CN109195989A - 用于癌症治疗的pd-1/pd-l1抑制剂 - Google Patents
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- CN109195989A CN109195989A CN201780032522.1A CN201780032522A CN109195989A CN 109195989 A CN109195989 A CN 109195989A CN 201780032522 A CN201780032522 A CN 201780032522A CN 109195989 A CN109195989 A CN 109195989A
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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Abstract
本发明涉及在对象中治疗癌症的方法,其包括向所述对象施用治疗有效量的PD‑1受体与其配体PD‑L1之间相互作用的抑制剂。
Description
本发明涉及治疗对象癌症的方法,其包括给对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。
背景技术
癌症
癌症是细胞的异常生长,这些细胞倾向以不受控的方式增殖,并且在一些情况下转移(扩散)。癌症不是一种疾病。它是由100多种不同且独特的疾病组成的群体。癌症可以涉及身体的任何组织并且在每个身体区域中具有许多不同的形式。大多数癌症以它们开始的细胞或器官的类型命名。如果癌症扩散(转移),新肿瘤与原(原发)肿瘤同名。特定癌症的发生频率可取决于性别。虽然皮肤癌是男性和女性最常见的恶性肿瘤类型,但男性中第二常见的类型是前列腺癌,而女性则是乳腺癌。
卵巢癌
对于全球女性而言,卵巢癌是第七大常见癌症,且也是癌症死亡的第八大原因(Globocan Population Fact Sheet 2012)。在美国,基于2007-2011年间病例得到的年龄标准化发病率(ASR)为每10万名妇女12.3例,相比于2000-2009年间病例估算的ASR每10万妇女8.1例有所增长。由于该疾病在早期阶段缺乏可察觉的症状,因此患者通常患有晚期疾病。
5年存活率约为30%至50%(SEER Stat Fact Sheet Ovary Cancer 2014)。将紫杉醇加入铂基化疗改善晚期疾病患者的无进展存活期(PFS)和总存活期(OS)。抗血管生成剂,例如贝伐单抗和帕唑帕尼(pazopanib),能延长无进展存活期,但不能延长总存活期。
添加到化疗中的PARP抑制剂(例如奥拉帕尼)显示出前景,但主要用于维持治疗。大多数患者经历复发通常与铂耐药性有关,因此使得卵巢癌成为常见的致命疾病,几乎没有批准的或有效的治疗选择(Luvero D,et al.Ther Adv Med Oncol.2014;6(5):229-239)。
肾细胞癌
肾细胞癌(RCC)是最常见的肾癌,且占成人所有恶性肿瘤的约3%。直到2005年,干扰素-α(IFN-α)和高剂量白细胞介素(IL)-2疗法才是晚期RCC(aRCC)患者的护理标准,尽管有效性一般。从那时起,开发和批准的多种血管内皮生长因子(VEGF)通路和哺乳动物雷帕霉素靶(mTOR)抑制剂已显著改善aRCC患者的转归(outcome)。这些药物包括VEGF受体(VEGFR)酪氨酸激酶抑制剂(TKI)舒尼替尼、帕唑帕尼、阿西替尼和索拉非尼,mTOR抑制剂替西罗莫司(temsirolimus)和依维莫司,以及抗VEGF单克隆抗体贝伐单抗。然而,尽管使用这些药物可显著改善患者的转归,但在aRCC患者中持久且完全应答并不常见;大多数患者最终会产生耐药性,在治疗期间出现疾病进展,并且由于转移性疾病而死亡。
霍奇金淋巴瘤
淋巴瘤是最常见的血癌。淋巴瘤的两种主要形式是霍奇金淋巴瘤(HL)和非霍奇金淋巴瘤(NHL)。当免疫系统细胞,称为淋巴细胞(一种白细胞)不受控地生长和增殖时,就会发生淋巴瘤。癌性淋巴细胞可转移到身体的许多部位,包括淋巴结、脾脏、骨髓、血液或其他器官,并形成称为肿瘤的肿块。身体有两种主要类型的淋巴细胞可发展成淋巴瘤:B淋巴细胞(B细胞)和T淋巴细胞(T细胞)。HL(也称为霍奇金病)不如NHL(非霍奇金淋巴瘤)常见。每年预计有大约9,000个新的HL病例。尽管HL可在儿童和成人中发生,但最常是在年龄为20至34岁的年轻人中诊断。
HL的特征在于存在称为里德-斯泰伯格氏(RS)细胞的巨大细胞,尽管可能存在其他异常细胞类型。HL通常从淋巴结开始;然而,它经常从一个淋巴结扩散到另一个淋巴结,并且还可扩散到其他器官。
HL的常见体征和症状包括淋巴结肿大(通常但不总是无痛)、发烧、盗汗、原因不明的体重减轻以及疲乏。虽然大多数有这些不适的人都不会患有HL,但是任何有持续症状的人应该看医生以确保淋巴瘤不存在。
HL分为两大类:经典型HL(CHL),占病例的90%至95%,以及结节性淋巴细胞为主的HL。患者的HL类型可能会影响他们的治疗选择。
经典型霍奇金淋巴瘤
结节性硬化CHL是HL最常见的亚型,占所有HL病例的60%至80%。在结节性(结节样)硬化CHL中,涉及的淋巴结含有与正常白细胞混合的RS细胞。淋巴结通常含有大量瘢痕组织,这是结节性硬化症(瘢痕形成)名字的起源。这种疾病在女性中比在男性中更常见,并且通常影响青少年和50岁以下的成年人。大多数患者通过目前的治疗方法治愈。
混合细胞CHL占所有HL病例的约15%至30%。这种疾病在男性中比在女性中更常见,并且主要影响老年人。对于这种类型的CHL,淋巴结除了几种其他细胞类型外还含有许多RS细胞。在诊断出这种亚型时,通常会出现更晚期的疾病。
很少诊断出淋巴细胞耗竭CHL。具有该亚型的患者的淋巴结中存在丰富的RS细胞和少量正常淋巴细胞,其具有侵袭性,并且通常直到其遍布全身才被诊断出。富含淋巴细胞的CHL占HL病例的不到5%。该疾病可以是弥散(扩散)或结节形式,且其特征在于存在许多看上去正常的淋巴细胞和经典RS细胞。成人的HL的这种亚型通常在早期阶段诊断出,并且具有低复发率(治疗后疾病复发率)。
淋巴细胞为主的霍奇金淋巴瘤
结节性淋巴细胞为主的HL占所有HL病例的5%至10%。比起女性,它更频繁地影响男性,并且通常在35岁之前被诊断出来。在结节性淋巴细胞为主的HL中,淋巴结中发现的大多数淋巴细胞是正常的(非癌性的)。通常在该亚型中未发现典型的RS细胞,但可看到大的、异常B细胞(有时称为爆米花细胞)以及小的B细胞,其可以以组织内的结节模式分布。该亚型通常在早期诊断出来并且不是非常具有侵袭性。在许多方面,这种形式的HL类似于具有晚期复发的惰性(生长缓慢的)B细胞NHL。
(来源为http:www.lymphoma.org)
头颈鳞状细胞癌(HNSCC)
在2016年,估计在美国将有61,760个人被诊断患有头颈癌,其中大约13,190人死于该疾病。大多数头颈癌患者在确诊时有转移性疾病(43%涉及区域性淋巴结,且10%为远处转移)。
头颈癌包括多种不常见的肿瘤,这些肿瘤通常在其生物学行为上具有侵袭性。此外,具有头颈癌病史的患者有可能发展成第二原发性肿瘤,这通常是由于习惯性吸烟。
这些新的原发性肿瘤以每年3%至7%的速率发生,并且50%至75%的此类新癌症发生在上呼吸消化道或肺部。烟草相关的头颈癌的发病率正在下降。然而,由人乳头瘤病毒(HPV)引起的癌症发病率继续以每年2%至4%的速度增加。
(来源为http:www.lymphoma.org)
附图说明
图1a(SEQ ID NO:7)示出了阿维单抗(Avelumab)的全长重链序列。
图1b(SEQ ID NO:8)示出了没有C-末端赖氨酸的阿维单抗的重链序列。
图2(SEQ ID NO:9)示出了阿维单抗的轻链序列。
发明内容
由于关于前述癌症类型的治疗仍然存在高度未满足的医学需求,本发明的一个方面是提供治疗对象的这些癌症类型的方法,其包括向对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。
本发明待治疗的特定类型的癌症包括但不限于卵巢癌、肾细胞癌或霍奇金淋巴瘤,这些癌症可以是未治疗的或先前治疗的、原发性的或转移性的、顽固性的或复发性的。
在本发明的一个实施方案中,对象是人,PD-1受体是人PD-1受体,且PD-L1是人PD-L1。
在本发明的一个优选实施方案中,抑制剂与PD-L1结合。
在一个更优选的实施方案中,抑制剂是抗PD-L1抗体。在一些实施方案中,抗PD-L1抗体包含来自图1a(SEQ ID NO:7)和图1b(SEQ ID NO:8)中所示的重链氨基酸序列的三个互补决定区(CDR)(SEQ ID NO:1、2和3)和来自图2(SEQ ID NO:9)所示的轻链氨基酸序列的三个CDR(SEQ ID NO:4、5和6),如下划线所示,并在WO2013079174中进一步详细描述。在一个更优选的实施方案中,抗PD-L1抗体是阿维单抗,其具有图1a或1b和2中所示的重链和轻链序列(SEQ ID NO:7或8和9)。
图1a(SEQ ID NO:7)示出了阿维单抗的全长重链序列。然而,经常观察到,在抗体产生过程中,重链的C-末端赖氨酸(K)被裂解。该修饰对抗体-抗原结合没有影响。因此,在一些实施方案中,不存在阿维单抗的重链序列的C-末端赖氨酸(K)。没有C-末端赖氨酸的阿维单抗的重链序列显示在图1b中(SEQ ID NO:8)。
在本发明的另一个实施方案中,抗PD-L1抗体每隔一周以10mg/kg体重的剂量施用(即每两周一次,或“Q2W”)。
在一个实施方案中,该方法在对象中引起客观应答,优选完全应答或部分应答。
在一个实施方案中,抑制剂通过静脉施用(例如,作为静脉输注)或皮下施用。优选地,抑制剂作为静脉输注施用。更优选地,抑制剂作为1小时静脉输注施用。
在一个实施方案中,抑制剂作为单个药物施用,即不作为组合疗法的一部分施用。
在一个方面,癌症是卵巢癌。
在一个实施方案中,患有卵巢癌的对象先前尚未接受卵巢癌治疗,即先前未治疗过卵巢癌。
在一个实施方案中,患有先前未治疗的卵巢癌的对象正在接受抑制剂与化疗的联合用药。
在一个实施方案中,患有先前未治疗的卵巢癌的对象在化疗后接受抑制剂。
在另一个实施方案中,所述化疗是铂基化疗。
在另一方面,癌症是肾细胞癌。
在一个实施方案中,肾细胞癌是转移性肾细胞癌。
在一个实施方案中,转移性肾细胞癌先前已接受全身性治疗。
在一个实施方案中,肾细胞癌用抑制剂作为单个药物治疗,即不作为组合疗法的一部分。
在另一方面,癌症是霍奇金淋巴瘤。
在一个实施方案中,霍奇金淋巴瘤是经典型霍奇金淋巴瘤。
在一个实施方案中,霍奇金淋巴瘤是晚期阶段。
在一个实施方案中,霍奇金淋巴瘤先前已接受化疗。
在另一方面,癌症是头颈鳞状细胞癌(HNSCC)。
在一个实施方案中,HNSCC是转移性的。
在一个实施方案中,HNSCC先前已接受化疗,所述化疗包括含铂化疗药物的化疗。
在一个实施方案中,HNSCC是铂难治的。
在一个实施方案中,HNSCC是不能使用铂的(platinum-ineligible)。
在一个实施方案中,HNSCC是转移性的,和铂难治的或不能使用铂的。
本发明还提供了抗PD-L1抗体在制备用于治疗个体癌症的药物中的用途。本发明还提供了用于治疗癌症的抗PD-L1抗体。
“抗体”是能够通过位于免疫球蛋白分子的可变区中的至少一个抗原识别位点特异性结合至靶标(例如碳水化合物、多核苷酸、脂质、多肽等)的免疫球蛋白分子。如本文所用,术语“抗体”不仅包括完整的多克隆或单克隆抗体,而且除非另有说明,否则还包括与完整抗体竞争特异性结合的任何抗原结合片段、包含抗原结合部分的融合蛋白(例如,抗体-药物缀合物)、包含抗原识别位点的免疫球蛋白分子的任何其他经修饰的构型、具有多表位特异性的抗体组合物、多特异性抗体(例如,双特异性抗体)。
抗原结合片段包括例如Fab、Fab'、F(ab')2、Fd、Fv、结构域抗体(dAb,例如鲨鱼和骆驼科动物抗体),包括互补决定区(CDR)的片段、单链可变片段抗体(scFv)、大抗体(maxibody)、微抗体(minibody)、胞内抗体(intrabody)、双抗体、三链抗体、四链抗体(tetrabody)、v-NAR和bis-scFv,以及含有至少一部分免疫球蛋白的多肽,所述一部分免疫球蛋白足以赋予多肽特异性抗原结合。
术语“免疫球蛋白”(Ig)在此与“抗体”可互换地使用。基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元和另外一个称为J链的多肽组成,且含有10个抗原结合位点,而IgA抗体包含2-5个可与J链相结合聚合形成多价组合的基本4链单元。对于IgG来说,4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个二硫键相互连接,这取决于H链同种型。每个H和L链还具有规则间隔的链内二硫键。每个H链在N末端具有可变结构域(VH),随后是每个α和γ链的三个恒定结构域(CH)和μ和ε同种型的四个CH结构域。每个L链在N末端具有可变结构域(VL),在其另一端具有恒定结构域。VL与VH对齐,且CL与重链的第一恒定结构域(CH1)对齐。人们认为特定的氨基酸残基在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质,参见例如Basic and Clinical Immunology,8th Edition,Daniel P.Sties,Abba I.Terrand Tristram G.Parsolw(eds),Appleton&Lange,Norwalk,CT,994,第71页和第6章。来自任何脊椎动物物种的L链可基于其恒定结构域的氨基酸序列分配至两种明显不同的类型(称为κ和λ)之一。取决于其重链(CH)的恒定结构域的氨基酸序列,可将免疫球蛋白分配至不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别称为α、δ、ε、γ和μ的重链。基于CH序列和功能的相对小的差异将γ和α类进一步分成亚类,例如,人表达以下亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
“分离的”抗体是已经从其产生环境(例如,天然的或重组的)的组分中鉴定、分离和/或回收的抗体。优选地,分离的多肽不与来自其产生环境的所有其他组分关联。其产生环境的污染组分,例如由重组转染细胞产生的组分,是通常会干扰抗体的研究、诊断或治疗用途的材料,并且可包括酶、激素和其他蛋白质或非蛋白质溶质。在优选的实施方案中,多肽将被纯化成:(1)大于95%重量的抗体,如通过例如Lowry方法测定的,并且在一些实施方案中,大于99%重量;(2)通过使用旋转杯测序仪足以获得至少N末端或内部氨基酸序列的15个残基的程度,或(3)使用考马斯蓝或优选银染在非还原或还原条件下通过SDS-PAGE达到均一性。分离的抗体包括重组细胞内的原位抗体,因为抗体的天然环境的至少一种成分将不存在。然而,通常用至少一个纯化步骤来制备分离的多肽或抗体。
抗体的“可变区”或“可变结构域”是指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可分别称为“VH”和“VL”。这些结构域通常是抗体中变化最大的部分(相对于同一类别的其他抗体)并含有抗原结合位点。
术语“可变”是指可变结构域的某些区段在抗体之间的序列差异很大的事实。V结构域介导抗原结合并定义特定抗体对其特定抗原的特异性。然而,可变性并非在整个可变结构域范围内均匀分布。相反,它集中在轻链和重链可变结构域中称为高变区(HVR)的三个区段中。可变区的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,主要采用β-折叠构型,通过三个HVR连接,其形成连接β-折叠结构的环,并且在一些情况下形成β-折叠结构的一部分。每个链中的HVR通过FR区紧密靠近地保持在一起,并且来自另一条链的HVR有助于抗体的抗原结合位点的形成(参见Kabat et al,Sequencesof Immunological Interest,Fifth Edition,National Institute of Health,Bethesda,MD(1991))。恒定结构域不直接参与抗体与抗原的结合,但表现出各种效应子功能,例如抗体参与抗体依赖性细胞毒性。
本文所用的术语“单克隆抗体”是指从基本上同质的抗体群体获得的抗体,即除了可能天然发生的突变和/或可能存在的少量翻译后修饰(例如,异构化、酰胺化),单个抗体包括的种群是相同的。单克隆抗体针对单个抗原性位点具有高度特异性。与通常包括针对不同决定簇(表位)的不同抗体的多克隆抗体制剂相反,每种单克隆抗体针对抗原上的单一决定簇。除了它们的特异性外,单克隆抗体的优势在于它们是通过杂交瘤培养合成的,未被其他免疫球蛋白污染。修饰语“单克隆”表示抗体是从基本上同质的抗体群体获得的特征,并且不应解释为需要通过任何特定方法产生抗体。例如,根据本发明使用的单克隆抗体可通过多种技术制备,包括例如杂交瘤方法(如Kohler and Milstein.,Nature,256:495-97(1975);Hongo et al,Hybridoma,14(3):253-260(1995),Harlow et al,Antibodies:ALaboratory Manual,(Cold Spring Harbor Laboratory Press,2nd ed.1988);Hammerling et al,in:Monoclonal Antibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981))、重组DNA方法(参见例如,美国专利号4,816,567)、噬菌体展示技术(参见例如,Clackson et al,Nature,352:624-628(1991);Marks et al,J.MolBiol.222:581-597(1992);Sidhu et al,J.Mol Biol.338(2):299-310(2004);Lee et al,J.Mol Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.ScL USA 101(34):12467-12472(2004);以及Lee et al,J.Immunol.Methods 284(1-2):119-132(2004)以及在具有部分或全部人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中产生人或类人抗体的技术(参见例如,WO1998/24893;WO 1996/34096;WO 1996/33735;WO 1991/10741;Jakobovits et al,Proc.Natl.Acad.ScL USA90:2551(1993);Jakobovits et al,Nature 362:255-258(1993);Bruggemann et al,Year in Immunol.7:33(1993);美国专利号5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;以及5,661,016;Marks etal,Bio/Technology 10:779-783(1992);Lonberg et al,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al,Nature Biotechnol 14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996);以及Lonberg and Huszar,Intern.Rev.Immunol.13:65-93(1995)。
抗体的“抗原结合片段”或“抗体片段”包含完整抗体的一部分,其仍然能够进行抗原结合和/或是完整抗体的可变区。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段;双抗体;线性抗体(参见U.S.专利5,641,870,实施例2;Zapata et al,Protein Eng.8HO):1057-1062[1995]);单链抗体分子和由抗体片段形成的多特异性抗体。木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称为“Fab”片段,和残留的“Fc”片段,“Fc”这一名称反映了其容易结晶的能力。Fab片段由整个L链以及H链的可变区结构域(VH)和一条重链(CH1)的第一恒定结构域组成。每个Fab片段就抗原结合而言是单价的,即它具有单个抗原结合位点。胃蛋白酶处理抗体产生单个大F(ab')2片段,其大致对应于具有不同抗原结合活性并且仍能够交联抗原的两个二硫键连接的Fab片段。Fab'片段与Fab片段的不同之处在于在CH1结构域的羧基末端具有一些额外的残基,包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH是本文中Fab'的名称,其中恒定结构域的半胱氨酸残基带有游离巯基。F(ab')2抗体片段最初是作为Fab'片段的配对产生的,它们之间具有铰链半胱氨酸。抗体片段的其他化学偶联也是已知的。
Fc片段包含通过二硫键保持在一起的两条H链的羧基末端部分。抗体的效应子功能由Fc区中的序列确定,该区域也被在某些类型的细胞上发现的Fc受体(FcR)识别。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该片段由紧密、非共价结合的一个重链可变区结构域和一个轻链可变区结构域的二聚体组成。从这两个结构域的折叠中发出六个高变环(来自H和L链各3个环),其贡献了用于抗原结合的氨基酸残基并赋予抗体抗原结合特异性。然而,即使单个可变结构域(或仅包含三个对抗原特异的HVR的Fv的一半)也具有识别和结合抗原的能力,尽管其亲和力比整个结合位点低。“单链Fv”,也简写为“sFv”或“scFv”,是包含连接成单一多肽链的VH和VL抗体结构域的抗体片段。优选地,sFv多肽还包含VH和VL结构域之间的多肽接头,其使sFv能够形成用于抗原结合的所需结构。关于sFv的综述,参见Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。本发明抗体的“功能性片段”包含完整抗体的一部分,通常包括完整抗体的抗原结合区或可变区或保留或具有经修饰的FcR结合能力的抗体的Fc区。抗体片段的实例包括线性抗体、单链抗体分子和由抗体片段形成的多特异性抗体。
术语“双抗体”是指通过在VH和VL结构域之间构建具有短接头(约5-10个残基)的sFv片段(参见前一段)制备的小抗体片段,使得实现V结构域的链间而不是链内配对,从而产生二价片段,即具有两个抗原结合位点的片段。双特异性双抗体是两个“交叉”sFv片段的异二聚体,其中两种抗体的VH和VL结构域存在于不同的多肽链上。双抗体更详细地描述于,例如,EP 404,097;WO 93/11161;Hollinger et al,Proc.Natl.Acad.ScL USA 90:6444-6448(1993)。
术语“纳米抗体”是指单结构域抗体,其是由单个单体可变抗体结构域组成的片段。像完整抗体一样,它们能够选择性地结合特定抗原。分子量仅为12-15kDa,单结构域抗体比普通抗体(150-160kDa)小得多。第一个单结构域抗体是从骆驼科动物中发现的重链抗体中提取的。Gibbs,W.Wayt(August2005)."Nanobodies".Scientific AmericanMagazine.
本文的单克隆抗体特别包括“嵌合”抗体(免疫球蛋白),其中一部分重链和/或轻链与来自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的其余部分与来自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及这些抗体的片段,只要它们表现出所需的生物学活性(美国专利4,816,567;Morrison etal,Proc.Natl.Acad.ScL USA,81:6851-6855(1984))。如本文所用,“人源化抗体”用作“嵌合抗体”的子集。
非人(例如鼠)抗体的“人源化”形式是嵌合抗体,其含有源自非人免疫球蛋白的最小序列。在一个实施方案中,人源化抗体是人免疫球蛋白(受者抗体),其中来自受者的HVR(下文定义)的残基被来自具有所需特异性、亲和力和/或能力的非人物种(供者抗体)如小鼠、大鼠、兔或非人灵长类动物的HVR的残基取代。在一些情况下,人免疫球蛋白的框架(“FR”)残基被相应的非人残基取代。此外,人源化抗体可包含在受者抗体或供者抗体中未发现的残基。可以进行这些修饰以进一步改善抗体性能,例如结合亲和力。通常,人源化抗体将包含至少一个且通常两个基本上全部的可变结构域,其中全部或基本上全部的高变环对应于非人免疫球蛋白序列的高变环,并且全部或基本上全部的FR区域是人免疫球蛋白序列的区域,尽管FR区域可以包括一个或多个单个FR残基取代,其改善抗体性能,例如结合亲和力,异构化,免疫原性等。FR中这些氨基酸取代的数量通常在H链中不超过6,在L链中不超过3。人源化抗体任选还包含至少一部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。进一步的细节参见例如,Jones et al,Nature 321:522-525(1986);Riechmann etal,Nature 332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。也可参见例如,Vaswani and Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle and Gross,Curr.Op.Biotech.5:428-433(1994);以及美国专利号6,982,321和7,087,409。
“人抗体”是具有对应于人产生的抗体的氨基酸序列的抗体和/或使用本文公开的制备人抗体的任何技术制备的抗体。人抗体的这种定义特异性地排除了包含非人抗原结合残基的人源化抗体。可使用本领域中已知的各种技术制备人抗体,包括噬菌体展示库。Hoogenboom and Winter,J.Mol.Biol,227:381(1991);Marks et al,J.Mol.Biol,222:581(1991)。也可为公众所获得的用于制备人单克隆抗体的方法被描述在Cole et al,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985);Boerner etal,J.Immunol,147(l):86-95(1991)中。还可参见van Dijk and van de Winkel,Curr.Opin.Pharmacol,5:368-74(2001)。可通过将抗原施用于转基因动物来制备人抗体,所述转基因动物已被修饰以在应答抗原攻击时产生这样的抗体,但其内源性基因座已被禁用,例如免疫xenomice(参见例如,美国专利号6,075,181和6,150,584关于XENOMOUSETM技术)。还可参见例如,Li et al,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)关于通过人B细胞杂交瘤技术产生的人抗体。
阿维单抗(以前称为MSB0010718C)是免疫球蛋白(Ig)G1同种型的完全人单克隆抗体。阿维单抗选择性地结合PD-L1并竞争性地阻断其与PD-1的相互作用。
与靶向T细胞的抗PD-1抗体相比,阿维单抗靶向肿瘤细胞,并因此预期具有较小的副作用,包括较低的自身免疫相关的安全性风险,因为PD-L1的阻断使得PD-L2—PD-1通路完整以促进外周自身耐受(Latchman Y,Wood CR,Chernova T,et al.PD-L1is a secondligand for PD-1and inhibits T cell activation.Nat Immunol 2001;2(3):261-68)。
阿维单抗(其序列及其许多特性已在WO2013079174中描述,其在WO2013079174中被命名为A09-246-2)具有根据SEQ ID NO:32和33的重链和轻链序列,如本专利申请图1(SEQ ID NO:7)和图2(SEQ ID NO:9)所示。如WO2013079174所示,阿维单抗的性质之一是其发挥抗体依赖性细胞介导的细胞毒性(ADCC)的能力,从而通过诱导其裂解而不显示任何显著毒性直接作用于携带PD-L1的肿瘤细胞。
通常,将抑制剂(例如本发明的抗体或抗体片段)整合入适于施用于对象的药物组合物中,其中药物组合物包含抑制剂,例如,抗体或抗体片段和药学上可接受的载体。如本文所用,“药学上可接受的载体”包括生理上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。药学上可接受的载体的实例包括水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等中的一种或多种,以及它们的组合。
在许多情况下,优选在组合物中包含等渗剂,例如糖、多元醇如甘露醇、山梨糖醇或氯化钠。药学上可接受的载体可进一步包含少量辅助物质,例如润湿剂或乳化剂、防腐剂或缓冲剂,其改善抑制剂,例如,抗体或抗体片段的保存期限或有效性。
本发明的组合物可有多种形式。这些包括例如液体、半固体和固体剂型,例如液体溶液(例如可注射和可输注溶液)、分散体或悬浮液、片剂、丸剂、粉末、脂质体和栓剂。优选的形式取决于预期的施用方式和治疗应用。典型的优选组合物是可注射或可输注溶液的形式,例如与用于人的被动免疫的组合物相似的那些。优选的施用方式是肠胃外的(例如静脉内、皮下、腹膜内、肌肉内)。在一个优选的实施方案中,抑制剂(例如抗体或抗体片段)通过静脉内输注或注射施用。在另一个优选的实施方案中,抑制剂(例如抗体或抗体片段)通过肌内或皮下注射施用。
治疗组合物在制造和储存条件下通常必须是无菌和稳定的。该组合物可配制成溶液、微乳液、分散液、脂质体或适于高药物浓度的其他有序结构。无菌可注射溶液可通过将在适当的溶剂中的所需量的活性化合物(如抑制剂,例如抗体或抗体片段)按需求整合一种以上列举的组分或其组合,然后过滤灭菌来制备。通常,通过将活性化合物整合入无菌载体中来制备分散液,所述无菌载体含有基础分散介质和来自上面列举的那些所需的其他成分。对于用于制备无菌可注射溶液的无菌粉末,优选的制备方法是真空干燥和冷冻干燥,其产生活性成分的粉末加上来自其先前无菌过滤的溶液的任何其他所需成分。例如,通过使用诸如卵磷脂的包衣(在分散的情况下通过保持所需的粒度)和通过使用表面活性剂,可保持溶液的适当流动性。通过在组合物中加入延迟吸收的试剂(例如单硬脂酸盐和明胶)可实现可注射组合物的延长的吸收。
抑制剂(例如本发明的抗体或抗体片段)的“治疗有效量”是指在必要的剂量和时间段内有效实现所期望的治疗结果的量。这样的治疗有效量可根据诸如个体的疾病状态、年龄、性别和体重的因素以及抑制剂(例如,抗体或抗体片段)在个体中引起所期待的应答的能力而变化。治疗有效量也是其中抑制剂(例如抗体或抗体片段)的治疗有益效果超过了它们的任何毒性或有害效果的量。
“化疗”是涉及“化疗药物”的疗法,“化疗药物”是用于治疗癌症的化学化合物。化疗药物的实例包括烷化剂如塞替哌和环磷酰胺;烷基磺酸酯,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶如苯并多巴、卡波醌、美妥替哌(meturedopa)和尿烷亚胺;乙撑亚胺和甲基蜜胺(methylamelamine),包括六甲蜜胺、三乙撑蜜胺、三乙撑磷酰胺、三乙撑硫代磷酰胺以及三羟甲蜜胺;多聚乙酰(特别是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));δ-9-四氢大麻酚(屈大麻酚);β-拉帕醌;拉帕醇;秋水仙碱;桦木酸;喜树碱(包括合成类似物托泊替康(CPT-11(伊立替康)、乙酰喜树碱、莨菪亭以及9-氨基喜树碱);苔藓抑素;培美曲塞;卡利他汀(callystatin);CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);鬼臼毒素;鬼臼酸;替尼泊甙(teniposide);念珠藻素(cryptophycin)(特别是念珠藻素1和念珠藻素8);多拉司他汀;多卡米星(包括合成的类似物、KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);TLK-286;CDP323,一种口服α-4整合素抑制剂;匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥诸如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、氮芥(mechlorethamine)、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、松龙苯芥、曲磷胺(trofosfamide)、尿嘧啶氮芥;亚硝基脲类(nitrosureas)诸如卡莫司汀、氯脲菌素、福莫司汀、罗氮芥、尼莫司汀以及雷莫司汀;抗生素诸如烯二炔类抗生素(例如加利车霉素,特别是加利车霉素γII和加利车霉素ωIl(参见例如,Nicolaou et ah,Angew.Chem Intl.Ed.Engl.,33:183-186(1994));达内霉素(dynemicin),包括达内霉素A;埃斯波霉素;以及新制癌菌素生色团和相关色素蛋白烯二炔类抗生素生色团)、阿克拉霉素、放线菌素、氨茴霉素(authramycin)、重氮丝氨酸、博来霉素、放线菌素c、卡柔比星、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉-多柔比星、多柔比星HCl脂质体注射剂以及脱氧多柔比星)、表柔比星、依索比星、伊达比星、马塞罗霉素、丝裂霉素类诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物诸如甲氨喋呤、吉西他滨、替加氟、卡培他滨、埃博霉素(epothilone)以及5-氟尿嘧啶(5-FU);叶酸类似物诸如二甲叶酸、甲氨喋呤、蝶罗呤、三甲曲沙;嘌呤类似物如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物诸如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷和伊马替尼(2-苯基氨基嘧啶衍生物)以及其它c-Kit抑制剂;抗肾上腺剂诸如氨鲁米特、米托坦、曲洛司坦;叶酸补偿剂诸如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;贝斯布西(bestrabucil);比生群;依达曲沙;地磷酰胺;地美可辛;地吖醌;依氟鸟氨酸;依利醋铵;乙环氧啶;硝酸镓;羟基脲;香菇多糖;氯尼达明;类美登素生物碱类(maytansinoid)诸如美登素和柄型菌素;米托胍腙;米托蒽醌;莫哌达醇;尼曲吖啶;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;2-乙基酰肼;丙卡巴肼;PSK多糖复合物(JHS天然产物,Eugene,OR);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢霉烯族化合物(特别是T-2毒素、疣孢菌素A(verracurin A)、杆孢菌素A以及蛇形菌素(anguidine);乌拉坦;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托星(gacytosine);阿糖胞苷(“Ara-C”);噻替哌;类紫杉烷化合物(taxoid),例如,紫杉醇、紫杉醇的白蛋白工程化的纳米颗粒制剂以及多西紫衫醇;苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤;巯嘌呤;甲氨喋呤;铂类似物诸如顺铂和卡铂;长春碱;铂;依托泊甙(VP-16);异环磷酰胺;米托蒽醌;长春新碱;奥沙利铂;亚叶酸(leucovovin);长春瑞滨;诺安托;依达曲沙;道诺霉素;氨基喋呤;伊班膦酸盐;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类视色素诸如视黄酸;任何上述药学上可接受的盐、酸或衍生物;以及两种或更多种上述的组合,诸如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙组合疗法的缩写)和FOLFOX(奥沙利铂联合5-FU和亚叶酸的治疗方案的缩写。
本文所用的铂基化疗是指用一种或多种铂基化疗药物治疗,任选地与一种或多种其他化疗药物组合。
短语“化疗后进展”是指癌症在接受化疗(即难治的)时的进展或完成化疗方案后12个月内(例如6个月内)癌症的进展。
“客观应答”是指可测量的应答,包括完全应答(CR)或部分应答(PR)。
“完全应答”或“完全缓解”是指对治疗产生应答而所有的癌症征候消失。它并非始终指癌症得到治愈。
“部分应答”是指对治疗产生应答而一种或多种肿瘤或病变的大小或体内癌症的程度的减小。
“PD-L1阳性”癌症是包括在其细胞表面存在PD-L1的细胞的癌症。优选地,当至少0.1%和至少10%之间的癌症细胞在其细胞表面有PD-L1时,根据本发明癌症是“PD-L1阳性”。更优选地,当至少0.5%和5%之间的癌症细胞在其细胞表面有PD-L1时,癌症是“PD-L1阳性”。更优选地,当至少1%的癌症细胞在其细胞表面有PD-L1时,癌症是“PD-L1阳性”。
术语“PD-L1阳性”还指在其细胞表面产生足够水平的PD-L1的癌症,使得抗PD-L1抑制剂(例如,抗体)具有由所述抗PD-L1抑制剂(例如,抗体)和PD-L1结合介导的治疗作用。
在优选的实施方案中,PD-L1表达由免疫组织化学(IHC)确定。
“晚期”癌症是通过局部侵袭或转移扩散到原位或原器官之外的癌症。因此,术语“晚期”癌症包括局部晚期疾病和转移性疾病。
“复发性”癌症是在对初始治疗(例如手术)产生应答后,在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后,在与先前治疗的癌症相同的位置出现的癌症。
“不能切除的”癌症是无法通过手术去除的。
“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
“局部晚期”癌症是指已扩散到附近组织或淋巴结但未转移的癌症。
“晚期不能切除的”癌症是通过局部侵袭或转移扩散到原位或原器官之外并且不能通过手术去除的癌症。
“对象”包括人类患者。患者可以是“癌症患者”,即患有或有风险患有一种或多种癌症症状的患者,特别是非小细胞肺癌的患者。
“输液”或“输注”是指通过静脉将含药物的溶液引入体内用于治疗目的。通常,这通过静脉注射(IV)袋实现。
“全身性治疗”是一种药物物质通过血流传送,到达并影响全身细胞的治疗。
应理解,提及的“治疗”包括预防以及缓解已确定的病症症状。因此,“治疗”状态、失调(disorder)或病症包括:(1)预防或延迟人发展的状态、失调或病症的临床症状的出现,这些人可能已经患有该状态、失调或病症或易患该状态、失调或病症,但尚未经历或表现出状态、失调或病症的临床或亚临床症状,(2)抑制状态、失调或病症或其至少一种临床或亚临床症状,即阻止、减少或延迟疾病的发展或其复发(在维持治疗的情况下),或(3)缓解或减轻疾病,即导致状态、失调或病症或其临床或亚临床症状中的至少一种消退。
“抗体依赖性细胞介导的细胞毒性”或ADCC是指细胞毒性的一种形式,其中分泌的Ig结合到某些细胞毒性细胞(例如,自然杀伤(NK)细胞、中性粒细胞和巨噬细胞)上存在的Fc受体(FcR)上,从而使这些细胞毒性效应细胞特异性结合携带抗原的靶细胞,并随后用细胞毒素杀死靶细胞。抗体“武装”细胞毒性细胞,并且其是通过该机制杀死靶细胞所必需的。介导ADCC、NK细胞的原代细胞仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。造血细胞上的Fc表达总结在Ravetch and Kinet,Annu.Rev.Immunol.9:457-92(1991)的第464页表3中。
具体实施方式
卵巢癌
本发明的一个具体方面提供了一种治疗对象卵巢癌的方法,包括给对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。
在本方面的一个实施方案中,接受卵巢癌治疗的对象是人,PD-1受体是人PD-1受体,且PD-L1是人PD-L1。
在一个实施方案中,抑制剂与PD-L1结合。优选地,抑制剂是抗PD-L1抗体或其抗原结合片段。更优选地,抗PD-L1抗体或其抗原结合片段包括在其重链中的根据SEQ ID NO:1、2和3的三个互补决定区(CDR),和在其轻链中的根据SEQ ID NO:4、5和6的三个互补决定区(CDR)。最优选地,抗PD-L1抗体是阿维单抗,具有图1a或1b和2中所示的重链和轻链序列(SEQ ID NO:7或8和9),或其抗原结合片段。
在一个实施方案中,患有卵巢癌的对象先前尚未接受过卵巢癌治疗。
在一个实施方案中,患有先前未治疗的卵巢癌的对象使用化疗和抑制剂的组合。
在一个实施方案中,所述组合疗法是同时施用的。在另一个实施方案中,所述组合疗法是依次施用的。
在一个实施方案中,患有先前未治疗的卵巢癌的对象在化疗后使用抑制剂。
在优选的实施方案中,所述化疗是铂基化疗。
在一个实施方案中,卵巢癌被鉴定为PD-L1阳性癌症。
在一个实施方案中,抑制剂是抗PD-L1抗体,其以每隔一周约10mg/kg体重的剂量施用。
在一个实施方案中,抗PD-L1抗体作为静脉输注施用或皮下施用。
在一个实施方案中,抗PD-L1抗体以1小时静脉输注施用。
在一个实施方案中,该方法导致客观应答,优选为完全应答或部分应答。
肾细胞癌
本发明的一个具体方面提供了一种治疗对象肾细胞癌的方法,其包括给对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。
在本方面的一个实施方案中,接受肾细胞癌治疗的对象是人,PD-1受体是人PD-1受体,且PD-L1是人PD-L1。
在一个实施方案中,抑制剂与PD-L1结合。优选地,抑制剂是抗PD-L1抗体或其抗原结合片段。更优选地,抗PD-L1抗体或其抗原结合片段包括在其重链中的根据SEQ ID NO:1、2和3的三个互补决定区(CDR),轻链中的根据SEQ ID NO:4、5和6的三个互补决定区(CDR)。最优选地,抗PD-L1抗体是阿维单抗,具有图1a或1b和2中所示的重链序列和轻链序列(SEQID NO:7或8和9),或其抗原结合片段。
在一个实施方案中,患有转移性肾细胞癌的对象先前已接受全身性治疗。
在一个实施方案中,肾细胞癌用抑制剂作为单个药物治疗。
在一个实施方案中,肾细胞癌被鉴定为PD-L1阳性癌症。
在一个实施方案中,抑制剂是抗PD-L1抗体,其以每隔一周约10mg/kg体重的剂量施用。
在一个实施方案中,抗PD-L1抗体作为静脉输注施用或皮下施用。
在一个实施方案中,抗PD-L1抗体以1小时静脉输注施用。
在一个实施方案中,该方法导致客观应答,优选为完全应答或部分应答。
霍奇金淋巴瘤
其他人先前的研究表明,PD-L1和PD-L2转录物在霍奇金淋巴瘤(HL)细胞系中是丰富的。具有增加的9p24.1拷贝的HL细胞系具有显著更高的PD-L1和PD-L2蛋白的细胞表面表达。一般认为,为了治疗霍奇金淋巴瘤,必须阻断PD-L1/PD-1相互作用和PD-L2/PD-1相互作用二者。(M.Shipp et al,Blood,Vol 116,No.17,2010)。令人惊讶地发现,作为PD-L1抑制剂的阿维单抗,对PD-L2没有已知的结合亲和力(Kd>1μM),在经典型霍奇金淋巴瘤患者中显示出有效性。
本发明的一个具体方面提供了一种治疗对象霍奇金淋巴瘤的方法,其包括给对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。优选地,抑制剂是抗PD-L1抗体,其以比其与人PD-L1结合的亲和力低至少10倍、100倍、1000倍、104倍、105倍或106倍的亲和力与人PD-L2结合。甚至更优选地,抑制剂是抗PD-L1抗体,其以比其与人PD-L1结合的亲和力低至少1000倍的亲和力与人PD-L2结合。
在本方面的一个实施方案中,接受霍奇金淋巴瘤治疗的对象是人,PD-1受体是人PD-1受体,且PD-L1是人PD-L1。
在一个实施方案中,抑制剂与PD-L1结合。优选地,抑制剂是抗PD-L1抗体或其抗原结合片段。更优选地,抗PD-L1抗体或其抗原结合片段包括在其重链中的根据SEQ ID NO:1、2和3的三个互补决定区(CDR),和在其轻链中的根据SEQ ID NO:4、5和6的三个互补决定区(CDR)。最优选地,抗PD-L1抗体是阿维单抗,具有图1a或1b和2中所示的重链序列和轻链序列(SEQ ID NO:7或8和9),或其抗原结合片段。
在一个实施方案中,霍奇金淋巴瘤是经典型霍奇金淋巴瘤。
在一个实施方案中,霍奇金淋巴瘤是晚期阶段。
在一个实施方案中,对象先前已接受化疗。
在一个实施方案中,抑制剂是抗PD-L1抗体,其以每隔一周约10mg/kg体重的剂量施用。
在一个实施方案中,抗PD-L1抗体作为静脉输注施用或皮下施用。
在一个实施方案中,霍奇金淋巴瘤是经典型霍奇金淋巴瘤,并且对象在施用抑制剂之前进行同种异体干细胞移植。
在该实施方案的一个方面,对象在施用抑制剂之前至少六个月,且优选至少十二个月进行同种异体干细胞移植。更优选地,对象在施用抑制剂之前的6个月至5年之间、6个月至4年之间、6个月至3年之间或6个月至2年之间进行同种异体干细胞移植。
在该实施方案的另一个方面,当施用抗PD-L1抗体时,对象没有提示严重的移植物抗宿主病的显著风险的病史。更具体地,对象在施用抑制剂之前3个月内未接受针对急性或慢性移植物抗宿主病(GVHD)的免疫抑制治疗;任何时候都没有3级或4级GVHD;在任何时候都没有持续超过6个月并需要全身性免疫抑制的慢性GVHD;和/或在施用抑制剂之前6个月内未接受供者淋巴细胞输注(DLI)。
在该实施方案的另一个方面,抑制剂是阿维单抗(一种抗PD-L1抗体)并且对象以每两周10-20mg/kg的剂量静脉内施用阿维单抗,每两周70-500mg的固定剂量或每三周70-500毫克的固定剂量施用阿维单抗。优选地,剂量为每两周至少70mg。更优选地,剂量为每两周70mg、每两周350mg或每两周500mg。优选地,当对象正在接受阿维单抗治疗一段时间时,该对象接受至少一剂、至少两剂、至少三剂或至少4剂阿维单抗。
在一个实施方案中,抗PD-L1抗体以1小时静脉输注施用。
缩略语
AE 不良事件
Allo-SCT 同种异体干细胞移植
AUC 曲线下面积
Av 阿维单抗
BOR 最佳总应答
CR 完全应答,
CTCAE 不良事件的常用术语标准
ECOG 东部合作肿瘤学组
EGFR 表皮生长因子受体
EORTC 欧洲癌症研究和治疗组织
EQ-5D EuroQOL五维问卷
GVHD 移植物抗宿主病
IERC 独立终端审查委员会
IHC 免疫组织化学
IV 静脉的
ITT 意图治疗
LA 局部晚期
NSCLC 非小细胞肺癌
ORR 客观应答率
OS 总存活期
pCR 病理完全应答
PD 进展性疾病
PFS 无进展存活期
PFS2 到第二次客观疾病进展的时间
PR 部分应答
QLQ-LC13 生活质量问卷-肺癌
Q2W 每隔一周
Q3W 每隔两周
RECIST1.1 修订的实体瘤应答评估标准指南
SAE 严重不良事件
SD 稳定疾病
SOC 护理标准
TEAE 治疗-紧急不良事件
实施例1
本实施例是关于一项开放标签、多中心、三臂III期临床试验,测试先前未治疗的卵巢癌患者与铂基化疗联合使用和/或在铂基化疗之后使用的阿维单抗。
主要目的是通过中心审查观察无进展存活期(PFS)来证明阿维单抗与前线化疗联合使用和/或在前线化疗之后使用优于单独使用化疗。入选标准包括在减瘤手术后或新辅助化疗之前新诊断的III期-IV期上皮卵巢癌、输卵管癌或原发性腹膜癌,而与PD-L1情况无关。化疗方案允许选择每周(80mg/m2)或Q3W(175mg/m2)紫杉醇和Q3W(每隔两周一次)卡铂。大约951名符合条件的患者将随机接受化疗,然后进行观察;化疗后施用阿维单抗;或者化疗和阿维单抗联合用药,然后施用阿维单抗。阿维单抗以10mg/kg Q3W与化疗联合施用。维持量为10mg/kg Q2W,最长24个月。每臂中的新辅助患者将在3个周期后进行间歇减瘤。次要终点包括总生存期、妇科癌症组间标准PFS、维持PFS pCR、PFS2、药代动力学、免疫原性、生活质量、安全性和肿瘤和血液中的生物标志物。
实施例2
该实施例是关于在患有转移性肾细胞癌的患者中测试阿维单抗的Ib期临床试验。
符合条件的患者组织学证实mRCC具有透明细胞成分(clear-cell component)、可测量的疾病、可获得的档案/新鲜肿瘤活检和0-1的ECOG表现分数。初始患者也需要1次mRCC全身性治疗失败。患者接受阿维单抗10mg/kg(1小时静脉输液)Q2W直至确认进展、不可接受的毒性或停药。通过RECIST1.1每6周评估肿瘤,并且通过NCI-CTCAE v4.0对不良事件(AE)进行分级。
到数据截止,19名患者接受阿维单抗治疗了中位数时间为20周(范围2-32)且随访≥13周。中位数年龄为69岁(范围30-80),且15名患者(78.9%)为男性。转移性诊断后的中位数时间为14.7个月,且晚期疾病患者的接受中位数为1的先前治疗线(prior line)(范围为1-5),包括9名施用激酶抑制剂的患者(47.4%)和8名化疗的患者(42.1%)。在阿维单抗治疗期间,14名患者(73.7%)有治疗相关(TR)AE;只在>10%的患者中发生疲劳(5例[26.3%])和输注相关反应(5例[26.3%])。只有1名患者(5.3%)患有3级TRAE(疲劳),且未发生4级TRAE或治疗相关的死亡。根据2个部分应答,未经证实的总应答率为10.5%(95%CI:1.3、33.1);两者都在上次评估中持续进行。另外14名患者(73.7%)病情稳定,其病情控制率为84.2%。未达到中位数数无进展生存期;12周的比率为64.9%(95%CI:38.0、82.5)。
结论:单个药物阿维单抗在二线治疗的mRCC患者中具有抗肿瘤活性和可控的安全性谱。根据观察到的应答,该组已扩大到招募>30名接受一线阿维单抗的mRCC患者。
实施例3
该实施例涉及阿维单抗在先前治疗的晚期经典型霍奇金淋巴瘤中的I期药代动力学-药效学研究。
该研究是一项1b期剂量发现研究,旨在评估阿维单抗在成人cHL患者中的药代动力学、药效学和初步抗肿瘤活性。该研究招募的患者要求是在一线挽救性化疗方案中失败的那些。治疗组将探讨标称剂量(nominal dose)、施用频率和基于体重的剂量与固定剂量的因素。在导入的数据中,共有N=30名患者将在5个治疗组中随机分配(1:1)。在剂量扩展中将扩展多达3个治疗组,其中N=36名额外患者将被随机分配(1:1)。剂量扩展组的选择标准包括:安全性,达到>90%的平均目标占用率(TO),以及观察每个恶性淋巴瘤应答标准≥3确认的客观应答。将进行生物标志物评估以评估靶标表达、浸润性免疫细胞的表型以及与免疫激活和耐受相关的标志物以及与免疫调节相关的细胞因子、趋化因子和可溶性受体的水平。该研究将定义阿维单抗药代动力学参数、确认TO并鉴定与cHL患者的肿瘤和临床应答相关的药效学效应和/或免疫表型。它还将确定PD-L2在驱动疾病表型中的功能相关性。
截至2017年3月,31名患者施用至少两周,但优选超过6周,从而允许我们评估药物的有效性。31名患者中有6名先前接受过同种异体干细胞移植(同种异体SCT)。采用以下施用方案之一用阿维单抗治疗患者:70mg阿维单抗Q2W,350mg阿维单抗Q2W,500mg阿维单抗Q3W,500mg阿维单抗Q2W和10mg/kg阿维单抗Q2W。患者应答在下表1(所有患者)和2(同种异体SCT后的患者)中示出。
表1所有患者
表2同种异体SCT后的患者*的应答
注意:*患者在施用阿维单抗前接受同种异体干细胞移植。
一名患者表现出完全应答(CR);该患者接受了500mg阿维单抗Q3W治疗,且之前曾接受同种异体干细胞移植。显示部分应答(PR)的患者包括:3名接受70mg阿维单抗Q2W的患者、1名接受350mg阿维单抗Q2W的患者、4名接受500mg阿维单抗Q3W的患者、3名接受500mg阿维单抗Q2W的患者和4名接受10mg/kg阿维单抗Q2W的患者。
在施用阿维单抗前接受同种异体干细胞移植的患者具有75%的总应答率(ORR)和12.5%的完全应答率(CR)和62.5%的部分应答率(PR)(表2)。相比之下,所有患者的应答率如下:ORR为54.8%、CR为6.5%以及PR为54.8%。
值得注意的是,一名同种异体SCT后的患者在仅施用一剂500mg的阿维单抗后达到完全应答。患者在第一剂阿维单抗后出现GVHD,且患者未接受额外剂量的阿维单抗。随后GVHD得到控制。
实施例4
该实施例是关于在具有铂难治性或不能使用铂的转移性头颈鳞状细胞癌(HNSCC)的患者中测试阿维单抗的Ib期试验。
患有铂难治性或不能使用铂的人乳头瘤病毒阳性或阴性的转移性HNSCC的患者接受阿维单抗10mg/kg(1h IV)Q2W治疗直至确认进展、不可接受的毒性或停药。每6周评估一次肿瘤(RECIST v1.1通过独立评估)。终点包括客观应答率(ORR)、无进展存活期(PFS)和安全性(NCI-CTCAE v4.0)。
截至2015年12月18日,153名患者接受了阿维单抗治疗。原发肿瘤部位为口腔(28.1%)、口咽(21.6%)、下咽部(13.1%)、喉部(10.5%)、其他(25.5%)或缺失(1.3%)。转移性诊断的中位数时间为13.7个月。48.3%的患者接受过≥2次针对晚期疾病的先前治疗线(范围为0-6)。中位数治疗持续时间为11.9周(范围2-34)。79名患者(51.6%)患有治疗相关(TR)AE;最常见(≥6%)是疲劳(9.8%)、发热(9.2%)和输注相关应答(8.5%)。8名患者(5.2%)患有3-4级TRAE。5名患者(3.3%)患有免疫介导的TRAE,包括1名3级患者(牛皮癣)。没有与治疗相关的死亡。在≥3个月的对90名患者的随访中,基于11个部分应答,未证实的ORR为12.2%(95%CI 6.3、20.8);9/11名患者(81.8%)在中止时持续;28名患者(31.1%)病情稳定。基于≥5%PD-L1染色阈值(76/90可评估),PD-L1+和PD-L1-肿瘤中的ORR为9.8%(5/51;95%CI:3.3、21.4)和16.0%(4/25;4.5、36.1)。所有接受治疗的患者的中位数PFS均为7.7周(95%CI 6.0、11.7),且可评估的PD-L1+或PD-L1-肿瘤患者的为6.0vs.6.4周。
结论:阿维单抗显示出有前途的临床活性,并且对于铂难治性或不能使用铂的HNSCC患者具有良好的耐受性。
序列表
<110> 默克专利股份有限公司
辉瑞公司
<120> 用于癌症治疗的PD-1/PD-L1抑制剂
<130> P 16/087
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<170> PatentIn version 3.5
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Claims (40)
1.一种在对象中治疗癌症的方法,其包括给所述对象施用治疗有效量的PD-1受体与其配体PD-L1之间相互作用的抑制剂。
2.根据权利要求1所述的方法,其中所述癌症是卵巢癌、肾细胞癌、霍奇金淋巴瘤或头颈鳞状细胞癌(HNSCC)。
3.根据权利要求1或2中任一项所述的方法,其中所述对象是人,所述PD-1受体是人PD-1受体,且所述PD-L1是人PD-L1。
4.根据权利要求1-3中任一项所述的方法,其中所述抑制剂与PD-L1结合。
5.根据权利要求1-4中任一项所述的方法,其中所述癌症被鉴定为PD-L1阳性癌症。
6.根据权利要求4或5所述的方法,其中所述抑制剂是抗PD-L1抗体。
7.根据权利要求6所述的方法,其中所述抗PD-L1抗体包含在其重链中的根据SEQ IDNO:1、2和3的三个互补决定区(CDR),以及在其轻链中的根据SEQ ID NO:4、5和6的三个互补决定区(CDR)。
8.根据权利要求6或7所述的方法,其中所述抗PD-L1抗体是阿维单抗,其具有根据SEQID NO:7或8的重链序列和根据SEQ ID NO:9的轻链序列。
9.根据权利要求6、7或8所述的方法,其中所述抗PD-L1抗体以每隔一周10mg/kg体重的剂量施用。
10.根据权利要求6-9中任一项所述的方法,其中所述抗PD-L1抗体作为静脉输注施用或皮下施用。
11.根据权利要求10所述的方法,其中所述抗PD-L1抗体以1小时静脉输注施用。
12.根据权利要求1-11中任一项所述的方法,其中所述方法导致客观应答,优选为完全应答或部分应答。
13.根据权利要求1-12中任一项所述的方法,其中所述抑制剂作为单个药物、不作为组合疗法的一部分施用。
14.根据权利要求1-13中任一项所述的方法,其中所述对象先前已接受过癌症治疗。
15.根据权利要求14所述的方法,其中所述癌症治疗是化疗。
16.根据权利要求15所述的方法,其中所述化疗包括含铂的化疗药物。
17.根据权利要求16所述的方法,其中所述化疗是含铂的双联化疗。
18.根据权利要求2-17中任一项所述的方法,其中所述癌症是卵巢癌。
19.根据权利要求18所述的方法,其中所述卵巢癌先前未被治疗。
20.根据权利要求18或19所述的方法,其中用所述抑制剂和化疗的组合治疗所述卵巢癌。
21.根据权利要求18或19所述的方法,其中在化疗后用所述抑制剂治疗所述卵巢癌。
22.根据权利要求20或21所述的方法,其中化疗是铂基化疗。
23.根据权利要求2-17中任一项所述的方法,其中所述癌症是肾细胞癌。
24.根据权利要求23所述的方法,其中所述肾细胞癌是转移性肾细胞癌。
25.根据权利要求24所述的方法,其中所述转移性肾细胞癌先前已接受全身性治疗。
26.根据权利要求2-17中任一项所述的方法,其中所述癌症是霍奇金淋巴瘤。
27.根据权利要求26所述的方法,其中所述抑制剂是抗PD-L1抗体,其以比其与人PD-L1结合的亲和力低至少10倍、100倍、1000倍、104倍、105倍或106倍的亲和力与人PD-L2结合。
28.根据权利要求26或27所述的方法,其中所述霍奇金淋巴瘤是经典型霍奇金淋巴瘤。
29.根据权利要求26-28中任一项所述的方法,其中所述霍奇金淋巴瘤是晚期阶段。
30.根据权利要求26-29中任一项所述的方法,其中所述霍奇金淋巴瘤先前已接受过化疗。
31.根据权利要求28所述的方法,其中所述对象在施用所述抑制剂之前进行同种异体干细胞移植(allo SCT)。
32.根据权利要求31所述的方法,其中所述对象在施用所述抑制剂之前至少6个月进行allo SCT。
33.根据权利要求32所述的方法,其中所述对象在施用所述抑制剂之前6个月至五年之间进行allo SCT。
34.根据权利要求31-33中任一项所述的方法,其中对象在施用所述抑制剂之前3个月内未接受针对急性或慢性移植物抗宿主病(GVHD)的免疫抑制治疗;任何时候都没有3级或4级GVHD;在任何时候都没有持续超过6个月并需要全身性免疫抑制的慢性GVHD;和/或在施用所述抑制剂之前6个月内未接受供者淋巴细胞输注(DLI)。
35.根据权利要求2-17中任一项所述的方法,其中所述癌症是HNSCC。
36.根据权利要求35所述的方法,其中所述HNSCC是转移性的HNSCC。
37.根据权利要求35或36所述的方法,其中所述HNSCC先前已接受包括含铂化疗药物的化疗。
38.根据权利要求37所述的方法,其中所述HNSCC是铂难治的HNSCC。
39.根据权利要求35或36所述的方法,其中所述HNSCC是不能使用铂的HNSCC。
40.根据权利要求35所述的方法,其中所述HNSCC是转移性的,并且是铂难治性的HNSCC或不能使用铂的HNSCC。
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KR20190012201A (ko) | 2019-02-08 |
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