CN117500524A - 三重组合疗法 - Google Patents
三重组合疗法 Download PDFInfo
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- CN117500524A CN117500524A CN202280042999.9A CN202280042999A CN117500524A CN 117500524 A CN117500524 A CN 117500524A CN 202280042999 A CN202280042999 A CN 202280042999A CN 117500524 A CN117500524 A CN 117500524A
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Abstract
描述了LAG‑3蛋白或其衍生物作为用于治疗癌症的组合疗法的一部分的用途。具体地,描述了(a)能够结合MHC II类分子的LAG‑3蛋白或其衍生物、(b)程序性细胞死亡蛋白‑1(PD‑1)途径抑制剂和(c)化疗剂在用于预防、治疗或改善受试者中的癌症的用途。还描述了组合制剂和药物组合物,其包含:(a)能够结合MHC II类分子的LAG‑3蛋白或其衍生物;(b)程序性细胞死亡蛋白‑1(PD‑1)途径抑制剂;和(c)化疗剂。还描述了该组合制剂和组合物作为药物的用途,特别是用于预防、治疗或改善癌症,以及用于该预防、治疗或改善癌症的方法。
Description
技术领域
本发明涉及LAG-3蛋白或其衍生物作为用于治疗癌症的组合疗法的一部分的用途。
背景技术
在过去的十年中,PD-1和CTLA-4免疫检查点抑制剂,诸如OPDIVO(纳武单抗)、KEYTRUDA(帕博利珠单抗)和YERVOY(伊匹单抗)已经成为许多形式的癌症的护理标准疗法,然而不幸的是,许多患者仍然未能对这些现代药物作出反应。在一些情况下,这些新药与化学疗法(chemo-IO)组合以改善应答率,尽管这可导致不期望的毒性作用。在其他情况下,使用免疫检查点抑制剂(IO-IO)的组合,但这也可导致不期望的毒性作用。
为了改善患者结局,已经开展了大量工作来研究其他免疫检查点,诸如LAG-3、TIM-3、VISTA、CD47、IDO和TIGIT。特别是LAG-3已经作为有前途的检查点出现,并且若干公司正在开发针对该检查点的新抑制剂。与目前批准的PD-1和CTLA-4抑制剂一样,LAG-3抑制剂的目的是阻断免疫系统的减量调节,即“重启”身体的免疫过程。还开展了大量工作来探索PD-1和CTLA-4免疫检查点抑制剂与其他批准的或实验性疗法的组合。
所研究的另一种类型的主动免疫疗法是抗原递呈细胞(APC)激活因子。APC激活因子经由MHC II分子结合抗原递呈细胞,诸如树突状细胞、单核细胞和巨噬细胞。这激活了APC,使得它们成为专职性抗原递呈细胞,从而将抗原递呈给适应性免疫系统。这导致CD4+(辅助)细胞和CD8+(细胞毒性)T细胞的激活和增殖。因此,APC激活因子的目的是“加强”身体的免疫系统。
Eftilagimod alpha(IMP321或efti),LAG-3的可溶性二聚重组形式,是临床开发中的第一类APC激活因子。通过MHC II类分子刺激树突状细胞和其他APC,IMP321诱导强大的抗癌T细胞应答。WO 2009/044273中描述了IMP321,其还描述了IMP321单独和与化疗剂组合用于治疗癌症的用途。此外,WO 2016/110593描述了IMP321与PD-1途径抑制剂组合用于治疗癌症和感染性疾病的用途。
本领域仍然需要改进的癌症疗法和治疗方案,从而为患者带来更好的结局。这对于用目前批准的药物进行治疗的患者的预后差和/或目前药物耐受性差的癌症尤其如此。
发明内容
在一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂,用于预防、治疗或改善受试者的癌症。
在另一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂在制备用于预防、治疗或改善受试者的癌症的药物中的用途。
在另一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂用于预防、治疗或改善受试者的癌症的用途。
在另一个实施方案中,本发明提供了一种预防、治疗或改善受试者的癌症的方法,该方法包括向需要此类预防、治疗或改善的受试者施用(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂。
在另一个实施方案中,本发明涉及一种能够结合MHC II类分子的LAG-3蛋白或其衍生物,用于预防、治疗或改善受试者的癌症,其中该LAG-3蛋白或其衍生物将与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在一个实施方案中,本发明涉及能够结合MHC II类分子的LAG-3蛋白或其衍生物在制备用于预防、治疗或改善受试者的癌症的药物中的用途,其中该LAG-3蛋白或其衍生物将与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在另一个实施方案中,本发明提供了一种预防、治疗或改善受试者的癌症的方法,该方法包括向需要此类预防、治疗或改善的受试者施用能够结合MHC II类分子的LAG-3蛋白或其衍生物,其中该LAG-3蛋白或其衍生物与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在另一个实施方案中,本发明提供了一种组合制剂,该组合制剂包含:
(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物,
(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂,和
(c)化疗剂。
在另一个实施方案中,本发明提供了一种药物组合物,该药物组合物包含:
(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物,
(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂,
(c)化疗剂,和
(d)药学上可接受的载体、赋形剂或稀释剂。
附图说明
图1示出了成熟人LAG-3蛋白的氨基酸序列。四个细胞外Ig超家族结构域位于以下氨基酸残基处:1-149(D1);150-239(D2);240-330(D3);和331-412(D4)。人LAG-3蛋白的D1结构域的环外结构的氨基酸序列以粗体下划线显示。
图2示出了通过计算机断层摄影术(CT)测量的NSCLC患者的靶肿瘤病灶的收缩(A:2021年8月和B:2022年5月)。病灶从直径22.62mm收缩至“可评估但不可测量”。病灶用虚线圆示出。
图3示出通过计算机断层摄影术(CT)测量的NSCLC患者的另一个靶肿瘤病灶的收缩(A:2021年8月和B:2022年5月)。病灶从35.92mm收缩至25.70mm(直径),并且用虚线圆示出。
具体实施方式
三重组合疗法
在一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂,用于预防、治疗或改善受试者的癌症。
在另一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂在制备用于预防、治疗或改善受试者的癌症的药物中的用途。
在另一个实施方案中,本发明涉及(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂用于预防、治疗或改善受试者的癌症的用途。
在另一个实施方案中,本发明提供了一种预防、治疗或改善受试者的癌症的方法,该方法包括向需要此类预防、治疗或改善的受试者施用(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂。
在另一个实施方案中,本发明涉及一种能够结合MHC II类分子的LAG-3蛋白或其衍生物,用于预防、治疗或改善受试者的癌症,其中该LAG-3蛋白或其衍生物将与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在一个实施方案中,本发明涉及能够结合MHC II类分子的LAG-3蛋白或其衍生物在制备用于预防、治疗或改善受试者的癌症的药物中的用途,其中该LAG-3蛋白或其衍生物将与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在另一个实施方案中,本发明提供了一种预防、治疗或改善受试者的癌症的方法,该方法包括向需要此类预防、治疗或改善的受试者施用能够结合MHC II类分子的LAG-3蛋白或其衍生物,其中该LAG-3蛋白或其衍生物与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
在另一个实施方案中,本发明提供了一种组合制剂,该组合制剂包含:
(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物,
(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂,和
(c)化疗剂。
在另一个实施方案中,本发明提供了一种药物组合物,该药物组合物包含:
(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物,
(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂,
(c)化疗剂,和
(d)药学上可接受的载体、赋形剂或稀释剂。
可根据本发明治疗的示例性癌症包括但不限于乳腺癌、皮肤癌、肺癌(例如,NSCLC或SCLC)、卵巢癌、肾癌(例如,肾细胞癌)、结肠癌、结肠直肠癌、胃癌、食管癌、胰腺癌、膀胱癌、尿路上皮癌、肝癌、黑素瘤(例如,转移性恶性黑素瘤)、前列腺癌(例如,激素难治性前列腺癌)、头颈部癌(例如,头颈部鳞状细胞癌)、宫颈癌、子宫内膜癌、子宫癌、甲状腺癌、成胶质细胞瘤、胶质瘤、白血病、淋巴瘤(例如,B细胞淋巴瘤或霍奇金淋巴瘤)、肾上腺癌、艾滋病相关癌、腺泡状软组织肉瘤、星形细胞肿瘤、骨癌、脑和脊髓癌、转移性脑肿瘤、颈动脉体瘤、软骨肉瘤、脊索瘤、皮肤良性纤维组织细胞瘤、促结缔组织增生性小圆细胞瘤、室管膜瘤、尤因瘤、骨外黏液样软骨肉瘤、骨纤维发育不全、骨纤维性结构不良、胆囊或胆管癌、妊娠滋养细胞疾病、生殖细胞瘤、血液恶性肿瘤、肝细胞癌、胰岛细胞瘤、卡波西氏肉瘤、肾脏癌、脂肪瘤/良性脂肪瘤性肿瘤、脂肪肉瘤/恶性脂肪瘤性肿瘤、髓母细胞瘤、脑膜瘤、梅克尔(Merkel)细胞癌、多发性内分泌瘤病、多发性骨髓瘤、骨髓增生异常综合征、成神经细胞瘤、神经内分泌肿瘤、乳头状甲状腺癌、甲状旁腺肿瘤、儿科癌症、周围神经鞘膜瘤、嗜铬细胞瘤、垂体瘤、前列腺癌、脉络膜黑素瘤、罕见血液系统异常、横纹肌样瘤、横纹肌肉瘤、肉瘤、软组织肉瘤、鳞状细胞癌、滑膜肉瘤、间皮瘤、皮肤鳞状细胞癌、睾丸癌、胸腺癌、胸腺瘤和甲状腺转移癌。
可根据本发明治疗的示例性癌症包括但不限于直肠癌、肛门癌、小肠癌、胃肠道间质瘤。
在一个实施方案中,癌症是肺癌。在另一个实施方案中,肺癌是非小细胞性肺癌(NSCLC)。在另一个实施方案中,肺癌是小细胞性肺癌(SCLC)。
NSCLC包括:(a)非鳞状细胞癌(腺癌、大细胞癌和未分化癌)、(b)鳞状细胞癌和(c)未另行说明的非小细胞癌。
在一个实施方案中,NSCLC是非鳞状NSCLC。在另一个实施方案中,NSCLC是鳞状NSCLC。
在一个实施方案中,癌症是胃肠道癌。合适地,胃肠道癌是肛门癌、胆管癌、结肠癌、直肠癌、食管癌、胆囊癌、胃肠道间质瘤、肝癌、胰腺癌、小肠癌或胃癌。
在一个实施方案中,癌症是头颈部癌。在另一个实施方案中,头颈部癌是头颈部鳞状细胞癌(HNSCC)。
在一个实施方案中,癌症是乳腺癌。合适地,乳腺癌是乳腺腺癌。
根据本发明的实施方案,癌症可能已经进展为转移性疾病。
在一个具体实施方案中,癌症是转移性NSCLC。在一个实施方案中,转移性NSCLC是非鳞状NSCLC。在另一个实施方案中,转移性NSCLC是鳞状NSCLC。
合适地,用三重组合疗法作为第1线疗法治疗转移性NSCLC患者。另选地,用三重组合疗法作为第2线疗法治疗转移性NSCLC患者。
PD-L1表达状态是对PD-1途径抑制剂(包括在NSCLC和HNSCC中)应答的众所周知的预测性标志物。例如,PD-L1表达通常在NSCLC的三组中报道:<1%、1%-49%和≥50%(肿瘤比例评分或TPS),并且在HNSCC中:<1、1-19和≥20(组合正评分或CPS)。具有高PD-L1状态的患者通常对PD-1途径抑制剂更具应答性,而具有低PD-L1状态的患者总体上应答性显著较低。
在一个实施方案中,受试者患有NSCLC和低PD-L1表达状态(例如,<50%、1%-49%或<1%),并且如果不是对于本发明的三重组合疗法,则将不太可能对使用PD-1途径抑制剂的疗法作出应答。
在一个实施方案中,受试者患有NSCLC并且在不考虑其PD-L1表达状态的情况下进行治疗。
在另一个实施方案中,受试者患有NSCLC并且PD-L1表达状态<50%。
在另一个实施方案中,受试者患有NSCLC并且PD-L1表达状态为1%-49%。
在另一个实施方案中,受试者患有NSCLC并且PD-L1表达状态<1%。
在另一个实施方案中,受试者患有NSCLC并且PD-L1表达状态≥1%。
在一个实施方案中,受试者患有NSCLC并且PD-L1表达状态≥50%。
合适地,NSCLC是转移性NSCLC。
LAG-3蛋白及衍生物
根据本发明的实施方案,LAG-3蛋白可以是分离的天然或重组LAG-3蛋白。LAG-3蛋白可包括来自任何合适物种的LAG-3蛋白的氨基酸序列,诸如灵长类或鼠LAG-3蛋白,但优选地人LAG-3蛋白。人和鼠LAG-3蛋白的氨基酸序列在Huard等人(Proc.Natl.Acad.Sci.USA,11:5744-5749,1997)的图1中提供。人LAG-3蛋白的序列在本文的图1中重复(SEQ ID NO:1)。人LAG-3的四个细胞外Ig超家族结构域(D1、D2、D3和D4)的氨基酸序列也在Huard等人的图1中鉴定,这些结构域位于以下氨基酸残基处:1-149(D1);150-239(D2);240-330(D3);和331-412(D4)。
LAG-3蛋白的衍生物包含能够结合MHC II类分子的LAG-3蛋白的可溶性片段、变体或突变体。已知LAG-3蛋白的几种衍生物能够结合MHC II类分子。此类衍生物的许多示例描述于Huard等人(Proc.Natl.Acad.Sci.USA,11:5744-5749,1997)的图1中提供。该文献描述了LAG-3蛋白上MHC II类结合位点的表征。描述了制备LAG-3突变体的方法,以及用于确定LAG-3突变体结合II类阳性Daudi细胞的能力的定量细胞粘附测定。确定了LAG-3的几种不同突变体与MHC II类分子的结合。一些突变能够减少II类结合,而其他突变增加了LAG-3对II类分子的亲和力。LAG-3与MHC II类蛋白结合所必需的许多残基聚集在LAG-3D1结构域中的大的30个氨基酸环外结构的碱基处。人LAG-3蛋白的D1结构域的环外结构的氨基酸序列是GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY(SEQ ID NO:2)。人LAG-3蛋白的D1结构域的环外结构的氨基酸序列在图1中以粗体下划线显示。
在本发明的一个实施方案中,LAG-3蛋白的衍生物包括人LAG-3D1结构域的30个氨基酸环外序列,或带有一个或多个氨基酸取代(例如,保守氨基酸取代)的此类序列的变体。该变体可包括与人LAG-3D1结构域的30个氨基酸环外序列具有至少70%、80%、90%或95%氨基酸同一性的氨基酸序列。
LAG-3蛋白的衍生物可包括LAG-3蛋白(优选地人LAG-3蛋白)的结构域D1、结构域D1和任选地D2或结构域D1和D2的氨基酸序列。
LAG-3蛋白的衍生物可包括与LAG-3蛋白(优选地人LAG-3蛋白)的结构域D1、结构域D1和任选地D2或结构域D1和D2具有至少70%、80%、90%或95%氨基酸同一性的氨基酸序列。
LAG-3蛋白的衍生物可包括LAG-3蛋白(优选地人LAG-3蛋白)的结构域D1、D2和D3、结构域D1、D2和D3和任选地D4或结构域D1、D2、D3和D4的氨基酸序列。
LAG-3蛋白的衍生物可包括与LAG-3蛋白(优选地人LAG-3蛋白)的结构域D1、D2和D3、结构域D1、D2、D3和任选地D4或结构域D1、D2、D3和D4具有至少70%、80%、90%或95%氨基酸同一性的氨基酸序列。
氨基酸序列之间的序列同一性可以通过比较序列的对比来确定。当比较序列中的等效位置被相同氨基酸占据时,则分子在该位置处是相同的。将对比评分为同一性百分比是在比较序列共享的位置处的相同氨基酸数量的函数。当比较序列时,最佳对比可能需要将空位引入到这些序列中的一个或多个序列中以考虑序列中可能的插入和缺失。序列比较方法可以采用空位罚分,使得对于正在比较的序列中的相同数量的相同分子,具有尽可能少的空位的序列对比(反映两个比较序列之间的较高相关性)将实现比具有许多空位的序列对比更高的得分。最大百分比同一性的计算涉及在考虑空位罚分的情况下产生最佳对比。
用于执行序列比较的合适计算机程序在商业和公共领域中广泛可用。示例包括MatGat(Campanella等人,2003,BMC Bioinformatics 4:29;可从http://bitincka.com/ledion/matgat获得的程序)、Gap(Needleman和Wunsch,1970,J.Mol.Biol.48:443-453),FASTA(Altschul等人,1990,J.Mol.Biol.215:403-410;可从http://www.ebi.ac.uk/fasta获得的程序)、Clustal W 2.0和X 2.0(Larkin等人,2007,Bioinformatics 23:2947-2948;可从http://www.ebi.ac.uk/tools/clustalw2获得的程序)和EMBOSS成对比对算法(Needleman和Wunsch,1970,同上;Kruskal,1983,在:时间扭曲,字符串编辑和大分子:序列比较的理论与实践(Time warps,string edits and macromolecules:the theory andpractice of sequence comparison)Sankoff&Kruskal(编辑),页码1-44,AddisonWesley;可从http://www.ebi.ac.uk/tools/emboss/align获得的程序)。所有程序可使用默认参数运行。
例如,可以使用EMBOSS逐对对比算法的“needle”方法进行序列比较,该方法确定两个序列在考虑其整个长度时的最佳对比(包含空位)并提供百分比同一性得分。氨基酸序列比较的默认参数(“蛋白质分子”选项)可以为:空位延伸罚分:0.5、空位开放罚分:10.0、Matrix:Blosum62。
可以在参考序列的全长上执行序列比较。
LAG-3蛋白的衍生物可以与免疫球蛋白Fc氨基酸序列,优选地人IgG1 Fc氨基酸序列融合,任选地通过接头氨基酸序列。
LAG-3蛋白的衍生物结合MHC II类分子的能力可使用定量细胞粘附测定来确定,如Huard等人(Proc.Natl.Acad.Sci.USA,11:5744-5749,1997)的图1中提供。LAG-3蛋白的衍生物对MHC II类分子的亲和力可以是人LAG-3蛋白对MHC II类分子的亲和力的至少20%、30%、40%、50%、60%、70%、80%、90%或100%。
优选地,LAG-3蛋白的衍生物对MHC II类分子的亲和力是人LAG-3蛋白对MHC II类分子的亲和力的至少50%、60%、70%、80%、90%、95%、99%或100%。
能够结合MHC II类分子的LAG-3蛋白的合适衍生物的示例包含包括以下的衍生物:
人LAG-3序列的氨基酸残基23至448;
LAG-3的结构域D1和D2的氨基酸序列;
LAG-3的结构域D1和D2的氨基酸序列,在以下位置中的一个或多个位置处具有氨基酸取代:位置30,其中ASP被ALA取代;位置56,其中HIS被ALA取代;位置73,其中ARG被GLU取代;位置75,其中ARG被ALA或GLU取代;位置76,其中ARG被GLU取代;或位置103,其中ARG被ALA取代;和
重组可溶性人LAG-3Ig融合蛋白(IMP321)-在中国仓鼠卵巢细胞中产生的160-kDa二聚体,这些细胞用编码与人IgG1 Fc融合的hLAG-3胞外结构域的质粒转染。IMP321的序列在US 2011/0008331的SEQ ID NO:17中给出。
在一个实施方案中,受试者是哺乳动物,优选地人。
根据本发明,以治疗有效量施用LAG-3蛋白或其衍生物。“治疗有效量”是指在施用后足以具有治疗效果的活性成分的量。活性成分的有效量可随例如所治疗的特定一种疾病或多种疾病、疾病的严重程度、治疗的持续时间和患者的特征(例如,性别、年龄、身高和体重)而变化。
在一个实施方案中,LAG-3蛋白或其衍生物以摩尔当量为约0.1mg至约60mg、约6mg至约60mg、约10mg至约50mg、约20mg至约40mg、约25g至约35mg或约30mg的LAG-3衍生物LAG-3Ig融合蛋白IMP321的剂量施用。
在另一个实施方案中,LAG-3蛋白或其衍生物以摩尔当量为约25mg、约26mg、约27mg、约28mg、约29mg、约30mg、约31mg、约32mg、约33mg、约34mg或约35mg的LAG-3衍生物LAG-3Ig融合蛋白IMP321的剂量施用。
合适地,LAG-3蛋白或其衍生物以摩尔当量为约30mg的LAG-3衍生物LAG-3Ig融合蛋白IMP321的剂量施用。
在又一个实施方案中,LAG-3蛋白或其衍生物以摩尔当量为约25mg至约60mg,诸如约25mg、约30mg、约35mg、约40mg、约45mg、约50mg、约55mg或约60mg的LAG-3衍生物LAG-3Ig融合蛋白IMP321的剂量施用。
在一个实施方案中,LAG-3蛋白或其衍生物是IMP321,并且以约0.1mg至约60mg、约6mg至约60mg、约10mg至约50mg、约20mg至约40mg、约25mg至约35mg或约30mg的剂量施用。
在另一个实施方案中,IMP321以约25mg、约26mg、约27mg、约28mg、约29mg、约30mg、约31mg、约32mg、约33mg、约34mg或约35mg的剂量施用。
合适地,IMP321以约30mg的剂量施用。
在其他实施方案中,IMP321以约25mg至约60mg,诸如约25mg、约30mg、约35mg、约40mg、约45mg、约50mg、约55mg或约60mg的剂量施用。
迄今为止,基于在癌症患者中获得的药代动力学数据的结果,IMP321每次皮下(s.c.)注射6mg-30mg的剂量已被证明是安全的并且提供可接受的全身暴露。在s.c.注射后至少24小时,注射IMP321剂量超过6mg的患者的IMP321的血液浓度高于1ng/ml。迄今为止没有观察到剂量限制性毒性。
在一个实施方案中,将LAG-3蛋白或其衍生物约每周一次施用于受试者。在另一个实施方案中,将LAG-3蛋白或其衍生物约每两周一次施用于受试者。在又一个实施方案中,将LAG-3蛋白或其衍生物约每三周一次施用于受试者。在另一个实施方案中,将LAG-3蛋白或其衍生物约每四周一次施用于受试者。在另一个实施方案中,将LAG-3蛋白或其衍生物约每月一次施用于受试者。如本领域的技术人员将会理解的,精确的治疗方案可根据所治疗的特定癌症和患者的特征而变化和调整。
在一个实施方案中,LAG-3蛋白或其衍生物在没有添加到药物组合物、组合制剂或药物中的任何额外抗原的情况下存在。
PD-1途径抑制剂
PD-1途径抑制剂是抑制PD-1与PD-L1和/或PD-L2结合的药剂。具体地,药剂可抑制人PD-1与人PD-L1和/或人PD-L2的结合。药剂可抑制PD-1与PD-L1和/或PD-L2的结合至少50%、60%、70%、80%或90%。通过表面等离子体共振(SPR)分析或流式细胞术分析确定PD-1与PD-L1或PD-L2结合的合适测定法描述于Ghiotto等人(Int.Immunol.2010年8月;22(8):651-660)中。药剂可抑制PD-1与PD-L1和/或PD-L2的结合,例如通过与PD-1、PD-L1或PD-L2结合。
药剂可以是抗体,合适地是单克隆抗体,诸如人单克隆抗体或人源化单克隆抗体。药剂可以是保留抑制PD-1与PD-L1和/或PD-L2结合的能力的抗体的片段或衍生物。
示例性PD-1途径抑制剂包括但不限于帕博利珠单抗、纳武单抗、西米普利单抗、斯巴达珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、阿替利珠单抗、阿维鲁单抗和德瓦鲁单抗,或其保留抑制PD-1与PD-L1和/或PD-L2结合的能力的片段或衍生物。
合适地,PD-1途径抑制剂是选自由以下项组成的组的抗PD-1抗体:帕博利珠单抗、纳武单抗、西米普利单抗、斯巴达珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗和多塔利单抗,或其保留抑制PD-1与PD-L1和/或PD-L2结合的能力的片段或衍生物。
合适地,PD-1途径抑制剂是选自由以下项组成的组的抗PD-L1抗体:阿替利珠单抗、阿维鲁单抗和德瓦鲁单抗,或其保留抑制PD-L1与PD-1结合的能力的片段或衍生物。
合适地,PD-1途径抑制剂是帕博利珠单抗。
合适地,PD-1途径抑制剂是纳武单抗。
合适地,PD-1途径抑制剂是西米普利单抗。
合适地,PD-1途径抑制剂是斯巴达珠单抗。
合适地,PD-1途径抑制剂是卡瑞利珠单抗。
合适地,PD-1途径抑制剂是信迪利单抗。
合适地,PD-1途径抑制剂是替雷利珠单抗。
合适地,PD-1途径抑制剂是特瑞普利单抗。
合适地,PD-1途径抑制剂是多塔利单抗。
合适地,PD-1途径抑制剂是阿替利珠单抗。
合适地,PD-1途径抑制剂是阿维鲁单抗。
合适地,PD-1途径抑制剂是德瓦鲁单抗。
其他示例性PD-1途径抑制剂包括JTX-4014、INCMGA00012、AMP-224、AMP-514、KN035、CK-301、AUNP12、CA-170和BMS-986189。
PD-1途径抑制剂的剂量将取决于所使用的特定PD-1途径抑制剂。一般来讲,用于人类受试者的PD-1途径抑制剂的通常处方剂量可以是0.1mg/kg至10mg/kg,例如0.1mg/kg至1mg/kg,或1mg/kg至10mg/kg。使用本文中的术语“通常处方剂量”以包括与向受试者(合适地为人类受试者)施用安全并且治疗有效的剂量相同或在剂量范围内的剂量。
在一个实施方案中,将PD-1途径抑制剂约每周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每两周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每三周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每四周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每月一次施用于受试者。在一个实施方案中,将PD-1途径抑制剂约每五周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每六周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每七周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每八周一次施用于受试者。在另一个实施方案中,将PD-1途径抑制剂约每两个月一次施用于受试者。
如本领域的技术人员将会理解的,精确的治疗方案可根据所治疗的特定癌症和患者的特征而变化和调整。
已知PD-1途径抑制剂的通常处方人类剂量的示例包括:
帕博利珠单抗:每三周200mg或每六周400mg。
纳武单抗:每两周240mg、每3周360mg或每4周480mg
阿维鲁单抗:每两周800mg(或如果体重<80kg,最大剂量10mg/kg)。
在一些实施方案中,PD-1途径抑制剂经肠外(包括通过皮下、静脉内或肌肉内注射)或口服施用。
合适地,PD-1途径抑制剂是静脉内施用的。
化疗剂
合适的化疗剂包括但不限于烷基化剂、植物生物碱、抗肿瘤抗生素、抗代谢物、拓扑异构酶抑制剂和各种抗肿瘤药以及它们的混合物。
合适地,化疗剂是烷基化剂。示例性烷基化剂包含芥子气衍生物,诸如二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、美法仑和异环磷酰胺;乙撑亚胺,诸如噻替派和六甲嘧胺;烷基磺酸盐,诸如白消安;肼和三嗪,诸如六甲蜜胺、甲基苄肼、氮烯唑胺和替莫唑胺;亚硝基脲,诸如卡氮芥、洛莫司汀和链脲菌素;和铂类化疗剂,诸如卡铂、顺铂、奥沙利铂、奈达铂、四硝酸三铂、菲铂、吡铂和沙铂。
合适地,化疗剂是植物生物碱。示例性植物生物碱包含长春花生物碱,诸如长春新碱、长春碱和长春瑞滨;紫杉烷,诸如紫杉醇、白蛋白结合紫杉醇、多西他赛、卡巴他赛、拉洛他赛、米拉他赛、奥他赛、DHA紫杉醇、聚谷氨酸紫杉醇、替司他赛和BMS-184476;鬼臼毒素,诸如依托泊苷和替尼泊苷;和喜树碱类似物,诸如伊立替康和拓扑替康。
合适地,化疗剂是抗肿瘤抗生素。示例性抗肿瘤抗生素包含蒽环类,诸如多柔比星、柔红霉素、表柔比星、米托蒽醌和伊达比星;色霉素,诸如更生霉素和普卡霉素;和各种抗肿瘤抗生素,诸如丝裂霉素和博来霉素。
合适地,化疗剂是抗代谢物。示例性抗代谢物包括叶酸拮抗剂,诸如甲氨蝶呤和培美曲塞;嘧啶拮抗剂,诸如5-氟尿嘧啶、替加氟、卡莫氟、去氧氟尿苷、氟尿苷、阿糖胞苷、卡培他滨和吉西他滨;嘌呤拮抗剂,诸如6-巯基嘌呤和6-硫鸟嘌呤;和腺苷脱氨酶抑制剂,诸如克拉屈滨、氟达拉滨、奈拉滨和喷司他丁。
合适地,化疗剂是拓扑异构酶抑制剂。示例性拓扑异构酶抑制剂包含拓扑异构酶I抑制剂,诸如伊立替康和拓扑替康;和拓扑异构酶II抑制剂,诸如安吖啶、依托泊苷、磷酸依托泊苷和替尼泊苷。
合适地,化疗剂是各种抗肿瘤药。示例性各种抗肿瘤药包含核糖核苷酸还原酶抑制剂,诸如羟基脲;肾上腺皮质类固醇抑制剂,诸如米托坦;酶,诸如天冬酰胺酶和培门冬酶;抗微管剂,诸如雌氮芥;和类维生素A,诸如贝沙罗汀、异维甲酸和维甲酸。
合适地,化疗剂是两种或更多种化疗剂的组合。
合适地,化疗剂是两种化疗剂的组合。
在一个实施方案中,化疗剂是培美曲塞和铂类化疗诸如卡铂、顺铂或奥沙利铂的组合。
在另一个实施方案中,化疗剂是培美曲塞和卡铂的组合。
在另一个实施方案中,化疗剂是卡铂和紫杉烷诸如紫杉醇或白蛋白结合紫杉醇。
在另一个实施方案中,化疗剂是卡铂和紫杉醇或白蛋白结合紫杉醇。
化疗剂以治疗有效量施用。治疗有效量是指在施用后足以具有治疗效果的化疗剂的量。化疗剂的有效量将随所选化疗剂、所治疗的特定一种疾病或多种疾病、疾病的严重程度、治疗的持续时间和患者的特征(例如,性别、年龄、身高和体重)而变化。
在一些实施方案中,化疗剂经肠外(包含通过皮下、静脉内或肌肉内注射)或口服施用。
合适地,化疗是静脉内施用的。
在一个实施方案中,将化疗剂约每周一次施用于受试者。在另一个实施方案中,将化疗剂约每两周一次施用于受试者。在另一个实施方案中,将化疗剂约每三周一次施用于受试者。在另一个实施方案中,将化疗剂约每四周一次施用于受试者。在另一个实施方案中,将化疗剂约每月一次施用于受试者。
在一个实施方案中,将LAG-3蛋白或其衍生物与PD-1途径抑制剂和化疗剂同时或相继施用。
在另一个实施方案中,将LAG-3蛋白或其衍生物与PD-1途径抑制剂和化疗剂相继施用。
在另一个实施方案中,施用化疗剂,并且随后相继施用LAG-3蛋白或其衍生物和PD-1途径抑制剂。
三重组合疗法的组分的剂量
应选择在根据本发明的三重组合疗法中使用的组分的剂量以在组合中提供治疗有效量的组分。三重组合疗法的“有效量”可以是导致与癌症相关的至少一种病理参数减少的量。例如,在一些实施方案中,三重组合疗法的有效量是与没有三重组合疗法的与癌症相关的参数的期望降低相比,有效实现病理参数降低至少约10%、20%、30%、40%、50%、60%、70%、80%或90%的量。例如,病理参数可以是肿瘤生长或肿瘤生长速率。
另选地,三重组合疗法的“有效量”可以是导致与癌症治疗相关的临床有益效果增加的量。例如,在一些实施方案中,组合疗法的“有效量”是与没有三重组合疗法的期望临床有益效果相比,有效实现临床有益效果增加至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、125%、150%、175%或200%的量。例如,临床有益效果可以是应答率、无进展生存期、总体生存期、疾病控制率、应答深度、应答持续时间、生活质量或对后续治疗的敏感性增加。
另选地,三重组合疗法的“有效量”可以是导致与癌症治疗相关的至少一个有益参数改变的量。例如,在一些实施方案中,三重组合疗法的“有效量”是与没有组合疗法的癌症治疗有关的参数的期望变化相比,有效实现参数的至少约10%、20%、30%、40%、50%、60%、70%、80%或90%的变化的量。例如,参数可以是循环的肿瘤抗原特异性CD8+T细胞数目的增加,或肿瘤抗原特异性调节T细胞数目的减少,或活化的T细胞,特别是活化的CD8+T细胞数目的增加,耗尽的抗原特异性CD8+T细胞数目的减少,或循环的功能性(即非耗尽的)抗原特异性CD8+T细胞数目的增加。
根据本发明,与(a)作为单一疗法的PD-1途径抑制剂和化疗剂的效果或(b)由PD-1途径抑制剂和化疗剂组成的组合疗法相比,可采用三重组合疗法来增加PD-1途径抑制剂和/或化疗剂的治疗效果。
也可采用三重组合疗法来降低组合中单个组分的剂量,同时防止或进一步降低单个组分的不希望的或有害的副作用的风险。
在一个实施方案中,PD-1途径抑制剂和/或化疗剂的剂量小于用PD-1途径抑制剂或化疗剂单一疗法的通常处方剂量,或低于由PD-1途径抑制剂和化疗剂组成的组合疗法的通常处方剂量,例如,PD-1途径抑制剂和/或化疗剂的通常处方剂量的约95%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%或约5%。
在另一个实施方案中,PD-1途径抑制剂和/或化疗剂的剂量小于用PD-1途径抑制剂或化疗剂单一疗法的通常处方剂量,或低于由PD-1途径抑制剂和化疗剂组成的组合疗法的通常处方剂量,例如,PD-1途径抑制剂和/或化疗剂的通常处方剂量的约25%至约75%,或约1%至约50%,或约0.5%至约25%。
在另一个实施方案中,PD-1途径抑制剂和化疗剂的剂量与规定的护理标准相对应。
适当地,三重组合疗法的疗程在例如约3个月、约4个月、约5个月、约6个月、约7个月、约8个月、约9个月、约10个月、约11个月或约12个月内进行。
类似地,组合疗法的疗程在例如约12周、约16周、约20周、约24周、约28周、约32周、约36周、约40周、约44周、约48周或约52周内进行。
在一个实施方案中,三重组合疗法的疗程在约16周内进行。在另一个实施方案中,三重组合疗法的疗程在约24周内进行。
适当地,在用三重组合疗法治疗受试者后,受试者进入到维持阶段。
在一个实施方案中,维持阶段包含LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂,其中该化疗剂是单一化疗剂。
适当地,维持阶段在约16周至约52周内进行,诸如约20周、约22周、约24周、约26周、约28周、约30周、约32周、约34周、约36周、约38周或约40周。
在一个实施方案中,维持阶段在约4个月至约12个月内进行,诸如约6个月。
在另一个实施方案中,受试者用三重组合疗法治疗至多24周,并且随后前进至总治疗持续时间至多52周的维持阶段。
在一个具体实施方案中,包括三重组合疗法和维持阶段的总治疗持续时间为至多约52周。
在另一个实施方案中,包括三重组合疗法和维持阶段的总疗法持续时间为约12个月、约15个月或约18个月。
另选地,在用三重组合疗法治疗受试者后,受试者进入到包含LAG-3蛋白或其衍生物和PD-1途径抑制剂的无化疗维持阶段。
无化疗维持阶段可以是例如约6个月、约9个月、约12个月、约15个月、约18个月、约21个月或约24个月。
组合制剂
在一个实施方案中,LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂单独包装。即,在该实施方案中,LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂是单独的单位剂型,其通常(但不一定)来源于不同的供应商,然后用于本发明的方法中。
在另一个实施方案中,LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂为组合制剂的形式。
可以存在“组合制剂”的三种组分:
(i)以一种称为固定剂量组合(FDC)的组合单位剂型,或
(ii)作为组分(a)的第一单位剂型;组分(b)的单独的第二单位剂型;和组分(c)的单独的第三单位剂型,并且其中该三个单独的剂型包装在一起,称为多部分试剂盒(kit-of-parts)。
要在组合制剂中施用的组合组分(a)、组合组分(b)和组合组分(c)的总量的比率是可以变化的,例如以应对待治疗的患者亚群体的需要,或患者的需要,这可以是由于例如患者的特定疾病、年龄、性别或体重。
即,根据本发明的组合制剂可以采取包含LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂的药物组合物的形式,或者另选地,作为包含LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂(作为单独组分但包装在一起)的多部分试剂盒。
因此,在一个实施方案中,本发明提供了一种组合制剂,该组合制剂包含:
(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物,
(b)PD-1途径抑制剂,和
(c)化疗剂。
组合制剂可包括多个剂量的LAG-3蛋白或其衍生物、多个剂量的PD-1途径抑制剂和/或多个剂量的化疗剂。
在另一个实施方案中,三种组分中的一种组分单独包装,并且另外两种组分作为组合制剂包装在一起。组合制剂的两种组分可作为(i)FDC或(ii)多部分试剂盒存在。
在一个实施方案中,单独包装LAG-3蛋白或其衍生物,并且PD-1途径抑制剂和化疗剂是组合制剂。
药物组合物
LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂与药学上可接受的载体、赋形剂或稀释剂配制以提供药物组合物。通常,这些将作为单独的药物组合物配制,尽管在固定剂量组合的情况下,LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂将与药学上可接受的载体、赋形剂或稀释剂一起配制。
单独的药物组合物可以以多部分试剂盒的形式包装在一起或单独来源以用于本发明的方法。
一般来讲,LAG-3蛋白或其衍生物、PD-1途径抑制剂和化疗剂可通过已知方式、以任何合适的药物组合物、通过任何合适的途径施用。
合适的药物组合物可使用药物制剂领域已知的常规方法制备,并在相关教科书和文献中描述,例如在Remington:药学科学与实践(The Science and Practice ofPharmacy)(Easton,Pa.:麦克出版公司(Mack Publishing Co.),1995)中。
特别有利的是将本发明的组合物配制成易于施用和剂量均匀的单位剂型。本文所用的术语“单位剂型”是指适于作为待治疗个体的单位剂量的物理上离散的单位。即,将组合物配制成离散的剂量单位,每个剂量单位含有预定的“单位剂量”量的活性剂,该活性剂经计算以与所需的药物载体、赋形剂或稀释剂结合产生期望的治疗效果。本发明的单位剂型的规格取决于待递送的活性剂的独特特征。剂量还可以参考成分的常规剂量和施用方式来确定。应当注意,在一些情况下,组合的两个或更多个单独剂量单位提供治疗有效量的活性剂。
根据本发明的用于胃肠外施用的制剂包含无菌水性和非水性溶液、混悬剂和乳剂。可注射水溶液含有水溶性形式的活性剂。非水性溶剂或媒介物的示例包含脂肪油,诸如橄榄油和玉米油;合成脂肪酸酯,诸如油酸乙酯或甘油三酯;低分子量醇,诸如丙二醇;合成亲水性聚合物,诸如聚乙二醇;脂质体等。胃肠外制剂还可以含有佐剂,诸如增溶剂、防腐剂、润湿剂、乳化剂、分散剂和稳定剂,并且水性混悬剂可以含有增加混悬剂粘度的物质,诸如羧甲基纤维素钠、山梨糖醇和葡聚糖。可注射制剂可通过掺入灭菌剂、通过截留细菌的过滤器过滤、辐照或加热来灭菌。它们还可以使用无菌可注射介质制造。活性剂也可以是干燥的,例如冻干的形式,其可以就在经由注射施用之前用合适的媒介物再水合。
优选地,与有效剂量的组分(a)、组分(b)和组分(c)中的一种或两种相比,三重组合疗法具有至少一种有益效果,例如有利的治疗效果(例如,总体应答率、无进展生存期、总体生存期、疾病控制率、应答深度或应答持续时间)、更少的副作用、更少的毒性或改善的生存质量。
实施例
现在仅以举例的方式参考附图来描述本发明的实施方案,其中:
实施例1:与PD-1途径抑制剂和化疗剂组合疗法的主动免疫疗法IMP321(试验洞悉
(INSIGHT),EudraCT号2016-002309-20)
进行临床研究以调查主动免疫疗法IMP321与PD-1途径抑制剂和化疗剂的组合在患有各种实体瘤(包括NSCLC)的患者中的安全性和有效性。计划招募20名患者。
具体地,非鳞状细胞第1线转移性NSCLC患者用两周一次的IMP321(30mg皮下注射)治疗,同时每三周施用一次培美曲塞(500mg/m2)、卡铂(AUC5)和帕博利珠单抗(200mg)的标准护理组合,持续至多24周。然后,患者进入到维持疗法,总研究持续时间至多52周。
维持疗法通常由每2周或每3周施用一次的IMP321(30mg皮下注射)和同时每3周施用一次的培美曲赛(500mg/m2)和帕博利珠单抗(200mg)组成。另选地,维持疗法可由仅用IMP321(30mg)和帕博利珠单抗(200mg)的疗法组成(无化学疗法)。
患者一直在研究中,直到疾病进展、不可接受的毒性、维持阶段完成或由于任何其他原因中止。在存在临床有益效果的情况下,疾病进展以外的治疗是一种选择。
在维持阶段后,跟踪患者至多12个月或直至疾病进展,以较早者为准。
允许额外的放射疗法。在骨癌细胞转移的情况下,允许施用双膦酸盐。不允许对靶病灶进行辐射。
截至2022年5月结束时,迄今为止,已将11/20个非鳞状第1线转移性NSCLC患者纳入该试验。在8名可评估的患者中,有4位确认部分反应,3位患者病情稳定,并且仅1位患者疾病进展(可评估患者中的中期疾病控制率:87.5%)。
在历史试验中,与用帕博利珠单抗和化学疗法的组合治疗相比,用三重组合疗法的治疗没有观察到额外的毒性。迄今为止,没有观察到导致试验中止的不良事件。
单个患者案例研究:
源于右下叶的双肺转移性肺癌
1949年出生
ECOG=1
腺癌
甲状腺转录因子(TTF)阴性
PD-L1:TPS=0(IC 0%)
无驱动突变
pT2a,pN0,R0
恶性等级G2
同侧胸膜播散(pM1a)
对侧(肺部左上叶)肺转移的组织学确认
预后更为有限的患者用三重组合疗法治疗,并且此后已经进入到仅用IMP321和帕博利珠单抗的组合的疗法的维持阶段。患者具有稳定的疾病并且保持在ECOG状态=1的治疗下。
患者胸部区域的CT扫描显示在治疗过程中靶肿瘤病灶的收缩。靶标病灶的收缩的示例在图2中示出,其中病灶从直径22.62mm收缩到“可评估但不可测量”。类似地,图3示出了另一靶标病灶的收缩:该病灶直径从35.92mm收缩到25.70mm。
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<120> 三重组合疗法
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Claims (14)
1.(a)能够结合MHC II类分子的LAG-3蛋白或其衍生物、(b)程序性细胞死亡蛋白-1(PD-1)途径抑制剂和(c)化疗剂在制备用于预防、治疗或改善受试者的癌症的药物中的用途。
2.能够结合MHC II类分子的LAG-3蛋白或其衍生物在制备用于预防、治疗或改善受试者的癌症的药物中的用途,其中所述LAG-3蛋白或其衍生物将与程序性细胞死亡蛋白-1(PD-1)途径抑制剂和化疗剂同时或相继施用。
3.根据权利要求1或2所述的用途,其中所述LAG-3蛋白的衍生物包含与LAG-3蛋白,优选地人LAG-3蛋白的结构域D1和任选地结构域D2具有至少70%氨基酸同一性的氨基酸序列。
4.根据任一前述权利要求所述的用途,其中所述LAG-3蛋白的衍生物包含与LAG-3蛋白,优选地人LAG-3蛋白的结构域D1、D2和D3以及任选地结构域D4具有至少70%氨基酸同一性的氨基酸序列。
5.根据任一前述权利要求所述的用途,其中所述癌症选自由以下项组成的组:乳腺癌、皮肤癌、肺癌(NSCLC或SCLC)、卵巢癌、肾癌(例如,肾细胞癌)、结肠癌、直肠癌、结肠直肠癌、肛门癌、小肠癌、胃肠道间质瘤、胃癌、食管癌、胰腺癌、膀胱癌、尿路上皮癌、肝癌、黑素瘤(例如,转移性恶性黑素瘤)、前列腺癌(例如,激素难治性前列腺癌)、头颈部癌(例如,头颈部鳞状细胞癌)、宫颈癌、子宫内膜癌、子宫癌、甲状腺癌、成胶质细胞瘤、胶质瘤、白血病、淋巴瘤(例如,B细胞淋巴瘤或霍奇金淋巴瘤)、肾上腺癌、艾滋病相关癌、腺泡状软组织肉瘤、星形细胞肿瘤、骨癌、脑和脊髓癌、转移性脑肿瘤、颈动脉体瘤、软骨肉瘤、脊索瘤、皮肤良性纤维组织细胞瘤、促结缔组织增生性小圆细胞瘤、室管膜瘤、尤因瘤、骨外黏液样软骨肉瘤、骨纤维发育不全、骨纤维性结构不良、胆囊或胆管癌、妊娠滋养细胞疾病、生殖细胞瘤、血液恶性肿瘤、肝细胞癌、胰岛细胞瘤、卡波西氏肉瘤、肾脏癌、脂肪瘤/良性脂肪瘤性肿瘤、脂肪肉瘤/恶性脂肪瘤性肿瘤、髓母细胞瘤、脑膜瘤、梅克尔细胞癌、多发性内分泌瘤病、多发性骨髓瘤、骨髓增生异常综合征、成神经细胞瘤、神经内分泌肿瘤、乳头状甲状腺癌、甲状旁腺肿瘤、儿科癌症、周围神经鞘膜瘤、嗜铬细胞瘤、垂体瘤、前列腺癌、脉络膜黑素瘤、罕见血液系统异常、横纹肌样瘤、横纹肌肉瘤、肉瘤、软组织肉瘤、鳞状细胞癌、滑膜肉瘤、间皮瘤、皮肤鳞状细胞癌、睾丸癌、胸腺癌、胸腺瘤和甲状腺转移癌。
6.根据任一前述权利要求所述的用途,其中所述癌症是肺癌,优选地NSCLC。
7.根据任一前述权利要求所述的用途,其中所述PD-1途径抑制剂选自由以下项组成的组:帕博利珠单抗、纳武单抗、西米普利单抗、斯巴达珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、阿替利珠单抗、阿维鲁单抗和德瓦鲁单抗。
8.根据任一前述权利要求所述的用途,其中所述PD-1途径抑制剂是帕博利珠单抗。
9.根据任一前述权利要求所述的用途,其中所述化疗剂是两种或更多种化疗剂的组合。
10.根据任一前述权利要求所述的用途,其中所述LAG-3衍生物是IMP321,所述PD-1途径抑制剂是帕博利珠单抗,所述化疗剂包含培美曲塞和卡铂的组合,并且所述癌症是NSCLC,优选地非鳞状NSCLC。
11.根据任一前述权利要求所述的用途,其中所述受试者的PD-L1表达水平<50%。
12.根据权利要求11所述的用途,其中所述受试者的所述PD-L1表达水平为1%-49%。
13.根据权利要求11所述的用途,其中所述受试者的所述PD-L1表达水平<1%。
14.根据任一前述权利要求所述的用途,其中所述受试者是人。
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- 2022-06-20 CA CA3222090A patent/CA3222090A1/en active Pending
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AU2022292126A1 (en) | 2024-01-18 |
CA3222090A1 (en) | 2022-12-22 |
BR112023026250A2 (pt) | 2024-02-27 |
WO2022263680A1 (en) | 2022-12-22 |
IL309240A (en) | 2024-02-01 |
GB202108718D0 (en) | 2021-08-04 |
KR20240023592A (ko) | 2024-02-22 |
EP4355365A1 (en) | 2024-04-24 |
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