Sphingomab Mitigates the Multiple Pathologies of Age-Related Macular Degeneration

鞘氨醇可减轻年龄相关性黄斑变性的多种病理学

• 批准号: 7395091
• 负责人: Roger A Sabbadini
• 金额: $ 141.83万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7395091
• 关键词: Address; Affect; Affinity; Age related macular degeneration; Age-Years; American; Antibodies; Architecture; Avastin; Blindness; Blood Vessels; CCL2 gene; Cells; Characteristics; Choroidal Neovascularization; Clinical Trials; Complex; Disruption; Dose; Drug Formulations; Drug Kinetics; Edema; Enzyme-Linked Immunosorbent Assay; Epidemic; Etiology; Exposure to; Extracellular Fluid; Extravasation; Exudative age-related macular degeneration; Eye; Fibroblast Growth Factor; Fibroblasts; Fibrosis; Fluorescein Angiography; Goals; Growth Factor; IL8 gene; Immunohistochemistry; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-6; Label; Lasers; Lead; Lesion; Link; Liquid substance; Lucentis; Lysophospholipids; Macaca fascicularis; Measures; Medical; Methods; Modality; Modeling; Molecular; Monoclonal Antibodies; Mus; National Eye Institute; Numbers; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Permeability; Phase; Phase II Clinical Trials; Plasma; Platelet-Derived Growth Factor; Porifera; Primates; Process; Production; Research; Resolution; Retinal; Retinal Edemas; Safety; Series; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Societies; Staging; Staining method; Stains; Testing; Therapeutic; Time; Tissues; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vision; Visual Acuity; base; bevacizumab; cell type; cytokine; humanized monoclonal antibodies; in vivo; migration; neovascular; neovascularization; nonhuman primate; novel; research and development; sphingosine 1-phosphate

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). Despite the epidemic of vision loss caused by AMD, only a few therapies can slow the progression of AMD and even fewer can reverse vision loss. Currently favored therapeutic modalities include Lucentis and off-label use of Avastin, both of which target a single growth factor VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of intra and sub-retinal edema, as the actual CNV lesion does not markedly involute. Exudative AMD-related vision loss however, is not due solely to CNV induced sub-retinal and intra-retinal edema. Pathologic disruption and remodeling of the retinal and subretinal architecture caused collectively by CNV, sub-retinal fibrosis, edema and inflammation results in the loss of visual acuity associated with AMD. These multiple causes of retinal injury are not addressed by available treatments. Agents having the ability to treat the multiple mechanisms which underlie exudative AMD-related vision loss, beyond just treating vascular leakage, would be of great value and are likely to fulfill the unmet medical need associated with exudative AMD. Lpath has recently developed Sonepcizumab, a novel humanized monoclonal antibody directed against the bioactive lysophospholipid, sphingosine-1-phosphate (S1P). Sonepcizumab represents the first successfully created monoclonal antibody against a lysophospholipid. Sonepcizumab acts as a molecular sponge to selectively and specifically with picomolar affinity, absorb S1P from the extracellular fluid, lowering the effective concentration of S1P. Growing evidence suggests that S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with exudative AMD. S1P has a pronounced non-VEGF dependent pro-angiogenic effect. S1P also stimulates migration, proliferation and survival of multiple cell types, including fibroblasts and endothelial and inflammatory cells that participate in the multiple maladaptive processes of exudative AMD. S1P is also linked to the production and activation of VEGF, FGF, PDGF MCP-1, IL-6, IL-8 and other growth factors implicated in the pathogenesis of exudative AMD. Inhibiting the action of S1P could therefore be an effective therapeutic treatment for exudative AMD that may offer significant advantages over exclusively anti-VEGF approaches or act synergistically with them to address the complex processes and multiple steps that ultimately lead to AMD associated visual loss. In Lpath's Phase I SBIR studies, the murine anti-S1P antibody demonstrated profound efficacy to reduce choroidal neovascularization as well as other vascular and extravascular processes of AMD in a murine model. In continuation of the R&D efforts initiated in Phase I, we hereby propose as series of Phase II studies to test whether neutralization of S1P with the humanized antibody, Sonepcizumab, is an effective strategy for the treatment of exudative AMD. The first goal of the Phase II research plan is to evaluate the pharmacological activity/efficacy of Sonepcizumab to reduce the multiple pathologies of exudative AMD in a laser-induced Cynomolgus monkey model of CNV. We will investigate the ability of Sonepcizumab to mitigate not only neovascularization and edema but also sub-retinal fibrosis and inflammation in comparison and synergistically with Lucentis, an anti-VEGF therapy. The second goal is to assess the safety of Sonepcizumab after repeat intravitreous administration to Cynomolgus monkeys. Finally, the mechanism of action by which Sonepcizumab is able to mitigate the multiple etiologies of AMD will be investigated. The successful completion of these Phase II studies will demonstrate the efficacy and safety profiles of Sonepcizumab to support an IND filing and subsequent clinical trials. Project Narrative Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). There are estimated to be 3 times this many cases worldwide. Despite the epidemic of vision loss caused by AMD, only a few therapies, mostly anti-VEGF based, can slow the progression of AMD and even fewer can reverse vision loss. Discovering new treatments for this form of pathologic neovascularization is therefore extremely important to society.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国失明的主要原因，目前影响超过1500万人（1350万干型和160万新血管型）。尽管由AMD引起的视力丧失流行，但只有少数疗法可以减缓AMD的进展，甚至更少的疗法可以逆转视力丧失。目前受欢迎的治疗方式包括Lucentis和Avastin的标签外使用，两者都靶向单一生长因子VEGF，并且似乎通过抗渗透作用发挥其大部分有益作用，导致视网膜内和视网膜下水肿消退，因为实际CNV病变并不明显渐开线。然而，渗出性AMD相关的视力丧失不仅仅是由于CNV诱导的视网膜下和视网膜内水肿。由CNV、视网膜下纤维化、水肿和炎症共同引起的视网膜和视网膜下结构的病理性破坏和重塑导致与AMD相关的视力丧失。视网膜损伤的这些多种原因没有通过可用的治疗来解决。除了治疗血管渗漏之外，能够治疗渗出性AMD相关视力丧失的多种机制的药物将具有巨大价值，并且可能满足与渗出性AMD相关的未满足的医疗需求。Lpath最近开发了Sonepcizumab，这是一种新型人源化单克隆抗体，针对生物活性溶血磷脂1-磷酸鞘氨醇（S1 P）。Sonepcizumab代表了第一个成功创建的针对溶血磷脂的单克隆抗体。Sonepcizumab作为分子海绵，以皮摩尔亲和力选择性和特异性地从细胞外液中吸收S1 P，降低S1 P的有效浓度。越来越多的证据表明，S1 P可能有助于与渗出性AMD相关的适应不良视网膜重塑的早期和晚期阶段。S1 P具有显著的非VEGF依赖性促血管生成作用。S1 P还刺激多种细胞类型的迁移、增殖和存活，包括参与渗出性AMD的多种适应不良过程的成纤维细胞、内皮细胞和炎性细胞。S1 P还与VEGF、FGF、PDGF、MCP-1、IL-6、IL-8和渗出性AMD发病机制中涉及的其他生长因子的产生和活化有关。因此，抑制S1 P的作用可能是渗出性AMD的有效治疗方法，其可能提供优于专门抗VEGF方法的显著优势，或与它们协同作用以解决最终导致AMD相关视力丧失的复杂过程和多个步骤。在Lpath的I期SBIR研究中，鼠抗S1 P抗体在鼠模型中表现出显著的减少脉络膜新生血管形成以及AMD的其他血管和血管外过程的功效。为了继续I期开始的研发工作，我们在此提出了一系列II期研究，以测试用人源化抗体Sonepcizumab中和S1 P是否是治疗渗出性AMD的有效策略。II期研究计划的第一个目标是在激光诱导的CNV食蟹猴模型中评价Sonepcizumab减少渗出性AMD多种病理的药理学活性/疗效。我们将研究Sonepcizumab与Lucentis（一种抗VEGF疗法）相比和协同作用下，不仅减轻新生血管形成和水肿，而且减轻视网膜下纤维化和炎症的能力。第二个目标是评估Sonepcizumab对食蟹猴重复玻璃体内给药后的安全性。最后，将研究Sonepcizumab能够减轻AMD的多种病因的作用机制。这些II期研究的成功完成将证明Sonepcizumab的疗效和安全性，以支持IND申请和后续临床试验。视网膜相关性黄斑变性（AMD）是美国失明的主要原因，目前影响超过1500万人（1350万干性和160万新生血管型）。据估计，全世界的病例数是这一数字的3倍。尽管由AMD引起的视力丧失流行，但只有少数疗法，主要是基于抗VEGF的疗法，可以减缓AMD的进展，甚至更少的疗法可以逆转视力丧失。因此，发现这种病理性新血管形成的新疗法对社会极其重要。