Antibody therapeutics - feasibility study on hormone-refrectory prostate cancer m

描述（由申请人提供）：我们提出评估人源化抗体药物DAPI- 01（抗FGFR 2-IIIc）在前列腺癌模型系统中的治疗可行性。该抗体的分子靶点是成纤维细胞生长因子受体-2（FGFR 2）亚型IIIc，其参与雄激素非依赖性肿瘤生长和转移。我们的专用抗体药物旨在靶向肿瘤上FGFR 2受体的“坏同种型”，但保留正常前列腺上皮上的“好同种型”FGFR 2-IIIb，其功能是抑制肿瘤生长。该第一阶段SBIR提案的目标包括使用激素非依赖性肿瘤细胞系DU 145和DU 9479进行体外和体内评估。将进行以下实验：1）测试DAPI-01的体外活性和细胞机制a.受体活化和信号传导的抑制B.阻断配体结合或受体二聚化。2）测试DAPI-01在人前列腺癌异种移植物中的体内功效这些研究的结果将成为SBIR II期研究的基础，该研究将专注于该候选药物的临床前开发。我们的长期目标是开发一种对难治性前列腺癌具有高效力的肿瘤选择性治疗剂。美国正在进行几项大型临床试验，以评估免疫药物治疗前列腺癌的疗效和安全性。这些候选药物的副作用一直是一个主要问题。拟议的候选药物抗FGFR-2 IIIc可能具有有吸引力的安全特性，因为它不与其他类似蛋白质发生交叉反应，其中包括抑制肿瘤生长和维持正常生理功能的“良好蛋白质同种型”。这种治疗策略可以达到维持前列腺上皮组织缓慢生长的更正常状态的结果，并杀死侵袭性癌细胞和防止转移性疾病。公共卫生相关性：我们提出了一个可行性研究的治疗候选人，一个人源化的抗体对生长因子受体变异体特异性表达的难治性前列腺癌（HRPC）。我们将从使用HRPC肿瘤细胞系的体外研究和使用裸鼠中的人异种移植物的体内研究中获得关于抗体的肿瘤杀伤活性的数据。

DESCRIPTION (provided by applicant): We propose to evaluate the therapeutic feasibility of a humanized antibody drug DAPI- 01 (anti-FGFR2-IIIc) in prostate cancer model systems. The molecular target of the antibody is fibroblast growth factor receptor-2 (FGFR2) isoform IIIc, which is involved in androgen-independent tumor growth and metastasis. Our specialized antibody drug is designed with the intention of targeting the "bad isoform" of FGFR2 receptor on tumor, but spare the "good isoform" FGFR2-IIIb on normal prostate epithelia that functions to suppress tumor growth. Objectives of this Phase-I SBIR proposal include both in vitro and in vivo evaluations using hormone-independent tumor lines, DU145 and DU9479. The following experiments will be conducted: 1) Testing DAPI-01 in vitro activity and cellular mechanism a. Inhibition of receptor activation and signaling b. Blocking ligand binding or receptor dimerization c. Effects on cell proliferation and apoptosis 2) Testing DAPI-01 in vivo efficacy in human prostate cancer xenografts d. Effect on inhibiting tumor growth, tumor angiogenesis The results of these studies will form the basis for SBIR phase-II study, which will focus on pre-clinical development of this drug candidate. Our long-range goal is to develop a tumor-selective therapeutic agent with high potency for hormone-refractory prostate cancer. Several large clinical trials are underway in the US to evaluate the efficacy and safety of immunotherapeutic drugs for prostate cancer. The side effects of these drug candidates had been a major concern. The proposed drug candidate, anti-FGFR-2IIIc may have attractive safety features because it does not cross-react with other similar proteins, which include the "good protein isoforms" that suppress tumor growth and maintain normal physiological functions. This therapeutic strategy may achieve the result of maintaining a more normal state of slow growth in the prostate epithelial tissue, and kill the invasive cancer cell and prevent metastatic diseases. PUBLIC HEALTH RELEVANCE: We propose a feasibility study for a therapeutic candidate, a humanized antibody against a growth factor receptor variant specifically expressed on hormone-refractory prostate cancer (HRPC). We will obtain data on antibody's tumor-killing activity from in vitro studies using HRPC tumor cell lines, and in vivo studies using human xenografts in nude mice.