CN109379889A - 通过经由globo系列抗原的免疫激活或免疫调节的癌症免疫疗法 - Google Patents
通过经由globo系列抗原的免疫激活或免疫调节的癌症免疫疗法 Download PDFInfo
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- CN109379889A CN109379889A CN201780036775.6A CN201780036775A CN109379889A CN 109379889 A CN109379889 A CN 109379889A CN 201780036775 A CN201780036775 A CN 201780036775A CN 109379889 A CN109379889 A CN 109379889A
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Abstract
本公开提供了用于癌症患者的免疫治疗的方法,包括施用针对Globo系列抗原(即Globo H、阶段特异性胚胎抗原3“SSEA3”和阶段特异性胚胎抗原4“SSEA4”)的疫苗。具体而言,该方法包括在患有转移性乳腺癌的患者中施用Globo H‑KLH(OBI‑822)。本公开还提供了一种方法,包括选择适合作为免疫疗法的治疗候选者的癌症患者。此外,本公开提供了治疗剂,包括与Globo系列抗原特异性结合的单克隆抗体(mAb)和可用于聚焦此类治疗和诊断方案的相关生物标志物。
Description
相关申请的交叉引用
本申请要求美国临时专利申请号62/326,623(2016年4月22日提交)、62/343,530(2016年5月31日提交)、62/345,755(2016年6月4日提交)和62/381,875(2016年8月31日提交)的优先权。上述申请的全部内容通过引用并入本文。
发明领域
本发明涉及用于癌症患者的免疫治疗的方法,包括向患者施用针对Globo系列抗原的疫苗。
发明背景
碳水化合物抗原Globo H(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)首先被分离为神经酰胺连接的糖脂,并于1984年由Hakomori等人从乳腺癌MCF-7细胞中鉴定出来。(Bremer E G,et al.(1984)J Biol Chem 259:14773-14777)。用抗Globo H单克隆抗体的进一步研究显示了Globo H存在于许多其他癌症(包括前列腺癌、胃癌、胰腺癌、肺癌、卵巢癌和结肠癌)上,以及在不容易接近免疫系统的正常分泌组织的内腔表面上仅最小的表达。(Ragupathi G,et al.(1997)Angew Chem Int Ed 36:125-128)。另外,已经证实了乳腺癌患者的血清含有高水平的抗GloboH抗体。(Gilewski T et al.(2001)Proc NatlAcad Sci USA 98:3270-3275;Huang C-Y,et al.(2006)Proc Natl Acad Sci USA 103:15-20;Wang C-C,et al.(2008)Proc Natl Acad Sci USA105(33):11661-11666)。与具有Globo H阴性肿瘤的患者相比,具有Globo H阳性肿瘤的患者显示更短的生存。(Chang,Y-J,et al.(2007)Proc Natl Acad Sci USA 104(25):10299-10304)。这些发现使Globo H(己糖表位)成为有吸引力的肿瘤标志物和对于癌症疫苗开发的可行的靶物。
发明内容
本公开的方面和实施方案提供了通过免疫疗法治疗患有癌症的受试者的方法,所述方法包括向有此需要的受试者施用靶向免疫原性剂(例如,OBI-822)的Globo系列抗原,其可用于诱导/调节免疫应答(IgG和/或IgM),所述方法包括通过调节Globo系列抗原相互作用来改善生存(包括总生存和/或无进展生存),从而改善受试者的生存。在一个方面,靶向免疫原性剂的Globo系列抗原是例如OBI-822。请参阅我们之前的PCT专利申请(公开号:WO2015159118A2和WO2016044326A1)。这些申请公开涵盖免疫原性/治疗性组合物,包括Globo H-KLH糖缀合物(OBI-822)和/或治疗性佐剂(OBI-821/OBI-834),以及制备和使用它们治疗增殖性疾病例如癌症的方法。治疗组合物部分地设想用作癌症疫苗,用于通过免疫系统增强身体保护自身的天然能力,免于由受损或异常细胞(例如癌细胞)造成的危险。
在一个实施方案中,免疫原性剂可以包括OBI-822和相关的变体。
在某些实施方案中,免疫应答可以包括:针对Globo H系列抗原/肿瘤的IgG(包括亚类IgG1、IgG2、IgG3、IgG4)、IgM、CTL(细胞毒性淋巴细胞)。
在某些实施方案中,临床上有意义的获益可以包括以下各项中的调节:无进展生存;总生存;(耐受性良好和/或没有重大安全问题);客观缓解率;进展时间;无病生存;肿瘤反应;改善生活质量;减少实体瘤的大小和/或减少肿瘤相关抗原(主要或包括Globo H)。
在某些方面,施用方案可以包括:施用疫苗两次或更多次(例如,3、4、5、6、7、8、9、10或更多次);调整两次连续施用之间的时间间隔和/或给药量方案;调整施用的途径和/或改变/交替注射部位/施用的位置或任何上述的任意组合,其中每次施用增加免疫应答[例如,滴度-IgG和/或IgM Ab量,和/或增加亲和力/亲合力;将Ab诱导至Globo H抗原缀合物的Globo H部分的免疫原性较低的位点(例如,在缀合物中可以较不易接近的Globo H抗原的部分)]。在某些方面,可以通过添加免疫应答增强剂来改变和/或补充注射。
在某些方面,Globo系列抗原相互作用的调节可以包括:用通过多轮疫苗接种增加的亲和力诱导抗Globo H抗体;扩增B细胞的生发中心至Globo H系列肿瘤抗原;优先扩增含有高亲和力抗Globo H抗体的生发中心;诱导通常不以足够数量存在的低频B细胞产生具有单次(或低次重复的暴露于抗原)的有意义的应答(例如,它们可以与少数抗体结合的表位结合);扩增抗体分泌浆细胞(“抗体分泌浆细胞”是B细胞分化成的)和记忆B细胞,其对于长期维持抗肿瘤反应可以是重要的;增加Ab类转换的动力学[需要良好的T细胞辅助功能或B细胞不会转换为IgG];增加抗体反应动力学(例如,与不与KLH缀合,不共同施用环磷酰胺,和/或不重复疫苗接种相比,连续疫苗接种可以导致抗体的更快速扩增);减少干扰上述抗肿瘤反应的发展和维持的Treg活性;诱导用于肿瘤杀伤的抗体依赖性细胞性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC);诱导抗Globo系列抗原IgM/IgG免疫应答以引发CDC和ADCC介导的肿瘤细胞杀伤;诱导抗Globo系列抗原抗体捕获从肿瘤细胞脱落的Globo系列抗原-神经酰胺,以阻断易位蛋白相关因子X(TRAX)依赖性血管发生;诱导抗Globo系列抗原抗体以阻断Globo系列抗原-神经酰胺诱导的Notch 1依赖性免疫抑制,并从而增强T细胞增殖和细胞因子产生;诱导抗Globo系列抗原抗体以导致凋亡;抑制Globo系列抗原诱导的血管发生;OBI-822疫苗接种诱导凋亡;诱导CTL(细胞毒性淋巴细胞)。
附图简述
错误!未找到参考源。OBI-822:活性癌症免疫疗法诱导ADCC和CDC用于肿瘤杀伤。通过OBI-822的Globo H-神经酰胺消耗有效地阻断TRAX依赖性血管发生并实现肿瘤消退。肿瘤分泌的可溶性因子与内皮细胞上的其各自的受体结合,引发磷脂酶C(PLC)活化和细胞内钙释放,并促进内皮细胞的增殖、迁移和管形成。PLC作为第二信使的“早期发生器”,驱动血管发生的早期阶段。PLC活性受几个结合配偶体的调节,包括阻断PLCβ1活性的易位蛋白相关因子X(TRAX)。该事件的分子机制涉及Globo-H神经酰胺与TRAX的结合,随后释放和激活PLCβ1。
错误!未找到参考源。OBI-822消耗Globo H-神经酰胺,其继而增加Notch1降解,阻断肿瘤免疫抑制作用,导致肿瘤消退。Notch信号传导通路在大多数生物体中是进化上保守的细胞信号传导系统,并且它可以调节细胞增殖、分化、凋亡和存活。Notch1的调节受E蛋白转录因子E2A及其天然抑制剂ID3控制。其通过经由E3泛素连接酶ITCH的泛素化降解。向免疫细胞中加入Globo-H神经酰胺可以抑制其增殖和细胞因子或免疫球蛋白的分泌。Globo-H神经酰胺可以诱导免疫抑制,其涉及通过伴随ITCH表达的ID3和EGR2/3诱导抑制Notch 1信号传导。
错误!未找到参考源。OBI-822导致凋亡。凋亡(程序性细胞死亡)有助于多细胞生物体的正常发育和组织重塑。黏着斑激酶(FAK)已涉及来自整联蛋白、癌基因和神经肽的信号的整合。在生长因子剥夺诱导的人脐静脉内皮细胞凋亡过程中,已经报道了胱天蛋白酶-3对FAK的蛋白水解切割,这意味着FAK与凋亡之间存在关联。
错误!未找到参考源。显示在接受9次研究药物的注射后的无进展存活(mITT)(分层时序检验,p=0.0542)。
错误!未找到参考源。显示在接受9次研究药物的注射后和基线时具有疾病的无进展存活(mITT)(分层时序检验,P=0.0362)。
错误!未找到参考源。显示与安慰剂相比,有/无IgG免疫应答(IgG标准1:640)的研究药物治疗的无进展存活(mITT)。
错误!未找到参考源。显示与安慰剂相比,有/无IgG免疫应答(IgG标准1:640)的研究药物治疗的总存活(mITT)。
错误!未找到参考源。显示与安慰剂相比,在第2周接受一次研究药物的注射后的无进展存活(mITT),有/无早期IgM免疫应答(IgM标准)。
图9显示在患者接受OBI-822疫苗的注射后存在高抗KLH IgG免疫应答。
图10显示OBI-822治疗的卵巢癌临床试验情况中的阴性对照(患者编号:065)。
图11显示OBI-822治疗的卵巢癌临床试验情况中的III期卵巢癌(患者编号:035)。
图12显示OBI-822治疗的卵巢癌临床试验情况中的IV期输卵管癌(患者编号:041)。
图13显示OBI-822治疗的卵巢癌临床试验情况中的III期卵巢癌(患者编号:060)。
图14显示研究药物混合的规程。
发明详述
本发明涉及用于患有疾病(例如癌症或传染病)的受试者的免疫治疗的方法,该方法包括向受试者施用包含治疗有效量的增强内源性免疫应答(刺激内源性反应的激活或抑制内源性反应的抑制)。更具体地,本公开提供了在患有癌症的受试者中增强内源性免疫应答以便由此治疗患者的方法,该方法包括向受试者施用治疗有效量的免疫原性剂。
定义:
“施用”如本文所用,施用方案的实施方案可以包括以下特征:1)施用疫苗两次或更多次(例如,3、4、5、6、7、8、9、10或更多次);2)每次施用增加免疫应答(见上文)[滴度-IgG和/或IgM Ab量,和/或增加亲和力/亲合力;将Ab诱导至Globo H抗原缀合物的Globo H部分的免疫原性较低的位点(例如,在缀合物中可以较不易接近的Globo H抗原的部分)]。
如本文所用,“治疗”是指试图改变所治疗的个体或细胞的自然进程的临床干预,并且可以用于预防或在临床病理学过程中实施。理想的治疗效果包括预防疾病的发生或复发、缓解症状、减少疾病的任何直接或间接的病理后果、预防或减少炎症和/或组织/器官损害、降低疾病进展率、改善或缓解疾病状态、缓解或改善预后。在一些实施方案中,本发明的抗体用于延迟疾病或病症的发展。
“有效量”是指在必要的剂量和时间段内有效实现所需治疗或预防结果的量。
本发明的物质/分子的“治疗有效量”可以根据因素(例如疾病状态、年龄、性别和个体的体重)和物质/分子在个体中引发所需反应的能力而变化。治疗有效量也是其中治疗有益效果超过该物质/分子的任何毒性或有害作用的量。“预防有效量”是指在必要的剂量和时间段内有效实现所需预防结果的量。通常但不是必须地,因为在受试者中预防剂量使用于疾病的早期阶段之前或在疾病的早期阶段,所以预防有效量将小于治疗有效量。
“不良事件”(AE)毒性将根据美国国家癌症研究所的癌症疗法评价计划开发的美国NCI常见毒性标准第4版来测量。不可接受的毒性的标准应包括任何≥四级毒性,除了局部皮肤反应、发烧,寒冷、出汗、荨麻疹和/或瘙痒,因为这些是抗体/佐剂施用的常见副作用,是可逆的,并且通过支持性管理来控制。从理论上讲,可以发生表现为皮肤、关节、肾脏或其他表现的免疫复合物病,但在没有先前暴露于小鼠蛋白质的情况下这些应该是罕见的。这些将是在受影响的受试者中停止治疗的指示,但新受试者的累积可以继续。不良事件是受试者从随机化日期开始并对于继续在随访期间的受试者直至随机化起两年经历的任何身体或临床的变化或疾病,无论是否认为与研究药物的使用有关。其包括新疾病的发作和先前存在的病症的恶化。对于在治疗期间退出治疗的受试者,应在研究治疗(OBI-822/OBI-821或对照)的最后一次施用后28天记录不良事件。
“抗体”(“Antibody”(Ab))、“抗体”(“Antibodies”(Abs))和“免疫球蛋白”(Ig)是具有相同结构特征的糖蛋白。虽然抗体显示出对特定抗原的结合特异性,但免疫球蛋白包括抗体和通常缺乏抗原特异性的其他抗体样分子两者。后一种的多肽是例如通过淋巴系统以低水平和骨髓瘤以增加的水平产生的。术语“抗体”和“免疫球蛋白”在最广泛的意义上可互换使用,并且包括单克隆抗体(例如,全长或完整单克隆抗体)、多克隆抗体、单价、多价抗体、多特异性抗体(例如,双特异性抗体,只要它们表现出所需的生物活性即可)并且还可以包括某些抗体片段(如本文中更详细描述的)。抗体可以是嵌合的、人的、人源化的和/或亲和力成熟的。
“可变”和“互补决定区”(CDR)
术语“可变”是指可变结构域的某些部分在抗体之间在序列上广泛不同,并且用于每种特定抗体对其特定抗原的结合和特异性的事实。然而,可变性不是均匀地分布在抗体的可变结构域中。它集中在轻链和重链可变结构域两者中称为互补决定区(CDR)或高变区的三个区段中。可变结构域的更高保守部分称为框架(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CDR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CDR通过FR区紧密靠近在一起,并且与来自另一个链的CDR一起有助于形成抗体的抗原结合位点(参见Kabat et al.,Sequences of Proteins of Immunological Interest,Fifth Edition,NationalInstitute of Health,Bethesda,Md.(1991))。恒定结构域不直接参与抗体与抗原的结合,但表现出各种效应功能,例如在抗体依赖性细胞毒性中抗体的参与。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,每个片段具有单个抗原结合位点,以及残留的“Fc”片段,其名称反映其易于结晶的能力。胃蛋白酶处理产生F(ab’)2片段,其具有两个抗原结合位点并且仍然能够交联抗原。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。在双链Fv种类中,该区域由紧密的、非共价结合的一个重链和一个轻链可变结构域的二聚体组成。在单链Fv种类中,一个重链和一个轻链可变结构域可以通过柔性肽接头共价连接,使得轻链和重链可以以与双链Fv种类中的类似的“二聚体”结构结合。在该构型中,每个可变结构域的三个CDR相互作用以在VH-VL二聚体的表面上限定抗原结合位点。共同地,六个CDR将抗原结合特异性赋予抗体。然而,即使单个可变结构域(或仅包含三个对抗原具有特异性的CDR的Fv的一半)也具有识别和结合抗原的能力,尽管其亲和力低于整个结合位点。
Fab片段还含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab’片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端添加了几个残基,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的巯醇基。F(ab’)2抗体片段最初是作为Fab'片段对产生的,它们之间具有铰链半胱氨酸。
来自任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”可以基于其恒定结构域的氨基酸序列分配为两个明显不同的类型之一,称为kappa(κ)和lambda(λ)。
根据其重链的恒定结构域的氨基酸序列,可以将抗体(免疫球蛋白)分配到不同的类别。免疫球蛋白有五大类:IgA、IgD、IgE、IgG和IgM,并且其中的几个可以进一步分为亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类的免疫球蛋白的重链恒定域分别称为α,δ,ε,γ和μ。不同类的免疫球蛋白的亚基结构和三维构型是众所周知的,并且通常描述于例如Abbas et al.Cellular and Mol.Immunology,4th ed.(2000)。抗体可以是较大融合分子的一部分,通过抗体与一个或多个其他蛋白质或肽的共价或非共价结合形成。
如本文所用,“分离的抗体”可以包括“分离的”抗体,其是已经从它的天然环境的成分中鉴定并分离和/或回收的抗体。其天然环境的污染成分是会干扰抗体的研究、诊断或治疗用途的物质,并且可以包括酶、激素和其他蛋白质或非蛋白质溶质。在一个实施方案中,抗体将被纯化(1)至以抗体的重量计大于95%,其如通过例如Lowry方法所测定的,并且在一些实施方案中,以重量计大于99%,(2)至足以通过使用例如转杯式测序仪获得N末端或内部氨基酸序列的至少15个残基的程度,或者(3)至在还原或非还原条件下通过使用例如考马斯蓝或银染色的SDS-PAGE的均一性。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,将通过至少一个纯化步骤制备分离的抗体。
如本文所用的术语“单克隆抗体”(mAB)是指从基本上同质的抗体的群体获得的抗体,例如,除了可以以少量存在的可能的天然发生的突变外,构成群体的各个抗体是相同的。因此,修饰语“单克隆”表示抗体的特征不是分立的抗体的混合物。此类单克隆抗体通常包括包含结合靶物的多肽序列的抗体,其中所述靶物结合多肽序列通过包括从多个多肽序列中选择单个靶物结合多肽序列的过程获得。例如,选择过程可以是从多个克隆中选择独特的克隆,例如杂交瘤克隆、噬菌体克隆或重组DNA克隆的库。应当理解的是,可以进一步改变所选择的靶结合序列,例如,以改善对靶的亲和力,以使靶结合序列人源化,以改善其在细胞培养物中的生产,以降低其在体内的免疫原性,以产生多特异性抗体等,以及包含改变的靶结合序列的抗体也是本发明的单克隆抗体。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,单克隆抗体制剂的每个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,单克隆抗体制剂的优点还在于它们通常不被其他免疫球蛋白污染。修饰语“单克隆”表示抗体的特征是从基本上同质的抗体的群体获得的,并且不应解释为需要通过任何特定方法生产抗体。例如,根据本发明使用的单克隆抗体可以通过多种技术制备,包括例如杂交瘤方法(例如,Kohler et al.,Nature,256:495(1975);Harlow etal.,Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,2nded.1988);Hammerling et al.,in:Monoclonal Antibodies and T-Cell hybridomas563-681(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.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Leeet al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);和Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004)),以及用于在具有部分或全部的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人样抗体的技术(参见,例如WO98/24893;WO96/34096;WO96/33735;WO91/10741;Jakobovits et al.,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovitset 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;5,661,016;Markset al.,Bio.Technology 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al.,NatureBiotechnol.14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996)和Lonbergand Huszar,Intern.Rev.Immunol.13:65-93(1995))。
“人单克隆抗体”(HuMAb)
“人单克隆抗体”是具有氨基酸序列的mAb,所述氨基酸序列对应于由人产生的和/或已经使用本文公开的用于制备人抗体的任何技术所制备的抗体的氨基酸序列。该人抗体的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。
“人源化抗体”
非人(例如小鼠)抗体的人源化的形式是嵌合抗体,其含有衍生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(受体抗体),其中来自受体的高变区的残基由具有所需的特异性、亲和力和/或能力的来自非人物种例如小鼠、大鼠、兔或非人灵长类动物的高变区(供体抗体)的残基取代。在一些情况下,人免疫球蛋白的框架区(FR)残基由相应的非人残基取代。此外,人源化抗体可以包含在受体抗体中或在供体抗体中未发现的残基。进行这些修饰以进一步改善抗体性能。通常,人源化抗体将包含基本上至少一个,并通常两个可变结构域的全部,其中所有或基本上所有的高变环对应于非人免疫球蛋白的高变环,并且所有或基本上所有的FR都是人免疫球蛋白序列的FR。人源化抗体任选地还将包含免疫球蛋白恒定区(Fc)的至少一部分,通常是人免疫球蛋白的恒定区。有关详细信息,参见Jones et al.,Nature 321:522-525(1986);Riechmann et al.,Nature332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。还参见以下综述文章和其中引用的参考文献:Vaswani and Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle andGross,Curr.Op.Biotech.5:428-433(1994)。
“嵌合抗体”
本文中的单克隆抗体具体地包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类或亚类的抗体中的相应的序列相同或同源,而链的其余部分与衍生自另一物种或属于另一抗体类或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们表现出所需的生物活性即可(美国专利号4,816,567;和Morrison etal.,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。
“抗原结合部分”或“抗体片段”
“抗体片段”仅包含完整抗体的一部分,其中该部分保留通常与当存在于完整抗体中时该部分相关的至少一种,以及大多数或全部的功能。在一个实施方案中,抗体片段包含完整抗体的抗原结合位点,并因此保留结合抗原的能力。
在另一个实施方案中,抗体片段,例如包含Fc区的抗体片段,保留通常与当存在于完整抗体中时Fc区相关的至少一种生物学功能,例如FcRn结合、抗体半衰期调节、ADCC功能和补体结合。在一个实施方案中,抗体片段是单价抗体,其具有基本上与完整抗体相似的体内半衰期。例如,此类抗体片段可以包含与能够赋予片段体内稳定性的Fc序列连接的抗原结合臂。
术语“癌症”和“癌性”是指或描述哺乳动物中通常以不受调节的细胞生长/增殖为特征的生理状况。癌症的实例包括但不限于癌、淋巴瘤(例如,霍奇金和非霍奇金淋巴瘤)、母细胞瘤、肉瘤和白血病。此类癌症的更具体的实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状细胞癌、腹膜癌、肝细胞癌(hepatocellular cancer)、胃肠癌、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞癌(hepatoma)、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌(liver cancer)、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、白血病和其他淋巴细胞增生性疾病,以及各种类型的头颈癌。如本文所用,“肿瘤”是指所有肿瘤细胞生长和增殖,无论是恶性的还是良性的,以及所有癌前和癌细胞和组织。术语“癌症”、“癌性”、“细胞增殖性疾病”、“增殖性疾病”和“肿瘤”如本文所提及的不是相互排斥的。
“免疫应答”是指免疫系统的细胞(例如,T淋巴细胞、B淋巴细胞、自然杀伤(NK)细胞、巨噬细胞、嗜酸性粒细胞、肥大细胞、树突状细胞和中性粒细胞)和由任何这些细胞或肝脏产生的可溶性大分子(包括Ab、细胞因子和补体)的作用,其导致选择性靶向、结合、损伤、破坏和/或从脊椎动物的体内消除入侵病原体、感染病原体的细胞或组织、癌性或其他异常细胞,或者在自身免疫或病理性炎症的情况下,正常的人细胞或组织。
“免疫调节剂”是指调节免疫应答的物质、药剂、信号传导途径或其组分。“调节(regulating)”、“修饰”或“调节(modulating)”免疫应答是指免疫系统的细胞或此类细胞的活性的任何改变。此类调节包括免疫系统的刺激或抑制,其可以通过各种细胞类型的数量的增加或减少,这些细胞的活性的增加或减少,或免疫系统内可以发生的任何其他变化来表现。抑制性和刺激性免疫调节剂两者均已得到鉴定,其中一些可以在癌症微环境中具有增强的功能。
“免疫疗法”是指通过包括诱导、增强、抑制或以其他方式改变免疫应答的方法治疗患有疾病,或有感染疾病或疾病复发风险的受试者。
受试者的“治疗”或“疗法”是指对受试者实施的任何类型的干预或过程或活性剂的施用,目的是逆转、缓解、改善、抑制、减缓或预防与疾病相关的症状、并发症、病症或生化指标的发作、进展、发展、严重程度或复发。
“增强内源性免疫应答”意指增加受试者中现有免疫应答的有效性或效力。例如,通过克服抑制内源性宿主免疫应答的机制或通过刺激增强内源性宿主免疫应答的机制,可以实现有效性和效力的这种增加。
“受试者”包括任何人或非人动物。
药物或治疗剂(例如本发明的Ab)的“治疗有效量”或“治疗有效剂量”是任何量的药物,所述药物当单独使用或与另一种治疗剂联合使用时,通过降低疾病症状的严重程度,增加疾病无症状期的频率和持续时间,或预防由于疾病折磨引起的损伤或残疾来证实,其保护受试者免于疾病的发作或促进疾病的消退。可以使用本领域技术人员已知的各种方法评估治疗剂促进疾病消退的能力,例如在临床试验期间的人类受试者中,在预测人类中的功效的动物模型系统中,或通过在体外测定中测定药剂的活性。
“促进癌症消退”是指单独或与抗肿瘤剂联合施用有效量的药物导致肿瘤生长或大小的减少,肿瘤的坏死,至少一种疾病症状的严重程度降低,疾病无症状期的频率和持续时间增加,或预防由疾病折磨引起的损伤或残疾。此外,关于治疗的术语“有效”和“有效性”包括药理有效性和生理安全性两者。药理有效性是指药物促进患者中癌症消退的能力。生理安全性是指由施用药物引起的细胞、器官和/或生物体水平的毒性的水平或其他不利的生理作用(不良作用)。
“免疫相关的”应答模式是指在用免疫治疗剂治疗的癌症患者中经常观察到的临床应答模式,所述免疫治疗剂通过诱导癌症特异性免疫应答或通过改变天然免疫过程产生抗肿瘤作用。该应答模式的特征在于在肿瘤负荷的初始增加或新病变的出现(其在传统化学治疗剂的评价中将被分类为疾病进展并且将与药物失效同义)之后的有益治疗效果。因此,对免疫治疗剂的适当评价可以需要长期监测这些药剂对目标疾病的影响。
治疗有效量的药物包括“预防有效量”,其是任何量的药物,所述药物当单独或与抗肿瘤剂联合施用于有发展癌症的风险的受试者(例如,具有恶变前病症的受试者)或患有癌症复发的风险的受试者,抑制癌症的发展或复发。在优选的实施方案中,预防有效量完全阻止癌症的发展或复发。“抑制”癌症的发展或复发意味着减少癌症的发展或复发的可能性,或者完全阻止癌症的发展或复发。
“肿瘤浸润炎症细胞”是通常参与受试者中的炎症反应并浸润肿瘤组织的任何类型的细胞。此类细胞包括肿瘤浸润淋巴细胞(TIL)、巨噬细胞、单核细胞、嗜酸性粒细胞、组织细胞和树突状细胞。
本发明产生的免疫原性剂和抗体可以在组合物(例如药物组合物)中构成,所述组合物含有一种Ab或Ab的组合,或其抗原结合部分,以及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。优选地,载体适用于静脉内、肌肉内、皮下、肠胃外、脊柱或表皮施用(例如,通过注射或输注)。本发明的药物组合物可以包括一种或多种药学上可接受的盐、抗氧化剂、水性和非水性载体和/或佐剂(例如防腐剂、润湿剂、乳化剂和分散剂)。
优选的受试者包括需要增强免疫应答的人类患者。本文公开的免疫治疗方法特别适用于治疗患有可以通过增强免疫应答来治疗的病症的人类患者。在某些实施方案中,所述方法用于治疗患有由感染原引起的疾病的受试者。在优选的实施方案中,所述方法用于治疗患有癌症或有患癌症的风险的受试者。
“癌症免疫疗法”
如本文所用,癌症免疫疗法可以包括但不限于能够减少患有转移性癌症的患者的肿瘤大小的基于免疫的疗法。目前,有三种主要的癌症免疫治疗的方法,通过刺激效应细胞和/或抑制调节细胞的非特异性刺激免疫反应、主动免疫以增强特异性抗肿瘤反应(称为癌症疫苗)以及被动转移抗肿瘤抗体或具有抗肿瘤活性的活化的免疫细胞(也称为过继免疫疗法)(DeVita et al.,2008)。
“联合治疗”在某些实施方案中,本文讨论的免疫调节剂可以与一种或多种抗增殖/化学治疗剂联合使用,所述抗增殖剂/化学治疗剂有效减轻肿瘤负荷而没有显著的全身毒性,并且可以起到改善免疫应答的有效性的作用。可以将药剂组合为共同施用联合治疗和/或共同配制的联合治疗。
在一些给药方案或施用形式中一起使用两种或多种药物的联合治疗通常具有一个或多个以下目标:(i)通过组合具有最小交叉抗性的药物来降低获得性抗性产生的频率,(ii)降低具有非重叠毒性和类似治疗特征的药物的剂量,以实现具有较少副作用的功效,即增加治疗指数,(iii)通过使用另一种药物使细胞对一种药物的作用敏感,例如改变细胞周期阶段或生长特性,以及(iv)通过利用两种药物的生物活性中的加和性或大于加和性效应来实现增强的效力(Pegram,M.,et al(1999)Oncogene 18:2241-2251;Konecny,G.,etal(2001)Breast Cancer Res.and Treatment 67:223-233;Pegram,M.,et al(2004)J.ofthe Nat.Cancer Inst.96(10):739-749;Fitzgerald et al(2006)Nature Chem.Biol.2(9):458-466;Borisy et al(2003)Proc.Natl.Acad.Sci.100(13):7977-7982)。Loewe加和性(Chou,T.C.and Talalay,P.(1977)J.Biol.Chem.252:6438-6442;Chou,T.C.andTalalay,P.(1984)Adv.Enzyme Regul.22:27-55;Berenbaum,M.C.(1989)Pharmacol.Rev.41:93-141)和Bliss独立性/协同性(Bliss,C.I.(1956)Bacteriol.Rev.20:243-258;Greco et al(1995)Pharmacol.Rev.47:331-385)是用于计算与单一治疗相比的联合治疗的预期剂量-反应关系的方法,基于参数例如IC50,达到50%目标抑制所需的药物剂量并在最简单的情况下等于Ki。
“化学治疗剂”是可用于治疗癌症的化学化合物,无论作用的机制如何。化学治疗剂的类别包括但不限于:烷化剂、抗代谢物、纺锤体毒植物生物碱、细胞毒性/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂和激酶抑制剂。化学治疗剂包括用于“靶向治疗”和常规化疗的化合物。化学治疗剂的实例包括:厄洛替尼(Genentech/OSIPharm.)、多西他赛(Sanofi-Aventis)、5-FU(氟尿嘧啶、5-氟尿嘧啶,CASNo.51-21-8)、吉西他滨(Lilly)、PD-0325901(CAS No.391210-10-9,Pfizer)、顺铂(顺-二胺,二氯铂(II),CAS No.15663-27-1)、卡铂(CAS No.41575-94-4)、紫杉醇(Bristol-Myers Squibb Oncology,Princeton,N.J.)、曲妥珠单抗(Genentech)、替莫唑胺(4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]壬-2,7,9-三烯-9-甲酰胺,CAS No.85622-93-1, ScheringPlough)、他莫昔芬((Z)-2-[4-(1,2-二苯基-1-丁烯)苯氧基]-N,N-二甲基乙胺,)和多柔比星Akti-1/2、HPPD以及雷帕霉素。
化学治疗剂的更多实例包括:奥沙利铂(Sanofi)、硼替佐米(Millennium Pharm.)、索坦(SU11248,Pfizer)、来曲唑(Novartis)、甲磺酸伊马替尼(Novartis)、XL-518(MEK抑制剂,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制剂,AZD6244,Array BioPharma,AstraZeneca)、SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(AstraZeneca)、亚叶酸钙(亚叶酸(folinic acid))、雷帕霉素(西罗莫司(sirolimus),Wyeth)、拉帕替尼(GSK572016,Glaxo SmithKline)、洛那法尼(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(BAY43-9006,Bayer Labs)、吉非替尼(AstraZeneca)、伊立替康(CPT-11,Pfizer)、替比法尼(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(无克列莫佛)、白蛋白工程化改造的紫杉醇纳米颗粒制剂(AmericanPharmaceutical Partners,Schaumberg,Il)、凡德他尼(rINN,ZD6474,AstraZeneca)、苯丁酸氮芥、AG1478、AG1571(SU 5271;Sugen),替西罗莫司(Wyeth)、帕唑帕尼(GlaxoSmithKline)、canfosfamide(Telik)、噻替哌和环磷酰胺 烷基磺酸盐类(alkyl sulfonate)例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridine)例如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)和乌瑞替派(uredopa);乙撑亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙烯磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)和三甲基蜜胺(trimethylomelamine);聚乙酸类(acetogenin)(特别是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成类似物拓扑替康(topotecan));苔藓抑素(bryostatin);卡利他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻环肽(cryptophycin)(具体地念珠藻环肽1和念珠藻环肽8);尾海兔素(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类(nitrogen mustard),例如苯丁酸氮芥、萘氮芥(chlornaphazine)、氯磷酰胺(chlorophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、甲二氯二乙胺(mechlorethamine)、甲二氯二乙胺氧化物盐酸盐(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、胆甾醇对苯乙酸氮芥(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracilmustard);亚硝基脲类(nitrosurea),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,例如烯二炔抗生素(例如卡奇霉素(calicheamicin)、卡奇霉素γ1I和卡奇霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin)、达内霉素A;双膦酸盐类(bisphosphonate),例如氯屈膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关色素蛋白烯二炔抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、氨茴霉素(authramycin)、偶氮丝氨酸(azaserine)、争光霉素(bleomycin)、放线菌素C(cactinomycin)、卡柔比星(carabicin)、洋红霉素(caminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycini)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、吗啉代-多柔比星(morpholino-doxorubicin)、氰基吗啉代-多柔比星(cyanomorpholino-doxorubicin)、2-吡咯啉基-多柔比星(2-pyrrolino-doxorubicin)和脱氧多柔比星(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)(例如丝裂霉素C)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泼非霉素(potfiromycin)、嘌呤霉素(puromycin)、奎那霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,例如氨甲蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如迪诺特宁(denopterin)、氨甲蝶呤、蝶罗呤(pteropterin)、曲美沙特(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如环胞苷(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素,例如卡芦睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺药,例如氨鲁米特、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);贝斯布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依洛尼塞(elfomithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);乙环氧啶(etoglucid);硝酸镓;羟基脲;蘑菇多糖(lentinan);氯尼达明(lonidainine);类美登素(maytansinoid),例如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙酰肼;丙卡巴肼;多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofuran);锗螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三亚胺醌(triaziquone);2,2′,2″-三氯三乙胺;单端孢霉烯(trichothecene)(T-2毒素、粘液霉素A(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇;二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿糖胞苷(arabinoside)(Ara-C);环磷酰胺;噻替派;6-硫代鸟嘌呤;巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,例如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌;长春新碱;长春瑞滨能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙;道诺霉素(daunomycin);氨基蝶呤(aminopterin);卡培他滨(capecitabine)(Roche);伊本膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类视黄醇,例如视黄酸;以及任何上述药学上可接受的盐、酸和衍生物。
“化学治疗剂”的定义中还包括:(i)起作用调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(枸橼酸他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、keoxifene、LY117018、奥那司酮和枸橼酸托瑞米芬;(ii)抑制酶芳香化酶的芳香化酶抑制剂,其调节肾上腺中的雌激素产生,例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、(醋酸甲地孕酮)、(依西美坦;Pfizer)、福美司坦(formestanie)、法倔唑(fadrozole)、(伏氯唑)、(来曲唑;Novartis)和(阿那曲唑;AstraZeneca);(iii)抗雄激素,例如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(α-1,3-二氧戊环核苷胞嘧啶类似物(α-1,3-dioxolane nucleoside cytosine analog));(iv)蛋白激酶抑制剂,例如MEK抑制剂(WO 2007/044515);(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是那些抑制与异常细胞增殖相关的信号传导途径中基因的表达的寡核苷酸,例如PKC-α、Raf和H-Ras,例如奥利默森(oblimersen)(Genta Inc.);(vii)核酶,例如VEGF表达抑制剂(例如,)和HER2表达抑制剂;(viii)疫苗,例如基因疗法疫苗,例如和 rIL-2;拓扑异构酶1抑制剂,例如 rmRH;(ix)抗血管生成剂,例如贝伐单抗(bevacizumab)(Genentech);以及任何上述药学上可接受的盐、酸和衍生物。
“化学治疗剂”的定义中还包括治疗性抗体,例如阿仑单抗(alemtuzumab)(Campath)、贝伐单抗(bevacizumab)(Genentech);西妥昔单抗(cetuximab)(Imclone);帕尼单抗(panitumumab)(Amgen)、利妥昔单抗(rituximab)(Genentech/Biogen Idec)、帕妥珠单抗(pertuzumab)(OMNITARGTM,2C4,Genentech)、曲妥珠单抗(trastuzumab)(Genentech)、托西莫单抗(tositumomab)(Bexxar,Corixia)以及抗体药物缀合物,吉妥珠单抗奥佐米星(gemtuzumab ozogamicin)(Wyeth)。
具有作为化学治疗剂的治疗潜力的人源化单克隆抗体与本发明的免疫原性/治疗剂组合可以包括或排除以下一种或多种:阿仑单抗(alemtuzumab)、阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、阿特立单抗(atlizumab)、巴匹珠单抗(bapineuzumab)、贝伐单抗(bevacizumab)、比伐单抗-DM1(bivatuzumab mertansine)、美坎珠单抗(cantuzumab mertansine)、西利珠单抗(cedelizumab)、培舍珠单抗(certolizumab pegol)、西弗斯妥珠单抗(cidfusituzumab)、西妥珠单抗(cidtuzumab)、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、非维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、吉妥珠单抗奥佐米星(gemtuzumab ozogamicin)、伊妥珠单抗奥佐米星(inotuzumab ozogamicin)、伊匹木单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、莫他珠单抗(motavizumab)、莫妥维珠单抗(motovizumab)、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、诺洛维珠单抗(nolovizumab)、努马维珠单抗(numavizumab)、奥瑞珠单抗(ocrelizumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、帕氟珠单抗(pecfusituzumab)、培妥珠单抗(pectuzumab)、帕妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、ralivizumab、来尼珠单抗(ranibizumab)、热利维珠单抗(reslivizumab)、瑞利珠单抗(reslizumab)、热西维珠单抗(resyvizumab)、罗维珠单抗(rovelizumab)、鲁利单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、希普利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、他珠单抗四氢西泮(tacatuzumabtetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、替非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、曲妥珠单抗(trastuzumab)、西莫白介素单抗(tucotuzumab celmoleukin)、图库斯珠单抗(tucusituzumab)、乌马维珠单抗(umavizumab)、乌珠单抗(urtoxazumab)和维西珠单抗(visilizumab)。
“标准护理治疗剂”是治疗过程,包括药物或药物的组合、放射治疗(RT)、手术或其他医疗干预,其被医疗从业者认为适当、接受和/或广泛用于某种类型的患者、疾病或临床环境。用于不同类型癌症的标准护理疗法是本领域技术人员所熟知的。例如,国家综合癌症网络(National Comprehensive Cancer Network(NCCN))是美国21个主要癌症中心的联盟,发布了肿瘤学NCCN临床实践指南(NCCN),其提供有关各种癌症的标准护理治疗的详细最新信息(参见NCCN2013)。
试剂盒:试剂盒也在本发明的范围内,包括用于治疗用途的药物试剂盒和诊断试剂盒。
如本文所用,本公开的另外的方面包括与剂量递增相关的方面和因素;患者分组;安全;和药代动力学/药效学分析。
从广义上讲,免疫系统可以分为固有免疫和适应性免疫。固有免疫是两者中较原始的,并且由非特异性防御,例如物理屏障(例如皮肤)、非特异性防御细胞(例如巨噬细胞)和多种细胞因子(例如IL1)组成。通常,疫苗不会将固有系统上调至特定的病原体或疾病,但添加到疫苗中的佐剂可以非特异性地激活固有免疫,其继而可以改善适应性免疫应答。适应性免疫可以进一步分为体液(即抗体)和细胞(例如细胞毒性T细胞)免疫应答。体液免疫应答的效应细胞由仅在适应性免疫中特化的细胞(例如,T和B淋巴细胞)组成;然而,固有免疫的细胞提供基本功能(例如,抗原呈递)。因此,例如,诱导针对病毒的抗体产生将需要几种细胞类型的一系列复杂相互作用。简而言之,这些将包括通过树突状细胞捕获和加工病毒组分(例如病毒的包膜蛋白),其继而将呈递给对所呈递的抗原具有特异性的T细胞。一旦被呈递的抗原激活,T细胞将“辅助”病毒特异性B细胞产生针对入侵病原体的抗体。
耐受
长期以来已认识到虽然免疫系统具有识别宿主抗原的能力,但通常没有观察到此类反应(即免疫系统表现出对自身的耐受性)。这种对自身的耐受包括“正常”以及肿瘤抗原两者。
在一个方面,本公开的特征在于能够破坏免疫系统对肿瘤抗原Globo H的耐受性的疫苗。
耐受的类型
耐受可以起因于中枢和/或外周耐受。中枢耐受阻止识别自身的T和B淋巴细胞成熟。自身耐受不是绝对的,并且在正常个体中可以发现一些产生抗自身抗体的B细胞。然而,由于缺乏对自身抗原的抗自身T细胞辅助(其是B细胞活化的重要组成部分),很少发现针对自身的抗体。外周耐受是对自身的免疫应答的持续主动抑制,并且被认为主要由Treg细胞维持。Treg被认为可以阻止诱导对自身抗原(其包括正常抗原和肿瘤抗原两者)的T细胞的辅助。
打破对自身的耐受的策略
在一个方面,本公开的特征在于克服针对Globo H系列肿瘤抗原的中枢和外周耐受两者的组合物和方法。例如,在一些方面,组合物和方法可用于减少Treg抑制和刺激T细胞对产生抗Globo H抗体的B细胞的辅助。
在一些方面,本公开的特征在于共同施用Treg下调剂以克服外周耐受。在一些方面,Treg下调剂可以是环磷酰胺、抗Treg抗体或[选择性]抑制Treg活性的其他药剂(比适应性免疫系统的其他细胞更多)。
因此,在一些方面,环磷酰胺可以与Globo H-KLH缀合物同时施用于患者,从而抑制Treg对抗Globo H抗体产生的抑制。在一些方面,Treg下调剂还可以刺激细胞毒性T淋巴细胞扩增至Globo H抗原阳性细胞,允许直接杀死表达Globo-H的肿瘤细胞。
认识到B细胞抗体的产生需要来自识别抗原的T细胞的辅助。然而,中枢耐受和/或抗原呈递缺陷可以导致Globo H(自身)抗原缺乏T细胞识别。因此,在一些实施方案中,本公开的特征在于通过将Globo H系列抗原与强免疫原性剂(例如KLH)缀合来刺激T细胞辅助B细胞产生抗Globo H抗体的组合物和方法。KLH是系统发生上遥远的生物体,并且具有较大的分子量(超过390,000),这两种属性都已知可增加免疫原性。当向患者施用Globo H缀合物时,树突状细胞和/或其他抗原呈递细胞将Globo H缀合物,例如Globo H-KLH缀合物加工成Globo H和KLH组分。T细胞识别KLH抗原,其然后辅助B细胞产生所需的抗Globo H抗体。
肿瘤疫苗的其他作用
增加抗体滴度:在一些实施方案中,本发明的组合物和方法的特征在于通过产生高于阈值滴度的抗体应答而具有临床获益。低于阈值滴度,抗肿瘤反应可以不足以产生有意义的临床获益。
增加抗Globo H抗体的亲和力:在一些实施方案中,本公开的方法的特征在于向患者施用Globo H缀合物2、3、4、5、6、7、8、9或10次或更多次。
在一些实施方案中,重复施用增加了所得抗体应答的亲和力,因为表达具有对Globo H的最高亲和力的表面抗体的B细胞优先被注射的抗原刺激,因为它们比表达较低亲和力抗体的B细胞更好地结合抗原。在一些实施方案中,每个施用周期增加抗体应答,增加抗体的亲和力和/或亲合力,和/或诱导抗体产生至Globo H缀合物的Globo H部分的免疫原性较低的位点。
在一些实施方案中,重复施用进一步诱导通常不以足够数量存在的低频B细胞产生具有单次(或低次重复的暴露于抗原)的有意义的应答(例如,它们可以与少数抗体结合的表位结合),扩增抗体分泌浆细胞(“抗体分泌浆细胞”是B细胞分化成的)和记忆B细胞,其对于长期维持抗肿瘤反应可以是重要的,并且增加Ab类转换的动力学。
在一些实施方案中,重复施用还导致B细胞的生发中心扩增至Globo H系列肿瘤抗原并且优先扩增含有高亲和力抗Globo H抗体的生发中心。
扩增IgG亚类:T细胞辅助能够诱导B细胞转换其重链类和亚类的表达。在人中,存在四种IgG亚类—IgG1、IgG2、IgG3和IgG4。每个IgG亚类具有生物效应功能,可将其与其他亚类区分开来。所有四个亚类的表达可以最大化抗Globo H应答的肿瘤杀伤活性。
增加抗体反应动力学:在一些实施方案中,Globo H-KLH缀合物、环磷酰胺和佐剂的重复接种导致抗体比未与KLH、环磷酰胺或具有佐剂的重复注射缀合获得的抗体更快速扩增。
在某些实施方案中,OBI-822可以通过减少Globo-H诱导的Notch信号传导来阻断癌症免疫抑制。
在某些方面,OBI-822可以抵消癌症治疗中Globo-H的某些负面特征。
在某些实施方案中,OBI-822消耗Globo H,其继而增加Notch 1降解,阻断肿瘤免疫抑制作用,导致肿瘤消退。
在某些实施方案中,OBI-822可以抵消Globo-H相关的T细胞增殖和细胞因子分泌的减少。
在某些实施方案中,OBI-822可以抵消Globo-H相关的B细胞分化和Ig分泌的抑制。
Globo系列抗原在癌症发展中的作用非常重要。在某些实施方案中,它们可以通过抑制胱天蛋白酶3活化来影响肿瘤存活。在某些实施方案中,使胱天蛋白酶3恢复失活,导致细胞凋亡。
在某些实施方案中,Globo系列聚簇通过抑制胱天蛋白酶3级联来增强肿瘤存活。
实施例
在支持肯定的免疫原性应答和治疗功效的申请人的本公开和例示性数据之前,先前未结论性证明/报告与成功使用OBI-821作为佐剂相关的如本文中公开的免疫调节剂的有效使用,如实施例部分中证明,包括Globo H疫苗的临床前研究;I期试验中的OBI-822和QS-21;和癌症临床试验中的OBI-822和OBI-821。
试验概述:Globo H是发现在乳腺癌中高度表达的糖脂。使用OBI-822(Globo H-KLH缀合物)和OBI-821(两项I期试验中的佐剂)的主动免疫疗法诱导Globo H特异性抗体,其可介导对表达Globo H的乳腺癌细胞的体外结合Globo H和细胞毒性。
方法:在国际、随机化、双盲和安慰剂对照的II/III期临床试验(NCT01516307)中,患有转移性乳腺癌的患者按2:1随机化以在第1、2、3、5、9、13、17、25、37周或直至PD接受皮下的OBI-822(30μg Globo H)/OBI-821(100μg)或对照(PBS),联合低剂量环磷酰胺(300mg/m2),所述患者具有≤2个疾病进展(PD)事件,并且在≥1个抗癌方案后实现至少疾病稳定(SD)。允许激素治疗。主要和次要疗效端点是无进展存活(PFS)和总存活(OS),与体液抗体应答相关。
结果:349名患者随机化,348名接受研究药物(ITT),168名(48%)接受了所有9次注射。70%具有激素受体阳性乳腺癌,13%是三阴性,而62%接受激素治疗。在所有患者中,PFS(HR,0.96[95%CI,0.74-1.25]P=0.77)或临时(interim)OS(HR,0.79[95%CI,0.51-1.22]P=0.29)中均未观察到差异,包括发生Globo H特异性IgG应答的患者和未发生GloboH特异性IgG应答的患者。然而,与对照(对于PFS,HR,0.71[95%CI,0.52-0.97]P=0.029;对于OS,HR,0.57[95%CI,0.33-0.97]P=0.04)和与非应答者(对于PFS,HR,0.52[95%CI,0.37-0.71]P<.0001;对于OS,HR,0.52[95%CI,0.29-0.92]P=0.025)相比,PFS和OS在50%的在治疗期间的任何时间以滴度≥1:160对OBI-822/OBI-821产生Globo H特异性IgG应答的患者中显著改善,其根据基线疾病状态和/或激素使用进行调整。在时间依赖性Cox模型中,与对照相比,PFS在接受所有9次OBI注射的患者中得到改善(HR,0.66[95%CI,0.42-1.01]P=0.057)。OBI-822/OBI-821耐受性良好;最常见的药物相关不良事件是1/2级注射反应。
结论:用OBI-822/OBI-821疫苗接种并未改善ITT中的PFS。然而,对于对疫苗产生免疫应答的患者,PFS和临时OS显著改善。这些亚组数据用于设计确定性的III期试验。
试验设计的基本原理:OBI-822是新的研究性抗癌治疗方法,属于新类型的主动免疫疗法。它是合成糖蛋白,由与载体蛋白钥孔戚血蓝蛋白(KLH)共价结合的与肿瘤相关的碳水化合物抗原(TACA)Globo H构成。OBI-821是基于皂苷的佐剂。Globo H在许多上皮癌的恶性肿瘤表面上以高水平表达,例如乳腺癌、前列腺癌、胃癌、肺癌、结肠癌、胰腺癌和卵巢癌等。通过将Globo H与KLH载体蛋白缀合以形成OBI-822(Globo H-KLH)并与佐剂OBI-821共同施用来增强抗原的免疫原性。
研究设计:国际、随机化、双盲和安慰剂对照II/III期临床试验(NCT01516307)由以下各项组成:在41周治疗期内9次注射OBI-822,随机化起长达2年的疾病进展随访期,和长达5年的存活随访期。总共349名先前接受过治疗的具有组织学或细胞学证实的转移性BC的女性被随机分配(2:1)至用皮下的OBI-822(30μg Globo H)/OBI-821(100μg)或对照(PBS),联合低剂量环磷酰胺(300mg/m2)的治疗。
合格标准:(确立了入选和排除标准)
1.入选标准
2.排除标准
研究规程时间表:
1.筛选阶段–随机化前3周(第1次随访)
2.治疗期:第1周-第3周(第2次随访-第5次随访)
3.治疗期:第5周-第41周(第6次随访-第19次随访)
4.随访期(每8周)
5.确立了早期终止标准
6.存活随访期(每12周)
7.为了完整性考虑其他研究规程
治疗计划:(考虑的项目)
1.随机化和盲化
2.环磷酰胺施用时间表
3.OBI-822/OBI-821和安慰剂施用时间表
毒性和治疗中断的管理:(考虑为设计的一部分的例示性因素)
1.综合管理
2.药物诱导毒性的管理
3.用于个体受试者研究治疗(OBI-822/OBI-821,安慰剂)中断的指南
4.用于环磷酰胺治疗中断的指南
研究期间允许和禁止的治疗:(考虑为设计的一部分的例示性因素)
1.研究期间允许的治疗
2.研究期间禁止的治疗
药物信息:(考虑为设计的一部分的例示性因素)
1.环磷酰胺
2.OBI-822(Globo H-KLH)
3.OBI-821
4.临床试验材料(CTM)供应、包装、标签和存储
研究端点:
1.功效评估
2.安全性评估
3.安全性变量
应答标准:
1.用于肿瘤病变的可测量性的定义
2.记录肿瘤病变
3.应答评价
4.从方案疗法中去除的标准
5.关闭研究标准
统计学考虑:
1.目标和假设
2.目标样本量
3.研究端点的评价
4.统计方法
5.安全性分析
不良事件:
1.不良事件的定义
2.与治疗的关系的评估
功效的证明:在某些实施方案中,与患有转移性乳腺癌的“非应答者”(没有IgG/IgM应答)相比,OBI-822/OBI-821与环磷酰胺改善了“应答者”(具有增加的Globo H特异性IgG/IgM)。
免疫后体液免疫应答(Globo H特异性IgG/IgM)的频率和程度及其与转移性乳腺癌患者的PFS和OS的相关性。
OBI-822/OBI-821与环磷酰胺相对于PBS与环磷酰胺的安全性和毒性概况。
作为具体实施例的临床试验:在患有转移性乳腺癌的受试者中使用Globo H-KLH(OBI-822)和OBI-821佐剂的主动免疫疗法的双盲随机化II/III期试验。
治疗计划:这是在患有转移性乳腺癌的受试者中进行的双盲、随机化、双臂、II/III期试验。
筛选时的肿瘤评估:在筛选时进行全身CT扫描(胸部、腹部和骨盆)并用作基线扫描。如果在筛选扫描的2周内已经实施了全身CT扫描,则该实施的扫描可以用作基线扫描。如果筛选前的全身CT扫描不可得,则在转移性乳腺癌的诊断后具有病变的切片必须具有来自CT或MRI扫描的成像以确认肿瘤状态。
肿瘤反应状态(SD、PR、CR)基于RECIST 1.1标准。将筛选(基线)时的确认性CT扫描与筛选前的先前全身CT扫描进行比较。筛选扫描之前扫描的疾病状态必须与筛选扫描是相同疾病状态。SD需要至少6周的间隔,PR和CR需要至少4周的间隔。
如果在筛选时检测到新的病变(即,肿瘤在先前的成像中不明显和/或肿瘤先前未在成像中记录),则该病例被认为是PD,并因此不符合入选。
用于分层的疾病状态分为有疾病的证据(PR/SD)或没有疾病的证据(CR)。
对于由于在筛查前切除转移性病变而没有疾病的证据(CR)的受试者,研究者需要确保在手术切除前通过成像记录肿瘤反应状态。
如果登记,则肿瘤状态被记录为疾病的证据(PR/SD)。
成像由现场放射科医师进行评估,并将副本发送至中心放射学实验室进行独立评估,该评估不会干扰现场的解释和决定。
受试者被随机化以在2:1分配中接受OBI-822/OBI-821(治疗组)或PBS(对照组)。
将受试者根据他们在研究时激素治疗的使用和加入时他们的疾病状态进行分层。
当作为激素治疗非使用者登记时,患者不允许在研究期间开始激素治疗。
如果作为激素治疗使用者登记,患者应该进行激素治疗。
允许由于来自先前激素治疗的毒性的不耐受性而改变为激素治疗的另一种方案。
有四个分层:
1.激素治疗使用者–有疾病的证据(PR/SD)
2.激素治疗使用者–没有疾病的证据(CR)
3.激素治疗非使用者–有疾病的证据(PR/SD)
4.激素治疗非使用者–没有疾病的证据(CR)
收集受试者肿瘤生检/组织样本以检测肿瘤Globo H表达并与治疗反应相关联。
在某些联合治疗实施方案中,在第1、5、9、13、17、25和37周(第2、6、8、10、12、14和17次访视)或直至疾病进展静脉内给予治疗受试者环磷酰胺(300mg/m2)。
在第1、2、3、5、9、13、17、25和37周(第3、4、5、7、9、11、13、15和18次访视)皮下给予OBI-822/OBI-821或对照(PBS)。随访受试者直至疾病进展或随机化起长达2年。
收集血液样品用于评价在治疗以及从治疗开始长达2年的随访期或直至疾病进展期间对Globo H-KLH的免疫应答。
研究期间的肿瘤评估
1.每8周进行全身CT扫描(胸部、腹部和骨盆)直至研究结束或直至疾病进展。
2.基于RECIST 1.1标准,对于无进展存活(PFS)和肿瘤反应状态(PD、SD、PR、CR),相对于基线扫描(筛选时)以及先前时间点比较来自每个时间点的CT扫描。
对于总存活(OS),对所有存活的受试者以12周的间隔随访,直至随机化起5年。
对于患有PD的受试者,在进展时或在将受试者从研究中撤出之前抽取血液和尿液样品。
实施例1:OBI-822的修正的意向性治疗(Mitt)群体的无进展存活(PFS)的临床试验数据
Kaplan-Meier图OBI-822(原名OPT-822)的修正的意向性治疗(mITT)群体的无进展存活(PFS)和总存活(OS)表明与安慰剂相比,患者完成9次OBI-822的注射后PFS和OS更高。
通过ELISA测定人抗Globo H IgG滴度的临床试验数据
试剂/缓冲液制备
包被抗原:将1mg/mL Globo H-神经酰胺溶解在乙醇(OBI Pharma Inc.)中;人血清的二抗:山羊抗人IgG-AP(Jackson Immunoresearch,Cat#109-055-008);10X PBS,pH7.4(Gibco,Cat#70011-044);Tween-20(Sigma-Aldrich,Cat#P2287);底物溶液:碱性磷酸酶黄色(pNPP)液体底物(Sigma-Aldrich,Cat#P7998);封闭缓冲液(Sigma-Aldrich,Cat#B6429);PBST:PBS中0.05%tween-20;终止溶液:碱性磷酸酶终止溶液(Sigma-Aldrich,Cat#A5852)。
测定规程
将Globo H-神经酰胺在乙醇中稀释至4μg/mL。将50μL稀释的Globo H-神经酰胺溶液加入到标准反应平板的每个孔中。将具有反应混合物的平板在室温下温育过夜。倾析平板并用PBST以200μL/孔洗涤三次。向每个孔中加入100μL封闭缓冲液,并在室温下温育30分钟。倾析平板并用PBST 200μL/孔洗涤三次。
血清样品稀释:样品在封闭缓冲液中进行两倍连续稀释,范围为20、40、80、160、320、640、1280至2560倍(将40μL血清样品加入到760μL封闭缓冲液中以制备20倍稀释液)。在包被的和未包被的平板中的每个孔中加入50μL血清样品,并在室温下温育60分钟。倾析平板并用PBST 200μL/孔洗涤三次。将40μL 0.3mg/mL储备抗人IgG-AP二抗加入到7960μL封闭缓冲液中用于1:200稀释。将50μL稀释的抗人IgG-AP加入到包被的和未包被的平板中的每个孔中,并在室温下温育45分钟。倾析平板并用PBST 200μL/孔洗涤三次。将100μL底物溶液加入到包被的和未包被的平板的每个孔中,并在37℃下温育20分钟。每孔加入50μL终止溶液。通过ELISA阅读器在光密度405nm处读取平板。
数据分析
通过仅来自包被平板的二抗的平均OD值与仅来自未包被的平板的二抗的平均OD值的差值加0.1获得截留值。
滴度定义为每个稀释度下包被平板的OD值与未包被平板的OD值的差值。截留值以上的最高稀释度是抗Globo H IgG滴度。使用GraphPad Prism 6软件进行统计学分析。
表1中列出了临床患者的特征。
表1:基线特征
无进展存活(PFS)表明OBI-822在几种生物亚型的乳腺癌(I期、II期、III期、ER(+)、PR(+)、HER2(+)或三阴性)中具有反应性。表2中列出了不同肿瘤亚型之间Globo H表达的概况。
表2A:PFS OBI-822/821免疫应答者对安慰剂
表2B:PFS OBI-822/821免疫应答者对比OBI-822/821非应答者
错误!未找到参考源。和5显示在接受9次研究药物的注射后的无进展存活(PFS)。其表明OBI-822疫苗可以以更长的时间延长乳腺癌患者的存活率。
错误!未找到参考源。和7显示在接受研究药物后的无进展存活(PFS)/总存活(OS),有/无IgG免疫应答(IgG标准1:640)。其表明OBI-822疫苗可以诱导IgG免疫应答并以更长的时间延长乳腺癌患者的存活率。
通过聚糖阵列(Glycan Array)测定人抗Globo H IgM滴度的临床试验数据
背景
聚糖阵列平台利用自动化Agnitio BioIC系统,其中在微流体盒内进行ELISA。微流体盒包含一列微流体泵和阀、通道网络、试剂储库、聚糖阵列反应区和废物储库。自动化Agnitio BioIC系统将试剂和样品从其各自的储库泵送到反应区,用于具有化学发光的多路复用ELISA反应。收集的数据由Agnitio Science and Technology Inc.提供的LabIT软件进行分析。Agnitio BioIC系统的设备的规格在先前的PCT专利申请(WO2017041027A1)中公开。
试剂/缓冲液制备
将66微升正常人血清(NHS)或来自220个乳腺癌患者样品和124个安慰剂样品的血清加入594μL样品稀释缓冲液(BioCheck Inc.,Cat#MB10175)中以形成十倍稀释液。通过在98μL缀合物缓冲液(SuperBlock(TBS)封闭缓冲液加0.2%Tween 20,Thermo FisherScientific Inc.,Cat#37535)中混合2μL辣根过氧化物酶(HRP)缀合的山羊抗人IgM(KPLInc.,Cat#474-1003)以形成50倍稀释液来制备二抗溶液。将40μL稀释的二抗溶液泵送入2360μL缀合物缓冲液中以形成二抗溶液(3000x稀释)。
测定规程
将620微升洗涤缓冲液(在0.2%(v/v)Tween 20(J.T.Baker,Cat#JTB-X251-07)中的磷酸盐缓冲盐水(Thermo Fisher Scientific Inc.,Cat#70011))加入到“洗涤”储库。将120μL封闭缓冲液(无蛋白质封闭缓冲液,Thermo Fisher Scientific Inc.,Cat#37571)加入到“封闭”储库。将120μL二抗溶液加入到“缀合物”储库。将100μL血清加入到“血清”储库。在十分钟内将120μL底物缓冲液(SuperSignal ELISA Femto最大灵敏度底物,ThermoFisher Scientific Inc.,Cat#37074)加入到“底物”储库。
数据分析
通过Agnitio BioIC泵机将聚糖阵列加压30分钟。使用Agnitio BioIC分析仪目视监测结合的血清。相对于抗人Globo H IgG,阵列的吸光度强度转换为“Ab水平(μg/mL)”。使用0.0625、0.125、0.25、0.5、0.75和1μg/mL人IgM实施内部曲线。使用每个芯片的内部曲线的线性回归来计算斜率和截距。在某些实例中,Ab水平(μg/mL)=[(原始数据-截距)/斜率]×0.1。
错误!未找到参考源。显示在第2周接受一次研究药物的注射后的无进展存活(PFS),有/无早期IgM免疫应答。其表明OBI-822疫苗可以诱导早期IgM免疫应答并以更长的时间延长乳腺癌患者的存活率。
使用基于人抗钥孔戚血蓝蛋白(KLH)IgG滴度测定的临床试验数据的功效证明
人抗钥孔戚血蓝蛋白(KLH)IgG滴度测定用于显示可以通过Globo系列抗原疫苗、Globo系列抗原和/或载体蛋白诱导通过Globo系列抗原疫苗的施用产生的免疫反应。
试剂/缓冲液制备
KLH(Sigma-Aldrich,Cat#H1158,ocean harvest,储液浓度5mg/mL);包被缓冲液:碳酸盐-碳酸氢盐缓冲液pH 9.2(Sigma-Aldrich,Cat#C3041-50CAP);二抗:山羊抗人IgG-HRP(KPL,Cat#474-1002);10X PBS,pH 7.4(Gibco,Cat#70011-044);Tween-20(Sigma-Aldrich,Cat#P2287);TMB底物溶液(Clinical,Cat#01016-1-500);封闭缓冲液(Sigma-Aldrich,Cat#B6429);PBST:PBS中0.05%tween-20;终止溶液:1N H2SO4。
测定规程
用包被缓冲液将KLH稀释至4μg/mL。将50微升稀释的KLH溶液加入标准孔的每个孔中。将平板在4℃温育过夜。倾析平板并用PBST以200μL/孔洗涤三次。向每个孔中加入100μL封闭缓冲液,并在室温下温育30分钟。倾析平板并用PBST 200μL/每孔洗涤三次。
血清样品稀释:样品用封闭缓冲液进行两倍连续稀释,范围为约1000、2000、4000、8000、16000、32000、64000至128000倍(将1μL血清样品加入到999μL封闭缓冲液中以制备1000倍稀释液)。在包被的和未包被的平板中的每个孔中加入50μL样品,并在室温下温育1.5小时。倾析平板并用PBST 200μL/孔洗涤三次。用封闭缓冲液将抗人IgG-HRP二抗稀释至1:20000。从1mg/mL储液中取1μL并加入到20mL封闭缓冲液中以制备1:20000稀释液。将50μL抗人IgG-HRP加入到包被的和未包被的平板中的每个孔中,并在室温下温育45分钟。倾析平板并用PBST 200μL/孔洗涤三次。将100μL TMB底物溶液加入到包被的和未包被的平板的每个孔中,然后在室温下温育5分钟。每孔加入100μL终止溶液。通过ELISA阅读器在光密度450nm处读取平板。
图9显示在患者接受OBI-822疫苗的注射后的高抗KLH IgG免疫应答。将总共30个临床血清样品分成三组(应答者:接受OBI-822疫苗注射,具有增加的抗Globo H IgG/IgM水平;非应答者:接受OBI-822疫苗注射,没有增加的抗Globo H IgG/IgM水平)。其证明了OBI-822疫苗的施用确实可以诱导抗KLH免疫应答。因此,可以通过Globo系列抗原疫苗、Globo系列抗原或载体蛋白诱导通过Globo系列抗原疫苗的施用产生的免疫反应。
实施例2:使用代表性卵巢癌模型的功效证明
作为具体实施例的临床试验:在患有非进展性上皮性卵巢或输卵管癌的女性中使用Globo H-KLH(OBI-822/821)的主动免疫疗法的开放标签的II期试验。
方法:这是女性中的开放标签的II期试验,所述女性针对新诊断的≥II期上皮性卵巢或输卵管癌,在接受了细胞减少性手术,随后接受基于铂的化疗后尚未进展。
对于参加接受治疗的受试者,在第1、2、3、4、12、20、28、36、44和52周(第1、2、3、4、5、6、7、8、9和10次访视)皮下给予OBI-822(30mcg Globo H)/OBI-821(100mcg)。根据并入RECIST 1.1标准的评价的结果确定疾病状态。基于客观RECIST 1.1标准评价受试者具有PD。用于RECIST标准的CT扫描/MRI在筛选第28周和第52周进行。在治疗期间以约24周的间隔在指定时间进行整个腹部(腹部和骨盆)CT扫描。CT扫描的窗口期是按照方案时间表的计划访视起的+/-14天。根据研究者的判断进行非安排的肿瘤评估,并且在评估时与基线处进行的检查一致。对于CT禁忌的受试者,进行MRI检查代替。
没有病变的、具有可测量的疾病的和具有测量不到的疾病的受试者有资格入选本研究。可测量的疾病由≥1个可测量的病变(使用螺旋计算机体层摄影[CT]扫描,最长直径[LD]≥10mm或者使用常规CT、磁共振成像[MRI]或X射线≥20mm)的存在来定义。代表所有涉及的病变的最多5个可测量病变(每个器官最多2个病变)鉴定为基线处的靶病变(TL)。表3中总结了用于确定TL的客观肿瘤反应的RECIST 1.1标准。
表3:靶病变的总体肿瘤反应
未记录为TL的所有其他病变(或疾病部位)鉴定为非靶病变(NTL)。表4中总结了用于确定NTL的客观肿瘤反应的RECIST标准。
表4:非靶病变的总体肿瘤反应
任何新病变的细节也得到记录;≥1个新病灶的存在评估为进展。表5中总结了总体反应的RECIST评价。
表5A:时间点反应:在基线处具有靶(+/-非靶)病变的受试者。
靶病变 | 非靶病变 | 新病变 | 总体反应 |
CR | CR、NA | 否 | CR |
CR | SD、NE | 否 | PR |
PR | CR、SD、NE、NA | 否 | PR |
SD | CR、SD、NE、NA | 否 | SD |
NE | CR、SD、NE、NA | 否 | NE |
PD | CR、SD、PD、NE、NA | 是、否 | PD |
CR、PR、SD、NE | PD | 是、否 | PD |
CR、PR、SD、NE | CR、SD、PD、NE、NA | 是 | PD |
表5B:时间点反应:仅在基线处具有非靶病变的受试者
靶病变 | 非靶病变 | 新病变 | 总体反应 |
NA | CR | 否 | CR |
NA | SD | 否 | SD |
NA | NE | 否 | NE |
NA | PD | 否 | PD |
NA | CR、SD、NE | 是 | PD |
表5C:时间点反应:在基线处没有靶和非靶病变的受试者
表5D:缩略语列表
AE | 不良事件 |
CR | 完全反应 |
CT | 计算机体层摄影 |
EVA | 可评估群体 |
FAS | 全分析集 |
IR | 不完全反应 |
ITT | 意向性治疗 |
LD | 最长直径 |
MRI | 磁共振成像 |
NA | 不适用 |
NE | 不可评估 |
NEJM | 新英格兰医学杂志(New England Journal of Medicine) |
NCI | 国家癌症研究所(National Cancer Institute) |
NTL | 非靶病变 |
PD | 疾病进展 |
PFS | 无进展存活 |
PP | 按方案 |
PR | 部分反应 |
PT | 优选术语 |
RECIST | 实体瘤临床疗效评价标准 |
SAE | 严重不良事件 |
SD | 疾病稳定 |
SOC | 系统器官类 |
TEAE | 治疗时出现的不良事件 |
TL | 靶病变 |
研究群体:
患者的处置:总结并呈现所有招募受试者的以下患者数据:筛选、接受研究药物、治疗期间完成和终止、随访期期间完成和中断的患者的数量和百分比。
研究组对所有招募患者得到的每个分析集中患者的数量和百分比以及排除原因。
研究组在数据库锁定之前审查方案违规行为,以确定哪些违规行为使患者丧失EVA群体资格。
临床结果:阴性对照(患者编号:065)(图10):评估日期在2015年3月18日或之前开始。其表明,OBI-822治疗不会在28周(第7次访视)内导致任何肿瘤产生。因此,OBI-822的安全性得以确认。
III期卵巢癌(患者编号:035)(图11):评估日期在2014年4月24日或之前开始。通过CT扫描,患者的原始症状是“亚厘米肠系膜结节肿瘤”(病变类别:非靶肿瘤)。其表明在28周(第7次访视)内OBI-822治疗后没有任何肿瘤进展/转移(SD)。因此,在28周内OBI-822的肿瘤抑制能力得以确认。
IV期输卵管癌(患者编号:041)(图12):评估日期在2014年5月22日或之前开始。通过CT扫描,患者的原始症状是“肺肿瘤”(病变类别:非靶肿瘤)。其表明在28周(第7次访视)内OBI-822治疗后没有任何肿瘤进展/转移(SD)。因此,在28周内OBI-822的肿瘤抑制能力得以确认。
III期卵巢癌(患者编号:060)(图13):评估日期在2015年1月6日或之前开始。通过CT扫描,患者的原始症状是“腹膜肿瘤”(病变类别:非靶肿瘤)。其表明在28周(第7次访视)内OBI-822治疗后没有任何肿瘤进展/转移(SD)。因此,在28周内OBI-822的肿瘤抑制能力得以确认。
实施例3:OBI-822和OBI-821的混合说明
储存条件:OBI-822及其安慰剂PBS小瓶储存在2-8℃。OBI-821及其安慰剂PBS小瓶储存在-15至-25℃。
研究组:
A组:主动治疗组;每次注射剂量:OBI-822(相当于30μg Globo H)/100μg OBI-821。总最终注射量:0.8mL。
B组:对照组;每次注射剂量:PBS。总最终注射量:0.8mL。
研究药物:
小瓶1a(PBS:OBI-821对照试验品)填充量-0.5mL。内容物:10mM磷酸钠、150mMNaCl,pH 6.8;
小瓶1b(OBI-821)填充量-0.5mL。内容物:10mM磷酸钠中250μg/mL OBI-821、150mMNaCl,pH 6.8;
小瓶2a(PBS:OBI-822对照试验品)填充量-0.75mL。内容物:100mM磷酸钠、150mMNaCl,pH 7.2;
小瓶2b(OBI-822)填充量-0.75mL。内容物:相当于100mM磷酸钠中75μg Globo H/mL OBI-822、150mM NaCl,pH 7.2;
OBI-822和OBI-821的混合说明
在治疗时,用注射器取出0.5mL小瓶2a(仅PBS)并置于小瓶1a(仅PBS)中或取出0.5mL小瓶2b(PBS中的OBI-822)并置于小瓶1b(PBS中的OBI-821)中。通过轻轻地翻转小瓶4-5次轻轻地将小瓶(小瓶1a或小瓶1b)的内容物混合。不要剧烈摇动小瓶。此时,该小瓶装有安慰剂(仅PBS)或治疗(OBI-822加OBI-821)并准备好注射。然后从该小瓶中取出0.8mL用于受试者注射。表6中总结了每个研究组的最终施用体积。
表6:研究组的最终施用体积的计算
组合的OBI-822和OBI-821的稳定性从在室温下重构时起长达10小时是稳定的。组合产品的施用应在自重建起2小时内发生,以使潜在的微生物生长最小化。如果在重建起2小时内无法施用,则应根据机构药房标准操作规程销毁组合产品,并记录在药物责任记录中。图14显示了研究药物的混合规程。
实施例4:允许和禁止的伴随药物
允许的伴随药物:
阿片类药物:其可以用于控制疼痛,也允许用于便秘的预防性治疗。
GCSF:如果医生认为有必要,则将允许。
二膦酸盐。
激素治疗(对于已经分层为激素治疗使用者的受试者)。
如果使用,激素治疗的选择的形式、剂量或用法需要是一致的,即不改变治疗、不添加更多治疗或增加剂量,除非由于毒性的不耐受。本研究中可以使用所有类型的激素治疗,常用的激素治疗如下所列。
雌激素抑制剂(例如他莫昔芬,Fareston)。
芳香化酶抑制剂(例如,阿那曲唑[Arimidex]、依西美坦[Aromasin]和来曲唑[Femara])。
垂体下调剂(例如戈舍瑞林[Zoladex]、亮丙瑞林[Lupron])-这些也称为LHRH类似物。
(他莫昔芬选择性雌激素受体调节剂,SERM)。
(雷洛昔芬,另一种SERM)。
(氟维司群,雌激素受体下调剂)。
抗凝血剂(来匹卢定(lepirudin)[Refludan])。
酶(拉布立酶(rasburicase)[Elitek])。
造血生长因子。
施用的方法优选在不存在表7中列出的伴随药物的情况下进行。
表7:伴随药物
禁止的伴随药物(例如,环孢素(cyclosporin)、雷帕霉素、他克莫司(tacrolimus)、利妥昔单抗等)。
东部肿瘤协作组(Eastern Cooperative Oncology Group)(ECOG)表现。
医生和研究人员使用这些量表和标准来评估受试者疾病的进展情况,评估疾病如何影响受试者的日常生活能力,并确定适当的治疗和预后。它们包含在表8中,用于医疗保健专业人员访问。
表8:东部肿瘤协作组(ECOG)表现
虽然已经描述并说明了本发明的特定方面,但是此类方面应该仅被认为是对本发明的说明,而不是对根据所附权利要求所解释的本发明的限制。本说明书中引用的所有出版物和专利申请均出于所有目的通过引用整体并入本文,如同每个单独的出版物或专利申请被具体地和单独地表明为了所有目的通过引用整体并入。尽管为了清楚理解的目的已经通过说明和实施例详细地描述了前述发明,但是根据本发明的教导,对于本领域普通技术人员来说显而易见的是,在不脱离所附权利要求的精神或范围的情况下,可以对其进行某些改变和修改。
Claims (70)
1.用于治疗乳腺癌的方法,所述方法包括向有此需要的受试者施用治疗有效剂量的Globo系列抗原疫苗和/或与Globo系列抗原疫苗的交叉反应物(cross-reacting)。
2.权利要求1的方法,其中所述Globo系列抗原疫苗包含与载体蛋白缀合的Globo系列抗原。
3.权利要求2的方法,其中所述Globo系列抗原包含选自以下的抗原:Globo H、阶段特异性胚胎抗原3(SSEA3)和阶段特异性胚胎抗原4(SSEA4)。
4.权利要求2的方法,其中所述载体蛋白包含KLH(钥孔戚血蓝蛋白)、DT-CRM 197(白喉毒素交叉反应物质197)、白喉类毒素或破伤风类毒素。
5.权利要求1的方法,其中所述Globo系列抗原疫苗作为药物组合物施用。
6.权利要求5的方法,其中所述药物组合物包含Globo H-KLH和佐剂。
7.权利要求6的方法,其中所述佐剂选自皂苷、弗氏佐剂或α-半乳糖神经酰胺(α-GalCer)佐剂。
8.权利要求5的方法,其中所述药物组合物包含OBI-822/OBI-821。
9.权利要求1的方法,其中由所述施用产生的免疫反应的特征在于由所述Globo系列抗原疫苗、所述Globo系列抗原和/或所述载体蛋白诱导的免疫应答。
10.权利要求1的方法,其中所述受试者为人。
11.权利要求1的方法,其中所述治疗有效剂量小于100μg。
12.权利要求1的方法,其中所述施用规程包括肌内注射、皮下注射、静脉内注射、腹膜内注射、动脉内注射、滑膜内注射、鞘内注射、硬膜外注射或胸腔内注射。
13.权利要求1的方法,其中所述疫苗以一周至五年或更长的时间间隔间歇地施用。
14.权利要求1的方法,其中所述疫苗每一周一次、每两周一次、每三周一次、每四周一次、每五周一次、每六周一次、每七周一次、每八周一次、每九周一次、每十周一次、每十一周一次或每十二周一次施用。
15.用于治疗患者中肿瘤的方法,包括向患者施用药学有效量的Globo系列抗原疫苗和/或与Globo系列抗原疫苗的交叉反应物。
16.权利要求15的方法,其中所述Globo系列抗原疫苗包含与载体蛋白缀合的Globo系列抗原。
17.权利要求16的方法,其中所述Globo系列抗原包含Globo H、阶段特异性胚胎抗原3(SSEA3)或阶段特异性胚胎抗原4(SSEA4)。
18.权利要求16的方法,其中所述载体蛋白包含KLH(钥孔戚血蓝蛋白)、DT-CRM 197(白喉毒素交叉反应物质197)、白喉类毒素或破伤风类毒素。
19.权利要求15的方法,其中所述Globo系列抗原疫苗包含Globo H-KLH和佐剂。
20.权利要求19的方法,其中所述佐剂选自皂苷、弗氏佐剂或α-半乳糖神经酰胺(α-GalCer)佐剂。
21.权利要求15的方法,其中所述Globo系列抗原疫苗包含OBI-822/OBI-821。
22.权利要求15的方法,其中所述Globo系列抗原疫苗包含OBI-822和药学上可接受的赋形剂。
23.权利要求15的方法,其中由所述施用产生的免疫反应的特征在于由所述Globo系列抗原疫苗、所述Globo系列抗原和/或所述载体蛋白诱导的免疫应答。
24.权利要求15的方法,其中所述Globo系列抗原疫苗或与Globo系列抗原疫苗的交叉反应物诱导针对Globo系列抗原的单克隆抗体的免疫原性产生。
25.权利要求24的方法,其中产生的抗体为IgG、IgM或两者。
26.权利要求15的方法,其中所述肿瘤为乳腺癌、肺癌、食管癌、直肠癌、胆管癌(biliary cancer)、肝癌、颊癌(buccal cancer)、胃癌、肠癌、结肠癌、鼻咽癌、肾癌、前列腺癌、卵巢癌、宫颈癌、子宫内膜癌、胰腺癌、睾丸癌、膀胱癌、头颈癌、口腔癌、神经内分泌癌、肾上腺癌、甲状腺癌、骨癌、胆囊癌、口咽癌、喉癌、皮肤癌、基底细胞癌、鳞状细胞癌、黑色素瘤或脑瘤。
27.权利要求15的方法,其中所述肿瘤为转移性或非转移性。
28.权利要求15至23的方法,其中将所述Globo系列抗原疫苗或与Globo系列抗原疫苗的交叉反应物与一种或多种抗增殖剂组合施用至所述患者。
29.权利要求28的方法,其中所述抗增殖剂选自以下各项:环磷酰胺、阿片剂、粒细胞集落刺激因子(GCSF)、雌激素抑制剂、芳香化酶抑制剂、垂体下调剂、他莫昔芬选择性雌激素受体调节剂、雷洛昔芬(Rolaxifene)、雌激素受体下调剂、抗凝剂、酶、造血生长因子、抗肿瘤剂(anti-neoplastic agent)、抗代谢物、各种细胞毒剂、长春花生物碱、表鬼臼毒素、烷化剂、紫杉烷类、抗肿瘤抗生素、喜树碱、亚硝基脲类、HER1/EGFR酪氨酸激酶抑制剂、VEGF蛋白抑制剂、HER-2/ErbB2抑制剂、干扰素、白细胞介素、单克隆抗体或糖皮质激素类固醇。
30.权利要求28的方法,其中所述抗增殖剂选自以下各项:厄洛替尼(erlotinib)、多西他赛(docetaxel)、吉西他滨(gemcitabine)、顺铂(cisplatin);卡铂(carboplatin);紫杉醇(paclitaxel)、曲妥珠单抗(trastuzumab)、替莫唑胺(temozolomide)、他莫昔芬(tamoxifen)、多柔比星(doxorubicin)、奥沙利铂(oxaliplatin)、硼替佐米(bortezomib)、索坦(sutent)、来曲唑(letrozole)、甲磺酸伊马替尼(imatinib mesylate)、MEK抑制剂、氟维司群(fulvestrant)、亚叶酸钙(leucovorin)(亚叶酸(folinic acid));雷帕霉素(rapamycin)、拉帕替尼(lapatinib)、洛那法尼(lonafarnib)、索拉非尼(sorafenib)、吉非替尼(gefitinib)、伊立替康(irinotecan)、替比法尼(tipifarnib)、无克列莫佛紫杉醇(Cremophor-free,paclitaxel)、凡德他尼(vandetanib)、苯丁酸氮芥(chloranmbucil)、替西罗莫司(temsirolimus)、帕唑帕尼(pazopanib)、canfosfamide、噻替哌(thiotepa)、环磷酰胺(cyclosphosphamide)、5-氟尿嘧啶(5-fluorouracil)(5-FU)、长春瑞滨(vinorelbine)、能灭瘤(novantrone)、替尼泊苷(teniposide)、依达曲沙(edatrexate)、柔红霉素(daunomycin)、氨基蝶呤(aminopterin)、卡培他滨(capecitabine)、伊班膦酸盐(ibandronate)、拓扑异构酶抑制剂RFS 2000、二氟甲基鸟氨酸(difluoromethylornithine)(DMFO)、他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、keoxifene、奥那司酮(onapristone)、枸橼酸托瑞米芬(toremifine citrate)、4(5)-咪唑、氨鲁米特(aminoglutethimide)、醋酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、福美司坦(formestanie)、法倔唑(fadrozole)、伏氯唑(vorozole)、来曲唑(letrozole)、阿那曲唑(anastrozole)、氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)、戈舍瑞林(goserelin)、曲沙他滨(troxacitabine)(α-1,3-二氧戊环核苷胞嘧啶类似物(α-1,3-dioxolane nucleosidecytosine analog))、脂质激酶抑制剂、奥利默森(oblimersen)、angiozyme、allovectin、leuvectin、vaxid、阿地白介素(aldesleukin)、勒托替康(lurtotecan)、阿巴瑞克(abarelix)、贝伐单抗(bevacizumab)、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、帕妥珠单抗(pertuzumab)、曲妥珠单抗(trastuzumab)、托西莫单抗(tositumomab)、吉妥珠单抗(gemtuzumab)或奥佐米星(ozogamicin)。
31.用于通过免疫疗法治疗患有癌症的受试者的方法,所述方法包括向有此需要的受试者施用治疗有效量的对诱导或调节免疫应答有用的免疫原性剂和/或与所述免疫原性剂的交叉反应物。
32.权利要求31的方法,其中所述免疫原性剂包含与载体蛋白缀合的Globo系列抗原。
33.权利要求32的方法,其中所述Globo系列抗原包含Globo H、阶段特异性胚胎抗原3(SSEA3)或阶段特异性胚胎抗原4(SSEA4)。
34.权利要求32的方法,其中所述载体蛋白包含KLH(钥孔戚血蓝蛋白)、DT-CRM 197(白喉毒素交叉反应物质197)、白喉类毒素或破伤风类毒素。
35.权利要求31的方法,其中所述免疫原性剂为OBI-822和相关的变体。
36.权利要求31的方法,其中由所述施用产生的免疫反应的特征在于由所述Globo系列抗原疫苗、所述Globo系列抗原和/或所述载体蛋白诱导的免疫应答。
37.权利要求31的方法,其中所述受试者为人。
38.权利要求31的方法,其中所述免疫应答包含IgG、IgM或细胞介导的应答。
39.权利要求38的方法,其中所述细胞为B细胞或T细胞。
40.权利要求31的方法,其中所述方法进一步包括通过调节Globo系列抗原相互作用来改善所述受试者的存活。
41.权利要求40的方法,其中所述存活包含总存活和/或无进展存活。
42.权利要求40的方法,其中所述Globo系列抗原相互作用的调节进一步包含以下各项的一个或多个:
(a)诱导抗体依赖性细胞性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC),用于肿瘤杀伤;
(b)诱导抗Globo系列抗原IgM/IgG免疫应答以引发抗体依赖性细胞性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)介导的肿瘤细胞杀伤;
(c)诱导抗Globo系列抗原抗体捕获从肿瘤细胞脱落的Globo系列抗原-神经酰胺以阻断易位蛋白相关因子X(TRAX)依赖性血管发生;
(d)诱导抗Globo系列抗原抗体以阻断Globo系列抗原-神经酰胺诱导的Notch 1依赖性免疫抑制,从而增强T细胞增殖和细胞因子产生;
(e)诱导抗Globo系列抗原抗体以导致凋亡;
(f)抑制Globo系列抗原诱导的血管发生;或
(g)OBI-822疫苗接种诱导凋亡。
43.用于诱导/增强受试者中免疫应答的方法,所述方法包括向所述受试者施用免疫原性剂和/或与所述免疫原性剂的交叉反应物。
44.权利要求43的方法,其中所述免疫原性剂为与载体蛋白缀合的Globo系列抗原。
45.权利要求44的方法,其中所述Globo系列抗原包含Globo H、阶段特异性胚胎抗原3(SSEA3)或阶段特异性胚胎抗原4(SSEA4)。
46.权利要求44的方法,其中所述载体蛋白包含KLH(钥孔戚血蓝蛋白)、DT-CRM 197(白喉毒素交叉反应物质197)、白喉类毒素或破伤风类毒素。
47.权利要求43的方法,其中所述免疫原性剂为OBI-822和相关的变体。
48.权利要求43的方法,其中由所述施用产生的免疫反应的特征在于由所述Globo系列抗原疫苗、所述Globo系列抗原和/或所述载体蛋白诱导的免疫应答。
49.权利要求43的方法,其中所述受试者为人。
50.权利要求43的方法,其中所述免疫应答为细胞免疫或体液免疫。
51.在有此需要的受试者中改善OBI-822疫苗诱导的免疫应答性的方法,所述方法包括:施用免疫原性有效量的包含OBI-822的药学上可接受的赋形剂以及选自以下各项的一个或多个:
(a)施用疫苗两次或更多次(例如3、4、5、6、7、8、9、10、11、12或更多次);
(b)调整两次连续施用之间的时间间隔和/或给药量方案;
(c)调整施用的途径和/或改变施用的注射位置;或
(d)上述各项的任何组合,其中每次施用增加抗体免疫应答和/或增加抗原-抗体结合亲和力。
52.权利要求51的方法,其中所述注射可以通过添加免疫应答增强剂来改变和/或补充。
53.权利要求51的方法,其中所述免疫应答为细胞免疫或体液免疫。
54.权利要求51的方法,其中所述免疫应答包含IgG、IgM或细胞介导的应答。
55.权利要求54的方法,其中所述细胞为B细胞或T细胞。
56.权利要求51的方法,其中所述受试者为人。
57.用于鉴定有此需要的对于癌症疗法适合的患者的方法,所述方法包括:
(a)向所述患者施用有效剂量的Globo系列抗原疫苗;
(b)评估所述患者的免疫应答;
(c)确定每个患者中Globo系列抗原的表达;和
(d)基于免疫应答的指数和所述Globo系列抗原的表达来分类所述患者的适合性;其中所述指数表明所述患者具有良好的恢复预后。
58.权利要求57的方法,其中所述Globo系列抗原疫苗包含与载体蛋白缀合的Globo系列抗原。
59.权利要求58的方法,其中所述Globo系列抗原包含Globo H、阶段特异性胚胎抗原3(SSEA3)或阶段特异性胚胎抗原4(SSEA4)。
60.权利要求58的方法,其中所述载体蛋白包含KLH(钥孔戚血蓝蛋白)、DT-CRM 197(白喉毒素交叉反应物质197)、白喉类毒素或破伤风类毒素。
61.权利要求57的方法,其中所述Globo系列抗原疫苗作为药物组合物施用。
62.权利要求61的方法,其中所述药物组合物包含Globo H-KLH和佐剂。
63.权利要求62的方法,其中所述佐剂选自皂苷、弗氏佐剂或α-半乳糖神经酰胺(α-GalCer)佐剂。
64.权利要求61的方法,其中所述药物组合物包含OBI-822/OBI-821。
65.权利要求57的方法,其中所述癌症为乳腺癌、肺癌、食管癌、直肠癌、胆管癌、肝癌、颊癌、胃癌、肠癌、结肠癌、鼻咽癌、肾癌、前列腺癌、卵巢癌、宫颈癌、子宫内膜癌、胰腺癌、睾丸癌、膀胱癌、头颈癌、口腔癌、神经内分泌癌、肾上腺癌、甲状腺癌、骨癌、胆囊癌、口咽癌、喉癌、皮肤癌、基底细胞癌、鳞状细胞癌、黑色素瘤或脑瘤。
66.权利要求57的方法,其中所述癌症为乳腺癌。
67.权利要求66的方法,其中所述乳腺癌为I期、II期、III期、ER(+)、PR(+)、HER2(+)、三阴性、转移性或非转移性。
68.权利要求57的方法,其中所述免疫应答的指数包含IgG滴度、IgM滴度、无进展存活(PFS)和/或总存活(OS)的评估。
69.用于确定有此需要的患者的癌症治疗和/或药物响应的预后的方法,所述方法包括:
(a)鉴定已被诊断患有癌症的患者;
(b)通过在接受权利要求1的治疗后确定所述患者的适合性来确定免疫应答的水平;
(c)分析权利要求57获得的数据。
70.权利要求69的方法,其中所述癌症为乳腺癌、肺癌、食管癌、直肠癌、胆管癌、肝癌、颊癌、胃癌、肠癌、结肠癌、鼻咽癌、肾癌、前列腺癌、卵巢癌、宫颈癌、子宫内膜癌、胰腺癌、睾丸癌、膀胱癌、头颈癌、口腔癌、神经内分泌癌、肾上腺癌、甲状腺癌、骨癌、胆囊癌、口咽癌、喉癌、皮肤癌、基底细胞癌、鳞状细胞癌、黑色素瘤或脑瘤。
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US201662326623P | 2016-04-22 | 2016-04-22 | |
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US201662343530P | 2016-05-31 | 2016-05-31 | |
US62/343,530 | 2016-05-31 | ||
US201662345755P | 2016-06-04 | 2016-06-04 | |
US62/345,755 | 2016-06-04 | ||
US201662381875P | 2016-08-31 | 2016-08-31 | |
US62/381,875 | 2016-08-31 | ||
PCT/US2017/029138 WO2017185089A2 (en) | 2016-04-22 | 2017-04-24 | Cancer immunotherapy by immune activation or immune modulation via globo series antigens |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114173778A (zh) * | 2019-04-26 | 2022-03-11 | 洪明奇 | Adam9抑制剂作为免疫调节剂的用途 |
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TW201739467A (zh) | 2017-11-16 |
RU2018140976A (ru) | 2020-05-22 |
AU2017252128A1 (en) | 2018-11-01 |
TWI697333B (zh) | 2020-07-01 |
EP3445395A4 (en) | 2019-12-25 |
SG11201809024UA (en) | 2018-11-29 |
IL262296B1 (en) | 2024-05-01 |
AU2017252128B2 (en) | 2024-06-06 |
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