CN102830223A - 一种筛选治疗哺乳动物肿瘤疾病药物的方法 - Google Patents
一种筛选治疗哺乳动物肿瘤疾病药物的方法 Download PDFInfo
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Abstract
本发明公开了一种筛选治疗哺乳动物肿瘤疾病药物的方法，在受测体给药前后分别提取包含疑似含有肿瘤细胞的细胞群的样本一和样本二，然后在样本一和样本二中加入含有SEQIDNO：1，SEQIDNO：2，SEQIDNO：3，SEQIDNO：4，SEQIDNO：5，SEQIDNO：6，SEQIDNO：7或SEQIDNO：8中记载的氨基酸序列的抗体，所述抗体用于标记胰岛素样生长因子I和胰岛素样生长因子II，以判断样本一和样本二中是否含有肿瘤细胞，如有，则对肿瘤细胞进行识别，比较样本一和样本二中的肿瘤细胞量，如样本二的肿瘤细胞量小于样本一，则说明所用药物对肿瘤疾病具有治疗效果。
Description
技术领域
本发明属于生物技术领域，具体涉及一种筛选治疗哺乳动物肿瘤疾病药物的方法。
背景技术
传统的治疗肿瘤疾病药物的筛选方式为：将肿瘤细胞株植入免疫缺陷鼠体内，待肿瘤长成后再给予不同剂量的筛选化合物，然后观察所试化合物是否能抑制肿瘤细胞的生长，甚至使肿瘤细胞死亡或消失。然后再作计算分析，得出最小抑制剂量、中位抑制剂量、LC50等指标，以这些指标作为衡量受试化合物的抗癌作用强度。这一方法的优点是得到的药物可穿过细胞膜以及某些生理屏障，缺点是所得到的药物仅对快速分裂的肿瘤（如白血病或淋巴瘤）疗效较好，而对实体瘤的治疗远不尽人意。而且，这种筛选方式只能针对确定患有肿瘤疾病的个体，而不能判断受测个体是否患有肿瘤，整个筛选所耗时间大部分用于肿瘤的培育，导致这种筛选方法效率低下。
细胞分裂和细胞增殖速率加快会导致肿瘤疾病的发病几率提高。近年来的临床研究表明，胰岛素样生长因子与多种常见肿瘤疾病（如乳腺癌、前列腺癌、肺癌和结肠癌等）的发病有直接关系。胰岛素样生长因子在有丝分裂中发挥调节细胞增殖、分化和凋亡的作用，它不仅刺激细胞酶原还抑制细胞凋亡，这对肿瘤的产生有直接影响。
所以有必要发展一种通过胰岛素样生长因子判断受测个体是否患有肿瘤疾病并筛选治疗哺乳动物肿瘤疾病药物的方法，以缩短筛选时间，提高筛选效率。
发明内容
本发明所需要解决的技术问题是提供一种筛选治疗哺乳动物肿瘤疾病药物的方法。通过将具有本申请所记载的特定氨基酸序列的抗体作用于样本，可判断样本是否含有肿瘤细胞，从而缩短筛选时间，提高筛选效率。
本发明解决上述技术问题所采用的技术方案如下：
一种筛选治疗哺乳动物肿瘤疾病药物的方法，它包括以下步骤：
A．在一个疑似患有肿瘤的个体的血液或组织中取样，得到样本一，样本一包括一个疑似含有肿瘤细胞的细胞群；
B．将候选药物给药至所述个体；
C．在所述个体的血液或组织中取样，得到样本二，样本二包括一个疑似含有肿瘤细胞的细胞群；
D．在样本一和样本二中加入含有SEQ ID NO：1，SEQ ID NO：2，SEQ ID NO：3，SEQ ID NO：4，SEQ ID NO：5，SEQ ID NO：6，SEQ ID NO：7或SEQ ID NO：8中记载的氨基酸序列的抗体；
所述抗体特异性地结合到胰岛素样生长因子I或胰岛素样生长因子I和胰岛素样生长因子II上，标记胰岛素样生长因子I和胰岛素样生长因子II；
E．检测样本一和样本二中是否存在胰岛素样生长因子I标记物或胰岛素样生长因子I标记物和胰岛素样生长因子II标记物；
F．如样本一和样本二中含有胰岛素样生长因子I标记物或胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，则对样本一和样本二进行分析，识别样本一和样本二中的肿瘤细胞，如样本二中的肿瘤细胞数量相较于样本一减少，说明所述的候选药物对于哺乳动物肿瘤疾病具有疗效。
所述的抗体与显像成分连接。
具体地，所述显像成分为荧光染料、放射性标记物、微泡造影剂、酶或热量法标记物。
进一步地，所述的荧光染料为硫氰酸荧光素、罗丹明或得克萨斯红。
所述的放射性标记物为3H、14C、35S、125I、121I、112In或99mTc。
所述的酶为辣根过氧化物酶、碱性磷酸酶或水解酶。
所述的所述的热量法标记物为纳米金珠、有色玻璃珠或塑料珠。
所述的肿瘤为转移性肿瘤或早期阶段肿瘤。
本发明的有益效果是：本发明将具有特定氨基酸序列的抗体用于标记胰岛素样生长因子I和胰岛素样生长因子II，以判断所述样本中是否包含肿瘤细胞，避免了肿瘤的培养，从而缩短筛选时间，提高筛选效率。
附图说明
图1展示了MK35A、MK35B和MK35C结合到胰岛素样生长因子I的情况
图2展示了MK35A、MK35B和MK35C结合到胰岛素样生长因子II的情况
图3展示了MK35C和MK35C-1结合到胰岛素样生长因子I和胰岛素样生长因子II的情况示。
具体实施方式
下面结合具体实施例对本发明作进一步详细描述，本发明的保护范围不仅限于下述实施例。
实施例1：
目前，大部分可用的胰岛素样生长因子抗体都不是来自人类，而是来自鼠类。发明人利用包含1010个不同噬菌体展示的人源性Fab库开发出针对胰岛素样生长因子的单克隆抗体。通过本领域技术人员所熟知的酶联免疫吸附法，利用胰岛素样生长因子I作为靶抗原，经过三轮筛选，得到200个随机个体噬菌体克隆。对能明显结合到胰岛素样生长因子I的单克隆抗体进行测序，其中3个单克隆抗体具有独特的序列，它们在噬菌体内以可溶性Fab表达。其中一个单克隆抗体MK35C在上述的酶联免疫吸附法检测中，对胰岛素样生长因子I和胰岛素样生长因子II都显示出较强的结合特异性，另外两个单克隆抗体，MK35A和MK35B则只对胰岛素样生长因子I显示出结合特异性。
人源性Fab库作为打乱库中特异性抗体轻链可变区基因VL全部组成部分的来源。在从人源性Fab库进行噬菌体的制备时，首先用Nco I和Spe I进行酶切，然后进行琼脂糖凝胶电泳，以去除所有的特异性抗体重链可变区基因VH。对单克隆抗体MK35C的VH区的基因编码进行扩增，引入随机突变，然后与CHI的基因片段相融合。融合片段通过Nco I和Spe I进行酶切，然后将其从凝胶中纯化出来，并连接到纯化的主体载体，得到打乱库中特异性抗体轻链可变区基因VL的全部组成部分。从打乱库中得到2×108个独立的单克隆抗体，所述单克隆抗体为MK35C的变异体。通过针对胰岛素样生长因子I共轭珠的两轮筛选，并通过酶联免疫吸附法进行第二轮筛选后得到200个单克隆抗体。对能明显结合到胰岛素样生长因子I和胰岛素样生长因子II的单克隆抗体进行测序，其中5个单克隆抗体 MK35C-1具有独特的序列，他对胰岛素样生长因子I和胰岛素样生长因子II都显示出很强的结合特异性。
其中，MK35A的特异性抗体重链可变区基因VH包含SEQ ID NO：1中记载的氨基酸序列，MK35A的特异性抗体轻链可变区基因VL包含SEQ ID NO：2中记载的氨基酸序列；
MK35B的特异性抗体重链可变区基因VH包含SEQ ID NO：3中记载的氨基酸序列，MK35B的特异性抗体轻链可变区基因VL包含SEQ ID NO：4中记载的氨基酸序列；
MK35C的特异性抗体重链可变区基因VH包含SEQ ID NO：5中记载的氨基酸序列，MK35C的特异性抗体轻链可变区基因VL包含SEQ ID NO：6中记载的氨基酸序列；
MK35C-1的特异性抗体重链可变区基因VH包含SEQ ID NO：7中记载的氨基酸序列，MK35C-1的特异性抗体轻链可变区基因VL包含SEQ ID NO：8中记载的氨基酸序列。
上述4种抗体与胰岛素样生长因子I或胰岛素样生长因子I和胰岛素样生长因子II特异性结合，抗体与胰岛素样生长因子受体存在竞争关系，从而阻止胰岛素样生长因子与胰岛素样生长因子受体结合，使得细胞增殖所需的信号介导被抑制。
如图1和图2所示，通过酶联免疫吸附法测试，MK35A和MK35B与胰岛素样生长因子I特异性结合，并不与胰岛素样生长因子II结合，MK35C与胰岛素样生长因子I和胰岛素样生长因子II特异性结合，并且其结合能力优于MK35A和MK35B。
如图3所示，通过酶联免疫吸附法测试，随着抗体浓度的提高，抗体与胰岛素样生长因子I和胰岛素样生长因子II的结合量逐渐增大，在浓度相同的情况下，MK35C-1的结合能力优于MK35C的结合能力。从中可以看出，MK35C-1是本发明的一个较佳实施方式。
实施例2：
本实施例在实施例1的基础上，选择MK35C-1对显像成分进行说明，所述显像成分不能对抗体与胰岛素样生长因子I或胰岛素样生长因子II的特异性结合产生重大影响。
MK35C-1与荧光染料共价结合，可选择的荧光染料有硫氰酸荧光素、罗丹明或得克萨斯红，上述荧光染料不会对MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II的特异性结合产生重大影响。MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II特异性结合后，荧光染料即可对胰岛素样生长因子I和胰岛素样生长因子II实现标记。硫氰酸荧光素溶于碱性溶液后会发出强烈的绿色荧光，可以通过肉眼进行观察。罗丹明和得克萨斯红可以通过感光胶片或电子检测器件（如CCD、光电倍增管等）进行检测。
MK35C-1与放射性标记物共价结合，可选择的放射性标记物有3H、14C、35S、125I、121I、112In或99mTc，上述放射性标记物不会影响MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II的特异性。MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II特异性结合后，放射性标记物即可对胰岛素样生长因子I和胰岛素样生长因子II实现标记。放射性标记物的检测可以通过含有一个闪烁计数器或感光胶片的放射自显影技术进行，该技术为本领域技术人员所熟知，此处不再赘述。
MK35C-1与酶共价结合，可选择的酶有辣根过氧化物酶、碱性磷酸酶或水解酶。上述酶不会影响MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II的特异性。MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II特异性结合后，酶即可对胰岛素样生长因子I和胰岛素样生长因子II实现标记。对酶的检测可以通过给酶提供合适的底物，然后检测其反应产物来进行，根据酶的种类的不通，底物和反应产物也有所区别。由于该技术为本领域技术人员所熟知，此处不再赘述。
MK35C-1与热量法标记物结合，可选择的热量法标记物有纳米金珠、有色玻璃珠或塑料珠。热量法标记物不会影响抗体与抗原的特异性。对于标记物的检测可以通过观察与标记物有关的颜色进行。
MK35C-1中还可以加入微泡造影剂，微泡造影剂同样不会对MK35C-1与胰岛素样生长因子I和胰岛素样生长因子II的特异性造成影响。对微泡造影剂的检测可通过本领域技术人员所熟知的超声波成像来完成。
实施例3：
本实施例用于说明本方法的实际效果，所以本实施例所使用的受测个体为植入转移性乳腺癌细胞株并成瘤的小鼠。
本实施例在实施例1和实施例2的基础上进行。
一种筛选治疗哺乳动物肿瘤疾病药物的方法，它包括以下步骤：
A．在所述小鼠的血液或组织中取样，得到样本一，样本一包括一个小鼠细胞群；
B．对所述小鼠注射环磷酰胺100mg，并培养6h；
C．在所述小鼠的血液或组织中取样，得到样本二，样本二包括一个小鼠细胞群；
D．在样本一和样本二中加入MK35C-1，MK35C-1与实施例2中所述的任意一种显影成分连接；
MK35C-1特异性结合到胰岛素样生长因子I和胰岛素样生长因子II上，标记胰岛素样生长因子I和胰岛素样生长因子II；
E．对样本一和样本二进行洗涤，去除其中未与胰岛素样生长因子I和胰岛素样生长因子II结合的MK35C-1，然后检测样本一和样本二中是否存在胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，检测方法根据步骤D中所选择的显影成分确定。检测结果发现样本一和样本二中都存在胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，说明该小鼠体内含有肿瘤细胞，其检测方法根据所述显像成分不同而有所区别，但都是本领域技术人员所熟知的，此处不再赘述；
F．对样本一和样本二进行分析，识别样本一和样本二中的肿瘤细胞，发现样本二中的肿瘤细胞数量为样本一中的肿瘤细胞数量的60%，说明环磷酰胺对转移性乳腺癌具有治疗效果。
实施例4：
本实施例为实施例2的对比例。本实施例所使用的受测个体为健康的小鼠。
一种筛选治疗哺乳动物肿瘤疾病药物的方法，它包括以下步骤：
A．在所述小鼠的血液或组织中取样，得到样本一，样本一包括一个小鼠细胞群；
B．对所述小鼠注射环磷酰胺100mg，并培养6h；
C．在所述小鼠的血液或组织中取样，得到样本二，样本二包括一个小鼠细胞群；
D．在样本一和样本二中加入含有实施例1所述的MK35C-1，MK35C-1与实施例2中所述的任意一种显影成分连接；由于小鼠为健康小鼠，样本一和样本二中不含有胰岛素样生长因子I和胰岛素样生长因子II；
E．对样本一和样本二进行洗涤，去除所有MK35C-1，然后检测样本一和样本二，在样本一和样本二中未发现胰岛素样生长因子I的标记物和胰岛素样生长因子II的标记物，说明所述小鼠为健康小鼠，其体内不含有肿瘤细胞。
实施例5：
本实施例用于说明本方法的实际效果，所以本实施例所使用的受测个体为植入转移性乳腺癌细胞株并成瘤的小鼠。
一种筛选治疗哺乳动物肿瘤疾病药物的方法，它包括以下步骤：
A．在所述小鼠的血液或组织中取样，得到样本一，样本一包括一个小鼠细胞群；
B．对所述小鼠注射青霉素100mg，并培养6h；
C．在所述小鼠的血液或组织中取样，得到样本二，样本二包括一个小鼠细胞群；
D．在样本一和样本二中加入含有实施例1所述的MK35C-1，MK35C-1与实施例2中所述的任意一种显影成分连接；
MK35C-1特异性结合到胰岛素样生长因子I和胰岛素样生长因子II上，标记胰岛素样生长因子I和胰岛素样生长因子II；
E．对样本一和样本二进行洗涤，去除其中未与胰岛素样生长因子I和胰岛素样生长因子II结合的MK35C-1，然后检测样本一和样本二中是否存在胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，检测方法根据步骤D中所选择的显影成分确定。检测结果发现样本一和样本二中都存在胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，说明该小鼠体内含有肿瘤细胞；
F．对样本一和样本二进行分析，识别样本一和样本二中的肿瘤细胞，发现样本二中的肿瘤细胞数量与样本一中的肿瘤细胞数量几乎相同，说明青霉素对转移性乳腺癌没有治疗效果。
本发明所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其原理并不针对于某一特定肿瘤疾病或某一特定药物。使用本发明所述方法即可实现对治疗哺乳动物肿瘤疾病药物的筛选。说明书中所述实施例已足以说明本发明的效果。未针对其它肿瘤疾病或药物进行说明并不能视为本发明的公开不充分。
SEQUENCE LISTING
<110> 四川汇宇制药有限公司
<120> 一种治疗哺乳动物体内肿瘤疾病的方法
<130> 一种治疗哺乳动物体内肿瘤疾病的方法
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Claims (8)
1.一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于，它包括以下步骤：
A．在一个疑似患有肿瘤的个体的血液或组织中取样，得到样本一，样本一包括一个疑似含有肿瘤细胞的细胞群；
B．将候选药物给药至所述个体；
C．在所述个体的血液或组织中取样，得到样本二，样本二包括一个疑似含有肿瘤细胞的细胞群；
D．在样本一和样本二中加入含有SEQ ID NO：1，SEQ ID NO：2，SEQ ID NO：3，SEQ ID NO：4，SEQ ID NO：5，SEQ ID NO：6，SEQ ID NO：7或SEQ ID NO：8中记载的氨基酸序列的抗体；
所述抗体特异性地结合到胰岛素样生长因子I或胰岛素样生长因子I和胰岛素样生长因子II上，标记胰岛素样生长因子I和胰岛素样生长因子II；
E．检测样本一和样本二中是否存在胰岛素样生长因子I标记物或胰岛素样生长因子I标记物和胰岛素样生长因子II标记物；
F．如样本一和样本二中含有胰岛素样生长因子I标记物或胰岛素样生长因子I标记物和胰岛素样生长因子II标记物，则对样本一和样本二进行分析，识别样本一和样本二中的肿瘤细胞，如样本二中的肿瘤细胞数量相较于样本一减少，说明所述的候选药物对于哺乳动物肿瘤疾病具有疗效。
2.根据权利要求1所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的抗体与显像成分连接。
3.根据权利要求2所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的显像成分为荧光染料、放射性标记物、微泡造影剂、酶或热量法标记物。
4.根据权利要求3所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的荧光染料为硫氰酸荧光素、罗丹明或得克萨斯红。
5.根据权利要求3所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的放射性标记物为3H、14C、35S、125I、121I、112In或99mTc。
6.根据权利要求3所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的酶为辣根过氧化物酶、碱性磷酸酶或水解酶。
7.根据权利要求3所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的所述的热量法标记物为纳米金珠、有色玻璃珠或塑料珠。
8.根据权利要求1所述的一种筛选治疗哺乳动物肿瘤疾病药物的方法，其特征在于：所述的肿瘤为转移性肿瘤或早期阶段肿瘤。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108114271A (zh) * | 2016-11-29 | 2018-06-05 | 中国科学院上海生命科学研究院 | 含胰岛素样生长因子-2的药物组合物及其应用 |
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