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

描述（由申请方提供）：拟定研究的目的是彻底表征结合并抑制人成纤维细胞生长因子2（FGF 2;碱性FGF）的人源化单克隆抗体（mAb），以用于癌症治疗。FGF 2可直接刺激肿瘤细胞增殖，并诱导内皮细胞迁移、增殖和分化，是一种强有力的血管生成因子。FGF 2在大多数神经胶质瘤和肾细胞癌（RCC）中强烈表达，有助于前列腺肿瘤的进展，并且是黑素瘤生长的因素，但与肝癌（肝细胞瘤）的主要形式肝细胞癌（HCC）最强烈相关。申请人已经产生了抗FGF 2 mAb，GAL-F2，并且显示其中和了FGF 2的所有测试的生物活性，并且重要的是，强烈抑制来自三种不同HCC细胞系的肿瘤异种移植物的生长。GAL-F2 mAb已经被人源化以产生HuGAL-F2，这是一种可能适用于人类患者给药的mAb。因此，拟定研究计划的总体目标是生成功能试验结果、作用机制发现、动物模型研究和初始安全性研究的数据包，以支持该人源化mAb的IND申请。更具体地，将精确地测定HuGAL-F2对人和小鼠FGF 2的结合亲和力，并将进行测定以用于HuGAL-F2抑制（i）FGF 2与其细胞受体FGFR 1 -4的结合，（ii）FGF 2诱导的磷酸化和细胞增殖，和（iii）FGF 2诱导的血管生成。将广泛探索HuGAL-F2抑制来自几种HCC和RCC细胞系的异种移植物生长的能力。在这些研究中，HuGAL-F2将作为单一药物和与其他药物联合使用进行测试：Nexavar，批准用于治疗HCC和RCC; Sutent，批准用于治疗RCC;和Avastin，目前正在进行HCC的临床试验。将通过测量来自用mAb处理的小鼠的异种移植物中的细胞增殖、血管生成和细胞凋亡来研究HuGAL-F2抗肿瘤生长的作用机制。为了将HuGAL-F2的潜在适应症扩展到脑癌，还将研究该mAb在治疗由胶质母细胞瘤（GBM）干细胞产生的原位异种移植物中的有效性，因为此类异种移植物以高保真度复制真实临床GBM的特征。最后，为了将人源化mAb推向临床试验IND，并帮助吸引企业合作伙伴/许可方赞助进一步开发，将在啮齿动物中进行标准组织交叉反应性研究和初步毒理学研究。 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。该计划的目标是测试一种单克隆抗体，该抗体靶向一种被认为与许多肿瘤有关的生长因子。该抗体将有可能成为治疗各种类型癌症的有效药物，包括肝癌，肾癌和脑癌。

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.