TW202208441A - 抗-ror2抗體、抗體片段、其免疫結合物及其用途 - Google Patents
抗-ror2抗體、抗體片段、其免疫結合物及其用途 Download PDFInfo
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- 239000000080 wetting agent Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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Abstract
本發明係關於一種特異性結合於Ror2蛋白質之具有重鏈可變區及/或輕鏈可變區之多肽,以及結合於Ror2蛋白質之含有該重鏈可變區及/或該輕鏈可變區之抗體及抗體片段。亦提供包含該多肽或含有該多肽之抗體及抗體片段的醫藥組合物及套組。
Description
本發明涉及抗-Ror2抗體、抗體片段及此類抗體及抗體片段之免疫結合物及該等抗體、抗體片段及免疫結合物在診斷及治療方法中之用途。
受體酪胺酸激酶(RTK)係經由經配體控制之酪胺酸激酶活性調節一系列正常細胞過程之細胞表面受體家族。在過去20年,已證實RTK之下調在癌症發展及進程中起關鍵作用。現將RTK視為預後分子生物標記且視為腫瘤治療劑之目標。
Ror2,亦稱為受體酪胺酸激酶樣孤兒受體2,係一種膜結合RTK,其在正常骨骼及軟骨發育期間經由其與Wnt5A糖蛋白之相關性藉由非典型Wnt信號傳導而活化。Ror2僅具有一個跨膜域,其分離其細胞外域及細胞內域(圖1)。已知Ror2在各種器官及組織之正常發育中起關鍵作用。在哺乳動物中,缺乏Ror2及缺乏Wnt5A之小鼠在發育形態發生期間展現類似異常,反映其在會聚伸展動作及平面細胞極性中之缺陷。此外,人類Ror2基因之突變會導致B型遺傳骨架病症顯性短指畸形及隱性羅賓症候群(Robinow syndrome)。已發現Ror2介導極化細胞遷移且Ror2之功能障礙引發可遺傳的骨架病症及腫瘤侵入(Minami等人, 「Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases」,Dev Dyn.
, 第239卷, 第1-15頁, 2010)。
亦報導Ror2具有促致瘤效應。US 2014/0322234揭示Ror2在各種癌症中之表現及活性與正常組織不同。因此,表明Ror2之失調在多種人類癌症之發病機制中起作用。US 2014/0322234亦涵蓋,抵抗Ror2之抗體可用於診斷癌症且抑制癌細胞生長。舉例而言,此類抗體可與對表現Ror2之癌細胞具有高度細胞毒性之細胞毒性劑結合,以使得細胞毒性劑可有效殺死癌細胞。Ror2基因亦可用於根據癌症中之Ror2表現模式將癌症分類。
Ford等人(「The dual role of the novel Wnt receptor tyrosine kinase, Ror2, in human carcinogenesis」, International Journal of Cancer, 第133卷, 第779-787頁, 2013)進一步探索Ror2在癌發生中之機制。此參考文獻揭示Ror2與癌症之顯現及進展有關。特定言之,發現Ror2在許多癌症之癌發生中起關鍵作用,該等癌症包括結腸癌、肝細胞癌、轉移性黑素瘤及腎細胞癌。舉例而言,Ror2過度表現於骨肉瘤、黑素瘤、腎細胞癌、前列腺癌、頭頸之鱗狀細胞癌及基質腫瘤中。因此,Ror2具有成為藉由抑制Wnt信號傳導路徑進行癌症治療之藥物目標的可能。
此外,Debebe等人(「Ror2 as a therapeutic target in cancer」,Pharmacol. Ther.
, 第50卷, 第143-148頁, 2015)揭示Ror2介導典型與非典型信號傳導路徑。Ror2非常表現於骨肉瘤及腎細胞癌,以及黑素瘤、結腸癌、頭頸之鱗狀細胞癌及乳癌中。在此等癌症類型中之大多數中,Ror2表現與更具侵襲性的癌症病況相關。因此此參考文獻亦表明Ror2係進行癌症治療之可能目標。
儘管抵抗Ror2之單株抗體可購得,但尚未報導適用於癌症治療之抗-Ror2抗體。本發明提供適用於治療及診斷用途,尤其適用於診斷及治療癌症之抗-Ror2抗體或抗體片段。一些抗-Ror2抗體或抗體片段與腫瘤中之Ror2具有相比於與存在於正常組織中之Ror2更高的結合親和力。與此項技術中已知之單株抗-Ror2抗體相比,本發明之此等抗-Ror2抗體或抗體片段具有至少類似的功效以及更長的半衰期,但具有降低的副作用。此情況可允許使用較高劑量之此等抗-Ror2抗體或抗體片段,因此在無對應的副作用顯著增加下提供更有效的治療性選項。
在一個態樣中,本發明提供一種特異性結合於Ror2蛋白質之分離之重鏈可變區多肽。該等多肽包括三個互補決定區H1、H2及H3序列,其中:
H1序列係GYTX1
TEX2
X3
X4
H (SEQ ID NO:1)或GYSITTGX29
YWN (SEQ ID NO:4);
H2序列係X5
X6
X7
X8
NNGGTGYNQKFKG (SEQ ID NO:2)或YITYDGSX30
NYNPSLKN (SEQ ID NO:5);且
H3序列係X9
X10
X11
SX12
YX13
YX14
X15
SYFX16
X17
X18
(SEQ ID NO:3)或CSX31
X32
X33
X34
VX35
X36
X37
LDX38
(SEQ ID NO:6);
其中
X1
係F或E,
X2
係Y或D,
X3
係T或C,
X4
係M或D或E或Y,
X5
係G或S,
X6
係I或E,
X7
係N或C或L或V,
X8
係T或D或E,
X9
係A或I或M或S或T,
X10
係R或Q或H,
X11
係G或E,
X12
係L或F,
X13
係S或G,
X14
係G或D,
X15
係N或E,
X16
係D或L,
X17
係Y或C或T,
X18
係W或L,
X29
係Y或E或R或T,
X30
係K或S,
X31
係R或G或H或W或Y,
X32
係F或C或N或Q,
X33
係E或S,
X34
係G或E或F或H或M或Q或S,
X35
係W或A或I或P或Q或T或V,
X36
係Y或G或N或Q,
X37
係G或S或T,且
X38
係Y或I。
在另一態樣中,將此分離之重鏈可變區多肽與包括三個互補決定區L1、L2及L3序列之分離之輕鏈可變區組合,其中:
L1序列係SATSSX19
X20
X21
MX22
(SEQ ID NO:7)或RASESVDRYGNSX39
IH (SEQ ID NO:10);
L2序列係X23
TSNLAS (SEQ ID NO:8)或X40
TYX41
LES (SEQ ID NO:11);且
L3序列係QX24
X25
SX26
YPFX27
X28
(SEQ ID NO:9)或QQX42
NX43
DPX44
TX45
(SEQ ID NO:12);
其中
X19
係V或E,
X20
係S或D,
X21
係Y或C或D,
X22
係H或G或L,
X23
係G或C或H或P,
X24
係Q或E,
X25
係R或H,
X26
係S或D或G或I或Q或V,
X27
係T或D,
X28
係F或D或E,
X39
係F或S或T,
X40
係R或C或D或E或W,
X41
係N或D,
X42
係T或D或I或P,
X43
係E或V,
X44
係W或T,且
X45
係F或S。
在又一態樣中,本發明提供一種包括本發明之分離之重鏈可變區多肽的抗-Ror2抗體或抗體片段。
在又一態樣中,本發明提供一種免疫結合物,其包括視情況結合於選自化學治療劑、放射性原子、細胞生長抑制劑及細胞毒性劑之藥劑的本發明之抗體或抗體片段。
在又一態樣中,本發明提供一種醫藥組合物,其包括本發明之多肽、抗體或抗體片段或免疫結合物以及醫藥學上可接受之載劑。
在又一態樣中,本發明提供一種用於診斷或治療之套組,其包括本發明之多肽、抗體或抗體片段或免疫結合物。
定義
為有助於理解本文提供之實例,某些頻繁出現之術語在本文中加以定義。
結合所量測量,如本文所用之術語「約」係指熟習此項技術者所預期使量測及操作與量測之目的及所用量測設備之精確度在所關心之量上相匹配的量測量之正常變化。除非另外指明,否則「約」係指所提供之值的+/-10%之變化。
如本文所用,術語「親和力」係指分子(例如抗體)之單一結合位點與其結合搭配物(例如抗原)之間的非共價相互作用的總和的強度。除非另外指明,否則如本文所用,「結合親和力」係指反映結合對(例如抗體與抗原)成員之間1:1相互作用之固有結合親和力。分子X對其搭配物Y之親和力一般可由解離常數(Kd)表示。可藉由此項技術中已知之常用方法(包括本文所描述之該等方法)來量測親和力。用於量測結合親和力之特定說明性及例示性實施例描述於下文中。
如本文所用,術語「親和力成熟」抗體係指相比於在一或多個高變區(HVR)中不具有一或多個改變之親本抗體,在一或多個高變區中具有此類改變之抗體,此類改變使抗體對抗原之親和力得以改良。
如本文所用,術語「胺基酸」係指含有胺基(--NH2
)及羧基(--COOH)之任何有機化合物;其較佳呈游離基團形式或者在縮合之後作為肽鍵之一部分。「二十個形成天然編碼之多肽的α胺基酸」在此項技術中已有所理解且係指:丙胺酸(ala或A)、精胺酸(arg或R)、天冬醯胺(asn或N)、天冬胺酸(asp或D)、半胱胺酸(cys或C)、麩胺酸(glu或E)、麩醯胺酸(gin或Q)、甘胺酸(gly或G)、組胺酸(his或H)、異白胺酸(ile或I)、白胺酸(leu或L)、離胺酸(lys或K)、甲硫胺酸(met或M)、苯丙胺酸(phe或F)、脯胺酸(pro或P)、絲胺酸(ser或S)、蘇胺酸(thr或T)、色胺酸(tip或W)、酪胺酸(tyr或Y)及纈胺酸(val或V)。
如本文所用,術語「抗體」係指能夠結合於抗原之抗原決定基的完整免疫球蛋白分子以及免疫球蛋白分子之片段,諸如Fab、Fab'、(Fab')2
、Fv及SCA片段。此等抗體片段可使用此項技術中熟知之方法製得(參見例如Harlow及Lane, 同上)且如下進一步描述,該等抗體片段保留一定的與其所源於之抗體之抗原(例如多肽抗原)選擇性結合的能力。抗體可以用以藉由免疫親和層析法分離製備量之抗原。此類抗體之各種其他用途係診斷及/或分級疾病(例如瘤形成)且用於治療疾病之治療性應用,該疾病係諸如:瘤形成、自體免疫性疾病、AIDS、心血管疾病、感染及其類似疾病。嵌合抗體、人類樣抗體、人類化抗體或全人類抗體尤其適用於向人類患者投與。
Fab片段由抗體分子之單價抗原結合片段組成,且可藉由用番木瓜蛋白酶消化全抗體分子來製造,產生由完整輕鏈及一部分重鏈組成之片段。
抗體分子之Fab'片段可藉由用胃蛋白酶處理全抗體分子、之後還原而獲得,產生由完整輕鏈及一部分重鏈組成分子。每個以此方式處理之抗體分子獲得兩個Fab'片段。
抗體之(Fab')2
片段可在無後續還原下藉由用胃蛋白酶處理全抗體分子獲得。(Fab')2
片段係兩個Fab'片段之二聚體,藉由兩個二硫鍵結合在一起。
Fv片段定義為含有輕鏈可變區及重鏈可變區且表現為兩條鏈之基因工程改造片段。
如本文所用,術語「抗體片段」係指除完整抗體外之分子,其包含完整抗體之一部分,且結合完整抗體所結合之抗原。抗體片段之實例包括(但不限於)Fv、Fab、Fab'、Fab'-SH、F(ab')2
;雙功能抗體;線性抗體;單鏈抗體分子(例如scFv);及由抗體片段形成之多特異性抗體。
如本文所用,術語「抗-Ror2抗體」、「Ror2抗體」及「結合於Ror2之抗體」係指能夠以足夠親和力結合Ror2之抗體,使得抗體適用作靶向ROr2之診斷劑及/或治療劑。在一個實施例中,如藉由放射免疫分析(RIA)所量測,抗-Ror2抗體與不相關的非Ror2蛋白質之結合程度低於抗體與Ror2之結合的約10%。在某些實施例中,結合於Ror2之抗體的解離常數(Kd)≦1 μM、≦100 nM、≦10 nM、≦1 nM、≦0.1 nM、≦0.01 nM或≦0.001 nM (例如10−8
M或更低,例如10−8
M至10−13
M,例如10−9
M至10−13
M)。在某些實施例中,抗-Ror2抗體結合於保存於來自不同物種之Ror2中的Ror2抗原決定基。
如本文所用,術語「結合」係指抗體之可變區或Fv與抗原之相互作用,其中該相互作用視抗原上特定結構(例如抗原決定子或抗原決定基)之存在而定。舉例而言,抗體可變區或Fv識別且結合於特定蛋白質結構而非一般蛋白質。如本文所用,術語「特異性結合(specifically binding/binding specifically)」意謂抗體可變區或Fv與特定抗原以比與其他蛋白質更頻繁、更快速、更大的持續時間及/或更大的親和力結合或締合。舉例而言,抗體可變區或Fv與其抗原以比其結合於其他抗原更大的親和力、親合力、更容易地及/或以更大的持續時間特異性結合。對於另一實例,抗體可變區或Fv與細胞表面蛋白質(抗原)以比其結合於相關蛋白質或其他細胞表面蛋白質或通常藉由多反應性天然抗體(亦即藉由已知結合人類中天然發現之多種抗原的天然產生之抗體)識別之抗原實質上更大的親和力結合。然而,「特異性結合」不一定需要排他性結合或不可偵測地結合另一抗原,此為術語「選擇性結合」之含義。在一個實例中,抗體可變區或Fv(或其他結合區)結合於抗原之「特異性結合」意謂抗體可變區或Fv與抗原以l00 nM或更小,諸如50nM或更小,例如20nM或更小,諸如15nM或更小,或10 nΜ或更小,或5nM或更小,2 nM或更小,或1 nM或更小之平衡常數(KD)結合。
如本文所用,術語「癌症」及「癌性」係指或描述哺乳動物中通常特徵為不受調控之細胞生長/增生的生理病狀。癌症之實例包括(但不限於)癌瘤、淋巴瘤(例如霍奇金氏(Hodgkin's)及非霍奇金氏淋巴瘤)、母細胞瘤、肉瘤及白血病。此類癌症之更特定實例包括鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺鱗狀癌、腹膜癌、肝細胞癌、胃腸癌、胰臟癌、神經膠母細胞瘤、子宮頸癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝腫瘤、乳癌、結腸癌、結腸直腸癌、子宮內膜或子宮癌、唾液腺癌、腎癌、肝癌(liver cancer)、前列腺癌、外陰癌、甲狀腺癌、肝癌(hepatic carcinoma)、白血病及其他淋巴增生病症,及各種類型的頭頸癌。
如本文所用,術語「細胞增生性病症」及「增生性病症」係指與異常一定程度之細胞增生相關之病症。在一個實施例中,細胞增生性病症為癌症。
如本文所用,術語「化學治療劑」係指適用於治療癌症之化學化合物。化學治療劑之實例包括烷基化劑,諸如噻替派(thiotepa)及環磷醯胺(cyclosphosphamide) (CYTOXAN®);磺酸烷基酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶(aziridine),諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);伸乙亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、曲他胺(triethylenemelamine)、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基三聚氰胺;多聚乙醯(尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));δ-9-四氫大麻酚(屈大麻酚(dronabinol),MARINOL®);β-拉帕酮(beta-lapachone);拉帕醇(lapachol);秋水仙鹼(colchicines);樺木酸(betulinic acid);喜樹鹼(camptothecin)(包括合成類似物拓朴替康(topotecan) (HYCAMTIN®)、CPT-11 (伊立替康(irinotecan),CAMPTOSAR®)、乙醯基喜樹鹼、東莨菪素(scopolectin)及9-胺基喜樹鹼);苔蘚蟲素(bryostatin);海洋抑素(callystatin);CC-1065 (包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);念珠藻環肽(cryptophycin) (尤其克瑞托欣1 (cryptophycin 1)及克瑞托欣8);海兔毒素(dolastatin);倍癌黴素(duocarmycin) (包括合成類似物,KW-2189及CB1-TM1);艾榴塞洛素(eleutherobin);盤克斯塔叮(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿抑素(spongistatin);氮芥(nitrogen mustard),諸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺(chlorophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、甲基二(氯乙基)胺(mechlorethamine)、鹽酸氧甲基二(氯乙基)胺(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、膽固醇對苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,諸如烯二炔抗生素(例如卡奇黴素(calicheamicin),尤其卡奇黴素γ1I及卡奇黴素ωI1 (參見例如,Nicolaou等人, Angew. Chem. Intl. Ed. Engl., 33: 183-186 (1994));CDP323,一種經口α-4整合素抑制劑;達米辛(dynemicin),包括達米辛A;埃斯培拉黴素(esperamicin);以及新抑癌蛋白發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放射菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博來黴素(bleomycin)、放線菌素C (cactinomycin)、卡拉比辛(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycin)、放線菌素D (dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、小紅莓(doxorubicin) (包括ADRIAMYCIN®、N-嗎啉基-小紅莓、氰基-N-嗎啉基-小紅莓、2-吡咯啉基-小紅莓、小紅莓HCl脂質體注射劑(DOXIL®)、脂質小紅莓TLC D-99 (MYOCET®)、聚乙二醇化脂質小紅莓(CAELYX®)及去氧小紅莓(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)(諸如絲裂黴素C)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非羅黴素(porfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤(methotrexate)、吉西他濱(gemcitabine) (GEMZAR®)、替加氟(tegafur) (UFTORAL®)、卡培他濱(capecitabine) (XELODA®)、埃坡黴素(epothilone)及5-氟尿嘧啶(5-fluorouracil) (5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、曲美沙特(trimetrexate);嘌呤類似物,諸如氟達拉賓(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素(androgen),諸如卡魯睾(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺藥,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);貝斯布西(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);埃坡黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲(hydroxyurea);磨菇多糖(lentinan);氯尼達明(lonidainine);類美登素(maytansinoid),諸如美登素(maytansine)及安絲菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫比達摩(mopidanmol);二胺硝吖啶(nitraerine);噴司他丁(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基醯肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK®多糖複合物(JHS Natural Products, Eugene, Oreg.);雷佐生(razoxane);根黴素(rhizoxin);西索菲蘭(sizofiran);螺旋鍺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2'-三氯三乙胺;單端孢黴烯(trichothecene) (尤其T-2毒素、弗納庫林A (verracurin A)、桿孢菌素A (roridin A)及胺癸叮(anguidine));尿烷(urethan);長春地辛(vindesine) (ELDISINE®、FILDESIN®);達卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(arabinoside)(「Ara-C」);噻替派(thiotepa);紫杉醇(taxoid),例如太平洋紫杉醇(paclitaxel) (TAXOL®)、太平洋紫杉醇之經白蛋白工程改造之奈米粒子調配物(ABRAXANE™)及多烯紫杉醇(docetaxel) (TAXOTERE®);苯丁酸氮芥(chloranbucil);6-硫代鳥嘌呤(6-thioguanine);巰嘌呤(mercaptopurine);甲胺喋呤;鉑藥劑,諸如順鉑(cisplatin)、奧沙利鉑(oxaliplatin) (例如ELOXATIN®)及卡鉑(carboplatin);長春花(vincas)(其預防微管蛋白聚合以免形成微管),包括長春鹼(vinblastine) (VELBAN®)、長春新鹼(vincristine) (ONCOVIN®)、長春地辛(vindesine) (ELDISINE®、FILDESIN®)及長春瑞賓(vinorelbine) (NAVELBINE®);依託泊苷(etoposide) (VP-16);異環磷醯胺(ifosfamide);米托蒽醌(mitoxantrone);甲醯四氫葉酸(leucovorin);米托蒽醌(novantrone);依達曲沙(edatrexate);柔紅黴素(daunomycin);胺基喋呤(aminopterin);伊班膦酸鹽(ibandronate);拓樸異構酶抑制劑RFS2000;二氟甲基鳥胺酸(difluoromethylornithine) (DMF®);類視黃素,諸如視黃酸(retinoic acid),包括貝瑟羅汀(bexarotene) (TARGRETIN®);雙膦酸鹽,諸如氯屈膦酸鹽(clodronate) (舉例而言,BONEFOS®或OSTAC®)、依替膦酸鹽(etidronate) (DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(zoledronic acid/zoledronate) (ZOMETA®)、阿侖膦酸鹽(alendronate) (FOSAMAX®)、帕米膦酸鹽(pamidronate) (AREDIA®)、替魯膦酸鹽(tiludronate) (SKELID®)或利塞膦酸鹽(risedronate) (ACTONEL®);曲沙他濱(troxacitabine) (1,3-二氧雜環戊烷核苷胞嘧啶類似物);反義寡核苷酸,尤其抑制信號傳導路徑中與異常細胞增生有關之基因表現之該等反義寡核苷酸,諸如PKC-α、Raf、H-ras及表皮生長因子受體(EGF-R);疫苗,諸如THERATOPE®疫苗及基因療法疫苗,例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗及VAXID®疫苗;1型拓樸異構酶抑制劑(例如LURTOTECAN®);rmRH (例如ABARELIX®);BAY439006 (索拉非尼(sorafenib);Bayer);SU-11248 (舒尼替尼(sunitinib),SUTENT®,Pfizer);哌立福新(perifosine)、COX-2抑制劑(例如塞內昔布(celecoxib)或依他昔布(etoricoxib))、蛋白酶體抑制劑(例如PS341);硼替佐米(bortezomib) (VELCADE®);CCI-779;替吡法尼(tipifarnib) (R11577);索拉非尼(orafenib)、ABT510;Bcl-2抑制劑,諸如奧利默森鈉(oblimersen sodium) (GENASENSE®);匹蒽醌(pixantrone);EGFR抑制劑(參見下文之定義);酪胺酸激酶抑制劑(參見下文之定義);絲胺酸-蘇胺酸激酶抑制劑,諸如雷帕黴素(rapamycin) (西羅莫司(sirolimus),RAPAMUNE®);法呢基轉移酶抑制劑,諸如洛那法尼(lonafarnib) (SCH6636,SARASAR™);及以上任一者之之醫藥學上可接受之鹽、酸或衍生物;以及以上藥劑中之兩者或兩者以上的組合,諸如CHOP,環磷醯胺、小紅莓、長春新鹼及潑尼龍之組合治療之縮寫;及FOLFOX,由與5-FU及甲醯四氫葉酸組合之奧沙利鉑(ELOXATIN™)實施之治療方案的縮寫。
如本文所定義之化學治療劑包括用來調節、減輕、阻斷或抑制可促進癌症生長之激素作用的「抗激素劑」或「內分泌治療劑」。其本身可為激素,包括(但不限於):具有混合促效劑/拮抗劑型態之抗雌激素,包括他莫昔芬(tamoxifen)(NOLVADEX®)、4-羥基他莫昔芬、托瑞米芬(toremifene) (FARESTON®)、艾多昔芬(idoxifene)、曲洛昔芬(droloxifene)、雷諾昔酚(raloxifene) (EVISTA®)、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)及選擇性雌激素受體調節劑(SERM) (諸如SERM3);不具有促效劑特性之純抗雌激素,諸如氟維司群(fulvestrant) (FASLODEX®)及EM800(此類藥劑可阻斷雌激素受體(ER)二聚、抑制DNA結合、增加ER轉換及/或遏制ER含量);芳香酶抑制劑,包括類固醇芳香酶抑制劑,諸如福美司坦(formestane)及依西美坦(exemestane) (AROMASIN®),及非類固醇芳香酶抑制劑,諸如阿那曲唑(anastrazole) (ARIMIDEX®)、來曲唑(letrozole) (FEMARA®)及胺魯米特(aminoglutethimide),及其他芳香酶抑制劑,包括伏羅唑(vorozole) (RIVISOR®)、乙酸甲地孕酮(megestrol acetate) (MEGASE®)、法屈唑(fadrozole)及4(5)-咪唑;黃體激素釋放激素促效劑,包括亮丙立德(leuprolide) (LUPRON®及ELIGARD®)、戈舍瑞林(goserelin)、布舍瑞林(buserelin)及曲特瑞林(tripterelin);性類固醇,包括助孕素(諸如乙酸甲地孕酮(megestrol acetate)及乙酸甲羥孕酮(medroxyprogesterone acetate))、雌激素(諸如己烯雌酚(diethylstilbestrol)及普雷馬林(premarin))及雄激素/類視黃素(諸如氟甲睾酮(fluoxymesterone)、所有反式視黃酸及非瑞替尼(fenretinide));奧那司酮(onapristone);抗孕酮;雌激素受體下調劑(ERD);抗雄激素,諸如氟他胺(flutamide)、尼魯胺(nilutamide)及比卡魯胺(bicalutamide);以及以上任一者之醫藥學上可接受之鹽、酸或衍生物;以及以上藥劑中之兩者或兩者以上的組合。
如本文所用,術語「嵌合」抗體係指重鏈及/或輕鏈之一部分來源於特定來源或物種,而該重鏈及/或輕鏈之其餘部分來源於不同來源或物種的抗體。
如本文所用,術語抗體之「類別」係指其重鏈所具有之恆定域或恆定區的類型。存在五個主要類別之抗體:IgA、IgD、IgE、IgG及IgM,且此等抗體中之若干個可進一步分成子類(同型),例如IgG1
、IgG2
、IgG3
、IgG4
、IgA1
及IgA2
。對應於不同類別免疫球蛋白之重鏈恆定域分別稱為α、δ、ε、γ及μ。
如本文所用,術語「條件性活性抗體」係指在腫瘤微環境中之條件下比在非腫瘤微環境中之條件下更具活性之抗體。腫瘤微環境中之條件包括與非腫瘤微環境相比更低的pH值、更高的乳酸酯及丙酮酸酯濃度、低氧、更低的葡萄糖濃度及略更高的溫度。舉例而言,條件性活性抗體在正常體溫下幾乎無活性,但在腫瘤微環境中在較高溫度下具有活性。在又一態樣中,條件性活性抗體在正常氧化血液中具較低活性,但在腫瘤中存在之氧化不佳的環境下更具活性。在又一態樣中,條件性活性抗體在正常生理pH 7.2-7.8中具較低活性,但在腫瘤微環境中存在之酸性pH 5.8-7.0或6.0-6.8下更具活性。在腫瘤微環境中存在熟習此項技術者已知的其他條件,其亦可用作使抗-Ror2抗體與Ror2具有不同結合親和力的本發明之條件。
如本文所用,如例如應用於Ror2活性之術語「組成性」係指受體激酶之連續信號傳導活性,其與配體或其他活化分子之存在無關。視受體激酶之性質而定,所有活性均可為組成性的或受體之活性可藉由其他分子(例如配體)之結合進一步活化。致使受體激酶活化之細胞事件已為一般技術者所熟知。舉例而言,活化可包括寡聚,例如二聚、三聚等,以達成高階受體複合物。複合物可包含單一蛋白質物種,亦即同聚體複合物(homomeric complex)。另外,複合物可包含至少兩個不同蛋白質物種,亦即異聚體複合物(heteromeric complex)。複合物形成可由例如正常或突變形式之受體於細胞表面上過度表現所致。複合物形成亦可由受體中之一或多個特異性突變所致。
如本文所用,術語「細胞生長抑制劑」係指在活體外或活體內阻滯細胞生長的化合物或組合物。因此,細胞生長抑制劑可為顯著降低S期細胞百分比之藥劑。細胞生長抑制劑之其他實例包括藉由誘導G0/G1阻滯或M期阻滯阻斷細胞週期進程之試劑。人類化抗-Her2抗體曲妥珠單抗(trastuzumab) (HERCEPTIN®)為誘導G0/G1阻滯之細胞生長抑制劑的實例。經典M期阻斷劑包括長春花(長春新鹼及長春鹼)、紫杉烷(taxane)及II型拓樸異構酶抑制劑,諸如小紅莓、表柔比星、道諾黴素、依託泊苷及博萊黴素。阻滯G1之該等藥劑亦深入到S期阻滯,例如DNA烷基化劑,諸如他莫昔芬、潑尼松(prednisone)、達卡巴嗪、甲基二(氯乙基)胺、順鉑、甲胺喋呤、5-氟尿嘧啶及阿糖胞苷。其他資訊可見於Mendelsohn及Israel編, The Molecular Basis of Cancer, 第1章, 名稱為「Cell cycle regulation, oncogenes, and antineoplastic drugs」, Murakami等人(W.B. Saunders, Philadelphia, 1995),例如第13頁。紫杉烷(太平洋紫杉醇及多烯紫杉醇)係源自紫杉樹之抗癌藥物。來源於歐洲紫杉的多烯紫杉醇(TAXOTERE®, Rhone-Poulenc Rorer)係太平洋紫杉醇(TAXOL®, Bristol-Myers Squibb)之半合成類似物。太平洋紫杉醇及多烯紫杉醇促進微管自微管蛋白二聚物組裝且藉由防止解聚合穩定微管,其致使抑制細胞中之有絲分裂。
如本文所用之術語「細胞毒性劑」係指抑制或妨礙細胞功能及/或引起細胞死亡或破壞之物質。細胞毒性劑包括(但不限於)放射性同位素(例如At211
、I131
、I125
、Y90
、Re186
、Re188
、Sm153
、Bi212
、P32
、Pb212
及Lu之放射性同位素);化學治療劑或藥物(例如甲胺喋呤、阿德力黴素(adriamicin)、長春花生物鹼(長春新鹼、長春鹼、依託泊苷)、小紅莓、美法侖、絲裂黴素C 、苯丁酸氮芥、道諾黴素或其他插入劑);生長抑制劑;酶及其片段,諸如核分解酶;抗生素;毒素,諸如小分子毒素或細菌、真菌、植物或動物來源之酶促活性毒素,包括其片段及/或變異體;以及以下所揭示之各種抗腫瘤或抗癌劑。
如本文所用,術語「雙功能抗體」係指具有兩個抗原結合位點之小抗體片段,該等片段包含連接至同一多肽鏈(VH
-VL
)中之輕鏈可變域(VL
)的重鏈可變域(VH
)。藉由使用過短以使得同一鏈上之兩個可變域之間不能配對的連接子,迫使可變域與另一條鏈之互補域配對,且產生兩個抗原結合位點。
如本文所用,術語「可偵測標記」係指藉由物理或化學方式進行直接或間接偵測或量測指示樣品中存在CTC之任何物質。適用的可偵測標記之代表性實例包括(但不限於)以下:可根據光吸收、螢光、反射率、光散射、磷光或螢光特性直接或間接偵測之分子或離子;可藉由其放射特性偵測之分子或離子;可藉由其核磁共振或順磁特性偵測之分子或離子。可根據光吸收或螢光間接偵測之分子組中包括例如各種酶,該等酶致使適當受質例如由非光吸收轉變為光吸收分子或由非螢光轉變為螢光分子。
如本文所用,術語「診斷」係指確定個體對疾病或病症之易感性、確定個體目前是否患有疾病或病症、患有疾病或病症之個體之預後(例如鑑別癌的轉移前或轉移狀態、癌症之階段或癌症對治療之反應)及度量療法(therametrics)(例如監測個體之病狀以提供關於治療效應或功效之資訊)。在一些實施例中,本發明之診斷方法尤其適用於偵測早期癌症。
如本文所用,術語「診斷劑」係指可直接或間接偵測且用於診斷目的之分子。診斷劑可向個體或樣品投與。可提供診斷劑本身或可與諸如條件性活性抗體之媒劑結合。
如本文所用,術語「效應功能」係指可歸因於抗體之Fc區之該等生物活性,其因抗體同型而異。抗體效應功能之實例包括:C1q結合及補體依賴性細胞毒性(CDC);Fc受體結合;抗體依賴性細胞介導之細胞毒性(ADCC);吞噬作用;細胞表面受體(例如B細胞受體)之減量下調;及B細胞活化。
如本文所用,術語藥劑(例如醫藥調配物)之「有效量」係指在所需劑量及時段下有效獲得所需治療性或預防性結果之量。
如本文所用,術語「Fc區」用以定義含有至少一部分恆定區之免疫球蛋白重鏈之C端區。該術語包括原生序列Fc區及變異型Fc區。在一個實施例中,人類IgG重鏈Fc區自Cys226或自Pro230延伸至重鏈之羧基端。然而,Fc區之C端離胺酸(Lys447)可存在或可不存在。除非本文另外說明,否則Fc區或恆定區中胺基酸殘基之編號係根據EU編號系統,亦稱為EU索引,如Kabat等人, Sequences of Proteins of Immunological Interest, 第5版, 美國公共衛生署(Public Health Service), 美國國家衛生研究院(National Institutes of Health), Bethesda, Md., 1991中所述。
如本文所用,術語「構架」或「FR」殘基係指除高變區(HVR或重鏈中之H1-3及輕鏈中之L1-3)殘基外之該等可變域殘基。可變域之FR一般由四個FR域組成:FR1、FR2、FR3及FR4。因此,在VH
(或VL
)中HVR及FR序列一般出現以下序列中:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
術語「全長抗體」、「完整抗體」或「全抗體」係指包含抗原結合可變區(VH
或VL
)以及輕鏈恆定域(CL)及重鏈恆定域CH1、CH2及CH3之抗體。恆定域可為原生序列恆定域(例如人類原生序列恆定域)或其胺基酸序列變異體。視其重鏈之恆定域之胺基酸序列而定,全長抗體可歸屬於不同「類別」。存在五個主要類別之全長抗體:IgA、IgD、IgE、IgG及IgM,且此等抗體中之若干個可進一步分成「子類」(同型),例如IgG1、IgG2、IgG3、IgG4、IgA及IgA2。對應於不同類別之抗體之重鏈恆定域分別稱為α、δ、ε、γ及μ。不同類別之免疫球蛋白的子單元結構及三維組態已熟知。
如本文所用,術語「宿主細胞」、「宿主細胞株」及「宿主細胞培養物」可互換使用且係指已引入外源核酸之細胞,包括此類細胞之後代。宿主細胞包括「轉型體」及「轉型細胞」,其包括初始轉型細胞及來源於其之後代(不考慮繼代次數)。後代之核酸含量與母細胞可能不完全相同,但可能含有突變。本文包括針對原始轉型細胞篩檢或選擇的具有相同功能或生物活性之突變型後代。
如本文所用,術語「人類抗體」係具有如下胺基酸序列之抗體,該胺基酸序列對應於由人類或人類細胞所產生之抗體或源自使用人類抗體譜系或其他人類抗體編碼序列之非人類來源之抗體的胺基酸序列。人類抗體之此定義特定排除包含非人類抗原結合殘基之人類化抗體。
如本文所用,術語「人類共同構架」係表示人類免疫球蛋白VL
或VH
構架序列之選擇中最常存在之胺基酸殘基的構架。一般而言,人類免疫球蛋白VL
或VH
序列係選自可變域序列之子組。一般而言,序列子組係如Kabat等人, Sequences of Proteins of Immunological Interest, 第五版, NIH Publication 91-3242, Bethesda MD (1991), 第1-3卷中之子組。在一個實施例中,對於VL
,子組係如Kabat等人, 同上中之子組κ I。在一個實施例中,對於VH
,子組係如Kabat等人, 同上中之子組III。
如本文所用,術語「人類化」抗體係指包含來自非人類HVR之胺基酸殘基及來自人類FR之胺基酸殘基的嵌合抗體。在某些實施例中,人類化抗體將包含至少一個且通常兩個可變域之實質上全部,其中全部或實質上全部HVR (例如CDR)對應於非人類抗體之HVR,且全部或實質上全部FR皆對應於人類抗體之FR。人類化抗體視情況可包含源自人類抗體之抗體恆定區的至少一部分。抗體(例如非人類抗體)之「人類化形式」係指已經歷人類化之抗體。
如本文所用,術語「高變區」或「HVR」係指抗體可變域中在序列上具有高變性及/或形成結構上定義之環(「高變環」)的各區域。一般而言,原生四鏈抗體包含六個HVR;三個位於VH
中(H1、H2、H3),且三個位於VL
中(L1、L2、L3)。HVR一般包含來自高變環及/或來自「互補決定區」(CDR)之胺基酸殘基,後者具有最高的序列可變性及/或與抗原識別相關。例示性高變環出現在胺基酸殘基26-32 (L1)、50-52 (L2)、91-96 (L3)、26-32 (H1)、53-55 (H2)及96-101 (H3)處。(Chothia及Lesk,J. Mol. Biol.
,
第196卷, 第901-917頁 1987)。例示性CDR (CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3)出現在L1之胺基酸殘基24-34、L2之胺基酸殘基50-56、L3之胺基酸殘基89-97、H1之胺基酸殘基31-35B、H2之胺基酸殘基50-65及H3之胺基酸殘基95-102處(Kabat等人, Sequences of Proteins of Immunological Interest, 第5版, 美國公共衛生署, 美國國家衛生研究院, Bethesda, Md. 1991)。除VH
中之CDR1之外,CDR一般包含形成高變環之胺基酸殘基。CDR亦包含「特異性決定殘基」或「SDR」,其為接觸抗原之殘基。SDR含於簡稱為-CDR或a-CDR之CDR區域內。例示性a-CDR (a-CDR-L1、a-CDR-L2、a-CDR-L3、a-CDR-H1、a-CDR-H2及a-CDR-H3)出現於L1之胺基酸殘基31-34、L2之胺基酸殘基50-55、L3之胺基酸殘基89-96、H1之胺基酸殘基31-35B、H2之胺基酸殘基50-58及H3之胺基酸殘基95-102處。(參見Almagro及Fransson,Front. Biosci.
, 第13卷, 第1619-1633頁, 2008)。除非另外指明,否則在本文中,根據Kabat等人, 同上對可變域中之HVR殘基及其他殘基(例如FR殘基)進行編號。
如本文所用,術語「免疫結合物」係結合於一或多個異源分子之抗體,該(等)分子包括(但不限於)細胞毒性劑。
如本文所用,術語「個體(individual/subject)」係指哺乳動物。哺乳動物包括(但不限於)家養動物(例如牛、羊、貓、狗及馬)、靈長類動物(例如人類及非人類靈長類動物,諸如猴)、兔及嚙齒動物(例如小鼠及大鼠)。在某些實施例中,該個體(individual/subject)為人類。
如本文所用,術語「抑制細胞生長或增生」意謂使細胞之生長或增生降低至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或100%,且包括誘發細胞死亡。
如本文所用,術語「分離之」抗體係已自其天然環境之組分分離之抗體。在一些實施例中,將抗體純化至如藉由例如電泳(例如SDS-PAGE、等電聚焦(IEF)、毛細管電泳)或層析(例如離子交換或逆相高效液相層析(HPLC))測定純度大於95%或99%。關於抗體純度評估方法之綜述,參見例如Flatman et al.,J. Chromatogr. B
, 第848卷, 第79-87頁, 2007。
如本文所用,術語「分離之」核酸係指已自其天然環境之組分分離之核酸分子。經分離核酸包括通常含有核酸分子之細胞中所含有的核酸分子,但該核酸分子存在於染色體外或在不同於其天然染色體位置之染色體位置處。
如本文所用,術語「編碼抗-Ror2抗體之分離之核酸」係指編碼抗體重鏈及輕鏈(或其片段)之一或多個核酸分子,包括單一載體或各別載體中之此類核酸分子,及存在於宿主細胞中之一或多個位置處之此類核酸分子。
如本文所用,如例如應用於受體信號傳導活性之術語「非配體依賴型」係指信號傳導活性與配體之存在無關。具有非配體依賴型激酶活性之受體不一定妨礙配體與該受體結合以使得激酶活性額外活化。
如本文所用,術語「癌轉移」係指所有涉及Ror2之過程,其支持癌細胞自原發腫瘤擴散,穿入淋巴管及/或血管,經由血流循環及遠距離聚焦(癌轉移)於體內其他地方之正常組織中生長。詳言之,其係指腫瘤細胞之細胞事件,諸如增生、遷移、固著非依賴性、逃避細胞凋亡或分泌血管生成因子,該等細胞事件係癌轉移之基礎且藉由Ror2之非催化或催化活性(較佳包括Ror2磷酸化及/或Ror2介導之信號轉導)刺激或介導。
如本文所用,術語「微環境」意謂組織或身體之任何部分或區域,其與組織之其他區域或身體之其他區域具有持久或暫時物理或化學差異。如本文所用,對於腫瘤,術語「腫瘤微環境」係指腫瘤存在之環境,其係腫瘤內之非細胞區域及剛好處於腫瘤組織外之區域,但並不涉及癌細胞本身之細胞內隔室。腫瘤及腫瘤微環境密切相關且不斷相互作用。腫瘤可改變其微環境,且微環境可影響腫瘤生長及擴散方式。通常,腫瘤微環境具有5.8至7.0範圍內,更通常6.0至6.8範圍內,6.2至6.8範圍內之低pH值。另一方面,正常生理pH值在7.2至7.8之範圍內。亦已知腫瘤微環境具有與血漿相比較低濃度之葡萄糖及其他養分,但具有較高濃度之乳酸。此外,腫瘤微環境可具有高於正常生理溫度0.3℃至1℃之溫度。腫瘤微環境已論述於Gillies等人, 「MRI of the Tumor Microenvironment」,Journal of Magnetic Resonance Imaging
, 第16卷, 第430-450頁, 2002中,其以全文引用的方式併入本文中。術語「非腫瘤微環境」係指除腫瘤外之部位的微環境。
如本文所用,術語「單株抗體」係指自基本上均質之抗體的群體獲得之抗體,亦即,除可能之變異抗體(例如含有天然產生之突變或在產生單株抗體製劑期間出現之突變的抗體,此類變異體一般以少量存在)以外,構成該群體之個別抗體相同及/或結合相同抗原決定基。相比於通常包括針對不同決定子(抗原決定基)之不同抗體的多株抗體製劑,單株抗體製劑之各單株抗體係針對抗原上之單一決定子。因此,修飾語「單株」指示抗體之特性為獲自實質上均質的抗體群體,且不應理解為需要藉由任何特定方法產生該抗體。舉例而言,根據本發明使用之單株抗體可藉由多種技術製得,包括(但不限於)融合瘤方法、重組DNA方法、噬菌體呈現方法及利用含有所有或部分人類免疫球蛋白基因座之轉殖基因動物的方法,此類方法及其他製備單株抗體之例示性方法在本文中加以描述。
如本文所用,術語「裸抗體」係指不結合於異源部分(例如細胞毒性部分)或放射性標記之抗體。裸抗體可以醫藥調配物形式存在。
如本文所用,術語「原生抗體」係指具有不同結構之天然產生之免疫球蛋白分子。舉例而言,原生IgG抗體為約150,000道爾頓(dalton)之雜四聚體醣蛋白,由二硫鍵鍵結之兩條相同輕鏈及兩條相同重鏈構成。自N端至C端,各重鏈具有可變區(VH
),亦稱為可變重域或重鏈可變域,接著為三個恆定域(CH1、CH2及CH3)。類似地,自N端至C端,各輕鏈具有可變區(VL
),亦稱為可變輕域或輕鏈可變域,接著為恆定輕鏈(CL
)域。抗體之輕鏈可根據其恆定域之胺基酸序列歸屬於兩種類型中之一種,稱為κ及λ。
如本文所用,術語「藥品說明書」用於指通常包括於治療性產品之商業包裝中之說明書,其含有關於與使用此類治療性產品有關之適應症、用法、劑量、投藥、組合療法、禁忌症及/或警告的資訊。
如本文所用,術語相對於參考多肽序列之「胺基酸序列一致性百分比(%)」定義為在比對序列且引入間隔(必要時)以獲得最大序列一致性百分比之後,候選序列中與參考多肽序列中之胺基酸殘基一致之胺基酸殘基的百分比,且不將任何保守取代視為序列一致性之一部分。出於測定胺基酸序列一致性百分比之目的之比對可以在此項技術內的各種方式實現,例如使用公開可獲得的電腦軟體,如BLAST、BLAST -2、ALIGN或Megalign (DNASTAR)軟體。熟習此項技術者可測定用於比對序列之適當參數,包括在所比較序列之全長內達成最大比對所需的任何算法。然而,出於本文之目的,使用序列比較電腦程式ALIGN-2產生胺基酸序列一致性%值。ALIGN-2序列比較電腦程式由Genentech, Inc.創作,且原始程式碼已在美國版權局(U.S. Copyright Office), Washington D.C., 20559申請用戶文檔,其在此註冊在美國版權註冊第TXU510087號下。ALIGN-2程式可公開購自Genentech, Inc., South San Francisco, California或可自原始程式碼編譯。ALIGN-2程序經編寫可用於UNIX操作系統,包括數位UNIX V4.0D。所有序列比較參數由ALIGN-2程序設定且不變化。
在採用ALIGN-2進行胺基酸序列比較之情形下,既定胺基酸序列A與既定胺基酸序列B之胺基酸序列一致性% (或者,其可表述為既定胺基酸序列A與既定胺基酸序列B具有或包含一定胺基酸序列一致性%)如下計算:
100乘以分數X/Y
其中X係在A與B之比對程式中藉由序列比對程程式ALIGN-2評為一致匹配之胺基酸殘基之數目,且其中Y係B中之胺基酸殘基之總數目。應瞭解,在胺基酸序列A之長度與胺基酸序列B之長度不相等之情況下,A相對於B之胺基酸序列一致性%與B相對於A之胺基酸序列一致性%將不相等。除非另外特定陳述,否則本文所使用之所有胺基酸序列一致性%值如緊接前述段落中所描述使用ALIGN-2電腦程式獲得。
如本文所用,術語「醫藥調配物」係指所呈形式允許其中所含活性成分之生物活性有效發揮,且不含對調配物將投與之個體具有不可接受毒性之其他組分的製劑。
如本文所用,術語「醫藥學上可接受之載劑」係指醫藥調配物中除活性成分外之對個體無毒之成分。醫藥學上可接受之載劑包括(但不限於)緩衝劑、賦形劑、穩定劑或防腐劑。
本文所用,術語「純化」及「分離」係指根據本發明之抗體或核苷酸序列,所指分子在實質上不存在其他同型生物大分子下存在。如本文所用,術語「純化」較佳意謂存在至少75重量%、更佳至少85重量%、又更佳至少95重量%、且最佳至少98重量%之同型生物大分子。編碼特定多肽之「分離」之核酸分子係指實質上不含其他不編碼多肽之核酸分子的核酸分子;然而,該分子可包括並不有害地影響組合物之基本特徵的一些額外鹼基或部分。
如本文所用,術語「重組抗體」係指由包含編碼抗體之核酸的重組宿主細胞表示之抗體(例如嵌合、人類化或人類抗體或其抗原結合片段)。製造重組抗體之「宿主細胞」之實例包括:(1)哺乳動物細胞,例如中國倉鼠卵巢(CHO)、COS、骨髓瘤細胞(包括Y0及NS0細胞)、幼倉鼠腎(BHK)、海拉及Vero細胞;(2)昆蟲細胞,例如sf9、sf21及Tn5;(3)植物細胞,例如屬於菸草屬之植物(例如菸草(Nicotiana tabacum
));(4)酵母細胞,例如屬於酵母屬(例如釀酒酵母(Saccharomyces cerevisiae
))或曲黴菌屬(例如黑麯黴(Aspergillus niger
))之該等酵母細胞;(5)細菌細胞,例如埃希氏桿菌細胞(Escherichia.coli
cell)或枯草桿菌細胞(Bacillus subtilis
cell)等。
如本文所用,術語「Ror2」係指受體酪胺酸激酶樣孤兒受體2,其係以Genbank寄存編號AAI30523所示之具有活體外蛋白質激酶活性之預測943胺基酸蛋白質。許多譜系限制性受體酪胺酸激酶首先鑑別為與已知受體同源之『孤兒』,且隨後僅用以鑑別其未知生長因子。DeChiara等人(2000)鑑別如圖1中所示由Ror2編碼之一個此類孤兒。
術語本發明抗體之「治療有效量」意謂足以按適用於任何醫學治療之合理的效益/風險比率治療該等癌症的抗體之量。然而,應瞭解,本發明之抗體及組合物之每日總用量將由主治醫師在正確醫學判斷範疇內來決定。對於任何特定患者之特定治療有效劑量水準將視多種因素而定,該等因素包括經治療之病症及該病症之嚴重度;所採用之特定活抗體之活性;所採用之特定組合物;患者之年齡、體重、總體健康狀況、性別及飲食;所採用之投藥時間、投藥途徑及特定抗體之排泄速率;治療持續時間;與所採用之特定抗體組合或同時使用之藥物;及醫學領域中熟知之類似因素。舉例而言,此項技術中熟知以低於實現所需治療效應所要之水準開始給與組合物,且逐漸增加劑量直至實現所需效應。
如本文所用,術語「單鏈Fv」(「scFv」)係共價連接之VH
::VL
雜二聚體,其通常由基因融合體表現,該基因融合體包括由肽編碼連接子連接之VH
及VL
編碼基因。「dsFv」為藉由二硫鍵穩定之VH
::VL
雜二聚體。二價及多價抗體片段可藉由單價scFvs之結合自發形成,或可藉由肽連接子(諸如二價sc(Fv)2
)偶聯單價scFvs來產生。
如本文所用,術語「治療(treatment/treat/treating)係指試圖改變所治療之個體之天然病程的臨床干預,且可為實現預防或在臨床病理學病程期間進行。所需治療效應包括(但不限於)預防疾病出現或復發、緩解症狀、減輕疾病之任何直接或間接病理性後果、預防癌轉移、降低疾病進展速率、改善(amelioration)或緩和疾病病況及緩解或改良(improved)預後。在一些實施例中,本發明之抗體用於延遲疾病顯現或減慢疾病進展。
如本文所用,術語「腫瘤」係指所有瘤性細胞生長及增生(無論惡性或良性),及所有癌前及癌細胞以及組織。術語「癌症」、「癌性」、「細胞增生性病症」、「增生性病症」及「腫瘤」不為互相排斥的,如本文中所提及。
如本文所用,術語「可變區」或「可變域」係指涉及抗體與抗原結合之抗體重鏈或輕鏈域。原生抗體之重鏈及輕鏈(分別為VH
及VL
)可變域一般具有類似的結構,其中各結構域均包含四個保守構架區(FR)及三個高變區(HVR)。(參見例如Kindt等人, Kuby Immunology, 第6版, W.H. Freeman and Co., 第91頁 (2007)。) 單一VH
或VL
域可足以賦予抗原結合特異性。此外,結合特定抗原之抗體可使用來自結合抗原之抗體的VH
域或VL
域分別篩檢互補VL
域或VH
域之庫來分離。參見例如Portolano等人,J. Immunol.
, 第150卷, 第880-887頁, 1993;Clarkson等人.,Nature
, 第352卷, 第624-628頁, 1991。
如本文所用,術語「載體」係指能夠傳播至其所連接之另一個核酸的核酸分子。該術語包括呈自我複製核酸結構之載體以及併入已引入其之宿主細胞之基因組中的載體。某些載體能夠導引可操作地連接其之核酸的表現。此類載體在本文中稱為「表現載體」。
為達成說明之目的,藉由參考各種例示性實施例來描述本發明之原理。儘管在本文中具體描述本發明之某些實施例,但一般熟習此項技術者將易於認識到相同原理同樣適用於且可用於其他系統及方法中。在詳細解釋本發明所揭示之實施例之前,應瞭解,本發明不將其應用限制於所顯示之任何特定實施例之細節。另外,本文所用之術語係出於描述而非限制之目的。此外,儘管參考以一定次序呈現於本文中之步驟來描述某些方法,但在許多情況下,可按可為熟習此項技術者理解之任何次序進行此等步驟;新穎方法因此不限於本文中所揭示之特定步驟排列。
必須注意,除非上下文另外明確說明,否則如本文及隨附申請專利範圍所用之單數形式「一(a/an)」及「該(the)」包括複數個參考物。此外,術語「一(a或an)」、「一或多個(種)」及「至少一個(種)」在本文中可互換使用。術語「包含」、「包括」、「具有」及「建構自」亦可互換使用。
除非另外指明,否則在說明書及申請專利範圍中所用之表示成分量、特性(諸如分子量、百分比、比率、反應條件等)之所有數目理解為在所有情況下均由術語「約」修飾,不論是否存在術語「約」。因此,除非有相反指示,否則說明書及申請專利範圍中所闡述之數值參數為近似值,其可視本發明設法獲得之所需特性而變化。最低限度地,且不試圖將均等論(doctrine of equivalents)之應用限於申請專利範圍之範疇,各數值參數至少應根據所報導之有效數位之數目且藉由應用一般捨入技術來解釋。儘管闡述本發明之廣泛範疇的數值範圍及參數為近似值,但儘可能精確地報告特定實例中所闡述之數值。然而,任何數值均固有地含有因其對應測試量測值中發現之標準差所必然引起的某些誤差。
應瞭解,本文揭示之各組分、化合物、取代基或參數解釋為單獨或與本文揭示之組分、化合物、取代基或參數中之各者及所有其他者中之一或多者組合使用而進行揭示。
亦應理解,本文揭示之各組分、化合物、取代基或參數之各量/值或量/值之範圍解釋為亦與針對本文揭示之任何其他組分、化合物、取代基或參數所揭示之各量/值或量/值之範圍組合進行揭示,且因此,出於本說明書之目的,兩種或更多種本文揭示之組分、化合物、取代基或參數量/值或量/值之範圍之任何組合亦彼此組合進行揭示。
進一步應瞭解,本文揭示之各範圍之各下限解釋為與本文針對相同組分、化合物、取代基或參數所揭示之各範圍之各上限之組合進行揭示。因此,兩個範圍之揭示內容解釋為藉由組合各範圍之各下限與各範圍之各上限所衍生之四個範圍之揭示內容。因此,三個範圍之揭示內容解釋為藉由組合各範圍之各下限與各範圍之各上限所衍生之九個範圍之揭示內容等。此外,描述或實例中所揭示之組分、化合物、取代基或參數之特定量/值解釋為範圍之下限或上限之揭示內容,且因此可與範圍之任何其他下限或上限或本申請案中其他地方所揭示之相同組分、化合物、取代基或參數之特定量/值組合,以形成該組分、化合物、取代基或參數之範圍。A. 抗 -Ror2 抗體
在一個態樣中,本發明提供一種特異性結合於人類Ror2蛋白質之分離之重鏈可變區多肽。該重鏈可變區多肽包含三個互補決定區H1、H2及H3序列,其中:
H1序列係GYTX1
TEX2
X3
X4
H (SEQ ID NO:1)或GYSITTGX29
YWN (SEQ ID NO:4);
H2序列係X5
X6
X7
X8
NNGGTGYNQKFKG (SEQ ID NO:2)或YITYDGSX30
NYNPSLKN (SEQ ID NO:5);且
H3序列係X9
X10
X11
SX12
YX13
YX14
X15
SYFX16
X17
X18
(SEQ ID NO:3)或CSX31
X32
X33
X34
VX35
X36
X37
LDX38
(SEQ ID NO:6);
其中
X1
係F或E,
X2
係Y或D,
X3
係T或C,
X4
係M或D或E或Y,
X5
係G或S,
X6
係I或E,
X7
係N或C或L或V,
X8
係T或D或E,
X9
係A或I或M或S或T,
X10
係R或Q或H,
X11
係G或E,
X12
係L或F,
X13
係S或G,
X14
係G或D,
X15
係N或E,
X16
係D或L,
X17
係Y或C或T,
X18
係W或L,
X29
係Y或E或R或T,
X30
係K或S,
X31
係R或G或H或W或Y,
X32
係F或C或N或Q,
X33
係E或S,
X34
係G或E或F或H或M或Q或S,
X35
係W或A或I或P或Q或T或V,
X36
係Y或G或N或Q,
X37
係G或S或T,且
X38
係Y或I。
重鏈可變區之比對示於圖2A-2B中。
在另一態樣中,本發明提供一種特異性結合於人類Ror2蛋白質之分離之輕鏈可變區多肽。輕鏈可變區多肽包含三個互補決定區L1、L2及L3序列,其中:
L1序列係SATSSX19
X20
X21
MX22
(SEQ ID NO:7)或RASESVDRYGNSX39
IH (SEQ ID NO:10);
L2序列係X23
TSNLAS (SEQ ID NO:8)或X40
TYX41
LES (SEQ ID NO:11);且
L3序列係QX24
X25
SX26
YPFX27
X28
(SEQ ID NO:9)或QQX42
NX43
DPX44
TX45
(SEQ ID NO:12);
其中
X19
係V或E,
X20
係S或D,
X21
係Y或C或D,
X22
係H或G或L,
X23
係G或C或H或P,
X24
係Q或E,
X25
係R或H,
X26
係S或D或G或I或Q或V,
X27
係T或D,
X28
係F或D或E,
X39
係F或S或T,
X40
係R或C或D或E或W,
X41
係N或D,
X42
係T或D或I或P,
X43
係E或V,
X44
係W或T,且
X45
係F或S。
輕鏈可變區之比對示於圖3A-3B中。
本發明經由美國專利第8,709,755號中所揭示之方法鑑別分別來自親本抗體之重鏈可變區及輕鏈可變區的此等分離之重鏈可變區及分離之輕鏈可變區。此產生條件性活性抗體之方法以引用的方式併入本文中。
編碼親本抗體之重鏈可變區及輕鏈可變區之DNA使用全面位置演化(CPE)演化以產生突變型抗體文庫,將親本抗體之重鏈可變區及輕鏈可變區中之各位置一次一個隨機分組。與親本抗體之重鏈可變區或輕鏈可變區相比(圖2A-2B及3A-3B),文庫中之各突變型重鏈/輕鏈僅具有一個單一點突變。藉由ELISA篩檢在pH 6.0下與人類Ror2之選擇性結合親和力優於pH 7.4下之文庫中之突變體。選擇在pH 6.0下之活性比pH 7.4下更高之突變型重鏈/輕鏈可變區作為條件性活性抗體之重鏈/輕鏈可變區,其中單一點突變示於各重鏈及輕鏈可變區中(表1及2,圖2A-2B及3A-3B)。表 1 . 條件性活性抗 -Ror2 抗體輕鏈可變區
表 2 . 條件性活性抗 -Ror2 抗體重鏈可變區
在另一態樣中,本發明包括如圖2A-2B中所呈現之重鏈可變區及圖3A-3B中所呈現之輕鏈可變區。重鏈可變區之胺基酸序列係SEQ ID NO:18-26。輕鏈可變區之胺基酸序列係SEQ ID NO:13-17及27。此等重鏈可變區及輕鏈可變區可特異性結合於人類Ror2。已發現包含此等重鏈可變區及輕鏈可變區中之一者的抗體或抗體片段與Ror2在腫瘤微環境中之pH下比在非腫瘤微環境中之pH下具有更高的結合親和力。舉例而言,抗體及抗體片段與Ror2在pH 6.0下比在pH 7.4下具有更高的結合親和力。
抗-Ror2抗體或抗體片段與腫瘤中之Ror2具有相比於其與正常組織中之Ror2的結合親和力更高的結合親和力。與此項技術中已知之單株抗-Ror2抗體相比,此等抗-Ror2抗體或抗體片段具有更長的半衰期及降低的副作用以及類似的功效。此等特徵允許使用較高劑量之待遞送至患者之此等抗-Ror2抗體或抗體片段,因此係更有效的治療選項。
儘管本發明包括圖2A-2B、3A-3B中所呈現且具有胺基酸序列SEQ ID NO:13-24之重鏈可變區及輕鏈可變區,但本發明亦提供可特異性結合於人類Ror2之其變異體。為得到此等變異體,重鏈可變區(H1-H3)之互補決定區(CDR)及輕鏈可變區(L1-L3)之互補決定區應保持完整。然而,互補決定區外之重鏈可變區及輕鏈可變區之胺基酸序列可根據如本申請案中所論述之取代、插入及缺失之原理突變。
在得到此等變異體時,藉由如本文所述之方法引導。重鏈可變區及輕鏈可變區之變異體可藉由將適當修飾引入至編碼重鏈可變區及輕鏈可變區之核苷酸序列中或藉由肽合成來製備。此類修飾包括例如自重鏈可變區及輕鏈可變區之胺基酸序列缺失殘基、及/或向其中插入殘基、及/或取代其內之殘基。可進行缺失、插入及取代之任何組合以獲得本發明之抗體或抗體片段,其限制條件為其具有所需特徵,例如與人類Ror2抗原結合及/或條件性活性。取代、插入及缺失變異體
在某些實施例中,提供具有一或多個胺基酸替代之抗體或抗體片段變異體。用於取代型突變誘發之相關位點包括CDR及構架區(FR)。保守取代展示於標題為「保守取代」之表3中。更多實質性變化以標題「例示性取代」提供於表3中,且參考胺基酸側鏈類別在下文進一步描述。胺基酸取代可引入至相關抗體或抗體片段中且針對所需活性,例如保留/改良之抗原結合或降低之免疫原性來篩檢產物。表 3 : 胺基酸取代
胺基酸可根據共有側鏈特性進行分組:
(1)疏水性:正白胺酸、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)鹼性:His、Lys、Arg;
(5)影響鏈取向之殘基:Gly、Pro;
(6)芳族:Trp、Tyr、Phe。
非保守取代將必然伴有將此等類別中之一者之成員換成另一個類別。
一種類型之取代型變異體涉及取代親本抗體(例如人類化或人類抗體)之一或多個高變區殘基。一般而言,選用於進一步研究之所得變異體相對於親本抗體將在某些生物特性方面具有修飾(例如改善)(例如親和力提高、免疫原性降低)及/或將實質上保留親本抗體之某些生物特性。一種例示性取代型變異體係親和力成熟抗體,其可例如使用基於噬菌體呈現之親和力成熟技術(諸如本文所描述之技術)便利地產生。簡言之,使一或多個CDR殘基突變且在噬菌體上呈現變異抗體且針對特定生物活性(例如結合親和力)篩檢。
變化(例如取代)可於CDR中進行在以例如改良抗體親和力。此類改變可於CDR「熱點」(亦即在體細胞成熟過程中經歷高頻率突變之由密碼子編碼之殘基)(參見例如Chowdhury,Methods Mol. Biol.
, 第207卷, 第179-196頁, 2008)及/或SDR (a-CDR)中進行,測試所得變異體VH或VL之結合親和力。藉由構築及自二級文庫再選擇進行親和力成熟已描述例如於Hoogenboom等人,Methods in Molecular Biology
, 第178卷, 第1-37頁, 2001)。在親和力成熟之一些實施例中,藉由多種方法(例如易錯PCR、鏈改組或寡核苷酸引導之突變誘發)中之任一種將多樣性引入經選擇用於成熟之可變基因中。隨後產生二級文庫。接著篩檢該庫以鑑別具有所需親和力之任何抗體變異體。引入多樣性之另一方法包括CDR定向途徑,其中將若干CDR殘基(例如一次4-6個殘基)隨機分組。涉及抗原結合之CDR殘基可例如使用丙胺酸掃描突變誘發或模型化來專門鑑別。特定言之,通常靶向CDR-H3及CDR-L3。
在某些實施例中,一或多個HVR內可存在取代、插入或缺失,只要此類改變不實質上降低抗體或抗體片段結合抗原之能力即可。舉例而言,不實質上降低結合親和力之保守改變(例如如本文所提供之保守取代)可於CDR中進行。此類改變可在CDR「熱點」或SDR之外。在上文所提供之變異體VH
及VL
序列的某些實施例中,各CDR未改變或含有不超過一個、兩個或三個胺基酸取代。
一種適用於鑑別突變誘發可靶向之抗體之殘基或區的方法稱為「丙胺酸掃描突變誘發」,如Cunningham及Wells,Science
, 第244卷, 第 1081-1085頁, 1989所描述。在此方法中,鑑別出一個殘基或一組標靶殘基(例如帶電荷殘基,諸如arg、asp、his、lys及glu)且將其置換為中性或帶負電胺基酸(例如丙胺酸或聚丙胺酸)以確定抗體或抗體片段與抗原之相互作用是否受到影響。可在對初始取代顯示功能敏感性之胺基酸位置處引入其他取代。或者或另外,抗原-抗體複合物之晶體結構用於鑑別抗體或抗體片段與抗原之間的接觸點。此類接觸殘基及鄰近殘基可作為取代候選物之標靶或排除在取代候選物之外。可篩檢變異體以判定其是否含有所需特性。
胺基酸序列插入包括在一個殘基至含有一百個或更多個殘基之多肽長度範圍內的胺基及/或羧基端融合物,以及具有單個或多個胺基酸殘基之序列內插入。末端插入之實例包括具有N末端甲硫胺醯基殘基之抗體。抗體之其他插入變異體包括抗體之N端或C端與酶(例如對於ADEPT而言)或延長抗體之血清半衰期之多肽的融合物。
涵蓋本文所述之抗體之胺基酸序列修飾。舉例而言,可能需要改良抗體之結合親和力及/或其他生物特性。已知當人類化抗體藉由僅將源自非人類動物之抗體之VH
及VL
中之CDR簡單移植於人類抗體之VH
及VL
之FR中來製造時,抗原結合活性相比於源自非人類動物之原始抗體降低。認為非人類抗體之VH
及VL
之若干胺基酸殘基不僅在CDR中而且在FR中與抗原結合活性直接或間接相關。因此,用源自人類抗體之VH
及VL
之FR的不同胺基酸殘基取代此等胺基酸殘基將降低結合活性。為解決該問題,在移植人類CDR之抗體中,試圖鑑別人類抗體之VH
及VL
之FR的胺基酸序列中之與結合於抗體直接相關,或與CDR之胺基酸殘基相互作用,或維持抗體之三維結構及與結合於抗原直接相關之胺基酸殘基。降低之抗原結合活性可藉由用源自非人類動物之原始抗體的胺基酸殘基替換鑑別之胺基酸而增加。
修飾及變化可於本發明抗體之結構中及於編碼其之DNA序列中進行,且仍可獲得具有所需特徵之編碼抗體之功能分子。
在胺基序列中進行該等變化時,可考慮胺基酸之親水指數。親水胺基酸指數在賦予蛋白質相互作用生物功能上之重要性一般在此項技術中有所瞭解。公認胺基酸之相對親水特性促成所得蛋白質之二級結構,該二級結構接著界定蛋白質與其他分子(例如酵素、受質、受體、DNA、抗體、抗原及其類似物)之相互作用。各胺基酸已基於其疏水性及電荷特徵指定親水指數,此等親水指數係:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8);苯丙胺酸(+2.8);半胱胺酸/胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸(-3.5);麩醯胺酸 (-3.5);天冬胺酸(-3.5);天冬醯胺(-3.5);離胺酸(-3.9);及精胺酸(-4.5)。
本發明之另一目的亦涵蓋本發明抗體之功能保守性變異體。
「功能保守性變異體」係在不改變多肽之總體構形及功能下蛋白質或酶中之既定胺基酸殘基已變化的該等變異體,包括(但不限於)用具有類似特性酸(諸如極性、氫鍵結可能性、酸性、鹼性、疏水性、芳族及其類似物)之胺基酸替換胺基。除指示為保守胺基酸外之胺基酸的蛋白質可不同,以使得如根據比對方案藉由諸如叢集法(Cluster Method)所測定,具有類似功能之兩種蛋白質之間的蛋白質或胺基酸序列相似性百分比可變化且可為例如70%至99%,其中相似性係基於MEGALIGN演算法。「功能保守性變異體」亦包括如藉由BLAST或FASTA演算法所測定具有至少60%、較佳至少75%、更佳至少85%、又較佳至少90%且甚至更佳至少95%胺基酸一致性且與其進行比較之原生或母體蛋白質具有相同或實質上類似特性或功能之多肽。
兩個胺基酸序列在相對於較短序列之全長,胺基酸之大於80%、較佳大於85%、較佳大於90%一致,或大於約90%、較佳大於95%類似(功能相同)時係「實質上同源的」或「實質上類似的」。較佳地,類似或同源序列藉由使用例如GCG (遺傳學電腦組(Genetics Computer Group),Program Manual for the GCG Package, 第7版, Madison, Wis.)堆積程式或諸如BLAST、FASTA等序列比較演算法中之任一者比對來鑑別。
舉例而言,某些胺基酸可經蛋白質結構中之其他胺基酸取代而不會顯著損失活性。因為蛋白質之相互作用能力及性質界定蛋白質生物功能活性,所以某些胺基酸取代可在蛋白質序列中,且當然在其DNA編碼序列中進行,同時卻獲得具有類似特性之蛋白質。因此,預期可在本發明之抗體或抗體片段之序列或編碼該抗體或抗體片段之相應DNA序列中進行各種變化而不會顯著損失其生物活性。
此項技術中已知某些胺基酸可經具有類似親水指數或評分之其他胺基酸取代,而仍產生具有類似生物活性之蛋白質,亦即仍獲得生物學功能上等效之蛋白質。
如上文所概述,胺基酸取代因此一般係基於胺基酸側鏈取代基之相對相似性,例如其疏水性、親水性、電荷、大小及其類似形式。考慮多種前述特徵之例示性取代為熟習此項技術者所熟知,且包括:精胺酸及離胺酸;麩胺酸及天冬胺酸;絲胺酸及蘇胺酸;麩醯胺酸及天冬醯胺;以及纈胺酸、白胺酸及異白胺酸。糖基化變異體
在某些實施例中,對本文所提供之抗體進行改變以增加或降低抗體糖基化之程度。向抗體中添加糖基化位點或使抗體缺失糖基化位點可藉由改變胺基酸序列以便產生或移除一或多個糖基化位點來便利地實現。
在抗體包含Fc區之情況下,可改變連接於其上之碳水化合物。由哺乳動物細胞產生之原生抗體通常包含分支鏈雙觸角寡醣,其一般藉由N鍵連接至Fc區之CH2域的Asn297。參見例如Wright等人,TIBTECH
, 第15卷, 第26-32頁, 1997。寡醣可包括各種碳水化合物,例如甘露糖、N-乙醯基葡糖胺(GlcNAc)、半乳糖及唾液酸,以及連接至雙觸寡醣結構之「主幹」中之GlcNAc的海藻糖。在一些實施例中,可對本發明抗體中之寡醣進行修飾以便形成具有某些改良特性之抗體變異體。
在一個實施例中,提供具有缺乏連接(直接或間接)於Fc區之海藻糖之碳水化合物結構的抗體變異體。舉例而言,此類抗體中之海藻糖含量可為1%至80%、1%至65%、5%至65%,或20%至40%。岩藻糖之量藉由計算相對於如藉由MALDI-TOF質譜分析量測之附接至Asn 297之所有醣結構(例如複合、雜交及高甘露糖結構)的總和,糖鏈內Asn297處之海藻糖之平均量來確定,如例如WO 2008/077546中所描述。Asn297係指位於Fc區中之約位置297 (Fc區殘基之Eu編號)處之天冬醯胺殘基;然而,由於抗體中之微小序列變化,Asn297亦可位於位置297上游或下游約±3個胺基酸處,即在位置294與300之間。此類海藻糖基化變異體可具有改良之ADCC功能。參見例如美國專利公開案第US 2003/0157108號 (Presta, L.);第US 2004/0093621號(Kyowa Hakko Kogyo Co., Ltd)。關於「去海藻糖基化」或「缺乏海藻糖」抗體變異體之公開案之實例包括:US 2003/0157108;WO 2000/61739;WO 2001/29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO2005/053742;WO2002/031140;Okazaki等人,J. Mol. Biol.
, 第336卷, 第1239-1249頁, 2004;Yamane-Ohnuki等人,Biotech. Bioeng.
, 第87卷, 第614-622頁, 2004。能夠產生去海藻糖基化抗體之細胞株之實例包括缺乏蛋白質海藻糖基化之Lec13CHO細胞(Ripka等人,Arch. Biochem. Biophys.
, 第249卷, 第533-545頁, 1986;美國專利申請案第US 2003/0157108 A號;及WO 2004/056312 A1,尤其實例11)及基因剔除細胞株,諸如α-1,6-海藻糖基轉移酶基因(FUT8)基因剔除CHO細胞(參見例如Yamane-Ohnuki等人,Biotech. Bioeng.
, 第87卷, 第614-622頁, 2004;Kanda, Y.等人,Biotechnol. Bioeng.,
第94卷, 第680-688頁, 2006;及WO2003/085107)。
抗體變異體進一步具備平分寡醣,例如其中附接於抗體之Fc區的雙觸角寡醣藉由GlcNAc平分。此類抗體變異體可具有減少之海藻糖基化及/或改良之ADCC功能。此類抗體變異體之實例描述於例如WO 2003/011878;美國專利第6,602,684號;及US 2005/0123546中。亦提供寡醣中之至少一個半乳糖殘基連接於Fc區之抗體變異體。此類抗體變異體可具有改良之CDC功能。此類抗體變異體描述於例如WO 1997/30087;WO 1998/58964;及WO 1999/22764中。Fc 區變異體
在某些實施例中,可將一或多個胺基酸修飾引入至本文所提供之抗體的Fc區中,從而產生Fc區變異體。Fc區變異體可包含人類Fc區序列(例如人類IgG1、IgG2、IgG3或IgG4 Fc區),其在一或多個胺基酸位置包含胺基酸修飾(例如取代)。
在某些實施例中,本發明涵蓋具有一些而非所有效應功能之抗體變異體,由此使得該抗體成為對於其中活體內抗體半衰期至關重要,而某些效應功能(諸如ADCC)為不必要或有害的應用合乎需要之候選物。可進行活體外及/或活體內細胞毒性分析以證實CDC及/或ADCC活性之降低/消除。舉例而言,可進行Fc受體(FcR)結合分析以確保抗體缺乏FcγR結合(因此可能缺乏ADCC活性),但保留FcRn結合能力。用於介導ADCC之初級細胞NK細胞僅表現FcγRIII,而單核細胞表現FcγRI、FcγRII及FcγRIII。FcR在造血細胞上之表現概述於Ravetch及Kinet,Annu. Rev. Immunol
. 第9卷, 第457-492頁, 1991之第464頁之表3中。評估相關分子之ADCC活性之活體外分析之非限制性實例描述於美國專利第5,500,362號(亦參見例如Hellstrom等人,Proc. Nat'l Acad. Sci. USA
, 第83卷, 第7059-7063頁, 1986)及Hellstrom, I等人,Proc. Nat'l Acad. Sci. USA
, 第82卷, 第1499-1502頁, 1985;美國專利第5,821,337號(亦參見Bruggemann等人,J. Exp. Med.
, 第166卷, 第1351-1361頁, 1987)中。或者,可採用非放射性分析方法(參見例如用於流式細胞測量術之ACTI™非放射性細胞毒性分析(CellTechnology, Inc. Mountain View, Calif.;及CytoTox 96®非放射性細胞毒性分析(Promega, Madison, Wis.)。適用於此類分析之效應細胞包括周邊血液單核細胞(PBMC)及天然殺手(NK)細胞。或者或另外,可例如在動物模型中活體內評估所關注之分子之ADCC活性,諸如Clynes等人,Proc. Nat'l Acad. Sci. USA
, 第95卷, 第652-656頁, 1998中所揭示。亦可進行C1q結合分析以確認抗體不能結合C1q且因此缺乏CDC活性。參見例如WO 2006/029879及WO 2005/100402中之C1q及C3c結合ELISA。為評估補體活化,可進行CDC分析(參見例如Gazzano-Santoro等人,J. Immunol. Methods
, 第202卷, 第163-171頁, 1996;Cragg, M. S.等人,Blood
, 第101卷, 第1045-1052頁, 2003;及Cragg, M. S及M. J. Glennie,Blood
, 第103卷, 第2738-2743頁, 2004)。亦可使用此項技術中已知之方法測定FcRn結合及活體內清除率/半衰期(參見例如Petkova, S. B.等人,Int'l. Immunol.
, 第18卷, 第1759-1769頁, 2006)。
效應功能降低之抗體包括取代Fc區殘基238、265、269、270、297、327及329中之一或多者的該等抗體(美國專利第6,737,056號)。此類Fc突變體包括在胺基酸位置265、269、270、297及327中之兩者或更多者處具有取代之Fc突變體,包括殘基265及297取代為丙胺酸之所謂的「DANA」Fc突變體(美國專利第7,332,581號)。
描述具有改良或降低之與FcR之結合的某些抗體變異體。(參見例如美國專利第6,737,056號;WO 2004/056312及Shields等人,J. Biol. Chem.
, 第9卷, 第6591-6604頁, 2001)。
在某些實施例中,抗體變異體包含具有一或多個改良ADCC之胺基酸取代,例如Fc區之位置298、333及/或334處(殘基之EU編號)之取代的Fc區。
在一些實施例中,在Fc區中進行改變,其致使C1q結合及/或補體依賴性細胞毒性(CDC)改變(亦即改良或降低),例如如美國專利第6,194,551號、WO 99/51642及Idusogie等人,J. Immunol.
, 第164卷, 第4178-4184頁, 2000中所述。
半衰期增加且與導致母本IgGs傳遞至胎兒之新生兒Fc受體(FcRn)之結合改良之抗體(Guyer等人,J. Immunol.
, 第117卷, 第587-593頁, 1976及Kim等人,J. Immunol.
, 第24卷, 第249頁, 1994)描述於US2005/0014934中。該等抗體包含具有一或多個取代之Fc區,該等取代改良Fc區與FcRn之結合。此類Fc變異體包括在以下Fc區殘基中之一或多者處具有取代之該等變異體:238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434,例如Fc區殘基434之取代(美國專利第7,371,826號)。關於Fc區變異體之其他實例,亦參見Duncan及Winter,Nature
, 第322卷, 第738-740頁, 1988;美國專利第5,648,260號;美國專利第5,624,821號;及WO 94/29351。半胱胺酸工程改造之抗體變異體
在某些實施例中,可能需要產生半胱胺酸工程改造之抗體,例如「thioMAb」,其中抗體之一或多個殘基經半胱胺酸殘基取代。在特定實施例中,經取代之殘基存在於抗體之可達位點處。藉由用半胱胺酸取代該等殘基,反應性硫醇基從而定位於抗體之可達位點處且可用於使抗體與其他部分(諸如藥物部分或連接子-藥物部分)結合以產生如本文中進一步描述之免疫結合物。在某些實施例中,以下殘基中之任一或多者可經半胱胺酸取代:輕鏈之V205 (Kabat編號);重鏈之A118 (EU編號);及重鏈Fc區之5400 (EU編號)。可如例如美國專利第7,521,541號中所述產生半胱胺酸工程改造之抗體。抗體衍生物
在某些實施例中,本文中所提供之抗體或抗體片段可經進一步修飾以含有此項技術中已知且可易於獲得之額外非蛋白質部分。適用於抗體或抗體片段衍生作用之部分包括(但不限於)水溶性聚合物。水溶性聚合物之非限制性實例包括(但不限於)聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纖維素、葡聚糖、聚乙烯醇、聚乙烯吡咯啶酮、聚-1,3-二氧雜環戊烷、聚-1,3,6-三噁烷、乙烯/順丁烯二酸酐共聚物、聚胺基酸(均聚物或無規共聚物)及葡聚糖或聚(n-乙烯吡咯啶酮)聚乙二醇、丙二醇均聚物、聚氧化丙烯/氧化乙烯共聚物、聚氧乙烯多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛因其於水中之穩定性而可具有製造優勢。聚合物可具有任何分子量,且可為分支鏈或未分支的。連接於抗體或抗體片段之聚合物數目可為變化的,及若連接超過一個聚合物,則其可為相同或不同分子。一般而言,用於衍生作用之聚合物之數目及/或類型可基於包括(但不限於)待改良抗體之特殊特性或功能,抗體衍生物是否將用於指定條件下之療法等考慮因素來確定。
在另一實施例中,提供抗抗體或抗體片段與可藉由暴露於輻射選擇性地加熱之非蛋白質部分之結合物。在一個實施例中,非蛋白質部分係碳奈米管(Kam等人,Proc. Natl. Acad. Sci. USA
, 第102卷, 第11600-11605頁, 2005)。輻射可具有任何波長,且包括(但不限於)不損害普通細胞但將非蛋白質部分加熱至殺死抗體-非蛋白質部分近側之細胞之溫度的波長。
在另一態樣中,本發明提供一種抗-Ror2抗體或抗體片段,其包括分離之重鏈可變區多肽或分離之輕鏈可變區多肽。分離之重鏈可變區多肽包含SEQ ID NO:1-6下之H1、H2及H3區。分離之輕鏈可變區多肽包含SEQ ID NO:7-12下之L1、L2及L3區。
本發明之抗-Ror2抗體或抗體片段與Ror2在腫瘤微環境中之條件下具有比在非腫瘤微環境中之條件下更高的結合親和力。在一個實施例中,腫瘤微環境中之條件及非腫瘤微環境中之條件均為pH值。因此,本發明之抗-Ror2抗體或抗體片段可在pH約5.8-6.8下選擇性結合於Ror2,但在正常生理環境中所遇到之pH約7.2-7.8下與Ror2將具有更低結合親和力。如實例1所示,抗-Ror2抗體或抗體片段與Ror2在pH 6.0下比在pH 7.4下具有更高的結合親和力。
在某些實施例中,本發明之抗-Ror2抗體或抗體片段在腫瘤微環境中之條件下與Ror2的解離常數(Kd)係約≦1 μM、≦100 nM、≦10 nM、≦1 nM、≦0.1 nM、≦0.01 nM或≦0.001 nM (例如10− 8
M或更小,或10− 8
M至10− 13
M,或10− 9
M至10− 13
M)。在一個實施例中,抗體或抗體片段與Ror2在腫瘤微環境中之條件值下之Kd與非腫瘤微環境中相同條件之不同值下之Kd的比率係至少約1.5:1、至少約2:1、至少約3:1、至少約4:1、至少約5:1、至少約6:1、至少約7:1、至少約8:1、至少約9:1、至少約10:1、至少約20:1、至少約30:1、至少約50:1、至少約70:1或至少約100:1。
在一個實施例中,Kd藉由放射性標記之抗原結合分析(RIA)量測,該分析利用相關抗體之Fab型式及其抗原使用以下分析進行。Fab對抗原之溶液結合親和力藉由在一系列滴定未標記抗原存在下用最低濃度之(125
I)標記抗原平衡Fab,接著用經抗-Fab抗體塗佈之盤捕捉結合抗原來量測(參見例如Chen等人,J. Mol. Biol.
293:865-881 (1999))。為確立分析條件,將MICROTITER®多孔盤(Thermo Scientific)用於50 mM碳酸鈉(pH 9.6)中之5 µg/ml捕獲抗Fab抗體(Cappel Labs)塗佈隔夜,且隨後在室溫(約23℃)下用於PBS中之2% (w/v)牛血清白蛋白阻斷兩小時至五小時。在無吸附劑板(Nunc號269620)中,將100 pM或26 pM [125
I]抗原與相關Fab之連續稀釋液混合(例如與抗-VEGF抗體Fab-12之評估一致,Presta等人, 57:4593-4599 (1997))。接著培育相關Fab隔夜;然而,培育可持續較長時間段(例如約65小時)以保證達到平衡。此後,在室溫下將混合物轉移至捕捉盤中以用於培育(例如持續一小時)。接著移除溶液且用含於PBS中之0.1%聚山梨醇酯20 (TWEEN-20®)洗滌盤八次。當盤乾燥時,添加150 µl/孔之閃爍體(MicroScint-20™;Packard),且在TOPCOUNT™ γ計數器(Packard)上對盤計數十分鐘。選擇提供小於或等於20%最大結合之各Fab的濃度用於競爭性結合分析。
根據另一實施例,Kd使用表面電漿子共振分析在25℃下使用具有約10個反應單位(RU)之固定抗原CM5晶片之BIACORE®-2000或BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.)來量測。簡言之,根據供應商之說明書,用N-乙基-N'-(3-二甲胺基丙基)-碳化二亞胺鹽酸鹽(EDC)及N-羥基丁二醯亞胺(NHS)活化羧甲基化聚葡聚糖生物感測器晶片(CM5, BIACORE, Inc.)。用10 mM乙酸鈉(pH 4.8)將抗原稀釋至5 μg/ml (約0.2 μM),隨後以5 μl/min之流動速率注射以獲得大約10個反應單位(RU)之偶合蛋白質。在注射抗原後,注射1 M乙醇胺以阻斷未反應之基團。關於動力學量測,在25℃下以大約25 µl/min之流動速率注射Fab於含0.05%聚山梨醇酯20 (TWEEN-20TM
)界面活性劑之PBS (PBST)中之兩倍連續稀釋液(0.78 nM至500 nM)。使用簡單的一比一朗格繆爾結合模型(one-to-one Langmuir binding model) (BIACORE®評估軟體,3.2版)、藉由同時擬合締合及解離感測圖譜來計算締合速率(kon
)及解離速率(koff
)。平衡解離常數(Kd)按比率koff
/kon
來計算。參見例如Chen等人,J. Mol. Biol.
293:865-881 (1999)。若藉由上述表面電漿子共振分析得到之締合速率超過106
M-1
s-1
,則締合速率可藉由使用螢光淬滅技術來測定,該技術量測PBS (pH 7.2)中之20 nM抗抗原抗體(Fab形式)在25℃下、在濃度遞增之抗原存在下之螢光發射強度(激發= 295 nm;發射= 340 nm,16 nm帶通)的增加或減少,如用光譜儀(諸如具有攪拌式比色管之止流裝備型分光光度計(Aviv Instruments)或8000系列SLM-AMINCO™分光光度計(ThermoSpectronic))所量測。
本發明之抗-Ror2抗體可為嵌合抗體、人類化抗體或人類抗體。在一個實施例中,採用抗-Ror2抗體片段,例如Fv、Fab、Fab'、Fab'-SH、scFv、雙功能抗體、三功能抗體、四功能抗體或F(ab')2
片段及由抗體片段形成之多特異性抗體。在另一實施例中,抗體係全長抗體,例如完整IgG抗體或如本文所定義之其他抗體類別或同型。關於某些抗體片段之綜述,參見Hudson等人,Nat. Med.
第9卷, 第129-134頁, 2003。關於scFv片段之綜述,參見例如Pluckthün, The Pharmacology of Monoclonal Antibodies, v第113卷, Rosenburg及Moore編, (Springer-Verlag, New York), 第269-315頁 (1994);亦參見WO 93/16185;及美國專利第5,571,894號及第5,587,458號。關於包含救助受體結合抗原決定基殘基及具有延長之活體內半衰期之Fab及F(ab')2
片段的論述,參見美國專利第5,869,046號。
本發明之雙功能抗體可為二價的或雙特異性的。關於雙功能抗體之實例,參見例如EP 404,097;WO 1993/01161;Hudson等人, Nat. Med
. 9:129-134 (2003);及Hollinger等人,Proc. Natl. Acad. Sci. USA
, 第90卷, 第6444-6448頁, 1993。三功能抗體及四功能抗體之實例亦描述於Hudson等人,Nat. Med.
, 第9卷, 第129-134頁, 2003中。
在一些實施例中,本發明包含有包含抗體之所有或一部分重鏈可變域或所有或一部分輕鏈可變域之單域抗體片段。在某些實施例中,單域抗體為人類單域抗體(Domantis, Inc., Waltham, Mass.;參見例如美國專利第6,248,516 B1號)。
抗體片段可藉由各種技術製得,包括(但不限於)完整抗體之蛋白水解消化以及藉由重組宿主細胞(例如大腸桿菌(E. coli
)或噬菌體)產生,如本文所描述。
在一些實施例中,本發明之抗-Ror2抗體可為嵌合抗體。某些嵌合抗體描述於例如美國專利第4,816,567號;及Morrison等人,Proc. Natl. Acad. Sci. USA
, 第81卷, 第6851-6855頁, 1984)中。在一個實例中,嵌合抗體包含非人類可變區(例如來源於小鼠、大鼠、倉鼠、兔或非人類靈長類動物(諸如猴)之可變區)及人類恆定區。在另一實例中,嵌合抗體係「類別轉換」抗體,其中相對於親本抗體之類別或子類,該抗體之類別或子類已有所變化。嵌合抗體包括其抗原結合片段。
在某些實施例中,本發明之嵌合抗體係人類化抗體。通常,對非人類抗體進行人類化以降低對人類之免疫原性,同時保留親本非人類抗體之特異性及親和力。一般而言,人類化抗體包含一或多個可變域,其中CDR(或其部分)源自非人類抗體,且FR (或其部分)源自人類抗體序列。人類化抗體可視情況亦包含人類恆定區之至少一部分。在一些實施例中,人類化抗體中之一些FR殘基經來自非人類抗體(例如CDR殘基所來源之抗體)之對應殘基取代,以例如恢復或改良抗體特異性或親和力。
人類化抗體及其製造方法綜述於例如Almagro及Fransson,Front. Biosci
.,
第13卷, 第1619-1633頁, 2008且進一步描述於例如Riechmann等人,Nature
, 第332卷, 第323-329頁, 1988;Queen等人,Proc. Nat'l Acad. Sci. USA
, 第86卷, 第10029-10033頁, 1989;美國專利第5,821,337號、第7,527,791號、第6,982,321號及第7,087,409號;Kashmiri等人,Methods
, 第36卷, 第25-34頁, 2005 (描述SDR (a-CDR)移植);Padlan,Mol. Immunol.
, 第28卷, 第489-498頁, 1991 (描述「表面重塑」);Dall'Acqua等人,Methods
, 第36卷, 第43-60頁, 2005 (描述「FR改組」);及Osbourn等人,Methods
, 第36卷, 第61-68頁, 2005及Klimka等人,Br. J. Cancer,
第83卷, 第252-260頁, 2000 (描述FR改組之「引導選擇」方法)。
可用於人類化之人類構架區包括(但不限於):使用「最佳擬合」方法選擇之構架區(參見例如Sims等人,J. Immunol.
, 第151卷, 第2296頁, 1993);源自具有特定子群輕鏈或重鏈可變區之人類抗體的共同序列之構架區(參見例如Carter等人,Proc. Natl. Acad. Sci. USA,
第89卷, 第4285頁, 1992;及Presta等人,J. Immunol.,
第151卷, 第2623頁, 1993);人類成熟(體細胞突變)構架區或人類生殖系構架區(參見例如Almagro及Fransson,Front. Biosci
., 第13卷, 第1619-1633頁, 2008);及源自篩檢FR文庫之構架區(參見例如Baca等人,J. Biol. Chem.
, 第272卷, 第10678-10684頁, 1997及Rosok等人,J. Biol. Chem.
, 第271卷, 第22611-22618頁, 1996)。
在一些實施例中,本發明之抗-Ror2抗體係多特異性抗體,例如雙特異性抗體。多特異性抗體係對至少兩個不同位點具有結合特異性之單株抗體。在某些實施例中,結合特異性中之一者係針對Ror2且另一者係針對另一抗原。在某些實施例中,雙特異性抗體可結合於Ror2之兩個不同抗原決定基上。雙特異性抗體亦可用於使細胞毒性劑定位至表現Ror2之細胞。雙特異性抗體可以全長抗體或抗體片段形式製備。
用於製備多特異性抗體之技術包括(但不限於)具有不同特異性之兩個免疫球蛋白重鏈-輕鏈對之重組共表現(參見Milstein及Cuello,Nature
,
第305卷, 第537-540頁, 1983),WO 93/08829及Traunecker等人,EMBO J.
第10卷, 第3655-3659頁, 1991)及「杵臼」工程改造(參見例如美國專利第5,731,168號)。亦可藉由以下來製備多特異性抗體:工程改造靜電轉向作用以製備抗體Fc-雜二聚體分子(WO 2009/089004A1);使兩個或更多個抗體或片段交聯(參見例如美國專利第4,676,980號及Brennan等人,Science
, 第229卷, 第81-83頁, 1985);使用白胺酸拉鏈以產生雙特異性抗體(參見例如Kostelny等人,J. Immunol
., 第148卷, 第1547-1553頁, 1992);使用「雙功能抗體」技術用於製造雙特異性抗體片段(參見例如Hollinger等人,Proc. Natl. Acad. Sci. USA,
第90卷, 第6444-6448頁, 1993);以及使用單鏈Fv (scFv)二聚體(參見例如Gruber等人,J. Immunol.
, 第152卷, 第5368-5374頁, 1994);以及製備三特異性抗體,如例如Tutt等人,J. Immunol.
, 第147卷, 第60-69頁, 1991中所描述。
本文中亦包括具有三個或更多個功能性抗原結合位點之工程改造之抗體,包括「章魚抗體(Octopus antibodies)」(參見例如US 2006/0025576A1)。
抗體或抗體片段亦可包括「雙作用Fab」或「DAF」,其包含結合於Ror2以及另一不同抗原(諸如Ror1,參見例如US 2008/0069820)之抗原結合位點。
本發明之抗-Ror2抗體或抗體片段可使用重組方法及組合物製造,其詳細描述於US 2016/0017040中。
本發明之抗-Ror2抗體或抗體片段之物理/化學特性及/或生物活性可藉由此項技術中已知之各種分析來測試及量測。一些此等分析描述於美國專利第8,853,369號中。B. 免疫結合物
在另一態樣中,本發明亦提供免疫結合物,其包含結合於一或多種細胞毒性劑之抗-Ror2抗體或抗體片段,該等細胞毒性劑係諸如化學治療劑或藥物、生長抑制劑、毒素(例如細菌、真菌、植物或動物來源之蛋白質毒素、酶活性毒素或其片段)或放射性同位素。
在一個實施例中,免疫結合物係抗體或抗體片段結合於一或多種藥物之抗體-藥物結合物(ADC),該等藥物包括(但不限於)類美登素(參見美國專利第5,208,020號、第5,416,064號及歐洲專利EP 0 425 235 B1);奧瑞他汀(auristatin),諸如單甲基奧瑞他汀藥物部分DE及DF (MMAE及MMAF)(參見美國專利第5,635,483號及第5,780,588號及第7,498,298號);海兔毒素;卡奇黴素或其衍生物(參見美國專利第5,712,374號、第5,714,586號、第5,739,116號、第5,767,285號、第5,770,701號、第5,770,710號、第5,773,001號及第5,877,296號;Hinman等人,Cancer Res.
, 第53卷, 第3336-3342頁, 1993;及Lode等人,Cancer Res.
, 第58卷, 第2925-2928頁, 1998);蒽環黴素(anthracycline),諸如柔紅黴素或小紅莓(參見Kratz等人,Current Med. Chem.
, 第13卷, 第477-523頁, 2006;Jeffrey等人,Bioorganic
&Med. Chem.
Letters, 第16卷, 第358-362頁, 2006;Torgov等人,Bioconj. Chem.
, 第16卷, 第717-721頁, 2005;Nagy等人,Proc. Natl. Acad. Sci. USA
, 第97卷, 第829-834頁, 2000;Dubowchik等人,Bioorg
. &Med. Chem. Letters
, 第12卷, 第1529-1532頁, 2002;King等人,J. Med. Chem.
, 第45卷, 第4336-4343頁, 2002;及美國專利第6,630,579號);甲胺喋呤;長春地辛;紫杉烷,諸如多烯紫杉醇、太平洋紫杉醇、拉洛他賽(larotaxel)、替司他賽(tesetaxel)及奧他賽(ortataxel);單端孢黴烯族毒素;及CC1065。
在另一實施例中,免疫結合物包含結合於酶促活性毒素或其片段之如本文所述之抗體或抗體片段,該酶促活性毒素或其片段包括(但不限於)白喉A鏈(diphtheria A chain)、白喉毒素(diphtheria toxin)之非結合活性片段、外毒素A鏈(來自綠膿桿菌(Pseudomonas aeruginosa
))、蓖麻毒素A鏈(ricin A chain)、相思子毒素A鏈(abrin A chain)、莫迪素A鏈(modeccin A chain)、α-帚麴菌素(alpha-sarcin)、油桐(Aleurites fordii
)蛋白、康乃馨(dianthin)蛋白、洋商陸(Phytolaca americana
)蛋白(PAPI、PAPII及PAP-S)、苦瓜(momordica charantia
)抑制劑、麻瘋樹毒蛋白(curcin)、巴豆毒素(crotin)、肥皂草(sapaonaria officinalis)抑制劑、白樹素(gelonin)、有絲分裂素(mitogellin)、侷限麴菌素(restrictocin)、酚黴素(phenomycin)、伊諾黴素(enomycin)及單端孢黴烯族毒素。
在另一實施例中,免疫結合物包含結合於放射性原子之如本文所述之抗體或抗體片段以形成放射性結合物。多種放射性同位素可用於製造放射性結合物。實例包括At211
、I131
、I125
、Y90
、Re186
、Re188
、Sm153
、Bi212
、P32
、Pb212
及Lu之放射性同位素。當放射性結合物用於偵測時,其可包含用於閃爍攝影研究之放射性原子,例如tc99m或I123;或用於核磁共振(NMR)成像(亦稱為磁共振成像,MRI)之自旋標記,諸如碘-123、碘-131、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。
可使用多種雙官能蛋白質偶合劑製得抗體/抗體片段與細胞毒性劑之結合物,該等雙官能蛋白質偶合劑係諸如N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、丁二醯亞胺基-4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸酯(SMCC)、亞胺基硫雜環戊烷(IT)、醯亞胺酯之雙官能衍生物(諸如二亞胺代己二酸二甲酯鹽酸鹽)、活性酯(諸如辛二酸二丁二醯亞胺酯)、醛(諸如戊二醛)、雙疊氮基化合物(諸如雙(對疊氮基苯甲醯基)己二胺)、雙重氮衍生物(諸如雙(對重氮苯甲醯基)-乙二胺)、二異氰酸酯(諸如甲苯2,6-二異氰酸酯)及雙活性氟化合物(諸如1,5-二氟-2,4-二硝基苯)。舉例而言,蓖麻毒素免疫毒素可如Vitetta等人,Science
, 第238卷, 第1098-頁, 1987中所述製備。碳14標記之1-異硫氰基苯甲基-3-甲基二伸乙三胺五乙酸(MX-DTPA)係用於使放射性核苷酸結合於抗體之例示性螯合劑。參見WO94/11026。連接子可為有助於細胞毒性藥物在細胞中釋放之「可裂解連接體」。舉例而言,可使用酸不穩定連接子、肽酶敏感性連接子、光不穩連接子、二甲基連接子或含二硫鍵之連接子(Chari等人,Cancer Res.
, 第52卷, 第127-131頁, 1992;美國專利第5,208,020號)。
本文之免疫結合物明確涵蓋(但不限於)用交聯試劑製備之結合物,該等交聯試劑包括(但不限於) BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SLAB、SMCC、SMPB、SMPH、磺酸基-EMCS、磺酸基-GMBS、磺酸基-KMUS、磺酸基-MBS、磺酸基-SIAB、磺酸基-SMCC及磺酸基-SMPB,及SVSB (丁二醯亞胺基-(4-乙烯基碸)苯甲酸酯),該等交聯試劑可購得(例如購自Pierce Biotechnology, Inc., Rockford, Ill., U.S.A)。
ADC之例示性實施例包含抗體或抗體片段(Ab),其靶向腫瘤細胞、藥物部分(D)及使Ab與D連接之連接子部分(L)。在一些實施例中,抗體經由一或多個胺基酸殘基,諸如離胺酸及/或半胱胺酸連接於連接子部分(L)。
例示性ADC具有式I:Ab-(L-D)p
,其中p係1至約20。在一些實施例中,可結合於抗體之藥物部分的數目由游離半胱胺酸殘基之數目限制。在一些實施例中,游離半胱胺酸殘基藉由本文所述之方法引入至抗體胺基酸序列中。例示性式I之ADC包括(但不限於)具有1、2、3或4個經工程改造之半胱胺酸胺基酸的抗體(Lyon等人,Methods in Enzym.
, 第502卷, 第123-138頁, 2012)。在一些實施例中,一或多個游離半胱胺酸殘基不使用工程改造已存在於抗體中,在此情況下現有游離半胱胺酸殘基可用於將抗體結合於藥物。在一些實施例中,抗體在抗體結合前暴露於還原條件以產生一或多個游離半胱胺酸殘基。a) 例示性連接子
「連接子」(L)係可用以將一或多個諸如藥物部分(D)之部分連接於抗體或抗體片段(Ab)以形成諸如式I之ADC的免疫結合物之雙功能或多功能部分。在一些實施例中,ADC可使用具有用於共價連接於藥物及抗體之反應性官能基的連接子製備。舉例而言,在一些實施例中,抗體或抗體片段(Ab)之半胱胺酸硫醇可與連接子或藥物-連接子中間物之反應性官能基形成鍵以製得ADC。
在一個態樣中,連接子具有能夠與抗體上存在之游離半胱胺酸反應形成共價鍵的官能基。非限制性例示性此類反應性官能基包括順丁烯二醯亞胺、鹵乙醯胺、α-鹵乙醯基、活化酯(諸如丁二醯亞胺酯、4-硝基苯基酯、五氟苯基酯、四氟苯基酯)、酸酐、酸氯化物、磺醯氯、異氰酸酯及異硫氰酸酯。參見例如Klussman等人,Bioconjugate Chemistry
, 第15卷, 第765-773頁, 2004中之第766頁之結合方法。
在一些實施例中,連接子具有能夠與抗體上存在之親電子基反應的官能基。例示性此類親電子基包括(但不限於)醛及酮羰基。在一些實施例中,連接子之反應性官能基之雜原子可與抗體上之親電子基反應且形成與抗體單元之共價鍵。非限制性例示性此類反應性官能基包括(但不限於)醯肼、肟、胺基、肼、硫半卡巴肼、肼羧酸酯及芳基醯肼。
連接子可包含一或多種連接子組分。例示性連接子組分包括6-順丁烯二醯亞胺基己醯基(「MC」)、順丁烯二醯亞胺基丙醯基(「MP」)、纈胺酸-瓜胺酸(「val-cit」或「vc」)、丙胺酸-苯丙胺酸(「ala-phe」)、對胺基苯甲氧基羰基(「PAB」)、N-丁二醯亞胺基4-(2-吡啶基硫基)戊酸酯(「SPP」)及4-(N-順丁烯二醯亞胺基甲基)環己烷-1羧酸酯(「MCC」)。各種連接子組分為此項技術中已知,其中一些在下文中加以描述。
連接子可為「可裂解連接子」,其促進藥物之釋放。非限制性例示性可裂解連接子包括酸不穩定連接子(例如包含腙)、蛋白酶敏感性(例如肽酶敏感性)連接子、光不穩定連接子或含二硫鍵之連接子(Chari等人,Cancer Research
, 第52卷, 第127-131頁, 1992;美國專利第5,208,020號)。
在某些實施例中,連接子具有以下式II:-Aa
-Ww
-Yy
-,其中A係「延伸子單元」,且a係0至1之整數;W係「胺基酸單元」,且w係0至12之整數;Y係「間隔子單元」,且y係0、1或2。包含式II之連接子的ADC具有式I(A):Ab-(Aa
-Ww
-Yy
-D)p
,其中Ab、D及p如上文式I所定義。此類連接子之例示性實施例描述於美國專利第7,498,298號中。
在一些實施例中,連接子組分包含將抗體連接於另一連接子組分或藥物部分之「延伸子單元」(A)。非限制性例示性延伸子單元示於下文中(其中波浪線指示共價連接於抗體、藥物或額外連接子組分之位點):
在一些實施例中,連接子組分包含「胺基酸單元」(W)。在一些此類實施例中,胺基酸單元允許連接子藉由蛋白酶裂解,由此促進藥物在暴露於胞內蛋白酶,諸如溶酶體酶時自免疫結合物釋放(Doronina等人,Nat. Biotechnol.
, 第21卷, 第778-784頁, 2003)。例示性胺基酸單元包括(但不限於)二肽、三肽、四肽及五肽。例示性二肽包括(但不限於)纈胺酸-瓜胺酸(vc或val-cit)、丙胺酸-苯丙胺酸(af或ala-phe);苯丙胺酸-離胺酸(fk或phe-lys);苯丙胺酸-高離胺酸(phe-高lys);及N-甲基-纈胺酸-瓜胺酸(Me-val-cit)。例示性三肽包括(但不限於)甘胺酸-纈胺酸-瓜胺酸(gly-val-cit)及甘胺酸-甘胺酸-甘胺酸(gly-gly-gly)。胺基酸單元可包含產生天然及/或微量胺基酸及/或非天然產生之胺基酸類似物的胺基酸殘基,諸如瓜胺酸。胺基酸單元可經設計及最佳化以用於藉由例如腫瘤相關蛋白酶、組織蛋白酶B、C及D或纖維蛋白溶酶蛋白酶之特定酶進行酶促裂解。
通常,肽型連接子可藉由在兩個或更多個胺基酸及/或肽片段之間形成肽鍵來製備。此類肽鍵可例如根據液相合成方法來製備(例如E. Schroder及K. Lübke (1965) 「The Peptides」, 第1卷, 第76-136頁, Academic Press)。
在一些實施例中,連接子組分包含使抗體直接或經由延伸子單元及/或胺基酸單元連接於藥物部分之「間隔子單元」(Y)。間隔子單元可為「自分解型」或「非自分解型」。「非自分解型」間隔子單元係在ADC裂解時部分或所有間隔子單元仍然結合於藥物部分之間隔子單元。非自分解型間隔子單元之實例包括(但不限於)甘胺酸間隔子單元及甘胺酸-甘胺酸間隔子單元。在一些實施例中,含有甘胺酸-甘胺酸間隔子單元之ADC藉由腫瘤細胞相關蛋白酶進行酶裂解,使得甘胺酸-甘胺酸-藥物部分自ADC之其餘部分釋放。在一些此類實施例中,甘胺酸-甘胺酸-藥物部分在腫瘤細胞中經歷水解步驟,因此自藥物部分裂解甘胺酸-甘胺酸間隔子單元。
「自分解型」間隔子單元允許釋放藥物部分。在某些實施例中,連接子之間隔子單元包含對胺基苯甲基單元。在一些此類實施例中,對胺基苯甲基醇經由醯胺鍵連接於胺基酸單元,且在苯甲醇與藥物之間製成胺基甲酸酯、甲基胺基甲酸酯或碳酸酯(Hamann等人,Expert Opin. Ther. Patents
, 第15卷, 第1087-1103頁, 2005)。在一些實施例中,間隔子單元包含對胺基苯甲氧基羰基(PAB)。在一些實施例中,包含自分解型連接子之ADC具有以下結構:
其中Q係-C1
-C8
烷基、-O-(C1
-C8
烷基)、-鹵素、-硝基或-氰基;m係0至4範圍內之整數;X可為一或多個額外間隔基單元或可不存在;且p在1至約20之範圍內。在一些實施例中,p在1至10、1至7、1至5、或1至4之範圍內。非限制性例示性X間隔基單元包括:;
其中R1
及R2
獨立地選自H及C1-
C6
烷基。在一些實施例中,R1
及R2
各係-CH3
。
自分解型間隔基之其他實例包括(但不限於)電子上類似於PAB基團之芳族化合物,諸如2-胺基咪唑-5-甲醇衍生物(美國專利第7,375,078號;Hay等人,Bioorg. Med. Chem. Lett.
, 第9卷, 第2237-頁, 1999)及鄰或對胺基苯甲基乙醛。在一些實施例中,可使用在醯胺鍵水解時經歷環化之間隔子,諸如經取代及未經取代之4-胺基丁酸醯胺(Rodrigues等人,Chemistry Biology
, 第2卷, 第223-頁, 1995),經適當取代之雙環[2.2.1]及雙環[2.2.2]環系統(Storm等人,J. Amer. Chem. Soc.
, 第94卷, 第5815-頁, 1972)及2-胺基苯基丙酸醯胺(Amsberry等人,J. Org. Chem.
, 第55卷, 第5867頁, 1990)。藥物與甘胺酸殘基之α-碳的連接為適用於ADC之自分解型間隔子的另一實例(Kingsbury等人,J. Med. Chem
., 第27卷, 第1447頁, 1984)。
在一些實施例中,連接子L可為用於經由分支之多官能連接子部分使超過一個藥物部分共價連接於抗體的樹突類型連接子(Sun等人,Bioorganic
&Medicinal Chemistry Letters
, 第12卷, 第2213-2215頁, 2002;Sun等人,Bioorganic
&Medicinal Chemistry
, 第11卷, 第1761-1768頁, 2003)。樹突狀連接子可增加藥物與抗體之莫耳比,亦即負載,其與ADC效能有關。因此,在抗體僅僅載有一個反應性半胱胺酸硫醇基情況下,可經由樹突狀連接子附接多個藥物部分。
下文展示在式I之ADC之情況下的非限制性例示性連接子:
其中R1
及R2
獨立地選自H及C1-
C6
烷基。在一些實施例中,R1
及R2
各係-CH3
。;
其中n係0至12。在一些實施例中,n係2至10。在一些實施例中,n係4至8。
其他非限制性例示性ADC包括如下結構:
Y係:;
各R獨立地係H或C1
-C6
烷基;且n係1至12。
在一些實施例中,連接子經調節溶解性及/或反應性之基團取代。作為一非限制性實例,諸如磺酸根(-SO3 -
)或銨之帶電取代基可增加連接子試劑之水溶性且促進連接子試劑與抗體及/或藥物部分之偶合反應,或促進Ab-L (抗體-連接子中間物)與D或D-L (藥物-連接子中間物)與Ab之偶合反應,視用於製備ADC之合成途徑而定。在一些實施例中,使連接子之一部分偶合至抗體且使連接子之一部分偶合至藥物,且接著使Ab-(連接子部分)a
偶合至藥物-(連接子部分)b
以形成式I之ADC。
本發明之化合物明確涵蓋(但不限於)用以下連接子試劑製備之ADC:雙-順丁烯二醯亞胺基-三氧基乙二醇(BMPEO)、N-(β-順丁烯二醯亞胺基丙基氧基)-N-羥基丁二醯亞胺酯(BMPS)、N-(ε-順丁烯二醯亞胺基己醯基氧基)丁二醯亞胺酯(EMCS)、N-[γ-順丁烯二醯亞胺基丁醯基氧基]丁二醯亞胺酯(GMBS)、1,6-己烷-雙-乙烯基碸(HBVS)、丁二醯亞胺基4-(N-順丁烯二醯亞胺基甲基)環己烷-1-羧基-(6-醯胺基己酸酯) (LC-SMCC)、間順丁烯二醯亞胺基苯甲醯基-N-羥基丁二醯亞胺酯(MBS)、4-(4-N-順丁烯二醯亞胺基苯基)丁酸醯肼(MPBH)、丁二醯亞胺基3-(溴乙醯胺基)丙酸酯(SBAP)、丁二醯亞胺基碘乙酸酯(SIA)、丁二醯亞胺基(4-碘乙醯基)胺基苯甲酸酯(SIAB)、N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、N-丁二醯亞胺基-4-(2-吡啶基硫基)戊酸酯(SPP)、丁二醯亞胺基4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸酯(SMCC)、丁二醯亞胺基4-(p-順丁烯二醯亞胺基苯基)丁酸酯(SMPB)、丁二醯亞胺基6-[(β-順丁烯二醯亞胺基丙醯胺基)己酸酯] (SMPH)、亞胺基硫雜環戊烷(IT)、磺酸基-EMCS、磺酸基-GMBS、磺酸基-KMUS、磺酸基-MBS、磺酸基-SIAB、磺酸基-SMCC及磺酸基-SMPB以及丁二醯亞胺基-(4-乙烯基碸)苯甲酸酯(SVSB),且包括雙-順丁烯二醯亞胺試劑:二硫基雙順丁烯二醯亞胺基乙烷(DTME)、1,4-雙順丁烯二醯亞胺基丁烷(BMB)、1,4-雙順丁烯二醯亞胺基-2,3-二羥基丁烷(BMDB)、雙順丁烯二醯亞胺基己烷(BMH)、雙順丁烯二醯亞胺基乙烷(BMOE)、BM(PEG)2
(下文展示)及BM(PEG)3
(下文展示);醯亞胺酯之雙官能衍生物(諸如二亞胺代己二酸二甲酯鹽酸鹽)、活性酯(諸如辛二酸二丁二醯亞胺酯)、醛(諸如戊二醛)、雙疊氮基化合物(諸如雙(對疊氮基苯甲醯基)己二胺)、雙重氮衍生物(諸如雙(對重氮苯甲醯基)-乙二胺)、二異氰酸酯(諸如甲苯2,6-二異氰酸酯)及雙活性氟化合物(諸如1,5-二氟-2,4-二硝基苯)。在一些實施例中,雙順丁烯二醯亞胺試劑允許抗體中半胱胺酸之硫醇基連接於含硫醇之藥物部分、連接子或連接子-藥物中間物。與硫醇基反應之其他官能基包括(但不限於)碘乙醯胺、溴乙醯胺、乙烯基吡啶、二硫鍵、吡啶基二硫鍵、異氰酸酯及異硫氰酸酯。
某些適用之連接子試劑可獲自各種商業來源,諸如Pierce Biotechnology, Inc. (Rockford, Ill)、Molecular Biosciences Inc.(Boulder, Colo),或根據此項技術中描述之程序合成;例如Toki等人,J. Org. Chem.
, 第67卷, 第1866-1872頁, 2002;Dubowchik,等人,Tetrahedron Letters,
第38卷, 第5257-60頁, 1997;Walker,J. Org. Chem.
, 第60卷, 第5352-5355頁, 1995;Frisch等人,Bioconjugate Chem.
, 第7卷, 第180-186頁, 1995;美國專利第6,214,345號;WO 02/088172;US2003130189;US2003096743;WO 03/026577;WO 03/043583;及WO 04/032828。
碳14標記之1-異硫氰基苯甲基-3-甲基二伸乙三胺五乙酸(MX-DTPA)係用於使放射性核苷酸結合於抗體之例示性螯合劑。參見例如WO94/11026。b) 例示性藥物部分 1) 美登素及類美登素
在一些實施例中,免疫結合物包含結合於一或多個類美登素分子之抗體。類美登素係美登素之衍生物,且係藉由抑制微管蛋白聚合起作用之有絲分裂抑制劑。美登素首次自東非灌木齒葉美登木(Maytenus serrata)分離而得(美國專利第3,896,111號)。隨後,發現某些微生物亦產生類美登素,諸如美登醇及C-3美登醇酯(美國專利第4,151,042號)。合成類美登素揭示於例如美國專利第4,137,230號;第4,248,870號;第4,256,746號;第4,260,608號;第4,265,814號;第4,294,757號;第4,307,016號;第4,308,268號;第4,308,269號;第4,309,428號;第4,313,946號;第4,315,929號;第4,317,821號;第4,322,348號;第4,331,598號;第4,361,650號;第4,364,866號;第4,424,219號;第4,450,254號;第4,362,663號;及第4,371,533號中。
類美登素藥物部分係抗體-藥物結合物中具有吸引力之藥物部分,因為其:(i)藉由醱酵或醱酵產物之化學改質或衍生而相對易於製備;(ii)易由適用於經由非二硫鍵連接子結合於抗體的官能基衍生;(iii)在血漿中穩定;及(iv)有效針對多種腫瘤細胞株。
適用作類美登素藥物部分之某些類美登素為此項技術中所已知,且可自天然來源根據已知方法分離,或使用基因工程改造技術產生(參見例如Yu等人,PNAS
, 第99卷, 第7968-7973頁, 2002)。類美登素亦可根據已知方法以合成方式製備。
例示性類美登素藥物部分包括(但不限於)具有經改質之芳環的類美登素藥物部分,諸如:C-19-去氯(美國專利第4,256,746號)(例如藉由氫化鋰鋁還原安莎黴素P2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)(例如藉由使用鏈黴菌或放線菌去甲基化或使用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)(例如藉由使用醯基氯醯化來製備)及在芳環其他位置具有改質之類美登素。
例示性類美登素藥物部分亦包括具有改質之類美登素藥物部分,諸如:C-9-SH (美國專利第4,424,219號) (例如藉由使美登醇與H2
S或P2
S5
反應來製備);C-14-烷氧基甲基(去甲氧基/CH2
OR)(美國專利第4,331,598號);C-14-羥基甲基或醯氧基甲基(CH2
OH或CH2
OAc) (美國專利第4,450,254號) (例如由諾卡菌屬(Nocardia
)製備);C-15-羥基/醯氧基(美國專利第4,364,866號) (例如藉由經鏈黴菌使美登醇轉化來製備);C-15-甲氧基(美國專利第4,313,946號及第4,315,929號) (例如自滑桃樹(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) (例如藉由經鏈黴菌使美登醇去甲基化來製備);及4,5-去氧(美國專利第4,371,533號) (例如藉由三氯化鈦/LAH還原美登醇來製備)。
類美登素化合物上之許多位置適用作連接位置。舉例而言,酯鍵可藉由使用習知偶合技術與羥基反應形成。在一些實施例中,反應可在具有羥基之C-3位置、經羥基甲基修飾之C-14位置、經羥基修飾之C-15位置及具有羥基之C-20位置發生。在一些實施例中,鍵在美登醇或美登醇類似物之C-3位置形成。
類美登素藥物部分包括具有以下結構之類美登素藥物部分:
其中波浪線指示類美登素藥物部分之硫原子共價連接至於ADC之連接子。各R可獨立地為H或C1
-C6
烷基。將醯胺基連接於硫原子之伸烷基鏈可為甲基、乙基或丙基,亦即m為1、2或3 (美國專利第633,410號;美國專利第5,208,020號;Chari等人,Cancer Res.
, 第52卷, 第127-131頁, 1992;Liu等人,Proc. Nall. Acad. Sci. USA
, 第93卷, 第8618-8623頁, 1996)。
本發明之ADC涵蓋類美登素藥物部分之所有立體異構體,亦即對掌性碳處R及S組態之任何組合(美國專利第7,276,497號;美國專利第6,913,748號;美國專利第6,441,163號;美國專利第633,410 (RE39151)號;美國專利第5,208,020號;Widdison等人 (2006)J. Med. Chem
. 49:4392-4408。在一些實施例中,類美登素藥物部分具有以下立體化學:
類美登素藥物部分之例示性實施例包括(但不限於) DM1;DM3;及DM4,具有以下結構:
其中波浪線指示藥物之硫原子共價連接於抗體-藥物結合物之連接子(L)。
其中DM1經由BMPEO連接子連接於抗體之硫醇基的例示性抗體-藥物結合物具有以下結構及縮寫:
其中Ab係抗體;n係0、1或2;且p係1至約20。在一些實施例中,p係1至10,p係1至7,p係1至5,或p係1至4。
含有類美登素之免疫結合物、其製造方法及其治療用途揭示於例如以下中:美國專利第5,208,020號及第5,416,064號;US 2005/0276812 A1;及歐洲專利EP 0 425 235 B1。亦參見Liu等人,Proc. Natl. Acad. Sci. USA
, 第93卷, 第8618-8623頁, 1996;及Chari等人,Cancer Research
, 第52卷, 第127-131頁, 1992。
在一些實施例中,抗體-類美登素結合物可藉由使抗體以化學方式連接於類美登素分子來製備,不顯著降低抗體或類美登素分子之生物活性。參見例如美國專利第5,208,020號。在一些實施例中,每個抗體分子平均結合3-4個類美登素分子之ADC已展示增強標靶細胞之細胞毒性的功效,不負面影響抗體之功能或溶解性。在一些情況下,與使用裸抗體相比,即使一個分子毒素/抗體亦預期增強細胞毒性。
製造抗體-類美登素結合物之例示性鍵聯基團包括例如本文所述之鍵聯基團及以下中所揭示之該等鍵聯基團:美國專利第5,208,020號;歐洲專利0 425 235 B1;Chari等人,Cancer
Research, 第52卷, 第127-131頁, 1992;US 2005/0276812 A1;及US 2005/016993 A1。2) 奧瑞他汀 (Auristatin) 及海兔毒素 (Dolastatin)
藥物部分包括海兔毒素、奧瑞他汀及其類似物及衍生物(美國專利第5,635,483號;美國專利第5,780,588號;美國專利第5,767,237號;美國專利第6,124,431號)。奧瑞他汀係海洋軟體動物化合物海兔毒素-10之衍生物。儘管不欲受任何特定理論束縛,但已展示海兔毒素及奧瑞他汀干擾微管動力學、GTP水解及核及細胞分裂(Woyke等人,Antimicrob. Agents and Chemother.
, 第45卷, 第3580-3584頁, 2001)及具有抗癌(美國專利第5,663,149號)及抗真菌活性(Pettit等人,Antimicrob. Agents Chemother.
, 第42卷, 第2961-2965頁, 1998)。海兔毒素/奧瑞他汀藥物部分可經由肽藥物部分之N(胺基)端或C(羧基)端連接於抗體(WO 02/088172;Doronina等人,Nature
Biotechnology, 第21卷, 第778-784頁, 2003;Francisco等人,Blood
, 第102卷, 第1458-1465頁, 2003)。
例示性奧瑞他汀實施例包括N端連接之單甲基阿瑞他汀藥物部分DE
及DF
,揭示於美國專利第7,498,298號及美國專利第7,659,241號:
其中DE
及DF
之波浪線指示共價連接於抗體或抗體-連接子組分之位點,且獨立地在各位置:
R2
係選自H及C1
-C8
烷基;
R3
係選自H、C1
-C8
烷基、C3
-C8
碳環、芳基、C1
-C8
烷基-芳基、C1
-C8
烷基-(C3
-C8
碳環)、C3
-C8
雜環及C1
-C8
烷基-(C3
-C8
雜環);
R4
係選自H、C1
-C8
烷基、C3
-C8
碳環、芳基、C1
-C8
烷基-芳基、C1
-C8
烷基-(C3
-C8
碳環)、C3
-C8
雜環及C1
-C8
烷基-(C3
-C8
雜環);
R5
係選自H及甲基;
或R4
及R5
共同形成碳環且具有式-(CRa
Rb
)n
-,其中Ra
及Rb
獨立地選自H、C1
-C8
烷基及C3
-C8
碳環且n係選自2、3、4、5及6;
R6
係選自H及C1
-C8
烷基;
R7
係選自H、C1
-C8
烷基、C3
-C8
碳環、芳基、C1
-C8
烷基-芳基、C1
-C8
烷基-(C3
-C8
碳環)、C3
-C8
雜環及C1
-C8
烷基-(C3
-C8
雜環);
各R8
係獨立地選自H、OH、C1
-C8
烷基、C3
-C8
碳環及O-(C1
-C8
烷基);
R9
係選自H及C1
-C8
烷基;
R10
係選自芳基或C3
-C8
雜環;
Z係O、S、NH或NR12
,其中R12
係C1
-C8
烷基;
R11
係選自H、C1-
C20
烷基、芳基、C3
-C8
雜環、-(R13
O)m
-R14
或-(R13
O)m
-CH(R15
)2
;
m係1-1000範圍內之整數;
R13
係C2
-C8
烷基;
R14
係H或C1
-C8
烷基;
R15
在每次出現時獨立地係H、COOH、-(CH2
)n
-N(R16
)2
、-(CH2
)n
-SO3
H或-(CH2
)n
-SO3
-C1
-C8
烷基;
R16
在每次出現時獨立地係H、C1
-C8
烷基或-(CH2
)n
-COOH;
R18
係選自-C(R8
)2
-C(R8
)2
-芳基、-C(R8
)2
-C(R8
)2
-(C3
-C8
雜環)及-C(R8
)2
-C(R8
)2
-(C3
-C8
碳環);且
n係0至6範圍內之整數。
在一個實施例中,R3
、R4
及R7
獨立地係異丙基或第二丁基且R5
係-H或甲基。在一例示性實施例中R3
及R4
各係異丙基,R5
係-H,且R7
係第二丁基。
在又一實施例中,R2
及R6
各係甲基,且R9
係-H。
在另一實施例中,在每次出現時R8
係-OCH3
。
在一例示性實施例中,R3
及R4
各係異丙基,R2
及R6
各係甲基,R5
係-H,R7
係第二丁基,R8
在每次出現時係-OCH3
,且R9
係-H。
在一個實施例中,Z係-O-或-NH-。
在一個實施例中,R10
係芳基。
在一例示性實施例中,R10
係-苯基。
在一例示性實施例中,當Z係-O-時,R11
係-H、甲基或第三丁基。
在一個實施例中,當Z係-NH時,R11
係-CH(R15
)2
,其中R15
係-(CH2
)n
-N(R16
)2
,且R16
係-C1
-C8
烷基或-(CH2
)n
-COOH。
在另一實施例中,當Z係-NH時,R11
係-CH(R15
)2
,其中R15
係-(CH2
)n
-SO3
H。
式DE
之例示性奧瑞他汀實施例係MMAE,其中波浪線指示與抗體-藥物結合物之連接子(L)的共價連接:
式DE
之例示性奧瑞他汀實施例係MMAF,其中波浪線指示與抗體-藥物結合物之連接子(L)的共價連接:
其他例示性實施例包括在五肽奧瑞他汀藥物部分之C端具有苯丙胺酸羧基修飾之單甲基纈胺酸化合物(WO 2007/008848)及在五肽奧瑞他汀藥物部分之C端具有苯丙胺酸側鏈修飾之單甲基纈胺酸化合物(WO 2007/008603)。
包含MMAF及各種連接子組分之式I之ADC的非限制性例示性實施例進一步包括Ab-MC-PAB-MMAF及Ab-PAB-MMAF 已展示藉由非蛋白分解可裂解之連接子連接於抗體的包含MMAF之免疫結合物具有與藉由蛋白分解可裂解連接子連接於抗體的包含MMAF之免疫結合物相當之活性(Doronina等人,Bioconjugate Chem.
, 第17卷, 第114-124頁, 2006)。在一些此類實施例中,咸信藥物釋放由抗體在細胞中降解實現。
通常,基於肽之藥物部分可藉由在兩個或更多個胺基酸及/或肽片段之間形成肽鍵來製備。此類肽鍵可例如根據液相合成方法來製備(參見例如E. Schröder及K. Lübke, 「The Peptides」, 第1卷, 第76-136頁, 1965, Academic Press)。在一些實施例中,奧瑞他汀/海兔毒素藥物部分可根據以下之方法製備:美國專利第7,498,298號;美國專利第5,635,483號;美國專利第5,780,588號;Pettit等人,J. Am. Chem. Soc.
, 第111卷, 第5463-5465頁, 1998;Pettit等人,Anti
-Cancer Drug Design
, 第13卷, 第243-277頁, 1998;Pettit等人,Synthesis,
第6卷,
第719-725頁, 1996;Pettit等人,J. Chem. Soc. Perkin Trans.
第15卷, 第859-863頁, 1996;及Doronina ,Nat. Biotechnol.
, 第21卷, 第778-784頁, 2003。
在一些實施例中,式DE
(諸如MMAE)及DE
(諸如MMAF)之奧瑞他汀/海兔毒素藥物部分及藥物-連接子中間物及其衍生物(諸如MC-MMAF、MC-MMAE、MC-vc-PAB-MMAF及MC-vc-PAB-MMAE)可使用以下中所述之方法製備:美國專利第7,498,298號;Doronina等人,Bioconjugate Chem.
, 第17卷, 第114-124頁, 2006;及Doronina等人,Nat. Biotech.
, 第21卷, 第778-784頁, 2003且接著結合於相關抗體。3) 卡奇黴素
在一些實施例中,免疫結合物包含結合於一或多個卡奇黴素分子之抗體或抗體片段。抗生素之卡奇黴素家族及其類似物能夠在低於皮莫耳濃度下產生雙鏈DNA斷裂(Hinman等人,Cancer Research
, 第53卷, 第3336-3342頁, 1993;Lode等人,Cancer Research
, 第58卷, 第2925-2928頁, 1998)。卡奇黴素具有胞內作用位點,但在某些情況中,不容易交叉質膜。因此,在一些實施例中,此等藥劑經由抗體介導之內化的細胞吸收可大大增強其細胞毒性作用。製備具有卡奇黴素藥物部分之抗體-藥物結合物之非限制性例示性方法描述於例如美國專利第5,712,374號;美國專利第5,714,586號;美國專利第5,739,116號;及美國專利第5,767,285號中。4) 吡咯并苯并二氮呯
在一些實施例中,ADC包含吡咯并苯并二氮呯(PBD)。在一些實施例中,PDB二聚體識別且結合於特定DNA序列。天然產物安麯黴素(anthramycin)(一種PBD)於1965年首次報導(Leimgruber等人,J. Am. Chem. Soc.,
第87卷, 第5793-5795頁, 1965;Leimgruber等人,J. Am. Chem. Soc.,
第87卷, 第5791-5793頁, 1965)。此後,已報導許多PBD,天然存在之PBD與PBD類似物(Thurston等人,Chem. Rev
. 第1994卷, 第433-465頁 1994,包括三環PBD骨架之二聚體(美國專利第6,884,799號;美國專利第7,049,311號;美國專利第7,067,511號;美國專利第7,265,105號;美國專利第7,511,032號;美國專利第7,528,126號;美國專利第7,557,099號)。不欲受任何特定理論束縛,咸信二聚體結構用B形式之DNA之小溝賦予適當等螺旋性三維形狀,使得在結合位點緊密貼合(Kohn, In Antibiotics III. Springer-Verlag, New York, 第3-11頁 (1975);Hurley及Needham-VanDevanter,Acc. Chem. Res.,
第19卷, 第230-237頁, 1986)。載有C2芳基取代基之二聚PBD化合物已展示適用作細胞毒性劑(Hartley等人Cancer Res.
, 第70卷, 第6849-6858頁, 2010;Antonow,J. Med. Chem.
第53卷, 第2927-2941頁, 2010;Howard等人,Bioorganic and Med. Chem. Letters
, 第19卷, 第6463-6466頁, 2009)。
PBD二聚體已結合於抗體且所得ADC展示具有抗癌特性。PBD二聚體上非限制性示例性鍵聯位點包括五員吡咯環(PBD單元與N10-C11亞胺基之間的繫栓)(WO 2009/016516;US 2009/304710;US 2010/047257;US 2009/036431;US 2011/0256157;WO 2011/130598)。
ADC之非限制性例示性PBD二聚體組分具有:
及其鹽及溶劑合物,其中:
波浪線指示共價連接於連接子之位點;
點線指示C1與C2或C2與C3之間視情況存在雙鍵;
R2
係獨立地選自H、OH、=O、=CH2
、CN、R、OR、=CH-RD
、=C(RD
)2
、O-SO2
-R、CO2
R及COR,且視情況進一步選自鹵基或二鹵基,其中RD
係獨立地選自R、CO2
R、COR、CHO、CO2
H及鹵基;
R6
及R9
係獨立地選自H、R、OH、OR、SH、SR、NH2
、NHR、NRR'、NO2
、Me3
Sn及鹵基;
R7
係獨立地選自H、R、OH、OR、SH、SR、NH2
、NHR、NRR'、NO2
、Me3
Sn及鹵基;
Q係獨立地選自O、S及NH;
R11
為H或R,或其中Q為O、SO3
M,其中M為金屬陽離子;
R及R'各自獨立地選自視情況經取代之C1-8
烷基、C1-12
烷基、C3-8
雜環基、C3-20
雜環及C5-20
芳基,且視情況與基團NRR'有關,R及R'連同其所連接之氮原子一起形成視情況經取代之4員、5員、6員或7員雜環;
R12
、R16
、R19
及R17
如分別關於R2
、R6
、R9
及R7
所定義;
R"係C3-12
伸烷基,該鏈可雜有一或多個雜原子,例如O、S、N(H)、NMe及/或芳環(例如苯或吡啶),該環視情況經取代;及
X及X'係獨立地選自O、S及N(H)。
在一些實施例中,R及R'各自獨立地選自視情況經取代之C1-12
烷基、C3-20
雜環及C5-20
芳基,且視情況與基團NRR'有關,R及R'連同其所連接之氮原子一起形成視情況經取代之4員、5員、6員或7員雜環。在一些實施例中,R9
及R19
係H。在一些實施例中,R6
及R16
係H。
在一些實施例中,R7
及R17
均為OR7A
,其中R7A
係視情況經取代之C1-4
烷基。在一些實施例中,R7A
係Me。在一些實施例中,R7A
係Ch2
Ph,其中Ph係苯基。在一些實施例中,X係O。在一些實施例中,R11
係H。在一些實施例中,各單體單元中C2與C3之間存在一雙鍵。
在一些實施例中,R2
及R12
係獨立地選自H及R。在一些實施例中,R2
及R12
獨立地係R。在一些實施例中,R2
及R12
獨立地係視情況經取代之C5-20
芳基或C5-7
芳基或C8-10
芳基。在一些實施例中,R2
及R12
獨立地係視情況經取代之苯基、噻吩基、萘基、吡啶基、喹啉基或異喹啉基。在一些實施例中,R2
及R12
係獨立地選自=O、=CH2
、=CH-RD
及=C(RD
)2
。在一些實施例中,R2
及R12
各係=CH2
。在一些實施例中,R2
及R12
各係H。在一些實施例中,R2
及R12
各係=O。在一些實施例中,R2
及R12
各係=CF2
。在一些實施例中,R2
及/或R12
獨立地係=C(RD
)2
。在一些實施例中,R2
及/或R12
獨立地係=CH-RD
。
在一些實施例中,當R2
及/或R12
係=CH-RD
時,各基團可獨立地具有下文所示之任一組態:
在一些實施例中,=CH-RD
呈組態(I)。在一些實施例中,R''係C3
伸烷基或C5
伸烷基。
PBD二聚體-val-cit-PAB-Ab及PBD二聚體-Phe-Lys-PAB-Ab之連接子係蛋白酶可裂解的,而PBD二聚體-順丁烯二醯亞胺-縮醛之連接子係酸不穩定的。
PBD二聚體及包含PBD二聚體之ADC可根據此項技術中已知之方法製備。參見例如WO 2009/016516;US 2009/304710;US 2010/047257;US 2009/036431;US 2011/0256157;WO 2011/130598。5) 蒽環黴素
在一些實施例中,ADC可包含蒽環黴素。蒽環黴素係顯示細胞毒活性之抗生素化合物。儘管不欲受任何特定理論束縛,但研究已指示蒽環黴素可藉由多種不同機制用以殺死細胞,包括:1)藥物分子插入至細胞DNA,由此抑制DNA依賴性核酸合成;2)藉由藥物產生自由基,接著自由基與細胞大分子反應,對細胞造成損害,及/或3)藥物分子與細胞膜相互作用(參見例如C. Peterson等人, 「Transport And Storage Of Anthracycline In Experimental Systems And Human Leukemia」Anthracycline Antibiotics In Cancer Therapy
;N. R. Bachur, 「Free Radical Damage」同上. 第97-102頁)。因為具有細胞毒性潛能,所以蒽環黴素已用於治療許多癌症,諸如白血病、乳癌、肺癌、卵巢腺癌及肉瘤(參見例如P. H-Wiernik,Anthracycline: Current Status And New Developments
,
第11頁)。
非限制性例示性蒽環黴素包括小紅莓、表柔比星、伊達比星、柔紅黴素、奈莫柔比星及其衍生物。已製備及研究道諾黴素及小紅莓之免疫結合物及前藥(Kratz等人,Current Med. Chem.
, 第13卷, 第477-523頁, 2006;Jeffrey等人,Bioorganic
&Med. Chem. Letters,
第16卷, 第358-362頁. 1996;Torgov等人,Bioconj. Chem.,
第16卷, 第717-721頁, 2005;Nagy等人,Proc. Natl. Acad. Sci. USA
, 第97卷, 第829-834頁, 2000;Dubowchik等人,Bioorg
. &Med. Chem. Letters,
第12卷, 第1529-1532頁, 2002; King等人,J. Med. Chem.
, 第45卷, 第4336-4343頁, 2002;EP 0328147;美國專利第6,630,579號)。抗體-藥物結合物BR96-小紅莓與腫瘤相關抗原路易斯-Y (Lewis-Y)特異性反應且已在I及II階段研究中評估(Saleh等人,J. Clin. Oncology
, 第18卷, 第2282-2292頁, 2000;Ajani等人,Cancer Jour.,
第6卷, 第78-81頁, 2000;Tolcher等人,J. Clin. Oncology
, 第17卷, 第478-484, 1999頁)。
PNU-159682係奈莫柔比星之有效代謝物(或衍生物)(Quintieri等人,Clinical Cancer
Research, 第11卷, 第1608-1617頁, 2005)。奈莫柔比星係在小紅莓之糖苷胺基上具有2-甲氧基嗎啉基之小紅莓半合成類似物,且已處於臨床評定下(Grandi等人,Cancer Treat. Rev.
第17卷, 第133-138頁, 1990;Ripamonti等人,Brit. J. Cancer
, 第65卷, 第703-707, 1992頁),包括針對肝細胞癌之階段II/III試驗(Sun等人,Proceedings of the American Society for Clinical Oncology
, 第22卷, Abs1448, 2003;Quintieri,Proceedings of the American Association of Cancer Research,
第44卷:第1版, Abs 4649, 2003;Pacciarini等人,Jour. Clin. Oncology
, 第24卷, 第14116頁, 2006)。
包括PNU-159682之蒽環黴素可經由若干鍵位點及多個連接子結合於抗體(US 2011/0076287;WO2009/099741;US 2010/0034837;WO 2010/009124),包括本文所述之連接子。
PNU-159682順丁烯二醯亞胺縮醛-Ab之連接子係酸不穩定的,而PNU-159682-val-cit-PAB-Ab, PNU-159682-val-cit-PAB-間隔子-Ab及PNU-159682-val-cit-PAB-間隔子(R1
R2
)-Ab之連接子係蛋白酶可裂解的。6) 其他藥物部分
藥物部分亦包括格爾德黴素(geldanamycin)(Mandler等人,J. Nat. Cancer Inst.
, 第92卷, 第1573-1581頁, 2000;Mandler等人,Bioorganic
&Med. Chem. Letters
, 第10卷, 第1025-1028頁, 2000;Mandler等人,Bioconjugate Chem.
, 第13卷, 第786-791頁, 2002);及酶活性毒素及其片段,包括(但不限於)白喉A鏈、白喉毒素之非結合活性片段、外毒素A鏈(來自綠膿桿菌)、篦麻毒素A鏈、相思子毒素A鏈、莫迪素A鏈、α-帚麴菌素、油桐(Aleurites fordii)蛋白、康乃馨蛋白、洋商陸(Phytolaca americana
)蛋白(PAPI、PAPII及PAP-S)、苦瓜(momordica charantia
)抑制劑、麻瘋樹毒蛋白、巴豆毒素、肥皂草抑制劑、白樹素、有絲分裂素、侷限麴菌素、酚黴素、伊諾黴素(enomycin)及黴菌毒素(tricothecene)。參見例如WO 93/21232。
藥物部分亦包括具有核分解活性之化合物(例如核糖核酸酶或DNA核酸內切酶)。
在某些實施例中,免疫結合物可包含高度放射性原子。多種放射性同位素可用於產生放射性結合之抗體。實例包括At211
、I131
、I125
、Y90
、Re186
、Re188
、Sm153
、Bi212
、P32
、Pb212
及Lu之放射性同位素。在一些實施例中,當免疫結合物用於偵測時,其可包含用於閃爍攝影研究之放射性原子,例如TC99
或I123
;或用於核磁共振(NMR)成像(亦稱為磁共振成像,MRI)之自旋標記,諸如鋯-89、碘-123、碘-131、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。鋯-89可與各種金屬螯合劑錯合且結合於抗體,例如用於PET成像(WO 2011/056983)。
放射性或其他標記可以已知方式併入免疫結合物中。舉例而言,肽可使用包含例如一或多個氟-19原子代替一或多個氫之適合胺基酸前驅體生物合成或化學合成。在一些實施例中,諸如Tc99
、I123
、Re186
、Re188
及In111
之標記可經由抗體中之半胱胺酸殘基連接。在一些實施例中,釔-90可經由抗體之離胺酸殘基連接。在一些實施例中,IODOGEN方法(Fraker等人,Biochem. Biophys. Res. Commun.
, 第80卷, 第49-57頁, 1978)可用於併入碘-123。「Monoclonal Antibodies in Immunoscintigraphy」(Chatal, CRC Press 1989)描述某些其他方法。
在某些實施例中,免疫結合物可包含結合於前藥活化酶之抗體。在一些此類實施例中,前藥活化酶將前藥(例如肽基化學治療劑,參見WO 81/01145)轉化為活性藥物,諸如抗癌藥物。在一些實施例中,此類免疫結合物適用於抗體依賴性酶介導之前藥療法(「ADEPT」)。可結合於抗體之酶包括(但不限於)鹼性磷酸酶,其適用於將含磷酸酯基之前藥轉化為游離藥物;芳基硫酸酯酶,其適用於將含硫酸酯基之前藥轉化為游離藥物;胞嘧啶脫胺酶,其適用於將無毒5-氟胞嘧啶轉化為抗癌藥物5-氟尿嘧啶;蛋白酶,諸如沙雷菌屬蛋白酶、嗜熱菌蛋白酶、枯草桿菌蛋白酶、羧基肽酶及組織蛋白酶(諸如組織蛋白酶B及L),其適用於將含肽前藥轉化為游離藥物;D-丙胺醯基羧基肽酶,其適用於轉化含有D-胺基酸取代基之前藥;碳水化合物裂解酶,諸如β-半乳糖苷酶及神經胺酸苷酶,其適用於將糖基化前藥轉化為游離藥物;β-內醯胺酶,其適用於將經β-內醯胺衍生之藥物轉化為游離藥物;以及青黴素醯胺酶,諸如青黴素V醯胺酶及青黴素G醯胺酶,其適用於將分別在胺氮經苯氧基乙醯基或苯乙基衍生之藥物轉化為游離藥物。在一些實施例中,酶可藉由此項技術中熟知之重組DNA技術共價結合於抗體。參見例如Neuberger等人,Nature
, 第312卷, 第604-608頁, 1984。c) 藥物負載
藥物負載由p表示,係式I分子中每個抗體之藥物部分之平均數目。藥物負載可在每個抗體1至20個藥物部分(D)之範圍內。式I之ADC包括與1至20個之範圍的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之平均數目可藉由諸如質譜分析、ELISA分析及HPLC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,可藉由諸如逆相HPLC或電泳之方式來實現其中p係來自具有其他藥物負載之ADC之一定值的均質ADC之分離、純化及表徵。
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,在連接係半胱胺酸硫醇之情況下,如在以上某些例示性實施例中,抗體可僅具有一個或若干個半胱胺酸硫醇基,或可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,ADC之平均藥物負載在1至約8、約2至約6;或約3至約5之範圍內。實際上,某些ADC已展示藥物部分/抗體之最佳比率可低於8,且可為約2至約5 (美國專利第7,498,298號)。
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)可用不同方式控制,且例如藉由如下來控制:(i)限制藥物-連接物中間物或連接子試劑相對於抗體之莫耳過量;(ii)限制結合反應時間或溫度;及(iii)針對半胱胺酸硫醇修飾之部分或限制還原條件。
應瞭解,若超過一個親核性基團與藥物-連接子中間物或連接子試劑反應,則所得產物係ADC與連接於抗體之一或多個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(參見例如McDonagh等人,Prot. Engr. Design & Selection
, 第19卷, 第299-307頁, 2006;Hamblett等人,Clin. Cancer Res
., 第10卷, 第7063-7070頁, 2004)。在某些實施例中,具有單一負載值之均質ADC可藉由電泳或層析自結合混合物分離。d) 製備免疫結合物之某些方法
作為式I之ADC免疫結合物可藉由若干途徑,採用熟習此項技術者已知之有機化學反應、條件及試劑製備,包括以下:(1)抗體之親核性基團與二價連接子試劑反應,經由共價鍵形成Ab-L,接著與藥物部分D反應;及(2)藥物部分之親核性基團與二價連接子試劑反應,經由共價鍵形成D-L,接著與抗體之親核性基團反應。經由後一途徑製備式I之ADC之例示性方法描述於美國專利第7,498,298號中。
抗體上之親核性基團包括(但不限於):(i) N端胺基;(ii)側鏈胺基,例如離胺酸;(iii)側鏈硫醇基,例如半胱胺酸;及(iv)糖羥基或胺基,其中抗體發生糖基化。胺、硫醇及羥基為親核性的且能夠與連接子部分及連接子試劑上之親電性基團反應形成共價鍵,該等親電性基團包括:(i)活性酯,諸如NHS酯、HOBt酯、鹵基甲酸酯及酸鹵化物;(ii)烷基及苯甲基鹵化物,諸如鹵乙醯胺;及(iii)醛、酮、羧基及順丁烯二醯亞胺基。某些抗體具有可還原鏈間二硫鍵,亦即半胱胺酸橋鍵。藉由用諸如DTT (二硫蘇糖醇)或三羰基乙基膦(TCEP)之還原劑處理,使得抗體完全或部分還原,可使抗體具有反應性,以與連接子試劑結合。理論上各半胱胺酸橋鍵將因此形成兩個反應性硫醇親核體。可經由例如使離胺酸殘基與2-亞胺基硫雜環戊烷(妥特氏試劑(Traut's reagent))反應,修飾離胺酸殘基,使胺轉化為硫醇,而將額外親核性基團引入至抗體中。亦可藉由引入一個、兩個、三個、四個或更多個半胱胺酸殘基(例如藉由製備包含一或多個非天然半胱胺酸胺基酸殘基之變異抗體),而將反應性硫醇基引入至抗體中。
本發明之抗體-藥物結合物亦可藉由抗體或抗體片段上之親電子基團(諸如醛或酮羰基)與連接子試劑或藥物上之親核性基團之間的反應製得。連接子試劑上之適用親核性基團包括(但不限於)醯肼、肟、胺基、肼、硫半卡巴肼、肼羧酸酯及芳基醯肼。在一個實施例中,抗體經修飾以引入能夠與連接子試劑或藥物上之親核性取代基反應之親電性部分。在另一個實施例中,糖基化抗體之糖可例如用過碘酸鹽氧化試劑氧化,以形成醛基或酮基,其可與連接子試劑或藥物部分之胺基反應。所得亞胺希夫鹼(Schiff base)基團可形成穩定鍵聯,或可例如藉由硼氫化物試劑還原,以形成穩定之胺鍵聯。在一個實施例中,糖基化抗體之碳水化合物部分與半乳糖氧化酶或偏過碘酸鈉反應可在抗體中產生羰基(醛及酮),其可與藥物(Hermanson, Bioconjugate Techniques)上之適當基團反應。在另一實施例中,含有N端絲胺酸或蘇胺酸殘基之抗體可與偏過碘酸鈉反應,產生醛而非第一胺基酸(Geoghegan & Stroh,Bioconjugate Chem.
, 第3卷, 第138-146頁, 1992;美國專利第5,362,852號)。此類醛可與藥物部分或連接子親核試劑反應。
藥物部分上之例示性親核性基團包括(但不限於):能夠與連接子部分及連接子試劑上之親電性基團反應形成共價鍵的胺、硫醇、羥基、醯肼、肟、肼、硫半卡巴肼、肼羧酸酯及芳基醯肼基團,該等親電性基團包括:(i)活性酯,諸如NHS酯、HOBt酯、鹵基甲酸酯及酸鹵化物;(ii)烷基及苯甲基鹵化物,諸如鹵乙醯胺;及(iii)醛、酮、羧基及順丁烯二醯亞胺基。
可用於製備ADC之非限制性例示性交聯試劑在本文中描述於標題為「例示性連接子」之章節下。使用此類交聯試劑連接兩個部分,包括蛋白質部分及化學部分之方法為此項技術中已知。在一些實施例中,包含抗體及細胞毒性劑之融合蛋白可例如藉由重組技術或肽合成來製備。重組DNA分子可包含編碼結合物之抗體及細胞毒性部分的區域,該等區域彼此相鄰或由編碼不破壞結合物之所需特性之連接子肽的區域分離。
在又一實施例中,抗體或抗體片段可結合於「受體」(諸如抗生蛋白鏈菌素)以用於腫瘤預靶向中,其中將抗體/抗體片段-受體結合物向患者投與,之後使用清除劑自循環移除未結合結合物,且接著投與結合於細胞毒性劑(例如藥物或放射性核苷酸)之「配體」(例如抗生素蛋白)。C. 用於診斷及偵測之方法及組合物
在某些實施例中,本文提供之抗-Ror2抗體或抗體片段中之任一者可用於偵測生物樣品中Ror2之存在。如本文所用,術語「偵測」涵蓋定量或定性偵測。在某些實施例中,生物樣品包含細胞或組織,諸如乳房、胰腺、食道、肺及/或大腦細胞或組織。
本發明之另一態樣係關於一種本發明之抗-Ror2抗體或抗體片段,其係用於診斷及/或監測在體內之至少一個位置Ror2表現量自正常生理水準增加或降低之癌症或另一疾病。
在一較佳實施例中,本發明之抗體或抗體片段可用諸如螢光分子、放射性分子或上述在此項技術中已知之任何其他標記之可偵測分子或物質標記。舉例而言,本發明之抗體或抗體片段可用放射性分子標記。舉例而言,適合放射性分子包括(但不限於)用於閃爍攝影研究之放射性原子,諸如123
I、124
I、111
In、186
Re及188
Re。本發明之抗體或抗體片段亦可用用於核磁共振(NMR)成像之自旋標記來標記,諸如碘-123、碘-131、銦-Ill、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。在投與抗體後,偵測患者內放射性標記抗體之分佈。可使用任何適合之已知方法。一些非限制性實例包括,計算斷層掃描(CT)、正電子發射斷層攝影(PET)、磁共振成像(MRI)、螢光、化學發光及超音波掃描。
本發明之抗體或抗體片段可適用於診斷及分級與Ror2過度表現相關之癌症及疾病。與Ror2過度表現相關之癌症可包括鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、胃癌、胰臟癌、膠細胞腫瘤(諸如神經膠母細胞瘤及神經纖維瘤)、子宮頸癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝腫瘤、乳癌、結腸癌、黑素瘤、結腸直腸癌、子宮內膜癌、唾液腺癌、腎癌(kidney cancer/renal cancer)、前列腺癌、外陰癌、甲狀腺癌、肝癌(hepatic carcinoma)、肉瘤、血液癌(白血病)、星形細胞瘤及各種類型之頭頸癌或其他Ror2表現或過度表現型過度增生性疾病。
本發明之抗體或抗體片段可適用於診斷Ror2表現增加或降低之除癌症外之疾病。可溶性或細胞Ror2形式均可以用於此類診斷。通常,此類診斷性方法涉及使用獲自患者之生物樣品。如本文所用,術語「生物樣品」涵蓋可用於診斷或監測分析之獲自個體之多種樣品類型。生物樣品包括(但不限於)血液及生物學來源之其他液體樣品、實體組織樣品(諸如活檢樣本)或組織培養基或來源於其的細胞及其子代。舉例而言,生物樣品包括獲自由懷疑患有與Ror2過度表現相關之癌症之個體收集之組織樣品的細胞,且在較佳實施例中,獲自神經膠質瘤、胃、肺、胰臟、乳房、前列腺、腎、肝臟及子宮內膜。生物樣品涵蓋臨床樣品、培養物中之細胞、細胞上清液、細胞溶胞物、血清、血漿、生物流體及組織樣品。
在一特定實施例中,本發明係一種診斷個體之與Ror2過度表現相關之癌症的方法,其係藉由使用本發明抗體偵測來自該個體之細胞上之Ror2而實現。詳言之,該方法可包括以下步驟:
(a) 使個體之生物樣品與根據本發明之抗體或抗體片段在適用於抗體或抗體片段之條件下接觸以與表現Ror2之生物樣品中之細胞形成複合物;及
(b) 偵測及/或定量該等複合物,由此該等複合物之偵測指示與Ror2過度表現相關之癌症。
為監測癌症之進展,可在不同時間重複根據本發明之方法以確定結合於樣品之抗體是否增加或減少,由此可判定癌症是否發展、消退或穩定。
在一特定實施例中,本發明係一種診斷與Ror2之表現或過度表現或可溶性形式之Ror2之減少或增加相關之疾病的方法。此類疾病之實例可包括人類免疫病症,血栓性疾病(血栓形成及動脈粥樣硬化血栓形成(atherothrombosis))及心血管病。
在一個實施例中,提供一種用於診斷或偵測方法之抗-Ror2抗體或抗體片段。在另一態樣中,提供一種偵測生物樣品中Ror2之存在的方法。在另一態樣中,提供一種定量生物樣品中之Ror2量的方法。在某些實施例中,該方法包含使生物樣品與如本文所述之抗-Ror2抗體或抗體片段在容許抗-Ror2抗體或抗體片段與Ror2結合之條件下接觸,及偵測抗-Ror2抗體或抗體片段與Ror2之間是否形成複合物。此類方法可在活體外或活體內進行。在一個實施例中,使用抗-Ror2抗體或抗體片段以選擇符合治療之個體。在一些實施例中,治療將包括向個體投與抗-Ror2抗體或抗體片段。
在某些實施例中,提供經標記抗-Ror2抗體或抗體片段。標記包括(但不限於)直接偵測之標記或部分(諸如螢光、發色、電子緻密、化學發光及放射性標記),以及例如經由酶反應或分子相互作用間接檢測之部分(諸如酶或配體)。例示性標記包括(但不限於)放射性同位素32
P、14
C、125
I、3
H及131
I;螢光團,諸如稀土螯合物或螢光素及其衍生物;若丹明(rhodamine)及其衍生物;丹醯基(dansyl);傘酮(umbelliferone);螢光素酶,例如螢火蟲螢光素酶及細菌螢光素酶(美國專利第4,737,456號);螢光素;2,3-二氫酞嗪二酮;辣根過氧化酶(HRP);鹼性磷酸酶;β-半乳糖苷酶;葡糖澱粉酶;溶菌酶;醣氧化酶,例如葡萄糖氧化酶、半乳糖氧化酶及葡萄糖-6-磷酸去氫酶;雜環氧化酶,諸如尿酸酶及黃嘌呤氧化酶,其與採用過氧化氫氧化染料前驅體之酶(諸如HRP、乳過氧化酶或微過氧化酶)偶合;生物素/抗生素蛋白;自旋標記;噬菌體標記;穩定自由基及其類似物。D. 醫藥調配物
抗-Ror2抗體或抗體片段具有細胞殺死活性。此細胞殺死活性延伸至多種不同類型的細胞株。此外,此等抗體或抗體片段,一旦結合於細胞毒性劑,即可降低腫瘤尺寸且可展現毒性降低。參見本申請案之實例2。因此,抗-Ror2抗體、其片段或免疫結合物可適用於治療與Ror2表現相關之增生性疾病。抗體、片段或免疫結合物可單獨或與任何適合之藥劑或其他習知治療組合使用。
抗-Ror2抗體或抗體片段可用於治療與Ror2表現、過度表現或活化相關之疾病。除對Ror2表現之要求外對可治療之癌症或組織之類型無特定限制。實例包括鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、胃癌、胰臟癌、膠細胞腫瘤(諸如神經膠母細胞瘤及神經纖維瘤)、子宮頸癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝腫瘤、乳癌、結腸癌、黑素瘤、結腸直腸癌、子宮內膜癌、唾液腺癌、腎癌(kidney cancer/renal cancer)、前列腺癌、外陰癌、甲狀腺癌、肝癌(hepatic carcinoma)、肉瘤、血液癌(白血病)、星形細胞瘤及各種類型之頭頸癌。更佳癌症係神經膠質瘤、胃癌、肺癌、胰臟癌、乳癌、前列腺癌、腎癌、肝癌及子宮內膜癌。
抗-Ror2抗體或抗體片段係先天性免疫反應之可能活化劑,且因此可用於治療人類免疫病症,諸如敗血症。本發明之抗-Ror2抗體或抗體片段亦可作為佐劑用於免疫接種,諸如用於疫苗,且用作抵抗例如細菌、病毒及寄生蟲之抗感染藥劑。
抗-Ror2抗體或抗體片段可用於保護免受、預防或治療血栓性疾病,諸如靜脈及動脈血栓形成及動脈粥樣硬化血栓形成。抗-Ror2抗體或抗體片段亦可用以保護免受、預防或治療心血管病以及預防或抑制諸如拉沙熱病(Lassa)及埃博拉(Ebola)病毒之病毒的侵入及治療病毒感染。
在本文所述之治療方法的各實施例中,抗-Ror2抗體、抗體片段或抗-Ror2抗體或抗體片段免疫結合物可以與尋求治療之疾病或病症之處理相關之習知方法一致的方式遞送。根據本發明,在足以預防或治療疾病或病症之一段時間及條件下向需要此類治療之個體投與有效量之抗體、抗體片段或免疫結合物。因此,本發明之一態樣係關於一種治療與Ror2表現相關之疾病的方法,其包含向有需要個體投與治療有效量之本發明之抗體、抗體片段或免疫結合物。
對於投與,可將抗-Ror2抗體、抗體片段或免疫結合物調配為醫藥組合物。包括抗-Ror2抗體、抗體片段或免疫結合物之醫藥組合物可根據製備醫藥組合物之已知方法調配。在此類方法中,通常將治療性分子與含有醫藥學上可接受之載劑的混合物、溶液或組合物組合。
醫藥學上可接受之載劑係接受者患者可耐受之物質。無菌磷酸鹽緩衝生理食鹽水係醫藥學上可接受之載劑之一個實例。其他合適的醫藥學上可接受之載劑為熟習此項技術者所熟知。(參見例如Gennaro (編), Remington's Pharmaceutical Sciences (Mack Publishing Company, 第19版 1995))。調配物可進一步包括一或多種賦形劑、防腐劑、增溶劑、緩衝劑、預防小瓶表面上蛋白質損失之白蛋白等。
醫藥組合物之形成、投藥途徑、劑量及方案天然視待治療之病狀、疾病之嚴重程度、患者之年齡、重量及性別等而定。熟習此項技術者可考慮此等考慮因素以調配適合的醫藥組合物。本發明之醫藥組合物可經調配用於局部、經口、非經腸、鼻內、靜脈內、肌肉內、皮下或眼內投與及其類似投與方式。
較佳地,醫藥組合物含有用於能夠注射之調配物的醫藥學上可接受之媒劑。此等媒劑尤其可為等張的無菌生理食鹽水溶液(磷酸單鈉或二鈉、氯化鈉、氯化鉀、氯化鈣或氯化鎂及其類似物或此類鹽之混合物),或乾燥,尤其冷凍乾燥之組合物,其在添加例如滅菌水或生理鹽水時,使得可復原成可注射溶液。
在一些實施例中,存在張力劑,有時稱為「穩定劑」以調節或維持組合物中液體之張力。當以大型帶電生物分子(諸如蛋白質及抗體)使用時,通常將其稱為「穩定劑」,因為其可與胺基酸側鏈之帶電基團相互作用,由此減小分子間及分子內相互作用之可能。張力劑可以醫藥組合物之0.1重量%至25重量%,較佳1重量%至5重量%之任何量存在。較佳張力劑包括多羥基糖醇,較佳包括三元醇或高級糖醇,諸如甘油、赤藻糖醇、阿拉伯糖醇、木糖醇、山梨糖醇或甘露糖醇。
額外賦形劑包括可充當以下中之一或多者的藥劑:(1)膨化劑、(2)溶解度增強劑、(3)穩定劑及(4)及防止變性或黏著於容器壁之藥劑。此類賦形劑可包括:多羥基糖醇(上問所列舉);胺基酸,諸如丙胺酸、甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸、離胺酸、鳥胺酸、白胺酸、2-苯丙胺酸、麩胺酸及蘇胺酸等;有機糖或糖醇,諸如蔗糖、乳糖、乳糖醇、海藻糖、水蘇糖、甘露糖、山梨糖、木糖、核糖、核糖醇、肌肉肌糖(myoinisitose)、肌肉肌醇(myoinisitol)、半乳糖、半乳糖醇、甘油、環醇(例如肌醇)、聚乙二醇;含硫還原劑,諸如脲、麩胱甘肽、硫辛酸、巰乙酸鈉、硫代甘油、α-單硫代甘油及硫代硫酸鈉;低分子量蛋白質,諸如人類血清白蛋白、牛血清白蛋白、明膠或其他免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;單醣(例如木糖、甘露糖、果糖及葡萄糖;雙醣(例如乳糖、麥芽糖、蔗糖);三醣,諸如棉子糖;及多醣,諸如糊精或葡聚糖。
可採用非離子型界面活性劑或清潔劑(亦稱為「潤濕劑」)以有助於溶解治療劑以及保護治療蛋白以抵抗攪動誘導之聚集,由此亦可使得調配物暴露於剪切表面應力而不會致使活性治療蛋白或抗體變性。非離子界面活性劑可按約0.05 mg/ml至約1.0 mg/ml,較佳約0.07 mg/ml至約0.2 mg/ml之濃度範圍存在。
適合的非離子型界面活性劑包括聚山梨醇酯(20、40、60、65、80等)、聚氧化物(polyoxamer)(184、188等)、PLURONIC®多元醇、TRITON®、聚氧乙烯脫水山梨糖醇單醚(TWEEN®-20、TWEEN®-80等)、聚桂醇400、聚乙二醇40硬脂酸酯、聚氧乙烯氫化蓖麻油10、50及60、甘油單硬脂酸酯、蔗糖脂肪酸酯、甲基纖維素及羧基甲基纖維素。可使用之陰離子清潔劑包括月桂基硫酸鈉、二辛基磺基丁二酸鈉及二辛基磺酸鈉。陽離子型清潔劑包括苯紮氯銨或苄索氯銨。
用於投與之劑量可隨各種參數而調適,且詳言之隨所用投藥模式、相關病理學或者所需治療持續時間而調適。為製備醫藥組合物,可將有效量之抗體或抗體片段溶解或分散於醫藥學上可接受之載劑或水性介質中。
適用於可注射使用之醫藥形式包括無菌水溶液或分散液;調配物,包括芝麻油、花生油或水性丙二醇;及用於無菌可注射溶液或分散液之臨時製備的無菌粉末。在所有情況下,形式必須為無菌的且必須在存在易於注射性之程度上為流體。其必須在製造及儲存條件下穩定,且必須保護其免遭微生物(諸如細菌及真菌)之污染作用。
呈游離鹼或藥理學上可接受之鹽形式之活性化合物的溶液可於水中適當地與界面活性劑混合來製備。亦可在甘油、液態聚乙二醇及其混合物中及在油中製備分散液。在普通的儲存及使用條件下,此等製劑含有防腐劑以防止微生物生長。
抗-Ror2抗體或抗體片段可調配成呈中性或鹽形式之組合物。醫藥學上可接受之鹽包括酸加成鹽(由蛋白質之游離胺基形成)且其由無機酸(諸如鹽酸或磷酸)或有機酸(諸如乙酸、草酸、酒石酸、杏仁酸及其類似酸)形成。由游離羧基形成之鹽亦可衍生自無機鹼,諸如氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣或氫氧化鐵;及有機鹼,諸如異丙胺、三甲胺、組胺酸、普魯卡因(procaine)及其類似鹼。
載劑亦可係含有例如水、乙醇、多元醇(例如甘油、丙二醇及液體聚乙二醇及其類似物)、其適合的混合物及植物油之溶劑或分散介質。舉例而言,可藉由使用包衣(諸如卵磷脂)、藉由維持就分散液而言所需粒度及藉由使用界面活性劑來維持適當的流動性。微生物作用之預防可藉由各種抗菌劑及抗真菌劑,例如對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞及其類似物來實現。在多種情況下,將較佳包括等張劑,例如糖或氯化鈉。可藉由在組合物中使用延緩吸收劑(例如單硬脂酸鋁及明膠)來延長可注射組合物之吸收。
無菌可注射溶液係如下製備:將所要量之活性化合物視需要與上文列舉之其他成分中之一或多者一起併入適當溶劑中,隨後過濾滅菌。一般而言,藉由將各種滅菌活性成分併入含有鹼性分散介質及來自上文列舉之彼等成分之所要其他成分的無菌媒劑中來製備分散液。在無菌粉末用於製備無菌可注射溶液之情況下,較佳製備方法係真空乾燥及冷凍乾燥技術,由其先前無菌過濾溶液產生活性成分加任何額外所需成分之粉末。
亦涵蓋製備更多或高濃度之用於直接注射之溶液,其中設想使用二甲亞碸(DMSO)作為溶劑產生極快滲透,遞送高濃度之活性劑至小腫瘤區域中。
在調配時,將以與劑量調配相容之方式且以治療有效之量投與溶液。調配物易於以各種劑型(諸如上文所描述之可注射溶液之類型)投與,但亦可採用藥物釋放膠囊及其類似劑型。
對於水溶液中之非經腸投與而言,例如必要時溶液應經適當緩衝且首先用充足生理食鹽水或葡萄糖賦予液體稀釋劑等張性。此等特定水溶液尤其適合於靜脈內、肌肉內、皮下及腹膜內投與。在此方面,根據本發明,可採用之無菌水性介質將為熟習此項技術者已知的。舉例而言,單次劑量可溶解於1 ml等張NaCl溶液中,且添加至1000 ml皮下灌注流體,或在建議之輸注位點注射,(參見例如「Remington's Pharmaceutical Sciences」,第15版,第1035-1038及1570-1580頁)。視所治療個體之病狀而定,將必然出現一些劑量變化。在任何事件中,負責投與之人員將判定個別個體之適當劑量。
抗體或抗體片段可調配於治療性混合物內以每劑量遞送約0.0001至10.0毫克,或約0.001至5毫克,或約0.001至1毫克,或約0.001至0.1毫克,或約0.1至1.0或甚至約10毫克。亦可以所選時間間隔投與多個劑量。
除經調配用於非經腸投與(諸如靜脈內或肌肉內注射)之化合物以外,其他醫藥學上可接受之形式包括例如錠劑或用於經口投與之其他固體;延時釋放膠囊;及目前所用之任何其他形式。
在某些實施例中,涵蓋使用脂質體及/或奈米粒子將抗體或抗體片段引入至宿主細胞中。脂質體及/或奈米粒子之形式及用途為熟習此項技術者已知。
奈米膠囊可一般以穩定及可複製方式裹住化合物。為避免由細胞內聚合物過載引起之副作用,此類超細粒子(尺寸為約0.1 µm)一般使用能夠在活體內降解之聚合物設計。涵蓋滿足此等要求之生物可降解氰基丙烯酸聚烷基酯奈米粒子以用於本發明,且此類顆粒可易於製得。
脂質體由磷脂形成,磷脂分散於水性介質中且自發形成多層同心雙層小泡(亦稱為多層小泡(MLV))。MLV一般具有25 nm至4 μm之直徑。MLV之音波處理使得形成直徑在200至500埃範圍內且在核心含有水溶液之小單層小泡(SUV)。脂質體之物理特徵視pH值、離子強度及二價陽離子之存在而定。
含有如本文所述之抗-Ror2抗體或抗體片段之醫藥調配物藉由將具有所需純度之此類抗體或抗體片段與一或多種視情況選用之醫藥學上可接受之載劑混合來製備(Remington's Pharmaceutical Sciences 第16版, Osol, A.編輯(1980)),呈凍乾調配物或水溶液形式。醫藥學上可接受之載劑在所用劑量及濃度下對於接收者一般無毒性,且包括(但不限於):緩衝劑,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如氯化十八烷基二甲基苯甲基銨;氯化六羥季銨;苯紮氯銨;苄索氯銨;苯酚、丁醇或苯甲醇;對羥苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(低於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸;單糖、雙糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖,諸如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成鹽相對離子,諸如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子型界面活性劑,諸如聚乙二醇(PEG)。
本文之例示性醫藥學上可接受之載劑進一步包括間質性藥物分散劑,諸如可溶性中性活性玻尿酸酶醣蛋白(sHASEGP),例如人類可溶性PH-20玻尿酸酶醣蛋白,諸如rhuPH20 (HYLENEX®
, Baxter International, Inc.)。某些例示性sHASEGP (包括rHuPH20)及使用方法描述於美國專利公開案第2005/0260186號及第2006/0104968號中。在一個態樣中,sHASEGP與一或多種額外葡萄糖胺聚糖酶(諸如軟骨素酶)組合。
例示性凍乾抗體調配物描述於美國專利第6,267,958號中。抗體調配物水溶液包括美國專利第6,171,586號及WO2006/044908中所述之彼等抗體調配物水溶液,WO2006/044908中所述之調配物包括組胺酸-乙酸鹽緩衝劑。
視所治療之特定適應症所之需要,在本文中,調配物亦可含有一種以上活性成分。較佳地,可將不會彼此不利影響之具有互補活性之成分組合成單一調配物。舉例而言,除本發明之抗-Ror2抗體、抗體片段或免疫結合物以外,可能需要提供EGFR拮抗劑(諸如埃羅替尼(erlotinib))、抗血管生成劑(諸如VEGF拮抗劑,其可為抗-VEGF抗體)或化學治療劑(諸如紫杉醇或鉑藥劑)。此類活性成分適合地以對預期目的有效之量組合存在。
可將活性成分包封於例如藉由凝聚技術或藉由界面聚合反應製備之微膠囊中。舉例而言,可採用分別於膠態藥物遞送系統(例如脂質體、白蛋白微球體、微乳液、奈米顆粒及奈米膠囊)或巨乳液中之羥基甲基纖維素或明膠微膠囊及聚(甲基丙烯酸甲酯)微膠囊。此類技術揭示於Remington's Pharmaceutical Sciences 第16版, Osol, A. Ed. (1980)中。
可製備持續釋放製劑。持續釋放製劑之適合實例包括含有抗體或抗體片段之固體疏水性聚合物之半滲透基質,該等基質呈成形製品形式,例如薄膜或微膠囊。
用於活體內投與之調配物通常為無菌的。無菌性可容易藉由例如經由無菌過濾膜過濾來實現。E. 治療方法及組合物
本文提供之抗-Ror2抗體或抗體片段中之任一者可用於治療方法中。在一個態樣中,提供一種抗-Ror2抗體或抗體片段,其用作藥劑。在其他態樣中,提供一種抗-Ror2抗體或抗體片段,其用於治療癌症(例如乳癌、非小細胞肺癌、胰臟癌、腦癌、胰腺癌、腦癌、腎癌、卵巢癌、胃癌、白血病、子宮內膜癌、結腸癌、前列腺癌、甲狀腺癌、肝癌、骨肉瘤及/或黑素瘤)。在某些實施例中提供一種抗-Ror2抗體或抗體片段,其用於之治療方法中。在某些實施例中,本發明提供一種抗-Ror2抗體或抗體片段,其用於治療患有癌症之個體之方法中,該方法包含向個體投與有效量之抗-Ror2抗體或抗體片段。在某些實施例中,本發明提供一種抗-Ror2抗體或抗體片段,其用於治療患有免疫病症(例如自體免疫病症)、心血管病症(例如動脈粥樣硬化、高血壓、血栓形成)、傳染病(例如埃博拉病毒、馬堡病毒(Marburg virus))或糖尿病之個體之方法中,該方法包含向個體投與有效量之抗-Ror2抗體或抗體片段。在一個此類實施例中,該方法進一步包含向個體投與有效量之至少一種例如如下文所述之額外治療劑。在其他實施例中,本發明提供一種抗-Ror2抗體或抗體片段,其用於抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能。
在某些實施例中,本發明提供一種抗Ror2抗體或抗體片段,其用於個體中抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能之方法中,包含向個體投與有效之抗-Ror2抗體或抗體片段以抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管發展(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能。根據以上實施例中之任一者的「個體」較佳係人類。
在另一態樣中,本發明提供抗-Ror2抗體或抗體片段之用途,其用於製造或製備藥劑。在一個實施例中,該藥劑用於治療癌症(在一些實施例中,乳癌、非小細胞肺癌、胰臟癌、腦癌、胰腺癌、腦癌、腎癌、卵巢癌、胃癌、白血病癌、子宮內膜癌、結腸癌、前列腺癌、甲狀腺癌、肝癌、骨肉瘤及/或黑素瘤)。在另一實施例中,該藥劑用於治療癌症之方法中,該方法包含向患有癌症之個體投與有效量之藥劑。在另一實施例中,該藥劑用於治療免疫病症(例如自體免疫病症)、心血管病症(例如動脈粥樣硬化、高血壓、血栓形成)、傳染病(例如埃博拉病毒、馬堡病毒)或糖尿病之方法中,該方法包含向個體投與有效量之抗-Ror2抗體或抗體片段。在一個此類實施例中,該方法進一步包含向個體投與有效量之至少一種例如如下文所述之額外治療劑。在另一實施例中,該藥劑用於抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管(例如瘤內血管或腫瘤相關血管)及/或抑制腫瘤基質功能。在另一實施例中,該藥劑用於個體中抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能之方法中,該方法包含向個體投與有效量之藥劑以抑制血管生成、抑制細胞增生、促進免疫功能、誘導發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管發展(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能。根據以上實施例中之任一者之「個體」可為人類。
在另一態樣中,本發明提供用於治療癌症之方法。在一個實施例中,該方法包含向患有此類癌症之個體投與有效量之抗-Ror2抗體或抗體片段。在一個此類實施例中,該方法進一步包含向個體投與有效量之至少一種如下文所述之額外治療劑。根據以上實施例中之任一者之「個體」可為人類。
在另一態樣中,本發明提供一種治療免疫病症(例如自體免疫病症)、心血管病症(例如動脈粥樣硬化、高血壓、血栓形成)、傳染病(例如埃博拉病毒、馬堡病毒)或糖尿病之方法。在一個此類實施例中,該方法進一步包含向個體投與有效量之至少一種如下文所述之額外治療劑。根據以上實施例中之任一者之「個體」可為人類。
在另一態樣中,本發明提供一種在個體中抑制血管生成、抑制細胞增生、抑制免疫功能、抑制發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能之方法。在一個實施例中,該方法包含向個體投與有效量之抗-Ror2抗體或抗體片段以抑制血管生成、抑制細胞增生、促進免疫功能、誘導發炎性細胞介素分泌(例如來自腫瘤相關之巨噬細胞)、抑制腫瘤血管發展(例如瘤內血管或腫瘤相關之血管)及/或抑制腫瘤基質功能。在一個實施例中,「個體」係人類。
在另一態樣中,本發明提供包含本文提供之抗-Ror2抗體或抗體片段中之任一者的醫藥調配物,其例如用於以上治療方法中之任一者中。在一個實施例中,醫藥調配物包含本文提供之抗-Ror2抗體或抗體片段中之任一者及醫藥學上可接受之載劑。在另一實施例中,醫藥調配物包含本文提供之抗-Ror2抗體或抗體片段中之任一者及至少一種例如如下文所述之額外治療劑。
在各及每一上文所述之治療中,本發明之抗體或抗體片段可單獨、以免疫結合物形式或與其他藥劑組合用於治療中。舉例而言,本發明之抗體可與至少一種額外治療劑共同投與。在某些實施例中,其他治療劑係抗血管生成劑。在某些實施例中,其他治療劑係VEGF拮抗劑(在一些實施例中,係抗-VEGF抗體,例如貝伐單抗(bevacizumab))。在某些實施例中,其他治療劑係EGFR拮抗劑(在一些實施例中,係埃羅替尼)。在某些實施例中,其他治療劑係化學治療劑及/或細胞生長抑制劑。在某些實施例中,其他治療劑係紫杉醇(例如太平洋紫杉醇)及/或鉑藥劑(例如卡鉑)。在某些實施例中,其他治療劑係增強患者之免疫性或免疫系統之藥劑。
上述此類組合療法涵蓋組合投與(其中兩種或更多種治療劑包括於相同或各別調配物中)及各別投與,在此情況下,抗體或抗體片段之投與可在其他治療劑及/或佐劑投與之前、同時及/或之後進行。抗體或抗體片段亦可與輻射療法組合使用。
抗體或抗體片段可以符合良好醫學實務之方式調配、給藥及投與。在此情形中考慮之因素包括所治療之特定病症、所治療之特定哺乳動物、個別患者之臨床病狀、病症起因、藥劑遞送部位、投與方法、投與時程及醫學從業者已知之其他因素。抗體或抗體片段無需但視情況與一或多種當前用於預防或治療所討論病症之藥劑一起調配。此類其他藥劑之有效量視存在於調配物中之抗體或抗體片段之量、病症或治療之類型及如上文所述之其他因素而定。此等藥劑一般以相同劑量且以如本文所述之投與途徑使用,或以本文所述之劑量之約1%至99%使用,或以任何劑量且以憑經驗/臨床上確定係適當之任何途徑使用。
為預防或治療疾病,抗體或抗體片段(當單獨或與一或多種其他額外治療劑組合使用時)之適當劑量將視待治療之疾病類型、抗體或抗體片段之類型、疾病之嚴重程度及病程、抗體或抗體片段係出於預防性抑或治療性目的投與、先前療法、患者之臨床病史及對抗體或抗體片段之反應及主治醫師之判斷而定。一次性或歷經一系列治療向患者適當地投與抗體或抗體片段。視疾病之類型及嚴重程度而定,約1 μg/kg至40 mg/kg之抗體或抗體片段可為例如藉由一或多次分別投與或藉由連續輸注向患者投與之初始候選劑量。一種典型日劑量可在約1 μg/kg至100 mg/kg或更多之範圍內,視上文所提及之因素而定。對於歷經數日或更長時間之重複投藥,視病狀而定,治療一般將持續至疾病症狀之所需抑制發生為止。此類劑量可間歇投與,例如每週或每三週投與(例如以使得患者接受約兩至約二十,或例如約六次抗體或抗體片段劑量)。可投與初始較高起始劑量,之後可投與一或多次較低劑量。然而,其他給藥方案可為適用的。此療法之進展易於藉由習知技術及分析監測。
應瞭解,以上調配物或治療方法中之任一者可替代或除抗-Ror2抗體以外使用本發明之抗體片段或免疫結合物進行。
增強宿主之免疫功能以對抗腫瘤係日益關注之主題。習知方法包括(i)APC增強,諸如(a)注射至編碼外來MHC同種異體抗原之DNA的腫瘤中,或(b)用增加腫瘤之免疫抗原識別概率之基因轉染活檢腫瘤細胞(例如免疫刺激細胞介素、GM-CSF、共刺激分子B7.1、B7.2),(iii)授受性細胞免疫治療,或用活化腫瘤特異性T細胞處理。授受性細胞免疫治療包括分離腫瘤浸潤性宿主T-淋巴球,諸如經由藉由IL-2或腫瘤或兩者刺激來活體外擴增群體。另外,功能異常之分離之T細胞亦可藉由活體外施用本發明之抗-PD-L1抗體來活化。接著可將共同活化之T細胞重新投與宿主。此等方法中之一或多者可與投與本發明之抗體、抗體片段或免疫結合物組合使用。
癌症之傳統療法包括以下:(i)輻射療法(例如放射線療法、X射線療法、輻照)或使用電離輻射以殺死癌細胞且使腫瘤收縮。輻射療法可經由外部光束放射線療法(EBRT)外部施與或經由近接療法內部施與;(ii)化學治療或應用一般影響細胞快速分化之細胞毒性藥;(iii)靶向療法或特定影響失調之癌細胞蛋白質的藥劑(例如酪胺酸激酶抑制劑伊馬替尼(imatinib)、吉非替尼(gefitinib);單株抗體、光動力療法);(iv)免疫療法,或增強宿主之免疫反應(例如疫苗);(v)激素療法,或阻斷激素(例如當腫瘤係激素敏感的時),(vi)血管生成抑制劑,或阻斷血管形成及生長,及(vii)緩解性護理,或針對改良護理品質以減輕疼痛、噁心、嘔吐、腹瀉及出血之治療。諸如嗎啡鹼(嗎啡鹼)及氧可酮(oxycodone)之止痛藥、諸如昂丹司瓊(ondansetron)及阿匹坦(aprepitant)之鎮吐藥可允許更具侵襲性的治療方案。
在癌症之治療中,可在投與抗-Ror2抗體或抗體片段之前、之後或同時進行治療癌症免疫性之上述習知治療中之任一者。另外,抗-Ror2抗體或抗體片段可在諸如投與腫瘤結合抗體(例如單株抗體、毒素結合單株抗體)及/或投與化學治療劑之習知癌症治療之前、之後或同時投與。F. 製品及套組
在本發明之另一態樣中,提供含有抗-Ror2抗體或抗體片段及適用於治療、預防及/或診斷上文所述病症之其他材料之製品。製品包含容器及容器上或容器隨附之標記或藥品說明書。適合的容器包括例如瓶子、小瓶、注射器、IV溶液袋等。容器可由各種材料形成,諸如玻璃或塑膠。容器容納組合物本身或組合物與可有效治療、預防及/或診斷病狀之另一組合物之組合,且可具有無菌接取口(例如容器可為具有可由皮下注射針刺穿之塞子的靜脈內溶液袋或小瓶)。組合物中之至少一種活性劑係本發明之抗體或抗體片段。標記或藥品說明書指示組合物用於治療所選病狀。此外,製品可包含(a)其中含有組合物之第一容器,其中該組合物包含抗體或抗體片段;及(b)其中含有組合物之第二容器,其中該組合物包含另一細胞毒性或其他治療劑。本發明之此實施例中之製品可進一步包含指示組合物可用於治療特定病狀之藥品說明書。或者或另外,製品可進一步包含第二(或第三)容器,其包含醫藥學上可接受之緩衝劑,諸如抑菌性注射用水(BWFI)、磷酸鹽緩衝鹽水、林格氏溶液(Ringer's solution)及右旋糖溶液。其可進一步包括就商業及使用者觀點而言所需之其他物質,包括其他緩衝劑、稀釋劑、過濾器、針及注射器。
應瞭解,替代或除抗-Ror2抗體或抗體片段以外,以上製品中之任一者可包括本發明之免疫結合物。
最終,本發明亦提供包含至少一種本發明之抗體或抗體片段之套組。含有本發明之多肽、抗體或抗體片段或抗體藥結合物之套組可用於偵測Ror2表現(增加或減少)或用於治療性或診斷性分析中。本發明之套組可含有偶合至固體支撐物(例如組織培養物盤或珠粒(例如瓊脂糖珠粒))之抗體。可提供含有抗體之套組用於例如在ELISA或西方墨點法中偵測及定量活體外Ror2。此類適用於偵測之抗體可具有標記,諸如螢光或放射性標記。
該套組進一步含有關於其用途之說明書。在一些實施例中,說明書包含美國食品和藥物管理局針對活體外診斷套組所要之說明書。在一些實施例中,該套組進一步包含根據樣品存在或不存在Ror2而診斷該樣品中存在或不存在腦脊髓液之說明書。在一些實施例中,該套組包含一或多種抗體或抗體片段。在其他實施例中,該套組進一步包含一或多種酶、酶抑制劑或酶活化劑。在一些實施例中,該套組包含一或多種層析化合物。在其他實施例中,該等套組進一步包含一或多種用以製備光譜分析用樣品之化合物。在其他實施例中,該等套組進一步包含比較參考物質以根據指示劑之強度、顏色光譜或其他物理屬性解釋Ror2存在或不存在。
以下實例說明但不限制本發明之軟明膠膠囊。本領域中通常遇到且對於熟習此項技術者明顯之多種條件及參數之其他合適修改及改編均在本發明之範疇內。實例 實例 1 : 抗 Ror2 之 條件性活性生物 (CAB) 抗體
抗人類Ror2之抗體在此實例中製得。將抗Ror2之人類化抗體用作野生型抗體以產生抗Ror2之CAB抗體。編碼野生型抗體(重鏈及輕鏈可變區)之DNA演化以產生突變型抗體重鏈及輕鏈可變區文庫。藉由ELISA篩檢在pH 6.0下與人類Ror2之選擇性結合親和力優於pH 7.4下之文庫中之突變型重鏈及輕鏈可變區(圖2A-2B及3A-3B)。同時,亦使突變型抗體之表現量最佳以達到在後續製造過程中提供較高產率之目的。在血清中使用FLAG標籤進行篩檢,此係因為血清中存在可導致篩檢假陽性之人類抗體。發現產生之條件性活性抗體與Ror2在pH 6.0下具有比其與Ror2在pH 7.4下之結合親和力更高的結合親和力(表1及2)。
CAB抗體不展示緩衝劑中之聚集,如圖4中所表明。藉由尺寸排阻層析分析CAB抗體。如圖4中所示,僅偵測到一個峰,表明抗體極少或不聚集。圖5展示一些所選突變型抗體(scFv),其表明與Ror2在pH 6.0下之結合親和力比與Ror2在pH 7.4下之結合親和力更高。另外,圖5亦展示溫度由室溫升高至60℃並不明顯改變抗體之選擇性。
如以下表4中所示,條件性活性抗體均展示高表現量,其中欄「純系」指示抗體,且表現量示於第二欄中,以mg/ml計。
將此等抗體之純系送至服務提供者中,其請求表現量表示預期表現量(「預定量」)。然而,若干此等抗體之實際表現量(「遞送量」)極高且超出預期表現量。至少三個純系之表現量超出預期表現量(BAP048.1.06-07、BAP048.7-C02D09及BAP048.7-A03F01)。表 4. 具有高表現量之抗體
亦使用表面電漿子共振(SPR)分析條件性活性抗體以測量其結合於Ror2之締合及解離速率。SPR分析可用以測量蛋白質結合之締合及解離速率。條件性活性抗體之活體內締合及解離速率(在動物及人類中)係重要特性。
觀察到,條件性活性抗體在pH值6.0下具有良好結合活性,且在pH 7.4下具有極少或無結合活性(圖6A-6B)。SPR分析顯示,相比於pH 7.4,此等相同條件性活性抗體在pH 6.0下具高度選擇性 (圖6A-6B)。實例 2 : 結合於模型毒素之抗 -Ror2 抗體
使本發明之抗-Ror2抗體結合於模型毒素(例如太平洋紫杉醇)以產生條件性活性抗體-藥物結合物(Ror2-CAB-ADC)。
藉由注射MDA-MB-436腫瘤細胞在小鼠中誘導腫瘤以產生異種移植小鼠。接著將Ror2-CAB-ADC以0.3或1 mg/kg之劑量一週一次注射至異種移植小鼠中持續2週。此研究中所用之對照包括作為媒劑之PBS緩衝劑及單獨毒素(太平洋紫杉醇)。該研究展示與對照相比,Ror2-CAB-ADC使腫瘤尺寸明顯大大減小(圖7A-7C)。0.3 mg/kg劑量組之結果呈現於圖7B中,且1 mg/kg劑量組之結果呈現於圖7C中。此研究展示抗-Ror2抗體與毒素結合有效減小腫瘤尺寸。實例 3. 條件性活性抗體 BAP048 之 pH 依賴性結合親和力
藉由pH滴定測試藉由本發明鑑別之條件性活性抗體中之一者BAP048 (或BAP048.7,如一些圖中所示)之結合親和力。使用野生型抗體作為對照。如圖8中所示,條件性活性抗體BAP048在低於pH 6.5之pH值下更具活性,但在pH 7.0下具較低活性。野生型抗體不展示其結合親和力之pH依賴性。實例 4. 條件性活性抗體 BAP048 之種間交叉結合親和力
選擇對人類Ror2具有條件性結合親和力之條件性活性抗體BAP048。使用ELISA測試此條件性活性抗體對三個標靶之結合親和力:人類Ror2 (hROR2)、食蟹獼猴Ror2 (cynoROR2)及小鼠Ror2 (mROR2) (圖9)。條件性活性抗體BAP048與人類及食蟹獼猴Ror2展示幾乎等同之結合親和力,但與小鼠Ror2之結合親和力明顯較低。三個標靶之條件性活性抗體BAP048之EC50經計算係:人類Ror2,201.4 ng/ml;食蟹獼猴Ror2,327.1 ng/ml;及小鼠Ror2,7653 ng/ml。實例 5. 藉由條件性活性抗體 BAP048-MMAE 結合物進行細胞殺死
使條件性活性抗體BAP048結合於化學治療藥物單甲基奧瑞他汀E (MMAE)以產生抗體藥結合物(ADC)。對於細胞表面上表現人類Ror2之HEK293細胞測試ADC。用於此測試之陰性對照為親和力相配抗體,但對人類Ror2不具有特異性。陰性對照亦結合於MMAE。
在兩個pH值下測試BAP048 ADC:6.0及7。相對於經陰性對照處理之細胞,治療之後仍存活之細胞的百分比呈現於圖10中。觀察到,在pH 6.0下在低於100 ng/ml之濃度的BAP048 ADC展示細胞殺死活性,而在7.4下約1000 ng/ml之BAP048 ADC展示細胞殺死,有效濃度之差異約10倍。
亦測試BAP048 ADC對LCLC103H細胞及HT1080細胞之細胞殺死活性。對於作為人類肺癌細胞株之LCLC103H細胞,在pH 6.0、6.2及6.4下測試BAP048 ADC之細胞殺死活性(圖11A-11C)。三個測試pH值中,BAP048 ADC之細胞殺死活性差無明顯不同,其IC50係1.819 ng/ml (pH 6.0)、1.232 ng/ml (pH 6.2)及3.318 ng/ml (pH 6.5)。
對於作為纖維肉瘤細胞株之HT1080細胞,亦在pH 6.0、6.2及6.4下測試BAP048 ADC之細胞殺死活性(圖12A-12C)。三個測試pH值中,BAP048 ADC之細胞殺死活性差無明顯不同,其IC50係2.897 ng/ml (pH 6.0)、3.138 ng/ml (pH 6.2)及2.601 ng/ml (pH 6.5)。實例 6. 藉由條件性活性抗體 BAP048-MMAE 結合物處理小鼠之腫瘤
將肺癌細胞LCLC103H注射至小鼠中以產生小鼠異種移植物(小鼠中之腫瘤)。使條件性活性抗體BAP048經由連接子硫橋鍵結合於MMAE,以產生ADC,其以兩個濃度1 mg/kg及6 mg/kg注射至小鼠中。陰性對照係無ADC之緩衝劑(媒劑)。一個劑量組係每週以1 mg/kg之劑量注射持續三次劑量,且另一劑量組係每4天以6 mg/kg之劑量注射持續4次劑量。
在研究期間量測腫瘤之體積。藉由BAP048-MMAE ADC觀察到,在6 mg/kg劑量組,第30天腫瘤尺寸收縮明顯。藉由BAP048-MMAE ADC得到,與媒劑對照相比,在1 mg/kg劑量組,腫瘤生長減緩(圖13)。實例 7. 連接子在條件性活性抗體 BAP048-MMAE 結合物中之作用
使用兩種不同連接子測試條件性活性抗體BAP048 MMAE結合之連接子作用:mc-vc-PAB及mc-PEG8-vc (圖14)。使用相同陰性對照(媒劑)。將此等兩種BAP048-MMAE結合物以1 mg/ml之單次劑量注射至小鼠異種移植中。在研究期間量測腫瘤之尺寸。觀察到,儘管與陰性對照相比,兩種BAP048-MMAE結合物明顯減緩腫瘤之生長,但兩種BAP048-MMAE結合物之間的差不顯著(圖14)。因此,連接子對BAP048-MMAE結合物之作用似乎不顯著。實例 8. 藉由條件性活性抗體 BAP048 處理 小鼠之腫瘤
此實例與實例6類似,但其中用以誘導小鼠腫瘤之細胞不同。用於此實例中之兩種細胞株係HT1080細胞(纖維肉瘤細胞株)及MDA-MB-436細胞(乳癌細胞株)。
對於藉由HT1080誘導之小鼠異種移植物,使條件性活性抗體BAP048由連接子mc-vc-PAB結合於MMAE。使用三個劑量組:6 mg/kg,每4天一次,持續4次劑量:10 mg/kg,每週一次,持續3次劑量;及10 mg/kg,每4天一次,持續4次劑量(圖15A)。使用兩種對照:一種係無抗體或MMAE之媒劑,另一種係不結合MMAE之BAP048抗體。
觀察到,在兩個對照組下腫瘤不斷生長。藉由條件性活性抗體BAP048-MMAE結合物使腫瘤體積之生長明顯減緩。腫瘤生長之抑制係劑量依賴性的,在最高劑量組之情況下,10 mg/kg,每4天一次,持續4次劑量,展示腫瘤生長之最大減低(圖15A)。
對於藉由MDA-MB-436誘導之小鼠異種移植物,使條件性活性抗體BAP048亦由連接子mc-vc-PAB結合於MMAE。僅存在一個劑量組:6 mg/kg,每4天一次,持續4次劑量,其中媒劑(無抗體或MMAE)作為對照(圖15B)。觀察到,在對照組下腫瘤不斷生長。藉由條件性活性抗體BAP048-MMAE結合物使腫瘤體積之生長明顯減低(圖15B)。
然而,應瞭解,儘管已於先前描述中連同本發明之結構及功能之細節一起闡述本發明之許多特徵及優勢,但本發明僅為例示性的,且可詳細地作出改變,尤其關於本發明之原理內之部分之形狀、尺寸及配置,其最大程度地藉由術語之廣泛一般含義所指示,在該等術語中表現所附申請專利範圍。
本文中提及之所有文獻均以全文引用的方式併入本文中,或者提供其特定依賴之本發明。本申請人並不意欲將任何所揭示之實施例均貢獻於公眾,且達到任何所揭示之修飾或變化字面上均不屬於申請專利範圍之範疇內,但其在等同原則下視為其一部分之程度。
親和力 ELISA 突變體 | |||
純系 | pH 6.0 | pH 7.4 | 比率,pH 6.0/7.4 |
LC-V029E | 0.406 | 0.129 | 3.15 |
LC-S030D | 0.733 | 0.252 | 2.91 |
LC-Y031C | 1.341 | 0.700 | 1.92 |
LC-Y031D | 0.911 | 0.405 | 2.25 |
LC-H033G | 1.103 | 0.536 | 2.06 |
LC-H033L | 0.690 | 0.332 | 2.08 |
LC-G049C | 0.468 | 0.133 | 3.52 |
LC-G049H | 1.873 | 0.118 | 15.87 |
LC-G049P | 0.660 | 0.268 | 2.46 |
LC-Q089E | 0.438 | 0.251 | 1.74 |
LC-R090H | 0.560 | 0.256 | 2.19 |
LC-S092D | 1.127 | 1.122 | 1.00 |
LC-S092V | 1.226 | 1.182 | 1.04 |
LC-T096D | 0.755 | 0.474 | 1.59 |
LC-F097D | 0.190 | 0.107 | 1.77 |
LC-F097E | 0.489 | 0.215 | 2.28 |
親和力 ELISA 突變體 | |||
純系 | pH 6.0 | pH 7.4 | 比率,pH 6.0/7.4 |
HC-F029E | 1.342 | 0.742 | 1.81 |
HC-Y032D | 1.470 | 0.510 | 2.88 |
HC-TD33C | 0.626 | 0.232 | 2.70 |
HC-M034D | 1.244 | 0.211 | 5.90 |
HC-M034E | 1.165 | 0.185 | 6.30 |
HC-M034Y | 0.903 | 0.391 | 2.31 |
HC-G050S | 0.828 | 0.318 | 2.60 |
HC-I051E | 1.039 | 0.100 | 10.39 |
HC-N052C | 0.995 | 0.431 | 2.31 |
HC-N052L | 0.911 | 0.433 | 2.10 |
HC-N052V | 0.870 | 0.340 | 2.56 |
HC-T053D | 1.108 | 0.222 | 4.99 |
HC-TQ53E | 0.540 | 0.157 | 3.44 |
HC-A097I | 1.892 | 1.730 | 1.892 |
HC-A097M | 1.977 | 1.701 | 1.977 |
HC-A097S | 1.666 | 1.692 | 1.666 |
HC-A097T | 1.834 | 1.692 | 1.666 |
HC-R098H | 0.928 | 0.353 | 2.63 |
HC-R098Q | 0.799 | 0.276 | 2.89 |
HC-G099E | 0.616 | 0.421 | 1.46 |
HC-L101F | 1.461 | 1.412 | 1.461 |
HC-S103G | 0.794 | 0.655 | 1.21 |
HC-G105D | 0.509 | 0.379 | 1.34 |
HC-N106E | 0.224 | 0.115 | 1.95 |
HC-D110L | 1.675 | 1.403 | 1.675 |
HC-Y111C | 1.079 | 0.793 | 1.36 |
HC-Y111T | 1.862 | 1.403 | 1.675 |
HC-W112L | 1.746 | 1.704 | 1.746 |
原始殘基 | 例示性取代 | 較佳取代 | ||
Ala (A) | Val;Leu;Ile | Val | ||
Arg (R) | Lys;Gln;Asn | Lys | ||
Asn (N) | Gln;His;Asp,Lys;Arg | Gln | ||
Asp (D) | Glu;Asn | Glu | ||
Cys (C) | Ser;Ala | Ser | ||
Gln (Q) | Asn;Glu | Asn | ||
Glu (E) | Asp;Gln | Asp | ||
Gly (G) | Ala | Ala | ||
His (H) | Asn;Gln;Lys;Arg | Arg | ||
Ile (I) | Leu;Val;Met;Ala;Phe;正白胺酸 | Leu | ||
Leu (L) | Norleucine;Ile;Val;Met;Ala;Phe | Ile | ||
Lys (K) | Arg;Gln;Asn | Arg | ||
Met (M) | Leu;Phe;Ile | Leu | ||
Phe (F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr | ||
Pro (P) | Ala | Ala | ||
Ser (S) | Thr | Thr | ||
Thr (T) | Val;Ser | Ser | ||
Trp (W) | Tyr;Phe | Tyr | ||
Tyr (Y) | Trp;Phe;Thr;Ser | Phe | ||
Val (V) | Ile;Leu;Met;Phe;Ala;正白胺酸 | Leu |
其中X係: |
純系 | [mg/mL] | 估計產率 | 實際產率 |
BAP048.1-06-07 | 4.9 | 100 | 137 |
BAP048.7-06-07 | 3.7 | 100 | 94 |
BAP048.7-C02D09 | 3.8 | 30 | 57 |
BAP048.7-A03F01 | 4.4 | 30 | 65 |
BAP048.7-A03C05 | 4.2 | 30 | 36 |
圖1係人類Ror2蛋白質之結構的示意圖。蛋白質在細胞外域中含有Ig樣域(Ig)、捲曲或富半胱胺酸(CRD)域及三環(Kr)域。細胞外域及細胞內域藉由跨膜(TM)域分離。胞內域含有酪胺酸激酶(TK)域及側接富絲胺酸/蘇胺酸(ST)域之富脯胺酸域(PR)。
圖2A-2B展示本發明之抗-Ror2抗體之例示性重鏈可變區之序列比對。
圖3A-3B展示本發明之抗-Ror2抗體之例示性輕鏈可變區之序列比對。
圖4展示如實例1中所述之指示本發明之抗-Ror2抗體不聚集之尺寸排阻層析。
圖5展示如中實例1所述之本發明之抗-Ror2抗體對於結合於Ror2之pH依賴性結合特徵。
圖6A-6B展示如實例1中所述之如藉由表面電漿子共振(SPR)分析所量測之本發明之條件性活性抗體之締合及解離速率。
圖7A-7C展示如實例2中所述之用結合太平洋紫杉醇之本發明之抗-Ror2抗體處理異種移植小鼠對腫瘤體積之作用。
圖8展示藉由pH滴定量測之例示性條件性活性抗體BAP048之pH依賴性結合親和力。
圖9展示條件性活性抗體BAP048對人類、食蟹獼猴及小鼠之Ror2蛋白質之結合親和力。
圖10展示結合單甲基奧瑞他汀E (Monomethyl auristatin E;MMAE)之條件性活性抗體BAP048對表現人類Ror2之HEK293細胞的細胞殺死。
圖11A-11C展示結合MMAE之條件性活性抗體BAP048對LCLC103H細胞之細胞殺死。
圖12A-12C展示結合MMAE之條件性活性抗體BAP048對HT1080細胞之細胞殺死。
圖13展示使用結合於MMAE之條件性活性抗體BAP048處理藉由LCLC103H誘導之小鼠腫瘤。
圖14展示使用經由不同連接子結合於MMAE之條件性活性抗體BAP048處理藉由LCLC103H誘導之小鼠腫瘤。
圖15A-15B展示使用結合於MMAE之條件性活性抗體BAP048處理分別藉由HT1080或MDA-MB-436誘導之小鼠腫瘤。
Claims (20)
- 一種條件性活性抗Ror2抗體或其抗原結合片段,其特異性結合於Ror2蛋白質,與Ror2蛋白質之結合親和力在腫瘤微環境中pH在pH 5.8至pH 6.8下之值相比於與Ror2蛋白質之結合親和力在非腫瘤微環境中發生之pH在pH 7.0至pH 7.6下之不同值之比率係至少1.5:1,該抗體或其抗原結合片段包含重鏈可變區及輕鏈可變區,該重鏈可變區包含之三個互補決定區具有H1、H2及H3序列,其中: (a) 該H1序列係GYTFTEYTMH (SEQ ID NO:28); (b) 該H2序列係GINTNNGGTGYNQKFKG (SEQ ID NO:29);且 (c) 該H3序列係AHGSLYSYGNSYFDYW (SEQ ID NO:30); 及 該輕鏈可變區包含之三個互補決定區具有L1、L2及L3序列,其中: (a) 該L1序列係SATSSVSYMH (SEQ ID NO:31); (b) 該L2序列係GTSNLAS (SEQ ID NO:32);且 (c) 該L3序列係QQRSSYPFTF (SEQ ID NO:33)。
- 如請求項1之條件性活性抗Ror2抗體或其抗原結合片段,其中該重鏈可變區具有選自SEQ ID NO:18及20-22之序列的胺基酸序列。
- 如請求項1之條件性活性抗Ror2抗體或其抗原結合片段,其中該輕鏈可變區具有選自SEQ ID NO:13、15及16之胺基酸序列。
- 如請求項1之條件性活性抗Ror2抗體或其抗原結合片段,其中該重鏈可變區具有選自SEQ ID NO: 20-22之胺基酸序列且該輕鏈可變區具有選自SEQ ID NO: 15及16之胺基酸序列。
- 如請求項4之條件性活性抗Ror2抗體或其抗原結合片段,其中該重鏈可變區具有SEQ ID NO: 20之胺基酸序列且該輕鏈可變區具有SEQ ID NO: 15之胺基酸序列。
- 如請求項4之條件性活性抗Ror2抗體或其抗原結合片段,其中該重鏈可變區具有SEQ ID NO: 21之胺基酸序列且該輕鏈可變區具有SEQ ID NO: 16之胺基酸序列。
- 如請求項4之條件性活性抗Ror2抗體或其抗原結合片段,其中該重鏈可變區具有SEQ ID NO: 22之胺基酸序列且該輕鏈可變區具有SEQ ID NO: 16之胺基酸序列。
- 如請求項1至7中任一項之條件性活性抗Ror2抗體或其抗原結合片段,其中該抗體或其抗原結合片段在腫瘤微環境中與Ror2蛋白質之結合親和力與在非腫瘤微環境中與Ror2蛋白質之結合親和力之比率係至少2:1、至少3:1、至少4:1、至少5:1、至少6:1、至少7:1、至少8:1、至少9:1、至少10:1、至少20:1、至少30:1、至少50:1、至少70:1或至少100:1。
- 如請求項1至7中任一項之條件性活性抗Ror2抗體或其抗原結合片段,其中該抗體或其抗原結合片段係嵌合抗體、多特異性抗體或人類化抗體。
- 一種免疫結合物,其包含如請求項1至9中任一項之抗體或其抗原結合片段。
- 如請求項10之免疫結合物,其中該免疫結合物包含至少一種選自化學治療劑、放射性原子、細胞生長抑制劑及細胞毒性劑之藥劑。
- 如請求項11之免疫結合物,其包含至少兩種該等藥劑。
- 如請求項11或12之免疫結合物,其中該抗體或其抗原結合片段及該至少一種或兩種藥劑共價鍵結至連接子分子。
- 如請求項11或12之免疫結合物,其中該至少一種或兩種藥劑係選自類美登素(maytansinoid)、奧瑞他汀(auristatin)、海兔毒素(dolastatin)、卡奇黴素(calicheamicin)、吡咯并苯并二氮呯(pyrrolobenzodiazepine)及蒽環黴素(anthracycline)。
- 一種醫藥組合物,其包含如請求項1至9中任一項之抗體或其抗原結合片段或如請求項10至14中任一項之免疫結合物及醫藥學上可接受之載劑。
- 如請求項15之醫藥組合物,其進一步包含張力劑。
- 一種如請求項15或16之醫藥組合物之用途,其係用於製造用以治療癌症之醫藥品。
- 一種套組,其係用於診斷或治療,該套組包含如請求項1至9中任一項之抗體或其抗原結合片段及使用該抗體或其抗原結合片段進行診斷或治療之說明書。
- 一種套組,其係用於診斷或治療,該套組包含如請求項10至14中任一項之免疫結合物及使用該免疫結合物進行診斷或治療之說明書。
- 一種套組,其係用於診斷或治療,該套組包含如請求項15或16之醫藥組合物及使用該醫藥組合物進行診斷或治療之說明書。
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Publication number | Priority date | Publication date | Assignee | Title |
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US11542332B2 (en) * | 2016-03-26 | 2023-01-03 | Bioatla, Inc. | Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof |
KR102585956B1 (ko) | 2016-08-31 | 2023-10-05 | 바이오아트라, 인코퍼레이티드 | 조건부 활성 폴리펩티드 및 이를 제조하는 방법 |
CN111378039B (zh) * | 2018-12-29 | 2021-08-24 | 深圳大学 | 治疗恶性肿瘤的抗体及其应用 |
CN111378040B (zh) * | 2018-12-29 | 2021-08-10 | 深圳大学 | 检测多种恶性肿瘤细胞的抗体及其应用 |
EP3936523A4 (en) * | 2019-01-08 | 2022-09-07 | Shenzhen University | ANTIBODY DETECTION OF MALIGNANT TUMOR CELLS AND THEIR APPLICATIONS |
MX2022005949A (es) * | 2019-11-18 | 2022-08-02 | Univ California | Anticuerpos anti-ror-2 y metodos de uso. |
WO2023164618A1 (en) * | 2022-02-25 | 2023-08-31 | Bioatla, Inc. | Cancer treatment with a conditionally active anti-ror2 antibody-drug conjugate |
Family Cites Families (271)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1308269A (en) | 1919-07-01 | I lanoqrapii co | ||
US1313946A (en) | 1919-08-26 | jenney | ||
US1361650A (en) | 1920-12-07 | Joseph varin | ||
US1309428A (en) | 1919-07-08 | Grease-cot | ||
US1317821A (en) | 1919-10-07 | Electric switch | ||
US1308268A (en) | 1919-07-01 | Planoorapii co | ||
US1307016A (en) | 1919-06-17 | Oil-cooling system foe | ||
US1315929A (en) | 1919-09-09 | Wiliiiam h | ||
US1322348A (en) | 1919-11-18 | Walter rosehhaiet md sydetey l | ||
US633410A (en) | 1898-09-22 | 1899-09-19 | George A Ames | Ice-cutter. |
US1362663A (en) | 1914-04-17 | 1920-12-21 | Us Light & Heat Corp | Commutator |
US1331598A (en) | 1916-06-22 | 1920-02-24 | Tibbetts George Wallace | Banker's booklet |
US1294757A (en) | 1917-12-22 | 1919-02-18 | Filippo Bentivegna | Ash-sifter. |
US1364866A (en) | 1919-04-18 | 1921-01-11 | Kirby Champeau Co Inc | Illuminating means |
US1450254A (en) | 1919-09-26 | 1923-04-03 | American Telephone & Telegraph | Balancing arrangement for multiplex carrier circuits |
US1371533A (en) | 1920-10-28 | 1921-03-15 | William J Wright | Wrench-handle |
US1424219A (en) | 1921-07-06 | 1922-08-01 | Firm Scintilla | Wire-clamping terminal for low-voltage installations |
US1737456A (en) | 1927-12-30 | 1929-11-26 | Sullivan Machinery Co | Pressure-fluid motor |
US1816567A (en) | 1928-03-26 | 1931-07-28 | Alemite Corp | Grease gun coupling |
US2087409A (en) | 1933-03-02 | 1937-07-20 | Woodstock Typewriter Co | Key lever adjusting mechanism |
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4797368A (en) | 1985-03-15 | 1989-01-10 | The United States Of America As Represented By The Department Of Health And Human Services | Adeno-associated virus as eukaryotic expression vector |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4737456A (en) | 1985-05-09 | 1988-04-12 | Syntex (U.S.A.) Inc. | Reducing interference in ligand-receptor binding assays |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US4777127A (en) | 1985-09-30 | 1988-10-11 | Labsystems Oy | Human retrovirus-related products and methods of diagnosing and treating conditions associated with said retrovirus |
US5139941A (en) | 1985-10-31 | 1992-08-18 | University Of Florida Research Foundation, Inc. | AAV transduction vectors |
US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
US5219740A (en) | 1987-02-13 | 1993-06-15 | Fred Hutchinson Cancer Research Center | Retroviral gene transfer into diploid fibroblasts for gene therapy |
AU600575B2 (en) | 1987-03-18 | 1990-08-16 | Sb2, Inc. | Altered antibodies |
US5770701A (en) | 1987-10-30 | 1998-06-23 | American Cyanamid Company | Process for preparing targeted forms of methyltrithio antitumor agents |
US5606040A (en) | 1987-10-30 | 1997-02-25 | American Cyanamid Company | Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group |
FI102355B (fi) | 1988-02-11 | 1998-11-30 | Squibb Bristol Myers Co | Menetelmä yhdistävän välikappaleen omaavien antrasykliini-immunokonjug aattien valmistamiseksi |
US6054270A (en) | 1988-05-03 | 2000-04-25 | Oxford Gene Technology Limited | Analying polynucleotide sequences |
US5700637A (en) | 1988-05-03 | 1997-12-23 | Isis Innovation Limited | Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays |
AU634186B2 (en) | 1988-11-11 | 1993-02-18 | Medical Research Council | Single domain ligands, receptors comprising said ligands, methods for their production, and use of said ligands and receptors |
US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
US6905680B2 (en) | 1988-11-23 | 2005-06-14 | Genetics Institute, Inc. | Methods of treating HIV infected subjects |
US5858358A (en) | 1992-04-07 | 1999-01-12 | The United States Of America As Represented By The Secretary Of The Navy | Methods for selectively stimulating proliferation of T cells |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
JP2752788B2 (ja) | 1989-01-23 | 1998-05-18 | カイロン コーポレイション | 感染および過剰増殖障害の為の組換え療法 |
US5800992A (en) | 1989-06-07 | 1998-09-01 | Fodor; Stephen P.A. | Method of detecting nucleic acids |
US5744101A (en) | 1989-06-07 | 1998-04-28 | Affymax Technologies N.V. | Photolabile nucleoside protecting groups |
US5527681A (en) | 1989-06-07 | 1996-06-18 | Affymax Technologies N.V. | Immobilized molecular synthesis of systematically substituted compounds |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
EP0487587A1 (en) | 1989-08-18 | 1992-06-03 | Chiron Corporation | Recombinant retroviruses delivering vector constructs to target cells |
US5585362A (en) | 1989-08-22 | 1996-12-17 | The Regents Of The University Of Michigan | Adenovirus vectors for gene therapy |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
CA2026147C (en) | 1989-10-25 | 2006-02-07 | Ravi J. Chari | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US6407213B1 (en) | 1991-06-14 | 2002-06-18 | Genentech, Inc. | Method for making humanized antibodies |
GB9114948D0 (en) | 1991-07-11 | 1991-08-28 | Pfizer Ltd | Process for preparing sertraline intermediates |
JP3534749B2 (ja) | 1991-08-20 | 2004-06-07 | アメリカ合衆国 | アデノウイルスが介在する胃腸管への遺伝子の輸送 |
US5362852A (en) | 1991-09-27 | 1994-11-08 | Pfizer Inc. | Modified peptide derivatives conjugated at 2-hydroxyethylamine moieties |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US5632957A (en) | 1993-11-01 | 1997-05-27 | Nanogen | Molecular biological diagnostic systems including electrodes |
WO1993010218A1 (en) | 1991-11-14 | 1993-05-27 | The United States Government As Represented By The Secretary Of The Department Of Health And Human Services | Vectors including foreign genes and negative selective markers |
GB9125623D0 (en) | 1991-12-02 | 1992-01-29 | Dynal As | Cell modification |
DE69333807T2 (de) | 1992-02-06 | 2006-02-02 | Chiron Corp., Emeryville | Marker für krebs und biosynthetisches bindeprotein dafür |
JPH05236997A (ja) | 1992-02-28 | 1993-09-17 | Hitachi Ltd | ポリヌクレオチド捕捉用チップ |
FR2688514A1 (fr) | 1992-03-16 | 1993-09-17 | Centre Nat Rech Scient | Adenovirus recombinants defectifs exprimant des cytokines et medicaments antitumoraux les contenant. |
ZA932522B (en) | 1992-04-10 | 1993-12-20 | Res Dev Foundation | Immunotoxins directed against c-erbB-2(HER/neu) related surface antigens |
US5427954A (en) | 1992-04-29 | 1995-06-27 | Shriner's Hospitals For Crippled Children | Compositions and methods for detection and treatment of human osteoarthritis |
JPH07507689A (ja) | 1992-06-08 | 1995-08-31 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 特定組織のターゲティング方法及び組成物 |
EP0644946A4 (en) | 1992-06-10 | 1997-03-12 | Us Health | VECTOR PARTICLES RESISTANT TO HUMAN SERUM INACTIVATION. |
GB2269175A (en) | 1992-07-31 | 1994-02-02 | Imperial College | Retroviral vectors |
DK0669836T3 (da) | 1992-11-13 | 1996-10-14 | Idec Pharma Corp | Terapeutisk anvendelse af kimære og radioaktivt mærkede antistoffer og humant B-lymfocytbegrænset differentieringsantigen til behandling af B-cellelymfom |
EP0905253A3 (en) | 1992-12-03 | 2000-11-02 | Genzyme Corporation | Adenoviral vector deleted of all E4-ORF except ORF6 |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
EP0714409A1 (en) | 1993-06-16 | 1996-06-05 | Celltech Therapeutics Limited | Antibodies |
ATE304604T1 (de) | 1993-06-24 | 2005-09-15 | Frank L Graham | Adenovirus vektoren für gentherapie |
ATE282630T1 (de) | 1993-10-01 | 2004-12-15 | Teikoku Hormone Mfg Co Ltd | Dolastatin-derivate |
DE69434594T2 (de) | 1993-10-25 | 2006-09-21 | Canji, Inc., San Diego | Rekombinante adenoviren-vektor und verfahren zur verwendung |
US6045996A (en) | 1993-10-26 | 2000-04-04 | Affymetrix, Inc. | Hybridization assays on oligonucleotide arrays |
US5965452A (en) | 1996-07-09 | 1999-10-12 | Nanogen, Inc. | Multiplexed active biologic array |
US6468742B2 (en) | 1993-11-01 | 2002-10-22 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US5807522A (en) | 1994-06-17 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for fabricating microarrays of biological samples |
US5556752A (en) | 1994-10-24 | 1996-09-17 | Affymetrix, Inc. | Surface-bound, unimolecular, double-stranded DNA |
US5830645A (en) | 1994-12-09 | 1998-11-03 | The Regents Of The University Of California | Comparative fluorescence hybridization to nucleic acid arrays |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5959098A (en) | 1996-04-17 | 1999-09-28 | Affymetrix, Inc. | Substrate preparation process |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6013516A (en) | 1995-10-06 | 2000-01-11 | The Salk Institute For Biological Studies | Vector and method of use for nucleic acid delivery to non-dividing cells |
US6022963A (en) | 1995-12-15 | 2000-02-08 | Affymetrix, Inc. | Synthesis of oligonucleotide arrays using photocleavable protecting groups |
SG83659A1 (en) | 1996-01-10 | 2001-10-16 | Kibun Shokuhin Kk | Cylindrical food consisting of plurality of concentric cylindrical layers of food material and method and apparatus for making the same |
GB9603256D0 (en) | 1996-02-16 | 1996-04-17 | Wellcome Found | Antibodies |
US6013440A (en) | 1996-03-11 | 2000-01-11 | Affymetrix, Inc. | Nucleic acid affinity columns |
US6300065B1 (en) | 1996-05-31 | 2001-10-09 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
WO1997046313A1 (en) | 1996-06-07 | 1997-12-11 | Eos Biotechnology, Inc. | Immobilised linear oligonucleotide arrays |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
PT994903E (pt) | 1997-06-24 | 2005-10-31 | Genentech Inc | Metodos e composicoes para glicoproteinas galactosiladas |
US6826296B2 (en) | 1997-07-25 | 2004-11-30 | Affymetrix, Inc. | Method and system for providing a probe array chip design database |
CN1273609A (zh) | 1997-08-15 | 2000-11-15 | 希斯克有限公司 | 检测或量化核酸物类的方法和组合物 |
DE69833698T2 (de) | 1997-09-11 | 2006-11-16 | Bioventures, Inc., Murfreesboro | Verfahren zur Herstellung von Arrays hoher Dichte |
US6465178B2 (en) | 1997-09-30 | 2002-10-15 | Surmodics, Inc. | Target molecule attachment to surfaces |
WO1999022764A1 (en) | 1997-10-31 | 1999-05-14 | Genentech, Inc. | Methods and compositions comprising glycoprotein glycoforms |
IL136544A0 (en) | 1997-12-05 | 2001-06-14 | Scripps Research Inst | Humanization of murine antibody |
US5994136A (en) | 1997-12-12 | 1999-11-30 | Cell Genesys, Inc. | Method and means for producing high titer, safe, recombinant lentivirus vectors |
ES2532910T3 (es) | 1998-04-02 | 2015-04-01 | Genentech, Inc. | Variantes de anticuerpos y fragmentos de los mismos |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6537749B2 (en) | 1998-04-03 | 2003-03-25 | Phylos, Inc. | Addressable protein arrays |
WO1999054342A1 (en) | 1998-04-20 | 1999-10-28 | Pablo Umana | Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity |
US6048695A (en) | 1998-05-04 | 2000-04-11 | Baylor College Of Medicine | Chemically modified nucleic acids and methods for coupling nucleic acids to solid support |
DE69930328T2 (de) | 1998-08-27 | 2006-12-14 | Spirogen Ltd., Ryde | Dimere Pyrrolobenzodiazepine |
US6277628B1 (en) | 1998-10-02 | 2001-08-21 | Incyte Genomics, Inc. | Linear microarrays |
US6277489B1 (en) | 1998-12-04 | 2001-08-21 | The Regents Of The University Of California | Support for high performance affinity chromatography and other uses |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
ES2694002T3 (es) | 1999-01-15 | 2018-12-17 | Genentech, Inc. | Polipéptido que comprende una región Fc de IgG1 humana variante |
US20090130718A1 (en) | 1999-02-04 | 2009-05-21 | Diversa Corporation | Gene site saturation mutagenesis |
ES2568899T3 (es) | 1999-04-09 | 2016-05-05 | Kyowa Hakko Kirin Co., Ltd. | Procedimiento para controlar la actividad de una molécula inmunofuncional |
US6221653B1 (en) | 1999-04-27 | 2001-04-24 | Agilent Technologies, Inc. | Method of performing array-based hybridization assays using thermal inkjet deposition of sample fluids |
US6653151B2 (en) | 1999-07-30 | 2003-11-25 | Large Scale Proteomics Corporation | Dry deposition of materials for microarrays using matrix displacement |
JP4668498B2 (ja) | 1999-10-19 | 2011-04-13 | 協和発酵キリン株式会社 | ポリペプチドの製造方法 |
US20010008765A1 (en) | 1999-12-06 | 2001-07-19 | Fuji Photo Film Co., Ltd. | DNA chip and reactive solid carrier |
ES2274823T3 (es) | 1999-12-29 | 2007-06-01 | Immunogen, Inc. | Agentes cototoxicos que comprenden doxorrubicinas y daunorrubicinas y su utilizacion terapeutica. |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
MXPA02008265A (es) | 2000-02-24 | 2004-09-10 | Xcyte Therapies Inc | Concentracion y estimulacion simultanea de calulas. |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US6908744B1 (en) | 2000-03-14 | 2005-06-21 | Regeneron Pharmaceuticals, Inc. | Methods of stimulating cartilage formation |
PL357939A1 (en) | 2000-04-11 | 2004-08-09 | Genentech, Inc. | Multivalent antibodies and uses therefor |
JP3924113B2 (ja) | 2000-05-15 | 2007-06-06 | 株式会社日立グローバルストレージテクノロジーズ | 複数のヘッドサスペンションアッセンブリを有するヘッドキャリッジアッセンブリ及びこれを用いた磁気ディスク装置 |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
ES2651952T3 (es) | 2000-10-06 | 2018-01-30 | Kyowa Hakko Kirin Co., Ltd. | Células que producen unas composiciones de anticuerpo |
US6946292B2 (en) | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
US7064191B2 (en) | 2000-10-06 | 2006-06-20 | Kyowa Hakko Kogyo Co., Ltd. | Process for purifying antibody |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
HUP0700103A3 (en) | 2001-08-03 | 2012-09-28 | Glycart Biotechnology Ag | Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity |
WO2003026577A2 (en) | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
CN100423777C (zh) | 2001-10-25 | 2008-10-08 | 杰南技术公司 | 糖蛋白组合物 |
EP1482972A4 (en) | 2001-11-20 | 2005-11-23 | Seattle Genetics Inc | TREATMENT OF IMMUNOLOGICAL DISORDERS USING ANTI-CD30 ANTIBODIES |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
WO2003085118A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Procede de production de composition anticorps |
US20050031613A1 (en) | 2002-04-09 | 2005-02-10 | Kazuyasu Nakamura | Therapeutic agent for patients having human FcgammaRIIIa |
EP1498491A4 (en) | 2002-04-09 | 2006-12-13 | Kyowa Hakko Kogyo Kk | METHOD FOR INCREASING THE ACTIVITY OF AN ANTIBODY COMPOSITION FOR BINDING TO THE FC GAMMA RECEPTOR IIIA |
AU2003236020B2 (en) | 2002-04-09 | 2009-03-19 | Kyowa Hakko Kirin Co., Ltd. | Cell with depression or deletion of the activity of protein participating in GDP-fucose transport |
JPWO2003084569A1 (ja) | 2002-04-09 | 2005-08-11 | 協和醗酵工業株式会社 | 抗体組成物含有医薬 |
CN1930288B (zh) | 2002-04-09 | 2012-08-08 | 协和发酵麒麟株式会社 | 基因组被修饰的细胞 |
EP1382969A1 (en) | 2002-07-17 | 2004-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Diagnosis and prevention of cancer cell invasion |
PT1545613E (pt) | 2002-07-31 | 2011-09-27 | Seattle Genetics Inc | Conjugados de auristatina e sua utilização para tratamento do cancro, de uma doença autoimune ou de uma doença infecciosa |
US20050180972A1 (en) | 2002-07-31 | 2005-08-18 | Wahl Alan F. | Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders |
DE60336149D1 (de) | 2002-08-16 | 2011-04-07 | Immunogen Inc | Vernetzer mit hoher reaktivität und löslichkeit und ihre verwendung bei der herstellung von konjugaten für die gezielte abgabe von kleinmolekularen arzneimitteln |
US7361740B2 (en) | 2002-10-15 | 2008-04-22 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
EP1944320A1 (en) | 2002-12-16 | 2008-07-16 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
JP4148883B2 (ja) | 2002-12-18 | 2008-09-10 | 株式会社パイオラックス | グローブボックス用リッドロック装置 |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
AU2003215821B2 (en) | 2003-03-31 | 2009-04-23 | Council Of Scientific And Industrial Research | Non-cross-linking pyrrolo(2,1-c)(1,4)benzodiazepines as potential antitumour agents and process thereof |
US7755007B2 (en) | 2003-04-17 | 2010-07-13 | K&H Manufacturing, Inc | Heated pet mat |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
AU2004279742A1 (en) | 2003-10-08 | 2005-04-21 | Kyowa Hakko Kirin Co., Ltd. | Fused protein composition |
JPWO2005035778A1 (ja) | 2003-10-09 | 2006-12-21 | 協和醗酵工業株式会社 | α1,6−フコシルトランスフェラーゼの機能を抑制するRNAを用いた抗体組成物の製造法 |
CA2543318C (en) | 2003-10-22 | 2013-01-08 | B. Rao Vishnuvajjala | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
HUE038955T2 (hu) | 2003-11-05 | 2018-12-28 | Roche Glycart Ag | Antigén-kötõ molekulák fokozott Fc receptor-kötõ affinitással és effektor funkcióval |
SG10201701737XA (en) | 2003-11-06 | 2017-04-27 | Seattle Genetics Inc | Monomethylvaline compounds capable of conjugation to ligands |
WO2005053742A1 (ja) | 2003-12-04 | 2005-06-16 | Kyowa Hakko Kogyo Co., Ltd. | 抗体組成物を含有する医薬 |
WO2005082023A2 (en) | 2004-02-23 | 2005-09-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
JP5166861B2 (ja) | 2004-03-09 | 2013-03-21 | スピロゲン リミティッド | ピロロベンゾジアゼピン |
US20050260711A1 (en) | 2004-03-30 | 2005-11-24 | Deepshikha Datta | Modulating pH-sensitive binding using non-natural amino acids |
MXPA06011199A (es) | 2004-03-31 | 2007-04-16 | Genentech Inc | Anticuerpos anti-tgf-beta humanizados. |
SG172616A1 (en) | 2004-04-13 | 2011-07-28 | Hoffmann La Roche | Anti-p-selectin antibodies |
BRPI0510883B8 (pt) | 2004-06-01 | 2021-05-25 | Genentech Inc | composto conjugado de droga e anticorpo, composição farmacêutica, método de fabricação de composto conjugado de droga e anticorpo e usos de uma formulação, de um conjugado de droga e anticorpo e um agente quimioterapêutico e de uma combinação |
CA2578217A1 (en) | 2004-08-23 | 2006-03-02 | Emory University | Improved selection of ph-dependent compounds for in vivo therapy |
TWI380996B (zh) | 2004-09-17 | 2013-01-01 | Hoffmann La Roche | 抗ox40l抗體 |
ES2579805T3 (es) | 2004-09-23 | 2016-08-16 | Genentech, Inc. | Anticuerpos y conjugados modificados por ingeniería genética con cisteína |
US20100111856A1 (en) | 2004-09-23 | 2010-05-06 | Herman Gill | Zirconium-radiolabeled, cysteine engineered antibody conjugates |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
JP5171621B2 (ja) | 2005-07-07 | 2013-03-27 | シアトル ジェネティックス, インコーポレイテッド | フェニルアラニン側鎖修飾をc末端に有するモノメチルバリン化合物 |
WO2007008848A2 (en) | 2005-07-07 | 2007-01-18 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus |
JP2009511067A (ja) | 2005-10-14 | 2009-03-19 | メディミューン,エルエルシー | 抗体ライブラリーの細胞提示 |
EP1813614B1 (en) | 2006-01-25 | 2011-10-05 | Sanofi | Cytotoxic agents comprising new tomaymycin derivatives |
PE20071309A1 (es) * | 2006-02-17 | 2008-02-13 | Wyeth Corp | Anticuerpos para la modulacion de formacion de huesos |
US7624657B2 (en) | 2006-07-12 | 2009-12-01 | Thermotion Corporation | Motor-driven actuator |
USRE47123E1 (en) | 2006-07-18 | 2018-11-13 | Sanofi | EPHA2 receptor antagonist antibodies |
EP2471816A1 (en) | 2006-08-30 | 2012-07-04 | Genentech, Inc. | Multispecific antibodies |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
US20080226635A1 (en) | 2006-12-22 | 2008-09-18 | Hans Koll | Antibodies against insulin-like growth factor I receptor and uses thereof |
WO2008127707A1 (en) | 2007-04-13 | 2008-10-23 | Dana Farber Cancer Institute, Inc. | Receptor tyrosine kinase profiling |
PL2019104T3 (pl) | 2007-07-19 | 2014-03-31 | Sanofi Sa | Środki cytotoksyczne obejmujące nowe pochodne tomaymycyny i ich zastosowanie terapeutyczne |
WO2009059235A2 (en) | 2007-11-01 | 2009-05-07 | Facet Biotech Corporation | Immunoglobulin display vectors |
ES2556214T3 (es) | 2007-11-12 | 2016-01-14 | U3 Pharma Gmbh | Anticuerpos para AXL |
CA2706549A1 (en) | 2007-11-15 | 2009-05-22 | Chugai Seiyaku Kabushiki Kaisha | Monoclonal antibody capable of binding to anexelekto, and use thereof |
PL2235064T3 (pl) | 2008-01-07 | 2016-06-30 | Amgen Inc | Sposób otrzymywania cząsteczek przeciwciał z heterodimerycznymi fc z zastosowaniem kierujących efektów elektrostatycznych |
EP2240495B1 (en) | 2008-02-01 | 2015-07-15 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
CA2727915C (en) | 2008-07-15 | 2016-04-26 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
ES2961498T3 (es) | 2008-08-26 | 2024-03-12 | Hope City | Método y composiciones para el funcionamiento mejorado del efecto antitumoral de las células T |
TWI686405B (zh) | 2008-12-09 | 2020-03-01 | 建南德克公司 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
AU2010222818B2 (en) | 2009-03-09 | 2015-05-14 | Bioatla, Llc | Mirac proteins |
EP2451844B1 (en) | 2009-07-10 | 2015-04-22 | Innate Pharma | Tlr3 binding agents |
ES2701931T3 (es) | 2009-07-17 | 2019-02-26 | Bioatla Llc | Selección y evolución simultáneas e integradas de rendimiento y expresión de anticuerpos/proteínas en huéspedes de producción |
TW201106972A (en) | 2009-07-27 | 2011-03-01 | Genentech Inc | Combination treatments |
FR2953841B1 (fr) | 2009-12-16 | 2011-12-30 | Centre Nat Rech Scient | Anticorps diriges contre le recepteur de la transferrine et leurs utilisations pour l'immunotherapie des tumeurs qui dependent du fer |
WO2011109726A2 (en) | 2010-03-05 | 2011-09-09 | Bioatla Llc | Homologous multi-specific antibodies |
US20110256157A1 (en) | 2010-04-15 | 2011-10-20 | Spirogen Limited | Pyrrolobenzodiazepines and conjugates thereof |
WO2011159980A1 (en) | 2010-06-18 | 2011-12-22 | Genentech, Inc. | Anti-axl antibodies and methods of use |
FI20105715A0 (fi) | 2010-06-18 | 2010-06-18 | Helsingin Yliopisto | Asetyloituun HMGB1:een sitoutuva polyklonaalinen vasta-aine |
DK2614077T3 (en) | 2010-09-08 | 2016-11-21 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Chimeric antigen receptors with an optimized hinge region |
CA2810668A1 (en) | 2010-09-08 | 2012-03-15 | Halozyme, Inc. | Methods for assessing and identifying or evolving conditionally active therapeutic proteins |
EP2622074B1 (en) | 2010-09-30 | 2014-11-12 | Board Of Trustees Of Northern Illinois University | Library-based methods and compositions for introducing molecular switch functionality into protein affinity reagents |
EA034333B1 (ru) | 2010-11-30 | 2020-01-29 | Дженентек, Инк. | Варианты антитела для переноса соединения через гематоэнцефалический барьер |
EA201391059A1 (ru) | 2011-01-18 | 2014-05-30 | Дзе Трастиз Оф Дзе Юниверсити Оф Пенсильвания | Композиции для лечения рака и способы их применения |
GB201108236D0 (en) | 2011-05-17 | 2011-06-29 | Ucl Business Plc | Method |
ES2795023T3 (es) | 2011-09-16 | 2020-11-20 | Baylor College Medicine | Reconocimiento específico del microambiente tumoral mediante el uso de células NKT manipuladas |
RU2732151C2 (ru) | 2011-09-30 | 2020-09-11 | Чугаи Сейяку Кабусики Кайся | Библиотека зависимых от концентрации ионов связывающих молекул |
US20140322234A1 (en) * | 2012-01-03 | 2014-10-30 | The Board Of Trustees Of The Leland Stanford Junior University | Analysis and Targeting of ROR2 in Cancer |
EP2814846B1 (en) | 2012-02-13 | 2020-01-08 | Seattle Children's Hospital d/b/a Seattle Children's Research Institute | Bispecific chimeric antigen receptors and therapeutic uses thereof |
KR20140135715A (ko) | 2012-02-22 | 2014-11-26 | 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 | 항종양 활성 및 car 지속을 증진시키기 위한 icos 기반 car의 용도 |
ES2959443T3 (es) | 2012-02-22 | 2024-02-26 | Univ Pennsylvania | Uso del dominio de señalización de CD2 en receptores de antígenos quiméricos de segunda generación |
EP2822970A1 (en) * | 2012-03-08 | 2015-01-14 | Halozyme, Inc. | Conditionally active anti-epidermal growth factor receptor antibodies and methods of use thereof |
US9511152B2 (en) | 2012-04-05 | 2016-12-06 | The Board Of Regents Of The University Of Texas System | Multicolored pH-activatable fluorescence nanoplatform |
US20130280220A1 (en) | 2012-04-20 | 2013-10-24 | Nabil Ahmed | Chimeric antigen receptor for bispecific activation and targeting of t lymphocytes |
IN2014DN09417A (zh) | 2012-05-10 | 2015-07-17 | Bioatla Llc | |
EP2872617A4 (en) | 2012-07-13 | 2015-12-09 | Univ Pennsylvania | EXTENSION OF EPITOPES IN RELATION TO T CAR LYMPHOCYTES |
CN109369808B (zh) * | 2012-08-24 | 2023-11-07 | 加利福尼亚大学董事会 | 用于治疗ror1癌症并抑制转移的抗体和疫苗 |
SG11201501471VA (en) | 2012-09-04 | 2015-03-30 | Cellectis | Multi-chain chimeric antigen receptor and uses thereof |
JP6450690B2 (ja) | 2013-02-15 | 2019-01-09 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | キメラ抗原受容体及びその使用方法 |
RU2019137208A (ru) | 2013-02-20 | 2020-02-19 | Новартис Аг | ЛЕЧЕНИЕ РАКА С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО АНТИГЕНСПЕЦИФИЧЕСКОГО РЕЦЕПТОРА НА ОСНОВЕ ГУМАНИЗИРОВАННОГО АНТИТЕЛА ПРОТИВ EGFRvIII |
KR20150127199A (ko) | 2013-03-14 | 2015-11-16 | 제넨테크, 인크. | 항-b7-h4 항체 및 면역접합체 |
US20160229918A1 (en) | 2013-07-11 | 2016-08-11 | Benovus Bio, Inc. | Tumor selective antibodies specific to oncofetal antigen/immature laminin receptor protein |
EP3039040B1 (en) | 2013-08-26 | 2021-12-22 | Hinrich Abken | Anti cd30 chimeric antigen receptor and its use |
JP6282745B2 (ja) | 2013-09-12 | 2018-02-21 | ハロザイム インコーポレイテッド | 修飾抗上皮成長因子受容体抗体およびその使用法 |
GB201402631D0 (en) | 2014-02-14 | 2014-04-02 | Alligator Bioscience Ab | Library |
US11111288B2 (en) | 2014-08-28 | 2021-09-07 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified t-cells |
US20170260261A1 (en) | 2014-08-28 | 2017-09-14 | Bioatla, Llc | Conditionally Active Chimeric Antigen Receptors for Modified T-Cells |
AU2015311911B2 (en) | 2014-09-03 | 2019-01-24 | Bioatla, Llc | Discovering and producing conditionally active biologic proteins in the same eukaryotic cell production hosts |
AU2016222830B2 (en) * | 2015-02-24 | 2021-02-25 | Bioatla Llc | Conditionally active biological proteins |
US11149088B2 (en) | 2016-04-15 | 2021-10-19 | Bioatla, Inc. | Anti-Axl antibodies, antibody fragments and their immunoconjugates and uses thereof |
KR102585956B1 (ko) | 2016-08-31 | 2023-10-05 | 바이오아트라, 인코퍼레이티드 | 조건부 활성 폴리펩티드 및 이를 제조하는 방법 |
EP3571229A1 (en) * | 2017-01-18 | 2019-11-27 | F1 Oncology, Inc. | Chimeric antigen receptors against axl or ror2 and methods of use thereof |
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