TW202317194A - 醫藥組合 - Google Patents
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Abstract
本發明大體上係關於免疫學及分子生物學領域。更特定言之,本發明提供包含 (A)針對LY75之抗體或其抗原結合部分及(B)第二抗癌實體之醫藥組合;編碼抗體組合之核酸;製備抗體組合之方法;以及治療諸如由LY75表現或活性介導之癌症的疾病之方法。
Description
本發明大體上係關於免疫學及分子生物學領域。更特定言之,本發明提供包含 (A)針對LY75之抗體或其抗原結合部分及(B)第二抗癌實體之醫藥組合;編碼抗體組合之核酸;製備抗體組合之方法;以及治療諸如由LY75表現或活性介導之癌症的疾病之方法。
白血病及淋巴瘤屬於一大組會影響血液、骨髓及淋巴系統之腫瘤;此等腫瘤稱為造血及淋巴組織腫瘤。
淋巴瘤為自淋巴細胞發展之一組血細胞腫瘤。病徵及症狀包括淋巴結增大、發熱、濕透式的出汗、非預期體重減輕、發癢以及一直感覺疲倦。淋巴瘤有多種亞型:淋巴瘤之兩種主要類別為霍奇金氏淋巴瘤(HL)及非霍奇金氏淋巴瘤(NHL)。世界衛生組織(WHO)包括兩種作為淋巴瘤之類型的其他類別:多發性骨髓瘤及免疫增生疾病。約90%之淋巴瘤為非霍奇金氏淋巴瘤。
白血病為一組通常始於骨髓中且導致大量異常白血球之癌症。症狀包括出血及瘀傷問題、感覺疲倦、發熱及感染之風險增加。此等症狀由於缺乏正常血細胞而出現。診斷通常藉由血液測試或骨髓活體組織切片來進行。存在四種主要類型之白血病:急性淋巴母細胞白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)及慢性骨髓性白血病(CML),以及多種不太常見之類型。
治療白血病及淋巴瘤包括一或多種化學療法、放射線療法、靶向療法及手術(以及在白血病之情況下,骨髓移植)。成功治療白血病取決於白血病之類型及個人之年齡。淋巴瘤治療結果取決於亞型,其中一些為可治癒的,且在大多數情況下治療會延長存活期。
此前已用於治療白血病之多種化學治療劑包括強的松(prednisone)、長春新鹼(vincristine)、蒽環黴素(anthracyclines)、L-天冬醯胺酶、環磷醯胺(cyclophosphamide)、甲胺喋呤(methotrexate)、6-巰基嘌呤、氟達拉賓(fludarabine)、噴司他丁(pentostatin)及克拉屈濱(cladribine)。用於治療淋巴瘤之化學治療劑包括環磷醯胺、羥基道諾黴素(hydroxydaunorubicin) (亦稱為阿黴素(doxorubicin)或阿德力黴素(adriamycin)、安可平(oncovin) (長春新鹼)、強的松、潑尼龍(prednisolone)、博萊黴素(bleomycin)、達卡巴嗪(dacarbazine)、依託泊苷(etoposide)及丙卡巴肼(procarbazine)。
組合化學療法涉及同時用兩種或超過兩種不同藥物治療患者。該等藥物之機制及副作用可不同。此之最大優點為對任一藥劑形成抗性之幾率降至最低。此外,藥物可常以較低劑量使用,降低毒性。用於治療霍奇金氏病之組合療法包括MOPP (氮芥(mustine)、長春新鹼、丙卡巴肼、潑尼龍)及ABVD (阿黴素、博萊黴素、長春鹼(vinblastine)、達卡巴嗪)。用於治療非霍奇金氏淋巴瘤之組合療法包括CHOP (環磷醯胺、阿黴素、長春新鹼、潑尼龍)。鑒於已知用於治療白血病及淋巴瘤之藥物數目,可能的藥物療法之排列及組合的數目顯然很大。此外,前述組合療法不包括抗體。
然而,仍需要對於白血病及淋巴瘤之新治療,且尤其需要有效組合療法。
淋巴細胞抗原75充當將自胞外空間捕捉之抗原引導至特定抗原處理區室之內飲受體且被認為造成B淋巴細胞增殖降低。已在胰臟癌、卵巢癌、乳癌、結腸直腸癌、食道癌、皮膚癌、甲狀腺癌及肺癌(非小細胞)以及多發性骨髓瘤及淋巴瘤及白血病之許多不同亞型中觀察到淋巴細胞抗原75之表現。WO2009/061996揭示與人類DEC-205 (LY75)結合之經分離單株抗體及基於相關抗體之組合物及分子。亦揭示包含該等抗體之醫藥組合物以及使用該等抗體之治療及診斷方法。WO2008/104806揭示能夠結合至LY75用於治療或預防癌症之親和力試劑。WO2015/052537揭示能夠結合至LY75之特異性分離抗體及其在治療不同癌症中之用途。
利妥昔單抗(Rituximab)為針對B細胞上廣泛表現之蛋白CD20的單株抗體(Oncogene (2003年10月20日), Smith MR, 「Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance」, 22(47): 7359-68)。利妥昔單抗破壞在其表面上具有CD20之正常及惡性B細胞兩者,且因此用以治療特徵為具有過多B細胞、過度活化B細胞或功能異常B細胞之疾病。利妥昔單抗此前已用以治療多種自體免疫疾病及一些類型之癌症,包括類風濕性關節炎、特發性血小板減少性紫癜、尋常天疱瘡、多發性硬化症、全身性紅斑性狼瘡症、非霍奇金氏淋巴瘤、慢性發炎性脫髓鞘多發性神經病、慢性淋巴球性白血病及自體免疫貧血。
依魯替尼(Ibrutinib) (依布魯維卡(Imbruvica))為永久結合至布魯頓氏酪胺酸激酶(BTK)的小分子藥物,BTK在B細胞中為重要的。依魯替尼此前已用以治療B細胞癌症,如套細胞淋巴瘤、慢性淋巴球性白血病及瓦爾登斯特倫巨球蛋白血症(Waldenström's macroglobulinemia)。
現已發現(i)某些抗LY75抗體與利妥昔單抗及(ii)某些抗LY75抗體與依魯替尼之組合展現協同作用,產生對淋巴瘤之治療。
在一個態樣中,本發明提供一種醫藥組合物,其包含:
(A)抗LY75抗體或其抗原結合部分,其與以下抗體競爭結合至LY75:該抗體包含含有以SEQ ID NO: 1所示之胺基酸序列的重鏈可變區,及含有SEQ ID NO: 2中所闡述之胺基酸序列的輕鏈可變區;或
抗LY75抗體或其抗原結合部分,該抗體包含:
a)重鏈可變區,其包含:
i)包含SEQ ID NO:5之第一vhCDR;
ii)包含SEQ ID NO: 6之第二vhCDR;及
iii)包含SEQ ID NO:7之第三vhCDR;及
b)輕鏈可變區,其包含:
i)包含SEQ ID NO:8之第一vlCDR;
ii)包含SEQ ID NO: 9之第二vlCDR;及
iii)包含SEQ ID NO:10之第三vlCDR;
視情況其中以上該等SEQ ID NO中之任意一或多者獨立地包含一個、兩個、三個、四個或五個胺基酸取代、添加或缺失;
及
(B)抗CD20抗體或其抗原結合部分,該抗體包含:
a)重鏈可變區,其包含:
i)包含SEQ ID NO: 40之第一vhCDR;
ii)包含SEQ ID NO: 41之第二vhCDR;及
iii)包含SEQ ID NO: 42之第三vhCDR;及
b)輕鏈可變區,其包含:
i)包含SEQ ID NO: 43之第一vlCDR;
ii)包含SEQ ID NO: 44之第二vlCDR;及
iii)包含SEQ ID NO: 45之第三vlCDR;
視情況其中以上該等SEQ ID NO中之任意一或多者獨立地包含一個、兩個、三個、四個或五個胺基酸取代、添加或缺失;
其中醫藥組合物呈用於同時、各別或依序使用之組合製劑之形式。
在第二態樣中,本發明提供一種醫藥組合物,其包含:
(A)抗LY75抗體或其抗原結合部分,其與以下抗體競爭結合至LY75:該抗體包含含有以SEQ ID NO: 1所示之胺基酸序列的重鏈可變區,及含有以SEQ ID NO: 2所示之胺基酸序列的輕鏈可變區;
或
抗LY75抗體或其抗原結合部分,該抗體包含:
a)重鏈可變區,其包含:
i)包含SEQ ID NO:5之第一vhCDR;
ii)包含SEQ ID NO: 6之第二vhCDR;及
iii)包含SEQ ID NO:7之第三vhCDR;及
b)輕鏈可變區,其包含:
i)包含SEQ ID NO:8之第一vlCDR;
ii)包含SEQ ID NO: 9之第二vlCDR;及
iii)包含SEQ ID NO:10之第三vlCDR;
視情況其中以上該等SEQ ID NO中之任意一或多者獨立地包含一個、兩個、三個、四個或五個胺基酸取代、添加或缺失;
及
(B)依魯替尼或其醫藥學上可接受之鹽,
其中醫藥組合物呈用於同時、各別或依序使用之組合製劑之形式。
在一個實施例中,該抗LY75或其抗原結合部分包含:包含1、2或3個選自由包含SEQ ID NO:5、6及7之CDR組成之群的CDR的重鏈可變區,及/或包含1、2或3個選自由包含SEQ ID NO:8、9及10之CDR組成之群的CDR的輕鏈可變區。
在一些實施例中,抗LY75抗體結合至LY75 (SEQ ID NO: 15)且能夠藉由表現LY75之細胞內化。
在另一實施例中,抗LY75抗體包含本文所述之特定抗體(例如在本文中稱為「LY75_A1」)之重鏈及/或輕鏈互補決定區(CDR)或可變區(VR)。因此,在一個實施例中,抗LY75抗體包含具有展示於SEQ ID NO:1中之序列之抗體LY75_A1的重鏈可變(VH)區的CDR1、CDR2及CDR3域,及/或具有展示於SEQ ID NO:2中之序列之LY75_A1的輕鏈可變(VL)區的CDR1、CDR2及CDR3域。
在另一實施例中,抗LY75抗體結合至人類LY75且包括包含SEQ ID NO:1及/或其保守序列修飾之重鏈可變區。抗體可進一步包括包含SEQ ID NO: 2及/或其保守序列修飾之輕鏈可變區。
在另一實施例中抗LY75抗體結合至人類LY75且包括重鏈可變區及輕鏈可變區,該等重鏈可變區及輕鏈可變區各別地包括以SEQ ID NO: 1及/或2所示之胺基酸序列及其保守序列修飾。
包括與以上序列中之任一者具有至少80%、或至少85%、或至少90%、或至少91%、或至少92%、或至少93%、或至少94%、或至少95%、或至少96%、或至少97%、或至少98%、或至少99%或超過99%序列一致性之重鏈及輕鏈可變區的抗體亦包括在本發明中。本發明同樣意欲涵蓋在上文所列舉之值中間的範圍,例如與以上序列中之任一者具有至少80-85%、85-90%、90-95%或95-100%序列一致性之重鏈及輕鏈可變區。
在一個實施例中,抗LY75抗體包含重鏈可變區,該重鏈可變區包含SEQ ID NO: 1或與SEQ ID NO: 1至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致之序列。在另一實施例中,抗LY75抗體包含輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 2或與SEQ ID NO: 2至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致之序列。在另一實施例中,抗LY75抗體包含重鏈構架區,該重鏈構架區包含如SEQ ID NO:16、17、18及19如中所展示與SEQ ID NO: 1之重鏈可變區之構架至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的胺基酸序列。在另一實施例中,抗LY75抗體包含輕鏈構架區,該輕鏈構架區包含如SEQ ID NO: 20、21、22及23中所展示與SEQ ID NO: 2之輕鏈可變區之構架至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的胺基酸序列。
在一個實施例中,抗LY75抗體與以下抗體競爭結合至LY75:該抗體包含重鏈及/或輕鏈可變區,其各別地包含以SEQ ID NO: 1及2所示之胺基酸序列或與其至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致之胺基酸序列。在另一實施例中,抗LY75抗體與以下抗體競爭結合至LY75:該抗體包含含有以SEQ ID NO: 1及2 (LY75_A1)所示之胺基酸序列之重鏈及/或輕鏈可變區。
本發明之其他抗體結合至相同抗原決定基或由本文所述之抗體識別之LY75上的抗原決定基。在另一特定實施例中,抗體結合至LY75上的抗原決定基,其藉由包含各別地含有以SEQ ID NO: 1及2所示之胺基酸序列或與其至少80%一致之胺基酸序列的重鏈及/或輕鏈可變區的抗體識別。在另一實施例中,抗體結合至LY75上之抗原決定基,其藉由包含含有以SEQ ID NO: 1及2 (LY75_A1)所示之胺基酸序列之重鏈及/或輕鏈可變區的抗體識別。
在另一實施例中,抗LY75抗體特異性結合至選自包含由以下組成之群的一或多種(例如,2種、3種、4種、5種、6種、7種、8種、9種或10種)肽或其片段:SEQ ID NO: 24、25、26、27、28、29、30、31、32、33、34、35、36或37,其中該等片段包含至少2個、至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個或至少10個鄰接胺基酸。在另一實施例中,由抗LY75抗體識別之抗原決定基包含選自由以下組成之群的一或多種肽、兩種或超過兩種或三種或超過三種肽或其片段:SEQ ID NO: 27、29、30、34、35、36或37,其中該等片段包含至少2個、至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個或至少10個鄰接胺基酸。在另一實施例中,由抗LY75抗體識別之抗原決定基包含選自由SEQ ID NO:30、36及37組成之群的一或多種肽、例如兩種或三種肽或其片段,其中該等片段包含至少2個、至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個或至少10個鄰接胺基酸。
在另一實施例中,抗LY75抗體包含與本文所述之親本抗體相比可變的CDR。因此,包含親本抗體之變異可變區的變異抗體,其中該親本抗體包括包含SEQ ID NO:5之第一vhCDR、包含SEQ ID NO:6之第二vhCDR、包含SEQ ID NO:7之第三vhCDR、包含SEQ ID NO:8之第一vlCDR、包含SEQ ID NO:9之第二vlCDR及包含SEQ ID NO:10之第三vlCDR,且其中該變異抗體在第一vhCDR、第二vhCDR、第三vhCDR、第一vlCDR、第二vlCDR及第三vlCDR之集合中總共具有1、2、3、4、5或6個胺基酸取代,其中1至4個、1至3個或1至2個取代具有特定用途,且其中該抗體保留與LY75之特異性結合。
本文所揭示之所有抗體可為全長,例如以下同型中之任一者:IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgD及IgE。或者,抗體可為片段,諸如抗原結合部分或單鏈抗體(例如Fab、F(ab')2、Fv、單鏈Fv片段、分離互補決定區(CDR)或兩種或超過兩種分離CDR之組合)。該等抗體可為任何種類之抗體,包括但不限於人類抗體、人類化抗體及嵌合抗體。
在其他實施例中,抗LY75抗體呈免疫結合物形式(亦即另外包括共價連接部分)。在一個特定實施例中,該部分為藥物,諸如類美登素(maytansinoid)、海兔毒素(dolastatin)、奧瑞他汀(auristatin)、新月毒素(trichothecene)、卡里奇黴素(calicheamicin)、CC1065或其衍生物。在一個較佳實施例中,該藥物部分為DM1或DM4。
在一個實施例中,抗LY75抗體包含重鏈可變區及輕鏈可變區,其各別地由包含SEQ ID NO: 3及4之核酸序列編碼,或由與前述核酸序列至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致之核酸序列或由於基因密碼簡併而不同於SEQ ID NO: 3及4之序列編碼。
在一個實施例中,抗CD20抗體為小鼠/人類嵌合抗體、人類化抗體或人類抗體。較佳地,抗CD20抗體為利妥昔單抗。
在本發明之另一態樣中,提供包含編碼本文所述之抗體之重鏈及輕鏈可變區的核酸的套組表現載體,其可操作地連接至一或多種調節元素。
在一較佳實施例中,宿主細胞包含表現載體,該表現載體包含編碼以下之核酸:
(i)抗LY75抗體或其抗原結合部分之重鏈;
(ii)抗LY75抗體或其抗原結合部分之輕鏈;
(iii)抗CD20抗體或其抗原結合部分之重鏈;及
(iv)抗CD20抗體或其抗原結合部分之輕鏈。
在另一態樣中提供一種治療患者體內之癌症之方法,該方法包含向有需要之患者同時、依序或各別投與治療有效量之本發明醫藥組合物之成分(A)及(B)。
在本發明之另一態樣中提供本發明之醫藥組合物,用於治療癌症。
亦提供如本文所定義之成分(A)及(B)用於製造醫藥組合物之用途,該醫藥組合物用於同時、各別或依序使用以治療癌症。在一個實施例中,癌症較佳為白血病或淋巴瘤。
在一些實施例中,癌症選自由以下組成之群:非霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、黏膜相關淋巴組織(MALT)之淋巴瘤、T細胞/組織細胞豐富之B細胞淋巴瘤、伯基特淋巴瘤、淋巴漿細胞淋巴瘤、小淋巴細胞性淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、周邊T細胞淋巴瘤、間變性大細胞淋巴瘤及血管免疫母細胞T細胞淋巴瘤、急性骨髓白血病及慢性淋巴球性白血病。更佳地,癌症為DLBCL或非霍奇金氏淋巴瘤。
包含本發明之醫藥組合物及視情況存在之使用說明書的套組亦在本發明之範疇內。套組可進一步含有至少一種額外試劑或一或多種額外抗體。
本發明之其他特徵及優勢將自以下實施方式及申請專利範圍顯而易見。
本發明係關於包含如本文所定義之成分(A)及(B)的醫藥組合,其中該醫藥組合物呈用於同時、各別或依序使用之組合製劑的形式。組分(A)係關於如本文所定義之抗LY75抗體。組分(B)係關於(i)如本文所定義之抗CD20抗體或(ii)依魯替尼或其醫藥學上可接受之鹽中之任一者。
LY75蛋白之一個實施例在此處SEQ ID NO: 15中給出。術語「抗LY75抗體」及「LY75抗體」在本文中可互換地使用。
本文所揭示之LY75抗體可在與表現LY75受體之細胞接觸時內化。如本文所論述,LY75受體在某些癌細胞上過度表現且/或有差異地表現,包含但不限於白血病,較佳急性骨髓白血病或慢性淋巴球性白血病;淋巴瘤,較佳DLBCLB細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、黏膜相關淋巴組織(MALT)之淋巴瘤、T細胞/組織細胞豐富之B細胞淋巴瘤、伯基特淋巴瘤、淋巴漿細胞淋巴瘤、小淋巴細胞性淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、周邊T細胞淋巴瘤、間變性大細胞淋巴瘤及血管免疫母細胞T細胞淋巴瘤。
由此,在本文所揭示之LY75抗體結合至藥物(在本文中有時稱作「抗體-藥物結合物」或「ADC」)時,此等ADC分子內化至癌細胞中引起細胞死亡且由此治療腫瘤。
抗LY75抗體具有特定結構特徵,諸如具有特定胺基酸序列之CDR區域。此處描述一組CDR,其可形成展現結合至LY75之親和力試劑,例如抗體。
因此,本發明提供抗體,較佳分離抗體(其如下文概述包括廣泛多種熟知抗體結構、衍生物、模擬物及結合物);編碼抗體組合之核酸;用以製造抗體組合之宿主細胞;製造抗體組合之方法;及包含該等抗體及視情況醫藥載劑之醫藥組合;包含使用該等醫藥組合之治療方法以及該等醫藥組合用於治療癌症之用途。
淋巴細胞抗原75充當將自胞外空間捕捉之抗原引導至特定抗原處理區室之內飲受體且被認為造成B淋巴細胞增殖降低。
根據SWISS-PROT,淋巴細胞抗原75表現於脾臟、胸腺、結腸及周邊血液淋巴細胞中。其已在骨髓細胞株及B淋巴樣細胞株中偵測到。本文稱為OGTA076b及OGTA076c之同功異型物表現於稱為霍奇金氏及李特-斯頓伯格(Hodgkin's and Reed-Sternberg,HRS)細胞之惡性霍奇金氏淋巴瘤細胞中。LY75充當將自胞外空間捕捉之抗原引導至特定抗原處理區室之內飲受體。其造成B淋巴細胞之增殖降低。
已在胰臟癌、膀胱癌、卵巢癌、乳癌(包括三陰性)、結腸直腸癌、食道癌、皮膚癌、甲狀腺癌及肺癌(非小細胞)以及多發性骨髓瘤及淋巴瘤(包括DLBCL)與白血病之許多不同亞型中觀察到LY75之表現。
抗LY75抗體可在某些情況中與來自除人類以外之物種之LY75交叉反應。舉例而言,為有助於臨床測試,抗LY75抗體可與鼠類或靈長類LY75分子交叉反應。或者,在某些實施例中,該等抗體可完全特異性針對人類LY75且可能不展現物種交叉反應性或其他類型之非人類交叉反應性。
本發明係關於抗LY75抗體以及在一些實施例中關於抗CD20抗體,總體上如本文所述之治療性抗體。在本發明中可用之抗體可呈如本文所述之許多形式,包括下文所述之傳統抗體以及抗體衍生物、片段及模擬物。在一個實施例中,本發明提供含有如本文所定義之一組6個CDR之抗體結構(包括如下所述之少量胺基酸變化)。
如本文中所用,「抗體」包括廣泛多種結構,如此項技術者將瞭解的,該等結構在一些實施例中含有最少如本文所定義之一組6個CDR;包括但不限於傳統抗體(包括單株及多株抗體兩者)、人類化及/或嵌合抗體、抗體片段、經工程改造抗體(例如下文概述之用胺基酸修飾)、多特異性抗體(包括雙特異性抗體)以及此項技術中已知之其他類似物。
傳統抗體結構單元通常包含四聚體。各四聚體通常由相同的兩對多肽鏈組成,各對具有一條「輕」鏈(通常具有約25 kDa之分子量)及一條「重」鏈(通常具有約50-70 kDa之分子量)。人類輕鏈分類為κ及λ (lambda)輕鏈。重鏈分類為μ、δ、γ、α或ε,且抗體之同型分別定義為IgM、IgD、IgG、IgA及IgE。IgG具有若干亞類,包括但不限於IgG1、IgG2、IgG3及IgG4。IgM具有亞類,包括但不限於IgM1及IgM2。因此,如本文所用之「同型」意謂藉由恆定區之化學及抗原特徵定義之免疫球蛋白之子類中之任一者。已知人類免疫球蛋白同型為IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgM1、IgM2、IgD及IgE。應理解,治療抗體亦可包含同型及/或子類之任何組合之混合物。
在多個實施例中,IgG同型用於本發明中,其中IgG1特定可用於多種應用中。
各鏈之胺基端部分包括主要負責抗原識別之具有約100至110個或超過110個胺基酸之可變區。在可變區中,對於重鏈及輕鏈之V域中之每一者聚集三個環以形成抗原結合位點。該等環中之每一者被稱作互補決定區(在下文中稱為「CDR」),其中胺基酸序列中之變化最顯著。「可變」係指可變區之某些片段在抗體中之序列中廣泛不同之事實。可變區內之變化性並非均勻分佈。替代地,V域由以下構成:15-30個胺基酸的相對恆定之伸長部(稱為構架區(FR)),其由各為9-15個胺基酸長或更長的極度可變之較短區域(稱為「高變區」)分隔開。
各VH及VL由三個高變區(「互補決定區」、「CDR」)及四個FR組成,自胺基端至羧基端按以下順序排列:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
高變區總體上涵蓋輕鏈可變區中約胺基酸殘基24-34 (LCDR1;「L」指示輕鏈)、50-56 (LCDR2)及89-97 (LCDR3)之胺基酸殘基及在重鏈可變區中約31-35B (HCDR1;「H」指示重鏈)、50-65 (HCDR2)及95-102 (HCDR3)周圍之胺基酸殘基;Kabat等人, SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 第5版 Public Health Service, 美國國家衛生研究院, 馬里蘭州貝塞斯達(1991)及/或形成高變環之彼等殘基(例如輕鏈可變區中之殘基26-32 (LCDR1)、50-52 (LCDR2)及91-96 (LCDR3)及重鏈可變區中之26-32 (HCDR1)、53-55 (HCDR2)及96-101 (HCDR3));Chothia及Lesk (1987) J. Mol. Biol. 196:901-917。下文所述本發明之特定CDR。
貫穿本發明,在提及可變域中之殘餘物時總體上使用Kabat編號系統(大致地,輕鏈可變區之殘基1-107及重鏈可變區之殘基1-113)(例如Kabat等人,前述(1991))。
CDR促進形成抗體之抗原結合,或更特定言之,抗原決定基結合位點。術語「抗原決定基」或「抗原決定子」係指免疫球蛋白或抗體所特異性結合之抗原上的位點。抗原決定基可由鄰接胺基酸或非鄰接胺基酸形成,此等胺基酸因蛋白質之三級摺疊而毗鄰。由鄰接胺基酸形成的抗原決定基通常在暴露於變性溶劑後保留,而藉由三級摺疊形成的抗原決定基在變性溶劑處理後通常消失。抗原決定基典型地以獨特的空間構形包括至少3、4、5、6、7、8、9、10、11、12、13、14或15個胺基酸。如本文所述,用於測定何種抗原決定基由給定抗體結合(亦即抗原決定基定位)之方法為此項技術中所熟知的且包括例如免疫墨點法及免疫沈澱分析,其中測試LY75之重疊或相連肽與給定抗LY75抗體之反應性。測定抗原決定基之空間構形之方法包括此項技術中之技術及本文所述之彼等技術,例如X射線結晶及2維核磁共振(參見例如
Methods in Molecular Biology中之
Epitope Mapping Protocols, 第66卷, G. E. Morris編 (1996))。術語「抗原決定基定位」係指鑑別用於抗體-抗原識別之分子決定子的方法。
各鏈之羧基端部分界定主要負責效應功能之恆定區。Kabat等人收集重鏈及輕鏈之可變區之許多一級序列。基於序列之保守度,他們將個別一級序列分類至CDR及構架中且製成其之列表(參見SEQUENCES OF IMMUNOLOGICAL INTEREST, 第5版, NIH出版, 第91-3242號, E.A. Kabat等人)。
在免疫球蛋白之IgG子類中,重鏈存在若干免疫球蛋白結構域。「免疫球蛋白(Ig)結構域」在本文中意指具有獨特三級結構之免疫球蛋白區。本發明中所關注的為重鏈結構域,包括恆定重鏈(CH)結構域及鉸鏈結構域。在IgG抗體之情形下,IgG同型各具有三個CH區。因此,在IgG之情形下,「CH」結構域如下:「CH1」係指根據如Kabat中之EU指數的位置118-220。「CH2」係指根據如Kabat中之EU指數的位置237-340,且「CH3」係指根據如Kabat中之EU指數的位置341-447。
重鏈之另一類型之Ig結構域為鉸鏈區。「鉸鏈」或「鉸鏈區」或「抗體鉸鏈區」或「免疫球蛋白鉸鏈區」在本文中意指包含抗體之第一與第二恆定結構域之間之胺基酸的可撓性多肽。在結構上,IgG CH1結構域在EU位置220處結束,且IgG CH2結構域在殘基EU位置237處開始。因此,對於IgG,抗體鉸鏈在本文中界定為包括位置221 (IgG1中之D221)至236 (IgG1中之G236),其中編號係根據如Kabat中之EU指數。在一些實施例中,例如在Fc區之情形下,包括下部鉸鏈,其中「下部鉸鏈」一般係指位置226或230。
本發明中尤其受關注的為Fc區。如本文所用,「Fc」或「Fc區」或「Fc結構域」意指包含抗體恆定區(第一恆定區免疫球蛋白結構域除外)及在一些情況下,鉸鏈之一部分的多肽。因此,Fc係指IgA、IgD及IgG之最後兩個恆定區免疫球蛋白結構域、IgE及IgM之最後三個恆定區免疫球蛋白結構域、及此等結構域之可撓性鉸鏈N端。對於IgA及IgM,Fc可包括J鏈。對於IgG,Fc結構域包含免疫球蛋白結構域Cγ2及Cγ3 (Cγ2及Cγ3)及Cγ1 (Cγ1)與Cγ2 (Cγ2)之間的下部鉸鏈區。雖然Fc區之邊界可改變,但人類IgG重鏈Fc區通常界定為包括殘基C226或P230至其羧基端,其中編號係根據如Kabat中之EU指數。在一些實施例中,如下文更充分地描述,對Fc區進行胺基酸修飾,例如以改變與一或多種FcγR受體或與FcRn受體之結合。
在一些實施例中,抗體為全長。「全長抗體」在本文中意指構成抗體之天然生物學形式的結構,包括可變區及恆定區,包括如本文所概述之一或多種修飾。
或者,抗體可為多種結構,包括(但不限於)抗體片段、單株抗體、雙特異性抗體、微型抗體、結構域抗體、合成抗體(有時在本文中稱為「抗體模擬物」)、嵌合抗體、人類化抗體、抗體融合物(有時稱為「抗體結合物」)、及對應地每一者的片段。依賴於使用一組CDR之結構包括在「抗體」之定義內。
在一個實施例中,該抗體為抗體片段。特異性抗體片段包括(但不限於):(i)由VL、VH、CL及CH1結構域組成之Fab片段,(ii)由VH及CH1結構域組成之Fd片段,(iii)由單一抗體之VL及VH結構域組成之Fv片段;(iv)由單一可變區組成之dAb片段(Ward等人, 1989, Nature 341:544-546,以引用的方式全部併入),(v)經分離CDR區,(vi)F(ab')2片段,包含兩個連接之Fab片段的二價片段,(vii)單鏈Fv分子(scFv),其中VH結構域及VL結構域藉由肽連接子連接,使得兩個結構域締合以形成抗原結合位點(Bird等人, 1988, Science 242:423-426,Huston等人, 1988, Proc. Natl. Acad. Sci. U.S.A. 85:5879-5883,以引用的方式全部併入),(viii)雙特異性單鏈Fv (WO 03/11161,以引用的方式併入本文中)及(ix)「雙功能抗體」或「三功能抗體」,藉由基因融合構築之多價或多特異性片段(Tomlinson等人, 2000, Methods Enzymol. 326:461-479;WO94/13804;Holliger等人, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:6444-6448,皆以引用的方式全部併入)。
在一些實施例中,抗體可為來自不同物種之混合物,例如嵌合抗體及/或人類化抗體。亦即,在本發明中,CDR組可與除由本文序列特定描述之構架區及恆定區以外的構架區及恆定區一起使用。
一般,「嵌合抗體」及「人類化抗體」係指使來自一種以上物種之區組合的抗體。舉例而言,「嵌合抗體」傳統上包含來自小鼠(或在一些情況下,大鼠)之可變區及來自人類之恆定區。「人類化抗體」一般係指已用人類抗體中發現之序列交換可變結構域構架區的非人類抗體。一般而言,在人類化抗體中,除CDR之外的整個抗體由人類來源之聚核苷酸編碼,或除在其CDR內之外,與此類抗體一致。一些或全部由來源於非人類生物體之核酸編碼的CDR移植至人類抗體可變區之β摺疊構架中以形成抗體,其特異性由移植之CDR決定。此類抗體之形成描述於例如WO 92/11018;Jones, 1986, Nature 321:522-525;Verhoeyen等人, 1988, Science 239:1534-1536中,其皆以引用的方式全部併入。常常需要使所選受體構架殘基「回復突變」成對應供體殘基以恢復初始移植構築體中損失之親和力(US 5530101;US 5585089;US 5693761;US 5693762;US 6180370;US 5859205;US 5821337;US 6054297;US 6407213,皆以引用的方式全部併入)。人類化抗體最佳亦應包含免疫球蛋白恆定區之至少一部分,通常為人類免疫球蛋白之免疫球蛋白恆定區,且因此應通常包含人類Fc區。人類化抗體亦可使用具有經基因工程改造之免疫系統的小鼠來產生。Roque等人, 2004, Biotechnol. Prog. 20:639-654,以引用的方式全部併入。用於使非人類抗體人類化及重塑之多種技術及方法為此項技術中所熟知(參見Tsurushita及Vasquez, 2004, Humanization of Monoclonal Antibodies, Molecular Biology of B Cells, 533-545, Elsevier Science (USA)及其中所引用之參考文獻,其皆以引用的方式全部併入)。人類化方法包括但不限於以下文獻中所述之方法:Jones等人, 1986, Nature 321:522-525;Riechmann等人, 1988; Nature 332:323-329;Verhoeyen等人, 1988, Science, 239:1534-1536;Queen等人, 1989, Proc Natl Acad Sci, USA 86:10029-33;He等人, 1998, J. Immunol. 160: 1029-1035;Carter等人, 1992, Proc Natl Acad Sci USA 89:4285-9;Presta等人, 1997, Cancer Res. 57(20):4593-9;Gorman等人, 1991, Proc. Natl. Acad. Sci. USA 88:4181-4185;O'Connor等人, 1998, Protein Eng 11:321-8,其皆以引用的方式完全併入。人類化或降低非人類抗體可變區免疫原性之其他方法可包括表面重修方法,如例如Roguska等人, 1994, Proc. Natl. Acad. Sci. USA 91:969-973中所述,其以全文引用的方式併入。在一個實施例中,親本抗體如此項技術中已知已為親和力成熟的。可採用基於結構之方法用於人類化及親和力成熟,如例如USSN 11/004,590中所述。基於選擇之方法可用以使抗體可變區人類化及/或親和力成熟,包括(但不限於)Wu等人, 1999, J. Mol. Biol. 294:151-162;Baca等人, 1997, J. Biol. Chem. 272(16):10678-10684;Rosok等人, 1996, J. Biol. Chem. 271(37): 22611-22618;Rader等人, 1998, Proc. Natl. Acad. Sci. USA 95: 8910-8915;Krauss等人, 2003, Protein Engineering 16(10):753-759中所述之方法,其皆以全文引用的方式併入。其他人類化方法可涉及移植僅部分CDR,包括(但不限於)USSN 09/810,510;Tan等人, 2002, J. Immunol. 169:1119-1125;De Pascalis等人, 2002, J. Immunol. 169:3076-3084中所述之方法,其皆以全文引用的方式併入。
本文所揭示之抗體可為經分離或重組。「經分離」在用於描述本文所揭示之各種多肽時,意指已自表現細胞或細胞培養物鑑定及分離及/或回收之多肽。因此,經分離抗體意欲指實質上不含具有不同抗原特異性之其他抗體的抗體(例如特異性結合至LY75之經分離抗體實質上不含特異性結合除LY75以外之抗原的抗體)。因此,「經分離」抗體為發現呈在自然界中正常未發現之形式的抗體(例如非天然存在的)。在一個實施例中,如本文所定義之經分離抗體可包括至少一個「天然」存在之抗體中不存在之胺基酸。此胺基酸可藉助於添加或取代引入。應瞭解,所引入之胺基酸可為天然存在或非天然存在之胺基酸。在一些實施例中,本發明之抗體為重組蛋白質、經分離蛋白質或實質上純的蛋白質。「經分離」蛋白質無在其天然狀態中與其正常締合之至少一些物質伴隨,例如佔給定樣品總蛋白質之至少約5重量%或至少約50重量%。應瞭解,經分離之蛋白質可視環境而定構成按總蛋白質之重量計之自5重量%至99.9重量%。舉例而言,蛋白質可經由使用誘導性啟動子或高表現啟動子而以顯著較高濃度製得,使得蛋白質以增加之濃度水準製得。就重組蛋白質而言,定義包括在此項技術中已知的廣泛多種生物體及/或宿主細胞中產生非天然產生之抗體。通常,經分離多肽將藉由至少一個純化步驟來製備。「經分離抗體」係指實質上不含具有不同抗原特異性之其他抗體的抗體。舉例而言,除了結合至CD20之抗體之外,特異性結合至LY75之經分離抗體實質上不含與除LY75之外之抗原特異性結合的抗體。
具有不同特異性之經分離單株抗體可組合在明確定義之組合物中。因此,舉例而言,本發明之抗體可視情況及單獨包括或排除在調配物中,如下文進一步論述。
本發明之抗LY75抗體與LY75 (例如SEQ ID NO: 15)特異性結合。本發明之抗CD20抗體與CD20特異性結合。「特異性結合」或「特異性結合至」或「對」特定抗原或抗原決定基「具有特異性」意謂可量測地不同於非特異性相互作用之結合。特異性結合可例如藉由與對照分子之結合相比測定分子之結合來量測,對照分子通常係不具有結合活性之具有類似結構的分子。舉例而言,可藉由與類似於標靶之對照分子之競爭測定特異性結合。
針對特定抗原或抗原決定基之特異性結合可例如藉由抗體對抗原或抗原決定基具有至少約10
-4M、至少約10
-5M、至少約10
-6M、至少約10
-7M、至少約10
-8M、至少約10
-9M、或者至少約10
-10M、至少約10
-11M、至少約10
-12M或更大之KD來顯現,其中KD係指特定抗體-抗原相互作用之解離速率。通常,特異性結合抗原之抗體相對於抗原或抗原決定基應之K
D比對照分子大20倍、50倍、100倍、500倍、1000倍、5,000倍、10,000倍或高於10,000倍。然而,在本發明中,當投與本發明之LY75抗體之ADC時,重要的是KD足以允許內化且因此使得細胞死亡而無顯著副作用。
另外,針對特定抗原或抗原決定基之特異性結合可例如藉由抗體對抗原或抗原決定基具有相對於對照對抗原決定基大至少20倍、50倍、100倍、500倍、1000倍、5,000倍、10,000倍或更多倍的K
A或K
a來顯現,其中K
A或K
a係指特定抗體-抗原相互作用之締合速率。
評估抗體對於LY75或CD20之結合能力的標準分析可在蛋白質或細胞水準上進行且為此項技術中已知的,包括例如ELISA、西方墨點、RIA、BIAcore®分析及流動式細胞量測術分析。在實例中詳細地描述合適分析。抗體之結合動力學(例如結合親和力)亦可藉由此項技術中已知之標準分析,諸如藉由Biacore
®系統分析來評估。為評估與Raji或Daudi B細胞腫瘤細胞之結合,可自公開可用之來源(諸如美國菌種保藏中心(American Type Culture Collection))獲得Raji (ATCC保藏號CCL-86)或Daudi (ATCC保藏號CCL-213)細胞且用於標準分析,諸如流動式細胞量測術分析。
結合至LY75 (SEQ ID NO: 15)之LY75抗體可在與細胞表面上表現LY75之細胞接觸時內化。此等抗體在本文中稱為「抗LY75」抗體,或為了易於描述稱為「LY75抗體」。兩個術語在本文中可互換地使用。
LY75抗體在與表面上表現LY75之細胞(尤其腫瘤細胞)接觸後內化。亦即,如本文所定義之亦包含藥物結合物之LY75抗體由腫瘤細胞內化,導致藥物釋放及隨後細胞死亡,允許治療展現LY75表現之癌症。內化在此情形中可以若干方式加以量測。在一個實施例中,LY75抗體使用諸如MAbZap之標準分析與細胞(諸如本文所概述之細胞株)接觸。技術人員應清楚,MabZap分析表示效應將預期在抗體-藥物結合物(ADC)之情況下見到。在後一情況中,ADC將經內化,由此獲取藥物至細胞中。毒性藥物將具有殺死細胞,亦即殺死靶向癌細胞之能力。熟習此項技術者可容易地接受來自MabZap分析之資料代表ADC分析(Kohls, M及Lappi, D., [2000] Biotechniques, 第28卷, 第1號, 162-165)。
在此等活體外分析實施例中,本發明之LY75抗體連同包含毒素之抗LY75抗體一起添加;舉例而言,LY75抗體可為鼠類或人類化的,且抗LY75抗體可為抗鼠類或抗人類化的且含有諸如沙泊寧(saporin)之毒素。在形成[LY75抗體]-[抗LY75抗體-藥物結合物]複合物時,複合物內化且釋放藥物(例如沙泊寧),導致細胞死亡。藥物僅在內化後釋放,且因此細胞在不存在內化之情況下保持活力。如下文所概述,在不受理論束縛的情況下,在治療性應用中,抗LY75抗體含有毒素且在內化後,抗體與毒素之間的鍵裂解,釋放毒素且殺死細胞。
在一個實施例中,抗LY75抗體包含本文所述之特定抗體(例如在本文中稱為「LY75_A1」)之重鏈及輕鏈互補決定區(CDR)或可變區(VR)。因此,在一個實施例中,抗體包含具有展示於SEQ ID NO:1中之序列之抗體LY75_A1的重鏈可變(VH)區的CDR1、CDR2及CDR3域,及具有展示於SEQ ID NO:2中之序列之抗體LY75_A1的輕鏈可變(VL)區的CDR1、CDR2及CDR3域。
在另一實施例中,抗LY75抗體包含:重鏈可變區,其包括包含SEQ ID NO:5之第一vhCDR;包含SEQ ID NO:6之第二vhCDR;及包含SEQ ID NO:7之第三vhCDR;及輕鏈可變區,其包括包含SEQ ID NO:8之第一vlCDR;包含SEQ ID NO:9之第二vlCDR;及包含SEQ ID NO:10之第三vlCDR。
在另一實施例中,抗LY75抗體結合至人類LY75且包括包含含有SEQ ID NO: 1之胺基酸序列及其保守序列修飾的重鏈可變區。抗體可進一步包括包含含有SEQ ID NO: 2之胺基酸序列及其保守序列修飾的輕鏈可變區。
在另一實施例中,抗LY75抗體結合至人類LY75且包括重鏈可變區及輕鏈可變區,其各別地包含以SEQ ID NO: 1及/或2所示之胺基酸序列及其保守序列修飾。如本文所用,術語保守序列修飾係指例如胺基酸經具有類似特徵之胺基酸取代。何種此類取代可視為保守為熟習此項技術者的公共常識。可視為保守序列修飾之其他修飾包括例如糖基化。
視情況,SEQ ID NO: 5-10中之一或多者獨立地包含一個、兩個、三個、四個或五個保守胺基酸取代;視情況,SEQ ID NO: 5-10中之一或多者獨立地包含一個或兩個保守胺基酸取代。
優選地,術語「保守序列修飾」意欲包含不會顯著影響或改變含有該胺基酸序列之抗體之結合特徵的胺基酸修飾。此類保守修飾包括胺基酸取代、添加及缺失。可藉由此項技術中已知之標準技術將修飾引入本發明抗體中,諸如定點突變誘發及PCR介導之突變誘發。保守胺基酸取代為胺基酸殘基經具有類似側鏈之胺基酸殘基置換之取代。此項技術中已限定具有類似側鏈之胺基酸殘基家族。此等家族包括具有鹼性側鏈(例如離胺酸、精胺酸、組胺酸)、酸性側鏈(例如天冬胺酸、麩胺酸)、不帶電極性側鏈(例如甘胺酸、天冬醯胺、麩醯胺酸、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸、色胺酸)、非極性側鏈(例如丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸)、β分支鏈側鏈(例如蘇胺酸、纈胺酸、異白胺酸)及芳族側鏈(例如酪胺酸、苯丙胺酸、色胺酸、組胺酸)之胺基酸。因此,本發明抗體之CDR區內的一或多個胺基酸殘基可用來自相同側鏈家族的其他胺基酸殘基置換且可使用此處描述之官能基分析針對殘留官能基測試改變的抗體。
包括與以上序列中之任一者具有至少80%、或至少85%、或至少90%、或至少91%、或至少92%、或至少93%、或至少94%、或至少95%、或至少96%、或至少97%、或至少98%、或至少99%或超過99%序列一致性之重鏈及輕鏈可變區的經分離抗體亦包括在本發明中。本發明同樣意欲涵蓋在上文所列舉之值中間的範圍,例如與以上序列中之任一者具有至少80-85%、85-90%、90-95%或95-100%序列一致性之重鏈及輕鏈可變區。在一個實施例中,抗LY75抗體包含重鏈可變區,該重鏈可變區包含SEQ ID NO: 1或與SEQ ID NO: 1至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的序列。在另一實施例中,抗LY75抗體包含輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 2或與SEQ ID NO: 2至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的序列。在另一實施例中,抗LY75抗體包含重鏈構架區,該重鏈構架區包含與包含SEQ ID NO: 16、17及18的SEQ ID NO: 1之重鏈可變區之構架至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的胺基酸序列。在另一實施例中,抗LY75抗體包含輕鏈構架區,該輕鏈構架區包含與包含SEQ ID NO:19、20及21的SEQ ID NO: 2之輕鏈可變區之構架至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%一致的胺基酸序列。
在一個實施例中,抗LY75抗體在本文中稱作「LY75_A1抗體」,其包含以下CDR以及含有有限數目之胺基酸變異的變體:
本文亦揭示包含本發明之CDR組之可變重鏈及輕鏈以及全長重鏈及輕鏈(例如亦包含恆定區)。如熟習此項技術者應瞭解,抗LY75抗體之CDR組可併入鼠類、人類化或人類恆定區(包括構架區)中。因此,本發明提供與本文所揭示之SEQ ID至少約90%-99%一致之可變重鏈及輕鏈,其中90、91、92、93、94、95、96、97、98及99%皆可用於本發明中。
在一些實施例中,抗LY75抗體為與以下抗體競爭結合至人類LY75之抗體:該抗體包含含有SEQ ID NO: 1中所闡述之胺基酸序列的重鏈可變區,及含有以SEQ ID NO: 2所示之胺基酸序列的輕鏈可變區。競爭結合之抗體可使用例行技術來識別。此類技術包括例如免疫分析,其展示一種抗體阻斷另一抗體結合至目標抗原的能力,亦即競爭性結合分析。競爭性結合在受測試之免疫球蛋白抑制參考抗體與諸如LY75之常見抗原之特異性結合的分析中加以測定。已知許多類型之競爭性結合分析,例如:固相直接或間接放射免疫分析(RIA)、固相直接或間接酶免疫分析(EIA)、夾心競爭分析(參見Stahli等人,
Methods in Enzymology9:242 (1983));固相直接生物素-抗生物素蛋白EIA (參見Kirkland等人,
J. Immunol.137:3614 (1986));固相直接標記分析、固相直接標記夾心分析(參見Harlow及Lane,
Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988));使用I-125標記之固相直接標記RIA (參見Morel等人,
Mol. Immunol.25(1):7 (1988));固相直接生物素-抗生物素蛋白EIA (Cheung等人,
Virology176:546 (1990));及直接標記RIA (Moldenhauer等人,
Scand. J. Immunol.32:77 (1990))。通常,此類分析涉及使用經純化抗原,該經純化抗原會結合至帶有未經標記之測試免疫球蛋白及經標記之參考免疫球蛋白中任一者的固體表面或細胞。競爭性抑制係藉由在測試免疫球蛋白存在下測定結合至固體表面或細胞之標記的量來量測。測試免疫球蛋白通常過量存在。通常,當競爭抗體過量存在時,其將抑制參考抗體與常見抗原之特異性結合至少50-55%、55-60%、60-65%、65-70%、70-75%、75-80%、80-85%、85-90%、90-95%、95-99%或超過99%。
單株抗體可藉由結合至LY75或CD20使用多種已知技術來表徵。一般而言,抗體最初藉由ELISA表徵。簡言之,微量滴定板可用含經純化LY75或CD20之PBS塗佈,且隨後用稀釋於PBS中之諸如牛血清白蛋白(BSA)之不相關蛋白質阻斷。將來自經LY75免疫小鼠或經CD20免疫小鼠的血漿稀釋液添加到各孔並且在37℃下培育1-2小時。板用PBS/吐溫20洗滌且隨後與結合至鹼性磷酸酶之山羊抗人類IgG Fc特異性多株試劑一起在37℃下培育1小時。在洗滌後,板用ABTS受質顯影且在OD 405下分析。較佳地,出現最高效價之小鼠將用於融合。
如上所述之ELISA分析可用於篩選展示與LY75/CD20免疫原之陽性反應性的抗體,且因此篩選產生該等抗體之融合瘤。可接著次選殖較佳以高親和力結合至LY75/CD20之融合瘤且進一步表徵。可接著自保留親本細胞之反應性(藉由ELISA)之各融合瘤選擇一個純系用於製造細胞庫及用於抗體純化。
為純化抗LY75抗體或抗CD20抗體,所選融合瘤可在滾瓶、兩公升轉瓶或其他培養系統中生長。可過濾上澄液且濃縮,隨後用蛋白質A-瓊脂糖(Pharmacia, Piscataway, NJ)親和層析以純化蛋白質。在緩衝液更換為PBS後,可藉由使用1.43消光係數之OD
280或較佳藉由濁度分析測定濃度。IgG可藉由凝膠電泳及藉由抗原特異性方法來檢查。
為測定所選抗LY75或抗CD20單株抗體是否結合至獨特抗原決定基,可使用市售試劑(Pierce, Rockford, IL)對每一抗體進行生物素標記。可使用抗生蛋白鏈菌素標記之探針偵測生物素標記之單抗結合。為測定經純化抗體之同型,可使用此項技術公認之技術進行同型ELISA。舉例而言,微量滴定板之孔可在4℃下用10 μg/ml抗Ig塗佈隔夜。在用5% BSA阻斷後,使板在環境溫度下與10 μg/ml單株抗體或經純化同型對照反應兩小時。可接著使孔與特異性結合探針之IgGl或其他同型反應。使板顯影,且如上文所描述進行分析。
為測試單株抗體與表現LY75或CD20之活細胞的結合,可使用流動式細胞測量術。簡言之,細胞株及/或表現人類PBMC之膜結合LY75或CD20(在標準生長條件下生長)與含有0.1% BSA的含不同濃度之單株抗體的PBS在4℃下混合1小時。在洗滌之後,使細胞與螢光素標記之抗人類IgG抗體在與初級抗體染色相同之條件下反應。樣品可藉由使用光散射及側向散射特性對單細胞進行閘控之FACScan儀器來分析,且測定經標記抗體之結合。除流動式細胞量測術分析之外或代替流動式細胞量測術分析,可使用螢光顯微法之替代性分析。細胞可如上所述準確染色且藉由螢光顯微法檢驗。此方法允許目測個別細胞,但可具有降低之靈敏度,視抗原密度而定。
可進一步針對反應性藉由西方墨點法用LY75抗原測試抗LY75 IgG;同樣可對抗CD20抗體進行。簡言之,可製備來自表現LY75/CD20之細胞的細胞提取物且進行十二烷基硫酸鈉聚丙烯醯胺凝膠電泳。在電泳之後,分離之抗原均轉移至硝化纖維膜,用20%小鼠血清阻斷,且用待測試之單株抗體探測。可使用抗IgG鹼性磷酸酶偵測IgG結合且藉由BCIP/NBT受質錠劑(Sigma Chem. Co., St. Louis, MO)顯影。
用於分析各種抗LY75抗體之結合親和力、交叉反應性及結合動力學的方法包括此項技術中已知的標準分析,例如使用Biacore
TM2000 SPR儀器(Biacore AB, Uppsala, Sweden之Biacore
TM表面電漿子共振(SPR)分析。
在一個實施例中,抗體特異性結合至包含SEQ ID NO: 15之人類LY75。優選地,抗LY75抗體以高親和力結合至人類LY75。
較佳地,抗LY75抗體以5×10
-8M或小於5×10
-8M之K
D結合至LY75蛋白質、以2×10
-8M或小於2×10
-8M之K
D結合至LY75蛋白質、以5×10
-9M或小於5×10
-9M之K
D結合至LY75蛋白質、以4×10
-9M或小於4×10
-9M之K
D結合至LY75蛋白質、以3×10
-9M或小於3×10
-9M之K
D結合至LY75蛋白質、以2×10
-9M或小於2×10
-9M之K
D結合至LY75蛋白質、以1×10
-9M或小於1×10
-9M之K
D結合至LY75蛋白質、以5×10
-10M或小於5×10
-10M之K
D結合至LY75蛋白質、或以1×10
-10M或小於1×10
-10M之K
D結合至LY75蛋白質。
在一個實施例中,抗LY75抗體與本文所述之特定抗LY75抗體(例如LY75_A1)競爭(例如交叉競爭)結合至LY75。此類競爭抗體可基於其在標準LY75結合分析中競爭性抑制一或多種mAb結合至LY75之能力來鑑定。舉例而言,可使用標準ELISA分析,其中將重組人類LY75蛋白質固定於板上,螢光標記一種抗體且評估未標記之抗體競爭去除經標記抗體之結合的能力。或者或另外,BIAcore分析可用於評估抗體交叉競爭之能力。測試抗體抑制本發明之抗LY75抗體與人類LY75之結合的能力表明測試抗體可與抗體競爭結合至人類LY75。
在一個實施例中,競爭抗體為與本文所述之特定抗LY75單株抗體(例如LY75_A1)結合至人類LY75上之相同抗原決定基的抗體。諸如x射線結晶及2維核磁共振之標準抗原決定基定位技術可用於測定抗體是否與參考抗體結合至相同抗原決定基(參見例如Epitope Mapping Protocols, Methods in Molecular Biology, 第66卷, G. E. Morris編 (1996))。
在一個實施例中,競爭結合至LY75及/或結合至人類LY75上之相同抗原決定基的抗體為人類抗體。
一旦已分離具有本文所述之所需特性的單一原型抗LY75 mAb,可產生具有類似特性(例如具有相同抗原決定基)之其他mAb。舉例而言,小鼠可經如本文所述之LY75免疫,產生融合瘤,且就與原型mAb競爭結合至LY75之能力篩檢所得mAb。小鼠亦可經含有原型mAb所結合之抗原決定基的LY75的較小片段免疫。抗原決定基可藉由例如篩檢與跨越LY75之一系列重疊肽的結合來定位。或者,可使用Jespers等人, Biotechnology 12:899, 1994之方法支配具有與原型mAb相同的抗原決定基且因此具有類似特性之mAb的選擇。使用噬菌體呈現,首先使原型抗體之重鏈與(較佳人類)輕鏈之譜系配對以選擇結合LY75之mAb,且隨後使新輕鏈與(較佳人類)重鏈之譜系配對以選擇具有與原型mAb相同的抗原決定基的(較佳人類)結合LY75之mAb。或者,可藉由編碼抗體重鏈及輕鏈之cDNA的突變誘發獲得原型mAb之變體。
為評估兩種抗體之間的競爭水準,可使用抗體之放射免疫分析或使用其他標記之分析。舉例而言,LY75抗原可與飽和量的與標記化合物(例如
3H、
125I、生物素或銣)結合之第一抗LY75抗體或其抗原結合片段在相同量之第二未標記抗LY75抗體存在下一起培育。接著評估在未標記之阻斷抗體存在下結合至抗原之經標記抗體之量,且與在不存在未標記之阻斷抗體的情況下的結合相比。競爭係藉由在未標記之阻斷抗體存在下,與不存在阻斷抗體相比之結合信號的變化百分比來測定。因此,若在阻斷抗體存在下經標記抗體之結合與無阻斷抗體存在下之結合相比存在50%抑制,則在兩種抗體之間存在50%之競爭。因此,提及第一與第二抗體之間50%或超過50%、60%或超過60%、70%或超過70%,諸如70%、71%、72%、73%、74%、75%、80%、85%、90%、95%、96%、97%、98%、99%或超過99%之競爭意指第一抗體抑制第二抗體(或反之亦然)與抗原之結合達50%、60%、70%、71%、72%、73%、74%、75%、80%、85%、90%、95%、96%、97%、98%、99%或超過99% (與無第一抗體存在下抗原與第二抗體之結合相比)。因此,第一抗體與抗原之結合由第二抗體抑制50%、60%、70%、71%、72%、73%、74%、75%、80%、85%、90%、95%、96%、97%、98%、99%或超過99%表明該兩種抗體結合至相同抗原決定基。
在一些實施例中,醫藥組合物之組分(B)為如本文所定義之抗CD20抗體。
B淋巴細胞抗原CD20,或CD20,為在所有B細胞之表面上表現的活化糖基化磷蛋白,其開始於前B期(CD45R+,CD117+)且濃度逐漸增加直至成熟期(Hardy, Richard (2008). 「第7章: B Lymphocyte Development and Biology」。於Paul, William. Fundamental Immunology (書) (第6版)中。Philadelphia: Lippincott Williams & Wilkins. 第237-269頁. ISBN 0-7817-6519-6)。
CD20表現於B細胞發育之除了第一及最後一個的所有階段;其存在於後期前B細胞至記憶細胞中,但不存在於早期前B細胞或漿母細胞及漿細胞中之任一者上。其存在於B細胞淋巴瘤、毛細胞白血病、B細胞慢性淋巴球性白血病及黑色素瘤癌症幹細胞中。CD20之表現藉由趨化介素通過CXCR4/SDF1軸傳信來調節。
免疫組織化學可用以測定組織學組織切片中CD20於細胞上之存在。
在人類中,CD20由MS4A1基因編碼。此基因編碼膜跨越4A基因家族之一員。
在一個實施例中,醫藥組合物之組分(B)包含抗CD20抗體或其抗原結合部分,所述抗體包含:
a) 重鏈可變區,其包含:
i)包含SEQ ID NO: 40之第一vhCDR;
ii)包含SEQ ID NO: 41之第二vhCDR;及
iii)包含SEQ ID NO: 42之第三vhCDR;及
b) 輕鏈可變區,其包含:
i)包含SEQ ID NO: 43之第一vlCDR;
ii)包含SEQ ID NO: 44之第二vlCDR;及
iii)包含SEQ ID NO: 45之第三vlCDR;
視情況其中以上該等SEQ ID NO中之任意一或多者獨立地包含一個、兩個、三個、四個或五個胺基酸取代、添加或缺失。
視情況,SEQ ID NO: 40-45中之一或多者獨立地包含一個、兩個、三個、四個或五個保守胺基酸取代;更佳地,上述SEQ ID NO中之任意一或多者獨立地包含一個或兩個保守胺基酸取代。
較佳地,抗CD-20抗體為單株抗體,更佳人類單株抗體,且甚至更佳完全人類IgG1單株抗體。
在本發明之一尤其較佳實施例中,抗CD20抗體為利妥昔單抗。利妥昔單抗為針對B細胞上廣泛表現之蛋白CD20的單株抗體(Oncogene (2003年10月20日), Smith MR, 「Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance」, 22(47): 7359-68)。利妥昔單抗破壞在其表面上具有CD20之正常及惡性B細胞兩者,且因此用以治療特徵為具有過多B細胞、過度活化B細胞或功能異常B細胞之疾病。利妥昔單抗此前已用以治療多種自體免疫疾病及一些類型之癌症,包括類風濕性關節炎、特發性血小板減少性紫癜、尋常天疱瘡、多發性硬化症、全身性紅斑性狼瘡症、非霍奇金氏淋巴瘤、慢性發炎性脫髓鞘多發性神經病、慢性淋巴球性白血病及自體免疫貧血。利妥昔單抗以商標名Rituxan®由羅氏出售。
較佳地,利妥昔單抗抗體之重鏈及/或輕鏈包含或其組成各別地為SEQ ID NO: 38及39在中所給出之胺基酸序列。
本發明亦涵蓋供變異抗體,有時稱為「抗體衍生物」或「抗體類似物」。亦即,可對本文所揭示之抗體進行許多修飾,包括但不限)CDR中之胺基酸修飾(親和力成熟)、構架區中之胺基酸修飾、Fc區中之胺基酸修飾、糖基化變體、其他類型之共價修飾(例如用於連接藥物結合物等)。
「變體」在本文中意指藉助於至少一個胺基酸修飾而與親本多肽不同的多肽序列。在此情況下,親本多肽為全長可變重鏈或輕鏈(例如各別地在SEQ ID NO: 1或2中所列出的),或對於LY75在SEQ ID NO 5-10及16-21中列出的重鏈及輕鏈之CDR區或構架區。胺基酸修飾可包括取代、插入及缺失,在多數情況下前者較佳。應瞭解,胺基酸取代可為保守或非保守取代,其中保守取代較佳。另外,該取代可為經天然或非天然存在之胺基酸取代。
一般,如本文所述,變體可包括任意數目之修飾,只要抗體之功能仍存在。亦即,例如LY75_A1,該抗體仍應特異性結合至人類LY75。類似地,抗CD20抗體仍應特異性結合至人類CD20。若例如產生具有Fc區之胺基酸變體,變體抗體應維持抗體之特定應用或適應症所需之受體結合功能。
在此情況下,可在列出的抗體CDR序列、構架區或Fc區中製得「變體」。
然而,一般使用1、2、3、4、5、6、7、8、9或10個胺基酸取代,因為目標常常係為以最小數目之修飾來改變功能。在一些情況下,係存在1至5個修飾(例如單獨胺基酸取代、插入或缺失),其中許多實施例中亦發現使用1-2個、1-3個及1-4個修飾。修飾之數目可視所修飾區之尺寸而定;舉例而言,CDR區中一般需要較少修飾。技術人員應瞭解,即使在CDR區內,修飾之位置仍可顯著改變效應。在一個實施例中,可在重鏈及/或輕鏈之CDR1、CDR2或CDR3中之任一者中進行修飾。在另一實施例中,在重鏈及/或輕鏈之CDR1或CDR2中之任一者中進行修飾。在再另一實施例中,修飾位於重鏈及/或輕鏈之CDR1中。
應注意,許多胺基酸修飾可在功能結構域內:例如,可能需要在野生型或經工程改造之蛋白質的Fc區中具有1-5個修飾,以及在例如Fv區中具有1至5個修飾。變異多肽序列較佳是擁有與親體序列(例如LY75_A1或利妥昔單抗之可變區、恆定區及/或重鏈及輕鏈序列及/或CDR)至少約80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致。應注意,視序列之尺寸而定,一致性百分比應視胺基酸之數目而定。
「胺基酸取代」或「取代」在本文中意指在親本多肽序列之特定位置的胺基酸經另一胺基酸置換,該另一胺基酸可為天然或非天然存在之胺基酸。舉例而言,取代S100A係指在位置100處之絲胺酸經丙胺酸置換之變體多肽。如本文所用之「胺基酸插入」或「插入」意指在親本多肽序列之特定位置添加胺基酸。如本文所用之「胺基酸缺失」或「缺失」意指移除在親本多肽序列之特定位置的胺基酸。
如本文所用之「親本多肽」、「親本蛋白質」、「前驅多肽」或「前驅蛋白質」意指隨後經修飾以產生變體之未經修飾之多肽。大體而言,本文中親本多肽為LY75_A1及利妥昔單抗。因此,如本文所用之「親本抗體」意指經修飾以產生變異抗體之抗體。
本文之「野生型」或「WT」或「天然」意指在自然界中發現之胺基酸序列或核苷酸序列,包括對偶基因變異。WT蛋白質、多肽、抗體、免疫球蛋白、IgG等具有未經有意修飾之胺基酸序列或核苷酸序列。
本文之「變異Fc區」意指藉助於至少一個胺基酸修飾而與野生型Fc序列不同的Fc序列。Fc變體可指Fc多肽本身、包含Fc變異多肽之組合物、或胺基酸序列。
在一些實施例中,在LY75_A1或利妥昔單抗之一或多個CDR中進行一或多個胺基酸修飾。一般,在任意單個CDR中僅取代1或2或3個胺基酸,且在一組6個CDR內一般進行不超過4、5、6、7、8、9或10個變化。然而,應瞭解,任意CDR中無取代、1、2或3個取代之任何組合可獨立地及視情況與任何其他取代組合。顯然,可在6個CDR中之任一者中進行取代。在一個實施例中,在重鏈及/或輕鏈之CDR1中進行取代。
在一些情況下,CDR中之胺基酸修飾稱為「親和力成熟」。「親和力成熟」抗體為在一或多個CDR中具有一或多個改變,導致與不具有彼等改變之親本抗體相比抗體對抗原之親和力改良的抗體。在一些情況下,雖然稀少,但可能需要降低抗體對其抗原之親和力,但此舉一般並非較佳。
可進行親和力成熟以使抗體對抗原之結合親和力與「親本」抗體相比增加至少約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%、約100%、約110%、約120%、約130%、約140%、約150%或超過150%、或1、2、3、4至5倍。較佳親和力成熟抗體將對目標抗原具有奈莫耳或甚至皮莫耳之親和力。親和力成熟抗體係藉由已知程序產生。參見例如,Marks等人, 1992, Biotechnology 10:779-783描述藉由可變重鏈(VH)及可變輕鏈(VL)結構域改組之親和力成熟。CDR及/或構架殘基之隨機突變誘發描述於例如Barbas等人 1994, Proc. Nat. Acad. Sci, USA 91:3809-3813;Shier等人, 1995, Gene 169:147-155;Yelton等人, 1995, J. Immunol. 155:1994-2004;Jackson等人, 1995, J. Immunol. 154(7):3310-9;及Hawkins等人, 1992, J. Mol. Biol. 226:889-896中。
或者,胺基酸修飾可在本發明抗體之一或多個「沉默」(例如不會顯著改變抗體對於抗原之親和力)的CDR中進行。可出於許多原因進行此等修飾,包括使表現最佳化(如可對編碼本發明抗體之核酸進行)。
因此,變異CDR及變異抗體包括在本文所揭示之CDR及抗體的定義內;亦即,本發明之抗體可包括LY75_A1或利妥昔單抗之一或多個CDR中之胺基酸修飾。此外,如下文所概述,亦可在CDR外之任何區域(包括如本文所述之構架區及恆定區)中獨立地及視情況進行胺基酸修飾。
在一些實施例中,本文所揭示之抗LY75抗體及/或抗CD20抗體包括變異Fc域。如此項技術中已知,抗體之Fc區與許多Fc受體及配位體相互作用,賦予一系列重要的功能性能力,稱為效應功能。此等Fc受體包括但不限於(在人類中)FcγRI (CD64),其包括同功異型物FcγRIa、FcγRIb及FcγRIc;FcγRII (CD32),其包括同功異型物FcγRIIa (包括異型H131及R131)、FcγRIIb (包括FcγRIIb-1及FcγRIIb-2)及FcγRIIc;及FcγRIII (CD16),其包括同功異型物FcγRIIIa (包括異型V158及F158,與抗體依賴性細胞毒性(ADCC)相關)及FcγRIIIb (包括異型FcγRIIIb-NA1及FcγRIIIb-NA2)、FcRn(新生受體)、C1q (參與補體依賴性細胞毒性(CDC)之補體蛋白質)及FcRn(參與血清半衰期之新生受體)。可在一或多個位置處進行適合之修飾,如例如美國專利申請案11/841,654及其中所引用之參考文獻、US 2004/013210、US 2005/0054832、US 2006/0024298、US 2006/0121032、US 2006/0235208、US 2007/0148170、USSN 12/341,769、美國專利第6,737,056號、美國專利第7,670,600號、美國專利第6,086,875號中所大體概述,其皆以全文引用之方式明確地併入,且尤其進行增加與Fc受體之結合的特定胺基酸取代。
除以上概述之修飾之外,可進行其他修飾。舉例而言,可藉由併入連接VH及VL域之二硫橋鍵使分子穩定(Reiter等人, 1996, Nature Biotech. 14:1239-1245,以全文引用的方式併入)。
此外,在半胱胺酸處之修飾尤其適用於抗體-藥物結合物(ADC)應用,其進一步描述如下。在一些實施例中,抗體之恆定區可經工程改造以含有尤其具有「硫醇反應性」之一或多個半胱胺酸,以便允許更具特異性及受控的置放藥物部分。參見例如美國專利第7,521,541號,其以全文引用的方式併入本文中。
此外,存在多種可如下文所概述進行之抗體的共價修飾。
抗體之共價修飾包括在本發明之範疇內,且一般(但未必總是)在轉譯後進行。舉例而言,抗體之若干類型之共價修飾藉由使抗體之特異性胺基酸殘基與能夠與所選擇的側鏈或N端或C端殘基反應之有機衍生試劑反應引入分子中。
最常使半胱胺醯基殘基與α-鹵基乙酸酯(及對應的胺) (諸如氯乙酸或氯乙醯胺)反應以產生羧甲基或羧醯胺基甲基衍生物。半胱胺醯基殘基亦可藉由與溴三氟丙酮、α-溴-β-(5-咪唑基)丙酸、氯乙醯基磷酸酯、N-烷基順丁烯二醯亞胺、3-硝基-2-吡啶基二硫化物、甲基2-吡啶基二硫化物、對氯汞苯甲酸酯、2-氯汞基-4-硝基苯酚或氯-7-硝基苯并-2-噁-1,3-二唑及其類似物反應而衍生。
組胺醯基殘基藉由在pH 5.5-7.0下與焦碳酸二乙酯反應而衍生化,因為此試劑對組胺醯基側鏈具相對特異性。對溴苯醯甲基溴亦為適用的;反應較佳在pH 6.0下於0.1M二甲胂酸鈉中進行。
離胺醯基及胺基末端殘基與丁二酸酐或其他羧酸酐反應。用此等試劑進行衍生作用具有逆轉離胺醯基殘基之電荷的作用。其他適用於衍生含有α-胺基之殘基的試劑包括醯亞胺酯,諸如吡啶甲醯亞胺酸甲酯;磷酸吡哆醛;吡哆醛;氯硼氫化物;三硝基苯磺酸;O-甲基異脲;2,4-戊二酮及轉胺酶催化之與乙醛酸酯之反應。
精胺醯基殘基藉由與一種或數種習知試劑(其中有苯基乙二醛、2,3-丁二酮、1,2-環己二酮及茚滿三酮)反應而進行修飾。由於胍官能基具有高pKa,因此精胺酸殘基之衍生作用需要反應在鹼性條件下進行。此外,此等試劑可與離胺酸之基團以及精胺酸ε-胺基反應。
可對酪胺醯基殘基進行特定修飾,其中尤其關注藉由與芳族重氮化合物或四硝基甲烷反應而將光譜標記引入酪胺醯基殘基中。最通常分別使用N-乙醯基咪唑及四硝基甲烷來形成O-乙醯基酪胺醯基物質及3-硝基衍生物。酪胺醯基殘基使用
125I或
131I碘化以製備用於放射免疫分析之經標記蛋白質,上文所述之氯胺T方法為適合的。
羧基側基(天冬胺醯基或麩胺醯基)藉由與碳化二亞胺(R'-N=C=N--R')反應而選擇性地修飾,其中R及R'為視情況選用之不同烷基,諸如1-環己基-3-(2-嗎啉基-4-乙基)碳化二亞胺或1-乙基-3-(4-氮鎓-4,4-二甲基戊基)碳化二亞胺。此外,天冬胺醯基及麩胺醯基殘基藉由與銨離子反應而轉化成天冬醯胺醯基及麩醯胺醯基殘基。
用雙官能劑衍生化適用於使抗體交聯至除下文所述之方法之外的多種方法所用的不溶於水的支撐基質或表面。常用交聯劑包括例如1,1-雙(重氮乙醯基)-2-苯乙烷、戊二醛、N-羥基丁二醯亞胺酯(例如與4-疊氮水楊酸之酯)、同雙官能醯亞胺酯(包括二丁二醯亞胺基酯,諸如3,3'-二硫代雙(丁二醯亞胺基丙酸酯)及雙功能順丁烯二醯亞胺(諸如雙-N-順丁烯二醯亞胺-1,8-辛烷)。諸如3-[(對疊氮苯基)二硫基]丙醯亞胺甲酯之衍生劑產生能夠在光存在下形成交聯之可光活化中間體。或者,採用不溶於水的反應性基質,諸如美國專利第3,969,287號;第3,691,016號;第4,195,128號;第4,247,642號;第4,229,537號及第4,330,440號中所述之賽諾莫根溴化物(cynomolgusogen bromide)活化之碳水化合物及反應性受質進行蛋白質固定,該等專利皆以全文引用的方式併入。
常使麩醯胺醯基及天冬醯胺醯基殘基脫去醯胺基以分別形成相應麩胺醯基及天冬胺醯基殘基。或者,此等殘基在適度酸性條件下脫去醯胺基。此等殘基之任一形式均屬於本發明範疇內。
其他修飾脯胺酸及離胺酸之羥基化、絲胺醯基或羥丁胺醯基殘基之羥基磷酸化、離胺酸、精胺酸及組胺酸側鏈之α-胺基甲基化(T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman及Co., San Francisco, 第79-86頁 [1983],以全文引用的方式併入)、N末端胺之乙醯化及任何C末端羧基之醯胺化。
此外,如熟習此項技術者應瞭解,標記(包括螢光、酶促、磁性、放射性等皆可添加至抗體(以及本發明之其他組合物)。
另一類型之共價修飾為糖基化之改變。在一些實施例中,本文所揭示之抗體可完全或部分經去糖基化,例如去海藻糖基化。
抗體之另一類型之共價修飾包含使抗體連接至各種非蛋白質聚合物,包括但不限於各種多元醇,諸如聚乙二醇、聚丙二醇或聚氧伸烷基,以例如Nektar Therapeutics之2005-2006 PEG目錄(可在Nektar網站獲得)、美國專利4,640,835;4,496,689;4,301,144;4,670,417;4,791,192或4,179,337中給出之方式,其皆以全文引用的方式併入。此外,如此項技術中已知,胺基酸取代可在抗體內之不同位置進行以有助於諸如PEG之聚合物的添加。參見例如美國公開案第2005/0114037A1號,其以全文引用的方式併入。
在其他實施例中,抗體可包含標記。「經標記」在本文中意指化合物連接有至少一個元素、同位素或化合物以便能夠偵測該化合物。一般,標記分成三個類別:a)同位素標記,其可為放射性同位素或重同位素;b)磁性、電、熱;及c)彩色或發光染料;但標記亦包括酶及諸如磁性粒子之粒子。較佳標記包括(但不限於)螢光鑭系元素絡合物(包括銪及鋱之彼等絡合物),且螢光標記包括(但不限於)量子點、螢光素、若丹明(rhodamine)、四甲基若丹明、伊紅(eosin)、赤藻紅(erythrosin)、香豆素、甲基-香豆素、芘、孔雀綠(Malacite green)、芪、螢光黃(Lucifer Yellow)、級聯藍(Cascade Blue)、德克薩斯紅(Texas Red)、Alexa染料、Cy染料及Richard P. Haugland之Molecular Probes Handbook第6版中所描述之其他標記,藉此以引用的方式明確地併入。
抗體 - 藥物結合物在一些實施例中,本文所揭示之抗LY75抗體與藥物結合以形成抗體-藥物結合物(ADC)。一般,ADC用於腫瘤學應用,其中使用抗體-藥物結合物進行細胞毒性劑或細胞生長抑制劑之局部傳遞允許將藥物部分靶向傳遞至腫瘤,其可使得功效較高、毒性較低等。此技術之概述提供於Ducry等人, Bioconjugate Chem., 21:5-13 (2010),Carter等人, Cancer J. 14(3):154 (2008)及Senter, Current Opin. Chem. Biol. 13:235-244 (2009)中,其皆以全文引用的方式併入本文中。
由此本發明提供包含尤其與藥物結合之抗LY75抗體的醫藥組合。一般而言,結合係藉由共價連接至抗體來進行,如下文進一步描述,且一般依賴於連接基團,常常為肽鍵(其如下所述,可經設計以在目標位點處對由蛋白酶裂解敏感或不敏感)。此外,如上所述,連接基團-藥物單元(LU-D)之鍵聯可藉由連接至抗體內之半胱胺酸來進行。如熟習此項技術者應瞭解,每一抗體之藥物部分之數目可變化,視反應條件而定,且可在1:1至10:1藥物:抗體之範圍內變化。如熟習此項技術者應瞭解,實際數目為平均值。
由此,抗LY75抗體可為結合至藥物。如下所述,ADC之藥物可為任意數目之藥劑,提供包括(但不限於)細胞毒性劑,諸如化學治療劑、生長抑制劑、毒素(例如細菌、真菌、植物或動物來源之酶促活性毒素或其片段)或放射性同位素(亦即放射性結合物)。在其他實施例中,本發明另外提供使用ADC之方法。
用於本發明之藥物包括細胞毒性藥物,尤其用於癌症療法之彼等細胞毒性藥物。此類藥物一般包括DNA損傷劑、抗代謝物、天然產物及其類似物。例示性類別之細胞毒性劑包括酶抑制劑,諸如二氫葉酸還原酶抑制劑及胸腺嘧啶核苷合成酶抑制劑、DNA嵌入劑 、DNA裂解劑、拓樸異構酶抑制劑、蒽環黴素家族之藥物、長春花藥物、絲裂黴素(mitomycin)、博來黴素(bleomycin)、細胞毒性核苷、喋啶家族之藥物、二炔烯類(diynenes)、足葉草毒素(podophyllotoxin)、海兔毒素(dolastatin)、類美登素(maytansinoid)、分化誘導劑及紫杉醇(taxol)。
此等類別之成員包括例如紫杉醇、甲胺喋呤(methotrexate)、甲胺喋呤(methopterin)、二氯甲胺喋呤、5-氟尿嘧啶、6-巰基嘌呤、胞嘧啶阿拉伯糖苷、美法侖(melphalan)、環氧長春鹼(leurosine)、洛諾德英(leurosideine)、放線菌素(actinomycin)、道諾黴素(daunorubicin)、小紅莓(doxorubicin)、絲裂黴素C、絲裂黴素A、洋紅黴素(caminomycin)、胺基喋呤、他利黴素(tallysomycin)、鬼臼毒素(podophyllotoxin)及鬼臼毒素衍生物,諸如依託泊苷(etoposide)或磷酸依託泊苷、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、包括紫杉醇、多西紫杉醇(taxotere)之紫杉烷(taxane)、視黃酸、丁酸、N8-乙醯基亞精胺、喜樹鹼(camptothecin)、卡奇黴素(calicheamicin)、埃斯培拉黴素(esperamicin)、烯-二炔、倍癌黴素A (duocarmycin A)、倍癌黴素SA、卡奇黴素(calicheamicin)、喜樹鹼、哈米特林(hemiasterlin)、類美登素(包括DM1)、單甲基阿瑞他汀E (monomethylauristatin E,MMAE)、單甲基阿瑞他汀F(MMAF)及類美登素(DM4)及其類似物。
毒素可用作抗體-毒素結合物且包括細菌毒素(諸如白喉毒素)、植物毒素(諸如蓖麻毒素))、小分子毒素(諸如格爾德黴素(geldanamycin)) (Mandler等人 (2000) J. Nat. Cancer Inst. 92(19):1573-1581;Mandler等人 (2000) Bioorganic & Med. Chem. Letters 10:1025-1028;Mandler等人 (2002) Bioconjugate Chem. 13:786-791)、類美登素(maytansinoids) (EP 1391213;Liu等人, (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623)及卡奇黴素(calicheamicin) (Lode等人 (1998) Cancer Res. 58:2928;Hinman等人 (1993) Cancer Res. 53:3336-3342)、哈米特林(hemiasterlin) (WO2004/026293;Zask等人, (2004) J. Med. Chem, 47: 4774-4786)。毒素可藉由包括微管蛋白結合、DNA結合或拓樸異構酶抑制之機制發揮其細胞毒性及細胞生長抑制效應。
亦可使用抗LY75抗體及諸如類美登素、海兔毒素、哈米特林、奧瑞他汀、單端孢黴烯族毒素、卡奇黴素、倍癌黴素(duocarmycin)、吡咯并苯并二氮雜卓(pyrrolobenzadiazepine)及CC1065之一或多種小分子毒素之結合物及與此等毒素之具有毒素活性之衍生物的結合物。
抗LY75抗體較佳結合至DM1或DM4,最佳結合至DM4。適於用作類美登素藥物部分之美登素(Maytansine)化合物為此項技術中所熟知,且可根據已知方法自天然來源分離,使用基因工程改造技術產生(參見Yu等人 (2002) PNAS 99:7968-7973),或為根據已知方法以合成方式製備之類美登素(maytansinol)及類美登素類似物。如下所述,藥物可藉由併入用於結合至抗體之諸如硫醇或胺基之官能活性基團而經修飾。
例示性類美登素藥物部分包括具有經修飾之芳環的彼等類美登素藥物部分,諸如:C-19-去氯(美國專利第4,256,746號)(藉由氫化鋰鋁還原安絲菌素(ansamytocin) P2來製備;C-20-羥基(或C-20-去甲基) +/-C-19-去氯(美國專利第4,361,650號及第4,307,016號)(藉由使用鏈黴菌屬(Streptomyces)或放線菌屬(Actinomyces)去甲基化或使用LAH去氯來製備);及C-20-去甲氧基、C-20-醯氧基(--OCOR)、+/-去氯(美國專利第4,294,757號)(藉由使用醯基氯醯化來製備)及在其他位置具有修飾之彼等類美登素藥物部分。
例示性類美登素藥物部分亦包括具有以下修飾之彼等類美登素藥物部分,諸如:C-9-SH (美國專利第4,424,219號)(藉由類美登素與H2S或P2S5之反應來製備);C-14-烷氧基甲基(去甲氧基/CH
2OR)(美國專利第4,331,598號);C-14-羥基甲基或醯氧基甲基(CH
2OH或CH
2OAc)(美國專利第4,450,254號)(由諾卡菌屬(Nocardia)製備);C-15-羥基/醯氧基(美國專利第4,364,866號)(藉由鏈黴菌屬轉化類美登素來製備);C-15-甲氧基(美國專利第4,313,946號及第4,315,929號)(自滑桃樹(Trewia nudlflora)分離);C-18-N-去甲基(美國專利第4,362,663號及第4,322,348號)(藉由鏈黴菌屬使類美登素去甲基化來製備);及4,5-去氧(美國專利第4,371,533號)(藉由三氯化鈦/LAH還原類美登素來製備)。
尤其使用DM1 (揭示於美國專利第5,208,020號中,其以引用的方式併入)及DM4 (揭示於美國專利第7,276,497號中,其以引用的方式併入)。亦參見5,416,064、WO/01/24763、7,303,749、7,601,354、USSN 12/631,508、WO02/098883、6,441,163、7,368,565、WO02/16368及WO04/1033272中之許多額外類美登素衍生物及方法,其皆以全文引用的方式明確地併入。
含有類美登素之ADC、其製造方法及其治療性用途揭示於例如美國專利第5,208,020號;第5,416,064號;第6,441,163號及歐洲專利EP 0 425 235 B1中,其揭示內容藉此以引用的方式明確地併入。Liu等人, Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996)描述ADC,其包含連接至針對人類結腸直腸癌之單株抗體C242的類美登素(稱為DM1)。發現該結合物對所培養之結腸癌細胞具有高細胞毒性且在活體內腫瘤生長分析中展示抗腫瘤活性。
Chari等人, Cancer Research 52:127-131 (1992)描述ADC,其中類美登素經由二硫化物連接子與結合至人類結腸癌細胞株上之抗原的鼠類抗體A7或結合HER-2/neu癌基因之另一種鼠類單株抗體TA.1結合。活體外測試TA.1-類美登素結合物對每一細胞表現3×105個HER-2表面抗原之人類乳癌細胞株SK-BR-3之細胞毒性。藥物結合物實現類似於游離類美登素藥物之細胞毒性程度,其可藉由增加每抗體分子之類美登素分子數目而增加。A7-類美登素結合物在小鼠體內展示出低全身性細胞毒性。
對於包含複數個抗體之組合物,藥物負載量由每一抗體之藥物分子的平均數目p表示。藥物負載可在每個抗體1至20個藥物(D)之範圍內。為結合反應製備之每抗體之平均藥物數量可藉由諸如質譜分析、ELISA分析及HPLC之習知手段來表徵。亦可根據p確定抗體-藥物-結合物之定量分佈。
在一些情況下,其中p為來自具有其他藥物負載量之抗體-藥物結合物的特定值,可藉由諸如逆相HPLC或電泳之手段來實現均質抗體-藥物結合物之分離、純化及表徵。在例示性實施例中,p為2、3、4、5、6、7或8或其分數。
抗體-藥物結合物化合物之產生可藉由熟習此項技術者已知的技術來實現。簡言之,抗體-藥物結合物化合物可包括抗LY75抗體作為抗體單元、藥物及視情況存在之使藥物與結合劑接合之連接基團。
多種不同反應可用於藥物及/或連接子至結合劑之共價連接。此可藉由結合劑(例如抗體分子)之胺基酸殘基,包括離胺酸之胺基、麩胺酸及天冬胺酸之游離羧酸基、半胱胺酸之巰基及芳族胺基酸之各個部分之反應來實現。共價連接之常用非特異性方法為碳化二亞胺反應以使化合物之羧基(或胺基)連接至抗體之胺基(或羧基)。此外,諸如二醛或亞胺酸酯之雙官能藥劑已經用於將化合物之胺基連接至抗體分子之胺基基團。
希夫鹼(Schiff base)反應亦可用於將藥物連接至結合劑。此方法涉及過碘酸鹽氧化含有二醇或羥基基團之藥物,由此形成隨後與結合劑反應之醛。連接經由利用結合劑之胺基形成希夫鹼而發生。異硫氰酸酯亦可用作為用於將藥物共價連接至結合劑之偶合劑。其他技術為熟習此項技術者所知且在本發明之範疇內。
在一些實施例中,中間物,亦即連接子之前驅物,在適當條件下與藥物反應。在其他實施例中,使用藥物及/或中間物上之反應性基團。藥物與中間物之間反應的產物或經衍生藥物隨後在適當條件下與本發明之抗LY75抗體反應。
應瞭解,亦可對所需化合物進行化學修飾,以使得該化合物之反應更便於製備本發明之結合物的目的。例如可將例如胺、羥基或硫氫基之官能基在對藥物之活性其他性質具有最低或可接受影響之位置處連接至藥物。
通常,抗體-藥物結合化合物在藥物單元與抗體單元之間包含連接子單元。在一些實施例中,連接子在細胞內或細胞外條件下可裂解,使得連接子在適當環境中裂解而自抗體釋放藥物單元。舉例而言,分泌某些蛋白酶之實體腫瘤可充當可裂解連接子之目標;在其他實施例中,其為所用的細胞內蛋白酶。在其他實施例中,連接子單元不可裂解且例如藉由在溶酶體中分解抗體而釋放藥物。
在一些實施例中,連接子為藉由細胞內環境(例如,溶酶體或核內體或胞膜窖內)中存在之裂解劑可裂解的。連接子可為例如由細胞內肽酶或蛋白酶裂解肽基連接子,該蛋白酶包括但不限於溶酶體或核內體蛋白酶。在一些實施例中,肽基連接子為至少兩個胺基酸長或至少三個胺基酸長或更長。
裂解劑可包括但不限於組織蛋白酶B及D及纖維蛋白溶酶,已知其均水解二肽藥物衍生物,導致靶細胞內部之活性藥物的釋放(參見例如Dubowchik及Walker, 1999, Pharm. Therapeutics 83:67-123)。肽基連接子為由表現LY75之細胞中存在之酶可裂解的。例如,可使用可藉由硫醇依賴性蛋白酶組織蛋白酶B裂解的肽基連接子(例如Phe-Leu或Gly-Phe-Leu-Gly連接子(SEQ ID NO: 52)),該組織蛋白酶B在癌性組織中為高度表現的。此類連接子之其他實例描述於(例如)美國專利第6,214,345號中,其以全文引用之方式且出於所有目的併入本文中。
在一些實施例中,由細胞內蛋白酶可裂解之肽基連接子為Val-Cit連接子或Phe-Lys連接子(參見例如,美國專利第6,214,345號,其描述使用val-cit連接子合成小紅莓)。
在其他實施例中,可裂解連接子為pH敏感的,亦即在某些pH值下對水解敏感。通常,pH敏感性連接子通常可在酸性條件下水解。舉例而言,可使用在溶酶體中可水解之酸不穩定性連接子(例如,腙、半卡巴腙、硫半卡巴腙、順式-烏頭醯胺、原酸酯、縮醛、縮酮或其類似物)。(參見例如美國專利第5,122,368號;第5,824,805號;第5,622,929號;Dubowchik及Walker, 1999, Pharm. Therapeutics 83:67-123;Neville等人, 1989, Biol. Chem. 264:14653-14661)。此類連接子在中性pH值條件(諸如血液中之pH值條件)下相對穩定,但在低於pH 5.5或5.0 (近似溶酶體之pH值)下不穩定。在某些實施例中,可水解連接子係硫醚連接子(諸如(例如)經由醯腙鍵連接至治療劑之硫醚(參見,例如美國專利第5,622,929號)。
在又其他實施例中,連接子為在還原條件下可裂解的(例如,二硫連接子)。各種二硫化物連接子在此項技術中已知,包括(例如)可使用SATA (N-丁二醯亞胺基-5-乙醯基硫基乙酸酯)、SPDP (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯)、SPDB (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丁酸酯)及SMPT (N-丁二醯亞胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯)形成之連接子。(參見,例如Thorpe等人,1987, Cancer Res. 47:5924-5931;Wawrzynczak等人,Immunoconjugates:Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel編, Oxford U.出版, 1987)。亦參見美國專利第4,880,935號。)
在其他實施例中,連接子為丙二酸酯連接子(Johnson等人, 1995, Anticancer Res. 15:1387-93)、順丁烯二醯亞胺基苯甲醯基連接子(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1299-1304)或3'-N-醯胺類似物(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1305-12)。
在又其他實施例中,連接單元不可裂解且藥物藉由抗體降解來釋放。(參見美國公開案第2005/0238649號,其以全文引用的方式併入本文中且用於所有目的)。
在許多實施例中,連接子為自我分解型。如本文所用,術語「自行分解之間隔基」係指能夠使兩個間隔開之化學部分共價鍵聯在一起成為穩定之三聯分子的雙官能化學部分。若其與第一部分之鍵裂解,則其將自發地與第二化學部分分離。參見例如WO 2007/059404A2、WO06/110476A2、WO05/112919A2、WO2010/062171、WO09/017394、WO07/089149、WO 07/018431、WO04/043493及WO02/083180,其係關於藥物-可裂解受質結合物,其中該藥物及可裂解受質視情況經由自我分解型連接子連接,且其皆以引用的方式明確地併入。
連接子常常實質上對細胞外環境不敏感。如本文所用,在連接子之情形下,「實質上對細胞外環境不敏感」意指當抗體-藥物結合化合物存在於細胞外環境(例如血漿)時,抗體-藥物結合化合物樣品中不超過約20%、15%、10%、5%、3%或不超過約1%之連接子裂解。
連接子是否實質上對細胞外環境不敏感可例如藉由使抗體-藥物結合化合物與血漿一起培育預定時段(例如,2、4、8、16或24小時),且隨後定量血漿中存在之游離藥物的量來測定。
在其他非互斥實施例中,連接子促進細胞內化。在某些實施例中,當與治療劑結合時(亦即,在如本文所述之抗體-藥物結合化合物的連接子-治療劑部分的背景中),連接子促進細胞內化。在其他實施例中,當與奧瑞他汀化合物及本發明之抗LY75抗體兩者結合時,連接子促進細胞內化。
多種可用於本發明組合物及方法之例示性連接子描述於WO 2004/010957、美國公開案第2006/0074008號、美國公開案第20050238649號及美國公開案第2006/0024317號中(其各者以全文引用的方式併入本文中且用於所有目的)。較佳地,連接子為SPDB (正丁二醯亞胺基-3-(2-吡啶基二硫基)丁酸酯)。
藥物負載由p表示,且為分子中每抗體之藥物部分之平均數目。藥物負載(「p」)可為每個抗體1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或超過20個部分(D),儘管平均數目時常為分數或小數。一般而言,1至4之藥物負載為頻繁使用的,且1至2之藥物負載亦適用。本發明之ADC包括與範圍介於1至20個(例如1-15個、1-10個、2-9個、3-8個、4-7個、5-6個)之藥物部分結合之抗體的集合。在由結合反應製備ADC時,每個抗體之藥物部分的平均數目可藉由諸如質譜及ELISA分析之習知方式表徵。
亦可測定就p而言之ADC之定量分佈。在一些情況下其中p為特定值的均質ADC自ADC與其他藥物負載之分離、純化及表徵可藉由諸如電泳之方法來達成。
對於一些抗體-藥物結合物,p可受抗體上之連接位點之數目限制。舉例而言,在連接為半胱胺酸硫醇之情況下,如在以上示例性實施例中,抗體可僅僅具有一個或若干個半胱胺酸硫醇基,或可僅僅具有一個或若干個可連接連接子之足夠反應性硫醇基。在某些實施例中,較高藥物負載(例如p>5)可造成某些抗體-藥物結合物之聚集、不可溶性、毒性或細胞滲透性喪失。在某些實施例中,用於本發明之ADC的藥物負載在1至約8;約2至約6;約3至約5;約3至約4;約3.1至約3.9;約3.2至約3.8;約3.2至約3.7;約3.2至約3.6;約3.3至約3.8;或約3.3至約3.7之範圍內。實際上已展示對於某些ADC,最優每抗體之藥物部分的比率可為小於8,且可為約2至約5。參見美國2005/0238649 A1 (以全文引用之方式併入本文中)。
在某些實施例中,在結合反應期間使少於理論最大值之藥物部分結合於抗體。抗體可含有例如不與藥物-連接子中間物或連接子試劑反應之離胺酸殘基,如下文所論述。一般而言,抗體不含有許多可連接於藥物部分之游離及反應性半胱胺酸硫醇基;實際上抗體中之大部分半胱胺酸硫醇殘基以二硫橋鍵之形式存在。在某些實施例中,抗體可用諸如二硫蘇糖醇(DTT)或三羰基乙基膦(TCEP)之還原劑在部分或完全還原條件下還原,產生反應性半胱胺酸硫醇基。在某些實施例中,抗體經受變性條件,展現反應性親核基團,諸如離胺酸或半胱胺酸。
ADC之負載(藥物/抗體比率)可以不同方式加以控制,例如藉由:(i)限制藥物-連接子中間物或連接子試劑相對於抗體莫耳過量,(ii)限制結合反應時間或溫度,(iii)用於半胱胺酸硫醇修飾之部分或限制性還原條件,(iv)藉由重組技術工程改造抗體之胺基酸序列,使得半胱胺酸殘基之數目及位置經修飾以控制連接子-藥物連接之數目及/或位置(諸如,如本文及WO2006/034488 (以全文引用的方式併入本文中)所揭示製備之thioMab或thioFab)。
應理解其中超過一個親核性基團與藥物-連接物中間物或連接子試劑反應,隨後與藥物部分試劑反應,隨後所得產物為ADC化合物與連接至抗體之一或多種藥物部分之分佈的混合物。每個抗體之藥物平均數目可藉由該對抗體具有特異性且對藥物具有特異性之雙重ELISA抗體分析由混合物計算。個別ADC分子可在混合物中藉由質譜分析鑑別至藉由HPLC,例如疏水性相互作用層析分離
在一些實施例中,具有單一負載值之均質ADC可藉由電泳或層析自結合物混合物分離。
測定 ADC 之細胞毒性效應的方法已知測定藥物或抗體-藥物結合物是否在細胞上發揮細胞生長抑制及/或細胞毒性效應之方法。一般而言,抗體藥物結合物之細胞毒性或細胞生長抑制活性可藉由以下來量測:將表現抗體藥物結合物之目標蛋白的哺乳細胞暴露於細胞培養基中;培養該等細胞約6小時至約5天之時段;及量測細胞成活力(viability)。基於細胞之活體外分析可用以量測本抗體藥物結合物之成活力(增殖)、細胞毒性及凋亡之誘導(卡斯蛋白酶活性)。
對於測定抗體藥結合物是否發揮細胞生長抑制作用,可使用胸苷結合分析。舉例而言,可將表現靶標抗原之癌細胞以5,000細胞/孔之密度之96孔板培養72小時時段,且在72小時時段之最後8小時期間暴露於0.5 μCi之
3H-胸苷。在抗體藥結合物存在及不存在下量測
3H-胸苷與培養物之細胞的結合。
為測定細胞毒性,可量測壞死或細胞凋亡(程式性細胞死亡)。壞死通常伴隨著質膜之磁導率增加;細胞膨脹及質膜破裂。細胞凋亡通常特徵在於膜起皰、細胞質凝聚及內源核酸內切酶活化。測定此等中之任一者對癌細胞的影響指示抗體藥結合物可用於治療癌症。
細胞成活力可藉由測定細胞中諸如中性紅、錐蟲藍或ALAMAR™藍之染料的吸收來量測(參見例如Page等人, 1993, Intl. J. Oncology 3:473-476)。在此類分析中,在含有染料之培養基中培育細胞,洗滌細胞,且以分光光度法量測剩餘染料,其反映細胞對染料之吸收。亦可使用蛋白質結合染料磺醯羅丹明B (SRB)來量測細胞毒性(Skehan等人, 1990, J. Natl. Cancer Inst. 82:1107-12)。
或者,在藉由偵測活的(但未死)細胞之哺乳動物細胞存活及增殖的定量比色分析中使用諸如MTT之四唑鎓鹽(參見例如Mosmann, 1983, J. Immunol. Methods 65:55-63)。
細胞凋亡可藉由量測例如DNA片段來定量。用於DNA片段之定量體外測定的市售光度方法為可獲得的。此類分析之實例,包括TUNEL (其偵測斷裂之DNA中經標記核苷酸的併入)及基於ELISA之分析,描述於Biochemica, 1999, 第2期, 第 34-37頁(Roche Molecular Biochemicals)中。
細胞凋亡亦可由量測細胞中之形態變化來測定。舉例而言,如同壞死,質膜完整性之損失可藉由量測對某些染料(例如螢光染料,如吖啶橙或溴化乙錠)之吸收來測定。用於量測凋亡細胞數目之方法已由Duke及Cohen, Current Protocols in Immunology (Coligan等人編, 1992, 第3.17.1-3.17.16頁)描述。細胞亦可用DNA染料(例如吖啶橙、溴化乙錠或碘化丙錠)標記且細胞觀測到沿內部核膜之染色體凝聚及邊聚。可經量測以測定細胞凋亡之其他形態變化包括例如細胞質凝聚、增加之膜起皰及細胞收縮。
可在培養物之附著區室及「漂浮」區室量測到凋亡細胞之存在。舉例而言,兩個區室均可藉由以下收集:移除上澄液、將連接細胞用蛋白胰酶消化、在離心洗滌步驟(例如在2000 rpm下10分鐘)之後合併製劑,並且偵測細胞凋亡(例如藉由量測DNA片段)。(參見例如,Piazza等人, 1995, Cancer Research 55:3110-16)。
可在適合之動物模型中評估本發明之抗LY75抗體之治療性組合物的活體內效應。舉例而言,可使用異種癌症模型,其中將癌症外植體或繼代異種移植組織引入諸如裸小鼠或SCID小鼠之免疫功能不全的動物中(Klein等人, 1997, Nature Medicine 3: 402-408)。可使用量測腫瘤形成、腫瘤消退或癌轉移之抑制作用的分析及其類似分析量測功效。
可將用於實施前文方法之治療性組合物調配至包含適用於所需遞送方法之載劑中的醫藥組合物中。合適載劑包括在與治療性組合物組合時保持治療性組合物之抗腫瘤功能且總體上對患者之免疫系統為非反應性的任何物質。實例包括但不限於多種標準醫藥載劑(諸如無菌磷酸鹽緩衝鹽水溶液、抑菌水及類似者)中之任一者(大體上參見Remington's Pharmaceutical Sciences第16版, A. Osal., 編, 1980)。
用於製造抗體之方法本文所揭示之抗體可藉由任何適合方法製得。此等方法包括培養含有編碼該等抗體之一或多種經分離核酸的宿主細胞。如熟習此項技術者應瞭解,此可以多種方式進行,視抗體之性質而定。在一些實施例中,在本發明抗體為全長傳統抗體之情況下,例如重鏈可變區及輕鏈可變區在一定條件下,使得抗體產生且可經分離。
LY75_A1之可變重鏈及輕鏈揭示於本文中(蛋白質序列及核酸序列兩者);如在此項技術中應瞭解,其可易於擴充以產生全長重鏈及輕鏈。亦即,在已提供如本文所概述之編碼V
H及V
K區段之DNA片段的情況下,此等DNA片段可另外藉由標準重組DNA技術操縱,例如以將可變區基因轉化成全長抗體鏈基因、Fab片段基因或scFv基因。在此等操縱中,編碼V
K或V
H之DNA片段可操作地連接至編碼另一蛋白質(諸如抗體恆定區或柔性連接子)之另一DNA片段。如本文中所用,術語「可操作地連接」意指兩個DNA片段以使得該兩個DNA片段所編碼之胺基酸序列保持同框的方式連接。
編碼V
H區之分離DNA可藉由將編碼V
H之DNA可操作地連接於編碼重鏈恆定區(C
H1、C
H2及C
H3)之另一DNA分子而轉變成全長重鏈基因。鼠重鏈恆定區基因之序列為此項技術中已知的[參見例如Kabat, E. A.,等人. (1991) Sequences of Proteins of Immunological Interest, 第五版, US Department of Health and Human Services, NIH公開案第91-3242號],且包含此等區之DNA片段可藉由標準PCR擴增來獲得。重鏈恆定區可為IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恆定區,但最佳為IgG1或IgG4恆定區。對於Fab片段重鏈基因,編碼V
H之DNA可操作地連接至另一個僅編碼重鏈CH1恆定區之DNA分子。
可藉由將編碼V
L之DNA可操作地連接至編碼輕鏈恆定區C
L之另一DNA分子而將編碼VL / VK區之分離DNA轉化成全長輕鏈基因(以及Fab輕鏈基因)。鼠輕鏈恆定區基因之序列為此項技術中已知的[參見例如Kabat, E. A., 等人 (1991) Sequences of Proteins of Immunological Interest, 第五版, US Department of Health and Human Services, NIH公開案第91-3242號]且包含此等區域之DNA片段可藉由標準PCR擴增來獲得。在較佳實施例中,輕鏈恆定區可為κ或λ恆定區。
為了形成scFv基因,可將編碼V
H及V
L/V
K之DNA片段可操作地連接至編碼柔性連接子(例如編碼胺基酸序列Gly
4-Ser)
3)之其他片段,以使得V
H及V
L/V
K序列可表現為其中V
L/V
K及V
H區藉由柔性連接子接合之連續單鏈蛋白[參見例如Bird等人 (1988) Science 242:423-426;Huston等人 (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883;McCafferty等人, (1990) Nature 348:552-554]。
提供編碼本文所揭示之抗體的核酸。此類聚核苷酸編碼各重鏈及輕鏈之可變及恆定區兩者,儘管亦涵蓋與此處描述之組成一致的其他組合。
聚核苷酸可呈RNA或DNA形式。呈DNA、cDNA、基因組DNA、核酸類似物及合成DNA形式之聚核苷酸亦為可用的。DNA可為雙股或單股,且若為單股則可為編碼(有義)股或非編碼(反義)股。編碼多肽之編碼序列可與本文提供之編碼序列一致,或可為不同編碼序列,該序列由於遺傳密碼之冗餘或簡併,編碼與本文提供之DNA相同的多肽。
在一些實施例中,將編碼本文所揭示抗體之一或多種核酸併入表現載體中,該等表現載體可為染色體外的或經設計以整合至所引入之宿主細胞的基因組中。表現載體可含有任意數目之適當調節序列(包括但不限於,轉錄及轉譯控制序列、啟動子、核糖體結合位點、強化子、複製起點等)或其他組件(選擇基因等),其皆如此項技術中所熟知般可操作地連接。在一些情況下,使用兩種核酸且將各者放入不同表現載體中(例如重鏈在第一表現載體中,輕鏈在第二表現載體中),或可將其放入相同表現載體中。熟習此項技術者應瞭解,一或多種表現載體之設計、包括選擇調節序列可取決於以下該等因素:如宿主細胞之選擇、所需蛋白之表現水準等。
大體而言,可將核酸及/或表現引入至合適的宿主細胞中以使用任何適於所選擇宿主細胞之方法(例如轉換、轉染、電穿孔、感染)形成重組宿主細胞,以使得一或多個核酸分子可操作地連接至一或多種表現控制元素(例如在載體中、在藉由細胞中之處理形成的構築體中、整合至宿主細胞基因組中)。所得重組宿主細胞可保持在適用於表現之條件下(例如在誘導劑存在下、在合適的非人類動物中、在補充有適當鹽、生長因子、抗生素、營養補充劑之合適培養基中等),在其中製造編碼之一或多種多肽。在一些情況下,在一個細胞中產生重鏈且在另一細胞中產生輕鏈。
作為用於表現之宿主可用的哺乳動物細胞株為此項技術中已知且包括購自美國菌種保藏中心(ATCC), Manassas, VA之許多永生化細胞株,包括(但不限於)中國倉鼠卵巢(CHO)細胞、HEK 293細胞、NSO細胞、HeLa細胞、幼倉鼠腎(BHK)細胞、猴腎細胞(COS)、人類肝細胞癌細胞(例如Hep G2)及許多其他細胞株。非哺乳動物細胞包含但不限於細菌、酵母、昆蟲,且亦可使用板來表現重組抗體。在一些實施例中,抗體可在諸如母牛或雞之轉殖基因動物中產生。
抗體分子生物學、表現、純化及篩檢之一般方法為所熟知的,例如參見美國專利第4,816,567號、第4,816,397號、第6,331,415號及第 7,923,221號以及Antibody Engineering, 由Kontermann及Dubel編, Springer, Heidelberg, 2001及2010 Hayhurst及Georgiou, 2001, Curr Opin Chem Biol 5:683-689;Maynard及Georgiou, 2000, Annu Rev Biomed Eng 2:339-76;及Morrison, S. (1985) Science 229:1202。
在本發明之另一實施例中,醫藥組合物之組分(B)為依魯替尼或其醫藥學上可接受之鹽。依魯替尼(Imbruvica®)為永久結合至布魯頓氏酪胺酸激酶(BTK)之小分子藥物。其此前已用以治療B細胞癌症,諸如套細胞淋巴瘤、慢性淋巴球性白血病及瓦爾登斯特倫巨球蛋白血症(非霍奇金氏淋巴瘤之一種形式)。以下給出依魯替尼之結構及化學式:
依魯替尼以商標名Imbruvica®出售。其可自Pharmacyclics, Inc. (美國)獲得。
醫藥組合物本發明之醫藥組合物呈用於同時、各別或依序使用之組合製劑之形式。同樣在本發明之方法中,醫藥組合物之成分(A)及(B)可同時、各別或依序向患者投與。
術語「組合製劑」包括固定組合及非固定組合兩者。
術語「固定組合」意謂活性成分(例如成分(A)及(B))呈單一實體或劑型形式。換言之,活性成分存在於單一組合物或調配物中。
術語「非固定組合」意謂活性成分(例如成分(A)及(B))存在於不同實體或劑型(例如各別組合物或調配物)中,例如作為分裝部分之套組。獨立成分(A)及(B)(在其所需組合物或調配物中)可隨後各別或依序、在相同時間點或不同時間點投與。
當依序投與時,投與第二組分之時延不應使得由於使用組合而喪失效應之益處。因此,在一個實施例中,依序治療涉及在11天之期間內投與該組合之各組分。在另一實施例中,此時間段為10天。在另一實施例中,此時間段為9天。在另一實施例中,此時間段為8天。在另一實施例中,此時間段為7天。在另一實施例中,此時間段為6天以內。在另一實施例中,此時間段為5天以內。在另一實施例中,此時間段為4天以內。在另一實施例中,此時間段為3天以內。在另一實施例中,此時間段為2天以內。在另一實施例中,此時間段為24小時以內。在另一實施例中,此時間段為12小時以內。
組分(A)及(B)可以任何順序投與,例如首先組分(A)且隨後組分(B);或首先組分(B)且隨後組分(A)。
待以組合製劑投與之組分(A)與組分(B)之總量的比率可變化,例如以便應對待治療之患者亞群之需要或單個患者之需要,該等不同需要可由於患者之年齡、性別體重等。
無論存在於單一組合物中或在各別組合物中,組分(A)及(B)可獨立地與一或多種醫藥學上可接受的載劑一起調配。本發明之醫藥組合亦可包括至少一種其他抗腫瘤劑、或抗發炎劑或免疫抑制劑。可用於組合療法之治療劑的實例更詳細地揭示於下文關於本文所述之抗體之用途的部分中。
如本文所用,「醫藥學上可接受之載劑」包括生理學上相容之任何及全部溶劑、分散介質、塗覆劑、抗細菌劑及抗真菌劑、等張劑及吸收延遲劑及類似物。較佳地,載劑適用於靜脈內、肌肉內、皮下、非經腸、脊椎或表皮投與(例如藉由注射或輸注)。視投藥途徑而定,活性化合物(亦即抗體、免疫結合物或雙特異性分子)可包覆在材料中以保護該化合物免受酸及可使該化合物不活化之其他天然條件作用。
組分(A)及/或(B)可呈一或多種醫藥學上可接受之鹽形式。「醫藥學上可接受之鹽」係指保持母體化合物之生物活性且並不賦予任何非所需毒理學作用之鹽[參見例如Berge, S. M.等人 (1977) J. Pharm. Sci. 66:1-19]。此類鹽之實例包括酸加成鹽及鹼加成鹽。酸加成鹽包括來源於無毒無機酸之彼等物,諸如鹽酸、硝酸、磷酸、硫酸、氫溴酸、氫碘酸亞磷酸及其類似物;以及來源於無毒有機酸之彼等物,諸如脂族單甲酸及脂族二甲酸、經苯基取代之烷酸、羥基烷酸、芳族酸、脂族及芳族磺酸及其類似物。鹼加成鹽包括衍生自鹼土金屬(諸如鈉、鉀、鎂、鈣及其類似物)以及衍生自無毒有機胺(諸如N,N'-二苯甲基乙二胺、N-甲基葡糖胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、普魯卡因(procaine)及其類似物)之鹽。
本發明之醫藥組合物或其部分亦可包括醫藥學上可接受之抗氧化劑。醫藥學上可接受之抗氧化劑之實例包括:(1)水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及其類似物;(2)油溶性抗氧化劑,諸如抗壞血酸棕櫚酸酯、丁基化羥基大茴香醚(BHA)、丁基化羥基甲苯(BHT)、卵磷脂、沒食子酸丙酯、α-生育酚及其類似物;及(3)金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸及其類似物。
可用於本發明醫藥組合中之適合水性及非水性載劑的實例包括水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇及其類似物)及其適合混合物、植物油(諸如橄欖油)及可注射有機酯(諸如油酸乙酯)。可例如藉由使用包衣材料(諸如卵磷脂)、藉由維持所需粒徑(就分散液而言)以及藉由使用界面活性劑來保持適當流動性。
此等組合或其部件也可含有佐劑,諸如防腐劑、潤濕劑、乳化劑及分散劑。預防微生物之存在可藉由滅菌程序(同前文獻=及藉由包括各種抗細菌及抗真菌劑(例如對羥基苯甲酸酯、氯丁醇、苯酚山梨酸及其類似物)來確保。亦可能需要在組合物中包括等張劑,諸如糖、氯化鈉及其類似物。另外,可注射醫藥形式之延長吸收可藉由包含延遲吸收之藥劑(諸如單硬脂酸鋁及明膠)來達成。
醫藥學上可接受之載劑包括無菌水溶液或分散液及用於臨時製備無菌可注射溶液或分散液之無菌散劑。此類介質及藥劑用於醫藥活性物質之用途為此項技術中已知的。除非任何習知介質或藥劑與活性化合物不相容,否則考慮將其用於本發明之醫藥組合物中。亦可在組合物中併入補充活性化合物。
治療組合物在製造及儲存條件下典型地必須為無菌且穩定的。組合物可調配為溶液、微乳液、分散液、脂質體或適合於較高藥物濃度之其他有序結構。載劑可為含有例如水、乙醇、多元醇(例如,甘油、丙二醇及液體聚乙二醇及其類似物)及其適合混合物之溶劑或分散液培養基。恰當流動性可例如藉由使用諸如卵磷脂之包衣、在分散液之情況下藉由維持所需粒度及藉由使用界面活性劑來維持。在諸多情況下,組合物中將較佳包括等張劑,例如糖、多元醇(諸如甘露醇、山梨糖醇)或氯化鈉。可注射組合物之延長吸收可藉由在組合物中包括延遲吸收劑(例如單硬脂酸鹽及明膠)來達成。
無菌可注射溶液可藉由將所需量之活性化合物與一種上文所枚舉之成分或成分組合一起併入適當溶劑中,並視需要接著滅菌微過濾來製備。一般而言,分散液藉由將活性化合物併入含有鹼性分散介質及來自以上所列舉的成分的所需其他成分的無菌媒劑中來製備。在無菌粉末用於製備無菌可注射溶液之情況下,較佳製備方法為真空乾燥及冷凍乾燥(凍乾),其自其預先無菌過濾溶液產生活性成分加任何額外所需成分之粉末。
可與載劑物質組合以產生單一劑型的活性成分之量將視所治療之個體、特定投藥模式而變化。可與載劑物質組合以產生單一劑型的活性成分之量一般為產生治療性效應之組合物的量。一般而言,在100%當中,此量應介於約0.01%至約99%活性成分之範圍內,較佳約0.1%至約70%、最佳約1%至約30%活性成分與醫藥學上可接受之載劑組合。
調節給藥方案以提供最佳所需反應(例如協同組合、治療反應)。舉例而言,可投與單一藥團,可隨時間投與若干分次劑量,或可依治療情況之緊急性所指示按比例減少或增加劑量。就投予之簡便性及劑量之均一性而言,將非經腸組合物調配成單位劑型尤其有利。如本文所使用之單位劑型係指適合作為單個劑量用於待治療之個體的實體上離散之單位;各單位含有與所需醫藥載劑結合,經計算以產生所需治療效果的預定量之活性化合物。本發明之單位劑型之規格係藉由下列情況指定且直接取決於下列情況:(a)活性化合物之獨特特徵及欲獲得之特定治療作用,及(b)混配此類用於治療個體敏感性之活性化合物之技術中的固有限制。
對於抗LY75抗體或抗CD20抗體之投與,劑型在約0.0001至100 mg/kg宿主體重範圍內,例如0.001至50mg/kg宿主體重、0.005至20 mg/kg宿主體重、0.01至10 mg/kg宿主體重且更通常0.01至5 mg/kg宿主體重。舉例而言,劑量可為0.05 mg/kg體重、0.1 mg/kg體重、0.3 mg/kg體重、0.3 mg/kg體重、0.5 mg/kg體重、1 mg/kg體重、2 mg/kg體重、3 mg/kg體重、4 mg/kg體重、5 mg/kg體重、6 mg/kg體重、7 mg/kg體重、8 mg/kg體重、9 mg/kg體重、10 mg/kg體重、12 mg/kg體重、15 mg/kg體重、20 mg/kg體重、25 mg/kg體重、30 mg/kg體重,或在0.1-20 mg/kg、0.5-15 mg/kg、1-10 mg/kg、2-8 mg/kg、3-7 mg/kg、4-6 mg/kg範圍內。例示性治療方案需要投與每天一次、每2天一次、每週一次、每兩週一次、每三週一次、每四週一次、一月一次、每6週一次、每3個月一次或每三至六個月一次。本發明之抗LY75抗體的較佳劑量方案包括經由靜脈內投與1 mg/kg體重或3 mg/kg體重,同時使用以下給藥時程中之一者給予抗體:(i)每四週六次劑量,接著每三個月;(ii)每三週;(iii)3 mg/kg體重一次,接著每三週1 mg/kg體重。
在一些實施例中,調節抗LY75抗體(例如LY75-DM4)劑型以達成血漿抗體濃度為0.01至1.5 nM或0.018至1.2 nM(例如約0.018、0.037、0.075、0.15、0.3、0.6或1.2 nM)。較佳地,調節抗LY75抗體以達成血漿抗體濃度為0.03 nM至0.30 nM。
在一些實施例中,將抗CD20抗體調配在10 mg/ml溶液中。在一些實施例中,抗CD20抗體以350-400 mg/m
2之劑量投與,較佳每週一次。在一些實施例中,調節抗CD20抗體(例如利妥昔單抗)劑量以達成血漿抗體濃度為約2.34至150 nM (例如約2.34、4.68、9.37、18.75、37.5、75或150 nM)。可將抗CD20抗體(例如利妥昔單抗)以約1400 mg/23,400單位之劑量皮下投與。在一些實施例中,劑量為200 mg、400 mg、600 mg、800 mg、1000 mg或1200 mg。抗CD20抗體(例如利妥昔單抗)可與環磷醯胺、羥基道諾黴素、安可平及強的松或潑尼龍(亦即CHOP療法)中之一或多者一起投與。
在一些實施例中,調節依魯替尼劑量以達成血漿濃度為約15.6至1000 nM (例如約15.6、31.2、62.5、125、250、500或1000 nM)。在其它實施例中,調節依魯替尼劑量以達成血漿濃度為約1.56至100 nM (例如約1.5、3.1、6.2、12.5、25、50或100 nM)。依魯替尼劑量可為約560 mg (例如四個140 mg膠囊)。其可經口投與。在一些實施例中,依魯替尼劑量為約100 mg、200 mg、300 mg、400 mg或500 mg。
較佳地,組分(A)及(B)之組合為協同組合。熟習此項技術者應瞭解協同組合為其中組合之效應大於個別組分之效應總和者。協同作用可使用Chou-Talalay聯合指數(CI)來定量(參見「Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses」, Zhao L,等人 Clin Cancer Res. (2004) Dec 1;10(23):7994-8004;及「Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design」, Chou TC, Motzer RJ, Tong Y, Bosl GJ., J. Natl. Cancer Inst. (1994) Oct 19;86(20):1517-24)。此聯合指數(CI)方法係基於衍生自質量作用定律之中位數效應原理的多種藥物效應等式。此對於以下提供定量定義:強協同作用(CI < 0.3)、協同作用(CI = 0.3-0.9)、累加效應(CI = 0.9-1.1)或拮抗作用/無益處(CI > 1.1),並且其向用於自動模擬藥物組合之電腦軟體提供演算法。其考量各單獨藥物及其組合之效能(D(m)值)及劑量效應曲線之形狀(m值)兩者。Chou-Talalay聯合指數(CI)可使用Synergy R package估算(參見「Preclinical versus Clinical Drugs Combination Studies」, Chou TC. Leuk. Lymphoma. (2008);49(11):2059-2080及其中參考文獻,以上所有以引用之方式專門併入本文中)。組合之CI可在合適的細胞株中測試,例如在實例26中所使用之條件下,例如在ABC-DLBLC細胞株(諸如TMD8或HBL1)中。
較佳地,本發明之醫藥組合為其中Chou-Talalay聯合指數(CI)小於0.9、0.8、0.7、0.6、0.5、0.4、0.3或0.2之協同組合。較佳地,CI為0.1-0.5、0.1-0.3或0.1-0.2。
詳言之,提供一種治療患者體內之癌症之方法,其包含向有需要之患者同時、依序或各別投與治療有效協同量的本發明醫藥組合之組分(A)及(B)。亦提供本發明之醫藥組合用於治療癌症,其中向患者同時、各別或依序投與協同量之組分(A)及(B)用於治療癌症。較佳地,向患者投與組分(A)及(B)之量以便提供上文揭示之血漿濃度。
亦提供協同量的本發明醫藥組合之組分(A)及(B)之用途,其用於製造同時、各別或依序使用以治療癌症用之醫藥組合。亦提供本發明之協同醫藥組合以用於療法或用作藥劑。
在一些方法中,同時投與具有不同結合特異性之兩種或兩種以上單株抗體,在此情況下,所投與之各抗體之劑量在所指示之範圍內。抗體通常多次投與。單次劑量之間的時間間隔可為例如每日、每週兩次、每週、每月、每三個月、每六個月或每年。時間間隔亦可為不規律的,如藉由量測患者中針對標靶抗原之抗體的血液含量所指示。在一些方法中,劑量經調節以達到約1-1000 μg/ml、5-750 μg/ml、10-600 μg/ml、15-500 μg/ml、20-400 μg/ml及在一些方法中約25-300μg/ml之血漿抗體濃度。
或者,抗LY75抗體及抗CD20抗體可作為持續釋放調配物投與,在此情況下所需投與頻率較低。劑量及頻率視患者中抗體之半衰期變化。一般而言,人類抗體展示最長半衰期,接著為人類化抗體、嵌合抗體及非人類抗體。投藥劑量及頻率可視治療是否為預防或治療而變化。在預防性應用中,在長時期內,以相對不頻繁之間隔投與相對低之劑量。一些患者在其餘生中持續接受治療。在治療性應用中,有時需要以相對短時間間隔投與相對高劑量,直至疾病之進展降低或終止,且較佳直至患者展示疾病之症狀部分或完全改善。在其之後,可向患者投與預防性方案。
本發明之醫藥組合中活性成分之實際劑量水準可變化,以獲得在對患者無毒性之情況下有效地達成特定患者、組合物及投藥模式之所需治療響應的活性成分之量。所選劑量含量將視多種藥物動力學因素而定,該等因素包括所採用之本發明之特定組合物、或其酯、鹽或醯胺之活性;投與途徑;投與時間;待採用之特定化合物之排泄速率;治療之持續時間與所採用特定組合物組合之其他藥物、化合物及/或材料;待治療患者之年齡、性別、體重、病狀、一般健康狀況及先前病史;及醫學技術中熟知之類似因素。
「治療有效劑量」之抗LY75抗體或抗CD20抗體較佳使得疾病症狀之嚴重程度降低、疾病無症狀期之頻率或持續時間增加,或預防疾病病痛所致之障礙或失能。舉例而言,對於治療LY75或CD20介導之腫瘤,相對於未經治療個體,「治療有效量」較佳抑制細胞生長或腫瘤生長達至少約20%、至少約30%、更佳至少約40%、至少約50%、甚至更佳至少約60%、至少約70%且再更佳至少約80%或至少約90%。可在預測在人類腫瘤中之功效的動物模型系統中評估化合物抑制腫瘤生長的能力。或者,組合物之此特性可藉由檢查化合物抑制細胞生長之能力來評估,此類抑制可藉由熟練的從業者已知的分析而活體外量測。治療有效量之治療化合物可以減少腫瘤尺寸,或以其他方式改善個體之症狀。一般熟習此項技術者將能夠基於如個體之尺寸、個體之症狀的嚴重程度及特定組合物或所選擇之投與途徑的此類因素來確定此類量。
本發明之醫藥組合可經一或多種投與途徑、使用此項技術中熟知之多種方法中之一或多者來投與。組分(A)及(B)可藉由同樣途徑或藉由不同途徑投與。如熟習此項技術者將瞭解,投與途徑及/或模式將視所需結果而變化。本發明之抗體的較佳投藥途徑包括靜脈內、肌肉內、皮內、腹膜內、皮下、脊椎或其他非經腸投藥途徑,例如藉由注射或輸注。如本文中所用之片語「非經腸投藥」意謂除腸內及表面投與以外通常藉由注射進行之投藥模式,且包括(但不限於)靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊柱內、硬膜外及胸骨內注射及輸注。
或者,抗LY75抗體或抗CD20抗體可經由非-非經腸途徑投與,諸如局部、表皮或黏膜投藥途徑,例如鼻內、經口、經陰道、經直腸、舌下或局部。
活性化合物可與將保護化合物免於快速釋放之載劑一起製備,該等載劑諸如控制釋放調配物,包括植入物、經皮貼劑及微膠囊化傳遞系統。可使用可生物降解、生物相容聚合物,諸如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。製備該等調配物之許多方法已獲專利或一般為熟習此項技術者已知[參見例如
Sustained and Controlled Release Drug Delivery Systems(1978) J. R. Robinson編, Marcel Dekker,Inc. N.Y]。
治療性組合物可用此項技術中已知的醫學裝置投與。舉例而言,在一較佳實施例中,組分(A)及/或(B)可藉由無針皮下注射裝置投與,諸如美國專利第5,399,163號;第5,383,851號;第5,312,335號;第5,064,413號;第4,941,880號;第4,790,824號;或第4,596,556號。可用於本發明的熟知植入物及模組之實例包括:美國專利第4,487,603號,其揭示以控制速率施配藥物之植入式微量輸注泵;美國專利第4,486,194號,其揭示經由皮膚投與藥劑之治療裝置;美國專利第4,447,233號,其揭示用於以精確輸注速率遞送藥物之藥物輸注泵;美國專利第4,447,224號,其揭示用於連續藥物遞送之可變流量植入式輸注設備;美國專利第4,439,196號,其揭示具有多腔室隔室之滲透性藥物遞送系統;以及美國專利第4,475,196號,其揭示滲透性藥物遞送系統。此等專利以引用的方式併入本文中。許多其他此類插入物、遞送系統及模組為熟習此項技術者已知的。
在某些實施例中,抗LY75抗體及/或抗CD20抗體可經調配以確保在活體內適當分佈。舉例而言,血腦障壁(BBB)排除多種高度親水性化合物。為確保治療性化合物穿過BBB(必要時),其可調配成例如脂質體。關於製造脂質體之方法,參見例如美國專利4,522,811;5,374,548;及5,399,331。脂質體可包含選擇性輸送至特定細胞或器官之一或多個部分,因此增強標靶藥物傳遞[參見例如V.V. Ranade 1989, J. Clin. Pharmacol. 29:685]。例示性標靶部分包括葉酸或生物素(參見例如美國專利5,416,016);甘露糖苷[Umezawa等人 (1988)
Biochem. Biophys. Res. Commun.153:1038];抗體[P. G. Bloeman等人 (1995)
FEBS Lett.357:140;M. Owais等人 (1995)
Antimicrob.Agents Chemother.39:180];界面活性劑蛋白A受體[Briscoe等人 (1995)
Am. J. Physiol.1233:134];p120 [Schreier等人 (1994)
J. Biol. Chem.269:9090];亦參見K. Keinanen;M. L. Laukkanen (1994)
FEBS Lett.346:123; J. J. Killion;I. J. Fidler (1994)
Immunomethods4:273。
用途及方法如本文中所用,術語「個體」意欲包括人類及非人類動物。非人類動物包括所有脊椎動物,例如哺乳動物及非哺乳動物,諸如非人類靈長類動物、綿羊、狗、貓、牛、雞、兩棲動物及爬行動物。較佳之個體包括患有由LY75活性及/或CD20活性介導之病症的人類患者。
方法尤其適用於治療患有與異常LY75表現及/或CD20表現相關之病症的人類患者。考慮到LY75在腫瘤細胞上之表現,本發明之組合及方法可用以治療患有致瘤病症(例如特徵在於存在表現LY75之腫瘤細胞的病症)之個體或用於製造供用治療此類病症之藥物,該等病症包含(例如)白血病,包括慢性淋巴球性白血病及急性骨髓性白血病;非霍奇金氏淋巴瘤,包括DLBCL、B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、黏膜相關淋巴組織(MALT)淋巴瘤、T細胞/組織細胞豐富之B細胞淋巴瘤、伯基特氏淋巴瘤、淋巴漿細胞淋巴瘤、小淋巴球性淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、周邊T細胞淋巴瘤、間變性大細胞淋巴瘤及血管免疫母細胞T細胞淋巴瘤。如下文實例5及7所說明,已顯示LY75在抗體結合時將內化,因此使得抗LY75抗體能夠用於任何有效負載作用機制,例如ADC方法、放射免疫結合物或ADEPT方法。
或者,抗LY75抗體一般以ADC形式投與,可用於抑制或阻斷LY75功能,繼而可與某些疾病症狀之預防或改善有關,由此暗示LY75為該疾病之介體。此可藉由使樣品及對照樣品與抗LY75抗體在允許在抗體與LY75之間形成複合物的條件下接觸來實現。在樣品及對照中偵測且比較在抗體與LY75之間形成之任何複合物。
活體內及活體外投與抗體組合物(例如單株抗體及免疫共軛物)之合適途徑為此項技術中所熟知且可由一般技術者來選擇。舉例而言,抗體組合物可藉由注射(例如靜脈內或皮下)投與。所用分子之適合劑量將視個體之年齡及體重以及抗體組合物之濃度及/或調配物而定。
如先前所描述,抗LY75抗體及/或抗CD20抗體可與一或多種其他治療劑(例如細胞毒性劑、放射毒性劑或免疫抑制劑)一起共同投與。抗體可連接至藥劑(以免疫複合物形式)或可與藥劑各別投與。在後一情況(各別投與)下,抗體可在藥劑之前、之後或與藥劑同時投與,或可與患有其他已知療法(例如抗癌療法,例如輻射)共投與。此類治療劑尤其包括抗贅生性劑,諸如阿黴素(阿德力黴素)、順鉑博萊黴素硫酸鹽(cisplatin bleomycin sulfate)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)及環磷醯胺羥基脲(cyclophosphamide hydroxyurea),其本身僅在對患者具毒性或亞毒性之含量下有效。順鉑每四週一次以100 mg/kg劑量靜脈內投與,且阿德力黴素每21天一次以60-75 mg/ml劑量靜脈內投與。適用於與本發明抗體共投與之其他藥劑包括用於治療癌症(例如胃癌、結腸直腸癌、前列腺癌、乳癌、卵巢癌或肺癌)之其他藥劑,諸如Avastin
®、5FU及吉西他濱。本發明之抗LY75抗體或其抗原結合片段與化學治療劑之共投與提供經由不同機制起作用的兩種抗癌劑,其對人類腫瘤細胞產生細胞毒性效應。此類共投與可解決因耐藥性出現或腫瘤細胞之抗原性改變而將使其不與抗體起反應所致的問題。
本發明之醫藥組合亦可與血清及/或補體一起投與。此等組合物在補體位於接近於抗體附近時可為有利的。或者抗體以及補體或血清可各別投與。
包含組分(A)及(B)連同使用說明書之套組亦在本發明之範疇內。該套組可另外含有一或多種額外試劑,諸如免疫抑制劑、細胞毒性劑或放射毒性劑,或一或多種額外抗體(例如具有不同於第一抗體之結合至LY75抗原中之抗原決定基之補充活性的抗體)。
因此,用本發明之醫藥組合治療之患者可(在本文所揭示之抗體投與之前、同時或之後)用另一治療劑(諸如細胞毒性或放射毒性劑)另外投與,其增強或加強抗體之治療效應。
在其它實施例中,個體可額外用調節(例如增強或抑制)Fcγ或Fcγ受體之表現或活性的藥劑治療,例如藉由用細胞介素治療個體。用於在經多特異性分子治療期間投與之較佳的細胞介素包括顆粒球群落刺激因子(G-CSF)、顆粒球巨噬細胞群落刺激因子(GM-CSF)、干擾素-γ (IFN-γ)及腫瘤壞死因子(TNF)。
本說明書中所引用之所有參考文獻,包括但不限於所有論文、公開案、專利、專利申請案、演示、文本、報導、手稿、手冊、書、網際網路公告、雜誌文章、期刊、產品說明書及其類似物,吾人據此以全文引用的方式併入本說明書中。本文參考文獻之論述僅意欲概述其作者之聲明且不承認任何參考文獻構成先前技術,且申請人保留攻擊所引用之參考文獻的準確性及相關性的權利。
儘管已出於清楚理解之目的藉由說明及實例相當詳細地描述前述發明,但根據本發明之教示,一般熟習此項技術者將顯而易見,可在不背離附屬申請專利範圍之精神或範圍之情況下對其進行某些變化及修改。
本發明進一步藉由以下實例說明,該等實例不應理解為進一步限制。
實例 1 : 產生針對 LY75 抗原之人類單株抗體按照標準程序,小鼠(異種小鼠IgG1)以CHO細胞進行免疫,該CHO細胞經以全長LY75轉染。
藉由流動式細胞測量術在轉染有LY75之HEK293細胞上且隨後在表現LY75之HT29細胞上測試所出現之抗體針對LY75的特異性。為測試抗體結合至細胞表面LY75蛋白質之能力,使抗體與表現LY75之細胞一起培育。細胞在FACS緩衝液(DPBS、2%FBS)中洗滌,離心且再懸浮於100 μl經稀釋之初級LY75抗體(亦稀釋於FACS緩衝液中)中。抗體-細胞株複合物在冰上培育60分鐘且隨後用如上所述之FACS緩衝液洗滌兩次。將細胞-抗體離心塊再懸浮於100 μl經稀釋之二級抗體(亦稀釋於FACS緩衝液中)中,且在冰上培育60分鐘。如前所述洗滌離心塊且再懸浮於200 μl FACS緩衝液中。將樣品負載於BD FACScanto II流式細胞儀上且使用BD FACSdiva軟體分析資料(結果未展示)。
實例 2 : 針對 LY75 之單株抗體的結構表徵使用標準PCR技術獲得編碼LY75_A1單株抗體之重鏈及輕鏈可變區的cDNA序列且使用標準DNA定序技術定序。
抗體序列可在一或多個殘基處誘變回復至生殖系殘基。
LY75_A1之重鏈可變區的核苷酸及胺基酸序列分別展示於SEQ ID NO: 3及1中。
LY75_A1之輕鏈可變區的核苷酸及胺基酸序列分別展示於SEQ ID NO: 4及2中。
LY75_A1重鏈免疫球蛋白序列與已知人類生殖系免疫球蛋白重鏈序列的比較表明LY75_A1重鏈利用來自人類生殖系V
H3-15之V
H區段及來自人類生殖系J
HJH4之J
H區段。使用CDR區測定之Kabat系統進一步分析LY75_A1 V
H序列描繪分別如SEQ ID NO: 5、6及7中所示之重鏈CDR1、CDR2及CDR3區。LY75_A1 CDR1、CDR2及CDR3 V
H序列與生殖系V
H3-15及生殖系J
HJH4序列之比對展示於圖1中。
LY75_A1輕鏈免疫球蛋白序列與已知人類生殖系免疫球蛋白輕鏈序列之比較表明LY75_A1輕鏈利用來自人類生殖系V
KO12之V
K區段及來自人類生殖系J
KJK4之J
K區段。使用CDR區測定之Kabat系統進一步分析LY75_A1 V
K序列描繪分別如SEQ ID NO: 8、9及10中所示之輕鏈CDR1、CDR2及CDR3區。LY75_A1 CDR1、CDR2及CDR3 V
K序列與生殖系V
KO12及生殖系J
KJK4序列之比對展示於圖2中。
實例 3 : 使用針對 LY75 之單株抗體的免疫組織化學使用特異性針對LY75之人類單株抗體對FFPE HT-29及A549細胞集結粒、FFPE非霍奇金氏淋巴瘤、及胰臟癌陣列及新冷凍的淋巴瘤/白血病腫瘤、卵巢癌、胰臟癌及乳癌切片及正常組織陣列進行免疫組織化學。
材料及方法材料
來自Fisher Scientific, PA, USA之二甲苯(X5P-1gal)。
來自Fisher Scientific, PA, USA之Histoprep 100%乙醇(HC-800-1GAL)。
來自Thermo Scientific, MA, USA之用於熱誘發性抗原決定基修復之10×檸檬酸鹽緩衝液(AP9003125)。
來自Thermo Scientific, MA, USA之Thermo Scientific* Pierce*過氧化酶抑制劑(35000)。
來自Dako, CA, USA之無血清蛋白質阻斷劑(X0909)
二級抗體:來自Jackson Immunoresearch, PA, USA之山羊抗人類IgG Fab-FITC結合物(109-097-003)
來自Jackson Immunoresearch, PA, USA之Chrome純人類IgG完整分子(09-000-003)
三級抗體:來自Abcam, MA, USA之小鼠抗FITC (ab10257)
來自R&D Systems, MN, USA之經純化人類IgG同型對照(1-001A)
來自Fisher Scientific, PA, USA之Tween-20 (BP337-100)
來自Fisher Scientific, PA, USA之丙酮(BP2403-4)
來自Dako, CA, USA之Dual Link EnVision+ HRP結合聚合物,小鼠及兔(K4063)。
來自Invitrogen, NY, USA之DAB 2-溶液套組(882014)。
來自Fisher Scientific, PA, USA之哈里斯蘇木精(Harris Hematoxylin)(23-245-677)。
來自Dako, CA, USA之Faramount封固劑(S302580)。
組織切片及陣列購自US Biomax Inc., MD, USA或Origene, MD, USA。
FFPE 載片之製備 : 脫蠟 及復水FFPE載片在二甲苯中脫蠟(2×3分鐘),接著經由1:1二甲苯:100%乙醇(1×3分鐘)、100%乙醇(2×3分鐘)、95%乙醇(1×3分鐘)、70%乙醇(1×3分鐘)、50%乙醇(1×3分鐘)及自來水(1×3分鐘)復水。
FFPE載片之製備:抗原修復(微波)。
在科普林缸(Coplin jar)中之50 mL 1×檸檬酸鹽緩衝液中,使用大功率微波加熱直至沸騰,接著低功率加熱10分鐘來修復LY75抗原。載片接著靜置冷卻至室溫再持續15分鐘,接著在自來水中洗滌3分鐘。用疏水屏障筆在各組織切片/TMA周圍畫環且接著在PBS中洗滌載片3次,每次洗滌3分鐘。
FF 載玻片之製備自-80℃之儲存器移出載片且使其在通風櫥中在室溫下乾燥20-30分鐘。載片在-20℃下冰冷的丙酮中固定10分鐘,接著使其在通風櫥中在室溫下乾燥20分鐘。洗滌載片且在PBS中復水,洗滌3次,每次3分鐘。用疏水屏障筆描繪切片的輪廓。
抗體複合物之製備將初級抗LY75抗體稀釋於無血清蛋白質阻斷劑(SFPB)中以獲得濃度比最終所需濃度大20倍的溶液(對於1 μg/mL最終濃度,20 μg/mL)。以類似方式在SFPB中製備二級抗體山羊抗人類免疫球蛋白G (IgG)抗原結合片段(Fab)以形成相同濃度之溶液。
將相同體積之初級及二級抗體合併於經標記管中,平緩地混合且在室溫下培育3分鐘,產生比所需最終濃度大10倍的初級抗體濃度(對於1 μg/mL最終濃度,10 μg/mL)。此混合物用SFPB 1:5稀釋,平緩地混合且在室溫下培育30分鐘,產生兩倍所需最終濃度之初級抗體濃度(對於1 μg/mL最終濃度,2 μg/mL)。
為產生最終染色複合物,在SFPB中製備人類IgG之1% (10 μg/μL)溶液且添加相同體積至初級/二級抗體混合物。此組合平緩地混合且在室溫下培育30分鐘,由初級抗體濃度一半之初級/二級抗體混合物稀釋且產生所需最終初級抗體濃度(1 μg/mL)。
免疫染色同時,藉由在室溫下在潮濕腔室中用過氧化酶抑制劑培育組織5-10分鐘來阻斷內源性組織過氧化酶活性。接著在PBS中洗滌載片3次,每次洗滌3分鐘。在室溫下,在潮濕腔室中,組織在SFPB中培育30分鐘。將最終染色複合物施用於每一組織切片及/或微陣列,且在室溫下在潮濕腔室中培育載片30分鐘。載片接著在PBS中洗滌一次且在PBST (PBS+0.125% Tween-20)中洗滌一次,每次洗滌3分鐘。在室溫下,在潮濕腔室中,三級抗體小鼠抗FITC以2 μg/mL濃度施用30分鐘。切片接著在PBS中洗滌一次且在PBST中洗滌一次,每次洗滌3分鐘。接著將Dual Link EnVision+抗小鼠/兔HRP結合聚合物施用於組織,且在室溫下在潮濕腔室中培育載片30分鐘。載片接著在PBS中洗滌一次,在PBST中洗滌一次,每次洗滌3分鐘。根據製造商說明書,在室溫下在製備之DAB溶液中培育組織10分鐘。載片接著在流動自來水中洗滌一次持續2分鐘,且在PBS中洗滌一次持續3分鐘。載片在室溫下用蘇木精對比染色30秒且用流動自來水洗滌。載片在室溫下乾燥30分鐘且接著使用Faramount封固劑將蓋玻片封固於載片上。
結果LY75_A1在FFPE三陰性乳癌樣品中展示陽性,其中77%切片展示陽性染色且55%顯現穩固(+++)染色。
FF正常組織中LY75之染色一般為不存在至低染色。乳房、唾液腺及胰腺之導管上皮顯現明顯的低至中度染色,且脾臟低陽性染色。因而,針對LY75之抗體可在一些測試癌症及可能展示LY75表現之其他癌症類型中具有作為治療劑及診斷劑之效用。
實例 4 : DM1 結合之抗 LY75 單株抗體在 HT-29 細胞中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3a中描繪之結果展示已知結合至LY75之抗體的亞群,其可誘導HT-29細胞之細胞殺死。此表明雖然抗體可結合至LY75,但當與DM1結合時,僅少數呈現功效。接著自亞群選擇抗體用於進一步細胞毒素活性分析。
實例 5 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在結腸直腸癌細胞中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3b展示與DM1及DM4結合之抗LY75抗體對HT-29細胞的細胞毒素活性。此等結果證明細胞毒素活性與抗體濃度及與毒素結合之其他抗LY75抗體(選自實例1)成比例增加。
實例 6 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在淋巴瘤細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3c展示與DM1及DM4結合之抗LY75抗體對RAJI細胞的細胞毒素活性。圖3d展示與DM1或DM4結合之抗LY75抗體在Namalwa細胞中之細胞毒性活性。圖3e展示與DM1及DM4結合之抗LY75抗體對Karpas 299細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度及與DM1及DM4結合之其他抗LY75抗體(選自實例1)成比例增加。
實例 7 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在胰臟癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3f展示與DM1及DM4結合之抗LY75抗體對BxPC3細胞的細胞毒素活性。圖3g展示與DM1或DM4結合之抗LY75抗體對HupT4細胞之細胞毒性活性。圖3h展示與DM1或DM4結合之抗LY75抗體對HPAFFII細胞之細胞毒性活性。此等結果表明細胞毒素活性與抗體濃度及與DM1及DM4結合之其他抗LY75抗體(選自實例1)成比例增加。
實例 8 : 與 DM1 結合及 DM4 結合之抗 LY75 單株抗體在慢性淋巴細胞性白血病細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3i展示與DM1及DM4結合之抗LY75抗體對EHEB細胞之細胞毒性活性。圖3j展示與DM1及DM4結合之抗LY75抗體對Mec-1細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度及與DM1及DM4結合之其他抗LY75抗體(選自實例1)成比例增加。
實例 9 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在急性單核細胞性白血病細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3k展示與DM1及DM4結合之抗LY75抗體對AML-193細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度及與DM1及DM4結合之其他抗LY75抗體(選自實例1)成比例增加。
實例 10 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在乳癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3l展示與DM1及DM4結合之抗LY75抗體對HCC 70 (ER陰性、PR陰性及Her2陰性)細胞的細胞毒素活性。圖3m展示與DM1及DM4結合之抗LY75抗體對HCC 1806 (ER陰性、PR陰性及Her2陰性)細胞的細胞毒素活性。圖3n展示與DM1及DM4結合之抗LY75抗體對MDA-MB-468細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 11 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在膀胱癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3o展示與DM1及DM4結合之抗LY75抗體對RT4細胞之細胞毒性活性。圖3p展示與DM1及DM4結合之抗LY75抗體對5637細胞的細胞毒素活性。圖3q展示與DM1及DM4結合之抗LY75抗體對SW780細胞之細胞毒性活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 12 : DM1 結合及 DM4 結合之抗 LY75 單株抗體在頭頸癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3r展示與DM1及DM4結合之抗LY75抗體對SCC-9細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 13 : 與結合 DM1 及與結合 DM4 之 抗 LY75 單株抗體在食道癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3s展示與DM1及DM4結合之抗LY75抗體對OE 19細胞之細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 14 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在卵巢癌細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3t展示與DM1及DM4結合之抗LY75抗體對OVCAR-3細胞的細胞毒素活性。圖3u展示與DM1及DM4結合之抗LY75抗體對SK-OV-3細胞的細胞毒素活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 15 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在多發性骨髓瘤細胞株中之功效 材料來自Fisher Scientific, PA, USA之細胞剝離液(非酶促細胞解離) (MT-25-056CI)。
來自Fisher Scientific, PA, USA之PBS pH 7.4 (1×) (SH30028LS)。
來自Fisher Scientific, PA, USA之RPMI 1640培養基(MT-10-041-CM)。
來自Promega, WI, USA之Cell Titer Glo (G7572)。
方法使用細胞剝離液解離細胞且計數。將5e3個細胞/孔短暫離心成離心塊(對於懸浮細胞,視細胞倍增時間而定,可使用更多,諸如10e3個細胞/孔)。將離心塊再懸浮於培養基中至1e5個細胞/毫升之濃度。
將50微升/孔細胞懸浮液添加至白邊、透明底的96孔板之孔中。抗體經稀釋且滴定至8點(3倍滴定),相當於0-20 nM之濃度(兩倍測試濃度)。將經稀釋之抗體或培養基(對於未經處理之樣品)(50微升/孔)添加至適當孔。將過量培養基(200微升/孔)添加至該板之外部列及行以防止蒸發。將板在37℃下培育72小時。
將板自培育箱移出且在室溫下培育30分鐘。同時解凍Cell Titer Glo溶液。輕彈該板且用100微升/孔PBS洗滌1次(對於懸浮細胞,首先將板離心以使細胞集結)。將100微升/孔PBS及100微升Cell titer glo添加至各孔且濕磨混合。將板在暗處在室溫下培育15分鐘且藉由顯微法目測以確保發生有效細胞溶解。接著在Glomax光度計上讀取該板。
結果圖3v展示與DM1及DM4結合之抗LY75抗體對MOLP-8細胞的細胞毒素活性。圖3w描繪與DM1及DM4結合之抗LY75抗體對RPMI8226細胞之細胞毒性活性。此等結果表明細胞毒素活性與抗體濃度成比例增加。
實例 16 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在 Raji 異種移植模型中之功效在皮下Raji伯基特氏淋巴瘤SCID小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷SCID小鼠皮下接種以Raji (人類伯基特氏淋巴瘤)腫瘤細胞。允許建立腫瘤且將小鼠分成五個治療組,每組3-6隻小鼠。當每組平均腫瘤體積達到129-132 mm3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;磷酸鹽緩衝生理食鹽水(PBS));組2 (LY75_DM1;10 mg/kg)、組3 (同型對照-DM1;10 mg/kg)、組4 (LY75_DM4;5 mg/kg)、組5 (同型對照-SPBDDM4;5 mg/kg)。一週後投與第二劑量。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤兩次。當腫瘤達到2000 mm3之腫瘤體積終點時或在60天後(無論哪個首先實現),將小鼠安樂死。由腫瘤生長延遲(TGD)、中位時間端點(TTE)增加及ADC處理小鼠對比PBS處理小鼠之Kaplan Meier存活曲線之差值對數秩分析測定功效。對首先達到終點之五隻經媒劑處理之對照小鼠進行腫瘤取樣,該等腫瘤藉由福馬林固定及石蠟包埋加工。
結果圖4a展示LY75_DM1及LY75_DM4各自顯示與對照相比在Raji伯基特氏淋巴瘤SCID小鼠異種移植模型中之顯著抗腫瘤活性及顯著延長的存活期;然而,5 mg/kg LY75_DM4劑量比10 mg/kg劑量之LY75_DM1顯著更有效,導致6隻小鼠中之5隻具有完全但暫時的腫瘤消退。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類非霍奇金淋巴瘤癌症患者治療中提供臨床益處的可能性。
實例 17 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在 Namalwa 異種移植模型中之功效在皮下Namalwa伯基特氏淋巴瘤SCID小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷SCID小鼠皮下接種以Namalwa (人類伯基特氏淋巴瘤)腫瘤細胞。允許建立腫瘤且將小鼠分成五個治療組,每組6隻小鼠。當每組平均腫瘤體積達到114 mm3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;磷酸鹽緩衝生理食鹽水(PBS));組2 (LY75_DM1;10 mg/kg)、組3 (同型對照-DM1;10 mg/kg)、組4 (LY75_DM4;5 mg/kg)、組5 (同型對照-SPBDDM4;5 mg/kg)。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤兩次。當腫瘤達到2000 mm3之腫瘤體積終點時或在60天後(無論哪個首先實現),將小鼠安樂死。由腫瘤生長延遲(TGD)、中位時間端點(TTE)增加及ADC處理小鼠對比PBS處理小鼠之Kaplan Meier存活曲線之差值對數秩分析測定功效。對首先達到終點之五隻經媒劑處理之對照小鼠進行腫瘤取樣,該等腫瘤藉由福馬林固定及石蠟包埋加工。
結果圖4b展示LY75_DM1及LY75_DM4各自顯示與對照相比在Namalwa伯基特氏淋巴瘤SCID小鼠異種移植模型中之顯著抗腫瘤活性及存活期延長;然而,5 mg/kg LY75_DM4劑量比10 mg/kg劑量之LY75_DM1顯著更有效,導致腫瘤體積短暫減小。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類非霍奇金淋巴瘤癌症患者治療中提供臨床益處的可能性。
實例 18 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在胰臟癌異種移植模型中之功效在皮下HPAFII胰腺癌無胸腺裸小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷無胸腺裸小鼠皮下接種以HPAFII (人類胰腺癌)腫瘤細胞。允許建立腫瘤且將小鼠分成五個治療組,每組6隻小鼠。當每組平均腫瘤體積達到~114 mm3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;磷酸鹽緩衝生理食鹽水(PBS));組2 (LY75_DM1;10 mg/kg)、組3 (同型對照-DM1;10 mg/kg)、組4 (LY75_DM4;5 mg/kg)、組5 (同型對照-SPBDDM4;5 mg/kg)。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤三次。當腫瘤達到2000 mm3之腫瘤體積端點時或在90天後(無論哪個首先實現),將小鼠安樂死。在ADC處理小鼠或PBS處理小鼠中由處理對腫瘤體積之作用及卡普蘭-邁耶(Kaplan-Meier)存活曲線之差值對數秩分析測定功效。自媒劑處理之對照小鼠進行腫瘤取樣,且該等腫瘤藉由福馬林固定及石蠟包埋加工。
結果圖4c展示LY75_DM1及LY75_DM4顯示與對照相比在HPAFII裸小鼠異種移植模型中之顯著及同樣有效的抗腫瘤活性及存活期延長。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類胰臟癌患者治療中提供臨床益處的可能性。
實例 19 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在膀胱癌異種移植模型中之功效在皮下SW780人類膀胱癌瘤SCID小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷無胸腺裸小鼠皮下接種以HPAFII (人類胰腺癌)腫瘤細胞。允許建立腫瘤且將小鼠分成五個治療組,每組6隻小鼠。當每組平均腫瘤體積達到約114 mm3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;磷酸鹽緩衝生理食鹽水(PBS));組2 (LY75_DM1;1 mg/kg)、組3 (LY75_DM1;2.5 mg/kg)、組4 (LY75_DM1;5 mg/kg)、組5 (LY75_DM4;1 mg/kg)、組6 (LY75_DM4;2.5 mg/kg)、組7 (LY75_DM4;5 mg/kg)、組8 (同型對照-SPBDDM4;5 mg/kg)。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤三次。當腫瘤達到2000 mm3之腫瘤體積端點時或在90天後(無論哪個首先實現),將小鼠安樂死。在ADC處理小鼠或PBS處理小鼠中由處理對腫瘤體積之作用及卡普蘭-邁耶存活曲線之差值對數秩分析測定功效。自經媒劑處理之對照小鼠進行腫瘤取樣,且該等腫瘤藉由福馬林固定及石蠟包埋加工。
結果圖4d展示LY75_DM1及LY75_DM4顯示與對照相比在SW780裸小鼠異種移植模型中之顯著及同樣有效的抗腫瘤活性及存活期延長。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類膀胱癌患者治療中提供臨床益處的可能性。
實例 20 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在乳癌異種移植模型中之功效在皮下MDA-MB-468無胸腺裸小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷無胸腺裸小鼠皮下接種以MDA-MB-468 (人類三陰性乳腺癌)腫瘤細胞。允許建立腫瘤且將小鼠分成七個處理組,每組10隻小鼠。當每組平均腫瘤體積達到167 mm3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;20 mM丁二酸鈉,pH 5.0、6%海藻糖、0.04%聚山梨醇酯);組2 (LY75_DM1;5 mg/kg)、組3 (LY75_DM1;10 mg/kg)、組4 (LY75_DM4;5 mg/kg)、組5 (LY75_DM4;2.5 mg/kg)、組6 (LY75_DM4;1 mg/kg)、組7 (同型對照-DM4;5 mg/kg)。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤兩次。在腫瘤接種後82天將小鼠安樂死。在ADC處理小鼠對比PBS處理小鼠中,由抗腫瘤活性(處理組之平均腫瘤尺寸/對照組之平均腫瘤尺寸×100)及平均時間端點(TTE)增加測定功效。在接種後第71天,在媒劑處理之對照小鼠中取樣五個最大的腫瘤,藉由福馬林固定及石蠟包埋加工。
結果圖4e展示LY75_DM1及LY75_DM4各自顯示與對照相比在MDA-MB-468裸小鼠異種移植模型中之顯著抗腫瘤活性。用LY75_DM4觀察劑量依賴性活性,其中2.5及5 mg/kg比1 mg/kg有效得多。在5 mg/kg下,LY75_DM1及LY75_DM4同樣有效。在10及5 mg/kg LY75_DM1下及在5及2.5 mg/kg LY75_DM4下觀察到平均腫瘤體積之持續消退。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類三陰性乳癌患者治療中提供臨床益處的可能性。
實例 21 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在結腸直腸癌異種移植模型中之功效在皮下COLO205結腸直腸腺癌無胸腺裸小鼠異種移植模型中測試LY75_DM1及LY75_DM4之功效。
免疫缺陷無胸腺裸小鼠皮下接種以COLO205 (人類結腸直腸腺癌)腫瘤細胞。允許建立腫瘤且將小鼠分成五個治療組,每組6隻小鼠。當每組平均腫瘤體積達到117 mm
3之平均尺寸時,各組用以指定劑量靜脈內投與之以下化合物中之一者處理:組1 (媒劑;磷酸鹽緩衝生理食鹽水(PBS));組2 (LY75_DM1;10 mg/kg)、組3 (同型對照-DM1;10 mg/kg)、組4 (LY75_DM4;5 mg/kg)、組5 (同型對照-DM4;5 mg/kg)。在第一劑量十二天後投與第二劑量。監測體重(BW),時常檢查小鼠之健康狀況及不良副作用,且每週量測腫瘤兩次。當腫瘤達到1000 mm
3之腫瘤體積端點時或在60天後(無論哪個首先出現),將小鼠安樂死。在ADC處理小鼠對比PBS處理小鼠之卡普蘭邁耶存活曲線中,由腫瘤生長延遲(TGD)、中位時間端點(TTE)增加及差值對數秩分析測定功效。對首先達到端點之五隻媒劑處理之對照小鼠進行腫瘤取樣,該等腫瘤藉由福馬林固定及石蠟包埋加工。
結果圖4f展示LY75_DM1及LY75_DM4顯現與對照相比在COLO205結腸直腸腺癌裸小鼠異種移植模型中之類似的適度抗腫瘤活性及存活期延長。所有處理為良好耐受的且未觀察到毒性臨床症狀。此等資料表明針對LY75之ADC (例如LY75_DM1及LY75_DM4)在人類結腸直腸癌患者治療中提供臨床益處的可能性。
實例 22 : 與 DM1 結合及與 DM4 結合之抗 LY75 單株抗體在食蟹獼猴中之毒性將六隻雄猴以每組2隻猴分配至研究。媒劑(PBS)、LY75_DM4 (可裂解)或LY75_DM1 (不可裂解)以0 mg/kg/劑量(PBS,媒劑)、5 mg/kg/劑量(LY75_DM4,可裂解)或10 mg/kg/劑量(LY75_DM1,不可裂解)藉由15分鐘靜脈內輸注投與兩次(在第1天及第29天)。在劑量開始(第1天)之前及每次劑量後1、2、3、7、14、21及28天採集血液樣品用於毒物動態學評估。在劑量開始(第1天)之前及每次劑量後1、3、7、14、21及28天(在第1劑量後28天亦充當第2劑量之劑量前時間點)採集血液樣品用於臨床病理學分析。在第57天最終血液採集後將所有研究動物安樂死且驗屍。將自每次抽取之血液分離之血漿隔離、冷凍且運送至Oxford BioTherapeutics, Inc.以便藉由ELISA分析ADC濃度。
治療相關臨床病理學結果包括輕度再生性貧血及血液白細胞概況(最值得注意地,嗜中性白血球計數)之暫時降低。在用5 mg/kg LY75_DM4處理之兩隻動物及用10 mg/kg LY75_DM1處理之兩隻動物中之一者中觀察到貧血。在所有動物中觀察到計數在給藥後一週處於最低點且快速恢復之重度嗜中性白血球減少症;在經LY75_DM4處理之動物中絕對嗜中性白血球計數最低點更低。對APTT及PT凝聚參數不存在測試製品相關作用。血清化學變化包括在投與5 mg/kg LY75_DM4及10 mg/kg LY75_DM1後,AST、CK、LDH (每一處理組之2隻動物之一)及球蛋白的暫時增加。此外,僅在經LY75_DM4處理之動物中觀察到肝特異性酶ALT之暫時增加。血清化學參數增加之短持續時間及/或量值表明其並非不良的。不存在測試製品相關尿分析結果。在4週恢復期後屍檢時,不存在治療相關總體病理學結果或絕對及相對器官重量之變化。僅甲狀腺(濾泡膠體形態改變)及腎臟(外皮質小管擴張)中之組織病理學結果分級為最低嚴重程度;不與其他研究參數之變化相關聯;並非不良且具有最小毒理學顯著性。結論:以5 mg/kg LY75_DM4或10 mg/kg LY75_DM1之兩種劑量重複給藥治療在食蟹獼猴中為良好耐受的。在4週恢復期後,所有處理相關毒性結果為可逆的。
實例 23 : LY75_A1 藉由競爭性螢光活化細胞分類 (FACS) 結合分析之抗原決定基表徵 方法用細胞剝離液(Cellgro, 目錄號MT-25-056CI)將COLO205細胞(ATCC, 目錄號CCL-222)自組織培養瓶分離。將細胞洗滌且再懸浮於FACS緩衝液(PBS + 2%FBS),用生長培養基中和且計數。以每孔50,000個細胞將細胞塗覆於V底96孔板中。細胞用FACS緩衝液(PBS (Fisher, 目錄號SH30028-03) + 2% FBS)洗滌一次。將抗LY75-mAb (選自實例1)或LY75_A1以250 nM起始添加至孔,連續稀釋3倍且施用於相關孔,於冰上持續45分鐘。將需要單個或多個染色步驟之測試孔按需要保留於FACS緩衝液中,以確保所有測試條件同時完成最終染色。兩個孔在FACS緩衝液中保持未染色作為對照。
在與阻斷抗體培育一起後,細胞在FACS緩衝液中洗滌兩次。將細胞再懸浮於含有與MCC-DM1結合之抗LY75-mAb (1 nM)之FACS緩衝液中且在冰上培育45分鐘。細胞如上洗滌且再懸浮於FACS緩衝液加1 μg/ml小鼠抗美登素抗體中,並於冰中培育45分鐘。細胞如上所述洗滌且再懸浮於含有2 μg/ml山羊抗小鼠κRPE之FACS緩衝液中。將細胞於冰上培育45分鐘接著如上所述洗滌。使細胞再懸浮於每孔200 μl之FACS緩衝液中。使用Guava EasyCyte Plus HT流式細胞儀(96孔板形式)測定每一樣品之平均螢光強度,且使用Guava Cytosoft分析原始資料。
結果圖5a展示用抗LY75-mAb-MCC-DM1阻斷減少抗LY75-mAb之結合。LY75_A1與COLO205細胞之結合的分析展示LY75_A1不能阻斷抗LY75-mAb-MCC-DM1之結合(參見圖5b)。因此,可確定抗LY75-mAb及LY75_A1為非競爭性抗體且LY75_A1識別與其他抗LY75抗體不同且獨特的LY75的抗原決定基。
實例 24 LY75_A1 藉由肽微陣列分析之抗原決定基表徵。 方法藉由LC Sciences, Houston TX進行肽微陣列分析,簡言之,該方法包含以下步驟:合成具有一個胺基酸重疊跨越全長LY75蛋白質之殘基216至1666之LY75蛋白質的相連8聚體肽且固定於微陣列晶片上。晶片包含三個面板,使得實驗一式三份地進行。微陣列經LY75_A1處理以鑑別與抗體結合之肽。在以下條件下進行結合分析:
包含一式三份相連肽之微陣列在4℃下用1 mL結合緩衝液洗滌20分鐘。隨後將其與1 µg/mL LY75_A1一起在4℃下在結合緩衝液(pH 7.0)中培育2小時。陣列再次在4℃下用0.5 mL洗滌緩衝液洗滌30分鐘,接著與25 ng/mL抗人類IgG Alexa 647結合物一起在4℃下在結合緩衝液(pH 7.0)中培育1小時。陣列再次在4℃下用0.5 mL洗滌緩衝液洗滌30分鐘。
陣列接著在635 nm及PMT 500下掃描且記錄信號強度。肽若存在於至少2/3法定重複物中,則歸類為可偵測的。複製物之平均信號強度記錄為最終信號強度。
結果如圖6可見,抗體LY75_A1展示特異性結合至位於陣列上之許多肽。對於LY75_A1結合可見之最大信號為25000 (標度1-65535),陣列上所有點之平均信號為約885。信號強度3000設定為非特異性結合之背景切點。基於可見的抗體結合信號強度水準,鑑定形成LY75_A1之抗原決定基的可能序列。此等區展示於圖6a-6j中且為SEQ ID NO: 22-31。
實例 25 LY75_A1 肽下拉分析 方法 1.1 下拉分析重組LY75蛋白質藉由珠粒上之胰蛋白酶蛋白分解(Promega, US)消化。使用C18捕捉管柱(Thermo Fisher Scientific)回收所得消化肽。經純化肽接著與200 μl與LY75A1抗體交聯之蛋白質A珠粒一起在4℃下培育隔夜。第二天,收集未結合之肽且用1 ml PBS洗滌珠粒兩次。抗體結合肽藉由在90℃下於100 μl PBS中加熱5分鐘而自珠粒溶離。重複此溶離步驟。
1.2 質譜分析使用裝備有nanoACQUITY UPLC BEH 130 C18管柱, 75 μm × 250 mm (186003545)及LTQ Orbitrap Velos (Thermo Fisher Scientific)之Waters nanoACQUITY UPLC系統,藉由液相層析-質譜分析樣品。經120分鐘用自3%增加至35%乙腈之300 nl/min梯度溶離肽。在Orbitrap中在60000解析力下得到在400-2000 m/z質量範圍之間的全掃描質譜。在每一循環中,選擇二十個最密集的肽用於在線性離子阱中用裝備於儀器上之nanospray離子源進行CID MS/MS掃描。
1.3 肽之胺基酸序列分析由LTQ Orbitrap Velos產生之原始資料經由使用Mowse算法(Curr Biol. 1993年6月1日;3(6):327-3)之Mascot軟體(Matrix Science)處理以藉由搜索由Ensembl (http://www.ensembl.org/index.html)、IPI (www.ebi.ac.uk/IPI/IPIhuman.html)及SwissProt (http://www.uniprot.org)組成之序列資料庫而自峰值列表推斷胺基酸序列以及污染物蛋白質序列。肽鑑別之準則包括胰蛋白酶消化、多至2個丟失的裂解位點及各種生物學及化學修飾(氧化甲硫胺酸、藉由MMTS或碘乙醯胺修飾半胱胺酸及絲胺酸、蘇胺酸及酪胺酸之磷酸化)。將位列1具有0.05%或低於0.05%期望值、高於28或28離子得分的肽加載至OGAP資料庫。
1.4 鑑別 LY75 相關之肽鑑別LY75之方法使用天然存在之人類蛋白質藉由如上所述之質譜以實驗方式獲得之肽序列鑑別及組織公開人類基因組序列中之編碼外顯子。此等以實驗方式測定之序列與OGAP®資料庫相比,該資料庫藉由肽質量、肽簽名、EST及公共領域基因組序列資料之處理及整合彙集而成,如國際專利申請案WO2009/087462中所述。
結果使用抗體LY75_A1之肽下拉分析的結果展示於下表1及圖7中。在下拉分析及微陣列分析中在肽溶離物1a及1b中鑑別之肽視為最可能形成抗原決定基之候選物。
表 1 :肽微陣列及肽下拉實驗之比較
表1展示在肽微陣列分析及肽下拉分析中,於溶離物1a及1b中鑑別出許多重疊LY75肽區。此等區視為最可能含有由抗體LY75_A1識別之抗原決定基,因為其由藉由兩種所用技術測試之LY75_A1結合。
實例 26使多種活化B細胞瀰漫性大B細胞淋巴瘤(ABC-DLBCL)細胞株(亦即TMD8及HBL1細胞株)暴露於單獨或與增加劑量之利妥昔單抗(2.34-4.68-9.37-18.75-37.5-75-150)或依魯替尼(15.6-31.2-62.5-125-250-500-1000 nM)組合的增加劑量之LY75_DM4(亦即0.018-0.037-0.075-0.15-0.3-0.6-1.2 nM)持續72小時。此繼之以MTT [3-(4,5-二甲基噻唑基-2)-2,5-二苯基四氮唑溴鹽]分析。
Chou-Talalay聯合指數(CI)使用Synergy R package來估算(Preclinical versus Clinical Drugs Combination Studies. Chou TC. Leuk. Lymphoma. 2008;49(11):2059-2080)。此提供對於以下之定量定義:強協同作用(<0.3)、協同作用(0.3-0.9)、累加效應(0.9-1.1)或拮抗作用/無益處(> 1.1)。
圖式8A-B展示LY75_DM4與利妥昔單抗之間存在的協同效應。圖9展示LY75_DM4與依魯替尼之間存在的協同效應。支持資料展示於以下表2、3及4中。
表 2 : 不同劑量之 LY75_DM4 與利妥昔單抗組合在三種 TMD8 ABC-DLBCL 細胞株上之 Chou-Talalay 聯合指數 (CI)
表 3 : 不同劑量之 LY75_DM4 與利妥昔單抗組合在三種 HBL-1 ABC-DLBCL 細胞株上之 Chou-Talalay 聯合指數 (CI)
表 4 :不同劑量之 LY75_DM4 與依魯替尼組合在三種 HBL-1 ABC-DLBCL 細胞株上之 Chou-Talalay 聯合指數 (CI)
序列:
序列表自定義文本 :SEQ ID NO: 38 <223> 利妥昔單抗VH序列
SEQ ID NO: 39 <223> 利妥昔單抗VL序列
SEQ ID NO: 40 <223> 利妥昔單抗VH_CDR1
SEQ ID NO: 41 <223> 利妥昔單抗VH_CDR2
SEQ ID NO: 42 <223> 利妥昔單抗VH_CDR3
SEQ ID NO: 43 <223> 利妥昔單抗VL_CDR1
SEQ ID NO: 44 <223> 利妥昔單抗VL_CDR2
SEQ ID NO: 45 <223> 利妥昔單抗VL_CDR3
SEQ ID NO: 52 <223> 連接子
SEQ ID NO: 53-163 <223> 肽
SEQ ID NO: 165-207 <223> 肽
A1 | SEQ ID NO |
可變重鏈CDR1 | 5 |
可變重鏈CDR2 | 6 |
可變重鏈CDR3 | 7 |
可變輕鏈CDR1 | 8 |
可變輕鏈CDR2 | 9 |
可變輕鏈CDR3 | 10 |
(R)-1-(3-(4-胺基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮。 |
SEQ ID NO: | 藉由微陣列分析鑑別之肽 | 藉由下拉分析鑑別之肽 |
區域1 (aa609-618) | - | |
區域2 (aa651-662) | - | |
46 | 區域3 (aa761-780) | GWHFYDDR (765-772) |
47 48 | 區域4 (aa883-901) | ISEWPIDDHFTYSR(877至890) FPVTFGEECLYMSAK(896-910) |
49 | 區域5 (aa1029-1040) | ELTYSNFHPLLVSGR(1030-1044) |
50 | 區域6 (aa1077-1093) | HFVSLCQK (1084-1091) |
51 | 區域7 (aa1107-1118) | QTLQNASETVK (1099-1109) |
區域8 (aa1368-1378) | - | |
區域9 (aa1518-1528) | - | |
區域10 (aa1535-1554) | - |
N ° | 利妥昔單抗 (nM) | LY75_DM4 (nM) | CI |
1 | 2.3438 | 0.01875 | 17.124 |
2 | 2.3438 | 0.075 | 0.225 |
3 | 2.3438 | 0.15 | 0.346 |
4 | 2.3438 | 0.3 | 0.583 |
5 | 2.3438 | 0.6 | 1.165 |
6 | 2.3438 | 1.2 | 2.514 |
7 | 2.3438 | 0.0375 | 0.145 |
8 | 4.6875 | 0.01875 | 1.499 |
9 | 4.6875 | 0.0375 | 0.147 |
10 | 4.6875 | 0.075 | 0.216 |
11 | 4.6875 | 0.15 | 0.346 |
12 | 4.6875 | 0.3 | 0.628 |
13 | 4.6875 | 0.6 | 1.165 |
14 | 4.6875 | 1.2 | 2.514 |
15 | 9.375 | 0.01875 | 2.918 |
16 | 9.375 | 0.0375 | 0.144 |
17 | 9.375 | 0.075 | 0.219 |
18 | 9.375 | 0.15 | 0.332 |
19 | 9.375 | 0.3 | 0.583 |
20 | 9.375 | 0.6 | 1.025 |
21 | 9.375 | 1.2 | 2.514 |
22 | 18.75 | 0.01875 | 0.8 |
23 | 18.75 | 0.0375 | 0.145 |
24 | 18.75 | 0.075 | 0.213 |
25 | 18.75 | 0.15 | 0.346 |
26 | 18.75 | 0.3 | 0.628 |
27 | 18.75 | 0.6 | 1.165 |
28 | 18.75 | 1.2 | 2.514 |
29 | 37.5 | 0.01875 | 11.427 |
30 | 37.5 | 0.075 | 0.216 |
31 | 37.5 | 0.15 | 0.332 |
32 | 37.5 | 0.3 | 0.583 |
33 | 37.5 | 0.6 | 1.165 |
34 | 37.5 | 1.2 | 2.655 |
35 | 37.5 | 0.0375 | 0.151 |
36 | 75 | 0.01875 | 0.216 |
37 | 75 | 0.0375 | 0.147 |
38 | 75 | 0.075 | 0.209 |
39 | 75 | 0.15 | 0.332 |
40 | 75 | 0.3 | 0.628 |
41 | 75 | 0.6 | 1.165 |
42 | 75 | 1.2 | 2.514 |
43 | 150 | 0.01875 | 45.466 |
44 | 150 | 0.0375 | 0.152 |
45 | 150 | 0.075 | 0.209 |
46 | 150 | 0.15 | 0.332 |
47 | 150 | 0.3 | 0.628 |
48 | 150 | 0.6 | 1.257 |
49 | 150 | 1.2 | 2.770 |
N ° | 利妥昔單抗 (nM) | LY75_DM4 (nM) | CI |
1 | 2.3438 | 0.0188 | 0.534 |
2 | 2.3438 | 0.0750 | 0.958 |
3 | 2.3438 | 0.1500 | 0.603 |
4 | 2.3438 | 0.3000 | 0.509 |
5 | 2.3438 | 0.6000 | 0.454 |
6 | 2.3438 | 1.2000 | 0.817 |
7 | 2.3438 | 0.0375 | 0.413 |
8 | 4.6875 | 0.0188 | 0.568 |
9 | 4.6875 | 0.0375 | 0.837 |
10 | 4.6875 | 0.0750 | 0.919 |
11 | 4.6875 | 0.1500 | 0.635 |
12 | 4.6875 | 0.3000 | 0.580 |
13 | 4.6875 | 0.6000 | 0.501 |
14 | 4.6875 | 1.2000 | 0.908 |
15 | 9.375 | 0.0188 | 0.249 |
16 | 9.375 | 0.0375 | 1.576 |
17 | 9.375 | 0.0750 | 0.717 |
18 | 9.375 | 0.1500 | 0.439 |
19 | 9.375 | 0.3000 | 0.618 |
20 | 9.375 | 0.6000 | 0.501 |
21 | 9.375 | 1.2000 | 0.908 |
22 | 18.75 | 0.0188 | 0.787 |
23 | 18.75 | 0.0375 | 0.497 |
24 | 18.75 | 0.0750 | 0.562 |
25 | 18.75 | 0.1500 | 0.545 |
26 | 18.75 | 0.3000 | 0.510 |
27 | 18.75 | 0.6000 | 0.366 |
28 | 18.75 | 1.2000 | 0.817 |
29 | 37.50 | 0.0375 | 0.734 |
30 | 37.50 | 0.0750 | 0.548 |
31 | 37.50 | 0.0188 | 0.543 |
32 | 37.50 | 0.1500 | 0.465 |
33 | 37.50 | 0.3000 | 0.476 |
34 | 37.50 | 0.6000 | 0.324 |
35 | 37.50 | 1.2000 | 0.648 |
36 | 75 | 0.0188 | 0.442 |
37 | 75 | 0.0375 | 1.578 |
38 | 75 | 0.0750 | 0.432 |
39 | 75 | 0.1500 | 0.493 |
40 | 75 | 0.3000 | 0.383 |
41 | 75 | 0.6000 | 0.409 |
42 | 75 | 1.2000 | 0.908 |
43 | 150 | 0.0188 | 0.680 |
44 | 150 | 0.0375 | 0.640 |
45 | 150 | 0.0750 | 0.911 |
46 | 150 | 0.1500 | 0.498 |
47 | 150 | 0.3000 | 0.355 |
48 | 150 | 0.6000 | 0.366 |
49 | 150 | 1.2000 | 0.817 |
N ° | 依魯替尼 (nM) | LY75_DM4 (nM) | CI |
1 | 1.5625 | 0.01875 | 0.481 |
2 | 1.5625 | 0.0375 | 0.627 |
3 | 1.5625 | 0.075 | 0.862 |
4 | 1.5625 | 0.15 | 0.360 |
5 | 1.5625 | 0.3 | 0.287 |
6 | 1.5625 | 0.6 | 0.270 |
7 | 1.5625 | 1.2 | 0.343 |
8 | 3.125 | 0.01875 | 0.411 |
9 | 3.125 | 0.0375 | 0.358 |
10 | 3.125 | 0.075 | 0.461 |
11 | 3.125 | 0.15 | 0.287 |
12 | 3.125 | 0.3 | 0.251 |
13 | 3.125 | 0.6 | 0.246 |
14 | 3.125 | 1.2 | 0.394 |
15 | 6.25 | 0.01875 | 0.204 |
16 | 6.25 | 0.0375 | 0.219 |
17 | 6.25 | 0.075 | 0.275 |
18 | 6.25 | 0.15 | 0.226 |
19 | 6.25 | 0.3 | 0.216 |
20 | 6.25 | 0.6 | 0.222 |
21 | 6.25 | 1.2 | 0.343 |
22 | 12.5 | 0.01875 | 0.205 |
23 | 12.5 | 0.0375 | 0.152 |
24 | 12.5 | 0.075 | 0.287 |
25 | 12.5 | 0.15 | 0.217 |
26 | 12.5 | 0.3 | 0.228 |
27 | 12.5 | 0.6 | 0.222 |
28 | 12.5 | 1.2 | 0.343 |
29 | 25 | 0.01875 | 0.152 |
30 | 25 | 0.0375 | 0.183 |
31 | 25 | 0.075 | 0.202 |
32 | 25 | 0.15 | 0.199 |
33 | 25 | 0.3 | 0.193 |
34 | 25 | 0.6 | 0.222 |
35 | 25 | 1.2 | 0.343 |
36 | 50 | 0.01875 | 0.374 |
37 | 50 | 0.0375 | 0.473 |
38 | 50 | 0.075 | 0.287 |
39 | 50 | 0.15 | 0.192 |
40 | 50 | 0.3 | 0.194 |
41 | 50 | 0.6 | 0.246 |
42 | 50 | 1.2 | 0.394 |
43 | 100 | 0.01875 | 0.715 |
44 | 100 | 0.0375 | 0.748 |
45 | 100 | 0.075 | 0.457 |
46 | 100 | 0.15 | 0.187 |
47 | 100 | 0.3 | 0.195 |
48 | 100 | 0.6 | 0.222 |
49 | 100 | 1.2 | 0.394 |
SEQ ID No | 描述 | 序列 |
1 | A1_VH aa | EVQLVESGGGLVKPGGSLRLSCAASGFTYSNAWMSWVRQAPGKGLEWVGRIKSKTDGGTTDYAAPVQGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTIFGVVSFDYWGQGTLVTVSS |
2 | A1_VL aa | DVQMTQSPSSLSASVGDRVTITCRASQSISDYLSWYQQRPGKAPNLLIYAASNLKTGVPSRFSGSGSGTDFTLTISTLQPEDFATYYCQQSYRSPWTFGQGTKVEIKR |
3 | A1_VH nt | gaggtgcagctggtggagtctgggggaggcttggtaaagccgggggggtcccttagactctcctgtgcagcctctggcttcacttacagtaacgcctggatgagctgggtccgccaggctccagggaaggggctggagtgggttggccgtattaaaagcaaaactgatggtgggacaacagactacgctgcacccgtgcaaggcagattcaccatctcaagagatgattcaaaaaacacgctgtatctgcaaatgaacagcctgaaaaccgaggacacagccgtgtattactgtacgatttttggagtggttagctttgactactggggccagggaaccctggtcaccgtctcctca |
4 | A1_VL nt | gacgtccagatgacccagtctccatcctccctgtctgcatctgttggagacagagtcaccatcacttgccgggcaagtcagagcattagcgactatttaagttggtatcagcagagaccagggaaagcccctaacctcctgatctatgctgcatccaatttaaagactggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcactctgcaacctgaagattttgcaacgtactactgtcaacagagttacaggtccccgtggacgttcggccaagggaccaaggtggaaatcaaacga |
5 | A1_VH_CDR1 aa | NAWMS |
6 | A1_VH_CDR2 aa | RIKSKTDGGTTDYAAPVQG |
7 | A1_VH_CDR3 aa | FGVVSFDY |
8 | A1_VL_CDR1 aa | RASQSISDYLS |
9 | A1_VL_CDR2 aa | AASNLKT |
10 | A1_VL_CDR3 aa | QQSYRSPWT |
11 | VH3|3-15/D4|411 | EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTTTVT |
12 | JH4 | YFDYWGQGTLVTVSS |
13 | O12 | DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYS |
14 | JK1 | WTFGQGTKVEIKR |
15 | LY75 (DEC-205) | MRTGWATPRRPAGLLMLLFWFFDLAEPSGRAANDPFTIVHGNTGKCIKPVYGWIVADDCDETEDKLWKWVSQHRLFHLHSQKCLGLDITKSVNELRMFSCDSSAMLWWKCEHHSLYGAARYRLALKDGHGTAISNASDVWKKGGSEESLCDQPYHEIYTRDGNSYGRPCEFPFLIDGTWHHDCILDEDHSGPWCATTLNYEYDRKWGICLKPENGCEDNWEKNEQFGSCYQFNTQTALSWKEAYVSCQNQGADLLSINSAAELTYLKEKEGIAKIFWIGLNQLYSARGWEWSDHKPLNFLNWDPDRPSAPTIGGSSCARMDAESGLWQSFSCEAQLPYVCRKPLNNTVELTDVWTYSDTRCDAGWLPNNGFCYLLVNESNSWDKAHAKCKAFSSDLISIHSLADVEVVVTKLHNEDIKEEVWIGLKNINIPTLFQWSDGTEVTLTYWDENEPNVPYNKTPNCVSYLGELGQWKVQSCEEKLKYVCKRKGEKLNDASSDKMCPPDEGWKRHGETCYKIYEDEVPFGTNCNLTITSRFEQEYLNDLMKKYDKSLRKYFWTGLRDVDSCGEYNWATVGGRRRAVTFSNWNFLEPASPGGCVAMSTGKSVGKWEVKDCRSFKALSICKKMSGPLGPEEASPKPDDPCPEGWQSFPASLSCYKVFHAERIVRKRNWEEAERFCQALGAHLSSFSHVDEIKEFLHFLTDQFSGQHWLWIGLNKRSPDLQGSWQWSDRTPVSTIIMPNEFQQDYDIRDCAAVKVFHRPWRRGWHFYDDREFIYLRPFACDTKLEWVCQIPKGRTPKTPDWYNPDRAGIHGPPLIIEGSEYWFVADLHLNYEEAVLYCASNHSFLATITSFVGLKAIKNKIANISGDGQKWWIRISEWPIDDHFTYSRYPWHRFPVTFGEECLYMSAKTWLIDLGKPTDCSTKLPFICEKYNVSSLEKYSPDSAAKVQCSEQWIPFQNKCFLKIKPVSLTFSQASDTCHSYGGTLPSVLSQIEQDFITSLLPDMEATLWIGLRWTAYEKINKWTDNRELTYSNFHPLLVSGRLRIPENFFEEESRYHCALILNLQKSPFTGTWNFTSCSERHFVSLCQKYSEVKSRQTLQNASETVKYLNNLYKIIPKTLTWHSAKRECLKSNMQLVSITDPYQQAFLSVQALLHNSSLWIGLFSQDDELNFGWSDGKRLHFSRWAETNGQLEDCVVLDTDGFWKTVDCNDNQPGAICYYSGNETEKEVKPVDSVKCPSPVLNTPWIPFQNCCYNFIITKNRHMATTQDEVHTKCQKLNPKSHILSIRDEKENNFVLEQLLYFNYMASWVMLGITYRNKSLMWFDKTPLSYTHWRAGRPTIKNEKFLAGLSTDGFWDIQTFKVIEEAVYFHQHSILACKIEMVDYKEEYNTTLPQFMPYEDGIYSVIQKKVTWYEALNMCSQSGGHLASVHNQNGQLFLEDIVKRDGFPLWVGLSSHDGSESSFEWSDGSTFDYIPWKGQTSPGNCVLLDPKGTWKHEKCNSVKDGAICYKPTKSKKLSRLTYSSRCPAAKENGSRWIQYKGHCYKSDQALHSFSEAKKLCSKHDHSATIVSIKDEDENKFVSRLMRENNNITMRVWLGLSQHSVDQSWSWLDGSEVTFVKWENKSKSGVGRCSMLIASNETWKKVECEHGFGRVVCKVPLGPDYTAIAIIVATLSILVLMGGLIWFLFQRHRLHLAGFSSVRYAQGVNEDEIMLPSFHD |
16 | A1_VH_FR1 | EVQLVESGGGLVKPGGSLRLSCAASGFTYS |
17 | A1_VH_FR2 | WVRQAPGKGLEWVG |
18 | A1_VH_FR3 | RFTISRDDSKNTLYLQMNSLKTEDTAVYYCTI |
19 | A1_VH_FR4 | WGQGTLVTVSS |
20 | A1_VL_FR1 | DVQMTQSPSSLSASVGDRVTITC |
21 | A1_VL_FR2 | WYQQRPGKAPNLLIY |
22 | A1_VL_FR3 | GVPSRFSGSGSGTDFTLTISTLQPEDFATYYC |
23 | A1_VL_FR4 | FGQGTKVEIKR |
24 | LY75 609-618 | WEVKDCRSFK |
25 | LY75 651-662 | PASLSCYKVFHA |
26 | LY75 761-780 | PWRRGWHFYDDREFIYLRPF |
27 | LY75 883-901 | DDHFTYSRYPWHRFPVTFG |
28 | LY75 1029-1040 | RELTYSNFHPLL |
29 | LY75 1077-1093 | FTSCSERHFVSLCQKYS |
30 | LY75 1107-1118 | TVKYLNNLYKII |
31 | LY75 1368-1378 | EAVYFHQHSIL |
32 | LY75 1518-1528 | KKLSRLTYSSC |
33 | LY75 1535-1554 | NGSRWIQYKGHCYKSDQALH |
34 | LY75 877-901 | ISEWPIDDHFTYSRYPWHRFPVTFG |
35 | LY75 1099-1118 | QTLQNASETVKYLNNLYKII |
36 | LY75 883-892 | DDHFTYSRYP |
37 | LY75 1077-1091 | FTSCSERHFVSLCQK |
38 | 利妥昔單抗VH | QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
39 | 利妥昔單抗VL | QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
40 | 利妥昔單抗 VH_CDR1 | SYNMH |
41 | 利妥昔單抗 VH_CDR2 | AIYPGNGDTSYNQKFKG |
42 | 利妥昔單抗 VH_CDR3 | STYYGGDWYFNV |
43 | 利妥昔單抗 VL_CDR1 | RASSSVSYIH |
44 | 利妥昔單抗 VL_CDR2 | ATSNLAS |
45 | 利妥昔單抗 VL_CDR3 | QQWTSNPPTF |
46 | (765-772) | GWHFYDDR |
47 | (877至890) | ISEWPIDDHFTYSR |
48 | (896-910) | FPVTFGEECLYMSAK |
49 | (1030-1044) | ELTYSNFHPLLVSGR |
50 | (1084-1091) | HFVSLCQK |
51 | (1099-1109) | QTLQNASETVK |
52 | 連接子 | Gly-Phe-Leu-Gly |
圖1描繪LY75_A1重鏈(SEQ ID NO:1)、人類VH 3-15生殖系(SEQ ID NO:11)及人類JH4生殖系(SEQ ID NO:12)之比對。 LY75_A1重鏈之CDR區帶下劃線。
圖2描繪LY75_A1輕鏈(SEQ ID NO:2)、人類VK O12生殖系(SEQ ID NO:13)及人類JK4生殖系(SEQ ID NO:14)之比對。 LY75_A1輕鏈之CDR區帶下劃線。
圖3a描繪與DM1結合之抗LY75單株抗體在HT-29中之細胞毒性活性,且展示雖然大部分抗體結合至LY75,但僅少數呈現功效。
圖3b描繪與DM1或DM4結合之抗LY75抗體在HT-29中之細胞毒性活性。
圖3c描繪與DM1或DM4結合之抗LY75抗體在RAJI細胞中之細胞毒性活性。
圖3d描繪與DM1或DM4結合之抗LY75抗體在Namalwa細胞中之細胞毒性活性。
圖3e描繪與DM1或DM4結合之抗LY75抗體在Karpas 299細胞中之細胞毒性活性。
圖3f描繪與DM1或DM4結合之抗LY75抗體在BxPC3細胞中之細胞毒性活性。
圖3g描繪與DM1或DM4結合之抗LY75抗體在HupT4細胞中之細胞毒性活性。
圖3h描繪與DM1或DM4結合之抗LY75抗體在HPAFFII細胞中之細胞毒性活性。
圖3i描繪與DM1或DM4結合之抗LY75抗體在EHEB細胞中之細胞毒性活性。
圖3j描繪與DM1或DM4結合之抗LY75抗體在Mec-1細胞中之細胞毒性活性。
圖3k描繪與DM1或DM4結合之抗LY75抗體在AML-193細胞中之細胞毒性活性。
圖3l描繪與DM1或DM4結合之抗LY75抗體在HCC 70細胞中之細胞毒性活性。
圖3m描繪與DM1或DM4結合之抗LY75抗體在HCC 1806細胞中之細胞毒性活性。
圖3n描繪與DM1或DM4結合之抗LY75抗體在MDA-MB-468細胞中之細胞毒性活性。
圖3o描繪與DM1或DM4結合之抗LY75抗體在RT4細胞中之細胞毒性活性。
圖3p描繪與DM1或DM4結合之抗LY75抗體在5637細胞中之細胞毒性活性。
圖3q描繪與DM1或DM4結合之抗LY75抗體在SW780細胞中之細胞毒性活性。
圖3r描繪與DM1或DM4結合之抗LY75抗體在SCC-9細胞中之細胞毒性活性。
圖3s描繪與DM1或DM4結合之抗LY75抗體在OE 19細胞中之細胞毒性活性。
圖3t描繪與DM1或DM4結合之抗LY75抗體在OVCAR-3細胞中之細胞毒性活性。
圖3u描繪與DM1或DM4結合之抗LY75抗體在SK-OV-3細胞中之細胞毒性活性。
圖3v描繪與DM1或DM4結合之抗LY75抗體在MOLP-8細胞中之細胞毒性活性.
圖3w描繪與DM1或DM4結合之抗LY75抗體在RPMI8226細胞中之細胞毒性活性。
圖4a描繪與DM1或DM4結合之抗LY75抗體在Raji伯基特氏淋巴瘤SCID小鼠異種移植模型中之功效。
圖4b描繪與DM1或DM4結合之抗LY75抗體在Namalwa伯基特氏淋巴瘤SCID小鼠異種移植模型中之功效。
圖4c描繪與DM1或DM4結合之抗LY75抗體在HPAFII胰腺癌無胸腺裸鼠異種移植模型中之功效。
圖4d描繪與DM1或DM4結合之抗LY75抗體在SW780人類膀胱癌SCID小鼠異種移植模型中之功效。
圖4e描繪與DM1或DM4結合之抗LY75抗體在MDA-MB-468無胸腺裸鼠中之功效。
圖4f描繪與DM1或DM4結合之抗LY75抗體在COLO205結腸直腸腺癌無胸腺裸鼠異種移植模型中之功效。
圖5a展示抗LY75-mAb與結合至MCC-DM1之抗LY75-mAb的競爭性結合。
圖5b展示LY75_A1及結合至MCC-DM1之抗LY75-mAb的非競爭性結合。
圖6a-6j展示抗體LY75_A1與肽微陣列上之LY75肽結合的圖示。
圖7展示在肽微陣列分析及肽下拉分析中由抗體LY75_A1結合之肽的胺基酸比對。突出顯示之肽為可能形成由抗體LY75_A1識別之抗原決定基的彼等肽。
圖8A及圖8B展示不同(nM)劑量之LY75_DM4作為單一治療或與利妥昔單抗組合對兩種不同ABC-DLBCL細胞株(TMD8及HBL1)之抗增生作用。(CI = Chou-Talalay聯合指數)。圖8A:中值CI = 0.27。圖8B:中值CI = 0.57。
圖9展示不同(nM)劑量之LY75_DM4作為單一治療或與依魯替尼組合對HBL-1細胞株(ABC-DLBCL)之抗增生作用。(CI = Chou-Talalay聯合指數)。中值CI = 0.24。
<![CDATA[<110> 德商柏林化學股份公司 (Berlin-Chemie AG)]]> <![CDATA[<120> 醫藥組合]]> <![CDATA[<140> ]]> <![CDATA[<141> ]]> <![CDATA[<150> GB 1703876.1 ]]> <![CDATA[<151> 2017-03-10]]> <![CDATA[<160> 207 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 1]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Gln Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Ile Phe Gly Val Val Ser Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 2]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 2]]> Asp Val Gln Met 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 Asp Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Lys Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Thr Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 3]]> <![CDATA[<211> 357]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 3]]> gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc cgggggggtc ccttagactc 60 tcctgtgcag cctctggctt cacttacagt aacgcctgga tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180 gactacgctg cacccgtgca aggcagattc accatctcaa gagatgattc aaaaaacacg 240 ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtacgatt 300 tttggagtgg ttagctttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357 <![CDATA[<210> 4]]> <![CDATA[<211> 324]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 4]]> gacgtccaga tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc gactatttaa gttggtatca gcagagacca 120 gggaaagccc ctaacctcct gatctatgct gcatccaatt taaagactgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcac tctgcaacct 240 gaagattttg caacgtacta ctgtcaacag agttacaggt ccccgtggac gttcggccaa 300 gggaccaagg tggaaatcaa acga 324 <![CDATA[<210> 5]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 5]]> Asn Ala Trp Met Ser 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 6]]> Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala Pro 1 5 10 15 Val Gln Gly <![CDATA[<210> 7]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 7]]> Phe Gly Val Val Ser Phe Asp Tyr 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 8]]> Arg Ala Ser Gln Ser Ile Ser Asp Tyr Leu Ser 1 5 10 <![CDATA[<210> 9]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 9]]> Ala Ala Ser Asn Leu Lys Thr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 10]]> Gln Gln Ser Tyr Arg Ser Pro Trp Thr 1 5 <![CDATA[<210> 11]]> <![CDATA[<211> 104]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 11]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Thr Thr Val Thr 100 <![CDATA[<210> 12]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 12]]> Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 15 <![CDATA[<210> 13]]> <![CDATA[<211> 93]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 13]]> Asp Ile Gln Met 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 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser 85 90 <![CDATA[<210> 14]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 14]]> Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <![CDATA[<210> 15]]> <![CDATA[<211> 1722]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 15]]> Met Arg Thr Gly Trp Ala Thr Pro Arg Arg Pro Ala Gly Leu Leu Met 1 5 10 15 Leu Leu Phe Trp Phe Phe Asp Leu Ala Glu Pro Ser Gly Arg Ala Ala 20 25 30 Asn Asp Pro Phe Thr Ile Val His Gly Asn Thr Gly Lys Cys Ile Lys 35 40 45 Pro Val Tyr Gly Trp Ile Val Ala Asp Asp Cys Asp Glu Thr Glu Asp 50 55 60 Lys Leu Trp Lys Trp Val Ser Gln His Arg Leu Phe His Leu His Ser 65 70 75 80 Gln Lys Cys Leu Gly Leu Asp Ile Thr Lys Ser Val Asn Glu Leu Arg 85 90 95 Met Phe Ser Cys Asp Ser Ser Ala Met Leu Trp Trp Lys Cys Glu His 100 105 110 His Ser Leu Tyr Gly Ala Ala Arg Tyr Arg Leu Ala Leu Lys Asp Gly 115 120 125 His Gly Thr Ala Ile Ser Asn Ala Ser Asp Val Trp Lys Lys Gly Gly 130 135 140 Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile Tyr Thr Arg 145 150 155 160 Asp Gly Asn Ser Tyr Gly Arg Pro Cys Glu Phe Pro Phe Leu Ile Asp 165 170 175 Gly Thr Trp His His Asp Cys Ile Leu Asp Glu Asp His Ser Gly Pro 180 185 190 Trp Cys Ala Thr Thr Leu Asn Tyr Glu Tyr Asp Arg Lys Trp Gly Ile 195 200 205 Cys Leu Lys Pro Glu Asn Gly Cys Glu Asp Asn Trp Glu Lys Asn Glu 210 215 220 Gln Phe Gly Ser Cys Tyr Gln Phe Asn Thr Gln Thr Ala Leu Ser Trp 225 230 235 240 Lys Glu Ala Tyr Val Ser Cys Gln Asn Gln Gly Ala Asp Leu Leu Ser 245 250 255 Ile Asn Ser Ala Ala Glu Leu Thr Tyr Leu Lys Glu Lys Glu Gly Ile 260 265 270 Ala Lys Ile Phe Trp Ile Gly Leu Asn Gln Leu Tyr Ser Ala Arg Gly 275 280 285 Trp Glu Trp Ser Asp His Lys Pro Leu Asn Phe Leu Asn Trp Asp Pro 290 295 300 Asp Arg Pro Ser Ala Pro Thr Ile Gly Gly Ser Ser Cys Ala Arg Met 305 310 315 320 Asp Ala Glu Ser Gly Leu Trp Gln Ser Phe Ser Cys Glu Ala Gln Leu 325 330 335 Pro Tyr Val Cys Arg Lys Pro Leu Asn Asn Thr Val Glu Leu Thr Asp 340 345 350 Val Trp Thr Tyr Ser Asp Thr Arg Cys Asp Ala Gly Trp Leu Pro Asn 355 360 365 Asn Gly Phe Cys Tyr Leu Leu Val Asn Glu Ser Asn Ser Trp Asp Lys 370 375 380 Ala His Ala Lys Cys Lys Ala Phe Ser Ser Asp Leu Ile Ser Ile His 385 390 395 400 Ser Leu Ala Asp Val Glu Val Val Val Thr Lys Leu His Asn Glu Asp 405 410 415 Ile Lys Glu Glu Val Trp Ile Gly Leu Lys Asn Ile Asn Ile Pro Thr 420 425 430 Leu Phe Gln Trp Ser Asp Gly Thr Glu Val Thr Leu Thr Tyr Trp Asp 435 440 445 Glu Asn Glu Pro Asn Val Pro Tyr Asn Lys Thr Pro Asn Cys Val Ser 450 455 460 Tyr Leu Gly Glu Leu Gly Gln Trp Lys Val Gln Ser Cys Glu Glu Lys 465 470 475 480 Leu Lys Tyr Val Cys Lys Arg Lys Gly Glu Lys Leu Asn Asp Ala Ser 485 490 495 Ser Asp Lys Met Cys Pro Pro Asp Glu Gly Trp Lys Arg His Gly Glu 500 505 510 Thr Cys Tyr Lys Ile Tyr Glu Asp Glu Val Pro Phe Gly Thr Asn Cys 515 520 525 Asn Leu Thr Ile Thr Ser Arg Phe Glu Gln Glu Tyr Leu Asn Asp Leu 530 535 540 Met Lys Lys Tyr Asp Lys Ser Leu Arg Lys Tyr Phe Trp Thr Gly Leu 545 550 555 560 Arg Asp Val Asp Ser Cys Gly Glu Tyr Asn Trp Ala Thr Val Gly Gly 565 570 575 Arg Arg Arg Ala Val Thr Phe Ser Asn Trp Asn Phe Leu Glu Pro Ala 580 585 590 Ser Pro Gly Gly Cys Val Ala Met Ser Thr Gly Lys Ser Val Gly Lys 595 600 605 Trp Glu Val Lys Asp Cys Arg Ser Phe Lys Ala Leu Ser Ile Cys Lys 610 615 620 Lys Met Ser Gly Pro Leu Gly Pro Glu Glu Ala Ser Pro Lys Pro Asp 625 630 635 640 Asp Pro Cys Pro Glu Gly Trp Gln Ser Phe Pro Ala Ser Leu Ser Cys 645 650 655 Tyr Lys Val Phe His Ala Glu Arg Ile Val Arg Lys Arg Asn Trp Glu 660 665 670 Glu Ala Glu Arg Phe Cys Gln Ala Leu Gly Ala His Leu Ser Ser Phe 675 680 685 Ser His Val Asp Glu Ile Lys Glu Phe Leu His Phe Leu Thr Asp Gln 690 695 700 Phe Ser Gly Gln His Trp Leu Trp Ile Gly Leu Asn Lys Arg Ser Pro 705 710 715 720 Asp Leu Gln Gly Ser Trp Gln Trp Ser Asp Arg Thr Pro Val Ser Thr 725 730 735 Ile Ile Met Pro Asn Glu Phe Gln Gln Asp Tyr Asp Ile Arg Asp Cys 740 745 750 Ala Ala Val Lys Val Phe His Arg Pro Trp Arg Arg Gly Trp His Phe 755 760 765 Tyr Asp Asp Arg Glu Phe Ile Tyr Leu Arg Pro Phe Ala Cys Asp Thr 770 775 780 Lys Leu Glu Trp Val Cys Gln Ile Pro Lys Gly Arg Thr Pro Lys Thr 785 790 795 800 Pro Asp Trp Tyr Asn Pro Asp Arg Ala Gly Ile His Gly Pro Pro Leu 805 810 815 Ile Ile Glu Gly Ser Glu Tyr Trp Phe Val Ala Asp Leu His Leu Asn 820 825 830 Tyr Glu Glu Ala Val Leu Tyr Cys Ala Ser Asn His Ser Phe Leu Ala 835 840 845 Thr Ile Thr Ser Phe Val Gly Leu Lys Ala Ile Lys Asn Lys Ile Ala 850 855 860 Asn Ile Ser Gly Asp Gly Gln Lys Trp Trp Ile Arg Ile Ser Glu Trp 865 870 875 880 Pro Ile Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro Trp His Arg Phe 885 890 895 Pro Val Thr Phe Gly Glu Glu Cys Leu Tyr Met Ser Ala Lys Thr Trp 900 905 910 Leu Ile Asp Leu Gly Lys Pro Thr Asp Cys Ser Thr Lys Leu Pro Phe 915 920 925 Ile Cys Glu Lys Tyr Asn Val Ser Ser Leu Glu Lys Tyr Ser Pro Asp 930 935 940 Ser Ala Ala Lys Val Gln Cys Ser Glu Gln Trp Ile Pro Phe Gln Asn 945 950 955 960 Lys Cys Phe Leu Lys Ile Lys Pro Val Ser Leu Thr Phe Ser Gln Ala 965 970 975 Ser Asp Thr Cys His Ser Tyr Gly Gly Thr Leu Pro Ser Val Leu Ser 980 985 990 Gln Ile Glu Gln Asp Phe Ile Thr Ser Leu Leu Pro Asp Met Glu Ala 995 1000 1005 Thr Leu Trp Ile Gly Leu Arg Trp Thr Ala Tyr Glu Lys Ile Asn 1010 1015 1020 Lys Trp Thr Asp Asn Arg Glu Leu Thr Tyr Ser Asn Phe His Pro 1025 1030 1035 Leu Leu Val Ser Gly Arg Leu Arg Ile Pro Glu Asn Phe Phe Glu 1040 1045 1050 Glu Glu Ser Arg Tyr His Cys Ala Leu Ile Leu Asn Leu Gln Lys 1055 1060 1065 Ser Pro Phe Thr Gly Thr Trp Asn Phe Thr Ser Cys Ser Glu Arg 1070 1075 1080 His Phe Val Ser Leu Cys Gln Lys Tyr Ser Glu Val Lys Ser Arg 1085 1090 1095 Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys Tyr Leu Asn Asn 1100 1105 1110 Leu Tyr Lys Ile Ile Pro Lys Thr Leu Thr Trp His Ser Ala Lys 1115 1120 1125 Arg Glu Cys Leu Lys Ser Asn Met Gln Leu Val Ser Ile Thr Asp 1130 1135 1140 Pro Tyr Gln Gln Ala Phe Leu Ser Val Gln Ala Leu Leu His Asn 1145 1150 1155 Ser Ser Leu Trp Ile Gly Leu Phe Ser Gln Asp Asp Glu Leu Asn 1160 1165 1170 Phe Gly Trp Ser Asp Gly Lys Arg Leu His Phe Ser Arg Trp Ala 1175 1180 1185 Glu Thr Asn Gly Gln Leu Glu Asp Cys Val Val Leu Asp Thr Asp 1190 1195 1200 Gly Phe Trp Lys Thr Val Asp Cys Asn Asp Asn Gln Pro Gly Ala 1205 1210 1215 Ile Cys Tyr Tyr Ser Gly Asn Glu Thr Glu Lys Glu Val Lys Pro 1220 1225 1230 Val Asp Ser Val Lys Cys Pro Ser Pro Val Leu Asn Thr Pro Trp 1235 1240 1245 Ile Pro Phe Gln Asn Cys Cys Tyr Asn Phe Ile Ile Thr Lys Asn 1250 1255 1260 Arg His Met Ala Thr Thr Gln Asp Glu Val His Thr Lys Cys Gln 1265 1270 1275 Lys Leu Asn Pro Lys Ser His Ile Leu Ser Ile Arg Asp Glu Lys 1280 1285 1290 Glu Asn Asn Phe Val Leu Glu Gln Leu Leu Tyr Phe Asn Tyr Met 1295 1300 1305 Ala Ser Trp Val Met Leu Gly Ile Thr Tyr Arg Asn Lys Ser Leu 1310 1315 1320 Met Trp Phe Asp Lys Thr Pro Leu Ser Tyr Thr His Trp Arg Ala 1325 1330 1335 Gly Arg Pro Thr Ile Lys Asn Glu Lys Phe Leu Ala Gly Leu Ser 1340 1345 1350 Thr Asp Gly Phe Trp Asp Ile Gln Thr Phe Lys Val Ile Glu Glu 1355 1360 1365 Ala Val Tyr Phe His Gln His Ser Ile Leu Ala Cys Lys Ile Glu 1370 1375 1380 Met Val Asp Tyr Lys Glu Glu Tyr Asn Thr Thr Leu Pro Gln Phe 1385 1390 1395 Met Pro Tyr Glu Asp Gly Ile Tyr Ser Val Ile Gln Lys Lys Val 1400 1405 1410 Thr Trp Tyr Glu Ala Leu Asn Met Cys Ser Gln Ser Gly Gly His 1415 1420 1425 Leu Ala Ser Val His Asn Gln Asn Gly Gln Leu Phe Leu Glu Asp 1430 1435 1440 Ile Val Lys Arg Asp Gly Phe Pro Leu Trp Val Gly Leu Ser Ser 1445 1450 1455 His Asp Gly Ser Glu Ser Ser Phe Glu Trp Ser Asp Gly Ser Thr 1460 1465 1470 Phe Asp Tyr Ile Pro Trp Lys Gly Gln Thr Ser Pro Gly Asn Cys 1475 1480 1485 Val Leu Leu Asp Pro Lys Gly Thr Trp Lys His Glu Lys Cys Asn 1490 1495 1500 Ser Val Lys Asp Gly Ala Ile Cys Tyr Lys Pro Thr Lys Ser Lys 1505 1510 1515 Lys Leu Ser Arg Leu Thr Tyr Ser Ser Arg Cys Pro Ala Ala Lys 1520 1525 1530 Glu Asn Gly Ser Arg Trp Ile Gln Tyr Lys Gly His Cys Tyr Lys 1535 1540 1545 Ser Asp Gln Ala Leu His Ser Phe Ser Glu Ala Lys Lys Leu Cys 1550 1555 1560 Ser Lys His Asp His Ser Ala Thr Ile Val Ser Ile Lys Asp Glu 1565 1570 1575 Asp Glu Asn Lys Phe Val Ser Arg Leu Met Arg Glu Asn Asn Asn 1580 1585 1590 Ile Thr Met Arg Val Trp Leu Gly Leu Ser Gln His Ser Val Asp 1595 1600 1605 Gln Ser Trp Ser Trp Leu Asp Gly Ser Glu Val Thr Phe Val Lys 1610 1615 1620 Trp Glu Asn Lys Ser Lys Ser Gly Val Gly Arg Cys Ser Met Leu 1625 1630 1635 Ile Ala Ser Asn Glu Thr Trp Lys Lys Val Glu Cys Glu His Gly 1640 1645 1650 Phe Gly Arg Val Val Cys Lys Val Pro Leu Gly Pro Asp Tyr Thr 1655 1660 1665 Ala Ile Ala Ile Ile Val Ala Thr Leu Ser Ile Leu Val Leu Met 1670 1675 1680 Gly Gly Leu Ile Trp Phe Leu Phe Gln Arg His Arg Leu His Leu 1685 1690 1695 Ala Gly Phe Ser Ser Val Arg Tyr Ala Gln Gly Val Asn Glu Asp 1700 1705 1710 Glu Ile Met Leu Pro Ser Phe His Asp 1715 1720 <![CDATA[<210> 16]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 16]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser 20 25 30 <![CDATA[<210> 17]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 17]]> Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 1 5 10 <![CDATA[<210> 18]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 18]]> Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile 20 25 30 <![CDATA[<210> 19]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 19]]> Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <![CDATA[<210> 20]]> <![CDATA[<211> 23]]> <![CDATA[<212>]]> PRT <![CDATA[<213> 人類]]> <![CDATA[<400> 20]]> Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <![CDATA[<210> 21]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 21]]> Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr 1 5 10 15 <![CDATA[<210> 22]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 22]]> Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Thr Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <![CDATA[<210> 23]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 23]]> Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <![CDATA[<210> 24]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 24]]> Trp Glu Val Lys Asp Cys Arg Ser Phe Lys 1 5 10 <![CDATA[<210> 25]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 25]]> Pro Ala Ser Leu Ser Cys Tyr Lys Val Phe His Ala 1 5 10 <![CDATA[<210> 26]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 26]]> Pro Trp Arg Arg Gly Trp His Phe Tyr Asp Asp Arg Glu Phe Ile Tyr 1 5 10 15 Leu Arg Pro Phe 20 <![CDATA[<210> 27]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 27]]> Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro Trp His Arg Phe Pro Val 1 5 10 15 Thr Phe Gly <![CDATA[<210> 28]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 28]]> Arg Glu Leu Thr Tyr Ser Asn Phe His Pro Leu Leu 1 5 10 <![CDATA[<210> 29]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 29]]> Phe Thr Ser Cys Ser Glu Arg His Phe Val Ser Leu Cys Gln Lys Tyr 1 5 10 15 Ser <![CDATA[<210> 30]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 30]]> Thr Val Lys Tyr Leu Asn Asn Leu Tyr Lys Ile Ile 1 5 10 <![CDATA[<210> 31]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 31]]> Glu Ala Val Tyr Phe His Gln His Ser Ile Leu 1 5 10 <![CDATA[<210> 32]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 32]]> Lys Lys Leu Ser Arg Leu Thr Tyr Ser Ser Cys 1 5 10 <![CDATA[<210> 33]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213>]]> 人類 <![CDATA[<400> 33]]> Asn Gly Ser Arg Trp Ile Gln Tyr Lys Gly His Cys Tyr Lys Ser Asp 1 5 10 15 Gln Ala Leu His 20 <![CDATA[<210> 34]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 34]]> Ile Ser Glu Trp Pro Ile Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro 1 5 10 15 Trp His Arg Phe Pro Val Thr Phe Gly 20 25 <![CDATA[<210> 35]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 35]]> Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys Tyr Leu Asn Asn Leu 1 5 10 15 Tyr Lys Ile Ile 20 <![CDATA[<210> 36]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 36]]> Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro 1 5 10 <![CDATA[<210> 37]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人類]]> <![CDATA[<400> 37]]> Phe Thr Ser Cys Ser Glu Arg His Phe Val Ser Leu Cys Gln Lys 1 5 10 15 <![CDATA[<210> 38]]> <![CDATA[<211> 451]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VH 序列]]> <![CDATA[<400> 38]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <![CDATA[<210> 39]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VL 序列]]> <![CDATA[<400> 39]]> Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 40]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VH_CDR1]]> <![CDATA[<400> 40]]> Ser Tyr Asn Met His 1 5 <![CDATA[<210> 41]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VH_CDR2]]> <![CDATA[<400> 41]]> Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 42]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VH_CDR3]]> <![CDATA[<400> 42]]> Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <![CDATA[<210> 43]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VL_CDR1]]> <![CDATA[<400> 43]]> Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <![CDATA[<210> 44]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VL_CDR2]]> <![CDATA[<400> 44]]> Ala Thr Ser Asn Leu Ala Ser 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 利妥昔單抗 VL_CDR3]]> <![CDATA[<400> 45]]> Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe 1 5 10 <![CDATA[<210> 46]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 46]]> Gly Trp His Phe Tyr Asp Asp Arg 1 5 <![CDATA[<210> 47]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 47]]> Ile Ser Glu Trp Pro Ile Asp Asp His Phe Thr Tyr Ser Arg 1 5 10 <![CDATA[<210> 48]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 48]]> Phe Pro Val Thr Phe Gly Glu Glu Cys Leu Tyr Met Ser Ala Lys 1 5 10 15 <![CDATA[<210> 49]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 49]]> Glu Leu Thr Tyr Ser Asn Phe His Pro Leu Leu Val Ser Gly Arg 1 5 10 15 <![CDATA[<210> 50]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 50]]> His Phe Val Ser Leu Cys Gln Lys 1 5 <![CDATA[<210> 51]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 51]]> Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys 1 5 10 <![CDATA[<210> 52]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子]]> <![CDATA[<400> 52]]> Gly Phe Leu Gly 1 <![CDATA[<210> 53]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 53]]> Trp Glu Val Lys Asp Cys Arg Ser 1 5 <![CDATA[<210> 54]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 54]]> Glu Val Lys Asp Cys Arg Ser Phe 1 5 <![CDATA[<210> 55]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 55]]> Val Lys Asp Cys Arg Ser Phe Lys 1 5 <![CDATA[<210> 56]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 56]]> Lys Asp Cys Arg Ser Phe Lys Ala 1 5 <![CDATA[<210> 57]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 57]]> Asp Cys Arg Ser Phe Lys Ala Leu 1 5 <![CDATA[<210> 58]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 58]]> Cys Arg Ser Phe Lys Ala Leu Ser 1 5 <![CDATA[<210> 59]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 59]]> Arg Ser Phe Lys Ala Leu Ser Ile 1 5 <![CDATA[<210> 60]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 60]]> Pro Ala Ser Leu Ser Cys Tyr Lys 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 61]]> Ala Ser Leu Ser Cys Tyr Lys Val 1 5 <![CDATA[<210> 62]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 62]]> Ser Leu Ser Cys Tyr Lys Val Phe 1 5 <![CDATA[<210> 63]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 63]]> Leu Ser Cys Tyr Lys Val Phe His 1 5 <![CDATA[<210> 64]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 64]]> Ser Cys Tyr Lys Val Phe His Ala 1 5 <![CDATA[<210> 65]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 65]]> Cys Tyr Lys Val Phe His Ala Glu 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 66]]> Tyr Lys Val Phe His Ala Glu Arg 1 5 <![CDATA[<210> 67]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 67]]> Lys Val Phe His Ala Glu Arg Ile 1 5 <![CDATA[<210> 68]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 68]]> Val Phe His Ala Glu Arg Ile Val 1 5 <![CDATA[<210> 69]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 69]]> Phe His Ala Glu Arg Ile Val Arg 1 5 <![CDATA[<210> 70]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 70]]> Asp Cys Ala Ala Val Lys Val Phe 1 5 <![CDATA[<210> 71]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 71]]> Ala Ala Val Lys Val Phe His Arg 1 5 <![CDATA[<210> 72]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 72]]> Val Lys Val Phe His Arg Pro Trp 1 5 <![CDATA[<210> 73]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 73]]> Val Phe His Arg Pro Trp Arg Arg 1 5 <![CDATA[<210> 74]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 74]]> His Arg Pro Trp Arg Arg Gly Trp 1 5 <![CDATA[<210> 75]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 75]]> Pro Trp Arg Arg Gly Trp His Phe 1 5 <![CDATA[<210> 76]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 76]]> Arg Arg Gly Trp His Phe Tyr Asp 1 5 <![CDATA[<210> 77]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 77]]> Gly Trp His Phe Tyr Asp Asp Arg 1 5 <![CDATA[<210> 78]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 78]]> His Phe Tyr Asp Asp Arg Glu Phe 1 5 <![CDATA[<210> 79]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 79]]> Tyr Asp Asp Arg Glu Phe Ile Tyr 1 5 <![CDATA[<210> 80]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 80]]> Asp Arg Glu Phe Ile Tyr Leu Arg 1 5 <![CDATA[<210> 81]]> <![CDATA[<21]]>1> 8]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 肽]]> <br/> <br/><![CDATA[<400> 81]]> <br/> <br/><![CDATA[Glu Phe Ile Tyr Leu Arg Pro Phe 1 5 <![CDATA[<210> 82]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 82]]> Pro Ile Asp Asp His Phe Thr Tyr 1 5 <![CDATA[<210> 83]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 83]]> Ile Asp Asp His Phe Thr Tyr Ser 1 5 <![CDATA[<210> 84]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 84]]> Asp Asp His Phe Thr Tyr Ser Arg 1 5 <![CDATA[<210> 85]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]>序列 <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 85]]> Asp His Phe Thr Tyr Ser Arg Tyr 1 5 <![CDATA[<210> 86]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 86]]> His Phe Thr Tyr Ser Arg Tyr Pro 1 5 <![CDATA[<210> 87]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 87]]> Phe Thr Tyr Ser Arg Tyr Pro Trp 1 5 <![CDATA[<210> 88]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 88]]> Thr Tyr Ser Arg Tyr Pro Trp His 1 5 <![CDATA[<210> 89]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 89]]> Tyr Ser Arg Tyr Pro Trp His Arg 1 5 <![CDATA[<210> 90]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 90]]> Ser Arg Tyr Pro Trp His Arg Phe 1 5 <![CDATA[<210> 91]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 91]]> Arg Tyr Pro Trp His Arg Phe Pro 1 5 <![CDATA[<210> 92]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 92]]> Tyr Pro Trp His Arg Phe Pro Val 1 5 <![CDATA[<210> 93]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 93]]> Pro Trp His Arg Phe Pro Val Thr 1 5 <![CDATA[<210> 94]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<40]]>0> 94]]> <br/> <br/><![CDATA[Trp His Arg Phe Pro Val Thr Phe 1 5 <![CDATA[<210> 95]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 95]]> His Arg Phe Pro Val Thr Phe Gly 1 5 <![CDATA[<210> 96]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 96]]> Arg Glu Leu Thr Tyr Ser Asn Phe 1 5 <![CDATA[<210> 97]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 97]]> Glu Leu Thr Tyr Ser Asn Phe His 1 5 <![CDATA[<210> 98]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 98]]> Leu Thr Tyr Ser Asn Phe His Pro 1 5 <![CDATA[<210> 99]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 99]]> Thr Tyr Ser Asn Phe His Pro Leu 1 5 <![CDATA[<210> 100]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 100]]> Tyr Ser Asn Phe His Pro Leu Leu 1 5 <![CDATA[<210> 101]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 101]]> Ser Asn Phe His Pro Leu Leu Val 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 102]]> Asn Phe His Pro Leu Leu Val Ser 1 5 <![CDATA[<210> 103]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 103]]> Phe His Pro Leu Leu Val Ser Gly 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 104]]> His Pro Leu Leu Val Ser Gly Arg 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 105]]> Pro Leu Leu Val Ser Gly Arg Leu 1 5 <![CDATA[<210> 106]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 106]]> Leu Leu Val Ser Gly Arg Leu Arg 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 107]]> Leu Val Ser Gly Arg Leu Arg Ile 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 108]]> Val Ser Gly Arg Leu Arg Ile Pro 1 5 <![CDATA[<210> 109]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 109]]> Phe Thr Ser Cys Ser Glu Arg His 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 110]]> Thr Ser Cys Ser Glu Arg His Phe 1 5 <![CDATA[<210> 111]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 111]]> Ser Cys Ser Glu Arg His Phe Val 1 5 <![CDATA[<210> 112]]> <![CDATA[<211> ]]>8 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 112]]> Cys Ser Glu Arg His Phe Val Ser 1 5 <![CDATA[<210> 113]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 113]]> Ser Glu Arg His Phe Val Ser Leu 1 5 <![CDATA[<210> 114]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 114]]> Glu Arg His Phe Val Ser Leu Cys 1 5 <![CDATA[<210> 115]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 115]]> Arg His Phe Val Ser Leu Cys Gln 1 5 <![CDATA[<210> 116]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 11]]>6 His Phe Val Ser Leu Cys Gln Lys 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 117]]> Phe Val Ser Leu Cys Gln Lys Tyr 1 5 <![CDATA[<210> 118]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 118]]> Val Ser Leu Cys Gln Lys Tyr Ser 1 5 <![CDATA[<210> 119]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 119]]> Ser Leu Cys Gln Lys Tyr Ser Glu 1 5 <![CDATA[<210> 120]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 120]]> Leu Cys Gln Lys Tyr Ser Glu Val 1 5 <![CDATA[<210> ]]>121 <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 121]]> Cys Gln Lys Tyr Ser Glu Val Lys 1 5 <![CDATA[<210> 122]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 122]]> Gln Lys Tyr Ser Glu Val Lys Ser 1 5 <![CDATA[<210> 123]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 123]]> Thr Val Lys Tyr Leu Asn Asn Leu 1 5 <![CDATA[<210> 124]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 124]]> Val Lys Tyr Leu Asn Asn Leu Tyr 1 5 <![CDATA[<210> 125]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 125]]> Lys Tyr Leu Asn Asn Leu Tyr Lys 1 5 <![CDATA[<210> 126]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 126]]> Tyr Leu Asn Asn Leu Tyr Lys Ile 1 5 <![CDATA[<210> 127]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 127]]> Leu Asn Asn Leu Tyr Lys Ile Ile 1 5 <![CDATA[<210> 128]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 128]]> Asn Asn Leu Tyr Lys Ile Ile Pro 1 5 <![CDATA[<210> 129]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 129]]> Asn Leu Tyr Lys Ile Ile Pro Lys 1 5 <![CDATA[<210> 130]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213]]>> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 肽]]> <br/> <br/><![CDATA[<400> 130]]> <br/> <br/><![CDATA[Leu Tyr Lys Ile Ile Pro Lys Thr 1 5 <![CDATA[<210> 131]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 131]]> Tyr Lys Ile Ile Pro Lys Thr Leu 1 5 <![CDATA[<210> 132]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 132]]> Lys Ile Ile Pro Lys Thr Leu Thr 1 5 <![CDATA[<210> 133]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 133]]> Ile Ile Pro Lys Thr Leu Thr Trp 1 5 <![CDATA[<210> 134]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 134]]> Ile Pro Lys Thr Leu Thr Trp His 1 5 <![CDATA[<210> 135]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 135]]> Pro Lys Thr Leu Thr Trp His Ser 1 5 <![CDATA[<210> 136]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 136]]> Lys Thr Leu Thr Trp His Ser Ala 1 5 <![CDATA[<210> 137]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 137]]> Thr Leu Thr Trp His Ser Ala Lys 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 138]]> Glu Ala Val Tyr Phe His Gln His 1 5 <![CDATA[<210> 139]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 139]]> Ala Val Tyr Phe His Gln His Ser 1 5 <![CDATA[<210> 140]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 140]]> Val Tyr Phe His Gln His Ser Ile 1 5 <![CDATA[<210> 141]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 141]]> Tyr Phe His Gln His Ser Ile Leu 1 5 <![CDATA[<210> 142]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 142]]> Phe His Gln His Ser Ile Leu Ala 1 5 <![CDATA[<210> 143]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223>]]> 肽 <![CDATA[<400> 143]]> Lys Lys Leu Ser Arg Leu Thr Tyr 1 5 <![CDATA[<210> 144]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 144]]> Lys Leu Ser Arg Leu Thr Tyr Ser 1 5 <![CDATA[<210> 145]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 145]]> Leu Ser Arg Leu Thr Tyr Ser Ser 1 5 <![CDATA[<210> 146]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 146]]> Ser Arg Leu Thr Tyr Ser Ser Arg 1 5 <![CDATA[<210> 147]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 147]]> Arg Leu Thr Tyr Ser Ser Arg Cys 1 5 <![CDATA[<210> 148]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 148]]> Asn Gly Ser Arg Trp Ile Gln Tyr 1 5 <![CDATA[<210> 149]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 149]]> Gly Ser Arg Trp Ile Gln Tyr Lys 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 150]]> Ser Arg Trp Ile Gln Tyr Lys Gly 1 5 <![CDATA[<210> 151]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 151]]> Arg Trp Ile Gln Tyr Lys Gly His 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 152]]> Trp Ile Gln Tyr Lys Gly His Cys 1 5 <![CDATA[<210> 153]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 153]]> Ile Gln Tyr Lys Gly His Cys Tyr 1 5 <![CDATA[<210> 154]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 154]]> Gln Tyr Lys Gly His Cys Tyr Lys 1 5 <![CDATA[<210> 155]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 155]]> Tyr Lys Gly His Cys Tyr Lys Ser 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 156]]> Lys Gly His Cys Tyr Lys Ser Asp 1 5 <![CDATA[<210> 157]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 157]]> Gly His Cys Tyr Lys Ser Asp Gln 1 5 <![CDATA[<210> 158]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 158]]> His Cys Tyr Lys Ser Asp Gln Ala 1 5 <![CDATA[<210> 159]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人]]>工序列 <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 159]]> Cys Tyr Lys Ser Asp Gln Ala Leu 1 5 <![CDATA[<210> 160]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 160]]> Tyr Lys Ser Asp Gln Ala Leu His 1 5 <![CDATA[<210> 161]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 161]]> Lys Ser Asp Gln Ala Leu His Ser 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 162]]> Ser Asp Gln Ala Leu His Ser Phe 1 5 <![CDATA[<210> 163]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 163]]> Asp Gln Ala Leu His Ser Phe Ser 1 5 <![CDATA[<210> 164]]> <![CDATA[<211> 1722]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 164]]> Met Arg Thr Gly Trp Ala Thr Pro Arg Arg Pro Ala Gly Leu Leu Met 1 5 10 15 Leu Leu Phe Trp Phe Phe Asp Leu Ala Glu Pro Ser Gly Arg Ala Ala 20 25 30 Asn Asp Pro Phe Thr Ile Val His Gly Asn Thr Gly Lys Cys Ile Lys 35 40 45 Pro Val Tyr Gly Trp Ile Val Ala Asp Asp Cys Asp Glu Thr Glu Asp 50 55 60 Lys Leu Trp Lys Trp Val Ser Gln His Arg Leu Phe His Leu His Ser 65 70 75 80 Gln Lys Cys Leu Gly Leu Asp Ile Thr Lys Ser Val Asn Glu Leu Arg 85 90 95 Met Phe Ser Cys Asp Ser Ser Ala Met Leu Trp Trp Lys Cys Glu His 100 105 110 His Ser Leu Tyr Gly Ala Ala Arg Tyr Arg Leu Ala Leu Lys Asp Gly 115 120 125 His Gly Thr Ala Ile Ser Asn Ala Ser Asp Val Trp Lys Lys Gly Gly 130 135 140 Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile Tyr Thr Arg 145 150 155 160 Asp Gly Asn Ser Tyr Gly Arg Pro Cys Glu Phe Pro Phe Leu Ile Asp 165 170 175 Gly Thr Trp His His Asp Cys Ile Leu Asp Glu Asp His Ser Gly Pro 180 185 190 Trp Cys Ala Thr Thr Leu Asn Tyr Glu Tyr Asp Arg Lys Trp Gly Ile 195 200 205 Cys Leu Lys Pro Glu Asn Gly Cys Glu Asp Asn Trp Glu Lys Asn Glu 210 215 220 Gln Phe Gly Ser Cys Tyr Gln Phe Asn Thr Gln Thr Ala Leu Ser Trp 225 230 235 240 Lys Glu Ala Tyr Val Ser Cys Gln Asn Gln Gly Ala Asp Leu Leu Ser 245 250 255 Ile Asn Ser Ala Ala Glu Leu Thr Tyr Leu Lys Glu Lys Glu Gly Ile 260 265 270 Ala Lys Ile Phe Trp Ile Gly Leu Asn Gln Leu Tyr Ser Ala Arg Gly 275 280 285 Trp Glu Trp Ser Asp His Lys Pro Leu Asn Phe Leu Asn Trp Asp Pro 290 295 300 Asp Arg Pro Ser Ala Pro Thr Ile Gly Gly Ser Ser Cys Ala Arg Met 305 310 315 320 Asp Ala Glu Ser Gly Leu Trp Gln Ser Phe Ser Cys Glu Ala Gln Leu 325 330 335 Pro Tyr Val Cys Arg Lys Pro Leu Asn Asn Thr Val Glu Leu Thr Asp 340 345 350 Val Trp Thr Tyr Ser Asp Thr Arg Cys Asp Ala Gly Trp Leu Pro Asn 355 360 365 Asn Gly Phe Cys Tyr Leu Leu Val Asn Glu Ser Asn Ser Trp Asp Lys 370 375 380 Ala His Ala Lys Cys Lys Ala Phe Ser Ser Asp Leu Ile Ser Ile His 385 390 395 400 Ser Leu Ala Asp Val Glu Val Val Val Thr Lys Leu His Asn Glu Asp 405 410 415 Ile Lys Glu Glu Val Trp Ile Gly Leu Lys Asn Ile Asn Ile Pro Thr 420 425 430 Leu Phe Gln Trp Ser Asp Gly Thr Glu Val Thr Leu Thr Tyr Trp Asp 435 440 445 Glu Asn Glu Pro Asn Val Pro Tyr Asn Lys Thr Pro Asn Cys Val Ser 450 455 460 Tyr Leu Gly Glu Leu Gly Gln Trp Lys Val Gln Ser Cys Glu Glu Lys 465 470 475 480 Leu Lys Tyr Val Cys Lys Arg Lys Gly Glu Lys Leu Asn Asp Ala Ser 485 490 495 Ser Asp Lys Met Cys Pro Pro Asp Glu Gly Trp Lys Arg His Gly Glu 500 505 510 Thr Cys Tyr Lys Ile Tyr Glu Asp Glu Val Pro Phe Gly Thr Asn Cys 515 520 525 Asn Leu Thr Ile Thr Ser Arg Phe Glu Gln Glu Tyr Leu Asn Asp Leu 530 535 540 Met Lys Lys Tyr Asp Lys Ser Leu Arg Lys Tyr Phe Trp Thr Gly Leu 545 550 555 560 Arg Asp Val Asp Ser Cys Gly Glu Tyr Asn Trp Ala Thr Val Gly Gly 565 570 575 Arg Arg Arg Ala Val Thr Phe Ser Asn Trp Asn Phe Leu Glu Pro Ala 580 585 590 Ser Pro Gly Gly Cys Val Ala Met Ser Thr Gly Lys Ser Val Gly Lys 595 600 605 Trp Glu Val Lys Asp Cys Arg Ser Phe Lys Ala Leu Ser Ile Cys Lys 610 615 620 Lys Met Ser Gly Pro Leu Gly Pro Glu Glu Ala Ser Pro Lys Pro Asp 625 630 635 640 Asp Pro Cys Pro Glu Gly Trp Gln Ser Phe Pro Ala Ser Leu Ser Cys 645 650 655 Tyr Lys Val Phe His Ala Glu Arg Ile Val Arg Lys Arg Asn Trp Glu 660 665 670 Glu Ala Glu Arg Phe Cys Gln Ala Leu Gly Ala His Leu Ser Ser Phe 675 680 685 Ser His Val Asp Glu Ile Lys Glu Phe Leu His Phe Leu Thr Asp Gln 690 695 700 Phe Ser Gly Gln His Trp Leu Trp Ile Gly Leu Asn Lys Arg Ser Pro 705 710 715 720 Asp Leu Gln Gly Ser Trp Gln Trp Ser Asp Arg Thr Pro Val Ser Thr 725 730 735 Ile Ile Met Pro Asn Glu Phe Gln Gln Asp Tyr Asp Ile Arg Asp Cys 740 745 750 Ala Ala Val Lys Val Phe His Arg Pro Trp Arg Arg Gly Trp His Phe 755 760 765 Tyr Asp Asp Arg Glu Phe Ile Tyr Leu Arg Pro Phe Ala Cys Asp Thr 770 775 780 Lys Leu Glu Trp Val Cys Gln Ile Pro Lys Gly Arg Thr Pro Lys Thr 785 790 795 800 Pro Asp Trp Tyr Asn Pro Asp Arg Ala Gly Ile His Gly Pro Pro Leu 805 810 815 Ile Ile Glu Gly Ser Glu Tyr Trp Phe Val Ala Asp Leu His Leu Asn 820 825 830 Tyr Glu Glu Ala Val Leu Tyr Cys Ala Ser Asn His Ser Phe Leu Ala 835 840 845 Thr Ile Thr Ser Phe Val Gly Leu Lys Ala Ile Lys Asn Lys Ile Ala 850 855 860 Asn Ile Ser Gly Asp Gly Gln Lys Trp Trp Ile Arg Ile Ser Glu Trp 865 870 875 880 Pro Ile Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro Trp His Arg Phe 885 890 895 Pro Val Thr Phe Gly Glu Glu Cys Leu Tyr Met Ser Ala Lys Thr Trp 900 905 910 Leu Ile Asp Leu Gly Lys Pro Thr Asp Cys Ser Thr Lys Leu Pro Phe 915 920 925 Ile Cys Glu Lys Tyr Asn Val Ser Ser Leu Glu Lys Tyr Ser Pro Asp 930 935 940 Ser Ala Ala Lys Val Gln Cys Ser Glu Gln Trp Ile Pro Phe Gln Asn 945 950 955 960 Lys Cys Phe Leu Lys Ile Lys Pro Val Ser Leu Thr Phe Ser Gln Ala 965 970 975 Ser Asp Thr Cys His Ser Tyr Gly Gly Thr Leu Pro Ser Val Leu Ser 980 985 990 Gln Ile Glu Gln Asp Phe Ile Thr Ser Leu Leu Pro Asp Met Glu Ala 995 1000 1005 Thr Leu Trp Ile Gly Leu Arg Trp Thr Ala Tyr Glu Lys Ile Asn 1010 1015 1020 Lys Trp Thr Asp Asn Arg Glu Leu Thr Tyr Ser Asn Phe His Pro 1025 1030 1035 Leu Leu Val Ser Gly Arg Leu Arg Ile Pro Glu Asn Phe Phe Glu 1040 1045 1050 Glu Glu Ser Arg Tyr His Cys Ala Leu Ile Leu Asn Leu Gln Lys 1055 1060 1065 Ser Pro Phe Thr Gly Thr Trp Asn Phe Thr Ser Cys Ser Glu Arg 1070 1075 1080 His Phe Val Ser Leu Cys Gln Lys Tyr Ser Glu Val Lys Ser Arg 1085 1090 1095 Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys Tyr Leu Asn Asn 1100 1105 1110 Leu Tyr Lys Ile Ile Pro Lys Thr Leu Thr Trp His Ser Ala Lys 1115 1120 1125 Arg Glu Cys Leu Lys Ser Asn Met Gln Leu Val Ser Ile Thr Asp 1130 1135 1140 Pro Tyr Gln Gln Ala Phe Leu Ser Val Gln Ala Leu Leu His Asn 1145 1150 1155 Ser Ser Leu Trp Ile Gly Leu Phe Ser Gln Asp Asp Glu Leu Asn 1160 1165 1170 Phe Gly Trp Ser Asp Gly Lys Arg Leu His Phe Ser Arg Trp Ala 1175 1180 1185 Glu Thr Asn Gly Gln Leu Glu Asp Cys Val Val Leu Asp Thr Asp 1190 1195 1200 Gly Phe Trp Lys Thr Val Asp Cys Asn Asp Asn Gln Pro Gly Ala 1205 1210 1215 Ile Cys Tyr Tyr Ser Gly Asn Glu Thr Glu Lys Glu Val Lys Pro 1220 1225 1230 Val Asp Ser Val Lys Cys Pro Ser Pro Val Leu Asn Thr Pro Trp 1235 1240 1245 Ile Pro Phe Gln Asn Cys Cys Tyr Asn Phe Ile Ile Thr Lys Asn 1250 1255 1260 Arg His Met Ala Thr Thr Gln Asp Glu Val His Thr Lys Cys Gln 1265 1270 1275 Lys Leu Asn Pro Lys Ser His Ile Leu Ser Ile Arg Asp Glu Lys 1280 1285 1290 Glu Asn Asn Phe Val Leu Glu Gln Leu Leu Tyr Phe Asn Tyr Met 1295 1300 1305 Ala Ser Trp Val Met Leu Gly Ile Thr Tyr Arg Asn Lys Ser Leu 1310 1315 1320 Met Trp Phe Asp Lys Thr Pro Leu Ser Tyr Thr His Trp Arg Ala 1325 1330 1335 Gly Arg Pro Thr Ile Lys Asn Glu Lys Phe Leu Ala Gly Leu Ser 1340 1345 1350 Thr Asp Gly Phe Trp Asp Ile Gln Thr Phe Lys Val Ile Glu Glu 1355 1360 1365 Ala Val Tyr Phe His Gln His Ser Ile Leu Ala Cys Lys Ile Glu 1370 1375 1380 Met Val Asp Tyr Lys Glu Glu Tyr Asn Thr Thr Leu Pro Gln Phe 1385 1390 1395 Met Pro Tyr Glu Asp Gly Ile Tyr Ser Val Ile Gln Lys Lys Val 1400 1405 1410 Thr Trp Tyr Glu Ala Leu Asn Met Cys Ser Gln Ser Gly Gly His 1415 1420 1425 Leu Ala Ser Val His Asn Gln Asn Gly Gln Leu Phe Leu Glu Asp 1430 1435 1440 Ile Val Lys Arg Asp Gly Phe Pro Leu Trp Val Gly Leu Ser Ser 1445 1450 1455 His Asp Gly Ser Glu Ser Ser Phe Glu Trp Ser Asp Gly Ser Thr 1460 1465 1470 Phe Asp Tyr Ile Pro Trp Lys Gly Gln Thr Ser Pro Gly Asn Cys 1475 1480 1485 Val Leu Leu Asp Pro Lys Gly Thr Trp Lys His Glu Lys Cys Asn 1490 1495 1500 Ser Val Lys Asp Gly Ala Ile Cys Tyr Lys Pro Thr Lys Ser Lys 1505 1510 1515 Lys Leu Ser Arg Leu Thr Tyr Ser Ser Arg Cys Pro Ala Ala Lys 1520 1525 1530 Glu Asn Gly Ser Arg Trp Ile Gln Tyr Lys Gly His Cys Tyr Lys 1535 1540 1545 Ser Asp Gln Ala Leu His Ser Phe Ser Glu Ala Lys Lys Leu Cys 1550 1555 1560 Ser Lys His Asp His Ser Ala Thr Ile Val Ser Ile Lys Asp Glu 1565 1570 1575 Asp Glu Asn Lys Phe Val Ser Arg Leu Met Arg Glu Asn Asn Asn 1580 1585 1590 Ile Thr Met Arg Val Trp Leu Gly Leu Ser Gln His Ser Val Asp 1595 1600 1605 Gln Ser Trp Ser Trp Leu Asp Gly Ser Glu Val Thr Phe Val Lys 1610 1615 1620 Trp Glu Asn Lys Ser Lys Ser Gly Val Gly Arg Cys Ser Met Leu 1625 1630 1635 Ile Ala Ser Asn Glu Thr Trp Lys Lys Val Glu Cys Glu His Gly 1640 1645 1650 Phe Gly Arg Val Val Cys Lys Val Pro Leu Gly Pro Asp Tyr Thr 1655 1660 1665 Ala Ile Ala Ile Ile Val Ala Thr Leu Ser Ile Leu Val Leu Met 1670 1675 1680 Gly Gly Leu Ile Trp Phe Leu Phe Gln Arg His Arg Leu His Leu 1685 1690 1695 Ala Gly Phe Ser Ser Val Arg Tyr Ala Gln Gly Val Asn Glu Asp 1700 1705 1710 Glu Ile Met Leu Pro Ser Phe His Asp 1715 1720 <![CDATA[<210> 165]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 165]]> Cys Ile Lys Pro Val Tyr Gly Trp Ile Val Ala Asp Asp Cys Asp Glu 1 5 10 15 Thr Glu Asp Lys Leu Trp Lys 20 <![CDATA[<210> 166]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 166]]> Cys Glu His His Ser Leu Tyr Gly Ala Ala Arg 1 5 10 <![CDATA[<210> 167]]> <![CDATA[<211> 34]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 167]]> Asp Gly His Gly Thr Ala Ile Ser Asn Ala Ser Asp Val Trp Lys Lys 1 5 10 15 Gly Gly Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile Tyr 20 25 30 Thr Arg <![CDATA[<210> 168]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 168]]> Lys Gly Gly Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile 1 5 10 15 Tyr Thr Arg <![CDATA[<210> 169]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 169]]> Gly Gly Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile Tyr 1 5 10 15 Thr Arg <![CDATA[<210> 170]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 170]]> Asp Gly His Gly Thr Ala Ile Ser Asn Ala Ser Asp Val Trp Lys 1 5 10 15 <![CDATA[<210> 171]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 171]]> Trp Gly Ile Cys Leu Lys Pro Glu Asn Gly Cys Glu Asp Asn Trp Glu 1 5 10 15 Lys <![CDATA[<210> 172]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 172]]> Ile Phe Trp Ile Gly Leu Asn Gln Leu Tyr Ser Ala Arg 1 5 10 <![CDATA[<210> 173]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 173]]> Leu His Asn Glu Asp Ile Lys Glu Glu Val Trp Ile Gly Leu Lys 1 5 10 15 <![CDATA[<210> 174]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 174]]> Thr Pro Asn Cys Val Ser Tyr Leu Gly Glu Leu Gly Gln Trp Lys 1 5 10 15 <![CDATA[<210> 175]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 175]]> Tyr Phe Trp Thr Gly Leu Arg Asp Val Asp Ser Cys Gly Glu Tyr Asn 1 5 10 15 Trp Ala Thr Val Gly Gly Arg 20 <![CDATA[<210> 176]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 176]]> Ser Val Gly Lys Trp Glu Val Lys Asp Cys Arg 1 5 10 <![CDATA[<210> 177]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 177]]> Trp Glu Val Lys Asp Cys Arg Ser Phe Lys 1 5 10 <![CDATA[<210> 178]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 178]]> Ala Leu Ser Ile Cys Lys Lys 1 5 <![CDATA[<210> 179]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 179]]> Pro Ala Ser Leu Ser Cys Tyr Lys Val Phe His Ala 1 5 10 <![CDATA[<210> 180]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 180]]> Arg Asn Trp Glu Glu Ala Glu Arg 1 5 <![CDATA[<210> 181]]> <![CDATA[<211> 33]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 181]]> Arg Ser Pro Asp Leu Gln Gly Ser Trp Gln Trp Ser Asp Arg Thr Pro 1 5 10 15 Val Ser Thr Ile Ile Met Pro Asn Glu Phe Gln Gln Asp Tyr Asp Ile 20 25 30 Arg <![CDATA[<210> 182]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 182]]> Thr Pro Val Ser Thr Ile Ile Met Pro Asn Glu Phe Gln Gln Asp Tyr 1 5 10 15 Asp Ile Arg <![CDATA[<210> 183]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 183]]> Pro Trp Arg Arg Gly Trp His Phe Tyr Asp Asp Arg Glu Phe Ile Tyr 1 5 10 15 Leu Arg Pro Phe 20 <![CDATA[<210> 184]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 184]]> Gly Trp His Phe Tyr Asp Asp Arg 1 5 <![CDATA[<210> 185]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 185]]> Ile Ser Glu Trp Pro Ile Asp Asp His Phe Thr Tyr Ser Arg 1 5 10 <![CDATA[<210> 186]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 186]]> Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro Trp His Arg Phe Pro Val 1 5 10 15 Thr Phe Gly <![CDATA[<210> 187]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 187]]> Phe Pro Val Thr Phe Gly Glu Glu Cys Leu Tyr Met Ser Ala Lys Thr 1 5 10 15 Trp Leu Ile Asp Leu Gly Lys Pro Thr Asp Cys Ser Thr Lys 20 25 30 <![CDATA[<210> 188]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 188]]> Thr Trp Leu Ile Asp Leu Gly Lys Pro Thr Asp Cys Ser Thr Lys 1 5 10 15 <![CDATA[<210> 189]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 189]]> Tyr Asn Val Ser Ser Leu Glu Lys 1 5 <![CDATA[<210> 190]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 190]]> Val Gln Cys Ser Glu Gln Trp Ile Pro Phe Gln Asn 1 5 10 <![CDATA[<210> 191]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 191]]> Arg Glu Leu Thr Tyr Ser Asn Phe His Pro Leu Leu 1 5 10 <![CDATA[<210> 192]]> <![CDATA[<211> 39]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 192]]> Glu Leu Thr Tyr Ser Asn Phe His Pro Leu Leu Val Ser Gly Arg Leu 1 5 10 15 Arg Ile Pro Glu Asn Phe Phe Glu Glu Glu Ser Arg Tyr His Cys Ala 20 25 30 Leu Ile Leu Asn Leu Gln Lys 35 <![CDATA[<210> 193]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 193]]> Tyr His Cys Ala Leu Ile Leu Asn Leu Gln Lys 1 5 10 <![CDATA[<210> 194]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 194]]> Phe Thr Ser Cys Ser Glu Arg His Phe Val Ser Leu Cys Gln Lys Tyr 1 5 10 15 Ser <![CDATA[<210> 195]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> ]]>人工序列 <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 195]]> His Phe Val Ser Leu Cys Gln Lys 1 5 <![CDATA[<210> 196]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 196]]> Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys 1 5 10 <![CDATA[<210> 197]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 197]]> Thr Val Lys Tyr Leu Asn Asn Leu Tyr Lys Ile Ile 1 5 10 <![CDATA[<210> 198]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 198]]> Thr Leu Thr Trp His Ser Ala Lys 1 5 <![CDATA[<210> 199]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 199]]> Asn Arg His Met Ala Thr Thr Gln Asp Glu Val His Thr Lys 1 5 10 <![CDATA[<210> 200]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 200]]> Ser His Ile Leu Ser Ile Arg 1 5 <![CDATA[<210> 201]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 201]]> Ser Leu Met Trp Phe Asp Lys Thr Pro Leu Ser Tyr Thr His Trp Arg 1 5 10 15 <![CDATA[<210> 202]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 202]]> Ser Leu Met Trp Phe Asp Lys 1 5 <![CDATA[<210> 203]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 203]]> Glu Ala Val Tyr Phe His Gln His Ser Ile Leu 1 5 10 <![CDATA[<210> 204]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 204]]> Lys Lys Leu Ser Arg Leu Thr Tyr Ser Ser 1 5 10 <![CDATA[<210> 205]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 205]]> Asn Gly Ser Arg Trp Ile Gln Tyr Lys Gly His Cys Tyr Lys Ser Asp 1 5 10 15 Gln Ala Leu His 20 <![CDATA[<210> 206]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 206]]> His Asp His Ser Ala Thr Ile Val Ser Ile Lys Asp Glu Asp Glu Asn 1 5 10 15 Lys Phe Val Ser Arg 20 <![CDATA[<210> 207]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 肽]]> <![CDATA[<400> 207]]> Val Glu Cys Glu His Gly Phe Gly Arg 1 5
Claims (6)
- 一種醫藥組合,其包含: 組分(A): 抗LY75抗體或其抗原結合部分,該抗體或其抗原結合部分包含: a)重鏈可變區,其包含: i)包含SEQ ID NO:5之第一vhCDR; ii)包含SEQ ID NO: 6之第二vhCDR;及 iii)包含SEQ ID NO:7之第三vhCDR;及 b)輕鏈可變區,其包含: i)包含SEQ ID NO:8之第一vlCDR; ii)包含SEQ ID NO: 9之第二vlCDR;及 iii)包含SEQ ID NO:10之第三vlCDR; 其中該抗LY75抗體或其抗原結合部分係共價連接至藥物,其中該藥物為DM1或DM4; 及 組分(B):依魯替尼(ibrutinib)或其醫藥學上可接受之鹽; 其中該醫藥組合呈以同時、各別或依序使用之組合製劑形式。
- 如請求項1之醫藥組合,其中該抗LY75抗體或其抗原結合部分包含與SEQ ID NO: 1之胺基酸序列至少80%、85%、90%、95%、99%或100%一致的重鏈可變區,及與SEQ ID NO: 2之胺基酸序列至少80%、85%、90%、95%、99%或100%一致的輕鏈可變區。
- 如請求項1之醫藥組合,其中該抗LY75抗體為人類IgG1單株抗體。
- 如請求項1之醫藥組合,其中組分(A)及/或組分(B)額外包含一或多種醫藥學上可接受的稀釋劑、賦形劑或載劑。
- 一種如請求項1之醫藥組合之組分(A)及組分(B)的用途,其用於製造同時、各別或依序使用以治療瀰漫性大B細胞淋巴瘤(DLBCL)之醫藥組合。
- 如請求項5之用途,其中該抗LY75抗體或其抗原結合部分係經表現LY75之細胞內化。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB1703876.1 | 2017-03-10 | ||
GBGB1703876.1A GB201703876D0 (en) | 2017-03-10 | 2017-03-10 | Pharmaceutical combinations |
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Publication Number | Publication Date |
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TW202317194A true TW202317194A (zh) | 2023-05-01 |
TWI844215B TWI844215B (zh) | 2024-06-01 |
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