Commercialization of ASONEP for the Treatment of Cancer

描述（由申请人提供）：Lpath Inc.开发了一种新型癌症治疗剂ASONEPTM，一种人源化单克隆抗体，可中和致瘤性和血管生成生长因子鞘氨醇-1-磷酸（S1P）。S1P是一种不寻常的靶标，因为它是一种生物活性脂质。因此，ASONEP有可能成为一流的抗癌药物。ASONEP目前正在癌症的1期临床试验中。对于这笔拨款，我们正在为ASONEP的临床开发和商业化申请配套资金。Lpath已经进行了一系列全面的临床前疗效和药代动力学研究，以证实抗s1p抗体的潜在抗癌效用。通过抗S1P单抗介导的细胞外S1P的中和可能导致人类癌症进展的显著减少，这是由于抑制肿瘤增殖和支持肿瘤生长所需的血管生长。此外，最近的研究表明，许多血管生成抑制剂也可以作为抗侵入性和抗转移性化合物，这也可以减缓癌症向远离初始肿瘤的部位的扩散。

DESCRIPTION (provided by applicant): Lpath Inc. has developed a novel cancer therapeutic agent, ASONEPTM, a humanized monoclonal antibody, which neutralizes the tumorigenic and angiogenic growth factor, sphingosine-1-phosphate (S1P). S1P is an unusual target as it is a bioactive lipid. Thus ASONEP potentially represents a first-in-class anti-cancer agent. ASONEP is currently in Phase 1 trials for cancer. For this grant, we are requesting matching funds for clinical development and commercialization of ASONEP. Lpath has performed a comprehensive series of pre-clinical efficacy and pharmacokinetic studies to confirm the potential anti-cancer utility of the anti-S1P antibody. The neutralization of extracellular S1P mediated by the anti-S1P mAb could result in a marked decrease in cancer progression in humans as a result of inhibition of tumor proliferation and the growing vasculature needed to support tumor growth. Furthermore, recent research suggests that many angiogenesis inhibitors may also act as anti-invasive and anti-metastatic compounds which could also mitigate the spread of cancer to sites distant from the initial tumor. Up-regulation of the oncogene, sphingosine kinase 1 (sphk1) and the resulting release of S1P into the tumor microenvironment represents an important mechanism by which cancer cells acquire resistance to treatment as the cancer progresses. We hypothesize that overexpression of the SphK1 enzyme and the increased production and release of its product, S1P, could be responsible for resistance to cytotoxics and other treatments in a wide variety of cancer lineages. Using S1P as a biomarker and SphK1 as a surrogate marker, we believe that it may be possible to identify patients whose resistance can be attributed to an up-regulation of the S1P system. We will investigate whether sensitivity to therapy can be promoted in these patients with ASONEP in combination with standard treatments against which the patient has developed resistance as a consequence of S1P up-regulation. In moving towards commercialization, we will conduct one Phase 1b safety trial and one Phase 2a clinical trial in selected cancer types based on potential efficacy in the Phase 1 study and/or those demonstrating a promise of efficacy from preclinical and clinical biomarker studies. As requested by the FDA, a 13-week safety study in nonhuman primates will be completed prior to initiation of these Phase 2a studies. In support of the Phase 1b and 2a studies, we will also conduct a biomarker study designed to provide validation of sphingolipid-specific biomarkers (i.e. plasma S1P) and surrogate markers (e.g., tissue SphK1) to help aid in the selection of patients and cancer disease types where resistance to standard treatment may be attributed to an up-regulation of the S1P signaling system. Multivariate analysis will also be performed to assess the correlation of S1P-specific biomarkers/surrogate markers with other relevant signals that will be obtained from genomic and proteomic arrays of patient samples. This aim will be used to support future Phase 0 biomarker studies not supported by the SBIR Bridge grant. As an additional specific aim of the project, we will conduct preclinical studies using animal xenografts and transgenic mouse models intending to demonstrate that acquired resistance to cytotoxics and other treatments could be reversed by anti-S1P treatment. Efficacy studies will determine whether the anti-S1P mAb treatment can re-establish sensitivity to treatment. These studies will be used in conjunction with the biomarker/surrogate marker studies to select primary indications for future Phase 2 efficacy trials.