Monoclonal Antibody to FGF2 for Treatment of Hepatocellular Carcinoma and Other C

用于治疗肝细胞癌和其他癌症的 FGF2 单克隆抗体

• 批准号: 7796709
• 负责人: K Jin Kim
• 金额: $ 11.76万
• 依托单位: GALAXY BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796709
• 关键词: Advanced Malignant Neoplasm; Agar; Angiogenesis Inducing Agents; Animal Model; Antibodies; Applications Grants; Binding; Biological Assay; Blood Vessels; Cell Line; Cell Proliferation; Clinical; Clinical Trials; Development; Epitopes; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor 2 Overexpression; Fibroblast Growth Factor Receptors; Goals; Grant; Growth; Growth Factor; Human; In Vitro; Liver; Malignant neoplasm of esophagus; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Medical; Monoclonal Antibodies; Nexavar; Outcome; Pancreas; Pharmaceutical Preparations; Phase; Play; Primary carcinoma of the liver cells; Property; Prostate; Protein Tyrosine Kinase; Reporting; Research; Retinoblastoma; Role; Scientific Advances and Accomplishments; Signal Transduction; System; Testing; Therapeutic; Thyroid carcinoma; Xenograft Model; Xenograft procedure; bevacizumab; cancer therapy; cancer type; hepatoma cell; humanized antibody; in vitro Assay; in vivo; melanoma; migration; mouse model; neoplastic; neoplastic cell; programs; public health relevance; receptor; research study; small molecule; tumor; tumor xenograft

DESCRIPTION (provided by applicant): The objective of the proposed research is to characterize a monoclonal antibody (mAb) that binds and blocks Fibroblast Growth Factor 2 (FGF2) for potential use in cancer therapy. The FGF family of growth factors is a large group of factors believed to play a role in the growth of many tumors, as well as in aspects of normal development. In particular, FGF2 (basic FGF) not only stimulates some tumor cells directly, but is a powerful inducer of angiogenesis, the new blood vessel formation needed by tumors to grow. Overexpression of FGF2 and/or correlation of FGF2 level with clinical features or outcome has been reported for melanoma, prostate cancer, pancreatic cancer, liver cancer (hepatoma), esophageal cancer, thyroid carcinoma and other types of cancer. The Applicant has already generated an anti-FGF2 mAb and in preliminary studies shown that it binds a different epitope than other anti-FGF2 mAbs, blocks a bioactivity of FGF2 and, importantly, strongly inhibits growth of a hepatoma tumor xenograft. In the proposed research plan, this anti-FGF2 mAb, designated GAL-F2, will be intensively studied both in vitro and in vivo, in order to provide the scientific justification for moving it toward clinical trials. The ability of GAL-F2 to bind to various forms of FGF2 and to block binding of FGF2 to the four FGF receptors, FGFR1-4, will be determined. The ability of GAL-F2 to inhibit FGF2- induced cell proliferation and migration, and to inhibit soft agar colony formation by human hepatoma cell lines, will be investigated. Another important aim will be to show that GAL-F2 has potent anti-angiogenic properties, for example by showing that the mAb inhibits blood vessel formation induced by xenografts of a highly angiogenic retinoblastoma cell line. Finally, experiments will be conducted to investigate the capability of the GAL-F2 mAb to block growth of human hepatoma tumor xenografts in mouse models; the results will be critical for the potential choice of hepatocellular carcinoma as the initial clinical indication for the mAb. It is expected that in Phase II of this grant proposal, more extensive animal model and mechanism of action studies will be conducted, and the GAL-F2 mAb will be converted into a humanized antibody suitable for clinical development. PUBLIC HEALTH RELEVANCE: Despite recent scientific advances, cancer remains a major medical problem. The objective of the planned program is to study a monoclonal antibody that targets a growth factor believed to be involved in many tumors. The antibody has the potential to be an effective drug for various types of cancer including liver, pancreatic, and prostate.

描述（由申请方提供）：拟定研究的目的是表征一种结合并阻断成纤维细胞生长因子2（FGF 2）的单克隆抗体（mAb），以用于癌症治疗。生长因子的FGF家族是被认为在许多肿瘤的生长以及正常发育方面起作用的一大组因子。特别是，FGF 2（碱性FGF）不仅直接刺激一些肿瘤细胞，而且是血管生成的强大诱导剂，肿瘤生长所需的新血管形成。已经报道了黑素瘤、前列腺癌、胰腺癌、肝癌（肝细胞瘤）、食管癌、甲状腺癌和其他类型的癌症的FGF 2过表达和/或FGF 2水平与临床特征或结果的相关性。申请人已经产生了抗FGF 2 mAb，并且在初步研究中显示，其与其他抗FGF 2 mAb结合不同的表位，阻断FGF 2的生物活性，并且重要的是，强烈抑制肝癌肿瘤异种移植物的生长。在拟议的研究计划中，将在体外和体内对这种抗FGF 2 mAb（命名为GAL-F2）进行深入研究，以便为将其推向临床试验提供科学依据。将测定GAL-F2与各种形式的FGF 2结合和阻断FGF 2与四种FGF受体FGFR 1 -4结合的能力。将研究GAL-F2抑制FGF 2诱导的细胞增殖和迁移以及抑制人肝癌细胞系软琼脂集落形成的能力。另一个重要目标是证明GAL-F2具有强效的抗血管生成特性，例如通过证明mAb抑制高度血管生成的视网膜母细胞瘤细胞系异种移植诱导的血管形成。最后，将进行实验以研究GAL-F2 mAb在小鼠模型中阻断人肝癌肿瘤异种移植物生长的能力;结果对于肝细胞癌作为mAb初始临床适应症的潜在选择至关重要。预计在本次资助申请的II期，将进行更广泛的动物模型和作用机制研究，并将GAL-F2 mAb转化为适合临床开发的人源化抗体。 公共卫生相关性：尽管最近的科学进步，癌症仍然是一个主要的医疗问题。该计划的目标是研究一种单克隆抗体，其靶向被认为与许多肿瘤有关的生长因子。该抗体有可能成为各种类型癌症的有效药物，包括肝癌，胰腺癌和前列腺癌。