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

描述(由申请人提供)：拟议研究的目标是彻底鉴定一种人源化的单抗(MAb)，它结合和抑制人成纤维细胞生长因子2(FGF2；基本成纤维细胞生长因子)，用于癌症治疗。FGF2可以直接刺激肿瘤细胞的增殖，也可以诱导内皮细胞的迁移、增殖和分化，是一种强有力的血管生成因子。FGF2在大多数胶质瘤和肾细胞癌(RCC)中强烈表达，有助于前列腺癌的发展，是黑色素瘤生长的一个因素，但与肝细胞癌(肝细胞癌)的相关性最强，肝细胞癌是肝癌的主要形式。申请人已经产生了一种抗FGF2的单抗GAL-F2，并表明它中和了所有测试的FGF2的生物活性，重要的是，它强烈地抑制了来自三个不同肝癌细胞系的肿瘤异种移植瘤的生长。Gal-F2单抗已经人源化，产生了HuGAL-F2，这是一种潜在的适合于人类患者给药的单抗。因此，拟议研究计划的总体目标是生成一个数据包，其中包括功能分析结果、作用机制发现、动物模型研究和初步安全性研究，这些研究将支持这种人源化单抗提交IND。更具体地说，HuGAL-F2与人和小鼠FGF2的结合亲和力将得到准确测定，并将进行HuGAL-F2抑制(I)FGF2与其细胞受体FGFR1-4的结合，(Ii)FGF2诱导的磷酸化和细胞增殖，以及(Iii)FGF2诱导的血管生成。HuGAL-F2抑制几种肝癌和肾癌细胞系异种移植瘤生长的能力将被广泛探索。在这些研究中，HuGAL-F2将作为单一药物进行测试，并与其他药物一起进行测试：被批准用于治疗肝细胞癌和肾癌的Nexavar；被批准用于治疗肾细胞癌的Sutent；以及目前处于肝细胞癌临床试验中的阿瓦斯丁。HuGAL-F2抗肿瘤生长的作用机制将通过检测单抗处理的小鼠移植瘤的细胞增殖、血管生成和细胞凋亡来探讨。为了扩大HuGAL-F2治疗脑癌的潜在适应症，还将研究这种单抗在治疗胶质母细胞瘤(GBM)干细胞生成的原位异种移植中的有效性，因为这种异种移植复制了真正的临床GBM的高保真特征。最后，为了将人源化mAb推向临床试验的IND，并帮助吸引企业合作伙伴/被许可人赞助进一步的开发，将在啮齿类动物身上进行标准组织交叉反应研究和初步毒理学研究。 公共卫生相关性：尽管最近取得了科学进展，但癌症仍然是一个主要的医学问题。这项计划的目标是测试一种针对一种生长因子的单抗，据信这种生长因子与许多肿瘤有关。该抗体将有可能成为治疗包括肝、肾和脑在内的各种癌症的有效药物。

DESCRIPTION (provided by applicant): The objective of the proposed research is to thoroughly characterize a humanized monoclonal antibody (mAb) that binds and inhibits human Fibroblast Growth Factor 2 (FGF2; basic FGF) for potential use in cancer therapy. FGF2 can directly stimulate tumor cell proliferation and also induces migration, proliferation and differentiation of endothelial cells, so is a potent angiogenic factor. FGF2 is strongly expressed in most gliomas and in renal cell cancer (RCC), contributes to progression of prostate tumors, and is a factor for the growth of melanomas, but has been most strongly associated with hepatocellular carcinoma (HCC), the predominant form of liver cancer (hepatoma). The Applicant has generated an anti-FGF2 mAb, GAL-F2, and shown that it neutralizes all tested biological activities of FGF2 and, importantly, strongly inhibits the growth of tumor xenografts from three different HCC cell lines. The GAL-F2 mAb has already been humanized to generate HuGAL-F2, a mAb potentially suitable for administration to human patients. Hence, the overall goal of the proposed research plan is to generate a data package of functional assay results, mechanism of action findings, animal model studies and initial safety studies that will support filing of an IND for this humanized mAb. More specifically, the binding affinity of HuGAL-F2 for human and mouse FGF2 will be precisely determined, and assays will be conducted for HuGAL-F2 inhibition of (i) binding of FGF2 to its cellular receptors FGFR1-4, (ii) FGF2-induced phosphorylation and cell proliferation, and (iii) FGF2-induced angiogenesis. The ability of HuGAL-F2 to inhibit growth of xenografts from several HCC and RCC cell lines will be explored extensively. In these studies, HuGAL-F2 will be tested both as a single agent and in combination with other drugs: Nexavar, approved for treatment of HCC and RCC; Sutent, approved for treatment of RCC; and Avastin, currently in clinical trials for HCC. The mechanism of action of HuGAL-F2 against tumor growth will be investigated by measuring cellular proliferation, angiogenesis and apoptosis in xenografts from mice treated with the mAb. To expand the potential indications for HuGAL-F2 to brain cancer, the effectiveness of this mAb in treating orthotopic xenografts generated from glioblastoma (GBM) stem cells will also be investigated, as such xenografts replicate the characteristics of true clinical GBMs with high fidelity. Finally, to advance the humanized mAb toward an IND for clinical trials and to help attract a corporate partner/licensee to sponsor further development, a standard tissue cross-reactivity study and an initial toxicology study in rodents will be performed. PUBLIC HEALTH RELEVANCE: Despite recent scientific advances, cancer remains a major medical problem. The objective of the planned program is to test a monoclonal antibody that targets a growth factor believed to be involved in many tumors. The antibody will have the potential to be an effective drug for various types of cancer including liver, kidney, and brain.