Commercialization of ASONEP for the Treatment of Cancer

ASONEP 用于癌症治疗的商业化

• 批准号: 8078957
• 负责人: Roger A Sabbadini
• 金额: $ 100万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-07 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078957
• 关键词: Angiogenesis Inhibitors; Animals; Antibodies; Antineoplastic Agents; Biological Markers; Cancer Etiology; Cancer Patient; Cancer Therapy Evaluation Program; Cause of Death; Cessation of life; Clinic; Clinical; Clinical Trials; Collaborations; Complement; Development; Development Plans; Disease; Distant; Drug Formulations; Drug Kinetics; Enzymes; Funding; Future; Genomics; Government; Grant; Growth; Growth Factor; Human; Lipids; Malignant Neoplasms; Marketing; Mediating; Monoclonal Antibodies; Multivariate Analysis; Mus; Oncogenes; Outcome; Patient Selection; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Production; Progress Reports; Proteomics; Research; Research Design; Resistance; Resistance development; SPHK1 enzyme; Safety; Sampling; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Sphingolipids; Surrogate Markers; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Transgenic Mice; Up-Regulation; Validation; Xenograft procedure; anticancer research; base; cancer cell; cancer diagnosis; cancer therapy; cancer type; chemotherapy; clinical efficacy; commercialization; cytotoxic; design; efficacy trial; extracellular; humanized monoclonal antibodies; mouse model; nonhuman primate; novel; oncology; overexpression; phase 1 study; pre-clinical; preclinical efficacy; preclinical study; programs; research and development; safety study; sphingosine 1-phosphate; standard care; success; tumor; tumor growth; tumor progression; tumorigenic

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.

描述（由申请人提供）：Lpath Inc.已经开发了一种新型癌症治疗剂ASONEPTM，一种人源化单克隆抗体，它能中和致瘤和血管生成生长因子鞘氨醇-1-磷酸（S1 P）。S1 P是一个不寻常的目标，因为它是一种生物活性脂质。因此，ASONEP潜在地代表了一流的抗癌剂。ASONEP目前正处于癌症的1期试验中。对于这笔赠款，我们正在为ASONEP的临床开发和商业化申请配套资金。Lpath进行了一系列全面的临床前疗效和药代动力学研究，以确认抗S1 P抗体的潜在抗癌效用。抗S1 P mAb介导的细胞外S1 P中和可导致人类癌症进展的显著降低，这是由于抑制了肿瘤增殖和支持肿瘤生长所需的生长血管系统。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袭和抗转移化合物，这也可以减轻癌症扩散到远离初始肿瘤的部位。 癌基因鞘氨醇激酶1（sphk 1）的上调和S1 P释放到肿瘤微环境中代表了癌细胞随着癌症进展对治疗产生抗性的重要机制。我们假设SphK 1酶的过度表达及其产物S1 P的产生和释放增加可能是导致多种癌症谱系对细胞毒性药物和其他治疗产生抗性的原因。使用S1 P作为生物标志物和SphK 1作为替代标志物，我们相信，有可能确定患者的耐药性可归因于S1 P系统的上调。我们将研究是否可以促进这些患者与ASONEP与标准治疗相结合的治疗敏感性，患者对标准治疗产生耐药性，作为S1 P上调的结果。 在迈向商业化的过程中，我们将根据1期研究的潜在疗效和/或临床前和临床生物标志物研究显示的疗效前景，在选定的癌症类型中进行一项1b期安全性试验和一项2a期临床试验。根据FDA的要求，在开始这些2a期研究之前，将在非人灵长类动物中完成一项为期13周的安全性研究。为了支持1b期和2a期研究，我们还将进行一项生物标志物研究，旨在验证鞘脂特异性生物标志物（即血浆S1 P）和替代标志物（例如，组织SphK 1），以帮助选择患者和癌症疾病类型，其中对标准治疗的抗性可能归因于S1 P信号系统的上调。还将进行多变量分析，以评估S1 P特异性生物标志物/替代标志物与从患者样本的基因组和蛋白质组阵列获得的其他相关信号的相关性。这一目标将用于支持未来的0期生物标志物研究，而SBIR Bridge赠款不支持这些研究。作为该项目的另一个具体目标，我们将使用动物异种移植物和转基因小鼠模型进行临床前研究，旨在证明对细胞毒性和其他治疗的获得性耐药性可以通过抗S1 P治疗逆转。疗效研究将确定抗S1 P mAb治疗是否可以重新建立对治疗的敏感性。这些研究将与生物标志物/替代标志物研究联合使用，以选择未来II期疗效试验的主要适应症。

项目成果

Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.

• DOI: 10.18632/oncotarget.3144
• 发表时间: 2015-05-30
• 期刊: Oncotarget
• 作者: Ader I;Gstalder C;Bouquerel P;Golzio M;Andrieu G;Zalvidea S;Richard S;Sabbadini RA;Malavaud B;Cuvillier O
• 通讯作者: Cuvillier O