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.
Public Health Relevance Statement: 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.
NIH Spending Category: Biotechnology; Cancer; Immunization
Project Terms: Adult; Affinity; Antibodies; Biochemical; Biological Assay; Biological Process; Blood Vessels; cancer type; Cell Line; cell motility; Cell Survival; Cells; cGMP production; Characteristics; Clinical; clinical application; Colonic Neoplasms; Combined Modality Therapy; commercialization; Development; Distant Metastasis; Dose; Drug Kinetics; Embryonic Development; Endocytosis; Endothelial Cells; EphB4 Receptor; Epithelial; Gene Amplification; Genetic; Human; humanized monoclonal antibodies; Immunocompetent; immunogenic; immunogenicity; In Vitro; in vivo; intraperitoneal; Intravenous; Kinetics; Lead; Lesion; Ligands; Lung; Lung Adenocarcinoma; Macaca fascicularis; Malignant Neoplasms; Mammalian Cell; Measures; Membrane; Modeling; Monitor; Monkeys; Monoclonal Antibodies; Mus; mutant; Mutation; neoplastic cell; new therapeutic target; Normal tissue morphology; Oncogenes; Organ; Pancreas; Pathway interactions; Pharmacodynamics; Phase; Play; pre-clinical; Pre-Clinical Model; Production; Protein Tyrosine Kinase; Proteins; Protocols documentation; receptor; Receptor Protein-Tyrosine Kinases; response; Rodent; Role; Route; Signal Transduction; Site; Specificity; standard care; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Tube; tumor; Tumor Angiogenesis; tumor growth; tumor xenograft; Venous; Work; Xenograft Model; Xenograft procedure
