CN114470189B - Ngf抗体在cipn性疼痛中的应用 - Google Patents
Ngf抗体在cipn性疼痛中的应用 Download PDFInfo
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- CN114470189B CN114470189B CN202011263674.2A CN202011263674A CN114470189B CN 114470189 B CN114470189 B CN 114470189B CN 202011263674 A CN202011263674 A CN 202011263674A CN 114470189 B CN114470189 B CN 114470189B
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Abstract
本发明涉及用NGF抗体在CIPN性疼痛中的应用，具体地，涉及NGF抗体阻断神经生长因子(NGF)与其受体的相互作用，从而能够治疗和/或预防化疗诱导性神经周围病变(CIPN)性疼痛。本发明的NGF抗体能够有效阻断NGF与其受体的作用，明显提高疼痛阈值，且副作用小。
Description
技术领域
本发明属于生物医药领域，具体地，本发明涉及一种NGF抗体在CIPN性疼痛中的应用。
背景技术
近年来，随着恶性肿瘤的发病率逐年上升，化疗药物的使用也日益广泛。而化疗药物所致疼痛严重影响患者生存质量，造成或加重抑郁、失眠、疲劳和其他症状，导致化疗剂量的改变，甚至化疗终止。其中，化疗诱导性周围神经病变(Chemotherapy-inducedperipheral neuropathy，CIPN)是癌症治疗常见的不良反应，化疗患者发生化疗诱导性周围神经病变(CIPN)性疼痛的比例从40％到70％不等，临床表现有疼痛、麻木和刺痛。
迄今为止，临床尚没有找到理想的药物和方法能够在不影响化疗药抗肿瘤活性的前提下，有效控制或预防化疗诱导性周围神经病变(CIPN)性疼痛。目前，治疗化疗诱导性周围神经病变(CIPN)性疼痛主要依赖于阿片类药物，但效果不理想，且阿片类药物的使用受到诸多限制。通常用于治疗神经性疼痛的药物，如阿米替林、加巴喷丁和普瑞加林，在CIPN性疼痛治疗中似乎并不比安慰剂效果好。度洛西汀是唯一被证明能够有效治疗CIPN性疼痛的非阿片类药物。度洛西汀是一种选择性的5-羟色胺(5-HT)和去甲肾上腺素(NE)再摄取抑制药。临床前研究结果显示，度洛西汀是神经元5-HT与NE再摄取的强抑制剂，对多巴胺再摄取的抑制作用相对较弱。体外研究结果显示，度洛西汀与多巴胺能受体、肾上腺素受体、胆碱能受体、组胺能受体、阿片受体、谷氨酸受体、GABA受体无明显亲和力。度洛西汀不抑制单胺氧化酶。度洛西汀在临床上具有抗抑郁作用，但是其在CIPN镇痛作用的机制尚未明确
基于临床上常见的镇痛药在治疗CIPN性疼痛方面效果不理想，因此CIPN性疼痛的机制可能与常见的急慢性疼痛不一致。正因如此，在其它疼痛中具有明显镇痛作用的药物，也无法直接用于CIPN性疼痛。由于化疗药物所致疼痛并不是由单一机制引起的，而是多因素、多环节相互影响、相互作用的结果。相应的治疗也比较复杂，影响治疗效果的因素也较多。目前在临床实践中以对症治疗为主的方案，虽然能在一定程度上暂时减轻化疗诱导的神经病理性疼痛患者的痛苦，但要获得满意疗效还需要进一步的研究和探索。
综上，本领域迫切需要开发一种能够应用于化疗诱导性周围神经病变(CIPN)性疼痛的抑制剂。我们在研究中发现用抗体阻断神经生长因子(NGF)与其受体的结合可以显著地降低化疗诱导性周围神经病变(CIPN)性疼痛，这个机制与已知的度洛西汀的药理作用机制完全不同。
发明内容
本发明目的是提供一种靶向神经生长因子(Nerve growth factor，NGF)的人源化重组单克隆抗体，其能够有效抑制化疗诱导性周围神经病变(CIPN)性疼痛。
在本发明的第一方面，提供一种靶向神经生长因子的单克隆抗体的用途，用于制备治疗和/或预防化疗诱导性周围神经病变性疼痛的药物中的用途，其中，所述的化疗诱导性周围神经病变是由化疗剂引起的。
在另一优选例中，化疗诱导性周围神经病变性疼痛是经常规的镇痛剂治疗后无效的，其中，所述的常规镇痛剂选自下组：***、***、四氢***碱及衍生物、***、芬太尼、可待因、二氢可达因酮甲氧萘丙酸(奈普生)、阿司匹林、阿米替林、加巴喷丁、对乙酰氨基酚、双氯灭痛、布洛芬、度洛西汀、或普瑞加林等***、***及非非甾体抗炎镇痛药物类等。
在另一优选例中，所述的单克隆抗体为人源化重组单克隆抗体。
在另一优选例中，所述的靶向神经生长因子的单克隆抗体的重链可变区具有SEQID NO:1所示的氨基酸序列。
在另一优选例中，所述的靶向神经生长因子的单克隆抗体的轻链可变区具有SEQID NO:2所示的氨基酸序列。
在另一优选例中，所述的靶向神经生长因子的单克隆抗体的重链可变区具有SEQID NO:1所示的氨基酸序列，并且轻链可变区具有SEQ ID NO:2所示的氨基酸序列。
在另一优选例中，所述的单克隆抗体的重链和轻链序列如SEQ ID NO:3和SEQ IDNO:4所示。
在另一优选例中，所述的化疗剂选自下组：紫杉烷类、铂类、长春花生物碱类、吉西他滨、硼替佐米、沙利度胺、长春瑞滨，或其组合。
在另一优选例中，所述的化疗剂选自下组：紫杉醇、顺铂、长春新碱，或其组合。
在另一优选例中，所述的一种或多种化疗剂用于癌症的治疗。
在另一优选例中，所述的癌症选自：卵巢癌、子***、结直肠癌、***癌、乳腺癌、睾丸癌、白血病、成神经细胞瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤和非小细胞肺癌。
在另一优选例中，所述的靶向神经生长因子的单克隆抗体在所述化学治疗剂给药之前、给药期间或给药之后给予。
在另一优选例中，所述的靶向神经生长因子的单克隆抗体的用量为50-2000mg/50kg。
在另一优选例中，靶向神经生长因子的单克隆抗体对CIPN性疼痛阈值明显提升。
在另一优选例中，靶向神经生长因子的单克隆抗体对CIPN性疼痛评分明显改善。
在本发明第二方面，提供一种药物组合物，其包含i)一种或多种靶向神经生长因子的单克隆抗体；
ii)一种或多种所述的化学治疗剂；和
iii)药学上可接受的载体。
在另一优选例中，所述的药物组合物中，所述的靶向神经生长因子的单克隆抗体为DS002。
在另一优选例中，所述的药物组合物还可包含其他治疗和/或预防化疗诱导性周围神经病变的药物，所述的其他治疗和/或预防化疗诱导性周围神经病变的药物包括小分子药物(如CXCR2抑制剂、PARP抑制剂等)。
在另一优选例中，所述的药物组合物为注射剂。
在另一优选例中，在治疗周期过程中每3天、每4天、每5天、每6天、每10天、每2周给予1-5次靶向神经生长因子的单克隆抗体或包含其的药物组合物，其中，治疗周期为6天、1周、2周、3周、4周、5周或6周。
在另一方面，提供一种治疗和/或预防化疗诱导性周围神经病变性疼痛的方法，所述方法包括向需要治疗的受试者施用治疗有效量的靶向神经生长因子的单克隆抗体。
在本发明第三方面，提供一种用于治疗和/或预防化疗诱导性周围神经病变性疼痛的药物的试剂盒，所述的试剂盒含有一容器，所述容器中靶向神经生长因子的单克隆抗体或含有其的药物组合物；以及标签或说明书，所述标签或说明书注明所述试剂盒用于治疗和/或预防化疗诱导性周围神经病变性疼痛。
在另一优选例，所述试剂盒还包括伴随诊断试剂，其用于检测NGF的试剂。
在另一优选例中，所述诊断试剂用于检测NGF数量、活性等。
在本发明第四方面，提供一种如第三方面所述的试剂盒的用途，用于治疗和/或预防化疗诱导性周围神经病变性疼痛。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1示出了向紫杉醇诱导的大鼠神经性疼痛模型给药的流程图。
图2示出了紫杉醇诱导模型试验期间各组动物机械性缩爪阈值变化柱状图。
图3示出了紫杉醇诱导模型试验期间各组动物机械性缩爪阈值变化曲线图。
图4示出了紫杉醇诱导模型试验期间各组动物丙酮诱发足部退缩反应评分变化。
图5示出了紫杉醇诱导模型试验期间各组动物冷触发痛反应频率。
图6示出了长春新碱诱导模型试验期间各组动物机械性缩爪阈值变化柱状图。
图7示出了长春新碱诱导模型试验期间各组动物机械性缩爪阈值变化曲线图。
图8示出了长春新碱诱导模型试验期间各组动物丙酮诱发足部退缩反应评分变化。
图9示出了长春新碱诱导模型试验期间各组动物冷触发痛反应频率。
图10示出了顺铂诱导模型试验期间各组动物机械性缩爪阈值变化柱状图。
图11示出了顺铂诱导模型试验期间各组动物机械性缩爪阈值变化曲线图。
图12示出了顺铂诱导模型试验期间各组动物丙酮诱发足部退缩反应评分变化。
图13示出了顺铂诱导模型试验期间各组动物冷触发痛反应频率。
图14示出了人源化重组单克隆抗体DS002的氨基酸序列。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地发现，靶向神经生长因子的人源化重组单克隆抗体(如DS002)能够有效抑制化疗诱导性周围神经病变(CIPN)性疼痛，并且副作用低。实验表明，出乎意料的是，对于化疗剂(如紫杉烷类、铂类、长春新碱类)所导致的CIPN性疼痛，常规的或强效的止痛剂无法有效地缓解，然而，本发明抗体(如DS002)居然可以有效地缓解这些难治性或顽固性的CIPN性疼痛。在此基础上，发明人完成了本发明。
术语
如本发明所用，术语“治疗”是指包括对动物特别是人的疾病和/或病症的任何治疗，包括：(i)抑制疾病和/或病症，即阻止其发展；(ii)减轻疾病和/或病症，即导致疾病和/或病症的消退。例如，治疗CIPN性疼痛包括阻止或减轻CIPN性疼痛、或缓解或减轻CIPN性疼痛的病症。
如本发明所用，术语“预防”指(i)防止疾病和/或病症的发展；和/或(ii)在疾病和/或病症已经发展的状态中防止疾病和/或病症恶化。
化疗诱导性周围神经病变(CIPN)
如本文所用，“化疗诱导性周围神经病变(CIPN)”主要指一组剂量依赖性肿瘤化疗药物诱导的周围神经病变。导致CIPN的药物主要包括铂类化疗药物、抗微管蛋白药物、舒拉明钠、沙利度胺(TLD)、埃坡霉素及硼替佐米等。CIPN的发生率主要取决于所选药物种类及使用疗程。CIPN是影响乳腺癌、结肠直肠癌、睾丸癌及造血***恶性肿瘤等患者化疗后生活。CIPN的最常见症状是疼痛(其可一直存在或可时有时无，如闪痛或刺痛)、灼烧感、刺痛感(“针刺”感觉或电/电击样疼痛)、感觉缺失(其可为麻木或者感觉压力、触摸、热或冷的能力减弱)等。
化疗剂
“化疗剂”或“抗肿瘤剂”是指使用有效量药物以减少、预防和/或延迟转移或肿瘤的生长，或使肿瘤细胞坏死或凋亡杀死肿瘤细胞从而减少、预防和/或延迟患有肿瘤疾病的受试者中肿瘤的转移或的生长的试剂。化疗是目前治疗癌症最有效的手段之一，和手术、放疗一起并称癌症的三大治疗手段。手术和放疗属于局部治疗，只对治疗部位的肿瘤有效，对于潜在的转移病灶(癌细胞实际已经发生转移，但因为目前技术手段的限制在临床上还不能发现和检测到)和已经发生临床转移的癌症就难以发挥有效治疗了。而化疗是一种全身治疗的手段，无论采用什么途径给药(口服、静脉和体腔给药等)，化疗药物都会随着血液循环遍布全身的绝大部分器官和组织。因此，对一些有全身播撒倾向的肿瘤及已经转移的中晚期肿瘤，化疗都是主要的治疗手段。
本发明所述化疗剂包括紫杉烷类(紫杉醇)、铂类(例如，顺铂、卡铂、奥沙利铂)、长春花生物碱类(长春新碱)、沙利度胺等。
紫杉醇(Paclitaxel)是一种从紫衫中提取的抗癌药物，主要通过促进细胞内的微管蛋白发生聚合，保持微管蛋白稳定，抑制细胞的有丝***而发挥抑制肿瘤细胞的恶性增殖作用。紫杉醇广泛应用于实体瘤的治疗中，紫杉醇化疗后的两个严重不良反应是骨髓抑制和神经病理性疼痛。紫杉醇所致的神经病理性疼痛主要表现为外周感觉性的痛觉超敏、灼痛、刺激和麻木等症状，此症状可持续至紫杉醇停药后数月至数年，是一种难治性痛症，目前尚无有效的治疗措施。一些接受紫杉醇治疗的癌症病人甚至会因为严重的疼痛而不得不中断治疗。
有文献报告，间断重复腹腔注射紫杉醇可以成功建立SD大鼠外周神经病理性疼痛模型，组织结构上出现坐骨神经髓鞘肿胀，部分髓鞘空泡变，部分许旺细胞结构破坏，许旺细胞核增多；机械刺激痛阈下降。
靶向神经生长因子的人源化重组单克隆抗体
靶向神经生长因子(Nerve growth factor，NGF)属于神经营养因子家族，最初在小鼠颌下腺和蛇毒液中提取，几乎存在于所有的脊椎动物中。NGF在不同种属中以不同的多聚体(前体)存在，其中β亚基具有完整的NGF生物学活性，被称为β-NGF；成熟的游离β-NGF由两条118个氨基酸多肽通过非共价键组成。目前研究认为在胚胎和幼年动物体内，NGF促进外周感觉和交感神经元生长、分化和损失修复，在成年动物上，NGF主要在损伤、炎症等情况下调节炎症反应、敏化伤害性感受器。NGF结合伤害性感受器表面的NGF功能性受体TrkA后，激活胞浆ERK、PLC/PKC等信号通路，降低神经元动作电位阈值，提高神经元兴奋性，进而敏化痛觉。
如本文所用，术语“本发明抗体”或“本发明的抗NGF抗体”可互换使用，指特异性靶向NGF(尤其是人NGF)的抗体。本发明的抗体优选是单克隆抗体。所述的抗体可以是完整的抗体或抗体活性片段。应理解，所述术语还包括单链抗体(scFv)、纳米抗体。此外，本发明抗体可以是动物源的(如鼠源)、人源化的、嵌合的、全人抗体、或其组合。
优选地，所述的靶向神经生长因子的人源化重组单克隆抗体的重链可变区的具有SEQ ID NO:1所示的氨基酸序列。
优选地，所述的靶向神经生长因子的人源化重组单克隆抗体的轻链可变区具有SEQ ID NO:2所示的氨基酸序列。
优选地，所述的靶向神经生长因子的人源化重组单克隆抗体的重链可变区具有SEQ ID NO:1所示的氨基酸序列，并且轻链可变区具有SEQ ID NO:2所示的氨基酸序列。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYLIEWVRQAPGQGLEWMGVINPRSGATNYNEKFKDRLTITKDTSKNQVVLTMTNMDPVDTATYYCARGNYRFEAYWGQGTLVTVSS(SEQ ID NO:1)。
DILMTQSQKFMSTSVGDRVSITCKASQNVRTAVAWYQQKPGQSPKALILASNRHTGVPDRFTGSGSGTDFTLTISNMQSEDLADYFCQQYSSYPFTFGSGTKLEIK(SEQ ID NO:2)。
如本文所用，“DS002”是一种靶向神经生长因子的人源化重组单克隆抗体是由两条重链和两条轻链通过二硫键连接而成的多结构域复合物，能够与NGF蛋白分子结合并阻断NGF蛋白分子与其受体TrkA蛋白分子的结合。DS002在结构上属于人IgG的IgG1亚型，轻链为κ型。
优选地，DS002重链序列和轻链序列如SEQ ID NO:3和SEQ ID NO:4所示
QVQLKESGPGLVAPSETLSITCTVSGFSLTGYGVNWVRQPPGKGLEWLGMIWADGDTDYNSALKSRLTISKDNSKSQVFLKVNNLQTDDTARYYCARDSYYYGYNFFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:3)。
DIQMTQSPSSLSASVGDRVTISCRASQDISNYLNWYQQKPEGTLKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISSLQQEDIATYFCQQGNTLPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:4)。
优选地，DS002的重链(a)和轻链(b)氨基酸序列如图14所示。
在本发明中，抗NGF抗体可在化疗剂使用之前、同时及之后使用。
在本发明中，本发明的抗体还包括其保守性变异体，指与本发明抗体的氨基酸序列相比，有至多10个，较佳地至多8个，更佳地至多5个，最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
| 最初的残基 | 代表性的取代 | 优选的取代 |
| Ala(A) | Val；Leu；Ile | Val |
| Arg(R) | Lys；Gln；Asn | Lys |
| Asn(N) | Gln；His；Lys；Arg | Gln |
| Asp(D) | Glu | Glu |
| Cys(C) | Ser | Ser |
| Gln(Q) | Asn | Asn |
| Glu(E) | Asp | Asp |
| Gly(G) | Pro；Ala | Ala |
| His(H) | Asn；Gln；Lys；Arg | Arg |
| Ile(I) | Leu；Val；Met；Ala；Phe | Leu |
| Leu(L) | Ile；Val；Met；Ala；Phe | Ile |
| Lys(K) | Arg；Gln；Asn | Arg |
| Met(M) | Leu；Phe；Ile | Leu |
| Phe(F) | Leu；Val；Ile；Ala；Tyr | Leu |
| Pro(P) | Ala | Ala |
| Ser(S) | Thr | Thr |
| Thr(T) | Ser | Ser |
| Trp(W) | Tyr；Phe | Tyr |
| Tyr(Y) | Trp；Phe；Thr；Ser | Phe |
| Val(V) | Ile；Leu；Met；Phe；Ala | Leu |
在本发明中，抗NGF抗体(如DS002)用量没有特别限制，可以是任何安全有效剂量。代表性的剂量可以是例如50-2000mg/50kg体重，较佳地100-1000mg/50kg体重。
靶向神经生长因子的单克隆抗体的用途
本发明提供了如上所述的靶向神经生长因子的单克隆抗体的用途，用于制备治疗和/或预防化疗诱导性周围神经病变性疼痛的药物或药物组合物，其中，所述的化疗诱导性周围神经病变是由化疗剂引起的，其中，所述化疗剂如上所述。
优选地，靶向神经生长因子的人源化重组单克隆抗体的重链可变区的氨基酸序列如SEQ ID NO:1所示。
优选地，靶向神经生长因子的人源化重组单克隆抗体的轻链可变区含有SEQ IDNO:2所示的氨基酸序列。
优选地，靶向神经生长因子的人源化重组单克隆抗体的重链可变区含有SEQ IDNO:1所示的氨基酸序列，并且轻链可变区含有SEQ ID NO:2所示的氨基酸序列。
优选地，所述的单克隆抗体为DS002，其中，DS002重链序列和轻链序列如SEQ IDNO:3和SEQ ID NO:4所示。
优选地，所述的化疗剂选自下组：紫杉醇、顺铂、长春新碱，或其组合。
药物组合物
本发明还提供了一种组合物。在优选例中，所述的组合物是药物组合物，它含有上述的靶向神经生长因子的人源化重组单克隆抗体(优选地为DS002)，以及药学上可接受的载体。通常，可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中，其中pH通常约为5-8，较佳地pH约为6-8，尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。
配制好的药物组合物可以通过常规途径进行给药，其中包括(但并不限于)：瘤内、腹膜内、静脉内、或局部给药。所述注射给药较佳地包括静脉注射、肌肉注射、腹腔注射、皮内注射或皮下注射等途径。所述的药物组合物为本领域常规的各种剂型，较佳地为固体、半固体或液体的形式，可以为水溶液、非水溶液或混悬液，更佳地为片剂、胶囊、颗粒剂、注射剂或输注剂等。
本发明所述的药物组合物是用于预防和/或治疗与a)化疗诱导性周围神经病变(CIPN)引起的疼痛的药物组合物。
本发明的药物组合物可直接用于结合NGF蛋白分子并阻断NGF蛋白分子与其受体TrkA蛋白分子的结合，因而可用于预防和治疗化疗诱导性周围神经病变(CIPN)引起的疼痛。
本发明的药物组合物含有安全有效量(如0.001-99wt％,较佳地0.01-90wt％，更佳地0.1-80wt％)的本发明上述的靶向神经生长因子的单克隆抗体(如DS002)以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量，例如每天约1微克/千克体重-约5毫克/千克体重。此外，本发明的多肽还可与其他治疗剂一起使用。
本发明中，较佳地，本发明所述的药物组合物还包括一种或多种药用载体。所述的药用载体为本领域常规药用载体，所述的药用载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料，较佳的包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地，所述的药物组合物包括0.01～99.99％的本发明的抗体和0.01～99.99％的药用载体，所述百分比为占所述药物组合物的质量百分比。
本发明中，较佳地，所述的药物组合物的施用量为有效量，所述有效量为能够缓解或延迟疾病、退化性或损伤性病症进展的量。所述有效量可以以个体基础来测定，并将部分基于待治疗症状和所寻求结果的考虑。本领域技术人员可以通过使用个体基础等上述因素和使用不超过常规的实验来确定有效量。
使用药物组合物时，是将安全有效量的免疫偶联物施用于哺乳动物，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约50毫克/千克体重，较佳地该剂量是约100微克/千克体重-约20毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(a)本发明的抗体(如DS002)能够明显提高化疗诱导性周围神经病变(CIPN)性疼痛阈值。
(b)发明的抗体(如DS002)在治疗和/或预防化疗诱导性周围神经病变(CIPN)性疼痛，副作用小。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例
实验方法
所有雌性SD大鼠分别在第-5天(D-5)及第-4天(D-4)进行von Frey机械性诱发痛和丙酮冷触诱发痛基础值的测量(以紫杉醇正式造模给药当天记为D0)。根据体重将SD大鼠随机分为5组，分别为空白对照(Blank control)组、溶媒对照(Vehicle control),s.c.,D-3/D3/D9组、DS002 0.1mg/kg,s.c.,D-3/D3/D9组、DS002 0.5mg/kg,s.c.,D-3/D3/D9组、DS002 2.5mg/kg,s.c.,D-3/D3/D9组。除空白对照组外，其余各组动物分别在D0、D2、D4和D6腹腔注射化疗剂溶液，建立化疗剂诱导的SD大鼠神经性疼痛模型。其中，von Frey为机械刺激性痛阈测定方法的刺激材料；丙酮为一种冷痛阈测定方法的刺激物质。
除空白对照组，其他四组分别在D-3、D3和D9进行皮下给予DS002治疗，并分别于D7、D14及D8、D15进行von Frey机械性诱发痛和丙酮冷触诱发痛的测量，记录其相应时间点的机械性缩爪阈值以及丙酮诱发足部退缩行为的评分及频率(测试与计算方法参见Yoon等，pain,59(3),369–376.&Flatters等，pain,2004,109(1-2):150-161)。
实施例1 DS002对紫杉醇诱导的大鼠神经性疼痛的药效实验
1.紫杉醇诱导的大鼠神经性疼痛模型构建
使用上述实验方法，除空白对照组外，其余各组动物分别在D0、D2、D4和D6腹腔注射化疗剂溶液(4mg/kg)，建立紫杉醇诱导的SD大鼠神经性疼痛模型,即CIPN疼痛模型。实验流程如图1所示。
2.实验结果
2.1对机械性触诱发痛的预防效应
试验期间各组动物机械性缩爪阈值变化柱状图及曲线图分别如图2(与溶媒对照组阈值的比，*表示0.01＜P＜0.05；**表示P＜0.01；***表示＜0.001)和图3所示，平均阀值如表1所示。
注：1.以紫杉醇正式造模给药当天记为D0；
2.与Vehicle control组比较，“*”表示0.01<P<0.05，"**"表示P<0.01；“***”表示P<0.001。
结果表明：相较于溶媒对照(Vehicle control)，注射本发明试剂DS002后，大鼠机械性缩爪阈值明显提升。
2.2对冷触诱发痛的预防效应
试验期间各组动物丙酮诱发足部退缩反应评分变化柱状图及冷触诱发痛反应频率柱状图分别如图4(与溶媒对照组阈值的比，*表示0.01＜P＜0.05；**表示P＜0.01)和图5(与溶媒对照组阈值的比，*表示0.01＜P＜0.05；**表示P＜0.01；***表示＜0.001)所示，总评分数均值及反应频率平均值见表2。
表2试验期间各组动物丙酮诱发足部退缩反应评分及冷触诱发痛反应频率平均值
注：1.以紫杉醇正式造模给药当天记为D0；
2.与Vehicle对照组比较，“*”表示0.01<P<0.05；“**”表示P<0.01；“***”表示P<0.00l。
结果表明：
每隔6天，连续3次皮下给予0.1～2.5mg/kg的DS002在紫杉醉诱导的大鼠神经性疼痛模型上能够预防性提高疼痛阈值，且表现出一定的剂量关系和明显的时效关系。
实施例2 DS002对长春新碱诱导的SD大鼠神经性疼痛模型的药效实验
1.长春新碱诱导的大鼠神经性疼痛模型构建
参照上述实验方法及实施例1，除空白对照组外，其余各组动物分别在在D0至D9腹腔注射长春新碱溶液(0.1mg/kg)，构建长春新碱诱导的SD大鼠神经性疼痛模型，即CIPN疼痛模型。
2.实验结果
2.1对机械性触诱发痛的预防效应
造模后第7天(D7)von Frey测试，空白对照组动物机械性缩爪阈值均值为14.63±0.28g；溶媒对照,s.c.,D-3/D3/D9组的机械性缩爪阈值均值为4.88±1.06g，与Blankcontrol组比较，存在显著差异(P<0.0001)，表明造模成功。受试样品DS002,0.1mg/kg,s.c.,D-3/D3/D9组动物机械性缩爪阈值分别为7.02±1.05g，与溶媒对照组比较，无显著差异(P>0.05)。受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9组及受试样品DS002,2.5mg/kg,s.c.,D-3/D3/D9组动物机械性缩爪阈值分别为8.20±1.78g及8.43±0.92g，与溶媒对照组比较，存在显著差异(P<0.05)。
试验期间各组动物机械性缩爪阈值变化柱状图及曲线图见图6和图7，平均阈值见表3。
表3机械性缩爪阈值
注：1.以长春新碱正式造模给药当天记为D0；
2.与Vehicle control组比较，“*”表示0.01<P<0.05；“****”表示P<0.0001。
结果表明：相较于溶媒对照(Vehicle control)，注射本发明试剂DS002后，大鼠机械性缩爪阈值明显提升。
2.2对冷触诱发痛的预防效应
造模后第8天(D8)丙酮测试，空白对照组动物丙酮诱发足部退缩行为总评分数均值为0.40±0.22，反应频率的均值为6.00±3.06％；溶媒对照,s.c.,D-3/D3/D9组的足部退缩行为总评分数均值为7.60±1.12，与空白对照组比较，存在显著差异(P<0.0001)，反应频率的均值为68.00±8.54％，与空白对照组比较，存在显著差异(P<0.001)，表明造模成功。受试样品DS002,0.1mg/kg,s.c.,D-3/D3/D9组动物足部退缩行为总评分数均值为5.10±0.80，与溶媒对照组比较，存在显著差异(P<0.01)；其反应频率的均值为58.00±6.96％，与溶媒对照组比较，无显著差异(P>0.05)。受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9组及受试样品DS002,2.5mg/kg,s.c.,D-3/D3/D9组动物足部退缩行为总评分数均值分别为3.50±0.83及3.60±0.52，与溶媒对照组比较，存在显著差异(P<0.0001)；其反应频率的均值分别为44.00±7.77％及44.00±4.99％，与溶媒对照组比较，存在显著差异(P<0.01)。试验期间各组动物丙酮诱发足部退缩反应评分变化柱状图及冷触诱发痛反应频率柱状图见图8、图9，总评分数均值及反应频率平均值见表4。
表4试验期间各组动物丙酮诱发足部退缩反应评分及冷触诱发痛反应频率平均值
注：1.以长春新碱正式造模给药当天记为D0；
2.与Vehicle control组比较，“*”表示0.01<P<0.05；“**”表示P<0.01；“***”表示P<0.001；“****”表示P<0.0001。
实施例3
1.顺铂诱导的大鼠神经性疼痛模型构建
参照上述实验方法及实施例1，除空白对照组外，其余各组动物分别在D0和D6尾静脉注射顺铂溶液(4mg/kg)，建立顺铂诱导的SD大鼠神经性疼痛模型,即CIPN疼痛模型。
2.实验结果
2.1对机械性触诱发痛的预防效应
造模前第-5天(D-5)和第-4天(D-4)分别机械性触诱发痛及冷触诱发痛基础值测定后，第-3天(D-3)根据动物体重，采用随机区组法将正常大鼠分为4组并开始给药，分组后各组动物平均体重约为250g。空白对照组、溶媒对照,s.c.,D-3/D3/D9/D16组、受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组及受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物的机械性缩爪阈值基础值分别为26.00±0.00g、23.95±1.63g、23.50±1.68g及22.77±1.71g；丙酮诱发足部退缩行为总评分数基础值分别为0.50±0.34、0.55±0.31、0.27±0.19及0.55±0.28；其反应频率基础值分别为6.00±4.27％、7.27±4.07％、3.64±2.44％及5.45±2.82％。
造模后第7天(D7)von Frey测试，空白对照组动物机械性缩爪阈值均值为23.20±1.41g；溶媒对照,s.c.,D-3/D3/D9/D16组的机械性缩爪阈值均值为8.00±1.60g，与空白对照组比较，存在显著差异(P<0.0001)，表明造模成功。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组及受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物机械性缩爪阈值分别为8.87±1.98g及7.62±1.18g，与溶媒对照组比较，无显著差异(P>0.05)。
造模后第14天(D14)von Frey测试，空白对照组动物机械性缩爪阈值均值为18.87±2.17g；溶媒对照,s.c.,D-3/D3/D9/D16组的机械性缩爪阈值均值为5.32±0.89g，与空白对照组比较，存在显著差异(P<0.001)，表明造模成功。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组动物机械性缩爪阈值均值为7.22±0.77g，与溶媒对照组比较，无显著差异(P>0.05)；受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物机械性缩爪阈值均值为10.73±1.60g，与溶媒对照组比较，存在显著差异(P<0.05)。
造模后第21天(D21)von Frey测试，空白对照组动物机械性缩爪阈值均值为19.50±2.38g；溶媒对照,s.c.,D-3/D3/D9/D16组的机械性缩爪阈值均值为6.22±0.88g，与空白对照组比较，存在显著差异(P<0.001)，表明造模成功。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组动物机械性缩爪阈值均值为14.22±2.63g，与溶媒对照组比较，存在显著差异(P<0.05)；受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物机械性缩爪阈值均值为16.37±2.36g，与溶媒对照组比较，存在显著差异(P<0.01)。
试验期间各组动物机械性缩爪阈值变化柱状图及曲线图见图10(与溶媒对照组阈值的比，*表示0.01＜P＜0.05；**表示P<0.01；***表示P<0.001，****表示P<0.0001)、图11，平均阈值见表5。
表5机械性缩爪阈值
结果表明：相较于溶媒对照(Vehicle control)，注射本发明试剂DS002后，大鼠机械性缩爪阈值明显提升。
2.2对冷触诱发痛的预防效应
造模后第8天(D8)丙酮测试，空白对照组动物丙酮诱发足部退缩行为总评分数均值为0.70±0.42，反应频率的均值为8.00±4.42％；溶媒对照,s.c.,D-3/D3/D9/D16组的足部退缩行为总评分数均值为0.73±0.27，与空白对照组比较，无显著差异(P>0.05)，反应频率的均值为10.91±4.15％，与空白对照组比较，无显著差异(P>0.05)。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组及受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物足部退缩行为总评分数均值分别为0.55±0.31及0.45±0.25，与溶媒对照组比较，无显著差异(P>0.05)；其反应频率的均值分别为7.27±4.07％及7.27±4.07％，与溶媒对照组比较，无显著差异(P>0.05)。
造模后第15天(D15)丙酮测试，空白对照组动物丙酮诱发足部退缩行为总评分数均值为0.80±0.49，反应频率的均值为12.00±6.11％；溶媒对照,s.c.,D-3/D3/D9/D16组的足部退缩行为总评分数均值为0.91±0.37，与空白对照组比较，无显著差异(P>0.05)，反应频率的均值为14.55±5.45％，与空白对照组比较，无显著差异(P>0.05)。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组及受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物足部退缩行为总评分数均值分别为1.18±0.55及0.45±0.25，与溶媒对照组比较，无显著差异(P>0.05)；其反应频率的均值分别为16.36±5.92％及7.27±4.07％，与溶媒对照组比较，无显著差异(P>0.05)。
造模后第22天(D22)丙酮测试，空白对照组动物丙酮诱发足部退缩行为总评分数均值为0.60±0.27，反应频率的均值为10.00±4.47％；溶媒对照,s.c.,D-3/D3/D9/D16组的足部退缩行为总评分数均值为1.00±0.40，与空白对照组比较，无显著差异(P>0.05)，反应频率的均值为14.55±4.74％，与空白对照组比较，无显著差异(P>0.05)。受试样品DS002,0.02mg/kg,s.c.,D-3/D3/D9/D16组及受试样品DS002,0.5mg/kg,s.c.,D-3/D3/D9/D16组动物足部退缩行为总评分数均值分别为0.64±0.31及0.73±0.30，与溶媒对照组比较，无显著差异(P>0.05)；其反应频率的均值分别为9.09±4.15％及10.91±4.15％，与溶媒对照组比较，无显著差异(P>0.05)。
试验期间各组动物丙酮诱发足部退缩反应评分变化柱状图及冷触诱发痛反应频率柱状图见图12、图13，总评分数均值及反应频率平均值见表6。
结果表明：相较于溶媒对照(Vehicle control)，注射本发明试剂DS002后，大鼠冷痛阈值无明显提升。
综上，本发明的靶向神经生长因子的人源化重组单克隆抗体DS002能够明显提高疼痛阈值。
讨论
由于化疗药物所致疼痛并不是由单一机制引起的，而是多因素、多环节相互影响、相互作用的结果，因此临床上常见的镇痛药如***等阿片类镇痛药以及非甾体类镇痛药等尽管在治疗其它临床疼痛中有显著疗效，然而在治疗CIPN性疼痛方面效果不理想。
度洛西汀是一种选择性的5-羟色胺(5-HT)和去甲肾上腺素(NE)再摄取抑制药，从机制尚看并不是一个传统的镇痛药，但是在治疗CIPN性疼痛方面有一定的效果。因此无法直接将在其它临床疼痛适应症中被证明的有效镇痛药直接应用于CIPN引起的疼痛中，反之亦反。
NGF抗体虽然已经被临床前和临床数据证明在骨关节炎、慢性下腰痛等适应症中具有明显的疗效，然而该类药品是否能应用于CIPN疼痛并无报道。在本发明的研究中，本发明人首次意外地发现，NGF抗体对CIPN疼痛具有令人惊奇的疗效，对于常规止痛药无效的或难治性CIPN疼痛具有显著的疗效，因此该类药物可作为抗CIPN疼痛的特效药，用于预防和/或治疗CIPN性疼痛。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 达石药业（广东）有限公司
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Claims (8)
1.靶向神经生长因子的单克隆抗体在制备治疗化疗诱导性周围神经病变性疼痛的药物中的用途，其中，所述的化疗诱导性周围神经病变是由化疗剂引起的；
所述的单克隆抗体的重链和轻链序列如SEQID NO:3和SEQ ID NO:4所示；
所述的化疗剂选自下组：紫杉烷类、铂类、长春花生物碱类，或其组合。
2.如权利要求1所述的用途，其特征在于，所述的单克隆抗体为人源化重组单克隆抗体。
3.如权利要求1所述的用途，其特征在于，所述的靶向神经生长因子的单克隆抗体在所述化疗剂给药之前、给药期间或给药之后给予。
4.如权利要求1所述的用途，其特征在于，所述的靶向神经生长因子的单克隆抗体的用量为50-2000mg/50kg。
5.一种药物组合物，其包含
i)靶向神经生长因子的单克隆抗体；所述的单克隆抗体的重链和轻链序列如SEQIDNO:3和SEQ ID NO:4所示；
ii)一种或多种化疗剂；和
iii)药学上可接受的载体。
6.根据权利要求5所述的药物组合物，其特征在于，所述的化疗剂选自下组：紫杉烷类、铂类、长春花生物碱类、吉西他滨、硼替佐米、沙利度胺、长春瑞滨，或其组合。
7.如权利要求5所述的药物组合物，其特征在于，所述的药物组合物为注射剂。
8.一种用于治疗化疗诱导性周围神经病变性疼痛的试剂盒，其特征在于，所述的试剂盒含有一容器，所述容器中包含靶向神经生长因子的单克隆抗体或含有所述单克隆抗体的药物组合物，所述的单克隆抗体的重链和轻链序列如SEQID NO:3和SEQ ID NO:4所示；以及标签或说明书，所述标签或说明书注明所述试剂盒用于治疗化疗诱导性周围神经病变性疼痛。
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