sEphB4-HSA A Pre-Clinical Candidate for Oncology

sEphB4-HSA 肿瘤学临床前候选药物

• 批准号: 8314951
• 负责人: valery G krasnoperov
• 金额: $ 14.96万
• 依托单位: VASGENE THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314951
• 关键词: Adult; Angiogenesis Inhibition; Blood Vessels; Cell Adhesion; Cell Line; Chimeric Proteins; Clinical; Colon; Data; Development; Disease; Dose; Drug Kinetics; Embryonic Development; Endothelial Cells; Endothelium; EphB4 Receptor; Extracellular Domain; Fibroblast Growth Factor 2; Growth; Growth Factor; Immunocompetent; In Vitro; Intravenous; Kidney; Kinetics; Ligands; Lung; Malignant Neoplasms; Mammalian Cell; Modeling; Monitor; Mus; Neoplasm Metastasis; Phase; Phosphotransferases; Play; Pre-Clinical Model; Proteins; Protocols documentation; Quality of life; Receptor Protein-Tyrosine Kinases; Relative (related person); Rodent; Role; Route; Signal Transduction; Site; Toxicology; Tube; Vascular Endothelial Growth Factors; Venous; Xenograft Model; Xenograft procedure; angiogenesis; cancer type; cell motility; clinical application; commercialization; cytotoxicity; design; immunogenicity; improved; in vivo; intraperitoneal; melanoma; neoplastic cell; novel; novel strategies; oncology; pre-clinical; response; tumor; tumor growth; tumor xenograft

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.

描述（由申请人提供）：这旨在可溶性EphB 4-HSA（sEphB 4-HSA）的临床前开发及其用于治疗各种癌症类型的最终商业化。选择sEphB 4-HSA作为临床前试验，因为在异种移植模型中直接比较的效果更好。每3天给药一次的sEphB 4-HSA融合蛋白的研究在多个异种移植物研究中显示出有效的抗肿瘤作用。我们已经产生了表达高水平sEphB 4-HSA的哺乳动物细胞系，并且已经开发了用于深入药代动力学分析和异种移植研究的sEphB 4-HSA的可缩放纯化方案。具体而言，将进行剂量递增研究，以确定以下方面的任何非线性： 融合蛋白的药代动力学，并作为异种移植模型给药的指导。除了已经进行的研究外，还将进行异种移植研究，以通过与AvastinTM直接比较，确定是否存在对sEphB 4-HSA治疗更敏感的特定肿瘤类型。此外，将使用sEphB 4-HSA和小鼠特异性融合蛋白（msEphB 4-MSA）在免疫活性啮齿动物中监测免疫原性，并进行初步毒理学筛选。 公共卫生关系：可溶性EphB 4-HSA抑制EphB 4受体激酶及其同源配体EphrinB 2之间的相互作用和双向信号传导。EphB 4-EphrinB 2在静脉和动脉内皮上表达，并且对于新形成的血管的成熟至关重要。sEphB 4抑制响应于各种血管生长促进剂的血管生成，因此具有广泛和新颖的抗血管生成活性。EphB 4在许多癌症中也被高度诱导，并且sEphB 4具有直接的肿瘤细胞毒性。因此，sEphB 4-HSA可能影响许多癌症患者的生存和生活质量。

项目成果

Design, synthesis, and validation of Axl-targeted monoclonal antibody probe for microPET imaging in human lung cancer xenograft.

• DOI: 10.1021/mp500307t
• 发表时间: 2014-11-03
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Liu S;Li D;Guo J;Canale N;Li X;Liu R;Krasnoperov V;Gill PS;Conti PS;Shan H;Li Z
• 通讯作者: Li Z

Small-Animal PET Imaging of Pancreatic Cancer Xenografts Using a 64Cu-Labeled Monoclonal Antibody, MAb159.

• DOI: 10.2967/jnumed.115.155812
• 发表时间: 2015-06
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Wang H;Li D;Liu S;Liu R;Yuan H;Krasnoperov V;Shan H;Conti PS;Gill PS;Li Z
• 通讯作者: Li Z

Axl-targeted cancer imaging with humanized antibody h173.

• DOI: 10.1007/s11307-013-0714-z
• 发表时间: 2014-08
• 期刊: MOLECULAR IMAGING AND BIOLOGY
• 影响因子: 3.1
• 作者: Li, Dan;Liu, Shuanglong;Liu, Ren;Park, Ryan;Yu, Haiyang;Krasnoperov, Valery;Gill, Parkash S.;Li, Zibo;Shan, Hong;Conti, Peter S.
• 通讯作者: Conti, Peter S.

EphB4 as a therapeutic target in mesothelioma.

EPHB4作为间皮瘤的治疗靶标。

• DOI: 10.1186/1471-2407-13-269
• 发表时间: 2013-05-30
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Liu R;Ferguson BD;Zhou Y;Naga K;Salgia R;Gill PS;Krasnoperov V
• 通讯作者: Krasnoperov V

EphB4-targeted imaging with antibody h131, h131-F(ab')2 and h131-Fab.

• DOI: 10.1021/mp400354y
• 发表时间: 2013-12-02
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Li D;Liu S;Liu R;Zhou Y;Park R;Naga K;Krasnoperov V;Gill PS;Li Z;Shan H;Conti PS
• 通讯作者: Conti PS