Development of Anti-ceramide scFv as Mitigator of the Radiation GI Syndrome

开发抗神经酰胺 scFv 作为放射胃肠道综合症的缓解剂

• 批准号: 9920659
• 负责人: Arthur Tinkelenberg
• 金额: $ 99.41万
• 依托单位: CERAMEDIX HOLDING, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920659
• 关键词: Acute; Advanced Development; Antibodies; Antigen Targeting; Apoptosis; Apoptotic; Bacteria; Binding; Biological; Biological Assay; Biological Markers; Bioshield; Blood Circulation; Blood Vessels; Cell Culture Techniques; Cell Survival; Cell membrane; Cells; Ceramides; Cessation of life; Chemistry; Chimeric Proteins; Collaborations; Columnar Cell; Control Animal; Coupling; Cyclic GMP; Data; Development; Development Plans; Diffusion; Dose; Endothelium; Escherichia coli; Evaluation; Exposure to; Functional disorder; Growth; Hour; Human; Immunoglobulins; Infection; Injury; Intestines; Investigational Drugs; Investigational New Drug Application; Ionizing radiation; Laboratories; Length; Lethal Dose 50; Light; Macaca mulatta; Mammalian Cell; Mediating; Mitotic; Modeling; Mucous Membrane; Mus; N-palmitoylsphingosine; NOEL; Nuclear Accidents; Outcome; Parents; Penetration; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Play; Proteins; Radiation; Radiation Toxicity; Radiation exposure; Recombinant Proteins; Recombinants; Research Institute; Role; Route; Safety; Second Messenger Systems; Serum; Signal Transduction; Small Intestines; Small intestine mucous membrane; Sphingomyelins; Structure of intestinal gland; Surface; Syndrome; Testing; Therapeutic; Time; Tissues; Toxic effect; Villus; acid sphingomyelinase; animal rule; antigen binding; base; cell injury; cohort; cost; efficacy evaluation; efficacy study; efficacy testing; experimental study; first-in-human; homologous recombination; immunoregulation; improved; irradiation; medical countermeasure; nonhuman primate; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; product development; progenitor; programs; radiation mitigation; radiation mitigator; radiation-induced injury; radioresistant; regenerative; stem cells; subcutaneous

Project Summary/Abstract Inhibition of ceramide protects mice from death from the Radiation GI Syndrome (RGS). Administration of anti- ceramide single-chain Fv (scFv) 24 h post radiation exposure increases survival in intestinal stem cells and dramatically improves overall survival in mice. These data indicate that anti-ceramide scFv represents the first effective mitigator of lethal RGS. To advance the development of anti-ceramide scFv towards an Investigational New Drug application filing, we propose to 1) characterize the PK/PD relation with efficacy in mice; and 2) utilize PK/PD to select doses of anti-ceramide scFv to evaluate in a pilot efficacy study in a non- human primate (NHP) model of the RGS. Successful completion of the proposed aims will provide rationale for evaluation of anti-ceramide scFv safety in humans and full evaluation of efficacy in a larger powered NHP trial. Single-chain antibody fusion proteins are smaller derivatives of full length antibodies, and thus offer the advantage of rapid entering into the bloodstream efficacy and increased penetration into tissue compared to full-length antibodies, and from a product development standpoint these fusion proteins can be produced easily and at minimal cost. As such, a neutralizing anti-ceramide single-chain antibody fusion protein represents a promising candidate to fulfill the Project BioShield mandate for development of countermeasures to mitigate acute radiation syndromes within the first 24 h after a nuclear disaster.

项目总结/摘要 神经酰胺的抑制可保护小鼠免于死于放射性GI综合征（RGS）。抗- 神经酰胺单链Fv（scFv）在辐射暴露后24小时增加肠干细胞的存活， 显著提高了小鼠的总体存活率。这些数据表明，抗神经酰胺scFv代表了第一个 有效缓解致命的RGS。为了将抗神经酰胺单链抗体的开发推向一个新的方向， 研究性新药申请文件，我们建议1）描述PK/PD与疗效的关系， 小鼠;和2）利用PK/PD选择抗神经酰胺scFv的剂量，以在非神经酰胺小鼠中的初步功效研究中进行评估。 RGS的人类灵长类动物（NHP）模型。成功完成拟议目标将为以下方面提供依据： 抗神经酰胺scFv在人体中的安全性评估和在更大的功效NHP试验中的功效的全面评估。 单链抗体融合蛋白是全长抗体的较小衍生物，因此提供了免疫原性。 快速进入血流功效和增加组织渗透的优势， 全长抗体，从产品开发的角度来看，这些融合蛋白可以很容易地生产 并且以最小的成本。因此，中和性抗神经酰胺单链抗体融合蛋白代表抗神经酰胺单链抗体融合蛋白。 有希望的候选人，以履行项目生物盾的任务，制定对策，以减轻 在核灾难后的第一个24小时内发生急性辐射综合征。