EphB4 Receptor Tyrosine Kinase RTK Targeted Humanized Monoclonal Antibody h131

描述（由申请人提供）：该项目旨在人源化MAb131 （h131）的临床前开发及其最终商业化，用于治疗各种癌症类型。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。在多次异种移植研究中，MAb131和人源化衍生物h131每周给药三次显示出有效的抗肿瘤作用。我们已经产生了一种表达高水平h131的哺乳动物细胞系，并开发了一种可扩展的纯化方案，用于深入的药代动力学分析和异种移植研究。具体来说，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。除了已经完成的研究外，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更容易受到h131治疗的影响，通过肿瘤消退而不是肿瘤生长速度的降低来衡量。此外，免疫原性将监测免疫能力强的啮齿动物和食蟹猴。

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.