EphB4 Receptor Tyrosine Kinase RTK Targeted Humanized Monoclonal Antibody h131

描述(由申请人提供)：这是针对人源化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是因为它能够诱导受体内吞、降解和抑制内皮细胞管的形成。每周给药三次的MAb131和人源化衍生物H131的研究显示，在多个异种移植研究中，具有强大的抗肿瘤作用。我们已经建立了一个高水平表达H131的哺乳动物细胞系，并开发了一种可规模化的H131生产纯化方案，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，以确定抗体药代动力学中的任何非线性，并作为给药异种移植模型的指导。在已经进行的异种移植研究之外，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更容易受到H131治疗的影响，这是通过肿瘤退化而不是肿瘤生长速度降低来衡量的。此外，将监测具有免疫能力的啮齿动物和食蟹猴的免疫原性。 公共卫生相关性：EphB4单抗MAb131可诱导EphB4内吞和降解。EphB4是一种新的治疗靶点，在许多上皮性癌组织中高表达，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。EphB4是突变的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。这一功能需要与动脉内皮细胞上表达的跨膜配体EPhinB2相互作用，然后进行双向信号转导。因此，靶向MAb131的EphB4具有直接靶向肿瘤细胞和调节肿瘤血管生成的双重功能。MAb131在人肿瘤移植瘤中具有很强的活性。MAb131已人源化(H131)，并保留了特异性、亲和力和有效性。在初步研究中，H131在Kras突变肿瘤中诱导肿瘤消退，并且缺乏正常的器官毒性。因此，H131被选为临床开发药物。我们希望在体内对更多的Kras突变肿瘤和EphB4基因扩增的肿瘤进行药代动力学、免疫原性分析和疗效研究。这项工作将导致cGMP的批量生产、毒代动力学研究、药效学研究，并进入I期人体试验。

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.