Development of Monoclonal Antibodies to Treat Pancreatic Cancer

开发治疗胰腺癌的单克隆抗体

• 批准号: 9321246
• 负责人: Sripathi M Sureban
• 金额: $ 109.4万
• 依托单位: COARE BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321246
• 关键词: Affinity; Animals; Antibodies; Antibody-Producing Cells; Automobile Driving; Back; Binding; Biotechnology; Brain; Cellular biology; Clinical Trials; Cloning; Collaborations; Colorectal; Complementary DNA; Consultations; Data; Development; Disease; Drug Kinetics; Drug resistance; Early Diagnosis; Engineering; Epithelial; Epitopes; Experimental Models; FDA approved; Failure; Feasibility Studies; Generations; Goals; Health; Health Sciences; Human; Immunology; Impairment; In Vitro; Intravenous; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Modeling; Molecular Analysis; Molecular Profiling; Monoclonal Antibodies; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Oklahoma; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Phosphotransferases; Preparation; Primary Neoplasm; Private Sector; Process; Property; RNA Interference; Recombinants; Research; Research Institute; S Phase; Small Business Innovation Research Grant; Source; Sprague-Dawley Rats; Supporting Cell; Surface Antigens; Survival Rate; Techniques; Technology; Therapeutic Monoclonal Antibodies; Tissues; Toxic effect; Toxicology; Tumor Stem Cells; Tumorigenicity; Universities; Work; antitumor effect; base; cancer cell; cancer stem cell; chemotherapy; circulating cancer cell; commercialization; cross reactivity; design; extracellular; gemcitabine; immunogenicity; improved; in vitro activity; in vivo; mouse model; nonhuman primate; novel; novel therapeutics; preclinical efficacy; preclinical safety; preclinical study; protein biomarkers; research and development; small molecule inhibitor; stem; success; targeted treatment; tumor; tumor xenograft; tumorigenesis; tumorigenic

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.

摘要：胰腺导管腺癌（PDAC）是一种毁灭性的癌症，5年生存率极低， 即使是那些早期诊断的人，生存率也很高。新的研究表明，这可能是由于 在原发性肿瘤发生之前或同时发生转移性播散。上皮- 间质转化（EMT）是胰腺癌侵袭和转移的关键途径之一， 与肿瘤干细胞表型相关。COARE生物技术研发团队认为，针对这一 这一过程最终将使我们能够显著提高患者的生存率。 COARE的主要专长是通过双皮质素样激酶1（DCLK 1）肿瘤干细胞靶向癌症 细胞标记。在COARE的I期SBIR研究中，针对 DCLK 1（CBT-1111）在体外和体内显示出有希望的结果，COARE生物技术工程化了一个 新一代的mAb被设计为利用DCLK 1的细胞表面抗原表达在 胰腺癌肿瘤，循环肿瘤细胞和转移，这导致了强大的抗肿瘤 在PDAC肿瘤异种移植物中的作用。对于这个II期项目，我们建议进一步开发这种mAb，称为 raphtumomab，为商业化和人体临床试验做准备。我们将继续努力实现这一目标， 以下三个具体目标： 目标1：COARE与Panorama研究所合作，将raphtumomab人源化， 雷妥珠单抗，并将通过BIAcore和其他技术确认对DCLK 1的保留结合亲和力。 目标2：COARE与俄克拉荷马州大学健康科学中心合作，将评估 雷妥珠单抗，以确定其药代动力学/动力学（PK/PD）特性、作用机制（MOA），以及 其在源自患者的PDAC原位模型中的持续临床前疗效。 目标3：COARE与WIL Research合作，将进行IND启动毒性和免疫原性研究 在Sprague-Dawley大鼠（SDR）和非人灵长类动物（NHP）中进行的雷妥珠单抗研究。 Milkadine：Raphtuzumab将显示保留的DCLK 1亲和力（InM）; DCLK 1 MOA（在DCLK 1中>70%的减少）。 EMT和DCLK 1表达）;持续的临床前疗效，包括患者来源的肿瘤细胞增殖减少>3倍。 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：SBIR第二阶段的成功提供了吸引私营部门参与所需的关键成果和数据 投资者/合作伙伴，以执行开始临床试验所需的监管批准的后续步骤 在PDAC患者中。临床试验的成功将导致最终的商业化。当雷妥珠单抗 到达市场，COARE生物技术设想，这将是第一个治疗PDAC， 显着提高患者的总生存率。

项目成果

Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer.

• DOI: 10.1002/ijc.31400
• 发表时间: 2018-09-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Ge Y;Weygant N;Qu D;May R;Berry WL;Yao J;Chandrakesan P;Zheng W;Zhao L;Zhao KL;Drake M;Vega KJ;Bronze MS;Tomasek JJ;An G;Houchen CW
• 通讯作者: Houchen CW