Development of sEphB4-HSA as Novel Therapeutic in Cancer

开发 sEphB4-HSA 作为癌症新疗法

• 批准号: 8648827
• 负责人: valery G krasnoperov
• 金额: $ 81.13万
• 依托单位: VASGENE THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648827
• 关键词: Adult; Affect; Arteries; Binding; Biological Markers; Bioreactors; Blood; Blood Pressure; Blood Vessels; Blood capillaries; Cancer Patient; Cell Survival; Cell physiology; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical trial protocol document; Combined Modality Therapy; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Drug Targeting; Embryonic Development; Epithelial; Evaluation; GMP lots; Genetic; Genetic Models; Growth Factor; Human; Immune response; Integral Membrane Protein; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Modeling; Monkeys; Mus; Mutation; Neoplasm Circulating Cells; Normal tissue morphology; Organ; Pancreas; Pathway interactions; Patient Selection; Patients; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Prevention; Production; Proto-Oncogene Proteins c-akt; Sampling; Serum; Serum Albumin; Small Business Innovation Research Grant; Stable Disease; System; Testing; Therapeutic; Time; Toxic effect; Toxicology; Treatment Protocols; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Veins; Venous; Xenograft procedure; angiogenesis; anti-cancer therapeutic; antiangiogenesis therapy; base; bevacizumab; cancer therapy; cancer type; capillary; chemotherapy; clinical efficacy; established cell line; experience; extracellular; inhibitor/antagonist; innovation; meetings; mutant; mutant mouse model; neoplastic cell; new technology; nonhuman primate; novel; novel therapeutics; pancreatic neoplasm; phase 2 study; pre-clinical; preclinical study; prevent; public health relevance; response; therapeutic angiogenesis; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): During embryonic development, EphB4 and EphrinB2 are both critically required for maturation of newly forming blood vessels. EphrinB2 and is critically required for activation of VEGFR2/3. EphrinB2 is up-regulated in tumor vasculature and loss of EphrinB2 led to arrested tumor angiogenesis and inhibited tumor growth. On the other hand, EphB4 is highly induced in many epithelial cancers and serves as a tumor survival factor. EphB4 expressed on tumor cells also interacts with EphrinB2 on tumor vessels and promotes both the tumor cell survival and the tumor angiogenesis. We have developed an EphB4-EphrinB2 inhibitor - the extracellular fragment of EphB4 fused with human serum albumin (sEphB4-HSA). In SBIR phase I project, we have shown that sEphB4-HSA inhibits tumor growth and causes tumor regression in many xenograft and spontaneous tumor models, and combination with chemotherapy agents has additive/synergistic effect. Particularly sEphB4-HSA is highly effective in regressing Kras mutant driven tumors in xenograft and genetic tumor models. We have produced GMP quality sEphB4-HSA and performed GLP pharmacokinetics (PK) and toxicology studies in mice and monkeys. The IND application has been approved and sEphB4-HSA now is in human phase I clinical trial. First three dose levels have been accrued and no dose limiting toxicity has been observed. None of the patients have experienced grade three or grade four toxicity. There are also signs of clinical benefit. One patient at the lowest dose (2.5mg/kg) has had stable disease at 4 months since the initiation of the treatment. Three patients including a kras lung adenocarcinoma at the second dose level (5mg/kg) have stayed on therapy for 3-4 months and all have had stable diseases and two have shown signs of tumor regression. Therefore, we will manufacture large quantity (1.7 kg) of sEphB4-HSA for the coming human Phase II clinical trials in Kras mutant lung and pancreatic cancers. To determine the treatment regimens, we will conduct efficacy studies in genetic Kras mutant mouse models (with or without concurrent p53 mutation). We will test sEphB4-HSA as a single agent and also combined with chemotherapy agents. Finally we will collect blood from patients at various time points and apply novel technology to isolate circulating tumor cells and analyze the expression of sEphB4-HSA targets. We will also analyze the circulating levels of VEGF and soluble VEGFR2, two known biomarkers of anti-angiogenesis therapies. These results will guide us to identify the pharmacodynamic biomarker of sEphB4-HSA, which will be very useful in the evaluation of patient responses in the clinic.

描述（申请人提供）：在胚胎发育过程中，EphB4和EphrinB2都是新血管成熟的关键。EphrinB2和对VEGFR2/3的激活至关重要。EphrinB2在肿瘤血管中表达上调，EphrinB2的缺失导致肿瘤血管生成受阻，抑制肿瘤生长。另一方面，EphB4在许多上皮性癌症中被高度诱导，并作为肿瘤存活因子。在肿瘤细胞上表达的EphB4还能与肿瘤血管上的EphrinB2相互作用，促进肿瘤细胞存活和肿瘤血管生成。我们开发了一种EphB4- ephrinb2抑制剂——EphB4的细胞外片段与人血清白蛋白（sEphB4-HSA）融合。在SBIR一期项目中，我们发现在许多异种移植和自发肿瘤模型中，sEphB4-HSA抑制肿瘤生长并导致肿瘤消退，并且与化疗药物联合具有相加/协同作用。特别是sEphB4-HSA在异种移植物和遗传肿瘤模型中对Kras突变驱动的肿瘤的消退非常有效。我们生产了GMP质量的sEphB4-HSA，并在小鼠和猴子身上进行了GLP药代动力学（PK）和毒理学研究。新药开发申请已获批，sEphB4-HSA目前处于人体I期临床试验阶段。前三个剂量水平已累计，未观察到剂量限制毒性。没有患者出现3级或4级毒性。也有临床益处的迹象。使用最低剂量（2.5mg/kg）的一名患者在开始治疗后4个月病情稳定。包括一名kras肺腺癌患者在内的三名患者在第二剂量水平（5mg/kg）的治疗中持续了3-4个月，所有患者病情稳定，其中两名患者出现肿瘤消退的迹象。因此，我们将为即将到来的Kras突变肺癌和胰腺癌的人类II期临床试验大量生产（1.7 kg） sEphB4-HSA。为了确定治疗方案，我们将在Kras基因突变小鼠模型（伴有或不伴有p53突变）中进行疗效研究。我们将测试sEphB4-HSA作为单一药物以及与化疗药物联合使用。最后，我们将采集患者不同时间点的血液，并应用新技术分离循环肿瘤细胞，分析sEphB4-HSA靶点的表达。我们还将分析血管内皮生长因子和可溶性VEGFR2的循环水平，这两种已知的抗血管生成治疗的生物标志物。这些结果将指导我们确定sEphB4-HSA的药效学生物标志物，这将对临床中患者反应的评估非常有用。