CN115531531A - 抗人vegf抗体和化疗联用在制备治疗结直肠癌药物中的用途 - Google Patents
抗人vegf抗体和化疗联用在制备治疗结直肠癌药物中的用途 Download PDFInfo
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Abstract
本发明涉及抗人VEGF抗体和化疗联用在制备治疗结直肠癌药物中的用途,具体涉及抗人VEGF抗体与化疗药物的联用、及将其用于治疗结直肠癌及用于制备治疗结直肠癌患者的药物。本发明有利于增加结直肠癌患者的选择,提高结直肠癌的治疗效果,使更多结直肠癌患者受益。
Description
本发明要求于2021年6月30日,向中国专利局提交的,申请号为202110743076.3,发明名称为“抗人VEGF抗体和化疗联用在制备治疗结直肠癌药物中的用途”的中国专利申请的优先权,该专利申请的全文通过引用结合至本发明中。
技术领域
本发明涉及医药领域,具体而言,涉及抗人VEGF抗体和化疗联用在制备治疗结直肠癌药物中的用途。
背景技术
结直肠癌(colorectal cancer,CRC)是常见的恶性肿瘤,全球每年约有102万新发病例,导致约53万患者死亡。发病率在我国居全部恶性肿瘤的第3位,占癌症死因的第5位,并有逐年上升的趋势。结直肠癌起病隐匿,早期症状不明显,许多患者在确诊时已经处于晚期。大约25%的患者初次就诊时就已经发生转移,另外,40%-50%新诊断患者将继续发展出现转移。仅仅少于5%的患者能存活5年以上。
血管内皮生长因子(Vascular endothelial growth factor,VEGF)是一种多功能的细胞因子,是目前已知的作用最强、特异性最高的促血管生成因子,它通过促进肿瘤血管生成、增加血管通透性和下调宿主抗肿瘤免疫应答等机制,参与实体肿瘤的发生发展。有研究显示抗人 VEGF抗体具有抑制实体瘤生长的作用。如何更好的实现抗人VEGF抗体抑制实体瘤生长的作用,实现治疗肿瘤,例如,结直肠癌,是本领域待解决的问题。
有鉴于此,特提出本发明。
发明内容
本发明公开抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康,及其治疗结直肠癌的方法和相应的制药用途,用于提高结直肠癌的治疗效果。
在第一方面,本发明提供抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康在制备用于治疗结直肠癌患者的药物中的用途,所述抗体包括重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其中:
所述HCDR1选自SEQ ID NO:5-7任一项所示序列;
所述HCDR2选自SEQ ID NO:8-10任一项所示序列;
所述HCDR3选自SEQ ID NO:11-12任一项所示序列;
所述LCDR1选自SEQ ID NO:13-14任一项所示序列;
所述LCDR2选自SEQ ID NO:15-16任一项所示序列;和,
所述LCDR3选自SEQ ID NO:17所示序列。
在一些具体的实施方式中,所述重链可变区具有如SEQ ID NO:1所示序列,或与SEQ ID NO:1相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链可变区具有如SEQ ID NO:3所示的序列,或与SEQ ID NO:3相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述抗体包括重链恒定区和轻链恒定区,所述重链恒定区具有如SEQ ID NO:2所示序列,或与SEQ ID NO:2相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链恒定区具有如SEQ ID NO:4所示的序列,或与SEQ ID NO:4相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述患者为转移性结直肠癌患者;优选地,所述患者为无法手术切除且至少接受过一次含奥沙利铂一线化疗方案失败的转移性结直肠腺癌患者。
在一些具体的实施方式中,所述患者为肝转移或淋巴结转移患者。
在一些具体的实施方式中,所述四氢叶酸类化合物为亚叶酸钙或左旋亚叶酸钙;优选的,所述亚叶酸钙的有效施用量为400mg/m2,所述左旋亚叶酸钙的有效施用量为200mg/m2。
在一些具体的实施方式中,所述5-氟尿嘧啶的有效施用量为2800mg/m2。
在一些具体的实施方式中,所述盐酸伊立替康的有效施用量为180mg/m2。
在一些具体的实施方式中,所述抗人VEGF抗体的有效施用量为1~5mg/kg,优选为1 mg/kg、2mg/kg、3mg/kg、4mg/kg或5mg/kg。
在一些具体的实施方式中,所述抗人VEGF抗体的剂型为单剂量剂型,每剂含有能够给予患者有效施用量的抗体量,优选地,所述抗体量为50~500mg,例如50mg、80mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg或500mg。
在第二方面,本发明还提供一种抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康的组合,所述组合用于治疗结直肠癌患者,所述抗人VEGF抗体包含重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含 LCDR1、LCDR2和LCDR3,其中:
所述HCDR1选自SEQ ID NO:5-7任一项所示序列;
所述HCDR2选自SEQ ID NO:8-10任一项所示序列;
所述HCDR3选自SEQ ID NO:11-12任一项所示序列;
所述LCDR1选自SEQ ID NO:13-14任一项所示序列;
所述LCDR2选自SEQ ID NO:15-16任一项所示序列;和,
所述LCDR3选自SEQ ID NO:17所示序列。。
在一些具体的实施方式中,所述重链可变区具有如SEQ ID NO:1所示序列,或与SEQ ID NO:1相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链可变区具有如SEQ ID NO:3所示的序列,或与SEQ ID NO:3相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述抗体包括重链恒定区和轻链恒定区,所述重链恒定区具有如SEQ ID NO:2所示序列,或与SEQ ID NO:2相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链恒定区具有如SEQ ID NO:4所示的序列,或与SEQ ID NO:4相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述患者为转移性结直肠癌患者;优选地,所述患者为无法手术切除且至少接受过一次含奥沙利铂一线化疗方案失败的转移性结直肠癌腺癌患者。
在一些具体的实施方式中,所述患者为肝转移或淋巴结转移患者。
在一些具体的实施方式中,所述四氢叶酸类化合物为亚叶酸钙或左旋亚叶酸钙;优选地,所述亚叶酸钙的有效施用量为400mg/m2,所述左旋亚叶酸钙的有效施用量为200mg/m2。
在一些具体的实施方式中,所述5-氟尿嘧啶的有效施用量为2800mg/m2。
在一些具体的实施方式中,所述盐酸伊立替康的有效施用量为180mg/m2。
在一些具体的实施方式中,所述抗人VEGF抗体的有效施用量为1~5mg/kg,优选为1 mg/kg、2mg/kg、3mg/kg、4mg/kg或5mg/kg。
在一些具体的实施方式中,所述抗人VEGF抗体的剂型为单剂量剂型,每剂含有能够给予患者有效施用量的抗体量,优选地,所述抗体量为50~500mg,例如50mg、80mg、100mg、 150mg、200mg、250mg、300mg、350mg、400mg、450mg或500mg。
在第三方面,本发明还提供一种治疗结直肠癌的方法,所述方法包括向受试者施用有效量的抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康,其中,抗体包括重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其中:
所述HCDR1选自SEQ ID NO:5-7任一项所示序列;
所述HCDR2选自SEQ ID NO:8-10任一项所示序列;
所述HCDR3选自SEQ ID NO:11-12任一项所示序列;
所述LCDR1选自SEQ ID NO:13-14任一项所示序列;
所述LCDR2选自SEQ ID NO:15-16任一项所示序列;和,
所述LCDR3选自SEQ ID NO:17所示序列。
在一些具体的实施方式中,所述重链可变区具有如SEQ ID NO:1所示序列,或与SEQ ID NO:1相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链可变区具有如SEQ ID NO:3所示的序列,或与SEQ ID NO:3相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述抗体包括重链恒定区和轻链恒定区,所述重链恒定区具有如SEQ ID NO:2所示序列,或与SEQ ID NO:2相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链恒定区具有如SEQ ID NO:4所示的序列,或与SEQ ID NO:4相比具有至少95%、 96%、97%、98%或99%同一性的序列。
在一些具体的实施方式中,所述患者为转移性结直肠癌患者;优选地,所述患者为无法手术切除且至少接受过一次含奥沙利铂一线化疗方案失败的转移性结直肠癌腺癌患者。
在一些具体的实施方式中,所述患者为肝转移或淋巴结转移患者。
在一些具体的实施方式中,所述四氢叶酸类化合物为亚叶酸钙或左旋亚叶酸钙;优选的,所述亚叶酸钙的有效施用量为400mg/m2,所述左旋亚叶酸钙的有效施用量为200mg/m2。
在一些具体的实施方式中,所述5-氟尿嘧啶的有效施用量为2800mg/m2。
在一些具体的实施方式中,所述盐酸伊立替康的有效施用量为180mg/m2。
在一些具体的实施方式中,所述抗人VEGF抗体的有效施用量为1~5mg/kg,优选为1 mg/kg、2mg/kg、3mg/kg、4mg/kg或5mg/kg。
在一些具体的实施方式中,所述抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康的给药周期为2周;优选地,所述抗人VEGF抗体在给药周期的第1天或第3天给药,所述四氢叶酸类化合物和盐酸伊立替康在给药周期的第1天给药,所述5-Fu按 400mg/m2的给药量在给药周期的第1天进行静脉推注,静脉推注结束当天和第2天按 1200mg/m2/d的给药量进行静脉输注。
在一些具体的实施方式中,所述药物还包括其他治疗剂,例如,免疫检查点抑制剂。
本发明所述VEGF抗体为人源化兔抗人VEGF单克隆抗体,联合四氢叶酸类化合物、5- 氟尿嘧啶和盐酸伊立替康,进行结直肠癌的治疗。基于临床实验的结果,本发明的治疗方案,能够更有效的实现结直肠癌的治疗,特别是转移性结直肠腺癌的治疗,有利于增加结直肠癌患者的选择,使更多结直肠癌患者受益。
术语定义和说明
除非本发明另外定义,与本发明相关的科学和技术术语应具有本领域普通技术人员所理解的含义。
此外,除非本文另有说明,本文单数形式的术语应包括复数形式,复数形式的术语应包括单数形式。更具体地,如在本说明书和所附权利要求中所使用的,除非另外明确指出,否则单数形式“一种”和“这种”包括复数指示物。
本文术语“包括”、“包含”和“具有”之间可互换使用,旨在表示方案的包含性,意味着所述方案可存在除所列出的元素之外的其他元素。同时应当理解,在本文中使用“包括”、“包含”和“具有”描述,也提供“由……组成”方案。
术语“和/或”在本文使用时,包括“和”、“或”和“由所属术语链接的要素的全部或任何其他组合”的含义。
本文术语“抗体”按最广义使用,是指包含来自免疫球蛋白重链可变区的足够序列和/或来自免疫球蛋白轻链可变区的足够序列,从而能够特异性结合至抗原的多肽或多肽组合。本文“抗体”涵盖各种形式和各种结构,只要它们展现出期待的抗原结合活性,示例性地,本文所述“抗体”包括完整抗体和抗原结合片段。本文所指“期待的抗原结合活性”是指例如抗体通常以高亲和力特异性结合抗原和实质上相同的抗原,但不以高亲和力结合不相关抗原。亲和力通常以平衡解离常数(equilibrium dissociation constant,KD)来反映,其中较低KD 表示较高亲和力。示例性地,高亲和力通常指具有约10-7M或更低、约10-8M或更低、约1 ×10-9M或更低、约1×10-10M或更低、1×10-11M或更低或1×10-12M或更低的KD。KD计算方式如下:KD=Kd/Ka,其中Kd表示解离速率,Ka表示结合速率。可采用本领域周知的方法测量平衡解离常数KD,如表面等离子共振(例如Biacore)或平衡透析法测定。
本文“抗体”包括一种典型的“四链抗体”,其属于由两条重链(HC)和两条轻链(LC)组成的免疫球蛋白;重链是指这样的多肽链,其在N端到C端的方向上由重链可变区(VH)、重链恒定区CH1结构域、铰链区(HR)、重链恒定区CH2结构域、重链恒定区CH3结构域组成;并且,当所述全长抗体为IgE同种型时,任选地还包括重链恒定区CH4结构域;轻链是在N端到C端方向上由轻链可变区(VL)和轻链恒定区(CL)组成的多肽链;重链与重链之间、重链与轻链之间通过二硫键连接,形成“Y”字型结构。由于免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同,故其抗原性也不同。据此,可将本文“免疫球蛋白”分为五类,或称为免疫球蛋白的同种型,即IgM、IgD、IgG、IgA和IgE,其相应的重链分别为μ链、δ链、γ链、α链和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别,又可分为不同的亚类,如IgG可分为IgG1、IgG2、IgG3、IgG4,IgA可分为IgA1和IgA2。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。
本文“抗体”可以来源于任何动物,包括但不限于人和非人动物,所述非人动物可选自灵长类动物、哺乳动物、啮齿动物和脊椎动物,例如骆驼科动物、大羊驼、原鸵、羊驼、羊、兔、小鼠、大鼠或软骨鱼纲(例如鲨)。
本文“全长抗体”、“完好抗体”和“完整抗体”在本文中可互换使用,是指具有基本上与天然抗体结构相似的结构。
本文术语“人源化抗体”是指,经基因工程改造的非人源抗体,其氨基酸序列经修饰以提高与人源抗体的序列的同源性。通常而言,人源化抗体的全部或部分CDR区来自于非人源抗体(供体抗体),全部或部分的非CDR区(例如,可变区FR和/或恒定区)来自于人源免疫球蛋白(受体抗体)。人源化抗体通常保留或部分保留了供体抗体的预期性质,包括但不限于,抗原特异性、亲和性、反应性、提高免疫细胞活性的能力、增强免疫应答的能力等。
本文术语“可变区”是指抗体重链或轻链中牵涉使抗体结合抗原的区域,“重链可变区”与“VH”、“HCVR”可互换使用,“轻链可变区”与“VL”、“LCVR”可互换使用。天然抗体的重链和轻链的可变域(分别是VH和VL)一般具有相似的结构,每个域包含四个保守的框架区(FR)和三个高变区(HVR)。参见例如Kindt et al.,Kuby Immunology,6th ed.,W.H.Freeman and Co.,p.91(2007)。单个VH或VL域可足以赋予抗原结合特异性。
本文术语“互补决定区”与“CDR”可互换使用,通常指重链可变区(VH)或轻链可变区(VL)的高变区(HVR),该部位因在空间结构上可与抗原表位形成精密的互补,故又称为互补决定区,其中,重链可变区CDR可缩写为HCDR,轻链可变区CDR可缩写为LCDR。本文术语“构架区”或“FR区”可互换,是指抗体重链可变区或轻链可变区中除CDR以外的那些氨基酸残基。通常典型的抗体可变区由4个FR区和3个CDR区按以下顺序组成: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
对于CDR的进一步描述,参考Kabat等人,J.Biol.Chem.,252:6609-6616(1977);Kabat 等人,美国卫生与公共服务部,“Sequences of proteins of immunologicalinterest”(1991); Chothia等人,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.等人,J.Mol.Biol.,273:927-948 (1997);MacCallum等人,J.Mol.Biol.262:732-745(1996);Abhinandan和Martin,Mol.Immunol., 45:3832-3839(2008);Lefranc M.P.等人,Dev.Comp.Immunol.,27:55-77(2003);以及Honegger 和Plückthun,J.Mol.Biol.,309:657-670(2001)。本文“CDR”可由本领域公知的方式加以标注和定义,包括但不限于Kabat编号系统、Chothia编号系统或IMGT编号系统,使用的工具网站包括但不限于AbRSA网站(http://cao.labshare.cn/AbRSA/cdrs.php)、abYsis网站 (www.abysis.org/abysis/sequence_input/key_annotation/key_annotation.cgi)和IMGT网站 (http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi#results)。
示例性地,SEQ ID NO:1或3所示VH或VL序列的CDR如下表所示:其中Kabat和Chothia使用abYsis网站,IMGT使用IMGT网站。
表1抗VEGF抗体重链及轻链CDR区氨基酸序列表
本文术语“重链恒定区”是指抗体重链的羧基端部分,其不直接参与抗体与抗原的结合,但是表现出效应子功能,诸如与Fc受体的相互作用,其相对于抗体的可变结构域具有更保守的氨基酸序列。“重链恒定区”至少包含:CH1结构域,铰链区,CH2结构域,CH3结构域,或其变体或片段。“重链恒定区”包括“全长重链恒定区”和“重链恒定区片段”,前者具有基本上与天然抗体恒定区基本相似的结构,而后者仅包括“全长重链恒定区的一部分”。示例性地,典型的“全长抗体重链恒定区”由CH1结构域-铰链区-CH2结构域-CH3结构域组成;当抗体为IgE时,其还包括CH4结构域;当抗体为重链抗体时,则其不包括CH1结构域。示例性地,典型的“重链恒定区片段”可选自CH1、Fc或CH3结构域。
本文术语“轻链恒定区”是指抗体轻链的羧基端部分,其不直接参与抗体与抗原的结合,所述轻链恒定区可选自恒定κ结构域或恒定λ结构域。
本文术语“Fc”是指完整抗体经木瓜蛋白酶水解而成的抗体羧基端部分,典型地,其包含抗体的CH3和CH2结构域。Fc区包括例如天然序列Fc区、重组Fc区和变体Fc区。尽管免疫球蛋白重链的Fc区的边界可以略微变化,但是人IgG重链的Fc区通常被定义为从Cys226位置的氨基酸残基或从Pro230延伸至其羧基末端。Fc区的C末端赖氨酸(根据Kabat编号系统的残基447)可以例如在抗体的产生或纯化过程中,或通过对编码抗体重链的核酸重组工程化而除去,因此,Fc区可包括或不包括Lys447。
本文术语“同一性”可通过以下方式计算获得:为确定两个氨基酸序列或两个核酸序列的“同一性”百分数,将所述序列出于最佳比较目的比对(例如,可以为最佳比对而在第一和第二氨基酸序列或核酸序列之一或二者中引入空位或可以为比较目的而抛弃非同源序列)。随后比较在对应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置由第二序列中对应位置处的相同氨基酸残基或核苷酸占据时,则所述分子在这个位置处是相同的。
考虑到为最佳比对这两个序列而需要引入的空位的数目和每个空位的长度,两个序列之间的同一性百分数随所述序列共有的相同位置变化而变化。
本文术语“药物”是指用以预防、治疗及诊断疾病的物质,包括“药物组合物”或“药物组合”,示例性地,所述药物还包括细胞治疗剂,例如治疗用CAR-T细胞或CAR-NK细胞。“药物组合物”是指这样的制剂,其以允许包含在其中的活性成分的生物学活性有效的形式存在,并且不含有对施用所述药物组合物的受试者具有不可接受的毒性的另外的成分。本文所用的术语“组合”或“药物组合”是指非固定组合,其中活性剂和至少一种另外的活性剂可以同时或在时间间隔内单独施用,特别是在这些时间间隔允许组合配偶体显示合作(例如,协同)效应的情况下。术语“非固定组合”意指活性成分(例如,一种活性剂和至少一种另外的活性剂)均作为分开的实体同时或在没有特定时间限制的情况下顺序地施用于患者,其中这种施用提供了患者体内两种化合物的治疗有效水平。
本文术语“治疗”是指外科手术或药物处理(surgical or therapeutictreatment),其目的是预防、减缓(减少)治疗对象中不希望的生理变化或病变,如癌症或肿瘤的进展。有益的或所希望的临床结果包括但不限于症状的减轻、疾病程度减弱、疾病状态稳定(即,未恶化)、疾病进展的延迟或减慢、疾病状态的改善或缓和、以及缓解(无论是部分缓解或完全缓解),无论是可检测的或不可检测的。需要治疗的对象包括已患有病症或疾病的对象以及易于患上病症或疾病的对象或打算预防病症或疾病的对象。当提到减缓、减轻、减弱、缓和、缓解等术语时,其含义也包括消除、消失、不发生等情况。
本文术语“患者”或者“受试者”是指接受对如本发明所述的特定疾病或病症的治疗的生物体。“患者”或者“受试者”的实例包括接受疾病或病症治疗的哺乳动物,如人、灵长类动物(例如,猴)或非灵长类哺乳动物。
本文术语“有效施用量”指单独给予或与另一治疗剂组合给予细胞、组织或对象时能有效防止或缓解疾病病症或该疾病进展的治疗剂用量。“有效施用量”还指足以缓解症状,例如治疗、治愈、防止或缓解相关医学病症,或治疗、治愈、防止或缓解这些病症的速度增加的化合物或具有治疗作用的细胞(例如CAR-T细胞,CAR-NK细胞)的用量。
本文术语“单剂量剂型”是指每剂包含单次给予受试者或患者有效施用量的药物。示例性地,单剂量剂型中所含的药物量可通过有效剂量换算。例如,按mg/m2计算的有效施用量,可根据人的体表面积,将单次的有效施用量换算成为单剂量剂型中每剂药的药物含量。例如,按mg/kg计算的有效施用量,可根据人的体重,将单次的有效施用量换算成单剂量剂型中每剂药的药物含量。
本文术语“治疗剂”是指具有药物活性的成分,其不仅包括抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康,还可以进一步包含其他具有药物活性的成分,示例性地,其包括但不限于免疫检查点抑制剂,例如靶向PD-1或PD-L1的抗体。
本文术语“癌症”指向或描述哺乳动物中典型地以不受调节的细胞生长为特征的生理状况。此定义中包括良性和恶性癌症。本文术语“肿瘤”或“瘤”是指所有赘生性(neoplastic) 细胞生长和增殖,无论是恶性的还是良性的,及所有癌前(pre-cancerous)和癌性细胞和组织。术语“癌症”和“肿瘤”在本文中提到时并不互相排斥。
本文术语“患者”或者“受试者”是指接受对如本发明所述的特定疾病或病症的治疗的生物体。“患者”或者“受试者”的实例包括接受疾病或病症治疗的哺乳动物,如人、灵长类动物(例如,猴)或非灵长类哺乳动物。
本文术语“转移性结直肠腺癌”(Metastatic Colorectal Cancer,mCRC)是指转移或扩散到原结直肠癌肿块之外的癌症,常见的转移部位包括淋巴结,肝脏,肺和腹膜。目前针对mCRC 的治疗方法包括但不限于手术切除和化疗,示例性地,mCRC的一线化疗方案包括含奥沙利铂的双药化疗方案。在本文中,“转移性结直肠腺癌”属于结直肠癌的下位概念,属于结直肠癌的下位适应症。
本文术语“Q2W”是指每2周给药1次。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
本发明实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
下述实施例使用的本发明所述VEGF抗体(注射用)由山东先声生物制药有限公司生产和提供,于2-8℃保存,抗体序列信息如下所示。
重链可变区(SEQ ID NO:1):
EVQLVESGGGLVKPGGSLRLSCAASGFSFSNNDVMCWVRQAPGKGLEWIGCIMTTDV VTEYANWAKSRFTVSRDSAKNSVYLQMNSLRAEDTAVYFCARDSVGSPLMSFDLWGPGTL VTVSS;
重链恒定区(SEQ ID NO:2):
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK;
轻链可变区(SEQ ID NO:3):
DIQMTQSPSSLSASVGDRVTINCQASQSIYNNNELSWYQQKPGKPPKLLIYRASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCGGYKSYSNDGNGFGGGTKVEIK;
轻链恒定区(SEQ ID NO:4):
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
实施例1注射用VEGF抗体联合化疗药物四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康治疗转移性结直肠癌患者的临床试验
研究目的
评价不同剂量的注射用VEGF抗体联合四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康治疗转移性结直肠癌患者的安全性及耐受性和有效性。
研究设计
本试验为多中心、开放、VEGF抗体剂量递增设计,联合化疗药物四氢叶酸类化合物、 5-氟尿嘧啶和盐酸伊立替康,治疗晚期结直肠癌患者。
试验分两部分:第一阶段为剂量递增方案,VEGF抗体剂量设计为3mg/kg、4mg/kg、5mg/kg。联合化疗药物,每2周给药一次,剂量递增完成2次给药周期(两次VEGF抗体联合化疗方案,一般为28天,最长不超过56天)内发生的剂量限制性毒性(DLTs)作为依据,期间采集血样标本用于药物浓度测定,以及VEGF和抗体滴度的测定。治疗结束后评价临床获益的受试者可以按原给药剂量和频率继续用药,直至疾病进展或出现不能耐受的不良反应或撤回知情同意/失访或开始新的抗肿瘤治疗。第二阶段为扩展入组阶段,以进一步考察本品的安全性和有效性,每个剂量组将扩展至8-12例。如果每个剂量组的前3例受试者在第1、2 周期结束时均未观察到DLT或前6例受试者在第1、2周期结束时仅1例受试者观察到DLT,则允许继续入组至8-12例。根据前期3个剂量组的数据,VEGF抗体3-5mg/kg联合化疗的最佳肿瘤应答达到80%,蛋白尿的发生频率达70%左右,其中3级蛋白尿发生率达33%,且呈剂量依赖性趋势。VEGF抗体兼顾安全性和药物的有效性,在扩展入组阶段以剂量递减方式增加2mg/kg、1g/kg两个剂量组。每组连续入组8-12例受试者。扩展入组阶段各组用药方法及采血方法与该剂量组已入组受试者相同。
终止标准
试验过程中符合以下其中一条即终止剂量递增:
(1)观察到MTD;
(2)如5mg/kg未观察到MTD,则不再进行剂量递增。
试验人群
入选标准
受试者必须符合下列所有标准才能入选:
1)年龄:18~74岁;
2)组织学或细胞学证实无法手术切除的转移性结直肠腺癌且至少接受过一次含奥沙利铂一线的化疗方案失败者。
一线化疗方案失败定义为标准化疗过程中,或距离末次用药3个月内出现疾病进展。
如果辅助治疗包括含奥沙利铂的化疗方案,则如果辅助治疗期间或者完成后6个月内出现复发或转移,则认为该辅助治疗是针对进展期疾病的一线全身化疗失败。
3)至少有一个可测量的肿瘤病灶(根据RECIST 1.1);
4)距最近一次化疗时间至少4周,如果接受过抗肿瘤生物制品,则至少需经过4个半衰期的洗脱期;
5)以往治疗引起的毒副反应,则需要恢复至≤1级(NCI CTC4.0);
6)ECOG PS评分0-1;
7)预计生存时间3个月以上;
8)受试者必须有适当的器官功能,入组前符合下列所有实验室检查结果:
i)骨髓储备基本正常:ANC≥1.5×109/L,HB≥90g/L,PLT≥100×109/L;
ii)肝功能基本正常:ALT≤2.5×ULN,AST≤2.5×ULN,TBIL≤1.5×ULN(肝转移患者 ALT≤5×ULN,AST≤5×ULN);
iii)肾功能正常:肌酐≤1×ULN,如(1×ULN≤肌酐≤1.5×ULN,则根据Cockroft-Gault公式计算,肌酐清除率≥60mL/min);
iv)凝血功能基本正常:INR≤1.5×ULN,APTT≤1.5×ULN;
9)有生育能力的合格患者(男性和女性)必须同意在试验期间和末次给药后至少12周内使用可靠的避孕方法(激素或屏障法或禁欲);育龄期的女性患者在入选前7天内的血妊娠试验必须为阴性;
10)受试者须在试验前对本研究知情同意,并自愿签署书面的知情同意书;
11)受试者能够与研究者进行良好的沟通并能够依照研究规定完成研究。
排除标准:
符合一条或多条下列标准的受试者将被排除:
1)丙肝病毒抗体(HCV)、梅毒螺旋体抗体(TP)、艾滋病毒(HIV)抗体任何一项检测为阳性且处于感染性活动期的患者;
2)既往接受过抗VEGF蛋白类药物治疗者;
3)既往接受过伊立替康治疗者;
4)已知有二氢嘧啶脱氢酶缺乏症;
5)已知患者有酒精或药物依赖;
6)在入组前4周内接受过其它临床试验的药物治疗;
7)活动性或慢性乙肝病毒感染,且HBV DNA>1.0*103IU/mL;
8)严重感染需要用静脉输注抗生素治疗;
9)有症状的脑转移患者;
10)有蛋白尿的患者(筛选期检查中发现尿蛋白≥1+;如尿蛋白为1+,24小时内复测正常的除外);
11)入组前6个月内患有腹腔瘘,胃肠穿孔,腹腔脓肿;
12)患有肠梗阻、炎症性肠病或其他以慢性腹泻为主要表现的肠道疾病者;
13)严重的未愈合的伤口、溃疡或骨折;
14)入组前4周内接受过大型外科手术(不包括穿刺活检)或出现过显著外伤;
15)入组前3个月内有活动性出血;
16)有出血倾向或有凝血障碍;
17)有动脉或静脉栓塞病史;
18)入组前6个月内出现过心肌梗死或脑卒中;
19)不稳定性心绞痛,充血性心力衰竭或,纽约心脏病学会(NYHA)Ⅱ级心衰,未能控制的心律失常;单药不可控制的高血压(年龄<60岁者,收缩压≥140mmHg和/或舒张压≥90 mmHg,年龄≥60岁者,收缩压≥150mmHg和/或舒张压≥90mmHg);
20)预计试验期间及末次给药后1个月内需要手术治疗;
21)研究者认为受试者存在任何临床或实验室检查异常而不适合参加本临床研究的;
22)妊娠期或哺乳期女性;
23)已知对方案使用的治疗药物或辅料过敏;
24)受试者可能因为其他原因而不能完成本研究。
给药方案
药物:
注射用VEGF抗体:由山东先声生物制药有限公司提供。
盐酸伊立替康、5-氟尿嘧啶、亚叶酸钙/左旋亚叶酸钙为市售药品。
给药剂量和方法:
VEGF抗体:1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg,静脉滴注。
化疗药物:
1)盐酸伊立替康:180mg/m2,静脉输注85-90分钟,后接,
2)亚叶酸钙:400mg/m2,静脉输注2小时(±5分钟),或左旋亚叶酸钙:200mg/m2等效于亚叶酸钙400mg/m2,后接,
3)5-FU:前2-4分钟静脉推注400mg/m2,然后1200mg/m2/d×2天持续静脉输注(总量2400mg/m2,输注46~48小时)。
第1给药周期:第1天先用化疗方案;第3天再给予相应剂量VEGF抗体;
第2给药周期及以后:第1天先使用相应剂量VEGF抗体,接着使用化疗方案。
每2周为一个给药周期。每个给药周期允许前后2天的时间窗,发生未恢复的毒性反应时,允许最多2周的治疗推迟。
治疗周期:治疗直至疾病进展或出现不可耐受的不良反应或满足其他退出标准。
评价指标
疗效评价终点:客观缓解率(ORR)、疾病控制率(DCR)、无进展生存期(PFS)及总生存期(OS)。
安全性指标:通过生命体征检查指标、实验室检查指标以及不良事件观察等评价安全性,不良事件从受试者首次用药起至末次用药后28天。不良事件采用NCI-CTC 4.0版进行评价。
统计方法
安全性分析
在安全性数据集中进行。所有的临床和/或统计学观察的安全性指标进行安全性和耐受性的评估。采用描述性统计对不良事件,实验室检查指标进行分析,计算不良反应的数量和发生率。每个剂量组,DLT将按血液学和非血液学进行分类总结,并用MedDRA医学术语进行描述。临床观察和实验室检查结果等不良事件将在频次表中列出,并用MedDRA医学术语按照器官系统进行分类总结。主要列出的统计学参数包括生命体征,心电图,QTc和实验室检查结果。全部不良事件将以表格形式列出,记录不良事件名称,发生时间,结束时间,严重程度,与试验相关相关性,采取措施,临床结局等。
有效性分析
客观缓解率(ORR),疾病控制率(DCR):剂量递增试验和扩展试验采用描述性统计,计算其例数和百分比,同时计算百分比的95%置信区间(Clopper-Pearson Interval)。
无进展生存期(PFS),总生存期(OS):剂量递增试验和扩展试验采用描述性统计,计算中位数及95%置信区间(“Brookmeyer and Crowley”法),采用Kaplan-Meier法估计生存曲线,并绘制生存曲线图。
肿瘤大小变化:对可测量肿瘤最长径总和(SLD)较基线变化的百分比进行描述性统计。并将每例患者SLD较筛选期减少的最大百分比做瀑布图。另外,还将列出每例患者用药后每次SLD较基线的变化百分比。
受试者描述
共入组56例受试者,所有受试者病理诊断均为腺癌,所有受试者均有转移病灶,且以肝脏转移为主(35例/62.50%),其次为淋巴结转移(27例/48.21%)。
有效性结果
入组56例受试者。其中1mg/kg组7例,2mg/kg组14例,3mg/kg组和4mg/kg组各12例,5mg/kg组11例。
根据RECIST1.1标准确认过的总体客观缓解率(ORR)为33.96%(95%CI 21.52%,48.27%),1mg/kg组ORR为28.57%(95%CI 3.67%,70.96%),2mg/kg组ORR为28.57%(95%CI 8.39%,58.10%),3mg/kg组33.33%(95%CI 9.92%,65.11%),4mg/kg组和5mg/kg组分别为27.27%(95%CI 6.02%,60.97%)和55.56%(95%CI 21.20%,86.30%)。共51例受试者临床获益,疾病控制率(DCR)为96.23%(95%CI 87.02%,99.54%),除5mg/kg组DCR为77.78%(95%CI 39.99%,97.19%)外,其余各个剂量组DCR均为100%。18例(33.96%) 受试者部分缓解,无完全缓解受试者。
未确证的总体客观缓解率(ORR)为54.72%(95%CI 40.45%,68.44%),51例受试者临床获益,疾病控制率(DCR)为96.23%(95%CI 87.02%,99.54%),无完全缓解受试者。29 例(54.72%)受试者部分缓解,其中1mg/kg组3例(42.86%),2mg/kg组6例(42.86%),3mg/kg组7例(58.33%),4mg/kg组6例(54.55%),5mg/kg组7例(77.78%)。22例受试者(41.51%)最佳疗效为疾病稳定(SD)。2例受试者(22.22%)最佳疗效为疾病进展(PD),为5mg/kg剂量组。
共随访到28例(52.83%)PFS事件,中位PFS为7.15个月。1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg,中位PFS分别为未达到、5.18个月、7.15个月、7.44个月、7.31个月。
共随访到29例(54.72%)OS事件,中位OS为15.41个月。1mg/kg中位OS未达到,2mg/kg剂量组中位OS为14.26个月,3mg/kg剂量组中位OS为16.10个月,4mg/kg中位OS 为14.95个月,5mg/kg剂量组为15.41个月。
安全性结果
本研究共出现2例DLT事件,分别为2mg/kg剂量组的乏力和4mg/kg剂量组的蛋白尿,转归均恢复或改善。VEGF抗体推荐给药剂量为2mg/kg Q2W。
所有56例受试者均发生至少一次给药后不良事件,绝大多数转归为恢复或改善,恢复或改善的比例分别为71.26%和10.54%。发生率最高的用药后不良事件为白细胞计数降低 (73.21%),其次为中性粒细胞计数降低(69.64%)和腹泻(69.64%)、呕吐(58.93%)、乏力(55.36%)。
所有受试者均发生与VEGF抗体相关的不良事件,发生率最高的用药后不良反应为白细胞计数降低(60.71%),其次为中性粒细胞降低(53.57%)、蛋白尿(46.43%)和乏力(42.86%)。
50例受试者(89.29%)发生特别关注的不良事件,发生率最高的用药后特别关注不良事件为蛋白尿(46.43%),其次为血压升高(35.71%)、鼻衄(30.36%)和尿蛋白检出(26.79%)。
发生率最高的3级及以上AE为中性粒细胞计数降低(44.64%),其次为白细胞计数降低(21.43%)和蛋白尿(17.86%)。
共发生1例次导致死亡的严重不良事件,为3mg/kg剂量组,由于受试者为外院突然死亡,死亡原因无法确定。研究者认为此严重不良事件与VEGF抗体可能无关,与化疗药物可能无关。18例受试者(32.14%)发生25例次严重不良事件,其中10例次严重不良事件被认为与 VEGF抗体相关,发生率最高的SAE为肠梗阻(7.14%)。
23例受试者发生37例次导致VEGF抗体停药的不良事件,发生率最高的为蛋白尿(12.50%),其次为尿蛋白检出(7.14%)和血小板计数降低(7.14%)。所有剂量组以4mg/kg剂量组发生率最高,共7例受试者(58.33%)发生12例次。
未发生非预期不良事件。
结论
注射用VEGF抗体联合化疗药物四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康治疗转移性结直肠癌患者总体安全性和耐受性良好,未发生非预期不良事件;在治疗转移性结直肠癌上有一定疗效,MTD未建立,综合考虑各剂量组的整体安全性及长期用药耐受性推荐VEGF 抗体2mg/kg Q2W联合四氢叶酸、5-氟尿嘧啶和盐酸伊立替康的标签剂量为治疗转移性结直肠癌的推荐剂量。
序列表
<110> 江苏先声药业有限公司
<120> 抗人VEGF抗体和化疗联用在制备治疗结直肠癌药物中的用途
<130> SR0441-CN
<141> 2022-06-30
<150> 2021107430763
<151> 2021-06-30
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Claims (10)
1.包括抗人VEGF抗体、四氢叶酸类化合物、5-氟尿嘧啶和盐酸伊立替康的治疗剂在制备用于治疗结直肠癌患者的药物中的用途,其特征在于,所述抗体包括重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其中:
所述HCDR1选自SEQ ID NO:5-7任一项所示序列;
所述HCDR2选自SEQ ID NO:8-10任一项所示序列;
所述HCDR3选自SEQ ID NO:11-12任一项所示序列;
所述LCDR1选自SEQ ID NO:13-14任一项所示序列;
所述LCDR2选自SEQ ID NO:15-16任一项所示序列;和,
所述LCDR3选自SEQ ID NO:17所示序列。
2.根据权利要求1所述的用途,其特征在于,所述重链可变区具有如SEQ ID NO:1所示序列,或与SEQ ID NO:1相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链可变区具有如SEQ ID NO:3所示的序列,或与SEQ ID NO:3相比具有至少95%、96%、97%、98%或99%同一性的序列。
3.根据权利要求1~2任一项所述的用途,其特征在于,所述抗体包括重链恒定区和轻链恒定区,所述重链恒定区具有如SEQ ID NO:2所示序列,或与SEQ ID NO:2相比具有至少95%、96%、97%、98%或99%同一性的序列;
所述轻链恒定区具有如SEQ ID NO:4所示的序列,或与SEQ ID NO:4相比具有至少95%、96%、97%、98%或99%同一性的序列。
4.根据权利要求1~3任一项所述的用途,其特征在于,所述患者为转移性结直肠癌患者;优选地,所述患者为无法手术切除且至少接受过一次含奥沙利铂一线化疗方案失败的转移性结直肠腺癌患者。
5.根据权利要求1~4任一项所述的用途,其特征在于,所述患者为肝转移或淋巴结转移患者。
6.根据权利要求1~5任一项所述的用途,其特征在于,所述四氢叶酸类化合物为亚叶酸钙或左旋亚叶酸钙;优选的,所述亚叶酸钙的有效施用量为400mg/m2,所述左旋亚叶酸钙的有效施用量为200mg/m2。
7.根据权利要求1~6任一项所述的用途,其特征在于,所述5-氟尿嘧啶的有效施用量为2800mg/m2。
8.根据权利要求1~7任一项所述的用途,其特征在于,所述盐酸伊立替康的有效施用量为180mg/m2。
9.根据权利要求1~8任一项所述的用途,其特征在于,所述抗人VEGF抗体的有效施用量为1~5mg/kg,优选为1mg/kg、2mg/kg、3mg/kg、4mg/kg或5mg/kg。
10.根据权利要求1~9所述的用途,其特征在于,所述抗人VEGF抗体的剂型为单剂量剂型,每剂含有能够给予患者有效施用量的抗体量,优选地,所述抗体量为50~500mg,例如50mg、80mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg或500mg。
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