Molecular basis and protective efficacy of cross-neutralizing antibodies against four major respiratory viruses

四种主要呼吸道病毒交叉中和抗体的分子基础和保护功效

• 批准号: 10657926
• 负责人: Jim Boonyaratanakornkit
• 金额: $ 81.49万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657926
• 关键词: Adult; Animal Model; Animals; Antibodies; Antibody Binding Sites; Antibody Therapy; Antigens; B-Lymphocytes; Binding; Biological Availability; Blood; Cell Separation; Childhood; Clinical; Clinical Trials; Communities; Data; Databases; Development; Disease; Dose; Drug Kinetics; Epitopes; Escape Mutant; Evolution; Failure; Frequencies; Future; Half-Life; Hamsters; Hematopoietic Stem Cell Transplantation; Histopathology; Human; Human Metapneumovirus; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunosuppression; In Vitro; Infant; Infection; Intervention; Irrigation; Knowledge; Life; Lower Respiratory Tract Infection; Lung; Lung infections; Magnetism; Malignant Neoplasms; Maps; Measures; Methods; Modeling; Modification; Molecular; Monitor; Monoclonal Antibodies; Mutation; Nasal Lavage Fluid; Nose; Para-Influenza Virus Type 1; Para-Influenza Virus Type 3; Passive Immunization; Patients; Persons; Phase; Positioning Attribute; Prevention; Prophylactic treatment; Research; Resistance; Resources; Respiratory syncytial virus; Risk Reduction; Serum; Site; Stem cell transplant; Target Populations; Techniques; Testing; Therapeutic; Time; Trachea; Transplant Recipients; Transplantation; Treatment Efficacy; Variant; Viral; Viral Antigens; Viral Respiratory Tract Infection; Virus; Virus Replication; Work; anticancer research; breakthrough infection; clinical development; clinical efficacy; combat; deep sequencing; design; efficacy testing; experience; fitness; in vivo; infection risk; innovation; mortality; mutant; mutation screening; neglect; neutralizing antibody; neutralizing monoclonal antibodies; next generation; nonhuman primate; novel; parainfluenza virus; pharmacologic; post-transplant; pre-clinical; preclinical evaluation; prevent; prophylactic; protective efficacy; respiratory; respiratory virus; screening; standard of care; success; viral fitness; viral resistance; virtual

PROJECT SUMMARY/ABSTRACT Tens of thousands of otherwise deadly cancers are cured worldwide each year by hematopoietic stem cell transplantation (HCT), but unfortunately over one in ten patients will develop a viral lower respiratory tract infection, with almost half of these patients succumbing to the infection. Without an intact immune system in the first few months after transplant, these life-threatening infections offset the benefit derived from potentially life- saving transplant. Over half of these infections are caused by four viruses: RSV, HMPV, HPIV3, and HPIV1, none of which currently have any pharmacologic interventions for treatment or prevention after HCT. Although adults are universally infected with these viruses in childhood, HCT recipients lose their immunity, making them vulnerable to severe complications. Passive immunization with monoclonal antibodies (mAbs) represents a strategy to reduce the risk of these infections. While several anti-RSV mAb candidates have progressed through clinical trials, their use is limited to infants in whom RSV is responsible for virtually all cases of lung infection. However, the clinical efficacy of these mAbs is expected to be substantially lower in HCT patients because other important viruses like HMPV, HPIV3, and HPIV1 contribute significantly to disease. To fill this clinical gap for HCT patients, we have discovered two cross-neutralizing mAbs: one that targets both RSV and HMPV and another that targets both HPIV3 and HPIV1. Together, these mAbs could be combined to simultaneously protect against the four viruses that cause most lung infections after HCT. To test efficacy, we will administer these mAbs prophylactically and therapeutically to immunocompetent and immunocompromised animals. We will also test the pharmacokinetics of these mAbs with modifications designed for increased half-life and lung bioavailability, such that a single dose could bridge the entire period of vulnerability after transplant. Another often neglected pitfall in bringing novel antibody therapies to the bedside is the potential for resistance. Recent failed clinical trials of anti-RSV mAbs have shown that the emergence of escape variants can cripple clinical development. How to predict success or failure during the preclinical phase before candidates progress into clinical trials is an important question, and the answers could save massive amounts of resources, effort, and time. To fill this knowledge gap, we have developed an innovative approach called deep mutational scanning that provides a comprehensive picture of the viral mutational landscape, allowing an unprecedented preclinical evaluation of resistance. Since the two cross-neutralizing mAbs described in this proposal bind to conserved epitopes, these and similar mAbs may have a high barrier of resistance. To prepare for and counter resistance by future viral variants, we will leverage predictions from our complete mutational maps to identify next- generation mAbs, allowing us to stay a few steps ahead of viral evolution. These novel cross-neutralizing mAbs and the innovative and rigorous approaches we have developed to vet them could provide a new standard of care for HCT patients and inform the design and testing of other candidates with the greatest chance for success.

项目摘要/摘要 每年造血干细胞每年在全球范围内治愈数以万计的致命癌症 移植（HCT），但不幸的是，超过十分之一的患者会出现病毒下呼吸道 感染，其中几乎一半的患者屈服于感染。没有完整的免疫系统 移植后的前几个月，这些威胁生命的感染抵消了潜在生命的益处 保存移植。这些感染的一半以上是由四种病毒引起的：RSV，HMPV，HPIV3和HPIV1， HCT后，目前尚无任何药物干预措施用于治疗或预防。虽然 成年人在童年时期普遍感染了这些病毒，HCT接受者失去了免疫力，使他们失去免疫力 容易发生严重并发症。用单克隆抗体（mAb）被动免疫代表 降低这些感染风险的策略。虽然几个反RSV mAb候选者已经通过 临床试验，它们的使用仅限于RSV几乎所有肺部感染病例的婴儿。 但是，由于其他 HMPV，HPIV3和HPIV1等重要病毒对疾病有显着贡献。填补此临床差距 HCT患者，我们发现了两个跨中和mAb：一个针对RSV和HMPV和HMPV和 另一个针对HPIV3和HPIV1的靶向。这些mab在一起可以合并以同时保护 针对HCT后引起大多数肺部感染的四种病毒。为了测试功效，我们将管理这些 通过预防性和治疗对免疫能力和免疫功能低下的动物进行预防性mab。我们也会 测试这些mAb的药代动力学，其修饰设计用于增加半衰期和肺 生物利用度，使得单剂可以弥合移植后的整个脆弱性。其他 在将新型抗体疗法带到床边通常被忽视的陷阱是抗药性的潜力。最近的 抗RSV mAB的临床试验失败表明，逃生变体的出现会削弱临床 发展。在候选人进步之前，如何在临床前阶段预测成功或失败 临床试验是一个重要的问题，答案可以节省大量资源，精力和 时间。为了填补这一知识差距，我们开发了一种创新的方法，称为“深度突变扫描” 这提供了病毒突变景观的全面图片，允许前所未有的临床前 电阻评估。由于此提案中描述的两个交叉中和单mab与保守 这些表位，这些和类似的mAb可能具有很高的电阻屏障。准备和抵抗抵抗力 通过将来的病毒变异，我们将利用完整的突变图的预测来确定接下来的 一代mabs，使我们能够在病毒进化之前保持几步。这些新颖的交叉中和mabs 我们开发的创新和严格的方法可以提供新的标准 照顾HCT患者，并为其他候选人的设计和测试提供了最大的成功机会。