Monoclonal Antibody to FGF Receptor 2 for Treatment of Gastric and Other Cancers

用于治疗胃癌和其他癌症的 FGF 受体 2 单克隆抗体

• 批准号: 7744743
• 负责人: K Jin Kim
• 金额: $ 12.22万
• 依托单位: GALAXY BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-08 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744743
• 关键词: Advanced Malignant Neoplasm; Angiogenesis Inducing Agents; Animal Model; Antibodies; Applications Grants; Binding; Biological Assay; Blood Vessels; Breast; Cancer cell line; Clinical; Clinical Trials; Development; Enzyme-Linked Immunosorbent Assay; Epithelial Cell Proliferation; FGF1 gene; FGF2 gene; FGF7 gene; FGFR2 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptor 2; Flow Cytometry; Goals; Grant; Growth; Growth Factor; Human; In Vitro; Ligands; Malignant Neoplasms; Medical; Monoclonal Antibodies; Mutation; Ovarian; Pancreas; Pharmaceutical Preparations; Phase; Play; Property; Protein Isoforms; Protein Tyrosine Kinase; Research; Role; Scientific Advances and Accomplishments; Signal Transduction; Stomach; Stomach Neoplasms; Time; Tumor Cell Line; Uterine Neoplasms; Xenograft Model; bevacizumab; cancer therapy; cancer type; humanized antibody; in vivo; keratinocyte growth factor; malignant stomach neoplasm; mouse model; mutant; neoplastic; overexpression; programs; public health relevance; receptor; receptor binding; research study; small molecule; tumor; tumor xenograft

DESCRIPTION (provided by applicant): The objective of the proposed research is to characterize monoclonal antibodies (mAbs) that bind and block the Fibroblast Growth Factor (FGF) Receptor 2 (FGFR2) 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) is a powerful stimulator of angiogenesis, the new blood vessel formation needed by tumors to grow, while FGF7 (Keratinocyte Growth Factor) potently stimulates epithelial cell proliferation. FGFR2 is a major cellular receptor for FGF1, FGF2, FGF7 and other FGFs, and mutation and/or overexpression of FGFR2 has been associated with gastric, pancreatic, breast, ovarian and uterine tumors, so FGFR2 is a logical target for therapy of these cancers. The Applicant has already generated a panel of anti-FGFR2 mAbs and in preliminary studies shown that one of them completely inhibits growth of a gastric tumor xenograft. In the proposed research plan, the anti-FGFR2 mAbs will be further characterized both in vitro and in vivo, with a view to choosing the best mAb for further development toward clinical trials. The ability of each mAb to bind the FGFR2IIIb and FGFR2IIIc isoforms of FGFR2 will first be determined by ELISA assays and flow cytometry, as these isoforms play different roles in cancer. Then the ability of the mAbs to block binding of FGF1, FGF2 and FGF7 to FGFR2 will be investigated, as an optimal mAb will block all ligand/receptor binding. Next, the extent to which selected mAbs can inhibit FGF-induced and ligand-independent proliferation of tumor cell lines will be determined. The ability of the mAbs to bind to FGFR2 having certain mutations associated with uterine and other cancers will also be determined. Finally, experiments will be conducted to investigate the capability of the most potent mAbs to block growth of human gastric tumor xenografts in mouse models. 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 most effective anti-FGFR2 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 select a monoclonal antibody that targets the receptor for 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 gastric, pancreatic, breast, ovarian and uterine.

描述（由申请人提供）：拟定研究的目的是表征结合并阻断成纤维细胞生长因子（FGF）受体2（FGFR 2）的单克隆抗体（mAb），以用于癌症治疗。生长因子的成纤维细胞生长因子家族是一大组因子，据信在许多肿瘤的生长以及正常发育方面发挥作用。特别是，FGF 2（碱性FGF）是血管生成的强大刺激剂，肿瘤生长所需的新血管形成，而FGF 7（角质细胞生长因子）有力地刺激上皮细胞增殖。FGFR 2是FGF 1、FGF 2、FGF 7和其他FGF的主要细胞受体，并且FGFR 2的突变和/或过表达与胃、胰腺、乳腺、卵巢和子宫肿瘤相关，因此FGFR 2是治疗这些癌症的合理靶点。申请人已经产生了一组抗FGFR 2 mAb，并且在初步研究中显示其中一种完全抑制胃肿瘤异种移植物的生长。在拟定的研究计划中，抗FGFR 2 mAb将在体外和体内进一步表征，以期选择最佳mAb用于进一步开发临床试验。每种mAb结合FGFR 2的FGFR 2 IIIb和FGFR 2 IIIc同种型的能力将首先通过ELISA测定和流式细胞术确定，因为这些同种型在癌症中发挥不同的作用。然后将研究mAb阻断FGF 1、FGF 2和FGF 7与FGFR 2结合的能力，因为最佳mAb将阻断所有配体/受体结合。接下来，将确定所选mAb可抑制肿瘤细胞系的FGF诱导的和配体非依赖性增殖的程度。还将确定mAb结合具有与子宫癌和其他癌症相关的某些突变的FGFR 2的能力。最后，将进行实验以研究最有效的mAb在小鼠模型中阻断人胃肿瘤异种移植物生长的能力。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，将最有效的抗FGFR 2 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。该计划的目标是选择一种单克隆抗体，其靶向被认为与许多肿瘤有关的生长因子的受体。该抗体将有可能成为各种类型癌症的有效药物，包括胃癌、胰腺癌、乳腺癌、卵巢癌和子宫癌。