Novel Monoclonal Antibody Therapy for Cancer

描述（由申请人提供）：这项工作的总体目标是开发用于癌症治疗的新型单克隆抗体。HGF是许多不同类型癌细胞的旁分泌血管生成因子和自分泌生长因子。因此，预期HGF拮抗性单克隆抗体具有广泛的抗癌治疗潜力。在本研究中，我们将（1）表征选定的阻断性抗HGF单克隆抗体（mAb）并产生更好的阻断性mAb;（2）证明抗HGF mAb的体外抗肿瘤活性和抗血管生成活性;（3）证明抗HGF mAb在异种移植裸鼠模型中对人肿瘤生长的抑制作用。II期研究将包括在异种移植裸鼠模型（包括转移模型）中测定一种或多种抗HGF mAb与一组更广泛的人肿瘤细胞系的抗肿瘤活性，并与标准化疗剂联合使用。将检查抗体剂量和给药时间的影响。作用机制（细胞凋亡、坏死等）还将进行研究，并对任何毒性进行初步观察。此外，我们将最有前途的mAb重新格式化为小鼠-人嵌合mAb和/或人源化mAb，以产生适用于人类患者临床试验的药物。

DESCRIPTION (provided by applicant): The overall goal of this work is to develop a novel monoclonal antibody for cancer therapy. HGF is a paracrine angiogenic factor and an autocrine growth factor for many different types of cancer cells. Thus antagonistic monoclonal antibodies to HGF are expected to have broad anti-cancer therapeutic potential. In this study, we will (1) characterize selected blocking anti-HGF monoclonal antibodies (mAbs) and generate better blocking mAbs; (2) demonstrate anti-tumor activities and anti-angiogenic activities of anti-HGF mAbs in vitro; and (3) demonstrate the inhibition of human tumor growth by anti-HGF mAbs in a xenograft nude mouse model. The PHASE II studies will include determination of the anti-tumor activities of one or more anti-HGF mAbs with a more extensive panel of human tumor cell lines in xenograft nude mouse model, including metastasis models, and in combination with standard chemotherapeutic agents. The effects of antibody dose and time of administration will be examined. The mechanism of action (apoptosis, necrosis, etc.) will also be investigated and preliminary observations of any toxicity will be made. In addition, we will reformat the most promising mAb as a mouse-human chimeric mAb and/or a humanized mAb to generate an agent suitable for clinical trials in human patients.