Specific and Broadly Active Monoclonal Antibody Therapeutics Against The Filoviruses

针对丝状病毒的特异性且广泛活性的单克隆抗体疗法

• 批准号: 10402338
• 负责人: Erica Ollmann Saphire
• 金额: $ 220.97万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402338
• 关键词: Address; Affect; Africa; Animal Model; Antibodies; Antibody Affinity; Antibody Therapy; Antibody-mediated protection; Biological Assay; Bundibugyo virus; Category A pathogen; Cells; Cessation of life; Characteristics; Collaborations; Communicable Diseases; Complex; Computer Models; Data; Data Set; Databases; Development; Disease; Disease Outbreaks; Ebola Hemorrhagic Fever; Ebola virus; Engineering; Epidemic; Evaluation; Filoviridae Infections; Filovirus; Glycoproteins; Goals; Government; Hand; Human; Immune; Immune response; Immunology; Immunotherapeutic agent; Industrialization; Industry Collaboration; Institution; Libraries; Long-Term Survivors; Machine Learning; Marburgvirus; Mechanics; Mediating; Modification; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; Patients; Performance; Resistance; Reston Ebola virus; Specific qualifier value; Statistical Data Interpretation; Structure; Sudan Ebola virus; Survivors; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Time; Toddler; Translating; Viral; Viral Hemorrhagic Fevers; Virus; animal rule; antibody test; base; biodefense; chimeric antibody; cross reactivity; efficacious treatment; forest; high throughput technology; immune function; improved; in vitro Assay; in vivo; in vivo evaluation; innovation; monoclonal antibody production; mortality; multidisciplinary; neutralizing antibody; nonhuman primate; novel; predictive modeling; product development; structural biology; therapeutic candidate; translational research program; vaccine candidate; vaccine evaluation; virology

Project 2: SUMMARY The filoviruses, including multiple ebolaviruses and two marburgviruses, have emerged over 30 times to cause outbreaks of severe disease with high mortality. The epidemic potential of these viruses is demonstrated by the 2013-2016 outbreak, which spread from a single infected toddler to 28,000 cases across multiple nations. No therapeutic interventions are yet approved for filovirus infections, and there remains an urgent need for efficacious treatments. In this academic and industry collaboration, we will advance both specific- and broadly reactive monoclonal antibody (mAb) treatments that we have already shown to provide complete protection in non-human primates. Importantly, this study builds upon results of a global collaboration, the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC), that yielded the most comprehensive dataset for anti-Ebola virus mAbs yet assembled. From that comprehensive study, we learned additional correlates of mAb-mediated protection and built improved, multivariate computational models, which predict treatment combinations that maximize antibody features that most strongly predict in vivo protection (including Fc-mediated effector functions, Fc glycoforms, and neutralization). Additional treatment combinations, one Ebola virus-specific and one broadly cross-reactive, predicted by that detailed study may offer even greater efficacy than the two already in hand. Using our therapeutic candidates and additional well-characterized VIC mAbs as controls, we will evaluate thresholds of protection and correlates of protection across standard and innovative animal models. On a broader level, this study will illuminate how faithfully particular mAb features (e.g., Fab-driven neutralization, species- specific Fc-driven protection) translate across animal models used to satisfy the FDA “two-animal rule” for therapeutic approval. We will further use innovative high-throughput technologies, standard cell-based assays, targeted glycoforms and a library of well-characterized Fc substitutions to optimize both Fv and Fc to enhance protective activity. For this project, we have engaged a multidisciplinary team of experts in structural biology, virology, immunology, in vivo evaluation in animal models, computer modeling and statistical analysis, and industrial mAb production and development. Our translational research program is informed by data that are more comprehensive than any previously available, will forward optimized therapeutic candidates against multiple viruses with epidemic potential, and will help establish a broadly applicable platform to treat filoviruses and other infectious diseases.

项目2：概述