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New strategy for pancreatic cancer. immunotargeting therapy by chimeric monoclonal antibody

胰腺癌的新策略。

基本信息

批准号：
13671330
负责人：
SAWADA Tetsuji
金额：
$ 2.05万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671330/
关键词：
pancreatic cancer monoclonal antibody targeting therapy chimeric Nd2

项目摘要

Chimeric Nd2 (c-Nd2) is a monoclonal antibody produced against pancreatic cancer mucin and its recognizing antigen epitope is supposed to be a core peptide of MUC5AC including cancer-associated carbohydrates. Chimeric Nd2 has been known to demonstrate almost no reaction to normal tissues, but specific reaction to pancreatic cancer by immunostaining study. In the present study, we investigated whether it can induce an antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) which are known to be an important for functioning effect in the use for immunotherapy of antibody. By in vitro investigation, c-Nd2 demonstrated the ability inducing ADCC during co-culture with targeting cells, pancreatic cancer cells (SW1990) and effector cells which were obtained from peripheral blood of healthy volunteers. The effector cells inducing ADCC by c-Nd2 were clarified not only mononuclear cells (monocytes and NK cells) but also polymorphonuclear neutrophils. The … More ADCC activity was enhanced by pretreatment of neutrophils with G-CSF. Furthermore, CDC could be found to be induced by c-Nd2 during target cells incubation with complement. Consequently, we investigated whether the in vivo anti-tumor effect can be induced by treatment of pancreatic cancer transplanted nude mice with c-Nd2. C-Nd2 demonstrated the growth inhibition of xenografted tumor by intra-peritoneal injection (i.p.) and enlonged the survival of nude mice which had orthotopic transplanted tumor. It could also inhibit liver metastasis induced by injecting cancer cells into spleen. When G-CSF were administered to xenografted nude mice, anti-tumor effect was enhanced by activating neutrophils corresponding to the in vitro results. According to the present results, c-Nd2 is suggested to have high clinical possibility as targeting immunotherapy for pancreatic cancer by its high specificity and ADCC or CDC inducing ability. In the current study, we are preparing to produce humanized antibody for the clinical application to more firmly reduce the immunogenicity and side effect in the actual clinical trial. Less

嵌合Nd 2（c-Nd 2）是针对胰腺癌粘蛋白产生的单克隆抗体，其识别抗原表位被认为是MUC 5AC的核心肽，包括癌症相关的碳水化合物。免疫组化研究表明，嵌合Nd 2对正常组织几乎没有反应，但对胰腺癌有特异性反应。在本研究中，我们研究了它是否可以诱导抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC），这是已知的重要功能效应，在使用抗体的免疫治疗。体外实验表明，c-Nd 2在与胰腺癌细胞（SW 1990）及健康志愿者外周血中的效应细胞共培养时，具有诱导ADCC的能力。c-Nd 2诱导ADCC的效应细胞不仅包括单核细胞（单核细胞和NK细胞），还包括多形核中性粒细胞。的 ...更多信息用G-CSF预处理中性粒细胞可增强ADCC活性。此外，CDC可以被发现的c-Nd 2诱导靶细胞与补体孵育过程中。因此，我们研究了是否可以通过用c-Nd 2治疗胰腺癌移植裸鼠来诱导体内抗肿瘤效果。C-Nd 2通过腹腔内注射（i. p.）延长裸鼠原位移植瘤的存活时间。对脾内注射癌细胞诱导的肝转移有抑制作用。当给予G-CSF到异种移植的裸鼠时，通过激活中性粒细胞增强抗肿瘤作用，与体外结果相对应。因此，c-Nd 2具有很高的特异性和ADCC或CDC诱导能力，有可能作为胰腺癌的靶向免疫治疗药物。在本研究中，我们准备生产人源化抗体用于临床应用，以便在实际临床试验中更牢固地降低免疫原性和副作用。少