Broad Spectrum Treatment of Hemmorrhagic Arenaviruses

出血性沙粒病毒的广谱治疗

• 批准号: 7452671
• 负责人: PHILIP E THORPE
• 金额: $ 37.86万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452671
• 关键词: Affinity; Animal Model; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Applications Grants; Arenavirus; Arenavirus Infections; Binding; Bioterrorism; Blood; Categories; Cavia; Cell membrane; Cells; Chronic Hepatitis C; Clinical; Clinical Trials; Collaborations; Development; Disease; Disease Progression; Dose; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Fc domain; Flow Cytometry; Glycoproteins; Goals; Human; Immune; In Vitro; Infection; Lassa Fever; Lead; Lipids; Measures; Modeling; Monitor; Mus; National Institute of Allergy and Infectious Disease; New Agents; Patients; Pharmacologic Substance; Phosphatidylserines; Phospholipids; Pichinde; Pichinde virus; Plasma Proteins; Property; Reaction; Resistance; Ribavirin; Route; Safety; Specificity; Surface; Therapeutic; Time; Tissues; Toxic effect; Viral; Viral Hemorrhagic Fevers; Viral Load result; Viral Physiology; Virion; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; base; chimeric antibody; immunogenic; immunogenicity; magnetic beads; man; mutant

THORPE, PHILIP E. Our goal is to develop new, broad spectrum anti-viral agents for the treatment of hemorrhagic fevers caused by hostile dissemination of NIAID category A arenaviruses. The new agents are antibodies that recognize normally-internal phospholipids (e.g. phosphatidylserine, PS) that become exposed on the surface of virally infected cells shortly after infection. PS is also present on the outer envelope of multiple viruses. We previously generated a human-mouse chimeric antibody called bavituximab, that binds PS through a PS-binding plasma protein, 2-glycoprotein 1 ( 2GP1). Bavituximab cured guinea pigs lethally infected with Pichinde virus (a model of Lassa fever). It also protected mice from lethal challenge with mCMV. However, it was discovered in clinical trials that bavituximab is immunogenic. Repeated treatment of humans induced antichimeric antibody responses against murine components of the antibody. In this grant application, we propose to evaluate a panel of fully human anti-PS antibodies that are less likely to evoke immune reactions in humans. The panel has already been generated in collaboration with our industrial partner Peregrine Pharmaceuticals, Inc. It consists of: 1) fully human bavituxiimab equivalents that cross-block bavituximab; 2) fully human antibodies that recognize non-crossblocking epitopes on 2GP1; 3) fully human antibodies that bind PS directly. The binding of the antibodies to immobilized antigens, virions and virally-infected cells will be characterized. The antibodies will be compared for their ability to protect guinea pigs from lethal Pichinde virus infections. Safety and toxicological parameters will be established. The lead therapeutic candidate antibody will be identified as having the best anti-viral activity, combined with minimal or no toxicity. These studies will promote further development of anti-PS antibodies for the treatment of human hemorrhagic arenavirus infections.

索普，菲利普·E。 我们的目标是开发新的，广泛的抗病毒药物，以治疗由Arenaviruses敌对传播的敌对传播引起的出血狂。新药物是抗体，这些抗体通常在感染后不久就会在病毒感染细胞的表面暴露在病毒感染细胞表面上。 PS也存在于多种病毒的外膜上。我们先前生成了一种称为bavituximab的人鼠嵌合抗体，该抗体通过PS结合血浆蛋白，2-糖蛋白1（2GP1）结合PS。 Bavituximab固化的豚鼠致命感染了Pichinde病毒（Lassa Fever模型）。它还保护小鼠免受MCMV的致命挑战。但是，在临床试验中发现了bavituximab是免疫原性的。对人类的反复治疗诱导抗毒抗体反应对抗体的鼠组分。在此赠款应用中，我们建议评估一组完全人类的抗PS抗体，这些抗体不太可能引起人类的免疫反应。该小组已经与我们的工业合作伙伴Peregrine Pharmaceuticals，Inc。生成。它包含：1）交叉块Bavituximab的完全人类Bavituxiimab等效物； 2）完全识别2GP1上非缝隙表位的人类抗体； 3）完全结合PS的完全人类抗体。将表征抗体与固定抗原，病毒体和病毒感染细胞的结合。将其保护豚鼠免受致命性皮钦德病毒感染的能力，将比较抗体。将建立安全性和毒理学参数。铅治疗候选抗体将被鉴定为具有最佳的抗病毒活性，结合最小或无毒性。这些研究将促进抗PS抗体的进一步开发，用于治疗人类出血性竞技场感染。