sEphB4-HSA A Pre-Clinical Candidate for Oncology

描述(申请人提供)：这是针对临床前开发的可溶性EphB4-HSA(sEphB4-HSA)及其用于治疗各种癌症类型的最终商业化。SEphB4-HSA被选为临床前试验，因为在异种移植模型的直接比较中有更好的疗效。每3天给药一次的sEphB4-HSA融合蛋白的研究在多个异种移植研究中显示出强大的抗肿瘤作用。我们已经建立了一个高水平表达sEphB4-HSA的哺乳动物细胞系，并开发了一种可规模化的sEphB4-HSA纯化方案，用于深入的药代动力学分析和异种移植研究。具体地说，将进行剂量递增研究，以确定 融合蛋白的药代动力学及其在异种移植模型给药中的指导作用。除了那些已经进行的移植研究外，还将进行异种移植研究，通过与阿伐他汀TM的直接比较，确定是否有特定的肿瘤类型比其他类型的肿瘤更容易受到sEphB4-HSA治疗。此外，将使用sEphB4-HSA和小鼠特异性融合蛋白(msEphB4-MSA)监测免疫活性啮齿动物的免疫原性，并进行初步毒理学筛选。 公共卫生相关性：可溶性EphB4-HSA抑制EphB4受体激酶与其同源配体EPhinB2之间的相互作用和双向信号转导。EphB4-EPhinB2在静脉和动脉内皮细胞上表达，是新生血管成熟所必需的。SEphB4在多种血管生长促进剂的作用下抑制血管生成，具有广泛而新颖的抗血管生成活性。EphB4在许多癌症中也有很高的诱导性，并且sEphB4具有直接的肿瘤细胞毒性。因此，sEphB4-HSA可能会影响许多癌症患者的生存和生活质量。

DESCRIPTION (provided by applicant): This is aimed at the pre-clinical development of soluble EphB4-HSA (sEphB4-HSA) and its ultimate commercialization for the treatment of various cancer types. sEphB4-HSA was chosen as a pre-clinical due to better efficacy in direct comparisons in xenograft models. Studies with the sEphB4-HSA fusion protein dosed every 3 days display potent anti-tumor effects in multiple xenograft studies. We have generated a mammalian cell line that expresses high levels sEphB4-HSA and have developed a scaleable purification protocol for sEphB4-HSA for in depth pharmacokinetic analysis and xenograft studies. Specifically, dose escalation studies will be performed to identify any non-linearities in the pharmacokinetics of the fusion protein and as guidance in dosing Xenograft models. Xenograft studies will be performed in addition to those already performed to determine if there are particular tumor types that are more susceptible to sEphB4-HSA treatment than others by direct comparison with AvastinTM. Additionally, immunogenicity will be monitored in immunocompetent rodents using sEphB4-HSA and mouse specific fusion protein (msEphB4-MSA) and preliminary toxicology screens will be performed. PUBLIC HEALTH RELEVANCE: Soluble EphB4-HSA inhibits the interaction between EphB4 receptor kinase and its cognate ligand EphrinB2 and bidirectional signaling. EphB4-EphrinB2 are expressed on venous and arterial endothelium and critically required for maturation of newly forming vessels. sEphB4 inhibits angiogenesis in response to various vascular growth promoting agents and thus has a broad and novel anti-angiogenic activity. EphB4 is also highly induced in many cancers and sEphB4 has direct tumor cell cytotoxicity. sEphB4-HSA thus may impact survival and quality of life of many cancer victims.