Multidimensional antibody engineering to enhance the potency and breadth of a betacoronavirus medical countermeasure

多维抗体工程可增强β冠状病毒医学对策的效力和广度

基本信息

批准号：
10699866
负责人：
Zachary A Bornholdt
金额：
$ 28.36万
依托单位：
EITR BIOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10699866
关键词：
2019-nCoV Acceleration Address Affinity Antibodies Antibody Binding Sites Antigens B-Lymphocytes Binding Biological Assay Biological Products Bispecific Antibodies COVID-19 COVID-19 pandemic COVID-19 vaccine Cattle Cell Line Chinese Hamster Ovary Cell Clinical Coronavirus spike protein Custom Dimensions Dose Drug Kinetics Elderly Epitopes Evaluation Formulation Future Generations Genetic Polymorphism Glycoproteins Goals Half-Life Hamsters Hour Immune response Immunity Immunize Immunocompromised Host Immunoglobulin G Immunotherapeutic agent Individual Infection Lead Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Modification Monoclonal Antibodies Mutagenesis Mutation Names Paxlovid Peripheral Blood Mononuclear Cell Phase Population Positioning Attribute Predisposition Production Proteins Public Health Rattus Refractory Resolution SARS-CoV-2 spike protein SARS-CoV-2 variant Sampling Serum Severe Acute Respiratory Syndrome Severity of illness Structure Testing Therapeutic Therapeutic Monoclonal Antibodies Tissues Toxic effect Transgenic Mice Vaccines Variant Viral Virus antibody engineering betacoronavirus cross reactivity group competition high risk population in vitro activity in vivo in vivo evaluation lead candidate medical countermeasure nanomolar nanotherapeutic novel pandemic disease preclinical development prophylactic response screening small molecule inhibitor stem technology platform therapeutic candidate vaccine failure variants of concern weapons

项目摘要

The magnitude and duration of the ongoing COVID-19 pandemic have underscored the need to have a well-equipped—and ideally prepositioned—arsenal of antiviral weapons to mount an adequate public health response. A key lesson is that multiple medical countermeasures (MCMs) are needed to maintain potency and efficacy in the face of a rapidly evolving virus. Several approved SARS-CoV-2 vaccines have been paramount to gaining control over the pandemic, reducing both the number of infections and severity of disease for much of the global population. Unfortunately, these vaccines provide little to no protection to immunocompromised individuals who are unable to mount an effective immune response. Half-life extended monoclonal antibodies (mAbs) offer an attractive alternative, as their long half-life and high potency offer instantaneous immunity and vaccine-like protection without requiring the generation of a robust immune response. While >10,000 mAbs and multiple mAb cocktails have been explored over the course of the pandemic and several advanced as therapeutic candidates, they have largely failed to maintain potent activity in the face of prevalent antigenic drift within the SARS-CoV-2 spike protein. Moreover, currently approved vaccines and immunotherapeutics offer no protection from a related b-CoV, Middle East respiratory syndrome (MERS) virus. While small molecule inhibitors such as Paxlovid have shown broad in vitro activity against SARS and MERS, significant issues with COVID-19 rebound following treatment suggest it may not remain efficacious against the more lethal MERS virus. A recently identified antibody, 1249A8 (renamed AR-703), that recognizes a unique and highly conserved epitope in the S2 domain of the coronavirus spike protein offers a potential solution, being refractory to antigenic drift and having broad activity b- CoV activity, inclusive of SARS and MERS. The goal of the proposal is to maximize the clinical utility of AR-703 through multidimensional structure-based approach to increase neutralization potency and expand breadth of AR-703. In parallel, bispecific antibody engineering utilizing a novel bovine ultra-long CDR3 (UL-CDR3) based bispecific platform technology will be explored to introduce synergistic neutralization and resist viral escape. The structures of bovine UL-CDR3s have a demonstrated ability to independently target cryptic highly conserved epitopes, vital to maintaining efficacy to novel viral variants. Combining AR-703 and pan-b-CoV UL-CDR3 into a single bispecific would enable dual engagement of highly conserved neutralizing epitopes offering a potent solution to SARS2 antigenic drift for the immunocompromised while also guarding against related lethal b-CoVs should they emerge in the future.

持续的 COVID-19 大流行的规模和持续时间凸显了以下必要性：拥有装备精良且预先部署理想的抗病毒武器库充分的公共卫生应对措施是一个重要的教训，即采取多种医疗对策（MCM）。面对快速进化的病毒，需要保持效力和功效。批准的 SARS-CoV-2 疫苗对于控制疫情至关重要，减少全球大部分人口的感染数量和疾病严重程度。不幸的是，这些疫苗对免疫功能低下的个体几乎没有提供保护无法产生有效的免疫反应的人。半衰期延长的单克隆抗体。（单克隆抗体）提供了一种有吸引力的替代方案，因为它们的半衰期长且效力高，可以瞬间无需产生强大的免疫系统即可获得免疫力和疫苗般的保护在整个课程中探索了超过 10,000 种 mAb 和多种 mAb 混合物。流行病和一些先进的治疗候选者，他们基本上未能面对 SARS-CoV-2 刺突内普遍存在的抗原漂移，保持有效的活性此外，目前批准的疫苗和免疫疗法无法提供保护。一种相关的b-CoV，中东呼吸综合征（MERS）病毒，同时也是小分子抑制剂。 Paxlovid 等药物已显示出广泛的针对 SARS 和 MERS 的体外活性，这是一个重大问题治疗后 COVID-19 反弹表明它可能不会继续有效最近发现的一种更具致命性的 MERS 病毒抗体 1249A8（更名为 AR-703）识别冠状病毒刺突 S2 结构域中独特且高度保守的表位蛋白质提供了一种潜在的解决方案，它对抗原漂移具有抵抗力并且具有广泛的活性 b- 冠状病毒活动，包括 SARS 和 MERS 该提案的目标是最大限度地提高临床效果。 AR-703 通过基于多维结构的方法来增强中和作用同时，利用 AR-703 的双特异性抗体工程。将探索基于牛超长CDR3（UL-CDR3）的新型双特异性平台技术引入协同中和作用并抵抗病毒逃逸。牛 UL-CDR3 的结构。具有独立靶向神秘高度保守表位的能力，这对于将 AR-703 和 pan-b-CoV UL-CDR3 组合成一个药物，维持对新病毒变体的功效。单个双特异性将能够实现高度保守的中和表位的双重参与为免疫功能低下者提供针对 SARS2 抗原漂移的有效解决方案，同时还可以提供保护如果将来出现相关的致命 b-CoV，则可针对它们进行预防。