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

• 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
• 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

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.

正在进行的Covid-19大流行的规模和持续时间强调了需要 设备齐全（理想的介词）抗病毒武器可容纳 一个关键的教训是多个医学对策（MCM） 面对快速发展的病毒，需要保持效力和效率。一些 批准的SARS-COV-2疫苗对于获得大流行的控制至关重要， 减少了大部分全球人口的感染次数和疾病严重程度。 不幸的是，这些疫苗对免疫功能低下的人几乎没有保护 他们无法实现有效的免疫反应。半衰期延长的单克隆抗体 （mabs）提供了一个有吸引力的替代品，因为它们的长半衰期和高效力提供了瞬时 免疫力和类似疫苗的保护，而无需产生强大的免疫 回复。虽然在本课程中探索了10,000个mab和多个mab鸡尾酒 在大流行和几个治疗候选人中，他们在很大程度上都没有 面对SARS-COV-2 Spike中普遍的抗原漂移，保持潜在活动 蛋白质。此外，目前已批准的疫苗和免疫治疗药物没有任何保护 相关的B-COV，中东呼吸道综合征（MERS）病毒。而小分子抑制剂 诸如paxlovid对SARS和MER的体外活性广泛，重大问题 在治疗后的Covid-19反弹后，它可能无法保持效率 更多致命的MERS病毒。最近确定的抗体，1249a8（更名为AR-703），该抗体，该抗体 认识到冠状病毒Spike的S2域中的独特且高度组成的情节 蛋白质提供了潜在的溶液，对抗原漂移难治性，并且具有广泛的活性B- COV活动，包括SARS和MERS。该提案的目的是最大化临床 通过基于多维结构的方法，AR-703的实用性增加神经化 效力和扩大AR-703的广度。同时，双特异性抗体工程使用 将探索新型牛超长CDR3（UL-CDR3）双特异性平台技术 引入协同神经化并抵抗病毒逃逸。牛UL-CDR3的结构 具有独立靶向高度组成的表位的能力，对 维持新型病毒变体的效率。将AR-703和PAN-B-COV UL-CDR3组合到一个 单个双特异性将实现高度保守的中和表位的双重互动 SARS2抗原漂移的潜在解决方案，用于免疫功能低下 反对相关的致命b-cov，他们将来会出现。