CN111801334B - 使用包含btk抑制剂的组合治疗惰性或侵袭性b-细胞淋巴瘤 - Google Patents
使用包含btk抑制剂的组合治疗惰性或侵袭性b-细胞淋巴瘤 Download PDFInfo
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Abstract
本申请公开了在个体中预防惰性或侵袭性B细胞淋巴瘤、延迟惰性或侵袭性B细胞淋巴瘤进展或治疗惰性或侵袭性B细胞淋巴瘤的方法,包括向有此需要的个体施用Btk抑制剂(特别是(S)‑7‑(1‑丙烯酰基哌啶‑4‑基)‑2‑(4‑苯氧基苯基)‑4,5,6,7‑四氢吡唑并[1,5‑a]嘧啶‑3‑甲酰胺或其药学上可接受的盐)与抗PD‑1抗体的组合。本申请的有效的和选择性的BTK抑制剂联合抗PD‑1抗体在惰性和侵袭性淋巴瘤患者中表现出毒性可控的特点。
Description
本申請要求2017年11月29日提交的本申请要求美国临时申请号U.S.62/592,1 11的优先权,在此以其整体引入作为参考。
以电子方式提交的文本文件的内容全部通过引用并入本文中:序列列表的计算机可读格式副本(文件名:BEIG-030 U 0lWOSeqList.TXT文件,日期记录为2018年11月29日,文件大小为126千字节)。
技术领域
本申请公开了在个体中预防惰性或侵袭性B细胞淋巴瘤、延迟惰性或侵袭性B细胞淋巴瘤进展或治疗惰性或侵袭性B细胞淋巴瘤的方法,包括向有此需要的个体施用Btk抑制剂(特别是(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺或其药学上可接受的盐)与抗PD-1抗体的组合。本申请的有效的和选择性的BTK抑制剂联合抗PD-1抗体在惰性和侵袭性淋巴瘤患者中表现出毒性可控的特点。
背景技术
淋巴系统由淋巴结、淋巴器官和淋巴管组成,并且淋巴系统携带淋巴液(一种含有淋巴细胞的无色液体)。淋巴细胞有几种类型,包括:B淋巴细胞或B细胞,以及T淋巴细胞或T细胞。
淋巴瘤是淋巴组织的癌症。这些癌症包括一类异源性癌症,分为非霍奇金淋巴瘤(NHL)和霍奇金淋巴瘤(HL)。淋巴瘤有两种主要类型:霍奇金淋巴瘤和非霍奇金淋巴瘤(NHL)。在西方国家,约90%的淋巴瘤患者患有B细胞非霍奇金淋巴瘤(https://www.cancer.net/cancer-types/lymphoma-non-hodgkin/subtypes)。
基于癌症生长的快慢,NHL可以归类为侵袭性NHL或惰性NHL。惰性NHL类型的预后相对较好,但在晚期临床阶段无法治愈。大多数惰性类型在形态上呈结节状(或滤泡状)。迄今为止,滤泡性淋巴瘤(FL)是惰性NHL中最常见的一种,并且占所有新发NHL病例的近25%。NHL的侵袭性类型(例如弥漫性大B细胞淋巴瘤(DLBCL))的预期寿命较短。
布鲁顿氏酪氨酸激酶(Bruton's tyrosine kinase,Btk)属于细胞质酪氨酸激酶的Tec家族,其为人中非受体激酶的第二大家族[Vetrie et al.,Nature 361:226-233,1993;Bradshaw,Cell Signal.22:1175-84,2010]。其表达在造血体系的除了T细胞的所有细胞谱系中,并定位于骨髓、脾和淋巴结组织中[Smith et al.,J.Immunol.152:557-565,1994]。编码Btk的基因中的失活突变造成人中的X连锁无γ球蛋白血症(XLA)和小鼠中的X连锁免疫缺陷(XID)[Conley et al.,Annu.Rev.Immunol.27:199-227,2009]。这两种疾病的特征是B细胞发育和功能的引人注目的缺陷,表明Btk对于B细胞发育和功能的关键作用。此外,Btk在B细胞中的结构性活化导致自体反应性血浆细胞的累积[Kersseboom et al.,Eur J Immunol.40:2643-2654,2010]。Btk由在BCR信号通路中的上游Src-家族激酶活化。一旦活化,Btk转而将磷脂酶-Cγ(PLCγ)磷酸化,导致Ca2+调动及NF-κB和MAP激酶通路的活化。这些近端信号传导事件促进涉及增殖和存活的基因的表达[Humphries et al.,J.Biol.Chem.279:37651,2004]。除了其作为BCR下游的必要调节作用之外,Btk活性在FcR信号传导中也发挥关键作用。经由FcRγ相关受体的信号传导通过细胞诸如巨噬细胞还促进Btk依赖性促炎症反应性细胞因子的产生[Di Paolo et al.,Nat.Chem.Biol.7:41-50,2011]。Btk由于其在BCR和FcR信号传导通路的近端位置已经是重要的靶标。临床前研究显示Btk缺失的小鼠对发展出胶原蛋白诱导的关节炎是抗性的。此外,利妥昔单抗(Rituxan)(一种消耗成熟B细胞CD20抗体)的临床研究,揭示B细胞在许多炎性疾病诸如类风湿性关节炎、系统性红斑狼疮和多发性硬化中的关键作用[Gurcan et al.,Int.Immunopharmacol.9:10-25,2009]。此外,Btk的异常活化在B细胞淋巴瘤的病因学中发挥重要作用,表明抑制Btk可用于治疗血液恶性肿瘤[Davis et al.,Nature 463:88-92,2010]。
WO2014/173289A1公开了一系列作为Btk抑制剂的具有如下通式(I)的稠合杂环化合物或其立体异构体或药学上可接受的盐,其显示出针对布鲁顿氏酪氨酸激酶的强效抑制活性。
WO2018/033853A2公开了WO 2014/173289 A1中的Btk抑制剂的晶型,特别是(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(下文称为化合物1)的晶型,用于治疗具有其中Btk发挥重要作用的B细胞受体(BCR)和FcR信号传导通路的畸变(aberration)的癌症。化合物1已经展示具有强效且不可逆的针对Btk的抑制活性。WO2014/173289和WO2018/033853公开的内容在此以其整体引入作为参考。
发明内容
本发明的发明人发现Btk抑制剂(特别是,上述化合物1)与抗PD-1抗体组合,可以用于治疗个体惰性或侵袭性B-细胞淋巴瘤。
在第一方面,本申请公开了在个体中预防惰性或侵袭性B-细胞淋巴瘤、延迟惰性或侵袭性B-细胞淋巴瘤进展或治疗惰性或侵袭性B-细胞淋巴瘤的方法,包括向有此需要的个体施用治疗有效量的式(I)的Btk抑制剂或其立体异构体或其药学上可接受的盐与治疗有效量的抗PD-1抗体的组合。
在第二方面,本申请公开了式(I)的Btk抑制剂或其立体异构体或其药学上可接受的盐,其与抗PD-1抗体组合,用于预防惰性或侵袭性B-细胞淋巴瘤、延迟惰性或侵袭性B-细胞淋巴瘤进展或治疗惰性或侵袭性B-细胞淋巴瘤。在该方面的一个实施方案中,本申请公开了抗PD-1抗体,其与式(I)的Btk抑制剂或其立体异构体或其药学上可接受的盐组合,用于预防惰性或侵袭性B-细胞淋巴瘤、延迟惰性或侵袭性B-细胞淋巴瘤进展或治疗惰性或侵袭性B-细胞淋巴瘤。
本申请所述的方法和药物组合产品,作为组合疗法,比任一单一药剂显著更有效。
在上述方面中每一个的一个实施方案中,所述抗PD-1抗体为单克隆抗体。
在上述两个方面中每一个的一个实施方案中,所述惰性或侵袭性B-细胞淋巴瘤为惰性或侵袭性霍奇金淋巴瘤。在其他实施方案中,所述惰性或侵袭性B细胞淋巴瘤为惰性或侵袭性非霍奇金淋巴瘤。在进一步的实施方案中,所述惰性或侵袭性B-细胞淋巴瘤为惰性或侵袭性慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、毛细胞白血病(HCL)、伯基特样白血病(BL)、B细胞前淋巴细胞性白血病(B-PLL)、弥散性大B细胞淋巴瘤(DLBCL)、生发中心B细胞弥散性大B细胞淋巴瘤(GCB-DLBCL)、非生发中心B细胞弥散性大B细胞淋巴瘤(非-GCB DLBCL)、未确定亚型的DLBCL、原发性中枢神经系统淋巴瘤(PCNSL)、乳房或睾丸起源的继发性中枢神经系统淋巴瘤(SCNSL)、多发性骨髓瘤、淋巴结外边缘区B细胞淋巴瘤、结内边缘区B细胞淋巴瘤、伯基特淋巴瘤、非伯基特高级别B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤(PMBL)、成免疫细胞大细胞淋巴瘤、前体B成淋巴细胞性淋巴瘤、B细胞前淋巴细胞性白血病、淋巴浆细胞性淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、浆细胞瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发渗透性淋巴瘤、淋巴瘤样肉芽肿病,或其组合。在上述方面中每一个的一个实施方案中,所述惰性或侵袭性B-细胞淋巴瘤为惰性或侵袭性弥散性大B细胞淋巴瘤(DLBCL)。在上述方面中每一个的一个实施方案中,DLBCL为活化的B细胞弥散性大B细胞淋巴瘤(ABC-DLBCL)、GCB-DLBCL或非-GCB DLBCL。在上述方面中每一个的一个实施方案中,所述惰性或侵袭性B-细胞淋巴瘤为惰性或侵袭性慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。在上述方面中每一个的一个实施方案中,所述惰性或侵袭性B-细胞淋巴瘤为惰性或侵袭性复发性或难治性(R/R)B细胞恶性肿瘤。在上述方面中每一个的一个实施方案中,所述复发性或难治性B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)。在上述方面中每一个的一个实施方案中,所述复发性或难治性DLBCL为活化的B细胞弥散性大B细胞淋巴瘤(ABC-DLBCL)、GCB-DLBCL或非-GCB DLBCL。在上述方面中每一个的一个实施方案中,所述复发性或难治性(R/R)B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。在上述方面中每一个的一个实施方案中,所述B细胞恶性肿瘤为转移性B细胞恶性肿瘤。在上述方面中每一个的一个实施方案中,所述转移性B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。
在上述方面中每一个的一个实施方案中,所述BTK抑制剂为(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物1),或其药学上可接受的盐。在上述方面中每一个的一个实施方案中,所述抗PD-1抗体为本申请所公开的抗体-1(Mab 1)。在上述方面中每一个的一个实施方案中,所述Btk抑制剂和抗-PD-1抗体同时、顺序或间歇施用。
附图简述
图1示出化合物1和抗体-1组合的试验设计。
图2示出当前节点的患者处置。
图3A和图3B示出惰性和侵袭性淋巴瘤患者分别的SPD最大改善。
图4A和图4B示出惰性和侵袭性和急性淋巴瘤患者分别的疗程。
图5A和图5B示出惰性和侵袭性淋巴瘤患者分别的无进展生存期。
图6示出化合物1结晶形式的X射线衍射图。
图7示出化合物1的晶型的1H-NMR。
图8示出化合物1的晶型的13C-NMR。
发明详述
缩写(1):
缩写(2):
定义
除非在本申请件中另外具体指定,否则本申请所使用的所有其他科学和技术术语具有本发明所属领域的技术人员通常理解的含义。
本申请包括所附权利要求使用的单数形式的词语如“一”、“一种”和“所述”,包括它们对应的复数指代,除非上下文清楚地表明其他情况。
术语“或”用来表示并可与术语“和/或”互换使用,除非上下文另外清楚表示其他含义。
在本说明书和权利要求书的全文中,除非上下文有其他要求,术语“包含”及变体如“含有”和“包括”,将会被理解隐含包括所述活性剂(例如,mAb或Btk抑制剂)或所述氨基酸序列,但是不排除任何其他活性成份或氨基酸序列。当本申请使用时,术语“包含”可与术语“含有”或“包括”互换。
术语“烷基”是指选自1-18,或1-12,或1-6个碳原子的直链或支链饱和烃基的烃基。烷基的实例包括甲基、乙基、1-丙基或正丙基(“n-Pr”)、2-丙基或异丙基(“i-Pr”)、1-丁基或正丁基(“n-Bu”)、2-甲基-1-丙基或异丁基(“i-Bu”)、1-甲基丙基或仲丁基(“s-Bu”)和1,1-二甲基乙基或叔丁基(“t-Bu”)。烷基的其他实例包括1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3-二甲基-2-丁基。低级烷基表示1-8、优选1-6、更优选1-4个碳原子;低级烯基或炔基表示2-8、2-6或2-4个碳原子。
术语“烯基”是指选自包含至少一个C=C双键和2-18或2-12或2-6个碳原子的直链烃基或支链烃基的烃基。烯基的实例选自乙烯基(ethenyl或vinyl)、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
术语“炔基”是指包含至少一个C≡C三键和2-18或2-12或2-6个碳原子的直链烃基或支链烃基的烃基。炔基的实例包括乙炔基、1-丙炔基、2-丙炔基(炔丙基)、1-丁炔基、2-丁炔基和3-丁炔基。
术语“环烷基”是指选自饱和及部分饱和的环状烃基的烃基,包括单环和多环(例如,二环和三环)基团。例如,环烷基可具有3-12或3-8或3-6个碳原子。再例如,环烷基可为具有3-12或3-8或3-6个碳原子的单环基团。单环环烷基的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基基团。二环环烷基的实例包括具有7-12个环原子的排列为选自[4,4]、[4,5]、[5,5]、[5,6]和[6,6]环体系二环的那些,或排列为选自二环[2.2.1]庚烷、二环[2.2.2]辛烷和二环[3.2.2]壬烷的桥接二环的那些。所述环可为饱和的或者具有至少一个双键(即,部分饱和的),但不是完全共轭的,且不是芳族的,如本申请所定义的芳族的。
本申请的术语“芳基”是指选自以下的基团:5和6元碳环芳族环,例如,苯基;二环体系诸如7-12元二环体系,其中至少一个环为碳环和芳族环,选自例如萘和茚满;和三环体系诸如10-15元三环体系,其中至少一个环为碳环和芳族环,例如,芴。例如,所述芳基选自稠合至任选含有至少一个选自N、O和S的杂原子的5至7元环烷基或杂环的5和6元碳环芳族环,条件是当碳环芳族环与杂环稠合时,连接点在碳环芳族环处,且当碳环芳族环与环烷基稠合时,连接点可位于碳环芳族环处或位于环烷基处。从经取代的苯衍生物形成的且在环原子处具有自由价的二价基团命名为经取代的亚苯基。通过以自由价从碳原子除去一个氢原子而衍生自名称以“-基”结尾的单价多环碳基团的二价基团通过将“亚”添加至对应的单价基团名称中,例如,具有两个连接点的萘基称为亚萘基。然而,芳基不包括下文分开定义的杂芳基或者与下文分开定义的杂芳基不重叠。因此,如果一个或多个碳环芳族环与杂环芳族环稠合,所得环体系为杂芳基,而不是如本申请定义的芳基。
术语“卤素”或“卤基”是指F、Cl、Br或I。
术语“杂烷基”是指包含至少一个杂原子的烷基。
术语“杂芳基”是指选自以下的基团:5-7元芳族单环,其包含1、2、3或4个选自N、O和S的杂原子且其余环原子为碳;8-12元二环,其包含1、2、3或4个选自N、O和S的杂原子且其余环原子为碳且其中至少一个环为芳族的且在芳族环中存在至少一个杂原子;和11-14元三环,其包含1、2、3或4个选自N、O和S的杂原子且其余环原子为碳且其中至少一个环为芳族的且在芳族环中存在至少一个杂原子。例如,杂芳基包括与5-7元环烷基环稠合的5-7元杂环芳环。就其中仅一个环包含至少一个杂原子的上述稠合二环杂芳基环系而言,连接点可位于杂芳环或环烷基环。当杂芳基中S和O原子的总数超过1时,那些杂原子不彼此相邻。在一些实施方案中,杂芳基中S和O原子的总数不大于2。在一些实施方案中,芳族杂环中S和O原子的总数不大于1。杂芳基的实例包括但不限于(由优先指定为1的连接位置开始编号),吡啶基(诸如2-吡啶基、3-吡啶基或4-吡啶基)、噌啉基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑并吡啶基、异噁唑基、噁唑基、噻唑基、异噻唑基、噻二唑基、四唑基、噻吩基、三嗪基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、异吲哚基、二氢吲哚基、酞嗪基、吡嗪基、哒嗪基、吡咯基、三唑基、喹啉基、异喹啉基、吡唑基、吡咯并吡啶基(诸如1H-吡咯并[2,3-b]吡啶-5-基)、吡唑并吡啶基(诸如1H-吡唑并[3,4-b]吡啶-5-基)、苯并噁唑基(诸如苯并[d]噁唑-6-基)、蝶啶基、嘌呤基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-硫杂-2,3-二唑基、1-硫杂-2,4-二唑基、1-硫杂-2,5-二唑基、1-硫杂-3,4-二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、二氮杂萘基、呋喃并吡啶基、苯并噻唑基(诸如苯并[d]噻唑-6-基)、吲唑基(诸如1H-吲唑-5-基)和5,6,7,8-四氢异喹啉基。
术语“杂环的”、“杂环”或“杂环基”是指选自4-12元单环、二环和三环饱和及部分不饱和环的环,其除1、2、3或4个选自氧、硫和氮的杂原子外还包含至少一个碳原子。“杂环”还指与5、6和/或7元环烷基、碳环芳环或杂芳环稠合的包含至少一个选自N、O和S的杂原子的5-7元杂环,条件是当杂环与碳环芳环或杂芳环稠合时,连接点位于杂环,而当杂环与环烷基稠合时,连接点可位于环烷基或杂环。
“杂环”还指包含至少一个选自N、O和S的杂原子的脂族螺环,条件是连接点位于杂环。所述环可为饱和的或具有至少一个双键(即部分不饱和的)。杂环可取代有氧代。连接点可为杂环中的碳或杂原子。杂环不是本申请定义的杂芳基。杂环的实例包括但不限于(由优先指定为1的连接位置开始编号),1-吡咯烷基、2-吡咯烷基、2,4-咪唑烷基、2,3-吡唑烷基、1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、2,5-哌嗪基、吡喃基、2-吗啉基、3-吗啉基、氧杂环丙基、氮杂环丙基、硫杂环丙基、氮杂环丁基、氧杂环丁基、硫杂环丁基、1,2-二硫杂环丁基、1,3-二硫杂环丁基、二氢吡啶基、四氢吡啶基、硫吗啉基、氧硫杂环己基、哌嗪基、高哌嗪基、高哌啶基、氮杂环庚基、氧杂环庚基、硫杂环庚基、1,4-氧硫杂环己基、1,4-二氧杂环庚基、1,4-氧硫杂环庚基、1,4-氧氮杂环庚基、1,4-二硫杂环庚基、1,4-硫氮杂环庚基、1,4-二氮杂环庚基、1,4-二噻烷基、1,4-氮硫杂环己基、氧氮杂基、二氮杂/>基、硫氮杂/>基、二氢噻吩基、二氢吡喃基、二氢呋喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、1,4-二噁烷基、1,3-二氧杂环戊基、吡唑啉基、吡唑烷基、二噻烷基、二硫杂环戊基、吡唑烷基、咪唑啉基、嘧啶酮基、1,1-二氧代-硫吗啉基、3-氮杂二环[3.1.0]己基、3-氮杂二环[4.1.0]庚基和氮杂二环[2.2.2]己基。经取代的杂环还包括取代有一个或多个氧代部分的环系,诸如哌啶基-N-氧化物、吗啉基-N-氧化物、1-氧代-1-硫吗啉基和1,1-二氧代-1-硫吗啉基。
取代基选自:卤素、-Ra、-ORa、=O、=NRa、=N-ORa、-NRaRb、-SRa、-SiRaRaRb、-OC(O)Ra、-C(O)Ra、-CO2Ra、-CONRaRb、-OC(O)NRaRb、-NRbC(O)Ra、-NRa-C(O)NRbRb、-NRa-SO2NRb、-NRbCO2Ra、-NH-C(NH2)=NH、-NRaC(NH2)=NH、-NH-C(NH2)=NRa、-S(O)Ra、-SO2Ra、-SO2NRaRb、-NRbSO2R、-CN和-NO2、-N3、-CH(Ph)2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数目为0至3,特别优选具有0、1或2个取代基的那些基团。Ra、Rb和Rc各自独立地指氢、未取代的(C1-C8)烷基和杂烷基、未取代的芳基、取代有1至3个卤素的芳基、未取代的烷基、烷氧基或硫代烷氧基或芳基-(C1-C4)烷基。当Ra和Rb连接至同一氮原子时,它们与氮原子结合形成5、6或7元环。因此,-NRaRb包括1-吡咯烷基和4-吗啉基,“烷基”包括诸如三卤代烷基(例如,-CF3和-CH2CF3)的基团,并且当芳基为1,2,3,4-四氢萘时,其可取代有经取代或未经取代的(C3-C7)螺环烷基。所述(C3-C7)螺环烷基可以如对"环烷基"定义的相同方式取代。优选的取代基选自:卤素、-Ra、-ORa、=O、-NRaRb、-SRa、-SiRaRaRb、-OC(O)Ra、-C(O)Ra、-CO2Ra、-CONRaRb、-OC(O)NRaRb、-NRbC(O)Ra、-NRbCO2Ra、-NRa-SO2NRbRb、-S(O)Ra、-SO2Ra、-SO2NRaRb、-NRbSO2R、-CN和-NO2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,其中Ra和Rb如上所定义。
本申请中的术语“稠合环”是指多环环系,例如二环或三环环系,其中两个环仅共享两个环原子和一个键。稠合环的实例可包括稠合二环环烷基环,诸如具有7-12个环原子的那些二环环烷基环,其排列成选自上述[4,4]、[4,5]、[5,5]、[5,6]和[6,6]环系的二环;稠合二环芳基环,诸如上述7至12元二环芳基环系;稠合三环芳基环,诸如上述10至15元三环芳基环系;稠合二环杂芳基环,诸如上述8至12元二环杂芳基环;稠合三环杂芳基环,诸如上述11至14元三环杂芳基环;及上述稠合二环或三环杂环基环。
当化合物含有烯烃双键时,除非另有指明,否则这种双键意在包括E和Z几何异构体两者。
一些化合物可存在有不同的氢连接点,称为互变异构体。例如,包括羰基-CH2C(O)-基团(酮形式)的化合物可经历互变现象形成羟基-CH=C(OH)-基团(烯醇形式)。当适用时,还意在包括酮和烯醇形式这两者,单独地以及其混合物。
术语“药学上可接受的盐”包括但不限于与无机酸形成的盐,选自,例如,盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐和硝酸盐;以及与有机酸形成的盐,选自,例如,苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐、烷醇盐诸如乙酸盐,和与HOOC-(CH2)n-COOH(其中n选自0至4)形成的盐。类似地,药学上可接受的阳离子的实例包括但不限于,钠、钾、钙、铝、锂和铵。
此外,如果得到的化合物为酸加成盐,游离碱可通过将酸盐的溶液碱化得到。相反,如果产物为游离碱,则加成盐诸如药学上可接受的加成盐可如下制备:根据从碱化合物制备酸加成盐的常规操作,将游离碱溶解于合适的有机溶剂中并以酸处理该溶液。本领域技术人员会认识到无需过度实验就可用于制备无毒性药学上可接受的加成盐的各种合成方法。
本申请中的术语“施用”、“给药”、“治疗”和“处置”,当应用于动物、人类、实验受试者、细胞、组织、器官或生物体液时,是指外源性药物、治疗剂、诊断剂或组合物与动物、人类、受试者、细胞、组织、器官或生物体液的接触。对细胞的处置包括试剂与细胞的接触及试剂与体液的接触,其中所述体液与细胞接触。术语“施用”和“处置”也指例如试剂、诊断剂、结合化合物或另一种细胞的体外和离体处置,例如对细胞的体外和离体处置。本申请中的术语“受试者”包括任何有机体,优选动物,更优选哺乳动物(例如,大鼠、小鼠、犬、猫、兔)且最优选人类。
“有效量”是指有效“治疗”受试者中的疾病或病症的至少一种化合物和/或其至少一种立体异构体和/或其至少一种药学上可接受的盐的量,并且该量在一定显著程度上会引起诸如当施用时正在寻求的组织、系统、动物或人的生物学或医学响应,该量足以预防待治疗病况或病症的一种或多种症状的发展或在一定程度上进行缓解。治疗有效量会根据化合物、疾病及其严重程度和待治疗的哺乳动物的年龄、重量等而变化。
术语“至少一个取代基”包括,例如,1至4个、如1至3个、进一步如1或2个取代基。例如,本申请中的“至少一个取代基R16”包括1至4个、诸如1至3个、进一步如1或2个选自本申请描述的R16列表的取代基。
本申请中的术语“抗体”以最广义使用且具体涵盖抗体(包括全长单克隆抗体)及抗体片段,只要其识别抗原诸如靶向抗原(例如,CD20)或免疫检查点(例如,PD-1)即可。抗体分子通常为单特异性的,但也可描述为独特特异性、异种特异性或多特异性的。抗体分子借助于特异性结合位点与抗原上的特异性抗原决定簇或表位结合。
本申请中的术语“单克隆抗体”或“mAb”或“Mab”是指基本上均质的抗体群,即包含在群中的抗体分子除可少量存在的可能天然存在的突变外在氨基酸序列方面是相同的。相反地,常规(多克隆)抗体制品通常包含多种不同的抗体,所述多种不同的抗体在其可变域特别是其CDR中具有不同的氨基酸序列,所述常规(多克隆)抗体制品通常对不同的表位都具有特异性。修饰语“单克隆”表示由基本上均质的抗体群获得的抗体的特征且不应被解释为需要通过任何特定方法产生抗体。单克隆抗体(mAb)可通过本领域技术人员已知的方法获得。参见例如美国专利4,376,110。本申请公开的mAb可为任何免疫球蛋白类别,包括IgG、IgM、IgD、IgE、IgA及其任何亚类。可对产生mAb的杂交瘤进行体外或体内培养。体内产生可获得高滴度的mAb,其中将来自各个杂交瘤的细胞腹膜内注射到小鼠(诸如原始-始发态(pristine-primed)Balb/c小鼠)中以产生含有高浓度期望mAb的腹水液。可使用本领域技术人员公知的柱色谱法由上述腹水液或培养物上清液纯化同种型IgM或IgG的mAb。
通常,基本抗体结构单元包含四聚体。每个四聚体包含两对相同的多肽链,每对具有一条“轻链”(约25kDa)和一条“重链”(约50-70kDa)。每条链的氨基末端部分包含主要负责抗原识别的具有约100-110个或更多个氨基酸的可变区。重链的羧基末端部分可限定主要负责效应子功能的恒定区。通常,人轻链被分类为κ和λ轻链。另外,人重链通常被分类为α、δ、ε、γ或μ且将抗体的同种型分别限定为IgA、IgD、IgE、IgG和IgM。在轻链和重链中,可变区和恒定区通过具有约12个或更多个氨基酸的“J”区连接,其中重链还包含具有约10个或更多个氨基酸的“D”区。
每个轻链/重链(Vl/Vh)对的可变区形成抗体结合位点。因此,完整抗体通常具有两个结合位点。除双功能或双特异性抗体外,两个结合位点通常是相同的。
通常,重链和轻链的可变结构域都包含位于相对保守的框架区(FR)之间的三个高变区(也称为“互补决定区(CDR)”)。CDR通常通过框架区来对齐,由此能够结合特异性表位。通常,从N末端到C末端,轻链和重链可变结构域两者均包含FR-1(或FR1)、CDR-1(或CDR1)、FR-2(或FR2)、CDR-2(或CDR2)、FR-3(或FR3)、CDR-3(或CDR3)和FR-4(或FR4)。通常,根据以下文献的定义将氨基酸指派至各个结构域:Sequences of Proteins of ImmunologicalInterest,Kabat等,National Institutes of Health,Bethesda,Md.,5<m>ed.,NIHPubl.No.91-3242(1991);Kabat(1978)Adv.Prot.Chem.32:1-75;Kabat等(1977)J.Biol.Chem.252:6609-6616;Chothia等(1987)J Mol.Biol.196:901-917;或Chothia等(1989)Nature 342:878-883。
术语“高变区”是指抗体的负责抗原结合的氨基酸残基。高变区包含来自“互补决定区”或“CDR”(即轻链可变结构域中的CDR-L1、CDR-L2和CDR-L3及重链可变结构域中的CDR-H1、CDR-H2和CDR-H3)的氨基酸残基。参见Kabat等(1991)Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,Md.(通过序列定义抗体的CDR区);另见Chothia and Lesk(1987)J.Mol.Biol.196:901-917(通过结构定义抗体的CDR区)。术语“框架”或“FR”是指除本申请定义为CDR残基的高变区残基外的那些可变结构域残基。
除非另有说明,否则“抗体片段”或“抗原结合片段”是指抗体的抗原结合片段,即保留与由全长抗体结合的抗原特异性结合的能力的抗体片段,例如保留一个或多个CDR区的片段。抗原结合片段的实例包括但不限于,Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体;单链抗体分子,例如,单链Fv(sc-Fv);纳米抗体;和由抗体片段形成的多特异性抗体。
与特定靶标蛋白“特异性结合”的抗体是与其它蛋白质相比优先与该靶标结合的抗体,但是该特异性不需要绝对结合特异性。若抗体的结合在例如不产生不期望的结果诸如假阳性的情况下决定样品中靶标蛋白的存在,则抗体被认为就其所预期的靶标而言是“特异性的”。可用于本发明的抗体或其结合片段将以比与非靶标蛋白的亲和力大至少2倍、优选大至少10倍、更优选大至少20倍且最优选大至少100倍的亲和力与靶标蛋白结合。据说,本申请抗体与包含给定氨基酸序列的多肽例如成熟人PD-1分子的氨基酸序列特异性结合,条件是其与包含该序列的多肽结合,但是不与不具有该序列的蛋白质结合。
本申请中的术语“人源抗体”是指仅包含人免疫球蛋白序列的抗体。若在小鼠、小鼠细胞或衍生自小鼠细胞的杂交瘤中产生,则人抗体可含有鼠型糖链。类似地,“小鼠抗体”或“大鼠抗体”是指分别仅包含小鼠或大鼠免疫球蛋白序列的抗体。
术语“人源化抗体”是指以下抗体形式,其含有来自非人类(例如,鼠类)抗体以及人抗体的序列。上述抗体含有衍生自非人类免疫球蛋白的最小序列。通常,人源化抗体将包含基本上所有至少一个且通常为两个可变结构域,其中所有或基本上所有高变环与非人类免疫球蛋白的那些高变环是对应的且所有或基本上所有FR区是人免疫球蛋白序列的那些FR区。人源化抗体任选还将包含免疫球蛋白恒定区(Fc)通常为人免疫球蛋白恒定区(Fc)的至少一部分。当必要时,将前缀“hum”、“hu”、“Hu”或“h”添加至抗体克隆名称以区分人源化抗体与亲本啮齿动物抗体。啮齿动物抗体的人源化形式通常将包含与亲本啮齿动物抗体相同的CDR序列,尽管可包括某些氨基酸取代以增加亲和力、增加人源化抗体的稳定性或出于其它原因。
本申请中的术语“疾病”是指任何病、不适、恙、症状或适应症,且可用术语“病症”或“病况”替代。
在一些实施方案中,所述B细胞恶性肿瘤为慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、毛细胞白血病(HCL)、伯基特样白血病(BL)、B细胞前淋巴细胞性白血病(B-PLL)、弥散性大B细胞淋巴瘤(DLBCL)、生发中心B细胞弥散性大B细胞淋巴瘤(GCB-DLBCL)、非生发中心B细胞弥散性大B细胞淋巴瘤(非-GCB DLBCL)、亚型未确定的DLBCL、原发性中枢神经系统淋巴瘤(PCNSL)、乳房或睾丸来源的继发性中枢神经系统淋巴瘤(SCNSL)、多发性骨髓瘤、淋巴结外边缘区B细胞淋巴瘤、结内边缘区B细胞淋巴瘤、伯基特淋巴瘤、非伯基特高级别B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤(PMBL)、成免疫细胞大细胞淋巴瘤、前体B成淋巴细胞性淋巴瘤、B细胞前淋巴细胞性白血病、淋巴浆细胞性淋巴瘤、脾边缘区淋巴瘤、浆细胞骨髓瘤、浆细胞瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发渗透性淋巴瘤、淋巴瘤样肉芽肿病,或其组合。在一些实施方案中,所述B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)。在一些实施方案中,所述DLBCL为活化的B细胞弥散性大B细胞淋巴瘤(ABC-DLBCL)、GCB-DLBCL或非-GCB DLBCL。在一些实施方案中,所述B细胞恶性肿瘤为慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。在一些实施方案中,所述B细胞恶性肿瘤为复发性或难治性(R/R)B细胞恶性肿瘤。在一些实施方案中,所述复发性或难治性(R/R)B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)。在一些实施方案中,所述复发性或难治性DLBCL为活化的B细胞弥散性大B细胞淋巴瘤(ABC-DLBCL)、GCB-DLBCL或非-GCB DLBCL。在一些实施方案中,所述复发性或难治性(R/R)B细胞恶性肿瘤为慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。在一些实施方案中,所述B细胞恶性肿瘤为转移性B细胞恶性肿瘤。在一些实施方案中,所述转移性B细胞恶性肿瘤为弥散性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、B细胞前淋巴细胞性白血病(B-PLL)、非-CLL/SLL淋巴瘤、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、瓦尔登斯特伦巨球蛋白血症(WM)、多发性骨髓瘤,或其组合。
术语“CDR”是指免疫球蛋白可变区中的互补性决定区,使用Kabat编码系统进行限定,除非另有指明。
抗PD-1抗体
PD-1为免疫检查点蛋白,其限制在对感染的炎性响应时外周组织中T细胞的活性且体外限制自身免疫性PD-1阻断,在混合淋巴细胞反应中通过特定抗原靶标或同种细胞增强响应于挑战的T细胞增殖和细胞因子产生。PD-1表达和响应之间的强的联系显示为PD-1的阻断(Pardoll,Nature Reviews Cancer,12:252-264,2012)。PD-1阻断可通过包括结合PD-1或其配体的抗体的多种机制来完成。PD-1和PD-L1阻断剂的实例,也称为PD-1和PD-L1抑制剂,描述于US 7488802;US 7943743;US 8008449;US 8,168,757;US 8217149及WO03042402、WO 2008156712、WO 2010089411、WO 2010036959、WO 2011066342、WO2011159877、WO 2011082400、WO 2011161699和WO 2015035606中。在一些实施方案中,所述PD-1抑制剂包括特异性结合PD-1的抗体或其抗原结合片段。在某些其他实施方案中,所述PD-1阻断剂包括抗PD-1抗体和类似的结合蛋白,诸如描述于US 8008449B2中的纳武单抗(nivolumab)(MDX 1106,BMS 936558,ONO-4538,),一种通过其配体PD-L1和PD-L2结合PD-1并阻断PD-1的活化的全人IgG4抗体;公开于US 8168757B2中的派姆单抗(pembrolizumab)(lambrolizumab,MK-3475或SCH 900475,/>),一种针对PD-1的人源化单克隆IgG4抗体;皮地利珠单抗(pidilizumab)(CT-011),一种结合PD-1的人源化抗体;AMP-224,一种B7-DC的融合蛋白;一种抗体Fc部分;BMS-936559(MDX-1105-01),用于PD-L1
(B7-H1)阻断,用于PD-1阻断。
在一些实施方案中,所述抗PD-1抗体为单克隆抗体。在一些实施方案中,所述抗PD-1抗体为纳武单抗(nivolumab)或皮地利珠单抗(pidilizumab)。
在一些实施方案中,所述抗PD-1抗体为在WO 2015/035606A1中公开的单克隆抗体或其片段。
优选地,所述抗PD-1单克隆抗体为包含重链可变区(Vh)和轻链可变区(Vl)的抗体,其含有下列互补决定区(CDR):
优选地,所述抗PD-1单克隆抗体为包含重链可变区(Vh)和轻链可变区(Vl)的抗体,其含有下列CDR的任意组合:
优选地,所述抗PD-1单克隆抗体为包含重链可变区(Vh)和轻链可变区(Vl)的抗体,其包含:
优选地,所述抗PD-1单克隆抗体为含有IgG4重链效应子或恒定域的抗体,其包含SEQ ID NO:83-88中的任一种。
优选地,所述抗PD-1单克隆抗体为含有F(ab)或F(ab)2的抗体,其包含上述结构域,包括重链可变区(Vh)、轻链可变区(Vl)和IgG4重链效应子或恒定域。
优选地,所述抗PD-1单克隆抗体为包含重链可变区(Vh)和轻链可变区(Vk)及IgG4重链效应子或恒定域的抗体,其包含SEQ ID NO:87或88,其中所述重链可变区(Vh)和轻链可变区(Vl)包含:
优选地,所述抗PD-1单克隆抗体为包含重链可变区(Vh)和轻链可变区(Vl)(各包含SEQ ID No 24和SEQ ID No 26)及IgG4重链效应子或恒定域(包含SEQ ID NO 88)的抗体,下文称为Mab 1,其特异性结合PD-1,特别是包括K45和I93或者I93、L95和P97的PD-1残基;并且抑制PD-1介导的细胞信号传导和免疫细胞的活性,抗体结合至一组其配体结合所要求的氨基酸残基。
所述抗PD1单克隆抗体及其抗体片段可根据WO 2015/035606 A1或US 2015-0315274中的公开内容制备,将其全文公开内容作为参考引入本申请。在优选的实施方案中,所述抗PD1单克隆抗体为抗体-1(Mab-1),其以约2mg/kg Q3W至约200mg/kg Q3W的剂量施用。优选地,以约2mg/kg Q3W、5mg/kg Q3W或200mg固定Q3W的剂量施用。
BTK抑制剂
“Btk抑制剂”是指式(I)化合物或其立体异构体或或其药学上可接受的盐。
如在上述五个方面中的每一个中所公开的,所述Btk抑制剂为式(I)化合物,
或其立体异构体或其药学上可接受的盐,
其中:
A为含0-3个N、S或O的杂原子的5或6元芳族环;
每个W独立地为-(CH2)-或-C(O)-;
L为键、CH2、NR12、O或S;
S/D为单键或双键,并且当为双键时,R5和R7不存在;
m为0、或1-4的整数;
n为0、或1-4的整数,其中当n大于1时,每个R2可不同;
p为0、或1-2的整数,其中当p为0时,m为非零,且当p大于1时,每个R6和每个R7可不同;
R1、R4、R5、R6和R7各自独立地为H、卤素、杂烷基、烷基、烯基、环烷基、芳基、饱和或不饱和杂环基、杂芳基、炔基、-CN、-NR13R14、-OR13、-COR13、-CO2R13、-CONR13R14、-C(=NR13)NR14R15、-NR13COR14、-NR13CONR14R15、-NR13CO2R14、-SO2R13、-NR13SO2NR14R15或-NR13SO2R14,其中所述烷基、烯基、炔基、环烷基、杂芳基、芳基及饱和或不饱和杂环基任选取代有至少一个取代基R16,其中(R4和R5)或(R4和R6)或(R6或R7)或(R6和R6,当p为2时),与它们所连接的原子一起,可形成选自以下的环:任选取代有至少一个取代基R16的环烷基、饱和或不饱和杂环、芳基和杂芳基环;
R2为卤素、烷基、-S-烷基、-CN、-NR13R14、-OR13、-COR13、-CO2R13、-CONR13R14、-C(=NR13)NR14R15、-NR13COR14、-NR13CONR14R15、-NR13CO2R14、-SO2R13、-NR13SO2NR14R15或-NR13SO2R14;
R12为H或低级烷基;
R13、R14和R15各自独立地为H、杂烷基、烷基、烯基、炔基、环烷基、饱和或不饱和杂环基、芳基或杂芳基;其中(R13和R14)和/或(R14和R15)与它们所连接的原子一起,各自可形成选自以下的环:任选取代有至少一个取代基R16的环烷基、饱和或不饱和杂环、芳基和杂芳基环;
R16为卤素、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的芳基、经取代或未经取代的杂芳基、经取代或未经取代的杂环基、氧代、-CN、-ORa、-NRaRb、-CORa、-CO2Ra、-CONRaRb、-C(=NRa)NRbRc、-NRaCORb、-NRaCONRaRb、-NRaCO2Rb、-SO2Ra、-SO2芳基、-NRaSO2NRbRc或-NRaSO2Rb,其中Ra、Rb和Rc独立地为氢、卤素、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的芳基、经取代或未经取代的杂芳基、经取代或未经取代的杂环基,其中(Ra和Rb)和/或(Rb和Rc)与它们所连接的原子一起可形成选自以下的环:环烷基、饱和或不饱和杂环、芳基和杂芳基环。
在一些实施方案中,式(I)化合物是光学纯的。
在一些实施方案中,S/D为双键,且R5和R7不存在;p为1且m为0、1或2;A为苯基;且R4和R6,与它们所连接的原子一起,形成下式的环:
其中Q为-CH2-;J为-CH2-;且d和b各自独立地为0、或1-4的整数;
S/D为单键;p为1且m为0、1或2;A为苯基;或
S/D为单键;p为0且R6和R7不存在;A为苯基。
在一些实施方案中,A为苯基;W为-(CH2)-;L为O;S/D为单键;m为1;n为0;p为1;R1为苯基;R2不存在;R5为H;且R6和R7为H;得到组合结构:
在一些实施方案中,R4为含N的C1-C8烷基、含N的C3-C8环烷基和苯基,各自任选经取代。
在一些实施方案中,R4为甲基氨基、苯胺基团、氮杂环丁烷基、吡咯烷基、哌啶基、氮杂环庚烯基,各自N取代有选自以下的部分:苄基、酰基、丙烯酰基、经取代的丙烯酰基、丙炔酰基和经取代的丙炔酰基。
在一些实施方案中,R4选自以下结构,
在一些实施方案中,所述式(I)Btk抑制剂具有通式结构(I-A),
或其立体异构体或其药学上可接受的盐,
其中:
A为苯基;
L为键、CH2、NR12、O或S;
n为0、1或2,其中当n大于1时,每个R2可不同;
R1为苯基,任选取代有至少一个取代基R16;
R4为含N的C1-C8烷基、含N的C3-C8环烷基和苯基,各自任选取代至少一个取代基R16a;
R5、R6和R7各自独立地为H、卤素、杂烷基、烷基、烯基、炔基、-CN、-NR13R14、-OR13或-COR13,其中所述烷基(包括杂烷基的烷基部分)、烯基和炔基任选取代有至少一个取代基R16,
R2为卤素、烷基、-S-烷基、-CN、-NR13R14或-OR13;
R12为H或C1-C3烷基;
R13和R14各自独立地为H、C1-C3烷基、C2-C3烯基或C2-C3炔基;
R16a为卤素、烷基、烯基、炔基、-CN、-ORa、-NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaCORb,-NRaCONRaRb,-NRaCO2Rb,其中Ra和Rb独立选自氢、卤素、C1-C3烷基、C2-C3烯基、C2-C3炔基;和
R16为卤素、烷基、烯基、炔基、-CN、-ORa或-NRaRb,其中Ra和Rb独立地为氢、卤素、C1-C3烷基、C2-C3烯基和C2-C3炔基。
在一些实施方案中,所述式(I)Btk抑制剂具有通式结构(I-A)或其立体异构体或其药学上可接受的盐,
A为苯基;
L为O;
N为0、1或2,其中当,其中当n大于1时,每个R2可不同;
R1为苯基,任意取代任选取代有至少一个取代基R16;
R4为含N的C3-C8环烷基,任选取代至少一个取代基R16a;
R5、R6和R7各自独立地为H、卤素、杂烷基、烷基、烯基、炔基、-CN、-NR13R14、-OR13或-COR13,其中所述烷基(包括杂烷基的烷基部分)、烯基和炔基任选取代有至少一个取代基R16,
R2为卤素、烷基、-S-烷基、-CN、-NR13R14或-OR13;
R12为H或C1-C3烷基;
R13和R14各自独立地为H、C1-C3烷基、C2-C3烯基或C2-C3炔基;
R16a为-C(O)CH=CH2、-C(O)C≡CCH3、-NHC(O)CH=CH2或-NHC(O)C≡CCH3;和
R16为卤素、烷基、烯基、炔基、-CN、-ORa或-NRaRb,其中Ra和Rb独立地为氢、卤素、C1-C3烷基、C2-C3烯基和C2-C3炔基。
如上述每个实施方案中,所述Btk抑制剂为式(II)化合物—即,化合物1,
或其药学上可接受的盐。
本申请公开的Btk抑制剂,诸如式(II)化合物,可通过在WO 2014/173289 A1和WO2018/03385中公开的合成路线合成,将其全部内容引入本申请作为参考。本申请公开的Btk抑制剂,即化合物1,可根据WO2018/03385中的方法制备,将其全部内容引入本申请作为参考。
组合疗法
组合疗法可按同时或分开或依序方案来施用。当依序施用时,组合可按两次或更多次给药来施用。组合施用包括使用分开的制剂共同施用和以任意顺序连续施用,其中优选存在两种(或所有)活性剂同时发挥其生物活性的时段。
在一些实施例中,本申请的组合疗法相对于任一使用单药疗法提供了协同和/或统计上改进的效果。例如,本申请的组合疗法在惰性和侵袭性B细胞恶性肿瘤中也能显著改善患者的预后。例如,在一些实施例中,组合疗法延长患者生存期和无进展生存期,同时在患有B细胞恶性肿瘤(包括惰性和侵袭性淋巴瘤)的患者中具有可管理的毒性特征。
任何上述共同施用的药剂的合适剂量是目前使用的那些剂量且可由于Btk抑制剂和靶向治疗剂或免疫检查点抑制剂的组合作用(协同作用)诸如增加的治疗指数或减轻的毒性或其它副作用或后果而降低。
在抗癌疗法的具体实施方案中,Btk抑制剂和抗PD-1抗体可进一步与手术疗法和放射疗法组合。
在上述各方面中每一个的一个实施方案中,本申请公开的Btk抑制剂和抗PD-1抗体的量及施用的相对时间安排通过待治疗的患者的个体需要、施用途径、疾病或病痛的严重程度、给药时间表以及指定医生所作出的评价和判断来确定。
本申请公开的Btk抑制剂和抗PD-1抗体可按多种已知方式施用,诸如口服、局部、经直肠、胃肠外、通过吸入喷雾或经由植入的储库,尽管任何给定情况下最合适的途径将取决于具体的宿主及施用活性成分所针对的病症的性质和严重程度。本申请使用的术语“胃肠外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。
在上述方面中每一个的一个实施方案中,本申请公开的Btk抑制剂和抗PD-1抗体可按不同途径施用。在优选的实施方案中,所述Btk抑制剂口服施用,而抗PD-1抗体肠胃外施用,诸如皮下、皮内、静脉内或腹膜内施用。在优选的实施方案中,所述BTK抑制剂每天一次(QD)、每天两次(BID)、每天三次(Q3D)、每天四次(Q4D)或每天五次(Q5D)施用,并且以约80mg/天至约640mg/天的剂量施用。在优选的实施方案中,所述BTK抑制剂以320mg QD或160mg BID的剂量施用。在优选的实施方案中,所述抗PD1单克隆抗体为抗体-1(Mab 1),其以约2mg/kg每三周一次(Q3W)至约200mg/kg Q3W的剂量施用,更优选地,其以约2mg/kgQ3W、5mg/kg Q3W或200mg固定Q3W的剂量施用。在一些实施方案中,其中所述抗PD-1抗体经静脉施用。在一些实施方案中,其中所述BTK抑制剂在抗PD-1抗体施用前至少30分钟施用,如果BTK抑制剂和抗PD-1抗体同一天施用。特别地,所述BTK抑制剂每天给药和抗-PD-1抗体每三周施用,且所述BTK抑制剂在抗PD-1抗体施用前至少30分钟(有时1小时或2小时)施用,如果BTK抑制剂和抗PD-1抗体同一天施用。
实施例
本发明进一步由解释本发明的以下实施例进行示例性说明,但是并不受其限制。
实施例1制备(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物1)及其晶型A
步骤1:合成BG-2
在氮气气氛下,于10℃向EA(5v)、HOBT(1.2当量)、EDCI(1.2当量)、4-苯氧基苯甲酸(BG-1,80Kg,1.0当量)和丙二腈(1.2当量)的溶液添加TEA(2.4当量)。然后混合物于室温搅拌直到反应完成。混合物然后离心且滤饼以EA洗涤。滤液以NaHCO3水溶液洗涤两次并以NH4Cl洗涤。有机相以1.5N H2SO4洗涤两次并搅拌。从甲醇和纯化水浓缩,析出。固体通过离心收集并经真空干燥。如此得到79.9Kg的BG-2。1H NMR(DMSO-d6)δ7.62(d,J=8.6Hz,2H),7.46-7.38(m,2H),7.18(t,J=7.4Hz,1H),7.06(d,J=8.0Hz,2H),6.94(d,J=8.6Hz,2H)。
步骤2:合成BG-3
在氮气气氛下,于85℃将BG-2(79.9kg,1.0当量)在MeCN(5.0v)中的溶液添加至三甲氧基甲烷(12.0v)。搅拌所得混合物直到反应完成。取样用于HPLC分析。真空浓缩。残余物从i-PrOH和己烷析出。混合物经离心,且滤饼以己烷洗涤并经真空干燥。如此得到71.7Kg的产物。1H NMR(400MHz,DMSO-d6)δ7.70(d,J=8.4Hz,2H),7.52-7.45(m,2H),7.28(t,J=7.6Hz,1H),7.22-7.06(m,4H),3.93(s,3H)。
步骤3:合成BG-4
在氮气气氛下,于低于15℃向反应器中,向BG-3(71.6kg,1.0当量)在乙醇(2.5v)中的溶液滴加在氢氧化肼(1.0当量)乙醇(0.6v)中的溶液。将溶液加热至室温并搅拌直到反应完成。将水(4.0v)添加至反应器。溶液然后冷却至5℃,离心且滤饼以水(1.0v)洗涤。滤饼真空干燥。如此得到66.9Kg的产物。1H NMR(DMSO-d6)δ12.11(br s,1H),7.80(d,J=8.8Hz,2H),7.46-7.39(m,2H),7.18(t,J=7.6Hz,1H),7.12-7.04(m,4H),6.43(br s,2H)。
步骤4至6:合成BG-8
于低于15℃,向DCM(8.0v)、BG-5(80.0Kg,1.0当量)、N,O-二甲基羟基胺盐酸盐(1.2当量)、HOBt(1.2当量)和EDCI(1.2当量)的混合物,滴加TEA(2.6当量)。混合物于室温搅拌直到反应完成,离心且滤饼以DCM(1.0v)洗涤两次。滤液以20%NH4Cl水溶液(3×4.0v)洗涤。滤液经真空浓缩得到粗产物BG-6,其不经进一步纯化用于后续步骤。残余物溶解在甲苯(5.0v)和THF(1.0v)中,冷却至10℃,于10℃滴加MeMgBr(1.4当量)且然后于室温搅拌直到反应完成。溶液冷却至低于10℃。于低于10℃滴加饱和NH4Cl水溶液。混合物经离心、分离、过滤,且有机相以NaCl水溶液洗涤两次。有机相经浓缩得到粗产物,其不经进一步纯化用于后续步骤。在DMF(2.5v)和DMF-DMA(2.5v)中的残余物于110℃搅拌直到反应完成。反应混合物经冷却且然后添加DCM。最终混合物以饱和NH4Cl水溶液洗涤。有机层经浓缩并通过添加己烷而析出。混合物经离心且收集滤饼。滤饼经真空干燥。如此得到82.2Kg的期望产物。1H NMR(DMSO-d6)δ7.49(d,J=12.6Hz,1H),5.01(d,J=12.6Hz,1H),3.99-3.82(m,2H),3.14-2.94(m,2H),2.89-2.61(m,6H),2.49-2.37(m,1H),1.66-1.56(m,2H),1.39(s,9H),1.39-1.20(m,2H)。
步骤7:合成BG-9
在氮气气氛下,将甲苯(8.0v)、AcOH(0.5v)、BG-8(1.2当量)和BG-4(66.9Kg1.0当量)的混合物加热至95℃并搅拌直到反应完成。混合物经冷却,浓缩并从甲醇析出。混合物经离心且滤饼以甲醇洗涤。滤饼经真空干燥。如此得到107.8Kg的产物。1H NMR(DMSO-d6)δ8.78(d,J=4.6Hz,1H),8.15-8.07(m,2H),7.51-7.41(m,2H),7.34(d,J=4.6Hz,1H),7.27-7.19(m,3H),7.17-7.10(m,2H),4.24-4.02(m,2H),3.81-3.69(m,1H),3.12-3.82(m,2H),2.15-2.04(m,2H),1.76-1.60(m,2H),1.43(s,9H)。
步骤8:合成BG-10
在N2下,向THF(10.0v)、BG-9(13.0Kg,1.0当量)和D-DBTA(1.0当量)的混合物添加Pd/C(10%w/w),将氢气引入反应器且将氢气压力保持至1.8MPa。反应器缓慢地加热至40℃并搅拌直到反应完成。混合物然后经冷却,过滤,且滤饼以THF洗涤。滤液经收集并真空浓缩。添加DCM。残余物经NaHCO3水溶液洗涤,浓缩并从MTBE和己烷析出,然后离心。收集滤饼并真空干燥,得到期望化合物(收率:94.8%和纯度:98.5%)。1H-NMR(DMSO-d6)δ7.82-7.76(m,2H),7.56-7.51(m,1H),7.45-7.37(m,2H),7.21-7.14(m,1H),7.12-7.03(m,4H),4.09-3.91(m,3H),3.30-3.22(m,2H),2.82-2.55(m,2H),2.18-1.99(m,2H),1.98-1.86(m,1H),1.69-1.58(m,1H),1.56-1.45(m,1H),1.38(s,9H),1.32-1.13(m,2H)。
步骤9:合成BG-11
在氮气气氛下,向BG-10(100.0Kg 1.0当量)在DCM(6.0v)中的溶液中滴加HCl/EtOH(20.9%w/w,2.0v)。搅拌混合物直到反应完成。将MTBE(4.0v)添加至溶液,冷却。各滤饼通过离心收集并以己烷(2.0V)洗涤,然后滤饼在己烷(5v)中浆料化,并再次离心。滤饼以己烷(2.0V)洗涤并经真空干燥。如此得到85.2Kg的产物。1H-NMR(DMSO-d6)δ9.25-8.85(m,2H),7.84-7.70(m,2H),7.47-7.37(m,2H),7.18(t,J=7.4Hz,1H),7.12-7.03(m,4H),5.73(br s,2H),4.12-4.03(m,1H),3.25-3.19(m,4H),2.90-2.73(m,2H),2.28-2.12(m,1H),2.10-2.00(m,1H),1.99-1.86(m,1H),1.84-1.52(m,4H)。
步骤10:合成BG-11A
BG-11(85.0Kg,1.0当量)在水(6.0v)和NaOH(3.0当量)中的混合物在室温搅拌直到反应完成。收集滤饼并在MTBE(6.0v)浆料化。混合物然后离心以收集滤饼。滤饼经真空干燥。如此得到71.3Kg产物。1H-NMR(DMSO-d6)δ7.82-7.74(m,2H),7.54-7.49(m,1H),7.45-7.38(m,2H),7.21-7.14(m,1H),7.12-7.04(m,4H),4.03-3.95(m,
1H),3.29-3.21(m,2H),3.00-2.87(m,2H),2.46-2.31(m,2H),2.11-1.83(m,3H),1.58-1.12(m,4H)。
步骤11:合成BG-11B
在氮气气氛下,将乙醇/水/乙酸(7:3:1,46v)和BG-11A(30kg,1.0当量)在反应器中的混合物加热至70±5℃,然后伴随不小于65℃的温度滴加D-DBTA(1.20当量)在乙醇/水/乙酸(7:3:1,4v)中的溶液。所得溶液于60-65℃搅拌16小时,然后冷却至室温。通过离心收集固体并且以乙醇(2.0v)洗涤。滤饼在乙醇/水/AcOH(7:3:1,20v)的混合溶剂中于55℃浆料化16小时并冷却至室温。固体通过离心收集,并以乙醇(2.0v)洗涤。滤饼经真空干燥(收率:37.9%)。1H-NMR(DMSO-d6)δ8.76(br s,2H),7.99-7.89(m,4H),7.83-7.75(m,2H),7.66-7.57(m,3H),7.52-7.45(m,4H),7.45-7.39(m,2H),7.21-7.14(m,1H),7.13-7.03(m,4H),5.64(s,2H),4.08-4.00(m,1H),3.29-3.19(m,4H),2.85-2.72(m,2H),2.21-1.40(m,7H)。
步骤12:合成BG-11C
在氮气气氛下,于室温向二氯甲烷(15.0v)和20.0%KOH水溶液(3.0v)的混合物分批添加BG-11B(48.0kg,1.0当量)。反应完成后,有机层经收集并且水层以二氯甲烷(5.0v)萃取。合并各有机层。于室温将浓HCl(0.36v)添加至上述有机层。搅拌所得混合物直到反应完成。固体通过离心收集并以二氯甲烷(1.0v)洗涤。收集的固体以MTBE(6.0v)浆料化。固体通过离心收集并以MTBE(1.0v)洗涤,然后真空干燥。如此得到31.5Kg的产物(收率:100%)。
步骤12:合成BG-11D(备选中间体)
将CAN(5.0v)、软水(10.0v)、KOH(5.0当量)添加至反应器并搅拌至少15min。将BG-11B(1.0当量)分份添加至反应器。搅拌混合物直到反应完成。滤饼通过离心收集,在ACN(1.0v)和软水(5.0v)中浆料化,并真空干燥得到产物。
步骤13:合成BG-12
在氮气气氛下,BG-11C(15.0Kg 1.0当量)在MsOH(2.5v)中的溶液于85℃搅拌直到反应完成。冷却至5℃后,纯化水(4.0v)滴加至体系中并保持温度不超过35℃(温度增加明显)。所得溶液于30℃搅拌16小时,且然后以DCM(2×3.0v)洗涤。水相经收集。将DCM(6.0v)添加至水相,混合物冷却至5℃。以20%NaOH水溶液将pH值调节至11~12(温度增加明显),伴随搅拌,温度不超过30℃。分开并收集有机相。水相以DCM(3.0v)萃取。合并各有机层经并浓缩。MTBE(4.0v)添加至该残余物。混合物然后经浓缩并从正庚烷中析出。固体通过离心收集并且在真空烘箱中干燥。由此得到12.55Kg产物(收率:94.9%)。1H-NMR(DMSO-d6)δ7.52-7.46(m,2H),7.45-7.38(m,2H),7.21-7.13(m,1H),7.12-7.03(m,4H),6.64(s,1H),3.99-3.90(m,1H),3.29-3.22(m,2H),3.03-2.90(m,2H),2.48-2.36(m,2H),2.03(dd,J=13.9,5.6Hz,2H),2.14-1.99(m,1H),1.97-1.85(m,1H),1.65-1.15(m,3H)。
步骤14:合成BG-13
在N2气氛下,将MeOH(13.5v)、纯化水(4.5v)和BG-12(8.5Kg,1.0当量)在反应器中的混合物加热至50℃。向混合物中滴加L-DBTA(0.7当量)在MeOH/纯化水(1.5v/0.5v)中的溶液,同时将温度保持在50℃。添加后,混合物于50℃搅拌至少2小时,且然后冷却至室温并于室温搅拌至少16小时。滤饼通过离心收集并以MeOH(2.0v)洗涤。滤饼在真空烘箱中干燥。如此得到9.08Kg的产物(收率:74.8%)。
步骤15:合成(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢
吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物1)
在N2气氛下,将CAN(12.0v)、水(12.5v)、BG-13(8.0Kg,1.0当量)和NaHCO3(2.5当量)添加至反应器。然后将混合物冷却至-5~0℃。向混合物中滴加丙烯酰氯(1.1当量)在MeCN(0.5v)中的溶液并搅拌直到反应完成。然后将EA(6.0v)添加至反应器中并搅拌。收集有机相。水层以EA(3.0v)进一步萃取。合并有机相并以盐水洗涤。收集有机层并浓缩。
残余物通过以3%w/w甲醇/DCM(21.0v)洗脱的硅胶(2wt)柱纯化。收集化合物1溶液并真空浓缩。残余物从EA/MTBE(2.0v)析出。滤饼通过离心收集为产物。
步骤15:合成(S)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢
吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物1,备选方法)
CH3CN(10.0v)、纯化水(5.0v)、NaOH(1.5当量)和BG-13(1.0当量)的混合物经搅拌得到澄清溶液。EtOAc(6.0v)然后添加至反应中并分离。有机相经收集并以15%盐水(3.0v)洗涤。上述制备的有机相经浓缩并且将溶剂交换为CH3CN(剩余体积:NMT 5.0v)。添加CH3CN(7.5v)和纯化水(12.5v)并冷却至15-20℃。将L-(+)-酒石酸(0.5当量)和NaHCO3(2.5当量)添加至反应混合物。丙烯酰氯(1.1当量)在CH3CN(0.5v)中的溶液滴加至反应混合物中。反应完成后,将EtOAc(6.0v)添加至反应混合物并收集有机层。水相进一步以EA(3.0v)萃取。合并各有机层,以15%盐水(5.0v)洗涤并浓缩。溶剂交换为DCM(剩余体积:1.5-2.0v)并通过硅胶柱纯化(硅胶:100-200筛,2.0w/w;洗脱剂:3%w/w MeOH/DCM(约50v)。收集的溶液经浓缩并交换为EtOAc(4.0v)。于50℃将MTBE(6.4v)滴加至残余物。然后冷却混合物至5℃且离心收集滤饼。
步骤16:制备化合物1的晶型A
化合物1的上述滤饼溶解在7.0体积的DCM中,且然后交换为溶剂EA。从EA/MTBE中重结晶后,离心收集滤饼,并真空干燥。如此得到4.44Kg产物(收率:70.2%)。
产物然后由在PANalytical Empyrean X射线粉末衍射仪上产生的X射线粉末衍射(XRPD)图方法表征,其中XRPD参数如下:X射线波长(Cu,kα,Kα11.540598,Kα2/>1.544426;Kα2/Kα1强度比:0.50);X射线管设置(45Kv,40mA);发散狭缝(自动);扫描模式(连续);扫描范围(°2TH)(3°-40);步长(°2TH)(0.0131);扫描速度(°/min)(约10)。XRPD结果发现所得到的产物为如图6所示的结晶。
在图7中所示的质子核磁共振(1H-NMR)在Bruker 400M NMR光谱仪上在DMSO-d6中收集。1H-NMR(DMSO-d6)δ7.50(d,J=8.6Hz,2H),7.46-7.38(m,2H),7.17(t,J=7.6Hz,1H),7.08(d,J=7.6Hz,2H),7.05(d,J=8.8Hz,2H),6.85-6.72(m,1H),6.67(s,1H),6.07(dd,J=16.8,2.2Hz,1H),5.64(dd,J=10.4Hz,2.2Hz,1H),4.55-4.38(m,1H),4.17-3.94(m,2H),3.33-3.22(m,2H),3.08-2.88(m,1H),2.67-2.51(m,1H),2.36-2.15(m,1H),2.12-1.82(m,2H),1.79-1.65(m,1H),1.63-1.49(m,1H),1.38-1.08(m,2H)。
如图8所示的碳核磁共振(13C-NMR)在Bruker 400M NMR光谱仪上在DMSO-d6中收集。化合物1的晶型A的13C-NMR光谱.
实施例2BTK抑制剂联合PD-1抑制剂在B细胞淋巴恶性肿瘤患者中的安全性和活性
方法学
研究了人类首次、开放标签、多中心、1b期试验,以评估化合物1联合抗体-1(Mab1)在B细胞恶性肿瘤患者中的安全性、耐受性和初步疗效(参见图1),所述B细胞恶性肿瘤包括复发性/难治性慢性淋巴细胞性白血病(CLL)/小淋巴细胞性淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、非生发中心B细胞(非GCB)弥散性大B细胞淋巴瘤(DLBCL)、GCB DLBCL、或未确定亚型的DLBCL、滤泡性淋巴瘤(FL)、边缘区淋巴瘤(MZL)、毛细胞白血病(HCL)、转化性FL、Richter转化、原发性中枢神经系统淋巴瘤(PCNSL)、和乳房或睾丸起源的继发性CNS淋巴瘤(SCNSL)。研究分为剂量递增和剂量扩增。
研究治疗
在有或没有食物的情况下,每天口服施用化合物1(320mg QD或160mg BID)。每21天(Q3W)静脉施用Mab 1(2.0mg/kg、5.0mg/kg或200mg固定剂量(flat dose),取决于分配的剂量水平群组)。当在同一天(收集两个PK样品的当天除外)施用2种研究药物时,在Mab 1输注前至少30分钟施用化合物1。所有周期(cycles)包括21天。
对于剂量递增,周期1包括28天,并且所有后续周期包括21天。在周期1的第1天、以及之后每天连续施用化合物1。在周期1的第8天、以及之后在所有后续周期的第1天施用Mab1。DLT的评估期为21天,从周期1的第8天到周期1的第28天。
对于剂量扩增,所有周期包括21天。除了如下所述的CNS淋巴瘤群组(群组4B)的10名受试者之外,在每个周期的第1天,在同一天施用化合物1和Mab 1。
对于PCNSL和SCNSL(群组4A和4B),最初有10名受试者(群组4A)以200mg静脉Q3W接受了单一药剂Mab 1,持续4个周期。在周期5的第1天及其后,这10名受试者以通过剂量递增定义的RP2D接受了化合物1和Mab 1的组合。对于群组4B,10名患有PCNSL和SCNSL的受试者以通过剂量递增定义的RP2D接受了化合物1和Mab 1的组合,所述剂量递增开始于周期1的第1天及其后所有周期。当在同一天(收集两个PK样本的当天除外)施用2种药物时,在Mab 1输注前至少30分钟施用化合物1。所有周期包括21天。
剂量递增
剂量递增的目的是确定该研究的MTD。在剂量递增期间,按以下顺序探索了三种剂量水平:
·剂量水平1:化合物1 320mg QD联合Mab 1 2.0mg/kg Q3W。如果清除了剂量水平3,则将受试者转换为剂量水平3给药。剂量水平-1(仅当剂量水平1超过MTD时适用):化合物1 160mg QD联合Mab 1 2.0mg/kg Q3W。可以允许进一步降低化合物1或Mab 1的剂量水平,直到确定安全的剂量组合。
·剂量水平2:化合物1 320mg QD与Mab 1 5.0mg/kg Q3W。如果清除了剂量水平3,则将受试者转换为剂量水平3给药。
·剂量水平3:化合物1 160mg BID与Mab 1 200mg固定剂量Q3W。
剂量递增遵循与标准3+3剂量递增设计所规定的原则相同的原则,其中基于观察到的剂量限制性毒性(DLT)数量对每个群组进行安全性评估。在确定后续群组的下一个剂量水平和剂量方案之前,需要评估在任何给定剂量水平下完成DLT评估的至少3名受试者的群组。如果在所有3名受试者的DLT窗口内未观察到DLT,则群组中的三名受试者是足够的。每个群组需要超过3名受试者,取决于观察到的DLT的数量,如下所示:
·纳入群组的<6名受试者:o 1名受试者在DLT评估期经历了DLT:所述群组必须纳入最少6名可评估DLT的受试者。
·≥2名受试者在DLT评估期经历了DLT:认为已超过MTD,并且不会以当前剂量或更高剂量治疗其他受试者。
·纳入群组的≥6名受试者:o 1名受试者在DLT评估期经历了DLT:认为所述群组是可耐受的且不会超过MTD。
·≥33%的受试者(即,6个中有2个)在DLT评估期经历了DLT:认为已超过MTD,并且不会以当前剂量或更高剂量治疗其他受试者。
剂量扩增
在剂量扩增中,存在以RP2D接受Mab 1和化合物1的组合的4个剂量扩增群组:
·群组1(n=20):GCB DLBCL
·群组2(n=20):非GCB DLBCL
·群组3(n=20):转化性淋巴恶性肿瘤
·群组4:原发性CNS淋巴瘤或者乳房或睾丸起源的SCNSL群组4A(n=10):开始于4个周期的单一药剂化合物1(200mg Q3W),开始于周期5的化合物1和Mab1的组合
·群组4B(n=10):开始于周期1的化合物1和Mab 1的组合
纳入标准2中定义了剂量扩增的群组。化合物1和Mab-1的组合的剂量和方案是如通过非CNS疾病类型(群组1-3)的SMC确定的RP2D。对于群组4,单一药剂Mab 1的剂量和方案为200mg IV Q3W,随后对于组合是RP2D。每个剂量扩增部分中纳入大约20名受试者。一旦确定RP2D,同时开始群组1、2、3和4A。在群组4A完成之前,可能无法入组群组4B。
剂量限制性毒性
剂量限制性毒性(DLT)是在DLT评估期(从周期1的第8天到周期1的第28天的21天)发生的毒性或不良事件(AE),其不能主要归因于除了化合物1和/或Mab 1之外的原因(例如疾病进展、潜在疾病、并发疾病、或伴随用药)且符合以下标准中的1个:
1)非血液学4级(或3级持续>3天)毒性,不包括:
a.研究人员认为不属严重性质的实验室异常
b.3级肿瘤耀斑
c.与3级输注有关的事件,其在28天内退为1级
d.3级恶心或呕吐
e.3级高血压
2)持续>7天的4级中性粒细胞减少症,不归因于骨髓的白血病或淋巴瘤浸润
3)持续>7天的4级血小板减少症,不归因于骨髓的白血病或淋巴瘤浸润
4)需要服用一种或两种研究药剂超过2周的任何毒性。
方法
主要终点
·剂量递增:如基于方案定义的剂量限制性毒性、安全性、耐受性和PK曲线的发生率确定的,Mab 1与化合物1组合的MTD和/或推荐的2期剂量(RP2D)。
·剂量扩增:如通过AE的发生率和严重程度(Common Terminology Criteria forAdverse Events[通用不良事件术语标准][CTCAE],第4版)评估的,化合物1和Mab 1的组合(群组1至3和4B)、或单一药剂Mab 1随后是化合物1和Mab 1的组合(群组4A)在先前治疗的患有B细胞恶性肿瘤的受试者中的安全性和耐受性。
次要终点
·化合物1和Mab 1的组合(群组1至3和4A)、或单一药剂Mab 1随后是化合物1和Mab 1的组合(群组4B)在先前治疗的患有指定B细胞恶性肿瘤的受试者中的抗肿瘤活性,如通过总体应答率(ORR,定义为按标准疾病特异性应答标准具有完全应答[CR]或部分应答[PR]的受试者比例)、应答持续时间([DOR];定义为对于那些具有经确认的PR或CR的受试者,从首次记录经确认的客观应答之日起到因任何原因导致的进展性疾病[PD]或死亡之日的时间)、和无进展生存期([PFS];定义为从首次服用研究药物到客观疾病进展或死亡的时间)确定的。
·Mab 1和化合物1的PK曲线。
·当与化合物1组合给药时,抗药物抗体发展为Mab 1的发生率。
结果
图2中示出了当前截止时的患者处置。中位随访时间为约5.1个月(范围为0.4-14.1);惰性淋巴瘤和侵袭性淋巴瘤分别为5.1(1.6-14.1)和4.2(0.4-14.4)。
表1-A示出了患者和疾病特征。表1-B示出了最佳响应。
DLT的评估期为从周期1的第8天到周期1的第28天的21天。在群组2(cohort 2)中,发生了两次溶血事件,其中1次符合DLT标准,参见表2。两次事件均发生在WM患者中,并且其他WM患者被排除在试验之外,且在WM排除后没有进一步的DLT事件。
表1-A患者和疾病特征
ECOG,东部肿瘤协作组;GBC,生发中心B细胞;LDH,乳酸脱氢酶;Q3W,每3周;QD,每天一次。
*最大直径>10cm的任何淋巴结
表1-B最佳响应(Best Response)
CR,完全缓解;MR,最小缓解;NO,未定义;NE,未评价;ORR,客观缓解率;PD,疾病进展;PR,部分缓解;PR-L,淋巴细胞增多的部分缓解;SD,疾病稳定;VGPR,非常好的部分缓解。
*在第一次反应评估或反应评估之前患者因除PD以外的原因中止治疗的,未评价或未完成。
表2剂量限制性毒性
DLT,剂量限制性毒性;WM,瓦尔登斯特伦巨球蛋白血症。
发现化合物1和Mab 1的组合分别在惰性和侵袭性淋巴瘤患者中实现了最大SPD改善,如图3A和3B所示。而且,发现所述组合分别延长了一些惰性和侵袭性淋巴瘤患者的寿命,如图4A和图4B所示,并且分别延长了惰性和侵袭性淋巴瘤患者的无进展生存期,如图5A和图5B所示。总之,有效的和选择性的BTK抑制剂联合检查点PD1抑制剂在惰性和侵袭性淋巴瘤患者中表现出毒性可控的特点。
上述实施例和一些实施方案的描述应理解为说明性,而并非是对本发明进行限制,本发明由权利要求限定。容易理解的是,可利用上述特征的多种变化和组合而不脱离权利要求中所述的本发明。所有这样的变化旨在包括于本发明的范围内。援引的全部参考文献通过引用以其整体并入本申请。
序列表
<110> 百济神州瑞士有限责任公司(BeiGene Switzerland Gmbh)
J·希尔格(Hilger, James)
X·张(Zhang, Xiaoping)
S·冯(Feng, Sibaou)
S·罗(Ro, Sunhee)
J·黄(Huang, Jane)
<120> 使用包含BTK抑制剂的组合治疗惰性或侵袭性B-细胞淋巴瘤
<130> BEIG-030/01WO
<150> US 62/592,111
<151> 2017-11-29
<160> 107
<170> PatentIn version 3.5
<210> 1
<211> 444
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<213> 智人(Homo sapiens)
<400> 1
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<213> 小家鼠(Mus musculus)
<400> 3
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcaaagaa cctgtccatc 60
acttgcactg tctctgggtt ttcattaacc agctatggtg tacactggat tcgccagcct 120
ccaggaaagg gactggaatg gctgggagta atatgggccg gtggaagcac aaattataat 180
tcggctctca tgtccagact gagcatcagc aaagacaact ccaggagcca agttttctta 240
agaatgaaca gtctgcaaac tgatgacaca gccatgtact actgtgccag agcctatggt 300
aactactggt acatcgatgt ctggggcgca gggaccacgg tcaccgtctc ctca 354
<210> 4
<211> 118
<212> PRT
<213> 小家鼠
<400> 4
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Lys
1 5 10 15
Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Arg Ser Gln Val Phe Leu
65 70 75 80
Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Ala Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 5
<211> 321
<212> DNA
<213> 小家鼠
<400> 5
gacattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca acagaagcca 120
gggcagtctc ctaaactgct gataaactat gcatttcatc gcttcactgg agtccctgat 180
cgtttcactg gcagtggata tgggacggat ttcattttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcaccag gcttatagtt ctccgtacac gttcggaggg 300
gggaccaagc tggaaatgaa a 321
<210> 6
<211> 107
<212> PRT
<213> 小家鼠
<400> 6
Asp Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105
<210> 7
<211> 342
<212> DNA
<213> 小家鼠
<400> 7
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacaata ataatggaga gccaacatat 180
gctgaagagt tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagagatgtt 300
atggactatt ggggtcaagg aacctcagtc accgtctcct ca 342
<210> 8
<211> 114
<212> PRT
<213> 小家鼠
<400> 8
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 9
<211> 330
<212> DNA
<213> 小家鼠
<400> 9
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60
atatcctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtac 120
cagcagaaac caggacagcc accccaactc ctcatctatc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag gcttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaagtaaaga atatccgacg 300
ttcggtggag gcaccaagct ggaagtcaaa 330
<210> 10
<211> 110
<212> PRT
<213> 小家鼠
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Gly Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys
100 105 110
<210> 11
<211> 10
<212> PRT
<213> 小家鼠
<400> 11
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 12
<211> 16
<212> PRT
<213> 小家鼠
<400> 12
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 13
<211> 12
<212> PRT
<213> 小家鼠
<400> 13
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 小家鼠
<400> 14
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 15
<211> 7
<212> PRT
<213> 小家鼠
<400> 15
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 16
<211> 9
<212> PRT
<213> 小家鼠
<400> 16
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 17
<211> 10
<212> PRT
<213> 小家鼠
<400> 17
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 18
<211> 17
<212> PRT
<213> 小家鼠
<400> 18
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 19
<211> 7
<212> PRT
<213> 小家鼠
<400> 19
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 20
<211> 15
<212> PRT
<213> 小家鼠
<400> 20
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 21
<211> 7
<212> PRT
<213> 小家鼠
<400> 21
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 22
<211> 8
<212> PRT
<213> 小家鼠
<400> 22
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 23
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 317-4B6 cDNA-Vh
<400> 23
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gatcggggtc atatacgccg atggaagcac aaattataat 180
ccctccctca agagtcgagt gaccatatca aaagacacct ccaagaacca ggtttccctg 240
aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 24
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 pro-Vh
<400> 24
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 25
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 317-4B6 cDNA-Vk
<400> 25
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca agtccagcga gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 26
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 pro-Vk
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 326-4A3 cDNA-Vh
<400> 27
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctgaagtg gatgggctgg atcaacaaca acaacgccga gcccacctac 180
gcccaggact tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt actactgcgc cagagacgtg 300
atggactact ggggccaggg caccctggtg accgtgagca gc 342
<210> 28
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 pro-Vh
<400> 28
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 29
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> 326-4A3 cDNA-Vk
<400> 29
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctgggaccg atttcaccct cacaattaat 240
cctgtggaag ctgaggatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 30
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 pro-Vk
<400> 30
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 31
<211> 10
<212> PRT
<213> 小家鼠
<400> 31
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 32
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 H-CDR2 or CDR-H2
<400> 32
Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 33
<211> 12
<212> PRT
<213> 小家鼠
<400> 33
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 L-CDR1 or CDR-L1
<400> 34
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 35
<211> 7
<212> PRT
<213> 小家鼠
<400> 35
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 36
<211> 9
<212> PRT
<213> 小家鼠
<400> 36
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> 小家鼠
<400> 37
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 38
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 H-CDR2 or CDR-H2
<400> 38
Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 39
<211> 7
<212> PRT
<213> 小家鼠
<400> 39
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 40
<211> 15
<212> PRT
<213> 小家鼠
<400> 40
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 41
<211> 7
<212> PRT
<213> 小家鼠
<400> 41
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 42
<211> 8
<212> PRT
<213> 小家鼠
<400> 42
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 43
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 pro-Vh
<400> 43
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 44
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 pro-Vk
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B5 pro-Vh
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 46
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B5 pro-Vk
<400> 46
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 317-1 cDNA-Vh
<400> 47
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gctgggggtc atatgggccg gtggaagcac aaattataat 180
ccctccctca agagtcgact gaccatatca aaagacaact ccaagagcca ggtttccctg 240
aagatgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 48
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-1 pro-Vh
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 49
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 317-1 cDNA-Vk
<400> 49
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca aggccagcca gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggcggg 300
gggaccaagc tggagatcaa a 321
<210> 50
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-1 pro-Vk
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3B1 pro-Vh
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 52
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-3B1 pro-Vk
<400> 52
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 53
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 pro-Vh
<400> 53
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 54
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 pro-Vk
<400> 54
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 55
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 326-1 cDNA-Vh
<400> 55
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctgg atcaacaaca acaacggcga gcccacctac 180
gcccagggct tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt acttctgcgc cagagacgtg 300
atggactact ggggccaggg caccaccgtg accgtgagca gc 342
<210> 56
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-1 pro-Vh
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 57
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> 326-1 cDNA-Vk
<400> 57
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctaggaccg atttcaccct cacaattaat 240
cctgtggaag ctaatgatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 58
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-1 pro-Vk
<400> 58
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 59
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-1 H-CDR2 or CDR-H2
<400> 59
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 H-CDR2 or CDR-H2
<400> 60
Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 61
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 L-CDR1 or CDR-L1
<400> 61
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 62
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-1 H-CDR2 or CDR-H2
<400> 62
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe Arg
1 5 10 15
Gly
<210> 63
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 H-CDR2 or CDR-H2
<400> 63
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 64
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3A1 pro-Vh
<400> 64
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 65
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3C1 pro-Vh
<400> 65
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 66
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3E1 pro-Vh
<400> 66
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 67
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3F1 pro-Vh
<400> 67
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 68
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3G1 pro-Vh
<400> 68
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 69
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3H1 pro-Vh
<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 70
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3I1 pro-Vh
<400> 70
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 71
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B1 pro-Vh
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 72
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B3 pro-Vh
<400> 72
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 73
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B4 pro-Vh
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Pro Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 74
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4A2 pro-Vk
<400> 74
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3A1 pro-Vh
<400> 75
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 76
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3C1 pro-Vh
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 77
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3D1 pro-Vh
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 78
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3E1 pro-Vh
<400> 78
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 79
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3F1 pro-Vh
<400> 79
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 80
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3B N55D pro-Vh
<400> 80
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asp Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 81
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A1 pro-Vk
<400> 81
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 82
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A2 pro-Vk
<400> 82
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 83
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt1 pro
<400> 83
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 84
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt2 pro
<400> 84
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 85
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt6 pro
<400> 85
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 86
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt8 pro
<400> 86
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Thr Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 87
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt9 pro
<400> 87
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 88
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt10 pro
<400> 88
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 89
<211> 367
<212> PRT
<213> 人工序列
<220>
<223> OS8 pro
<400> 89
Met Glu Arg His Trp Ile Phe Leu Leu Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
145 150 155 160
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
165 170 175
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
180 185 190
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser
195 200 205
Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser
210 215 220
Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
225 230 235 240
Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
245 250 255
Glu Ile Asn Ser Ser Val Val Pro Val Leu Gln Lys Val Asn Ser Thr
260 265 270
Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr Gly
275 280 285
Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser Val
290 295 300
Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
305 310 315 320
Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu Ile Ile Thr Leu
325 330 335
Ile Cys Tyr His Arg Ser Arg Lys Arg Val Cys Lys Cys Pro Arg Pro
340 345 350
Leu Val Arg Gln Glu Gly Lys Pro Arg Pro Ser Glu Lys Ile Val
355 360 365
<210> 90
<211> 304
<212> PRT
<213> 人工序列
<220>
<223> P3Z pro
<400> 90
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Arg
180 185 190
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
195 200 205
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
210 215 220
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
225 230 235 240
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
245 250 255
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
260 265 270
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
275 280 285
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
290 295 300
<210> 91
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-233P
<400> 91
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Glu Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 92
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234V
<400> 92
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 93
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-235A
<400> 93
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 94
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234V-235A
<400> 94
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 95
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234A
<400> 95
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 96
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234A-235A
<400> 96
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 97
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-233P-234A-235A
<400> 97
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 98
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234V-235A-265A
<400> 98
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 99
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-234A-235A-265A
<400> 99
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 100
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-233P-234A-235A-265A
<400> 100
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 101
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-265A
<400> 101
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 102
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-309V
<400> 102
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 103
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区 228P-409K
<400> 103
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 104
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-309V-409K
<400> 104
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 105
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-265A-309V-409K
<400> 105
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 106
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-233P-234A-235A-265A-309V-409K
<400> 106
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 107
<211> 327
<212> PRT
<213> 智人(Homo sapiens)
<400> 107
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
Claims (11)
2.权利要求1的用途,其中所述惰性或侵袭性B细胞淋巴瘤为惰性或侵袭性的霍奇金淋巴瘤、惰性或侵袭性非霍奇金淋巴瘤。
3.权利要求2的用途,其中所述惰性或侵袭性非霍奇金淋巴瘤是惰性或侵袭性的慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、非生发中心B细胞弥散性大B细胞淋巴瘤(非-GCB DLBCL)、生发中心B细胞弥散性大B细胞淋巴瘤(GCBDLBCL)或亚型不确定的DLBCL、滤泡性淋巴瘤(FL)或转移的FL、边缘区淋巴瘤(MZL)、毛细胞白血病(HCL)、Richter’s综合征、原发性中枢神经系统淋巴瘤(PCNSL)、乳房或睾丸起源的继发性中枢神经系统淋巴瘤(SCNSL)或其两种或更多种的组合。
4.权利要求2所述的用途,其中所述B-细胞淋巴瘤是慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、非生发中心B细胞弥散性大B细胞淋巴瘤(非-GCB DLBCL)、生发中心B细胞弥散性大B细胞淋巴瘤(GCB DLBCL)、滤泡性淋巴瘤(FL)或转移的FL、边缘区淋巴瘤(MZL)、毛细胞白血病(HCL)或Richter’s综合征。
5.权利要求1的用途,其中所述BTK抑制剂以320mg QD或160mg BID的剂量施用。
6.权利要求5的用途,其中所述BTK抑制剂与食物或不与食物同时施用。
7.权利要求1的用途,其中所述抗PD-1抗体以2mg/kg Q3W至200mg/kg Q3W的剂量施用。
8.权利要求7的用途,其中所述抗PD-1抗体以2mg/kg Q3W,5mg/kg Q3W,或200mg固定Q3W的剂量施用。
9.权利要求8的用途,其中所述抗PD-1抗体以固定剂量200mg Q3W,每21天一次施用。
10.权利要求1的用途,其中所述抗PD-1抗体经静脉施用。
11.权利要求1的用途,其中所述BTK抑制剂在抗PD-1抗体施用前至少30分钟施用,如果BTK抑制剂和抗PD-1抗体同一天施用。
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PCT/US2018/063068 WO2019108795A1 (en) | 2017-11-29 | 2018-11-29 | Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors |
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Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101793807B1 (ko) | 2013-04-25 | 2017-11-03 | 베이진 엘티디 | 단백질 키나제 억제제로서의 융합된 헤테로시클릭 화합물 |
EP4130044A1 (en) | 2013-09-13 | 2023-02-08 | BeiGene Switzerland GmbH | Anti-pd1 antibodies and their use as therapeutics and diagnostics |
KR102130600B1 (ko) | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
AU2017293423B2 (en) | 2016-07-05 | 2023-05-25 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
WO2018033853A2 (en) | 2016-08-16 | 2018-02-22 | Beigene, Ltd. | Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
WO2018033135A1 (en) | 2016-08-19 | 2018-02-22 | Beigene, Ltd. | Use of a combination comprising a btk inhibitor for treating cancers |
WO2018137681A1 (en) | 2017-01-25 | 2018-08-02 | Beigene, Ltd. | Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof |
CA3066518A1 (en) | 2017-06-26 | 2019-01-03 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
WO2019034009A1 (en) | 2017-08-12 | 2019-02-21 | Beigene, Ltd. | BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY |
US11786529B2 (en) | 2017-11-29 | 2023-10-17 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors |
CN110845504A (zh) * | 2019-12-19 | 2020-02-28 | 武汉九州钰民医药科技有限公司 | 合成赞布替尼的新方法 |
EP4110331A4 (en) * | 2020-02-27 | 2023-10-04 | BeiGene Switzerland GmbH | METHODS OF TREATING DLBCL USING BTK INHIBITORS AND THEIR COMBINATIONS |
WO2021259732A1 (en) | 2020-06-24 | 2021-12-30 | Sandoz Ag | Multi-component compounds comprising zanubrutinib and a benzoic acid derivative |
JPWO2022102715A1 (zh) * | 2020-11-13 | 2022-05-19 | ||
US11786531B1 (en) | 2022-06-08 | 2023-10-17 | Beigene Switzerland Gmbh | Methods of treating B-cell proliferative disorder |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090217401A1 (en) * | 2005-05-09 | 2009-08-27 | Medarex, Inc | Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics |
US20110008369A1 (en) * | 2008-03-12 | 2011-01-13 | Finnefrock Adam C | Pd-1 binding proteins |
US20150079109A1 (en) * | 2013-09-13 | 2015-03-19 | Beigene, Ltd. | Anti-PD1 Antibodies and their Use as Therapeutics and Diagnostics |
US20150259354A1 (en) * | 2013-04-25 | 2015-09-17 | Beigene, Ltd. | Fused heterocyclic compounds as protein kinase inhibitors |
WO2017046746A1 (en) * | 2015-09-15 | 2017-03-23 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor and a gitr binding molecule, a 4-1bb agonist, or an ox40 agonist |
WO2017059224A2 (en) * | 2015-10-01 | 2017-04-06 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
Family Cites Families (224)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE792533A (fr) | 1971-12-09 | 1973-06-08 | Int Chem & Nuclear Corp | Nouvelles pyrazolo (1,5a) pyrimidines et leur procede de preparation |
DE3883899T3 (de) | 1987-03-18 | 1999-04-22 | Sb2 Inc | Geänderte antikörper. |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US5994514A (en) | 1991-08-14 | 1999-11-30 | Genentech, Inc. | Immunoglobulin variants |
EP0640094A1 (en) | 1992-04-24 | 1995-03-01 | The Board Of Regents, The University Of Texas System | Recombinant production of immunoglobulin-like domains in prokaryotic cells |
EP0714409A1 (en) | 1993-06-16 | 1996-06-05 | Celltech Therapeutics Limited | Antibodies |
CA2143491C (en) | 1994-03-01 | 2011-02-22 | Yasumasa Ishida | A novel peptide related to human programmed cell death and dna encoding it |
JP2778921B2 (ja) | 1994-11-18 | 1998-07-23 | 三共株式会社 | イミダゾピラゾール誘導体 |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
EP2386574A3 (en) | 1999-01-15 | 2012-06-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
JP4896327B2 (ja) | 1999-08-23 | 2012-03-14 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | Pd−1、b7−4の受容体、およびその使用 |
WO2001014556A1 (en) | 1999-08-23 | 2001-03-01 | Dana-Farber Cancer Institute, Inc. | Novel b7-4 molecules and uses therefor |
JP2003508401A (ja) | 1999-08-27 | 2003-03-04 | アボット・ラボラトリーズ | Cox−2阻害薬として有用なスルホニルフェニルピラゾール化合物 |
CZ2002936A3 (cs) | 1999-09-17 | 2002-10-16 | Abbott Gmbh & Co. Kg | Pyrazolopyrimidiny jako terapeutické prostředky |
CZ20023203A3 (cs) | 2000-03-24 | 2003-08-13 | Micromet Ag | Multifunkční polypeptidy obsahující vazebné místo k epitopu receptorového komplexu NKG2D |
EP2264072A1 (en) | 2000-04-13 | 2010-12-22 | The Rockefeller University | Enhancement of antibody-mediated cytotoxicity. |
US7041298B2 (en) | 2000-09-08 | 2006-05-09 | California Institute Of Technology | Proteolysis targeting chimeric pharmaceutical |
US20020094989A1 (en) | 2000-10-11 | 2002-07-18 | Hale Jeffrey J. | Pyrrolidine modulators of CCR5 chemokine receptor activity |
WO2002039813A1 (fr) | 2000-11-15 | 2002-05-23 | Ono Pharmaceutical Co., Ltd. | Souris sans pd-1 et utilisation de celle-ci |
EP2357187A1 (en) | 2000-12-12 | 2011-08-17 | MedImmune, LLC | Molecules with extended half-lives, compositions and uses thereof |
AU2002231139B2 (en) | 2000-12-21 | 2007-03-22 | Bristol-Myers Squibb Company | Thiazolyl inhibitors of tec family tyrosine kinases |
US20030133939A1 (en) | 2001-01-17 | 2003-07-17 | Genecraft, Inc. | Binding domain-immunoglobulin fusion proteins |
KR100900176B1 (ko) | 2001-03-07 | 2009-06-02 | 메르크 파텐트 게엠베하 | 하이브리드 이소타입 항체 부분구조를 포함하는 단백질을위한 발현 기술 |
ES2251582T3 (es) | 2001-03-09 | 2006-05-01 | Pfizer Products Inc. | Compuestos antiinflamatorios de bencimidazol. |
AR036993A1 (es) | 2001-04-02 | 2004-10-20 | Wyeth Corp | Uso de agentes que modulan la interaccion entre pd-1 y sus ligandos en la submodulacion de respuestas inmunologicas |
WO2003004497A1 (fr) | 2001-07-05 | 2003-01-16 | Sumitomo Pharmaceuticals Company, Limited | Compose heterocyclique |
US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
US7662925B2 (en) | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US7595048B2 (en) | 2002-07-03 | 2009-09-29 | Ono Pharmaceutical Co., Ltd. | Method for treatment of cancer by inhibiting the immunosuppressive signal induced by PD-1 |
CA2494700C (en) | 2002-08-26 | 2011-06-28 | Takeda Pharmaceutical Company Limited | Calcium receptor modulating compound and use thereof |
CN1771231B (zh) | 2002-08-26 | 2011-05-25 | 武田药品工业株式会社 | 钙受体调节性化合物及其用途 |
CA2499300A1 (en) | 2002-10-31 | 2004-05-21 | Genentech, Inc. | Methods and compositions for increasing antibody production |
CN1753912B (zh) | 2002-12-23 | 2011-11-02 | 惠氏公司 | 抗pd-1抗体及其用途 |
US7960512B2 (en) | 2003-01-09 | 2011-06-14 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
EP2368578A1 (en) | 2003-01-09 | 2011-09-28 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
JP4532409B2 (ja) | 2003-01-23 | 2010-08-25 | 小野薬品工業株式会社 | ヒトpd−1に対し特異性を有する物質 |
US8084582B2 (en) | 2003-03-03 | 2011-12-27 | Xencor, Inc. | Optimized anti-CD20 monoclonal antibodies having Fc variants |
US20060183746A1 (en) | 2003-06-04 | 2006-08-17 | Currie Kevin S | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
WO2005014599A1 (en) | 2003-06-04 | 2005-02-17 | Cellular Genomics, Inc. | Imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton’s tyrosine kinase by such compounds |
US7393848B2 (en) | 2003-06-30 | 2008-07-01 | Cgi Pharmaceuticals, Inc. | Certain heterocyclic substituted imidazo[1,2-A]pyrazin-8-ylamines and methods of inhibition of Bruton's tyrosine kinase by such compounds |
CN1860118A (zh) | 2003-07-29 | 2006-11-08 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
AU2004266159A1 (en) | 2003-08-22 | 2005-03-03 | Biogen Idec Ma Inc. | Improved antibodies having altered effector function and methods for making the same |
US20060134105A1 (en) | 2004-10-21 | 2006-06-22 | Xencor, Inc. | IgG immunoglobulin variants with optimized effector function |
WO2005047290A2 (en) | 2003-11-11 | 2005-05-26 | Cellular Genomics Inc. | Imidazo[1,2-a] pyrazin-8-ylamines as kinase inhibitors |
US20050249723A1 (en) | 2003-12-22 | 2005-11-10 | Xencor, Inc. | Fc polypeptides with novel Fc ligand binding sites |
GB0400440D0 (en) | 2004-01-09 | 2004-02-11 | Isis Innovation | Receptor modulators |
CA2580981C (en) | 2004-09-22 | 2013-10-22 | Kirin Beer Kabushiki Kaisha | Stabilized human igg4 antibodies |
JP2008519843A (ja) | 2004-11-10 | 2008-06-12 | シージーアイ ファーマスーティカル インコーポレーテッド | 特定のイミダゾ[1,2−a]ビラジン−8−イラミンズ、その生成方法及びそれに関する使用方法 |
EP1831168B1 (en) | 2004-12-16 | 2014-07-02 | Vertex Pharmaceuticals Inc. | Pyrid-2-ones useful as inhibitors of tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases. |
TW200639163A (en) | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
KR101357524B1 (ko) | 2005-03-10 | 2014-02-03 | 질레드 코네티컷 인코포레이티드 | 특정 치환된 아미드, 그의 제조 방법, 및 사용 방법 |
PL2397156T3 (pl) | 2005-06-08 | 2017-07-31 | Dana-Farber Cancer Institute, Inc. | Sposoby i kompozycje do leczenia uporczywych infekcji i nowotworu poprzez hamowanie ścieżki zaprogramowanej śmierci komórki 1 (PD-1) |
KR101607288B1 (ko) | 2005-07-01 | 2016-04-05 | 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. | 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체 |
WO2007027729A1 (en) | 2005-08-29 | 2007-03-08 | Vertex Pharmaceuticals Incorporated | 3, 5-disubstituted pyrid-2-ones useful as inhibitors of tec family of non-receptor tyrosine kinases |
JP2009507792A (ja) | 2005-08-29 | 2009-02-26 | バーテックス ファーマシューティカルズ インコーポレイテッド | 非受容体型チロシンキナーゼのtecファミリーの阻害剤として有用な3,5−二置換ピリド−2−オン |
WO2007026720A1 (ja) | 2005-08-31 | 2007-03-08 | Taisho Pharmaceutical Co., Ltd. | 縮環ピラゾール誘導体 |
RU2008112290A (ru) | 2005-09-01 | 2009-10-10 | Астеллас Фарма Инк. (Jp) | Производные пиридазинона, используемые для лечения боли |
ZA200804679B (en) | 2005-12-08 | 2010-02-24 | Millenium Pharmaceuticals Inc | Bicyclic compounds with kinase inhibitory activity |
JP2009523724A (ja) | 2006-01-13 | 2009-06-25 | ファーマサイクリクス,インコーポレイテッド | チロシンキナーゼ阻害剤およびその使用方法 |
ATE492561T1 (de) | 2006-03-23 | 2011-01-15 | Bioartic Neuroscience Ab | Verbesserte protofibrilselektive antikörper und deren verwendung |
US7442808B2 (en) | 2006-05-15 | 2008-10-28 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
EP2027087A2 (en) | 2006-05-18 | 2009-02-25 | MannKind Corporation | Intracellular kinase inhibitors |
JO3235B1 (ar) | 2006-05-26 | 2018-03-08 | Astex Therapeutics Ltd | مركبات بيررولوبيريميدين و استعمالاتها |
CN101104640A (zh) | 2006-07-10 | 2008-01-16 | 苏州大学 | 抗人pd-l1单克隆抗体制备及应用 |
AR063946A1 (es) | 2006-09-11 | 2009-03-04 | Cgi Pharmaceuticals Inc | Determinadas pirimidinas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden. |
PE20080839A1 (es) | 2006-09-11 | 2008-08-23 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas |
PE20081370A1 (es) | 2006-09-11 | 2008-11-28 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas |
EP2068849A2 (en) | 2006-09-11 | 2009-06-17 | CGI Pharmaceuticals, Inc. | Kinase inhibitors, and methods of using and identifying kinase inhibitors |
SI2530083T1 (sl) | 2006-09-22 | 2016-09-30 | Pharmacyclics Llc | Inhibitorji Bruton tirozin kinaze |
CN101522026A (zh) | 2006-10-06 | 2009-09-02 | Irm责任有限公司 | 蛋白激酶抑制剂及其应用方法 |
ES2403546T3 (es) | 2006-11-03 | 2013-05-20 | Pharmacyclics, Inc. | Sonda de actividad de la tirosina-cinasa de Bruton y procedimiento de utilización |
CN101730699A (zh) | 2007-03-21 | 2010-06-09 | 百时美施贵宝公司 | 可用于治疗增殖性、变应性、自身免疫性和炎症性疾病的稠合杂环化合物 |
WO2008144253A1 (en) | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
AU2008255352B2 (en) | 2007-05-31 | 2014-05-22 | Genmab A/S | Stable IgG4 antibodies |
KR101562580B1 (ko) | 2007-06-18 | 2015-10-22 | 머크 샤프 앤 도메 비.브이. | 사람 프로그램된 사멸 수용체 pd-1에 대한 항체 |
US9243052B2 (en) | 2007-08-17 | 2016-01-26 | Daniel Olive | Method for treating and diagnosing hematologic malignancies |
CL2008002793A1 (es) | 2007-09-20 | 2009-09-04 | Cgi Pharmaceuticals Inc | Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras |
JO3076B1 (ar) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | نظم العلاج المناعي المعتمد على حالة apoe |
TWI552752B (zh) | 2007-10-19 | 2016-10-11 | 賽基艾維洛米斯研究股份有限公司 | 雜芳基化合物及其用途 |
US7989465B2 (en) | 2007-10-19 | 2011-08-02 | Avila Therapeutics, Inc. | 4,6-disubstituted pyrimidines useful as kinase inhibitors |
EP2426109B1 (en) | 2007-10-23 | 2013-12-18 | F. Hoffmann-La Roche AG | Novel kinase inhibitors |
JP5643105B2 (ja) | 2007-12-14 | 2014-12-17 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 新規イミダゾ[1,2−a]ピリジン及びイミダゾ[1,2−b]ピリダジン誘導体 |
AU2009211514B2 (en) | 2008-02-05 | 2014-02-20 | F. Hoffmann-La Roche Ag | Novel pyridinones and pyridazinones |
PL2250279T3 (pl) | 2008-02-08 | 2016-11-30 | Przeciwciała anty-ifnar1 o zmniejszonym powinowactwie do liganda fc | |
US8426424B2 (en) | 2008-05-06 | 2013-04-23 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
US8338439B2 (en) | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
JP2011526299A (ja) | 2008-06-27 | 2011-10-06 | アビラ セラピューティクス, インコーポレイテッド | ヘテロアリール化合物およびそれらの使用 |
PT2300459E (pt) | 2008-07-02 | 2013-07-04 | Hoffmann La Roche | Novas fenilpirazinonas utilizadas como inibidores de cinase |
ES2552681T3 (es) | 2008-07-15 | 2015-12-01 | F. Hoffmann-La Roche Ag | Nuevas fenil-imidazopiridinas y piridazinas |
AU2009270856B2 (en) | 2008-07-16 | 2013-07-25 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors |
AU2009272838B2 (en) | 2008-07-18 | 2014-04-10 | F. Hoffmann-La Roche Ag | Novel phenylimidazopyrazines |
WO2010011837A1 (en) | 2008-07-24 | 2010-01-28 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful as kinase modulators |
WO2010027828A2 (en) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Pd-1 antagonists and methods of use thereof |
CN102405284B (zh) | 2008-09-05 | 2016-01-20 | 新基阿维罗米克斯研究公司 | 设计不可逆抑制剂的算法 |
EP2342229A1 (en) | 2008-09-12 | 2011-07-13 | ISIS Innovation Limited | Pd-1 specific antibodies and uses thereof |
CA2736816C (en) | 2008-09-12 | 2018-05-22 | Isis Innovation Limited | Pd-1 specific antibodies and uses thereof |
US8552154B2 (en) | 2008-09-26 | 2013-10-08 | Emory University | Anti-PD-L1 antibodies and uses therefor |
KR101050829B1 (ko) | 2008-10-02 | 2011-07-20 | 서울대학교산학협력단 | 항 pd-1 항체 또는 항 pd-l1 항체를 포함하는 항암제 |
PE20131197A1 (es) | 2008-10-31 | 2013-11-06 | Genentech Inc | Compuestos de pirazolopirimidina como inhibidores de jak y composiciones farmaceuticas que los contienen |
US20120028981A1 (en) | 2008-11-05 | 2012-02-02 | Principia Biopharma Inc. | Kinase Knockdown Via Electrophilically Enhanced Inhibitors |
WO2010056875A1 (en) | 2008-11-12 | 2010-05-20 | Cgi Pharmaceuticals, Inc. | Pyridazinones and their use as btk inhibitors |
CA2744449C (en) | 2008-11-28 | 2019-01-29 | Emory University | Methods for the treatment of infections and tumors |
US8426428B2 (en) | 2008-12-05 | 2013-04-23 | Principia Biopharma, Inc. | EGFR kinase knockdown via electrophilically enhanced inhibitors |
SG196798A1 (en) | 2008-12-09 | 2014-02-13 | Genentech Inc | Anti-pd-l1 antibodies and their use to enhance t-cell function |
WO2010068788A1 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Heterocyclic amides as btk inhibitors |
WO2010068806A1 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Amide derivatives as btk inhibitors in the treatment of allergic, autoimmune and inflammatory disorders as well as cancer |
WO2010068810A2 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
MX2011006171A (es) | 2008-12-19 | 2011-06-20 | Squibb Bristol Myers Co | Compuestos de carbazol carboxamida utiles como inhibidores de cinasa. |
US20100197924A1 (en) | 2008-12-22 | 2010-08-05 | Millennium Pharmaceuticals, Inc. | Preparation of aminotetralin compounds |
US9266890B2 (en) | 2009-01-06 | 2016-02-23 | Dana-Farber Cancer Institute, Inc. | Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders |
EP3192811A1 (en) | 2009-02-09 | 2017-07-19 | Université d'Aix-Marseille | Pd-1 antibodies and pd-l1 antibodies and uses thereof |
US8299077B2 (en) | 2009-03-02 | 2012-10-30 | Roche Palo Alto Llc | Inhibitors of Bruton's tyrosine kinase |
ES2513915T3 (es) | 2009-04-24 | 2014-10-27 | F. Hoffmann-La Roche Ag | Inhibidores de la tirosina quinasa de Bruton |
WO2010126960A1 (en) | 2009-04-29 | 2010-11-04 | Locus Pharmaceuticals, Inc. | Pyrrolotriazine compounds |
EP2440204B1 (en) | 2009-06-12 | 2013-12-18 | Bristol-Myers Squibb Company | Nicotinamide compounds useful as kinase modulators |
AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
US8846673B2 (en) | 2009-08-11 | 2014-09-30 | Bristol-Myers Squibb Company | Azaindazoles as kinase inhibitors and use thereof |
WO2011028952A1 (en) | 2009-09-02 | 2011-03-10 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
JP5699149B2 (ja) | 2009-09-04 | 2015-04-08 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | Bruton型チロシンキナーゼ阻害薬 |
WO2011029043A1 (en) | 2009-09-04 | 2011-03-10 | Biogen Idec Ma Inc. | Heteroaryl btk inhibitors |
US7741330B1 (en) | 2009-10-12 | 2010-06-22 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase |
EP2494062B1 (en) | 2009-10-28 | 2016-12-28 | Janssen Biotech, Inc. | Anti-glp-1r antibodies and their uses |
US10053513B2 (en) | 2009-11-30 | 2018-08-21 | Janssen Biotech, Inc. | Antibody Fc mutants with ablated effector functions |
LT3053932T (lt) | 2010-02-19 | 2020-11-10 | Xencor, Inc. | Nauji ctla4-ig imunoadhezinai |
MX341925B (es) | 2010-03-29 | 2016-09-07 | Zymeworks Inc | Anticuerpos con funcion efectora suprimida o mejorada. |
KR101954044B1 (ko) | 2010-05-07 | 2019-03-04 | 질레드 코네티컷 인코포레이티드 | 피리돈 및 아자-피리돈 화합물 및 사용 방법 |
NZ603643A (en) | 2010-05-31 | 2014-07-25 | Ono Pharmaceutical Co | Purinone derivative |
EP2575818A4 (en) | 2010-06-03 | 2013-11-06 | Pharmacyclics Inc | USE OF INHIBITORS OF BRUTON TYROSINE KINASE (BTK) |
WO2011159857A1 (en) | 2010-06-16 | 2011-12-22 | Bristol-Myers Squibb Company | Carboline carboxamide compounds useful as kinase inhibitors |
LT2975042T (lt) | 2010-06-23 | 2019-01-25 | Hanmi Science Co., Ltd. | Naujieji kondensuoti pirimidino dariniai, skirti tirozino kinazės aktyvumo slopinimui |
US20120053189A1 (en) | 2010-06-28 | 2012-03-01 | Pharmacyclics, Inc. | Btk inhibitors for the treatment of immune mediated conditions |
US20120100166A1 (en) | 2010-07-15 | 2012-04-26 | Zyngenia, Inc. | Ang-2 Binding Complexes and Uses Thereof |
EP2603081B1 (en) | 2010-08-10 | 2016-10-05 | Celgene Avilomics Research, Inc. | Besylate salt of a btk inhibitor |
AR082590A1 (es) | 2010-08-12 | 2012-12-19 | Hoffmann La Roche | Inhibidores de la tirosina-quinasa de bruton |
US9249123B2 (en) | 2010-09-01 | 2016-02-02 | Genentech, Inc. | Pyridinones/pyrazinones, method of making, and method of use thereof |
BR112013007499A2 (pt) | 2010-09-01 | 2016-07-12 | Genentech Inc | piridazinonas - métodos de criação e usos |
KR101941514B1 (ko) | 2010-12-22 | 2019-01-23 | 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 | 개선된 반감기를 가지는 변형된 항체 |
RS57895B1 (sr) | 2011-03-29 | 2019-01-31 | Roche Glycart Ag | Fc varijante antitela |
WO2012135408A1 (en) | 2011-03-31 | 2012-10-04 | Merck Sharp & Dohme Corp. | Stable formulations of antibodies to human programmed death receptor pd-1 and related treatments |
US8703767B2 (en) | 2011-04-01 | 2014-04-22 | University Of Utah Research Foundation | Substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase BTK inhibitors |
CA2760174A1 (en) | 2011-12-01 | 2013-06-01 | Pharmascience Inc. | Protein kinase inhibitors and uses thereof |
ES2669310T3 (es) | 2011-04-20 | 2018-05-24 | Medimmune, Llc | Anticuerpos y otras moléculas que se unen con B7-H1 y PD-1 |
CN103596958A (zh) | 2011-04-20 | 2014-02-19 | 葛兰素集团有限公司 | 用作抗结核病化合物的四氢吡唑并[1,5-a]嘧啶 |
US9376438B2 (en) | 2011-05-17 | 2016-06-28 | Principia Biopharma, Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
US20140107151A1 (en) | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
JP5859640B2 (ja) | 2011-05-17 | 2016-02-10 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | ブルトンチロシンキナーゼ阻害剤 |
EP2710005B1 (en) | 2011-05-17 | 2016-10-05 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
CN103596982B (zh) | 2011-06-06 | 2016-11-02 | 诺沃—诺迪斯克有限公司 | 治疗性抗体 |
KR20150144817A (ko) | 2011-06-10 | 2015-12-28 | 메르크 파텐트 게엠베하 | Btk 억제 활성을 갖는 피리미딘 및 피리딘 화합물의 조성물 및 제조방법 |
BR112013032899A2 (pt) | 2011-06-22 | 2017-01-24 | Inserm Inst Nat De La Santé Et De La Rech Médicale | anticorpos anti-axl e utilizações dos mesmos |
CA2841111A1 (en) | 2011-07-08 | 2013-01-17 | Novartis Ag | Novel pyrrolo pyrimidine derivatives |
JP6238459B2 (ja) | 2011-08-01 | 2017-11-29 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニストとmek阻害剤を使用する癌の治療方法 |
PT2785375T (pt) | 2011-11-28 | 2020-10-29 | Merck Patent Gmbh | Anticorpos anti-pd-l1 e usos destes |
WO2013106643A2 (en) | 2012-01-12 | 2013-07-18 | Yale University | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
JP6226752B2 (ja) | 2012-02-09 | 2017-11-08 | 中外製薬株式会社 | 抗体のFc領域改変体 |
US10011660B2 (en) | 2012-04-30 | 2018-07-03 | Medimmune, Llc | Molecules with reduced effector function and extended half-lives, compositions, and uses thereof |
SG10201700698WA (en) | 2012-05-15 | 2017-02-27 | Bristol Myers Squibb Co | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
EP2854843A4 (en) | 2012-05-31 | 2016-06-01 | Sorrento Therapeutics Inc | ANTIGEN BINDING PROTEINS THAT BIND PD-L1 |
WO2014007982A2 (en) | 2012-07-03 | 2014-01-09 | Janssen Alzheimer Immunotherapy | C-terminal and central epitope a-beta antibodies |
WO2014055897A2 (en) | 2012-10-04 | 2014-04-10 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-pd-l1 antibodies and methods of use |
US20140377269A1 (en) | 2012-12-19 | 2014-12-25 | Adimab, Llc | Multivalent antibody analogs, and methods of their preparation and use |
AR093984A1 (es) | 2012-12-21 | 2015-07-01 | Merck Sharp & Dohme | Anticuerpos que se unen a ligando 1 de muerte programada (pd-l1) humano |
GB201311910D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel Compounds |
TWI635098B (zh) | 2013-02-01 | 2018-09-11 | 再生元醫藥公司 | 含嵌合恆定區之抗體 |
WO2014130690A1 (en) | 2013-02-20 | 2014-08-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals with modified immunoglobulin heavy chain sequences |
JP6404314B2 (ja) | 2013-03-15 | 2018-10-10 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | Il−33拮抗薬とその使用法 |
CA3175360A1 (en) | 2013-05-31 | 2014-12-04 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind pd-1 |
TWI617309B (zh) * | 2013-10-25 | 2018-03-11 | 製藥公司 | 使用布魯頓氏酪胺酸激酶抑制劑之治療及免疫療法 |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
KR102130600B1 (ko) | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
WO2016008411A1 (en) | 2014-07-18 | 2016-01-21 | Beigene, Ltd. | 5-amino-4-carbamoyl-pyrazole compounds as selective and irreversible t790m over wt-egfr kinase inhibitors and use thereof |
DK3179992T3 (da) | 2014-08-11 | 2022-07-11 | Acerta Pharma Bv | Terapeutisk kombination af en btk-inhibitor, en pd-1-inhibitor og/eller en pd-l1-inhibitor |
US10071164B2 (en) | 2014-08-11 | 2018-09-11 | Yale University | Estrogen-related receptor alpha based protac compounds and associated methods of use |
WO2016025720A1 (en) | 2014-08-14 | 2016-02-18 | Assia Chemical Industries Ltd. | Solid state forms of ibrutinib |
TW201625304A (zh) | 2014-10-24 | 2016-07-16 | 美國禮來大藥廠 | 泌尿上皮癌之療法 |
WO2016087994A1 (en) | 2014-12-05 | 2016-06-09 | Acerta Pharma B.V. | Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment |
BR112017013022A2 (pt) | 2014-12-18 | 2018-02-27 | Principia Biopharma Inc | métodos para tratar uma doença inflamatória e/ou autoimune aguda num mamífero que a necessite onde a terapia de corticosteróides é utilizada como terapia de primeira ou segunda linha e/ou para tratar uma doença inflamatória e/ou autoimune num mamífero que a necessite, onde a terapia de corticosteróides é utilizada como terapia de manutenção de primeira ou segunda linha e/ou para eliminar ou reduzir dose terapêutica de corticosteróides utilizado no tratamento de uma doença inflamatória e/ou autoimune num mamífero que a necessite, onde a terapia de corticosteróides é utilizada como terapia de manutenção crônica de primeira ou segunda linha e/ou de tratamento de uma doença autoimune e/ou inflamatória num mamífero que a necessite |
WO2016105582A1 (en) | 2014-12-24 | 2016-06-30 | Nunn Philip A | Compositions for ileo-jejunal drug delivery |
US9139653B1 (en) | 2015-04-30 | 2015-09-22 | Kymab Limited | Anti-human OX40L antibodies and methods of treatment |
GB201504314D0 (en) | 2015-03-13 | 2015-04-29 | Univ Dundee | Small molecules |
WO2016149668A1 (en) | 2015-03-18 | 2016-09-22 | Arvinas, Inc. | Compounds and methods for the enhanced degradation of targeted proteins |
CN104777137B (zh) | 2015-03-25 | 2018-06-19 | 深圳市贝沃德克生物技术研究院有限公司 | 生物标志物检测用光谱位置调节装置 |
WO2016196298A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Therapeutic and diagnolstic methods for cancer |
BR112017025975B1 (pt) | 2015-06-04 | 2023-12-12 | Arvinas Operations, Inc | Composto, composição, método in vitro para induzir degradação de uma proteína alvo em uma célula, e, uso de uma composição |
US20180147202A1 (en) | 2015-06-05 | 2018-05-31 | Arvinas, Inc. | TANK-BINDING KINASE-1 PROTACs AND ASSOCIATED METHODS OF USE |
CA2988430A1 (en) | 2015-07-10 | 2017-01-19 | Arvinas, Inc. | Mdm2-based modulators of proteolysis and associated methods of use |
BR112017028269A2 (pt) | 2015-07-13 | 2018-09-04 | Arvinas Inc | composto, composição farmacêutica, uso de uma quantidade efetiva de um composto, estado ou condição de doença, e, método para identificar um composto. |
WO2017024465A1 (en) | 2015-08-10 | 2017-02-16 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
WO2017030814A1 (en) | 2015-08-19 | 2017-02-23 | Arvinas, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
EP3370715A4 (en) | 2015-11-02 | 2019-05-15 | Yale University | CHIMERIC COMPOUNDS PROVIDED AGAINST PROTEOLYSIS AND METHOD FOR THE PRODUCTION AND USE THEREOF |
CN109311867A (zh) | 2016-04-20 | 2019-02-05 | 葛兰素史克知识产权开发有限公司 | 包含ripk2抑制剂的共轭物 |
CN109562113A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的螺环降解决定子体 |
WO2017197056A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Bromodomain targeting degronimers for target protein degradation |
WO2017197051A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Amine-linked c3-glutarimide degronimers for target protein degradation |
WO2017197046A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
PL3458101T3 (pl) | 2016-05-20 | 2021-05-31 | F. Hoffmann-La Roche Ag | Koniugaty PROTAC-przeciwciało i sposoby ich stosowania |
EP3468500A4 (en) | 2016-06-09 | 2020-03-04 | Blinkbio Inc. | THERAPEUTIC PAYLOADS BASED ON SILANOLE |
GB201610147D0 (en) | 2016-06-10 | 2016-07-27 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
AU2017293423B2 (en) | 2016-07-05 | 2023-05-25 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
WO2018033853A2 (en) | 2016-08-16 | 2018-02-22 | Beigene, Ltd. | Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
GB201614134D0 (en) | 2016-08-18 | 2016-10-05 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
WO2018033135A1 (en) | 2016-08-19 | 2018-02-22 | Beigene, Ltd. | Use of a combination comprising a btk inhibitor for treating cancers |
SG11201901548SA (en) | 2016-08-26 | 2019-03-28 | Beigene Ltd | Anti-tim-3 antibodies and use thereof |
US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
EP3512842B1 (en) | 2016-09-15 | 2024-01-17 | Arvinas, Inc. | Indole derivatives as estrogen receptor degraders |
EP3519051B1 (en) | 2016-09-27 | 2021-09-22 | Beigene, Ltd. | Treatment of cancers using combination comprising parp inhibitors |
HRP20230414T1 (hr) | 2016-10-11 | 2023-07-07 | Arvinas Operations, Inc. | Spojevi i postupci za ciljanu razgradnju androgenog receptora |
EP3526240A1 (en) | 2016-10-14 | 2019-08-21 | Xencor, Inc. | Bispecific heterodimeric fusion proteins containing il-15/il-15ralpha fc-fusion proteins and pd-1 antibody fragments |
EP3544975B1 (en) | 2016-11-22 | 2022-01-05 | Dana-Farber Cancer Institute, Inc. | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and use |
EP3544957A4 (en) | 2016-11-22 | 2020-09-02 | Dana-Farber Cancer Institute, Inc. | KINASE PROTEIN DEGRADATION BY CONJUGATION OF KINASE PROTEIN INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE |
WO2018137681A1 (en) | 2017-01-25 | 2018-08-02 | Beigene, Ltd. | Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof |
KR20190137151A (ko) | 2017-04-20 | 2019-12-10 | 에이디씨 테라퓨틱스 에스에이 | 병용 요법 |
CA3066518A1 (en) | 2017-06-26 | 2019-01-03 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
WO2019034009A1 (en) | 2017-08-12 | 2019-02-21 | Beigene, Ltd. | BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY |
US11786529B2 (en) | 2017-11-29 | 2023-10-17 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors |
WO2019157353A1 (en) | 2018-02-09 | 2019-08-15 | Beigene, Ltd. | Immunotherapy for urothelial carcinoma |
GB201803746D0 (en) | 2018-03-08 | 2018-04-25 | Ultrahuman Eight Ltd | PD1 binding agents |
CA3093847A1 (en) | 2018-03-21 | 2019-09-26 | Mei Pharma, Inc. | Combination therapy |
TW202112369A (zh) | 2019-06-10 | 2021-04-01 | 英屬開曼群島商百濟神州有限公司 | 口服膠囊劑及其製備方法 |
EP3981399A4 (en) | 2019-06-10 | 2023-05-31 | BeiGene Switzerland GmbH | ORAL SOLID TABLET WITH A TYROSINE KINAS INHIBITOR AND METHOD OF MANUFACTURE THEREOF |
US20220281876A1 (en) | 2019-07-26 | 2022-09-08 | Beigene, Ltd. | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use |
-
2018
- 2018-11-29 US US16/766,803 patent/US11786529B2/en active Active
- 2018-11-29 WO PCT/US2018/063068 patent/WO2019108795A1/en active Application Filing
- 2018-11-29 CN CN201880077703.0A patent/CN111801334B/zh active Active
-
2023
- 2023-08-15 US US18/450,256 patent/US20240009197A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090217401A1 (en) * | 2005-05-09 | 2009-08-27 | Medarex, Inc | Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics |
US20110008369A1 (en) * | 2008-03-12 | 2011-01-13 | Finnefrock Adam C | Pd-1 binding proteins |
US20150259354A1 (en) * | 2013-04-25 | 2015-09-17 | Beigene, Ltd. | Fused heterocyclic compounds as protein kinase inhibitors |
US20150079109A1 (en) * | 2013-09-13 | 2015-03-19 | Beigene, Ltd. | Anti-PD1 Antibodies and their Use as Therapeutics and Diagnostics |
WO2017046746A1 (en) * | 2015-09-15 | 2017-03-23 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor and a gitr binding molecule, a 4-1bb agonist, or an ox40 agonist |
WO2017059224A2 (en) * | 2015-10-01 | 2017-04-06 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
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