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

描述（由申请人提供）：我们建议评估人源化抗体药物DAPI- 01（抗fgfr2 - 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 （FGFR2）异构体IIIc，其参与雄激素不依赖型肿瘤的生长和转移。我们专门设计的抗体药物旨在针对肿瘤上FGFR2受体的“坏亚型”，而保留正常前列腺上皮上具有抑制肿瘤生长功能的“好亚型”FGFR2- iiib。这项i期SBIR提案的目标包括使用激素非依赖性肿瘤系DU145和DU9479进行体外和体内评估。将进行以下实验：1)检测DAPI-01的体外活性和细胞机制a.抑制受体激活和信号传导b.阻断配体结合或受体二聚化c.对细胞增殖和凋亡的影响2)检测DAPI-01在人前列腺癌异种移植物中的体内疗效d.抑制肿瘤生长、肿瘤血管生成的作用这些研究结果将构成SBIR ii期研究的基础，该研究将重点关注该候选药物的临床前开发。我们的长期目标是开发一种高效的肿瘤选择性治疗激素难治性前列腺癌的药物。美国正在进行几项大型临床试验，以评估前列腺癌免疫治疗药物的有效性和安全性。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 - 2iiic可能具有吸引人的安全性，因为它不会与其他类似蛋白交叉反应，其中包括抑制肿瘤生长和维持正常生理功能的“良好蛋白异构体”。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，杀死侵袭性癌细胞和预防转移性疾病的结果。公共卫生相关性：我们提出了一项治疗候选的可行性研究，针对激素难治性前列腺癌（HRPC）特异性表达的生长因子受体变异的人源化抗体。我们将从HRPC肿瘤细胞系的体外研究和人类异种移植裸鼠的体内研究中获得抗体的肿瘤杀伤活性数据。

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.