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

• 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
• 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; 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

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 五个新世界哺乳动物病毒（NWMS）引起威胁生命的病毒出血热。 NWM 传播到人类最常见的是通过吸入气溶性病毒颗粒或直接引起 接触含病毒的啮齿动物排泄物或秘密。致病性NWM被认为是优先病原体 联邦和国际公共卫生机构是因为它们构成了重大的公共卫生风险和威胁 国家安全。因此，迫切需要制定新的策略来治疗NWM感染。一个 致病性NWM的区分特征是通过人转铁蛋白受体1进入细胞1 （TFR1），也称为CD71。 NWMS与TFR1的结合通过其信封的相互作用发生 糖蛋白GP1亚基至TFR1的顶端结构域，在转铁蛋白（TF）结合位点之外 提出了开发广泛活跃的治疗剂的目标 而不会干扰细胞摄取铁。我们已经开发了一种小鼠/人嵌合抗体（AB）， CH128.1/IgG1，针对人类TFR1的顶端域，该域有效地与致病性NWM竞争 细胞进入体外，并在我们使用的致命JUNV疾病模型中提供保护 表达人TFR1的转基因小鼠（HUTFR1 TG小鼠）。与AB的竞争性质一致 动作机理，使用CH128.1/IgG1突变体的FCGR和C1Q的机理优越 结合，导致缺乏AB FC受体效应子功能（FC静音； FC/S）。与人类数据一致，我们 还发现，升高的干扰素A（IFN-A）血液水平在严重NWM的发病机理中很重要 感染。我们最近还开发了CH128.1/IgG1（HU128.1）的人源化版本，不仅 增加了AB变量区域的人类含量以用于人类使用，但也保留了嵌合AB 性质和表现出卓越的热稳定性，使其成为更好的治疗候选者。我们假设 该TFR1可以用作中和NWM感染的有效靶标，不仅使用抗TFR1 AB CH128.1/IgG1 FC/S，但也使用新的HU128.1 FC/S作为单体IgG1，也用作聚合物IgM类IgG1 ab。我们还假设使用对IFN-A/B受体IFNAR-1（MAR1-5A3）的使用特异 AB）有效预防严重的NWM疾病，用作单一疗法或与抗TFR1结合 腹肌。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作为单一疗法或联合疗法抑制/消除HUTFR1 TG小鼠的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感染的新型治疗性ABS； AIM 3：定义HU128.1 FC/S和类似IgM的Hu128.1 IgG1 FC/S的抗病毒活性在细胞培养和HUTFR1中 TG小鼠NWM感染模型；和目标4：定义非人类中选定的抗TFR1 AB的特性 灵长类动物（NHP）。该项目将开发使用新型抗TFR1和抗抗的科学基础 IFNAR-1 ABS治疗NWM感染，并更好地了解相关疾病。