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.
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.
| Wang, Hui; Li, Dan; Liu, Shuanglong et al. (2015) Small-Animal PET Imaging of Pancreatic Cancer Xenografts Using a 64Cu-Labeled Monoclonal Antibody, MAb159. J Nucl Med 56:908-13 |
| Liu, Shuanglong; Li, Dan; Guo, Jiacong et al. (2014) Design, synthesis, and validation of Axl-targeted monoclonal antibody probe for microPET imaging in human lung cancer xenograft. Mol Pharm 11:3974-9 |
| Li, Dan; Liu, Shuanglong; Liu, Ren et al. (2014) Axl-targeted cancer imaging with humanized antibody h173. Mol Imaging Biol 16:511-8 |
| Li, Dan; Liu, Shuanglong; Liu, Ren et al. (2013) EphB4-targeted imaging with antibody h131, h131-F(ab')2 and h131-Fab. Mol Pharm 10:4527-33 |
| Liu, Shuanglong; Li, Dan; Park, Ryan et al. (2013) PET imaging of colorectal and breast cancer by targeting EphB4 receptor with 64Cu-labeled hAb47 and hAb131 antibodies. J Nucl Med 54:1094-100 |
| Liu, Ren; Ferguson, Benjamin D; Zhou, Yue et al. (2013) EphB4 as a therapeutic target in mesothelioma. BMC Cancer 13:269 |
