Development of Monoclonal Antibodies to Treat Pancreatic Cancer

摘要：胰腺导管腺癌是一种5年生存率极低的破坏性癌症。 即使是那些被早期诊断的患者的存活率也是如此。新的研究表明，这可能是 在原发肿瘤发展之前或同时发生的转移性扩散。上皮性- 间充质转化(EMT)是胰腺癌侵袭转移的关键途径之一。 与肿瘤干细胞表型有关。COARE生物技术研发团队认为，针对这一点 这一过程最终将使我们能够显著提高患者的存活率。 COARE的主要专长是通过双重皮质醇样激酶1(DCLK1)肿瘤干细胞靶向癌症 细胞标记。在COARE的I期SBIR研究中，一种针对小鼠的单抗 DCLK1(CBT-1111)在体外和体内显示出有希望的结果，COARE生物技术公司设计了一种 利用DCLK1‘S细胞表面抗原表达的新一代单抗 胰腺癌、循环中的肿瘤细胞和转移，这些导致了强大的抗肿瘤作用 在PDAC肿瘤移植瘤中的作用。对于这个第二阶段的项目，我们建议进一步开发这种单抗，称为 该药物正在为商业化和人体临床试验做准备。我们将致力于实现这一目标 以下三个具体目标： 目标1：COARE与Panorama Research Institute合作，将使raphumomab人性化，以创造 Raphtuzumab，并将通过Biacore和其他技术确认保留的DCLK1结合亲和力。 AIM2：COARE与俄克拉荷马大学健康科学中心合作，将评估 Raphtuzumab以确定其药代动力学/动力学(PK/PD)性质、作用机制(MOA)和 其在患者衍生的PDAC原位模型中的持续临床前疗效。 目标3：COARE与WIL Research合作，将执行IND使能毒性和免疫原性 在SD大鼠(SDR)和非人灵长类动物(NHP)中的raphtuzumab的研究。 里程碑：Raphtuzumab将显示保留的DCLK1亲和力(1 NM)；DCLK1 MOA(&gt；减少70% EMT和DCLK1表达)；持续的临床前疗效，包括患者来源的 原位模型肿瘤发生；SDR和NHP中合适的PK/PD、毒性和免疫原性。 预期成果：第二阶段SBIR的成功提供了与私营部门接触所需的关键成果和数据 投资者/合作伙伴执行下一步，以获得开始临床试验所需的监管批准 在PDAC患者中。临床试验的成功将导致最终的商业化。当raphtuzumab 进入市场，COARE生物技术公司设想它将是第一种治疗PDAC的方法，可以 显著提高患者的总体存活率。

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an extremely low 5-year survival rate even for those who are diagnosed early. Novel research suggests that this may be the result of metastatic dissemination preceding or concurrent to the development of the primary tumor. Epithelial- mesenchymal transition (EMT) is one of the key pathways in pancreatic cancer invasion and metastasis and is linked to a tumor stem cell phenotype. The COARE Biotechnology R&D team believes that targeting this process will ultimately allow us to significantly increase patient survival. COARE's primary expertise is in targeting cancer through the doublecortin-like kinase 1 (DCLK1) tumor stem cell marker. During COARE's Phase I SBIR study of a mouse monoclonal antibody (mAb) raised against DCLK1 (CBT-1111) that showed promising results in vitro and in vivo, COARE Biotechnology engineered a newer generation of mAb designed to take advantage of DCLK1's cell surface antigen expressed on pancreatic cancer tumors, circulating tumor cells, and metastases, which led to a powerful anti-tumorigenic effect in PDAC tumor xenografts. For this Phase II project, we propose to further develop this mAb, termed raphtumomab, in preparation for commercialization and human clinical trials. We will pursue this objective with the following three specific aims: Aim 1: COARE, in collaboration with Panorama Research Institute, will humanize raphtumomab to create raphtuzumab and will confirm retained binding affinity for DCLK1 by BIAcore and other techniques. Aim2: COARE, in collaboration with the University of Oklahoma Health Sciences Center, will assess raphtuzumab to determine its pharmacokinetic/dynamic (PK/PD) properties, mechanism of action (MOA), and its continued preclinical efficacy in patient-derived orthotopic models of PDAC. Aim 3: COARE, in collaboration with WIL Research, will perform IND-enabling toxicity and immunogenicity studies of raphtuzumab in Sprague-Dawley rats (SDR) and non-human primates (NHPs). Milestones: Raphtuzumab will demonstrate retained DCLK1 affinity (1 nM); a DCLK1 MOA (>70% reduction in EMT and DCLK1 expression); continued preclinical efficacy including a >3-fold reduction in patient-derived orthotopic model tumorigenesis; suitable PK/PD, toxicity, and immunogenicity in SDR and NHPs. Desired Outcome: Phase II SBIR success provide the key results and data needed to engage private-sector investors/partners in carrying out the next steps toward the regulatory approval required to begin clinical trials in PDAC patients. Success with the clinical trials will lead to ultimate commercialization. When raphtuzumab reaches the market, COARE Biotechnology envisions that it will be the first treatment for PDAC that can significantly increase patient overall survival.