100 mM檸檬酸鈉,pH 7.4中之Applied Biosystems Poros A/20管柱及用200 mM NaCl,100 mM檸檬酸,pH 2.5於Agilent HPLC 1100系統上溶離。經溶離之抗體係藉由UV吸光度及峰面積之積分定量。經純化之標準IgG1抗體充當標準。
或者,細胞培養上清液中之抗體及衍生物之濃度係藉由Sandwich-IgG-ELISA量測。簡而言之,StreptaWell High Bind Streptavidin A-96孔微量滴定板(Roche Diagnostics GmbH, Mannheim, Germany)係經100 µL/孔之生物素化抗-人類IgG捕獲分子F(ab’)2<h-Fcγ> BI (Dianova)以0.1 µg/mL在室溫下塗覆1小時或者在4℃下塗覆整夜及接著用200 µL/孔PBS,0.05%吐溫(PBST, Sigma)清洗三次。其後,將含有100 µL/孔之各自抗體之細胞培養上清液於PBS (Sigma)中之稀釋系列添加至該等孔中及在室溫下於振動器上培養1至2小時。該等孔用200 µL/孔PBST清洗三次及經結合之抗體用100 µl F(ab‘)2<hFcγ>POD (Dianova)在0.1 µg/mL下偵測,而偵測抗體在室溫下在振動器上培養1至2小時。未結合之偵測抗體係藉由用200 µL/孔PBST清洗三次移除。結合之偵測抗體係藉由添加100 µL ABTS/孔,接著培養而進行偵測。吸光度之偵測係於Tecan Fluor分光光度計上在405 nm(參考波長492 nm)之量測波長下進行。
製備型抗體純化參考標準方案,抗體係純化自經過濾之細胞培養上清液。簡而言之,將抗體施加至蛋白A瓊脂糖管柱(GE healthcare)上及用PBS清洗。抗體之溶離係在pH 2.8下達成,接著立即中和。經聚集之蛋白質係藉由於PBS或於包含150 mM NaCl之20 mM組胺酸緩衝劑(pH 6.0)中之尺寸排阻層析術(Superdex 200, GE Healthcare)以分離自單體抗體。單體抗體部分係經池化,使用(例如)MILLIPORE Amicon Ultra (30 MWCO)離心濃縮器濃縮(若需要),冷凍及儲存於-20℃或-80℃下。提供部分樣品用於後續之蛋白分析及分析特性描述,例如,藉由SDS-PAGE、尺寸排阻層析術(SEC)或質譜法。
SDS-PAGENuPAGE® Pre-Cast凝膠系統(Invitrogen)係根據製造商之說明書使用。特定言之,使用10%或4至12%之NuPAGE® Novex® Bis-TRIS Pre-Cast凝膠(pH 6.4)及NuPAGE® MES (還原凝膠,具有NuPAGE®抗氧化電泳緩衝劑添加物)或MOPS (非還原凝膠)電泳緩衝劑。
CE-SDS純度及抗體完整性係藉由CE-SDS使用微流體晶片實驗室技術(PerkinElmer, USA)進行分析。因此,為CE-SDS分析使用HT蛋白表現試劑套組根據製造商之說明書製備5 µl之抗體溶液及於使用HT蛋白表現晶片於實驗室晶片GXII系統上進行分析。資料係使用實驗室晶片GX軟體進行分析。
分析尺寸排阻層析術用於測定抗體之聚集及寡聚狀態之尺寸排阻層析術(SEC)係藉由HPLC層析術進行。簡而言之,將經蛋白A純化之抗體施加至於300 mM NaCl,50 mM KH
2PO
4/K
2HPO
4緩衝劑(pH 7.5)中於Dionex Ultimate®系統(Thermo Fischer Scientific)上之Tosoh TSKgel G3000SW管柱或施加至於2 x PBS中於Dionex HPLC-系統上之Superdex 200管柱(GE Healthcare)。經溶離之抗體係藉由UV吸光度及峰面積之積分量化。BioRad凝膠過濾標準151–1901充當標準。
質譜法此章節描述雙特異性抗體之特性描述,該特性描述強調其等正確組裝。預期一級結構係藉由去醣化完整抗體之電灑游離質譜(ESI-MS)及在經去醣化/受限LysC消化之抗體之特定情況下進行分析。
抗體係用於磷酸鹽或Tris緩衝劑中之N-醣苷酶F在37℃下在1 mg/ml之蛋白濃度下去醣化長達17 h。受限LysC (Roche Diagnostics GmbH, Mannheim, Germany)消化係用於Tris緩衝劑(pH 8)中之100 µg去醣化抗體分別在室溫下進行120小時或在37℃下進行40分鐘。在質譜法前,樣品係經由HPLC於Sephadex G25管柱(GE Healthcare)上去鹽。總質量係經由ESI-MS於配備TriVersa NanoMate源(Advion)之maXis 4G UHR-QTOF MS系統(Bruker Daltonik)上測定。
化學降解測試將樣品分為三等份及分別重新緩衝為20 mM His/His*HCl,140 mM NaCl,pH 6.0或緩衝為PBS,及儲存於40℃ (His/NaCl)或37℃ (PBS)下。對照樣品係儲存於-80℃下。
培養結束後,樣品係針對相對活性濃度(BIAcore)、聚集(SEC)及斷裂(毛細血管電泳或SDS-PAGE)進行分析及與未經處理之對照進行比較。
熱穩定性樣品係在1 mg/mL之濃度下於20 mM組胺酸/組胺酸氯化物,140 mM NaCl,pH 6.0中製得,藉由離心通過0.4 µm過濾板轉移至光學384孔板內及用石蠟油覆蓋。流體力學半徑係藉由於DynaPro板讀數器(Wyatt)上之動態光散射重複量測,同時該等樣品係以0.05℃/min之速率自25℃加熱至80℃。
或者,將樣品轉移至10 µL微量光析槽陣列內及用Optim1000儀器(Avacta Inc.)記錄靜態光散射資料及用266 nm雷射激發後之螢光資料,同時以0.1℃/min之速率將其等自25℃加熱至90℃。
聚集開始溫度係定義為其中流體動力學半徑(DLS)或散射光強度(Optim1000)開始增大時之溫度。
或者,將樣品轉移至9 µL多光析槽陣列中。將該多光析槽陣列於Optim1000儀器(Avacta Analytical Inc.)中以0.1℃/分鐘之恆定速率自35℃加熱至90℃。該儀器以約每0.5℃之資料點連續記錄266 nm雷射之散射光之強度。針對溫度相對光散射強度進行繪圖。聚集開始溫度(T_agg)係定義為其中散射光強度開始增大時之溫度。
熔化溫度係定義為螢光強度相對於波長曲線圖中之轉折點。
實例 1表現及純化
雙特異性抗體係如上文於一般材料及方法章節中之描述產生。
雙特異性抗體係自上清液藉由蛋白A親和性層析術及尺寸排阻層析術之組合來純化。獲得之產物係藉由質譜法及分析性質(諸如藉由CE-SDS之純度、單體含量及穩定性)而表徵身份。
預期一級結構係藉由去醣化完整抗體及去醣化/經胞漿素消化或或者如一般方法章節中描述之經去醣化/受限LysC消化之抗體之電灑游離質譜(ESI-MS)進行分析。
額外分析方法(例如,熱穩定性、質譜法及功能評估)係僅在蛋白A及SEC純化後施加。
實例 2對轉鐵蛋白受體活體外結合之測定
雙特異性抗體對鼠類轉鐵蛋白受體之結合係藉由FACS分析針對小鼠X63.AG8-563骨髓瘤細胞進行測試。若Aβ抗體顯示某種非特異性結合至Ag8細胞之趨勢,則特異性結合可藉由與20倍過量之抗-小鼠-TfR抗體共培養定量。細胞係藉由離心獲得,用PBS清洗一次及5x10
4個細胞用1.5 pM至10 nM稀釋系列之多肽融合物培養(添加或不添加於100 µL RPMI/10% FCS中之200 nM抗-小鼠TfR抗體)於冰上培養1.5小時。在用RPMI/10% FCS清洗2次後,細胞用偶合至藻紅蛋白(Jackson Immunoresearch)之山羊-抗-人類IgG以於RPMI/19% FCS中之1:600稀釋液於冰上培養1.5小時。細胞經再次清洗,重懸浮於RPMI/10% FCS中及於FACS-陣列儀器(Becton-Dickinson)上量測藻紅蛋白螢光。
實例 3用於人類TfR–抗體相互作用之基於表面電漿子共振之結合分析
該結合實驗係於配備經抗人類Fab抗體(GE Healthcare, cat.no 28-9583-25)使用標準胺偶合化學程式根據供應商之說明書預處理之C1感測器晶片(GE Healthcare, cat.no. BR1005-35)之BIAcore B 4000 (GE Healthcare)上進行。
就動力學量測而言,在25℃下施用60秒接觸時間及10 µL/min之流動速率將樣品抗體固定於磷酸鹽緩衝生理鹽水(pH 7.4)、0.05%吐溫20中。以漸增濃度施用重組His6標誌人類轉鐵蛋白受體(R&D系統,cat.no 2474-TR-050)並經時監測信號。記錄30 µL/min流動速率下之150秒結合時間及600秒解離時間之平均時間跨度。資料使用1:1結合模式(朗繆爾等溫線)擬合。
抗體 | 0039 | 0040 | 0041 | 0042 |
c [µg/ml] | 8.4 | 25.3 | 32 | 22.5 |
數量[mg] | 29.4 | 88.6 | 112.0 | 78.8 |
抗體 | 莫耳質體比率 | 相對峰面積(非還原) [%] | |||
½ mAb 孔 | 孔-孔鏈二聚物 | 抗體單體 | |||
0039 | 1:3 | LC+HC-孔:CrossLC+HC節 | 9 | 10 | 80 |
0039 | 1:4 | 6 | 6 | 88 | |
0039 | 1:3:2 | LC+HC-孔:CrossLC+HC節:CrossLC | 17 | 9 | 74 |
0039 | 1:4:2 | 10 | 5 | 85 | |
0039 | 1:1:3 | LC : LC+HC-孔:CrossLC+HC節 | 6 | 6 | 88 |
0039 | 1:1:4 | 3 | 4 | 93 | |
0040 | 1:3 | LC+HC-孔:CrossLC+HC節 | 10 | 18 | 72 |
0040 | 1:4 | 6 | 7 | 87 | |
0040 | 1:3:2 | LC+HC-孔:CrossLC+HC節:CrossLC | 5 | 7 | 89 |
0040 | 1:4:2 | 3 | 5 | 92 | |
0040 | 1:1:3 | LC : LC+HC-孔:CrossLC+HC節 | 16 | 48 | 35 |
0040 | 1:1:4 | 6 | 23 | 69 | |
0041 | 1:3 | LC+HC-孔:CrossLC+HC節 | 3 | 5 | 92 |
0041 | 1:4 | 1 | 2 | 97 | |
0041 | 1:3:2 | LC+HC-孔:CrossLC+HC節:CrossLC | - | 2 | 98 |
0041 | 1:4:2 | - | 1 | 99 | |
0041 | 1:1:3 | LC : LC+HC-孔:CrossLC+HC節 | - | 3 | 97 |
0041 | 1:1:4 | - | 2 | 97 | |
0042 | 1:2 | LC+HC-孔:CrossLC+HC節 | - | 1 | 99 |
抗體 | 莫耳質體比率 | 蛋白A產物單體後獲得3公升之發酵物 (CE-SDS非還原/ 產率) | 副產物分佈 (CE-SDS非還原) | |||
LC | HC孔 | ½ mAb孔 | 孔-孔二聚物+ 3/ 4mAb | |||
0039 | 1:3:2 | 55% 26 mg | 16 | 6 | 11 | 12 |
0040 | 1:3:2 | 44% 74.5 mg | 23 | 8 | 7 | 17 |
0041 | 1:3:2 | 82% > 80 mg | 11 | 0 | 0 | 7 |
0042 | 1:2 | 83% 68.4 mg | 9 | 0 | 0 | 8 |
抗體 | 質體比率 | 蛋白A及製備型SEC產品單體後獲得3公升發酵物 (CE-SDS非還原/ 產率) | 副產物分佈 (CE-SDS非還原) | |||
LC | HC孔 | ½ mAb孔 | 孔-孔二聚物+ 3/ 4mAb | |||
0039 | 1:3:2 | 8.2 mg 73% | 10 | 0 | 2 | 15 |
0040 | 1:3:2 | 29.7 mg 77% | 10 | 0 | 0 | 14 |
0041 | 1:3:2 | > 44 mg 79% | 8 | 0 | 0 | 13 |
0042 | 1:2 | 43.6 mg > 90% | 3 | 0 | 0 | 3 |
抗體 | 質體比率 | 蛋白A純化單體SEC後獲得3l | 副產物SEC [%] | 最終產物SEC | 副產物SEC [%] | ||
HMW | LMW | HMW | LMW | ||||
0039 | 1:3:2 | 90% | 2 | 7 | 95% | 0 | 5 |
0040 | 1:3:2 | 89% | 5 | 6 | 96.5% | 1 | 2.5 |
0041 | 1:3:2 | 94% | 6 | 0 | 97.5% | 0.5 | 2 |
0042 | 1:2 | 95% | 2 | 3 | 97% | 1 | 2 |
抗體 | 使用蛋白A產物單體(CE-SDS)之微純化 | 蛋白A純化單體後獲得3l (產率/ CE-SDS 非還原) | 最終產物(製備型蛋白A及製備型SEC純化) (產率/ CE-SDS非還原) | |
CHO-K1 | HEK293 | CHO | CHO | |
0039 | 80% | 93% | 7.4 mg/l 55% | 8.2 mg 73% |
0040 | 83% | 92% | 21.3 mg/l 44% | 29.7 mg 77% |
0041 | 85% | 99% | > 21 mg/l 82% | > 44 mg 79% |
0042 | 91% | 99% | 19 mg/l 83% | 43.8 mg 94% |
原始殘基 | 例示性取代 | 較佳取代 |
Ala (A) | Val;Leu;Ile | Val |
Arg (R) | Lys;Gln;Asn | Lys |
Asn (N) | Gln;His;Asp, Lys;Arg | Gln |
Asp (D) | Glu;Asn | Glu |
Cys (C) | Ser;Ala | Ser |
Gln (Q) | Asn;Glu | Asn |
Glu (E) | Asp;Gln | Asp |
Gly (G) | Ala | Ala |
His (H) | Asn;Gln;Lys;Arg | Arg |
Ile (I) | Leu;Val;Met;Ala;Phe;正白胺酸 | Leu |
Leu (L) | 正白胺酸;Ile;Val;Met;Ala;Phe | Ile |
Lys (K) | Arg;Gln;Asn | Arg |
Met (M) | Leu;Phe;Ile | Leu |
Phe (F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro (P) | Ala | Ala |
Ser (S) | Thr | Thr |
Thr (T) | Val;Ser | Ser |
Trp (W) | Tyr;Phe | Tyr |
Tyr (Y) | Trp;Phe;Thr;Ser | Phe |
Val (V) | Ile;Leu;Met;Phe;Ala;正白胺酸 | Leu |
<![CDATA[<110> 瑞士商赫孚孟拉羅股份公司(F. Hoffmann-La Roche AG)]]> <![CDATA[<120> 雙特異性抗‐人類CD20∕人類轉鐵蛋白受體抗體及使用方法]]> <![CDATA[<130> TW 105131522]]> <![CDATA[<150> EP15188067.1]]> <![CDATA[<151> 2015-10-02]]> <![CDATA[<160> 22 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0041-LC1]]> <![CDATA[<400> 1]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg 115 120 125 Lys Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 2]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0041-HC1]]> <![CDATA[<400> 2]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser 355 360 365 Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 3]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0041-LC2]]> <![CDATA[<400> 3]]> Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn 85 90 95 Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ser 100 105 110 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 115 120 125 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 130 135 140 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 145 150 155 160 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 165 170 175 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 180 185 190 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205 Lys Val Glu Pro Lys Ser Cys 210 215 <![CDATA[<210> 4]]> <![CDATA[<211> 229]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0041-Fab]]> <![CDATA[<400> 4]]> Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser 50 55 60 Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser 65 70 75 80 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr 85 90 95 Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro 115 120 125 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 130 135 140 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 145 150 155 160 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 165 170 175 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 180 185 190 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 195 200 205 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 210 215 220 Asn Arg Gly Glu Cys 225 <![CDATA[<210> 5]]> <![CDATA[<211> 297]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro 1 5 10 15 Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30 Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45 Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60 Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile 65 70 75 80 Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95 Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110 Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125 Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140 His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro 145 150 155 160 Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175 Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190 Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205 Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220 Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile 225 230 235 240 Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255 Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270 Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285 Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 295 <![CDATA[<210> 6]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0039-LC1]]> <![CDATA[<400> 6]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg 115 120 125 Lys Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 7]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0039-HC1]]> <![CDATA[<400> 7]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser 355 360 365 Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 8]]> <![CDATA[<211> 229]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0039-LC2]]> <![CDATA[<400> 8]]> Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser 50 55 60 Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser 65 70 75 80 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr 85 90 95 Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro 115 120 125 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 130 135 140 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 145 150 155 160 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 165 170 175 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 180 185 190 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 195 200 205 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 210 215 220 Asn Arg Gly Glu Cys 225 <![CDATA[<210> 9]]> <![CDATA[<211> 681]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0039-HC2]]> <![CDATA[<400> 9]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 465 470 475 480 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 485 490 495 Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 500 505 510 Leu Ile Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 515 520 525 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 530 535 540 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser 545 550 555 560 Ser Asn Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 565 570 575 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 580 585 590 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 595 600 605 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 610 615 620 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 625 630 635 640 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 645 650 655 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 660 665 670 Asp Lys Lys Val Glu Pro Lys Ser Cys 675 680 <![CDATA[<210> 10]]> <![CDATA[<211> 695]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0041-HC2]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser 465 470 475 480 Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser 485 490 495 Tyr Ala Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp 500 505 510 Ile Gly Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala 515 520 525 Lys Ser Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys 530 535 540 Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 545 550 555 560 Arg Tyr Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp 565 570 575 Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala 580 585 590 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 595 600 605 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 610 615 620 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 625 630 635 640 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 645 650 655 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 660 665 670 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 675 680 685 Ser Phe Asn Arg Gly Glu Cys 690 695 <![CDATA[<210> 11]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0040-LC1]]> <![CDATA[<400> 11]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 12]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0040-HC1]]> <![CDATA[<400> 12]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser 355 360 365 Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 13]]> <![CDATA[<211> 695]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0040-HC2]]> <![CDATA[<400> 13]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser 465 470 475 480 Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser 485 490 495 Tyr Ala Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp 500 505 510 Ile Gly Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala 515 520 525 Lys Ser Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys 530 535 540 Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 545 550 555 560 Arg Tyr Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp 565 570 575 Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala 580 585 590 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 595 600 605 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 610 615 620 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 625 630 635 640 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 645 650 655 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 660 665 670 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 675 680 685 Ser Phe Asn Arg Gly Glu Cys 690 695 <![CDATA[<210> 14]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0042-LC1]]> <![CDATA[<400> 14]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg 115 120 125 Lys Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 15]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0042-HC1]]> <![CDATA[<400> 15]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser 355 360 365 Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 16]]> <![CDATA[<211> 229]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0042-LC2]]> <![CDATA[<400> 16]]> Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser 50 55 60 Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser 65 70 75 80 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr 85 90 95 Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro 115 120 125 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 130 135 140 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 145 150 155 160 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 165 170 175 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 180 185 190 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 195 200 205 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 210 215 220 Asn Arg Gly Glu Cys 225 <![CDATA[<210> 17]]> <![CDATA[<211> 674]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0042-HC2]]> <![CDATA[<400> 17]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Gly 210 215 220 Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ile Gln Leu Thr Gln Ser 225 230 235 240 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 245 250 255 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys 260 265 270 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Arg Ala Ser Thr Leu Ala 275 280 285 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 290 295 300 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 305 310 315 320 Cys Gln Gln Asn Tyr Ala Ser Ser Asn Val Asp Asn Thr Phe Gly Gly 325 330 335 Gly Thr Lys Val Glu Ile Lys Ser Ser Ala Ser Thr Lys Gly Pro Ser 340 345 350 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 355 360 365 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 370 375 380 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 385 390 395 400 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 405 410 415 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 420 425 430 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 435 440 445 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 450 455 460 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 465 470 475 480 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 485 490 495 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 500 505 510 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 515 520 525 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 530 535 540 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile 545 550 555 560 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 565 570 575 Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 580 585 590 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 595 600 605 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 610 615 620 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 625 630 635 640 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 645 650 655 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 660 665 670 Pro Gly <![CDATA[<210> 18]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗-CD20抗體VH]]> <![CDATA[<400> 18]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 19]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗-CD20抗體VL]]> <![CDATA[<400> 19]]> Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 20]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 299-023 VH人類化變體_DASG]]> <![CDATA[<400> 20]]> Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser 50 55 60 Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser 65 70 75 80 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr 85 90 95 Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 21]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 299-009 VL人類化變體_NYA]]> <![CDATA[<400> 21]]> Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn 85 90 95 Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 22]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220>]]> <![CDATA[<223> 0040-LC2]]> <![CDATA[<400> 22]]> Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn 85 90 95 Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ser 100 105 110 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 115 120 125 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 130 135 140 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 145 150 155 160 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 165 170 175 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 180 185 190 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205 Lys Val Glu Pro Lys Ser Cys 210 215
Claims (7)
- 一種雙特異性抗體,其包含:a)一種抗體,其包含兩對抗體輕鏈及抗體重鏈,其中由各對重鏈及輕鏈所形成之結合位點特異性結合至第一抗原,及b)另一Fab片段,其中該另一Fab片段之結合位點特異性結合至第二抗原,其中該第一抗原係人類CD20蛋白及該第二抗原係人類轉鐵蛋白受體;且該雙特異性抗體包含:1)具有SEQ ID NO:06至09之胺基酸序列之四個多肽;2)具有SEQ ID NO:01至03及SEQ ID NO:10之胺基酸序列之四個多肽;3)具有SEQ ID NO:11至13及SEQ ID NO:22之胺基酸序列之四個多肽;或4)具有SEQ ID NO:14至17之胺基酸序列之四個多肽。
- 如請求項1或2之雙特異性抗體,其中該抗體係單株抗體。
- 如請求項1或2之雙特異性抗體,其用作藥劑。
- 如請求項1或2之雙特異性抗體,其用於治療多發性硬化症。
- 一種醫藥調配物,其包含如請求項1或2之雙特異性抗體及醫藥上可接受之載劑。
- 一種如請求項1或2之雙特異性抗體之用途,其係用於製備治療多發性硬化症之醫藥品。
- 一種如請求項1或2之雙特異性抗體之用途,其係用於製備去除(depleting)可表現CD20之經腦隔離B細胞(brain sequestered B-cells)之醫藥品。
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