EphB4 Receptor Tyrosine Kinase RTK Targeted Humanized Monoclonal Antibody h131

EphB4受体酪氨酸激酶RTK靶向人源化单克隆抗体h131

• 批准号: 8395850
• 负责人: valery G krasnoperov
• 金额: $ 11.25万
• 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: 2012-09-17 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395850
• 关键词: Adult; Affinity; Antibodies; Biochemical; Biological Assay; Biological Process; Blood Vessels; Cell Line; Cell Survival; Cells; Characteristics; Clinical; Colonic Neoplasms; Combined Modality Therapy; Development; Distant Metastasis; Dose; Drug Kinetics; Embryonic Development; Endocytosis; Endothelial Cells; EphB4 Receptor; Epithelial; Gene Amplification; Genetic; Human; Immunocompetent; In Vitro; Intravenous; Kinetics; Lead; Lesion; Ligands; Lung; Lung Adenocarcinoma; Macaca fascicularis; Malignant Neoplasms; Mammalian Cell; Measures; Membrane; Modeling; Monitor; Monkeys; Monoclonal Antibodies; Mus; Mutation; Normal tissue morphology; Oncogenes; Organ; Pancreas; Pathway interactions; Pharmacodynamics; Phase; Play; Pre-Clinical Model; Production; Protein Tyrosine Kinase; Proteins; Protocols documentation; Receptor Protein-Tyrosine Kinases; Rodent; Role; Route; Signal Transduction; Site; Specificity; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Tube; Tumor Angiogenesis; Venous; Work; Xenograft Model; Xenograft procedure; cGMP production; cancer type; cell motility; clinical application; commercialization; humanized monoclonal antibodies; immunogenic; immunogenicity; in vivo; intraperitoneal; mutant; neoplastic cell; new therapeutic target; pre-clinical; receptor; response; standard care; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): This is aimed at the pre-clinical development of humanized MAb131 (h131) and its ultimate commercialization for the treatment of various cancer types. H131 was chosen for its ability to induce receptor endocytosis, degradation, and inhibition of endothelial cell tube formation. Studies with the MAb131 and the humanized derivative h131 dosed three times a week display potent anti-tumor effects in multiple xenograft studies. We have generated a mammalian cell line that expresses high levels of h131 and have developed a scaleable purification protocol for production of h131 used 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 antibody and as guidance in dosing xenograft models. Xenograft studies will be performed in addition to those already done to determine if Kras mutant tumors or tumors with EphB4 gene amplification are more susceptible to h131 treatment measured by tumor regression instead of reduction in the rate of tumor growth. Additionally, immunogenicity will be monitored in immunocompetent rodents and cynomolgus monkey. PUBLIC HEALTH RELEVANCE: EphB4 monoclonal antibody MAb131 induces EphB4 endocytosis and degradation. EphB4 is a novel therapeutic target highly expressed on many epithelial cancers but not normal tissue. It is induced by gene amplification, PI3K activation and most importantly Kras mutation. EphB4 is necessary for mutant Kras to transform target cells. EphB4 is also required for newly forming tumor vessels to mature. This function requires interaction with trans-membrane ligand EphrinB2 expressed on arterial endothelial cells followed by bi-directional signaling. EphB4 targeting MAb131 thus has dual function: targeting tumor cells directly and modulating tumor angiogenesis. MAb131 has profound activity in human tumor xenografts. MAb131 has been humanized (h131) and it retains specificity, affinity and efficacy. h131 induces tumor regression in Kras mutant tumors and lacks normal organ toxicity in preliminary studies. h131 is thus selected for clinical development. We wish to conduct pharmacokinetics, immunogenic response assays and efficacy studies against additional Kras mutant tumors and tumors with EphB4 gene amplification in vivo. This work will lead to bulk cGMP production, toxicokinetics study, pharmacodynamics study, and entry to phase I human trial.

描述（由申请人提供）：这旨在人源化MAb131（h131）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H131是因为其诱导受体内吞、降解和抑制内皮细胞管形成的能力。MAb131和人源化衍生物h131每周给药三次的研究在多个异种移植研究中显示出有效的抗肿瘤作用。我们已经产生了一个哺乳动物细胞系，表达高水平的h131，并已开发出一个规模化的纯化方案，用于生产h131用于深入的药代动力学分析和异种移植研究。具体而言，将进行剂量递增研究以鉴定抗体药代动力学中的任何非线性，并作为异种移植物模型给药的指导。除了已经进行的研究外，还将进行异种移植研究，以确定Kras突变肿瘤或EphB4基因扩增的肿瘤是否对h131治疗更敏感，通过肿瘤消退而不是肿瘤生长速率的降低来测量。此外，将在免疫活性啮齿动物和食蟹猴中监测免疫原性。 公共卫生相关性：EphB4单克隆抗体MAb131诱导EphB4内吞和降解。EphB4是一种新型的治疗靶点，在许多上皮癌中高度表达，但在正常组织中不表达。它是由基因扩增，PI3K激活和最重要的Kras突变诱导的。EphB 4是突变型Kras转化靶细胞所必需的。EphB4也是新形成的肿瘤血管成熟所必需的。这种功能需要与动脉内皮细胞上表达的跨膜配体EphrinB2相互作用，然后进行双向信号传导。因此，靶向MAb131的EphB4具有双重功能：直接靶向肿瘤细胞和调节肿瘤血管生成。MAb131在人肿瘤异种移植物中具有显著的活性。MAb131已被人源化（h131），并且其保留特异性、亲和力和功效。 h131在Kras突变肿瘤中诱导肿瘤消退，并且在初步研究中没有正常器官毒性。 因此选择H131用于临床开发。我们希望进行药代动力学、免疫原性应答测定和针对另外的Kras突变体肿瘤和具有EphB4基因扩增的肿瘤的体内功效研究。这项工作将导致大量cGMP生产，毒代动力学研究，药效学研究，并进入I期人体试验。