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.

持续的COVID-19大流行的规模和持续时间强调了需要 有一个装备精良的-和理想的前置-抗病毒武器库安装一个 充分的公共卫生应对措施。一个关键的教训是，多种医学对策（MCM） 在面对快速进化的病毒时保持效力和功效。几 批准的SARS-CoV-2疫苗对于控制大流行至关重要， 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保护作用 他们无法产生有效的免疫反应半衰期延长的单克隆抗体 单克隆抗体（mAb）提供了一种有吸引力的替代方案，因为它们的长半衰期和高效力提供了瞬时的抗肿瘤活性。 免疫和疫苗样保护，而不需要产生强大的免疫 反应虽然在课程中已经探索了> 10，000种mAb和多种mAb混合物， 大流行和几个先进的治疗候选人，他们在很大程度上未能 面对SARS-CoV-2刺突内的普遍抗原漂移， 蛋白此外，目前批准的疫苗和免疫治疗剂不能提供保护， 一种相关的b-CoV，中东呼吸综合征（MERS）病毒。虽然小分子抑制剂 例如Paxlovid已经显示出抗SARS和MERS广泛的体外活性， 治疗后COVID-19反弹表明， 更致命的MERS病毒最近鉴定的抗体1249 A8（重命名为AR-703）， 识别冠状病毒刺突蛋白S2结构域中的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，其对抗原漂移是难治的，并且具有广泛的活性b B- CoV活动，包括SARS和MERS。该提案的目标是最大限度地提高临床 AR-703通过基于多维结构的方法增加中和作用的效用 AR-703的效力和扩展广度。平行地，利用免疫球蛋白的双特异性抗体工程化可用于制备抗体。 将探索新的基于牛超长CDR 3（UL-CDR 3）的双特异性平台技术 以引入协同中和并抵抗病毒逃逸。牛UL-CDR 3的结构 具有独立靶向隐蔽的高度保守表位的能力， 维持对新病毒变体的效力。将AR-703和pan-b-CoV UL-CDR 3组合成 单一双特异性将使得高度保守的中和表位的双重接合成为可能， 一个有效的解决方案，以SARS 2抗原漂移的免疫功能低下，同时也保护 来对抗未来可能出现的致命的b型冠状病毒