Novel Monoclonal Antibody Therapy for Cancer

新型单克隆抗体治疗癌症

• 批准号: 7112302
• 负责人: K Jin Kim
• 金额: $ 65.55万
• 依托单位: GALAXY BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112302
• 关键词: angiogenesis; antineoplastics; apoptosis; biotechnology; breast neoplasms; cell line; chemical models; colon neoplasms; cytotoxicity; drug screening /evaluation; glioma; growth factor receptors; hepatocyte growth factor; immunologic substance development /preparation; immunopharmacology; laboratory mouse; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer transplantation; neutralizing antibody; nonhuman therapy evaluation; receptor binding; receptor expression; therapy design /development; xenotransplantation

DESCRIPTION (provided by applicant): The overall objective of the application is to perform necessary studies in preparation for conducting clinical trials in cancer of a humanized antibody that neutralizes hepatocyte growth factor (HGF). Previously, a novel mouse monoclonal antibody (mAb) L2G7 was generated that inhibits the ability of HGF to bind to its receptor Met, to induce proliferation of normal and cancer cells, and to induce angiogenesis. Moreover, L2G7 almost completes inhibits growth of two glioma tumor cell lines in mouse xenograft models. The current goal is to develop a humanized form of L2G7, while conducting additional in vivo studies of the mAb in mouse models to justify clinical trials and to identify the most promising types of cancer to treat. The first specific aim is to investigate the effect of treatment with mAb L2G7 on the in vivo growth of a variety of human tumor cells, including breast and colon, by using established mouse xenograft models. Tumor cells that both secrete HGF and express Met (HGF+/Met+), which therefore utilize HGF in an autocrine manner, will be tested directly. Tumor cells that do not secrete HGF (HGF-/Met+), which are stimulated by HGF in a paracrine manner, will be tested by co-injecting them into mice with human MRC5 fibroblast cells to serve as a surrogate for stromal cells and provide a source of human HGF. The second aim is to more thoroughly investigate the effect of L2G7 treatment on gliomas, a deadly type of brain tumor that usually expresses both HGF and Met. In addition to determining the effect of L2G7 on a larger number of glioma cell lines in standard xenograft models, the ability of L2G7 to inhibit growth of glioma tumor cells that are inoculated directly into the brains of mice will be tested. This is necessary to verify that L2G7 can pass through the leaky blood-brain barrier in brain tumors, as has been suggested by previous studies with other mAbs. The third aim is to investigate the mechanism of anti-tumor action of L2G7, in particular its ability to induce apoptosis (programmed cell death) of tumor cells and to inhibit angiogenesis (new blood vessel formation) in tumors, by analyzing tumor specimens from mice that have been treated with L2G7. The fourth aim, which will be carried out concurrently with the other aims, is to develop a humanized form of L2G7 by using established methods of molecular modeling and genetic engineering. The humanized L2G7 mAb is expected to be essentially non-immunogenic in human patients and thus suitable for repeat dosing. Relevance. Despite recent scientific advances, cancer remains a major medical problem, and brain tumors are a particularly deadly form of cancer. The objective of the planned program is to research and develop a humanized monoclonal antibody suitable for testing in human patients, which will have the potential to be an effective drug for the treatment of brain tumors and possibly other types of cancer.

描述（由申请人提供）：本申请的总体目的是进行必要的研究，为在癌症中进行中和肝细胞生长因子（HGF）的人源化抗体的临床试验做准备。以前，产生了一种新的小鼠单克隆抗体（mAb）L2 G7，其抑制HGF结合其受体Met、诱导正常细胞和癌细胞增殖以及诱导血管生成的能力。此外，L2 G7在小鼠异种移植模型中几乎完全抑制两种胶质瘤肿瘤细胞系的生长。目前的目标是开发L2 G7的人源化形式，同时在小鼠模型中进行mAb的额外体内研究，以证明临床试验的合理性，并确定最有希望治疗的癌症类型。 第一个具体目的是通过使用已建立的小鼠异种移植模型，研究mAb L2 G7治疗对多种人肿瘤细胞（包括乳腺和结肠）体内生长的影响。将直接检测分泌HGF和表达Met（HGF+/Met+）的肿瘤细胞，因此这些肿瘤细胞以自分泌方式利用HGF。不分泌HGF（HGF-/Met+）的肿瘤细胞（以旁分泌方式受HGF刺激）将通过将其与人MRC 5成纤维细胞共注射到小鼠体内进行检测，以作为基质细胞的替代物并提供人HGF的来源。第二个目的是更彻底地研究L2 G7治疗对神经胶质瘤的影响，神经胶质瘤是一种致命的脑肿瘤，通常表达HGF和Met。除了在标准异种移植模型中确定L2 G7对大量神经胶质瘤细胞系的作用之外，还将测试L2 G7抑制直接接种到小鼠脑中的神经胶质瘤肿瘤细胞生长的能力。这对于验证L2 G7可以通过脑肿瘤中渗漏的血脑屏障是必要的，正如先前使用其他mAb的研究所表明的那样。第三个目的是研究L2 G7的抗肿瘤作用的机制，特别是其诱导肿瘤细胞凋亡（程序性细胞死亡）和抑制肿瘤中血管生成（新血管形成）的能力，通过分析来自用L2 G7治疗的小鼠的肿瘤标本。第四个目的将与其他目的同时进行，其是通过使用分子建模和基因工程的已建立方法来开发L2 G7的人源化形式。预期人源化L2 G7 mAb在人类患者中基本上无免疫原性，因此适合重复给药。 本案无关尽管最近的科学进步，癌症仍然是一个主要的医学问题，脑肿瘤是一种特别致命的癌症。该计划的目标是研究和开发一种适用于人类患者测试的人源化单克隆抗体，这将有可能成为治疗脑肿瘤和其他类型癌症的有效药物。

项目成果

A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts.

• DOI: 10.1158/1535-7163.mct-11-0813
• 发表时间: 2012-04
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Wang L;Park H;Chhim S;Ding Y;Jiang W;Queen C;Kim KJ
• 通讯作者: Kim KJ

Monoclonal antibodies to fibroblast growth factor receptor 2 effectively inhibit growth of gastric tumor xenografts.

• DOI: 10.1158/1078-0432.ccr-10-0531
• 发表时间: 2010-12-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Zhao WM;Wang L;Park H;Chhim S;Tanphanich M;Yashiro M;Kim KJ
• 通讯作者: Kim KJ