Novel Targeted Therapy for Breast Cancer

描述（由申请人提供）：乳腺癌仍然是影响和导致妇女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，尽量减少对健康细胞的损害。这些靶点对肿瘤的恶性表型至关重要，但对宿主的正常组织没有作用，从而改善了治疗效果，同时最大限度地减少了全身副作用。抗her2药物赫赛汀（Herceptin）在乳腺癌靶向治疗方面处于领先地位，对一小部分特定患者有明确疗效。很明显，需要更多的治疗选择，包括其他新的靶向治疗。88 kDa的自分泌生长因子pc -细胞衍生生长因子（PCDGF），也被称为颗粒蛋白前体（GP88），是一种新的临床前验证的候选选择，因为它在乳腺癌细胞生物学中起着关键作用，例如：1) GP88是乳腺癌细胞的自分泌生长/生存因子，2)GP88在乳腺癌细胞中表达增加与致瘤性增加有关，3)GP88介导肿瘤细胞血管生成和侵袭性，4)过表达GP88的乳腺癌细胞对目前的治疗方法——他莫昔芬、法洛德、阿霉素和赫赛汀具有耐药性，5) GP88在乳腺癌组织中的表达升高与预后不良的临床参数相关，正常乳腺组织和良性乳腺组织均为阴性；6)预后不良患者血清GP88水平升高。这些结果表明，通过开发抗GP88治疗性中和单克隆抗体（mab）， GP88是一种新的乳腺癌靶向治疗方法。我们已经使用多种GP88特异性免疫原生成了一个大型的GP88小鼠单克隆抗体文库。初步结果表明，抗GP88抗体可以消除GP88的功能活性。这个第一阶段的SBIR应用程序的重点是充分表征这个单克隆抗体库，以确定具有最佳特性的单克隆抗体作为开发候选。具体目标是：1。通过Biacore分析表征抗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鉴定具有最大功效和效力的单抗。3. 确定裸鼠异种移植物致瘤性模型的疗效和效力。在I期结束时，我们将确定一种（或多种）小鼠单抗，在体外和体内具有最佳的临床前疗效和靶向乳腺癌的效力。这些单克隆抗体将需要进一步的开发活动，作为潜在的治疗候选药物，以便在乳腺癌二期临床试验中被考虑。第一步将是从第一阶段选择的小鼠候选单抗中产生小鼠-人嵌合单抗，然后将进一步进入临床前开发。这和其他开发活动将作为SBIR II期应用的基础，作为开发新型乳腺癌生物疗法的基础。乳腺癌仍然是影响和导致妇女死亡的三大癌症之一。目前治疗的主要缺点是在患者中引起的高水平副作用和不足的疗效，特别是对于晚期疾病患者。这一创新的乳腺癌治疗方案将针对乳腺癌固有的机制，同时避免当前许多乳腺癌治疗方法的副作用。

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.