Novel Monoclonal Antibody Therapy for Cancer

描述(由申请人提供)：申请的总体目标是进行必要的研究，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。此前，一种新的鼠单抗(MAb)L2G7被产生，它抑制HGF与其受体Met结合的能力，诱导正常细胞和癌细胞的增殖，并诱导血管生成。此外，在小鼠异种移植模型中，L2G7几乎完全抑制了两种胶质瘤细胞系的生长。目前的目标是开发一种人源化的L2G7，同时在小鼠模型中对mAb进行更多的体内研究，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已建立的小鼠异种移植模型，研究单抗L2G7对包括乳腺和结肠在内的各种人类肿瘤细胞在体内生长的影响。既分泌HGF又表达Met(HGF+/Met+)的肿瘤细胞因此以自分泌方式利用HGF，将直接进行检测。不分泌HGF(HGF-/Met+)的肿瘤细胞受到HGF的旁分泌刺激，将它们与人MRC5成纤维细胞共同注射到小鼠体内进行测试，作为基质细胞的替代品，并提供人HGF的来源。第二个目的是更彻底地研究L2G7治疗对胶质瘤的影响，胶质瘤是一种致命的脑瘤，通常同时表达HGF和Met。除了在标准的异种移植模型中确定L2G7对更多胶质瘤细胞系的影响外，还将测试L2G7抑制直接接种到小鼠大脑中的胶质瘤细胞生长的能力。这对于证实L2G7可以通过脑瘤中漏水的血脑屏障是必要的，这一点已经在之前的mAb研究中得到了证明。第三个目的是通过分析L2G7处理过的小鼠的肿瘤标本，研究L2G7的抗肿瘤作用机制，特别是其诱导肿瘤细胞凋亡(程序性细胞死亡)和抑制肿瘤血管生成(新血管形成)的能力。第四个目标将与其他目标同时进行，即利用已有的分子建模和基因工程方法开发人源化的L2G7。人源化的L2G7单抗在人类患者中基本上是非免疫原性的，因此适合重复给药。 关联性。尽管最近取得了科学进展，癌症仍然是一个主要的医学问题，而脑瘤是一种特别致命的癌症。这项计划的目标是研究和开发一种人源化的单抗，适合在人类患者身上进行测试，这将有可能成为治疗脑瘤和可能的其他类型癌症的有效药物。

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.