The identification of signaling components that promote tumor growth is a critical step in discovering therapeutic interventions that reduce the morbidity, and mortality associated with cancer. Research has recently validated sphingosine kinase (SK) as an oncogenic protein, suggesting that it is a novel therapeutic target. This kinase produces an extracellular sphingolipid signaling molecule, sphingosine-1 -phosphate (S1P), which promotes tumor growth. Tumor growth is promoted both directly and indirectly by S1P's growth factor actions related to tumor cell proliferation, metastasis and protection from cell death, as well as S1P's pro-angiogenic effects. We have produced a monoclonal anti-S1P antibody (anti-S1P mAb) that could be used as a therapeutic molecular sponge to selectively neutralize S1P, thus lowering the effective extracellular concentrations of this growth factor. In Phase I, we demonstrated that the anti-S1P mAb was able to neutralize the effects of S1P on tumor cell proliferation, protection from cell death and invasiveness in vitro using several cancer cell lines representing multiple cancer types. In vivo the anti-S1P mAb was able to potently inhibit tumor angiogenesis and reduce tumor growth in three orthotopic murine models of human cancer. This Phase I effort not only validated S1P as a therapeutic target, but also suggested that the anti-S1P mAb may be useful clinically in reducing cancer progression by neutralizing S1P's proliferative, metastatic, anti-apoptotic and pro-angiogenic effects. Successful completion of the Phase I project, positions us for a Phase II project designed to conduct more in depth pre-clinical studies necessary for IND filing with the FDA. Studies are aimed to further characterize the antibody in terms of anti-cancer efficacy, evaluate potential therapeutic regimens, perform safety studies in mice and develop a theranostic platform. The Company is currently perusing humanization of the antibody which will be completed during the year of funding. In Phase II, we propose to characterize the strength and nature of the binding of the humanized antibody to S1P to determine the minimum binding characteristic necessary to achieve efficacy in humans. The company will also support ? funding for the necessary GLP qualified safety evaluation of the antibody in monkeys as well as GMP manufacturing and quality control as required for IND filing. The ultimate goal of the Phase II research is to position the Company for an IND with the FDA so that a humanized anti-S1P mAb can be taken to Phase I Clinical Trials. In consultation with our collaborators at MD Anderson Cancer Center, we have designed a Phase I Clinical Trial to be performed at MD Anderson Cancer Center. The Phase I study will be a multiple disease cancer trial with inclusion criteria that could allow us to observe efficacy of the antibody treatment. These inclusion criteria will rely on the use of the anti-S1P mAb in an in vitro assay for S1P levels in patient serum samples to access who might show favorable delay in disease progression with an anti-S1P mAb treatment. ? ? ? ? ?
