CN117999098A - 用于杀死肿瘤细胞的医药品 - Google Patents
用于杀死肿瘤细胞的医药品 Download PDFInfo
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- CN117999098A CN117999098A CN202280064270.1A CN202280064270A CN117999098A CN 117999098 A CN117999098 A CN 117999098A CN 202280064270 A CN202280064270 A CN 202280064270A CN 117999098 A CN117999098 A CN 117999098A
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Abstract
本发明的课题在于提供一种副作用小的用于杀死肿瘤细胞的医药品。根据本发明,可以提供一种用于杀死肿瘤细胞的医药品,其包含:与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物;以及他拉泊芬钠、卟吩姆钠或维替泊芬,在投予与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物1~4天后,投予他拉泊芬钠、卟吩姆钠或维替泊芬,在投予他拉泊芬钠、卟吩姆钠或维替泊芬的1~4小时后,照射对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长。
Description
技术领域
本发明涉及一种用于杀死肿瘤细胞的医药品,其包含与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物;以及他拉泊芬钠、卟吩姆钠或维替泊芬。
背景技术
日本国内因癌症死亡的人数已上升至每年37万人,是1982年以来延续至今的首要死因。迄今为止,尽管日本国内外已开发出众多针对癌症的治疗方法,但尚未出现特效药。
虽然开发了所谓的低分子的抗癌剂(癌症化学疗法),但不仅药效并不总是很强,而且因强烈副作用给患者造成的痛苦大,并不能说是理想的医药品。抗体药物由于对癌症的特异性强的特征,能够减轻在低分子抗癌剂中观察到的强烈副作用,从而被广泛使用,但对实体癌有效的抗体药物的数量很少。为了强化药效,开发了ADC(抗体药物复合体),但包括毒性方面在内尚未达到令人满意的要求。
另外,作为新型抗体药物的免疫治疗抗体(检查点抑制剂)以新的机理对广泛的癌症种类显示强的药效,但是,已知有效的患者并不是很多,且根据情况表现出甚至死亡的严重副作用。
另一方面,从治疗部位局部化、减轻副作用的考虑出发,开发了PDT(PhotoDynamic Therapy:光动力疗法)。PDT通过对患处照射使聚集于肿瘤部位的光敏色素活化的波长的光进行治疗的方法,在肺癌等中表现出一定的效果,但不能说获得了令人满意的药效。
发明内容
发明所要解决的技术问题
在这样的状况下,本发明的发明人感到开发副作用小、药效强的医药品的必要性,从而完成了本发明的开发。本发明将提供一种副作用小的用于杀死肿瘤细胞的医药品及其给药方法作为所要解决的技术问题。
用于解决技术问题的技术方案
PDT是使光敏色素聚集于肿瘤组织,对其照射光,由此破坏肿瘤细胞的方法。作为PDT中使用的光敏色素,已知有他拉泊芬钠(Talaporfin Sodium)、卟吩姆钠(PorfimerSodium)或维替泊芬(Verteporfin)等水溶性高、肿瘤聚集性高的光敏色素,均已经用于肺癌等的治疗中。PDT是侵袭性小的治疗方法,但存在药效并不一定能满足要求的缺点。
PCI(PhotochemicalInternalization,光化学内化法)是通过使光敏化剂聚集于内体膜并对其照射光而破坏内体膜的方法。据认为由此将被封入内体膜内的抗癌剂、免疫毒素释放到细胞质内,将肿瘤细胞破坏。出于聚集于内体膜的目的,PCI的色素与PDT不同,使用磺化四苯基卟吩(TPCS2a)、铝酞菁(AlPcS2a)等两亲性的光敏化剂。
然而,两亲性的磺化四苯基卟吩(TPCS2a)、铝酞菁(AlPcS2a)担心存在如下的缺点:(1)担心神经毒性;(2)聚集于内体膜以外的细胞膜而产生细胞损伤性;(3)肿瘤聚集性低,产生非特异性副作用等。
为了解决目前为止的问题,我们进行了深入努力,结果发现,水溶性高的他拉泊芬钠、卟吩姆钠或维替泊芬在低浓度时具有提高内体膜的透过性的预料不到的效果。进而发现,通过将与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物、以及他拉泊芬钠、卟吩姆钠或维替泊芬组合,能够显著强化细胞损伤性和肿瘤特异性。
在上述方法中,在照射光时,光敏化剂和免疫毒素等与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物在同时聚集于内体时产生效果。然而,代谢速度快的光敏色素虽然具有减轻副作用的效果,但是使其与免疫毒素等与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物同时聚集并不容易。因此认为需要与以往不同的给药相关的研究。我们为了探索这样的条件而进行了专心努力,结果发现在投予免疫毒素等与肿瘤细胞表面的靶标物质结合的物质后,放置数天进行向肿瘤的聚集后,投予光敏化剂,在其数小时后进行光照射的方法,由此完成了本发明。
根据本发明,提供以下的发明。
<1>一种用于杀死肿瘤细胞的医药品,其包含:
与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物;和
他拉泊芬钠、卟吩姆钠或维替泊芬,
在投予与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物1~4天后,投予他拉泊芬钠、卟吩姆钠或维替泊芬,在投予他拉泊芬钠、卟吩姆钠或维替泊芬1~4小时后,照射对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长。
<2>如<1>所述的医药品,其中,与肿瘤细胞表面的靶标物质结合的物质为抗体、抗体片段、配体或肽。
<3>如<1>或<2>所述的医药品,其中,细胞毒素为皂草素、白树毒素或绿脓杆菌外毒素。
<4>如<1>~<3>中任一项所述的医药品,其中,肿瘤细胞为在细胞表面表达有表皮生长因子受体(Epidermal Growth Factor Receptor:EGFR、ERBB1、ERBB2、ERBB3、ERBB4)、间皮素(Mesothelin)、肝配蛋白A型受体2(Ephrin type-A receptor 2)(EphA2)、磷脂酰肌醇蛋白聚糖(Glypican3,GPC3)、钙黏蛋白17(Cadherin17,CDH17)或环形交叉轴突导向受体同源物1(Roundabout homolog 1,Robo1)的细胞。
<5>如<1>~<4>中任一项所述的医药品,其中,肿瘤细胞为头颈癌、肺癌、肝癌、大肠癌、皮肤癌、食管癌、胃癌、***、子宫内膜癌、间皮瘤、脑肿瘤、恶性黑色素瘤、乳腺癌、胆管癌、胰腺癌、卵巢癌、肾癌、膀胱癌、***癌或恶性淋巴瘤、骨肉瘤中的任意癌细胞。
<6>如<1>~<5>中任一项所述的医药品,其中,对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长为600~800nm。
<A>一种杀死肿瘤细胞的方法,其包括:
(1)使与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物接触肿瘤细胞的工序;
(2)在进行(1)的工序1~4天后,使他拉泊芬钠、卟吩姆钠或维替泊芬与上述肿瘤细胞接触的工序;和
(3)在进行(2)的工序1~4小时后,以对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长照射上述肿瘤细胞,由此将上述细胞杀死的工序。
发明的效果
根据本发明,能够提供副作用小的、用于杀死肿瘤细胞的医药品。
附图说明
图1表示确认荷瘤小鼠的肿瘤缩小效果的结果。
具体实施方式
以下,对本发明的实施方式进行详细说明。
<本发明的概要>
本发明的发明人对药效强、副作用少的肿瘤的治疗方法进行了研究,结果认为:通过光来局部增强药效的PDT、PCI的方法有可能解决上述课题。但是,PDT存在药效弱的缺点,PCI在药效、毒性上均不能令人满意。
因此,本发明的发明人进行了认真努力,结果首次发现了作为水溶性光敏色素的他拉泊芬、卟吩姆钠或维替泊芬通过光照射,使内体的透过性提高。发现了通过将该“色素”、“与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物”与“向肿瘤的光照射”组合而使药效强且副作用可能性低的治疗方法,从而完成了本发明。
即,在本发明中,与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物,在与肿瘤结合后内包于内体中。据认为向另行(或同时)添加的他拉泊芬钠、卟吩姆钠或维替泊芬照射光,使内体内的免疫毒素(或其降解物)释放到细胞质内,能够杀死肿瘤细胞。
他拉泊芬钠、卟吩姆钠和维替泊芬是水溶性的,具有如两亲性的磺化四苯基卟吩(TPCS2a)、铝酞菁(AlPcS2a)这种定位于膜上造成的副作用的风险小的优点。此外,吸收波长为与血红蛋白的吸收波长不重复的664nm,因此光的到达深度也深。
作为对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长,优选为600~800nm,更优选为600~750nm,进一步优选为600~700nm,特别优选为650~680nm。
<杀死细胞的方法>
在本发明中,(1)在投予与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物后,(2)投予他拉泊芬钠、卟吩姆钠或维替泊芬,然后(3)照射使他拉泊芬钠、卟吩姆钠或维替泊芬活化的波长的光。
在投予与肿瘤细胞表面的靶标物质结合的物质后,到投予他拉泊芬钠、卟吩姆钠或维替泊芬为止的间隔为1天~4天,优选为1~3天,例如为2天。
在投予他拉泊芬钠、卟吩姆钠或维替泊芬后,到进行光照射为止的间隔为1~4小时,优选为1~3小时,例如为2小时。
<光敏色素>
在本发明中,使用他拉泊芬钠、卟吩姆钠或维替泊芬作为增感剂。
他拉泊芬钠也被称为Laserphyrin、NPe6、Monoaspartyl Chlorin e6,是PDT中使用的光敏色素。
另外,作为其它方式,也可以使用卟吩姆钠(Porfimer Sodium)作为光敏色素。卟吩姆钠是也被称为光敏素(Photofrin)的PDT色素。
另外,作为其它方式,也可以使用维替泊芬(Verteporfin)作为光敏色素。维替泊芬是也被称为维速达尔(Visudyne)的PDT色素。
<与肿瘤细胞表面的靶标物质结合的物质>
作为与肿瘤细胞表面的靶标物质结合的物质,可以列举抗体、抗体片段、配体或肽等,但没有特别限定。
在作为与肿瘤细胞表面的靶标物质结合的物质使用抗体的情况下,可以使用与肿瘤细胞表面上的靶标物质(例如表皮生长因子受体EGFR、ERBB1、ERBB2、ERBB3、ERBB4)、间皮素、肝配蛋白A型受体2(EphA2)、磷脂酰肌醇蛋白聚糖(GPC3)、钙黏蛋白17(CDH17)、钙黏蛋白3(CDH3)、环形交叉轴突导向受体同源物1(Robo1)等蛋白质特异性结合的抗体。
本发明中使用的抗体的种类没有特别限制,可以为小鼠抗体、人抗体、大鼠抗体、兔抗体、绵羊抗体、骆驼抗体、鸡抗体等,或以使对人的异种抗原性降低等为目的而人工改造的基因重组型抗体,例如嵌合抗体、人源化抗体等中的任意一种。基因重组型抗体可以使用已知的方法来制造。嵌合抗体为包含人以外的哺乳动物、例如小鼠抗体的重链、轻链的可变区和人抗体的重链、轻链的恒定区的抗体,能够通过将编码小鼠抗体的可变区的DNA与编码人抗体的恒定区的DNA连接,将其整合到表达载体并导入宿主使其产生来获得。人源化抗体是将人以外的哺乳动物、例如小鼠抗体的互补决定区(CDR)移植到人抗体的互补决定区得到的,其通常的基因重组方法也是已知的。具体而言,由制作为具有与末端部重叠的部分的数个寡核苷酸通过PCR法合成以连接小鼠抗体的CDR与人抗体的框架区(frameworkregion;FR)的方式设计的DNA序列。将所得到的DNA与编码人抗体恒定区的DNA连接,接着重组入表达载体,将其导入宿主使其产生来获得(EP 239400号公报、国际公开WO96/02576号公报等)。
另外,人抗体的取得方法也是已知的。例如,将人淋巴细胞在体外(in vitro)用所希望的抗原或表达所希望的抗原的细胞敏化,使敏化淋巴细胞与人骨髓瘤细胞、例如U266融合,也能够得到具有对抗原的结合活性的所希望的人抗体(参照日本特公平1-59878)。另外,能够通过将具有人抗体基因的全部谱系(repertoire)的转基因动物用所希望的抗原来免疫,获得所希望的人抗体(参照WO93/12227、WO92/03918、WO94/02602、WO94/25585、WO96/34096、WO96/33735)。此外,还已知使用人抗体文库通过淘选来获得人抗体的技术。例如,能够使人抗体的可变区作为单链抗体(scFv)通过噬菌体展示法在噬菌体的表面表达,选择与抗原结合的噬菌体。如果分析所选择的噬菌体的基因,则能够确定编码与抗原结合的人抗体的可变区的DNA序列。得知与抗原结合的scFv的DNA序列后,能够将该序列制作适当的表达载体,获得人抗体。这些方法已经是公知的,能够参考WO92/01047、WO92/20791、WO93/06213、WO93/11236、WO93/19172、WO95/01438、WO95/15388。
与肿瘤细胞结合的抗体优选为人源化或人抗体,但不限定于此。
另外,这些抗体只要不丧失识别肿瘤细胞表面上的由抗原基因编码的蛋白质的全长或一部分的特性即可,也可以为抗体片段(Fragment)等低分子化抗体或抗体的修饰物等。抗体的片段是指保持着与ROBO1的结合能力的抗体的部分。作为抗体片段的具体例,例如能够列举Fab、Fab’、F(ab’)2、Fv、Diabody、单链抗体片段(scFv)等。为了得到这样的抗体片段,构建编码这些抗体片段的基因,将其导入表达载体后,在适当的宿主细胞中使其表达即可。作为抗体的修饰物,也可以使用与聚乙二醇(PEG)等各种分子结合的抗体。
编码单克隆抗体的DNA能够通过惯用的方法(例如使用能够与编码单克隆抗体的重链和轻链的基因特异性结合的寡核苷酸探针)容易地分离、测序。杂交瘤细胞是这样的DNA的优选起始材料。一旦分离后,就能够将DNA***表达载体,重组到E.coli细胞、COS细胞、CHO细胞或不转化就不产生免疫球蛋白的骨髓瘤细胞等宿主细胞中,由重组宿主细胞产生单克隆抗体。
作为与肿瘤细胞表面的靶标物质结合的物质,能够使用配体。在肿瘤细胞表面上的靶标物质例如为表皮生长因子受体(EGFR、ERBB1、ERBB2、ERBB3、ERBB4)、间皮素、肝配蛋白A型受体2(EphA2)等受体的情况下,能够使用针对上述受体的配体。
作为与肿瘤细胞表面的靶标物质结合的物质,也能够使用肽。只要是本领域技术人员,就能够设计和制造与肿瘤细胞表面的靶标物质结合的肽。
<细胞毒素>
细胞毒素优选具有细胞毒性的蛋白质,但不限定于此,可以是博莱霉素这样的合成或天然的具有抗癌作用的化合物、或ADC中使用的化合物。
作为具有细胞毒性的蛋白质的优选方式,能够列举皂草素、白树毒素、绿脓杆菌外毒素、赖氨酸A链、脱糖链赖氨酸A链、核糖体失活蛋白质、α-箒曲菌素(α-Sarcin)、曲霉素、局限曲霉素(Restrictocin)、核糖核酸酶、表鬼臼毒素、白喉毒素、雪卡毒素及其突变体、基因重组体。
<与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物>
与肿瘤细胞表面的靶标物质结合的物质和细胞毒素必须直接或间接地结合。
在作为与肿瘤细胞表面的靶标物质结合的物质使用抗体或其片段的情况下,使其与细胞毒素直接化学结合的方法可以使用已知的ADC(Antibody Drug Conjugate;抗体药物复合体)中所用的结合方法。另外,在细胞毒素为蛋白质的情况下,也可以使用2官能性的交联剂。
另外,在细胞毒素为蛋白质的情况下,也可以通过制成将毒素与抗体或其片段进行基因重组地融合而成的蛋白质,制作免疫毒素。
另外,作为其他方法,也可以使用将抗体或其片段与细胞毒素利用第二结合对间接地结合的方法。作为第二结合对的例子,可以利用亲和素-生物素、抗体-半抗原等。
另外,在本发明中,也可以代替抗体与毒素结合而成的免疫毒素,而使用与肿瘤细胞表面的靶标物质结合的肽或配体与毒素的结合物。
<给药方法和给药量>
将本发明的医药品向存在肿瘤(例如癌等)的受试体给药时的给药方法没有特别限定。
与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物例如能够通过静脉给药、动脉给药、肌肉内给药、皮下给药、皮内给药、腹腔内给药或口服给药来进行给药。另外,还有对肿瘤组织及其周边以局部注射、涂布、喷雾等的方式给药的方法。
他拉泊芬钠、卟吩姆钠或维替泊芬可以通过例如静脉给药、动脉给药、肌肉内给药、皮下给药、皮内给药、腹腔内给药或口服给药来给药。另外,还有向肿瘤组织及其周边局部注射、涂布、喷雾等的方式给药等的方法。
与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合的给药量没有特别限定,例如能够以1μg/体重kg~100mg/体重kg、优选以10μg/体重kg~10mg/体重kg给药。
他拉泊芬钠、卟吩姆钠或维替泊芬的给药量没有特别限定,例如能够以1μg/体重kg~100mg/体重kg、优选以10μg/体重kg~10mg/体重kg给药。
给药次数没有特别限定,可以进行1次以上到多次(1次到20次、优选为1次到10次),例如每2~4周、或每1~2个月进行。另外,光照射次数也没有特别限定,可以进行1次以上到多次。
<作为对象的细胞、疾病>
作为本发明的医药品的给药对象的肿瘤是在表面表达有表皮生长因子受体(EGFR、ERBB1、ERBB2、ERBB3、ERBB4)、间皮素、肝配蛋白A型受体2(EphA2)、磷脂酰肌醇蛋白聚糖(GPC3)、钙黏蛋白17(CDH17)、钙黏蛋白3(CDH3)、或环形交叉轴突导向受体同源物1(Robo1)等的肿瘤。
具体而言,能够列举头颈癌、肺癌、肝癌、大肠癌、皮肤癌、食管癌、胃癌、***、子宫内膜癌、间皮瘤、脑肿瘤、恶性黑色素瘤、乳腺癌、胆管癌、胰腺癌、卵巢癌、肾癌、膀胱癌、***癌或恶性淋巴瘤、骨肉瘤等的癌症。
另外,本发明除了人类(人)的疾病的治疗以外,还可以用于狗、猫、马等人以外的动物类的治疗。
实施例
实施例:通过使用IT-西妥昔单抗(IT-Cetuximab)和他拉泊芬钠(Laserphyrin)的iTAP治疗确认荷瘤小鼠的肿瘤缩小效果
<材料获得>
作为EGFR表达株,从株式会社KAC(京都、日本)获得A549(人肺癌细胞)。作为抗EGFR抗体,从Selleck Biotech株式会社(东京、日本)获得西妥昔单抗。另外,从MeijiSeika Pharma Co.,Ltd.(东京、日本)获得他拉泊芬钠。
<免疫毒素制备>
将溶解于PBS(-)的西妥昔单抗和溶解于超纯水的EZ-LINK磺基-NHS-LC-生物素化试剂(Thermo Fisher Scientific、马萨诸塞州)以成为1:40的摩尔比的方式混合,使其反应后,使用PD SpinTrap G-25(GE Healthcare Life Sciences、英国)进行纯化。将所得到的生物素化西妥昔单抗和链霉亲和素-皂草素(streptavidin-saporin,Biotin-ZInternalization Kit[KIT-27-Z],Advanced Targeting Systems,加利福尼亚)逐次当量混合,在室温反应30分钟,由此得到附加了皂草素的西妥昔单抗(IT-西妥昔单抗)。
<细胞培养>
A549使用在Dulbecco改良Eagle培养基(DMEM)的含高葡萄糖的培养基中添加有10%胎牛血清的培养基,在37℃、CO2浓度5%的条件下进行培养。
<A549细胞株异种移植小鼠制作>
将另外培养得到的A549调制成1×107cells/100μL,在7周龄雄性BALB/c Slc-nu/nu小鼠的右大腿部将细胞进行皮下给药(SC),制作异种移植小鼠(荷瘤小鼠)。肿瘤的大小通过以下的式子计算。
肿瘤体积(mm3)=长径(mm)×短径(mm)×短径(mm)×0.5
<通过使用IT-西妥昔单抗和他拉泊芬钠的iTAP治疗,研究荷瘤小鼠的肿瘤缩小效果>
1.给药和照射
在小鼠的肿瘤的大小平均达到约150mm3时,对以下的组进行随机分组(n=3)。
条件(1)对照组无给药
条件(2)他拉泊芬钠(5mg/kg)给药和664nm激光(30J/cm2)照射组
条件(3)IT-西妥昔单抗(3mg/kg)给药组
条件(4)他拉泊芬钠(5mg/kg)、IT-西妥昔单抗(3mg/kg)给药和664nm激光(30J/cm2)照射组
将IT-西妥昔单抗向小鼠的腹腔内给药,在2天后将他拉泊芬钠进行尾静脉给药。进而在他拉泊芬钠给药2小时后,对肿瘤部位局部照射664nm的激光。
2.观察
给药后每3~5天测定肿瘤尺寸
<结果>
将给药后的肿瘤尺寸的测定结果表示于图1。
在(4)的IT-西妥昔单抗+他拉泊芬钠联用组中,相对于(1)对照组、(2)他拉泊芬钠单独组或者(3)IT-西妥昔单抗单独组,确认到对肿瘤增大的显著抑制。
另外,(1)对照组、(2)他拉泊芬钠单独组或者(3)IT-西妥昔单抗单独组即使用肉眼也确认到了肿瘤的增大,与之相对,在(4)的IT-西妥昔单抗+他拉泊芬钠联用组中,在激光照射的数日后在照射部位形成痂皮,之后随着痂皮脱落,确认到了肿瘤缩小。
由该结果可知,本方法的肿瘤抑制效果显著。
Claims (6)
1.一种用于杀死肿瘤细胞的医药品,其特征在于,包含:
与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物;和
他拉泊芬钠、卟吩姆钠或维替泊芬,
在投予与肿瘤细胞表面的靶标物质结合的物质和细胞毒素的结合物1~4天后,投予他拉泊芬钠、卟吩姆钠或维替泊芬,在投予他拉泊芬钠、卟吩姆钠或维替泊芬1~4小时后,照射对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长。
2.如权利要求1所述的医药品,其特征在于:
与肿瘤细胞表面的靶标物质结合的物质为抗体、抗体片段、配体或肽。
3.如权利要求1或2所述的医药品,其特征在于:
细胞毒素为皂草素、白树毒素或绿脓杆菌外毒素。
4.如权利要求1~3中任一项所述的医药品,其特征在于:
肿瘤细胞为在细胞表面表达有表皮生长因子受体(EGFR、ERBB1、ERBB2、ERBB3、ERBB4)、间皮素、肝配蛋白A型受体2(EphA2)、磷脂酰肌醇蛋白聚糖3(GPC3)、钙黏蛋白17(CDH17)或环形交叉轴突导向受体同源物1(Robo1)的细胞。
5.如权利要求1~4中任一项所述的医药品,其特征在于:
肿瘤细胞为头颈癌、肺癌、肝癌、大肠癌、皮肤癌、食管癌、胃癌、***、子宫内膜癌、间皮瘤、脑肿瘤、恶性黑色素瘤、乳腺癌、胆管癌、胰腺癌、卵巢癌、肾癌、膀胱癌、***癌或恶性淋巴瘤、骨肉瘤中的任意癌细胞。
6.如权利要求1~5中任一项所述的医药品,其特征在于:
对于使他拉泊芬钠、卟吩姆钠或维替泊芬活化有效的波长为600~800nm。
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GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
AU665190B2 (en) | 1990-07-10 | 1995-12-21 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
KR100272077B1 (ko) | 1990-08-29 | 2000-11-15 | 젠팜인터내셔날,인코포레이티드 | 이종 항체를 생산할 수 있는 전이유전자를 가진 인간이외의 동물 |
WO1993012227A1 (en) | 1991-12-17 | 1993-06-24 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
DE69229477T2 (de) | 1991-09-23 | 1999-12-09 | Cambridge Antibody Tech | Methoden zur Herstellung humanisierter Antikörper |
PT1696031E (pt) | 1991-12-02 | 2010-06-25 | Medical Res Council | Produção de auto-anticorpos a partir de reportórios de segmentos de anticorpo e exibidos em fagos |
WO1993019172A1 (en) | 1992-03-24 | 1993-09-30 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
JPH07509137A (ja) | 1992-07-24 | 1995-10-12 | セル ジェネシス,インク. | 異種抗体の生産 |
CA2161351C (en) | 1993-04-26 | 2010-12-21 | Nils Lonberg | Transgenic non-human animals capable of producing heterologous antibodies |
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CA2219361C (en) | 1995-04-27 | 2012-02-28 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
CA2219486A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
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