Antibody therapeutics against biodefense-related diseases

针对生物防御相关疾病的抗体疗法

• 批准号: 8349357
• 负责人: Dimiter S Dimitrov
• 金额: $ 24.13万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349357
• 关键词: Active Immunization; Acute; Animal Model; Animal Testing; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Antiviral Agents; Bacteremia; Binding; Calcium; Capsid; Categories; Clinical; Communicable Diseases; Crimean-Congo Hemorrhagic Fever Virus; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Diagnosis; Diagnostic; Disease; Ebola virus; Epitopes; Exhibits; FDA approved; Frankfurt-Marburg Syndrome Virus; Glycoproteins; Goals; Hendra Virus; Henipavirus; Human; Incidence; Infection; Libraries; Microbe; Modeling; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Nipah Virus; Palivizumab; Passive Immunization; Patients; Peptides; Phage Display; Plague; Prevention; Prophylactic treatment; Proteins; Reagent; Recombinants; Recording of previous events; Reporting; Research; Surface; Testing; Therapeutic; Therapeutic antibodies; Time; Toxin; Vaccines; Viral Hemorrhagic Fevers; Virulent; Virus; Yersinia pestis; animal model development; base; biodefense; biothreat; human monoclonal antibodies; in vitro testing; interest; killings; mortality; mouse model; neutralizing monoclonal antibodies; novel; pathogen; prophylactic; research and development; research study; resistant strain; response; therapeutic vaccine; tool development

We have continued to identify and characterize neutralizing mAbs to the following biodefense-related microbes which are on the NIAID list of category A or C pathogens: Nipah and Hendra viruses (Henipaviruses) (causing acute infections with high, up to 70%, mortality, category C), Ebola and Marburg viruses (causing hemorrhagic fever with high, up to 90%, mortality, category A), Crimean-Congo virus (CCHFV) (causing hemorrhagic fever with relatively high, up to 50%, mortality, category C), and dengue virus (which causes dengue hemorrhagic fever with relatively low mortality, category A). 1) Previously, we reported the isolation of henipavirus-neutralizing recombinant hmAbs including one, m102.4, which exhibited exceptionally potent and cross-reactive inhibitory activity against both HeV and NiV. HeV is categorized as a biosafety level 4 agent, which has made development of animal models and testing of potential therapeutics and vaccines challenging. The results from two animal studies and three humans administered with this mAb confirm our proposition that m102.4 has potential as a therapeutic for treatment of diseases caused by henipaviruses, and could save human lives now. It could be also used for prophylaxis, diagnosis and as a research reagent. Animal studies with this antibody continue and more are planned with GMP produced m102.4. 2) We have previously identified several novel potent hmAbs against Yersinia pestis which are the first human antibodies against this category A agent. Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a nave phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans. 3) We have also performed experiments to identify neutralizing hmAbs against dengue virus and Ebola virus. Several mAbs against dengue virus were identified and are being characterized. The mAbs against dengue could be used as candidate therapeutics and diagnostics and as tools for development of vaccine immunogens.

We have continued to identify and characterize neutralizing mAbs to the following biodefense-related microbes which are on the NIAID list of category A or C pathogens: Nipah and Hendra viruses (Henipaviruses) (causing acute infections with high, up to 70%, mortality, category C), Ebola and Marburg viruses (causing hemorrhagic fever with high, up to 90%, mortality, category A），Crimean-Congo病毒（CCHFV）（导致相对较高的出血热，高达50％，死亡率，C类C）和登革热病毒（这会导致登革热出血性发烧，死亡率相对较低，A类A类）。 1）以前，我们报道了HENIPAVIRUS中和重组HMAB的分离，其中包括一个M102.4，该HMAB对HEV和NIV表现出异常有效和交叉反应性抑制活性。 HEV被归类为生物安全4级代理，它使动物模型的开发以及对潜在治疗剂和疫苗充满挑战的测试。两项动物研究的结果和三名用MAB施用的人证实了我们的主张，即M102.4具有治疗由HENIPAVIRAS引起的疾病的治疗，现在可以挽救人类的生命。它也可用于预防，诊断和研究试剂。该抗体的动物研究继续进行，并计划使用GMP产生的M102.4进行更多研究。 2）我们以前已经确定了针对Yersinia Pestis的几种新型有效的HMAB，这是针对该类别的A剂的第一个人类抗体。耶尔西尼亚·佩斯蒂斯（Yersinia Pestis）是瘟疫的病因学特工，在整个人类记录的历史中，杀死了超过2亿人。抗生素可能几乎可以为患有较高菌血症的患者或感染了鼠疫抗生素抗菌菌株的患者提供几乎立即缓解。柴油蛋白质的两个有毒因素是衣壳F1蛋白和低钙反应（LCR）V蛋白或V-抗原已被证明是主动和被动免疫的靶标。有小鼠单克隆抗体（mAb）针对F1和V-抗原，可以在鼠疫的鼠模型中被动保护小鼠。但是，没有用于人类预防性或治疗性治疗的抗耶尔森氏菌氏虫单克隆抗体。我们通过将一个纯粹的噬菌体 - 播放型FAB文库与F1-和V-抗原固定，鉴定了一个抗F1特异性人MAB（M252）和两个抗V特异性人MAB（M253，M254）。将FAB转换为IgG1，并评估其结合和保护活性。 M252与位于F1 N末端的肽弱结合，其中保护性小鼠抗F1 MAB也结合。 M253与V-抗原肽强烈结合，表明线性表位； M254没有与53肽的面板中的任何肽结合，表明其表位可能是构象的。 M252比M253和M254在鼠疫小鼠模型中显示出更好的保护。当组合三种抗体时，观察到协同作用。在挑战后不同时间给出M252时，无法完成完全保护。可以进一步研究这些抗体，以确定它们作为人类鼠疫感染的治疗剂或预防剂的潜力。 3）我们还进行了实验，以鉴定针对登革热病毒和埃博拉病毒的中和HMAB。鉴定了几个针对登革热病毒的单元格，并正在表征。针对登革热的mAB可以用作候选治疗疗法和诊断，并用作开发疫苗免疫原子的工具。