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LOS ANGELES, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.61K | Year: 2012

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 112.48K | Year: 2012

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 necessaryfor 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.


Patent
Vasgene Therapeutics, Inc | Date: 2011-06-06

In certain embodiments, this present invention provides polypeptide compositions (e.g., antibodies and antigen binding portions thereof that bind to EphB4), and methods for inhibiting EphB4 activity. In other embodiments, the present invention provides methods and compositions for treating cancer or for treating angiogenesis-associated diseases.


Patent
Vasgene Therapeutics, Inc | Date: 2013-05-06

In certain embodiments, this present invention provides polypeptide compositions, including compositions containing a modified polypeptide, and methods for inhibiting Ephrin B2 or EphB4 activity. In other embodiments, the present invention provides methods and compositions for treating cancer or for treating angiogenesis-associated diseases.


Patent
Vasgene Therapeutics, Inc | Date: 2011-02-04

In certain embodiments, this present invention provides antibodies that act as either agonists or antagonists of Delta-like 4 (Dll4) signaling.

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