During embryonic development, EphB4 and EphrinB2 are both critically required for maturation of newly forming blood vessels. EphrinB2 and is critically required for activation of VEGFR2/3. EphrinB2 is up-regulated in tumor vasculature and loss of EphrinB2 led to arrested tumor angiogenesis and inhibited tumor growth. On the other hand, EphB4 is highly induced in many epithelial cancers and serves as a tumor survival factor. EphB4 expressed on tumor cells also interacts with EphrinB2 on tumor vessels and promotes both the tumor cell survival and the tumor angiogenesis. We have developed an EphB4-EphrinB2 inhibitor - the extracellular fragment of EphB4 fused with human serum albumin (sEphB4-HSA). In SBIR phase I project, we have shown that sEphB4-HSA inhibits tumor growth and causes tumor regression in many xenograft and spontaneous tumor models, and combination with chemotherapy agents has additive/synergistic effect. Particularly sEphB4-HSA is highly effective in regressing Kras mutant driven tumors in xenograft and genetic tumor models. We have produced GMP quality sEphB4-HSA and performed GLP pharmacokinetics (PK) and toxicology studies in mice and monkeys. The IND application has been approved and sEphB4-HSA now is in human phase I clinical trial. First three dose levels have been accrued and no dose limiting toxicity has been observed. None of the patients have experienced grade three or grade four toxicity. There are also signs of clinical benefit. One patient at the lowest dose (2.5mg/kg) has had stable disease at 4 months since the initiation of the treatment. Three patients including a kras lung adenocarcinoma at the second dose level (5mg/kg) have stayed on therapy for 3-4 months and all have had stable diseases and two have shown signs of tumor regression. Therefore, we will manufacture large quantity (1.7 kg) of sEphB4-HSA for the coming human Phase II clinical trials in Kras mutant lung and pancreatic cancers. To determine the treatment regimens, we will conduct efficacy studies in genetic Kras mutant mouse models (with or without concurrent p53 mutation). We will test sEphB4-HSA as a single agent and also combined with chemotherapy agents. Finally we will collect blood from patients at various time points and apply novel technology to isolate circulating tumor cells and analyze the expression of sEphB4-HSA targets. We will also analyze the circulating levels of VEGF and soluble VEGFR2, two known biomarkers of anti-angiogenesis therapies. These results will guide us to identify the pharmacodynamic biomarker of sEphB4-HSA, which will be very useful in the evaluation of patient responses in the clinic.
We are developing a novel anti-cancer therapeutic sEphB4-HSA. sEphB4-HSA targets EphB4-EphrinB2 and has both anti-angiogenesis and anti-tumor cell activity. Pre-clinical studies show that sEphB4-HSA inhibits tumor growth and causes tumor regression in many xenograft and spontaneous tumor models. When combined with chemotherapy agents sEphB4-HSA has additive/synergistic effect. Particularly sEphB4-HSA is highly effective in regressing Kras mutant driven tumors in xenograft and genetic tumor models. sEphB4- HSA is currently in human Phase I clinical trial and no dose limiting toxicity has been observed for the first three dose levels. In addition, there are also signs of clinical benefit: thee patients (including a Kras lung adenocarcinoma) at the second dose level (5mg/kg) have stayed on therapy for 3-4+ months and all of them have had stable diseases and two have tumor regression. Based on preclinical data and up-to-date Phase I clinical trial results, we plan to perform Phase II clinical trials in Kras mutant lung and pancreatic cancers. In this project we propose to manufacture additional sEphB4-HSA for human Phase II clinical trials. We will also select treatment regimens for Phase II clinical trials by performing pre-clinical efficacy studies using spontaneous Kras mutant lung and pancreas tumor models. Finally we will identify the pharmacodynamic biomarker(s) of sEphB4-HSA treatment by analyzing human blood/plasma samples collected in clinical trials. This is a highly innovative project with the following novel findings and therapeutic potentials: 1. EphB4-EphrinB2 are a pair of transmembrane proteins expressed in the vein and artery respectively and necessary for newly forming arterial-venous capillaries to fuse and mature. Their expression is low in adult vessels and normal tissues but induced in tumor vessels, as well as tumor cells. 2. sEphB4-HSA targets EphrinB2, blocks its binding to EphB4 and blocks new vessel formation and maturation and as such has broad anti-angiogenesis function: it can block angiogenesis induced by many growth factors. 3. sEphB4-HSA inhibits tumor growth and induces regression of many cancer types, and also complete tumor regression in combination therapy. 4. EphB4 is required for Kras mutant driven tumor development and sEphB4-HSA is effective in prevention and regression of Kras mutant driven tumor in genetic model. Thus sEphB4-HSA is expected to be effective in treating human Kras cancers that have unmet need. 5. sEphB4-HSA is safe in non-human primates and well tolerated in Phase I clinical trials at three dose levels tested. No immune response is detected in all patient sera. It is therefore expected to enter human Phase II clinical trials soon.
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| 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 |
