Novel Targeted Therapy for Breast Cancer

描述(申请人提供)：乳腺癌仍然是影响和导致女性死亡的三大癌症之一。目前治疗的主要缺点是副作用高，疗效不足，特别是对转移性疾病患者。靶向癌症治疗的目的是只治疗癌细胞，并将对健康细胞的损害降至最低。这些靶点对肿瘤的恶性表型很关键，但对宿主的正常组织并不重要，在改善结果的同时将全身副作用降至最低。抗HER2，Herceptin是乳腺癌靶向治疗的领头羊，在特定但为数不多的患者中具有明确的疗效。显然需要更多的治疗选择，包括其他新的靶向治疗。88 kDa自分泌生长因子PC细胞衍生生长因子(PCDGF)，也被称为颗粒蛋白前体(GP88)，是一个新的和临床前验证的候选分子，因为它在乳腺癌细胞生物学中发挥着关键作用，例如：1)GP88是乳腺癌细胞的自分泌生长/生存因子，2)乳腺癌细胞中GP88的表达增加与肿瘤的增加有关，3)GP88介导肿瘤细胞的血管生成和侵袭性，4)过表达GP88的乳腺癌细胞对目前的治疗方法-他莫昔芬、Faslodex、阿霉素和赫赛汀-耐药，5)乳腺癌组织中GP88的表达升高与预后不良的临床参数有关，而正常乳腺组织和良性乳腺组织中的表达均为阴性；6)预后不良的患者血清中的GP88水平升高。这些结果表明，通过开发抗GP88的治疗性中和单抗(MAbs)，GP88是一种新的乳腺癌靶向治疗方法。我们已经使用各种GP88特异性免疫原产生了大量针对GP88的鼠单抗。初步结果表明，抗GP88抗体可以消除GP88的功能活性。第一阶段SBIR应用的重点是充分描述该单抗文库的特征，以便确定具有最佳特征的单抗作为开发候选者。具体目的是：1.用Biaccore分析方法研究抗GP88单抗的结合动力学和特异性。2.在相关的体外功能细胞模型中筛选出具有最大疗效和效力的单抗。3.检测裸鼠移植瘤模型的疗效和潜能。在这一阶段的结束时，我们将已经确定了一种在体外和体内具有最佳临床前疗效和效力的针对乳腺癌的小鼠单抗。这些单抗将需要进一步的开发活动作为潜在的治疗候选，以便在第二阶段被考虑用于乳腺癌的临床试验。第一步将是从第一阶段选择的鼠单抗候选产生人-鼠嵌合单抗，然后这种嵌合单抗将进一步进入临床前开发。这项开发活动和其他开发活动将作为第二阶段SBIR应用的基础，作为开发乳腺癌新生物疗法的基础。乳腺癌仍然是影响和导致女性死亡的三大癌症之一。目前治疗的主要缺点是患者副作用高，疗效不足，特别是对晚期疾病患者。这项提案中将开发的创新乳腺癌疗法将针对乳腺癌固有的机制，但避免与目前许多乳腺癌疗法相关的副作用。

DESCRIPTION (provided by applicant): Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects and insufficient efficacy, particularly for patients with metastatic disease. Targeted cancer therapy is designed to treat only the cancer cells and minimize damage to healthy cells. These targets are critical to the tumor's malignant phenotype but not to the host's normal tissues, improving outcomes while minimizing systemic side effects. Anti-HER2, Herceptin, leads the way for targeted therapy in breast cancer with a definite efficacy in a specific but small subset of patients. There is a clear need for additional therapeutic options including other novel targeted therapies. The 88 kDa autocrine growth factor PC-Cell Derived Growth Factor (PCDGF), also known as granulin precursor (GP88), is a novel and preclinically validated candidate of choice as it plays a critical role in breast cancer cell biology, exemplified by the following: 1) GP88 is an autocrine growth/survival factor for breast cancer cells, 2) increased GP88 expression in breast cancer cells is associated with increased tumorigenicity, 3) GP88 mediates tumor cell angiogenesis and invasiveness, 4) breast cancer cells overexpressing GP88 are resistant to current therapies - Tamoxifen, Faslodex, doxorubicin and Herceptin, 5) increased GP88 expression in breast cancer tissue correlates with clinical parameters of poor prognosis while normal and benign breast tissue are negative, 6) patients with poor prognosis have elevated GP88 serum levels. These results highlight GP88 as a novel targeted therapy of breast cancer via the development of anti-GP88 therapeutic neutralizing monoclonal antibodies (Mabs). We have generated a large library of mouse monoclonal antibodies specific to GP88 using a variety of GP88-specific immunogens. Initial preliminary results indicate that an anti-GP88 antibody can abrogate GP88 functional activity. This phase I SBIR application is focused on fully characterizing this Mabs library in order to identify the Mabs with the optimal characteristics to serve as development candidates. The Specific Aims are: 1. Characterize the binding kinetics and specificity of anti-GP88 Mabs by Biacore analysis. 2. Identify Mab's with maximal efficacy and potency in relevant in vitro functional cellular models. 3. Determine efficacy and potency in nude mouse xenograft tumorigenicity models. At the conclusion of this Phase I, we will have identified a mouse Mab (or Mabs) with the optimal in vitro and in vivo pre-clinical efficacy and potency for targeting breast cancer. These Mabs will require further development activities as potential therapeutic candidates in order to be considered for clinical trials in breast cancer during phase II. The first step will be to generate a mouse-human chimeric Mab from the mouse Mab candidate selected during phase I. This chimeric Mab will then be taken further into pre-clinical development. This and other development activities will serve as the basis for a Phase II SBIR application as a basis for the development of novel biological therapy for breast cancer. Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects induced in patients and insufficient efficacy, particularly for patients with advanced disease. The innovative breast cancer therapy to be developed in this proposal will target a mechanism inherent in breast cancer but avoid the side effects associated with many current breast cancer therapies.