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.开发了一种新型的癌症治疗剂AsOnePTM，一种人源化的单克隆抗体，它中和肿瘤菌和血管生长因子，鞘氨酸-1-磷酸盐（S1P）。 S1P是一个不寻常的靶标，因为它是生物活性脂质。因此，作为一个可能代表一流的抗癌剂。 ASONEP目前正在癌症的第1阶段试验中。对于这笔赠款，我们要求提供匹配资金，以供ASONEP的临床开发和商业化。 LPATH已进行了一系列综合的临床前功效和药代动力学研究，以确认抗S1P抗体的潜在抗癌实用性。抗S1P mAb介导的细胞外S1P的中和可能导致人类癌症进展显着降低，这是由于抑制肿瘤增殖的结果以及支持肿瘤生长所需的日益增长的脉管系统。此外，最近的研究表明，许多血管生成抑制剂也可能充当抗侵入性和抗转移性化合物，这也可以减轻癌症向远离最初肿瘤的部位的扩散。 癌基因，鞘氨酸激酶1（SPHK1）的上调和S1P释放到肿瘤微环境中的上调是一种重要机制，癌细胞随着癌症的发展而对治疗的抗药性。我们假设SPHK1酶的过表达以及其产物S1P的产生和释放可能是对各种癌症谱系中细胞毒素和其他治疗的抗性。将S1P用作生物标志物和SPHK1作为替代标记，我们认为可以鉴定出耐药性可以归因于S1P系统的上调的患者。我们将研究这些ASONEP与标准疗法结合使用的患者是否可以促进对治疗的敏感性，因为S1P上调，患者与患者产生了抗药性。 在朝着商业化方面迈进时，我们将基于1阶段研究中的潜在疗效和/或证明临床前和临床生物标志物研究的疗效希望的癌症类型的一阶段安全试验和一项2A期临床试验。根据FDA的要求，在启动这些2A期研究之前，将完成一项13周的非人类灵长类动物的安全研究。为了支持1B和2A研究，我们还将进行一项生物标志物研究，旨在提供鞘脂特异性生物标志物（即血浆S1P）和替代标记物（例如，组织SPHK1）的验证，以帮助选择对标准治疗的患者的选择，以帮助选择标准系统的患者的选择可以归因于S11的信号系统。还将进行多变量分析，以评估S1P特异性生物标记物/替代标记与其他相关信号的相关性，这些信号将从患者样本的基因组和蛋白质组学阵列中获得。该目标将用于支持SBIR Bridge Grant不支持的未来0阶段生物标志物研究。作为该项目的另一个具体目的，我们将使用动物异种移植物和旨在证明获得对细胞毒素和其他治疗的抗性的转基因小鼠模型进行临床前研究。功效研究将确定抗S1P 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/替代标记物研究一起使用，以选择未来2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