Antibody-based therapeutic strategy for New World mammarenavirus hemorrhagic fever

新世界乳腺病毒出血热的抗体治疗策略

基本信息

批准号：
10573912
负责人：
Brian B. Gowen
金额：
$ 76.76万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-15 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573912
关键词：
Advanced Development Affinity Americas Antibodies Antibody Therapy Antigens Antiviral Therapy Apical Argentinian Hemorrhagic Fever Attenuated Autoimmune Diseases Avidity Binding Binding Sites Biodistribution Blood Bolivian Hemorrhagic Fever Virus Case Fatality Rates Cell Culture Techniques Cells Clinic Clinical Combined Modality Therapy Complement 1q Cross Reactions DNA Development Dimensions Disease Disease Outbreaks Dose Drug Kinetics Exhibits FDA approved Fc Receptor Functional disorder GTPBP1 gene Glycoproteins Goals Hemochromatosis Human IFNAR1 gene IgG1 Immunoglobulin M Impairment In Vitro Infection Inhalation Interferon alpha International Iron Junin virus Life Ligands Light Macaca fascicularis Mammalian Cell Membrane Glycoproteins Modeling Molecular Weight Monitor Morbidity - disease rate Mus National Security Nature Organ Pathogenesis Pathogenicity Population Property Proteins Public Health Risk Rodent Surface Plasmon Resonance Survivors Syndrome TFRC gene Testing Therapeutic Therapeutic antibodies Toxic effect Transferrin Transgenic Mice Vaccines Viral Viral Hemorrhagic Fevers Viral Load result Viral Physiology Virus Zoonoses aerosolized antigen binding antiviral drug development chimeric antibody convalescent plasma human data interest interferon alpha receptor monomer mortality mutant nonhuman primate novel novel therapeutic intervention novel therapeutics particle polymeric IgM prevent priority pathogen receptor therapeutic candidate therapeutic target transmission process uptake vector virus envelope

项目摘要

SCIENTIFIC ABSTRACT Five New World mammarenaviruses (NWMs) cause life-threatening viral hemorrhagic fever. NWM transmission to humans most commonly occurs through inhalation of aerosolized viral particles or direct contact with virus-containing rodent excreta or secreta. Pathogenic NWMs are considered priority pathogens by federal and international public health agencies because they pose a significant public health risk and threat to national security. Thus, there is an urgent need to develop new strategies to treat NWM infection. A distinguishing feature of the pathogenic NWMs is the ability to enter cells through human transferrin receptor 1 (TfR1), also known as CD71. Binding of NWMs to TfR1 occurs through the interaction of their envelope glycoprotein GP1 subunit to the apical domain of TfR1, outside of the transferrin (Tf) binding site, which presents a target for the development of broadly active therapeutics that disrupt viral GP1 attachment to TfR1 without interfering with cellular uptake of iron. We have developed a mouse/human chimeric antibody (Ab), ch128.1/IgG1, targeting the apical domain of human TfR1 that effectively competes with pathogenic NWM cellular entry in vitro and provides protection in a model of lethal JUNV disease that we developed using transgenic mice expressing human TfR1 (huTfR1 Tg mice). Consistent with the competitive nature of the Ab mechanism of action, protection was superior using a ch128.1/IgG1 mutant with impaired FcgR and C1q binding, resulting in lack of Ab Fc receptor effector functions (Fc silent; Fc/s). Consistent with human data, we also found that increased interferon-a (IFN-a) blood levels are important in the pathogenesis of severe NWM infection. We have also recently developed a humanized version of ch128.1/IgG1 (hu128.1), which not only increases the human content of the Ab variable regions for human use but also retains the chimeric Ab properties and exhibits superior thermal stability, making it a better therapeutic candidate. We hypothesize that TfR1 can be used as an effective target to neutralize NWM infection, not only using the anti-TfR1 Ab ch128.1/IgG1 Fc/s but also using a new hu128.1 Fc/s as monomeric IgG1 and also as polymeric IgM-like IgG1 Ab. We also hypothesize that the use of an antagonistic Ab specific for IFN-a/b receptor IFNAR-1 (MAR1-5A3 Ab) would be effective in preventing severe NWM disease, used as a monotherapy or combined with anti-TfR1 Abs. To test our hypotheses, we have four Specific Aims. Aim 1: Define the ability of ch128.1 Fc/s and MAR1- 5A3 as monotherapy or combination therapy to inhibit/eliminate NWM infection in huTfR1 Tg mice; Aim 2: Develop a hu128.1 Fc/s and an IgM-like hu128.1 IgG1 Fc/s as novel therapeutic Abs against NWM infection; Aim 3: Define the antiviral activity of hu128.1 Fc/s and IgM-like hu128.1 IgG1 Fc/s in cell culture and huTfR1 Tg mice NWM infection models; and Aim 4: Define the properties of a selected anti-TfR1 Ab in non-human primates (NHPs). This project will develop the scientific basis for the use of novel anti-TfR1 and anti- IFNAR-1 Abs to treat NWM infection and result in a better understanding of the associated disease.

科学摘要五种新世界乳房病毒 (NWM) 会引起危及生命的病毒性出血热。西北WM 人类传播最常见的途径是吸入雾化病毒颗粒或直接接触接触含有病毒的啮齿动物排泄物或分泌物。致病性 NWM 被认为是优先病原体联邦和国际公共卫生机构，因为它们构成重大公共卫生风险和威胁为了国家安全。因此，迫切需要开发新的策略来治疗 NWM 感染。一个致病性 NWM 的显着特征是能够通过人转铁蛋白受体 1 进入细胞 (TfR1)，也称为CD71。 NWM 与 TfR1 的结合是通过其包膜的相互作用发生的糖蛋白 GP1 亚基连接到 TfR1 的顶端结构域，位于转铁蛋白 (Tf) 结合位点之外，提出了开发广泛活性疗法的目标，该疗法可破坏病毒 GP1 与 TfR1 的附着不干扰细胞对铁的吸收。我们开发了小鼠/人嵌合抗体（Ab）， ch128.1/IgG1，靶向人类 TfR1 的顶端结构域，有效与致病性 NWM 竞争体外细胞进入，并为我们开发的致命 JUNV 疾病模型提供保护表达人类 TfR1 的转基因小鼠（huTfR1 Tg 小鼠）。与抗体的竞争性质一致作用机制，使用 FcgR 和 C1q 受损的 ch128.1/IgG1 突变体的保护效果更好结合，导致 Ab Fc 受体效应功能缺失（Fc 沉默；Fc/s）。与人类数据一致，我们还发现，血液中干扰素-a (IFN-a) 水平升高对于严重 NWM 的发病机制很重要感染。我们最近还开发了ch128.1/IgG1的人源化版本（hu128.1），它不仅增加了供人类使用的抗体可变区的人类含量，但也保留了嵌合抗体特性并表现出优异的热稳定性，使其成为更好的治疗候选者。我们假设 TfR1可以作为中和NWM感染的有效靶点，而不仅仅是使用抗TfR1抗体 ch128.1/IgG1 Fc/s，但也使用新的 hu128.1 Fc/s 作为单体 IgG1 以及聚合 IgM 样 IgG1 阿布。我们还假设使用对 IFN-a/b 受体 IFNAR-1 (MAR1-5A3) 具有特异性的拮抗抗体 Ab) 可有效预防严重的 NWM 疾病，用作单一疗法或与抗 TfR1 联合使用绝对值。为了检验我们的假设，我们有四个具体目标。目标 1：定义 ch128.1 Fc/s 和 MAR1- 的能力 5A3作为单一疗法或组合疗法来抑制/消除huTfR1 Tg小鼠中的NWM感染；目标 2：开发 hu128.1 Fc/s 和 IgM 样 hu128.1 IgG1 Fc/s 作为针对 NWM 感染的新型治疗抗体；目标 3：确定细胞培养物和 huTfR1 中 hu128.1 Fc/s 和 IgM 样 hu128.1 IgG1 Fc/s 的抗病毒活性 Tg小鼠NWM感染模型；目标 4：确定选定的抗 TfR1 Ab 在非人类体内的特性灵长类动物（NHP）。该项目将为新型抗TfR1和抗-TfR1的使用奠定科学基础。 IFNAR-1 Abs 用于治疗 NWM 感染并更好地了解相关疾病。