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）：与年龄相关的黄斑变性（AMD）是美国失明的主要原因，目前影响超过1500万人（1,350万人干燥和160万新生血管形式）。尽管AMD引起的视力丧失流行，但只有少数疗法可以减慢AMD的进展，甚至更少的疗法可以逆转视力丧失。目前有利的治疗方式包括卢森蒂斯（Lucentis）和标签的使用avastin，这两种方法都针对单个生长因子VEGF，并且似乎通过抗渗透性作用发挥了大部分有益作用，导致分辨出内部和下视网膜下水肿，作为实际的CNV病变并未显着渗透。然而，与AMD相关的视力丧失不仅归因于CNV诱导的视网膜下和视网膜内水肿。 CNV，视网膜下纤维化，水肿和炎症共同引起的视网膜和下视网膜下结构的病理破坏和重塑导致与AMD相关的视力丧失。可用的治疗方法无法解决视网膜损伤的这些多重原因。具有治疗多种机制的代理，这些机制是基于渗出性AMD相关的视力丧失（不仅治疗血管泄漏）的价值，而且很有价值，并且很可能满足与渗出性AMD相关的未满足的医疗需求。 LPATH最近开发了针对生物活性溶血磷脂，鞘氨醇1-磷酸（S1P）的新型人源性单克隆抗体。 Sonepcizumab代表了第一个成功创建了针对溶血磷脂的单克隆抗体。 sonepcizumab充当分子海绵，特定于皮摩尔亲和力，从细胞外液中吸收S1P，从而降低了S1P的有效浓度。越来越多的证据表明，S1P可能有助于与渗出性AMD相关的适应性视网膜重塑的早期和晚期阶段。 S1P具有明显的非VEGF依赖性促血管生成效应。 S1P还刺激了多种细胞类型的迁移，增殖和存活，包括参与渗出性AMD多种不良适应过程的成纤维细胞以及内皮细胞和炎症细胞。 S1P还与VEGF，FGF，PDGF MCP-1，IL-6，IL-8的生产和激活有关，以及与渗出性AMD发病机理有关的其他生长因子。因此，抑制S1P的作用可能是对渗出性AMD的有效治疗方法，该治疗方法可能比仅具有抗VEGF方法具有显着优势，或者与它们协同作用，以解决最终导致AMD相关的视觉损失的复杂过程和多个步骤。在LPATH的I期SBIR研究中，鼠抗S1P抗体在鼠模型中表现出了降低脉络膜新生血管形成以及AMD的其他血管和血管外过程的深刻疗效。在继续在第一阶段开始的研发工作中，我们在此提议作为II期研究的一系列研究，以测试用人源化抗体Sonepcizumab对S1P的中和，这是治疗渗出性AMD的有效策略。 II期研究计划的第一个目标是评估Sonepcizumab的药理活性/功效，以减少激光诱导的CNV cynomolgus猴子模型中渗出症的多种病理。我们将研究sonepcizumab不仅减轻新血管形成和水肿的能力，而且还与抗VEGF疗法Lucentis相比和协同性。第二个目标是在重复静脉内给予cynomolgus猴子后评估sonepcizumab的安全性。最后，将研究SONEPCIZUMAB能够减轻AMD多元病因的作用机理。这些第二阶段研究的成功完成将证明Sonepcizumab支持IND归档和随后的临床试验的功效和安全性。项目叙事与年龄相关的黄斑变性（AMD）是美国失明的主要原因，目前影响超过1500万人（1,350万人的干式和160万新生血管形式）。据估计，这是全球许多案例的3倍。尽管AMD引起的视力丧失流行，但只有少数几种基于反VEGF的疗法可以减慢AMD的进展，甚至更少可以逆转视力丧失。因此，发现这种形式的病理性新血管化的新疗法对社会极为重要。