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. ? ? ?
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