Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails

先进的泛拉沙免疫治疗混合物的临床前评估

• 批准号: 10158449
• 负责人: Robert F Garry
• 金额: $ 183.19万
• 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/10158449
• 关键词: Adult; Africa; African; Animal Model; Antibodies; Antibody Formation; Antibody titer measurement; Arenavirus; Bispecific Antibodies; CRISPR/Cas technology; Cavia; Cell Line; Characteristics; Chemistry; Chinese Hamster Ovary Cell; Clinical; Clinical Research; Clinical Trials; Complement; Complex; Convalescence; Crystallization; Data; Derivation procedure; Disease; Disease Outbreaks; Dose; Drug Kinetics; Economics; Engineering; Epitopes; Escape Mutant; Etiology; Evaluation; GP2 gene; GTPBP1 gene; Generations; Geography; Glycoproteins; HIV-1; IgG1; Immune system; Immunization Programs; Immunotherapeutic agent; Individual; Infection; Infection prevention; Infectious Agent; Intoxication; Investigational Drugs; Investigational New Drug Application; Lassa Fever; Lassa virus; Malignant Neoplasms; Modeling; Modification; Names; National Institute of Allergy and Infectious Disease; Nigeria; Patients; Performance; Pharmacology; Pharmacology and Toxicology; Phase; Polysaccharides; Production; Property; Readiness; Recommendation; Recrudescences; Reporting; Resolution; Rodent; Structure; Therapeutic; Toxic effect; Vaccines; Viral; Viral Antigens; Viral Hemorrhagic Fevers; Virion; Virus; antibody engineering; antimicrobial drug; base; design; emerging pathogen; experience; first-in-human; human monoclonal antibodies; improved; in vivo; in vivo evaluation; infectious disease treatment; machine learning algorithm; monomer; neutralizing monoclonal antibodies; next generation; nonhuman primate; novel; open label; pre-clinical; preclinical evaluation; prophylactic; protective efficacy; social; structural glycoprotein; surveillance data; therapeutic candidate; volunteer; weapons

Lassa fever (LF) is an often-fatal viral hemorrhagic fever (VHF) endemic in West Africa. A combination of three broadly neutralizing human monoclonal antibodies (BNhMAbs) derived from West African patients who survived LF (Arevirumab-3) rescued 100% of nonhuman primates (NHPs), even after delay in initiation of treatment to 8 days post-infection. Recently, we solved the crystal structure of the pre-fusion form of the Lassa virus glycoprotein complex (GPC) bound to a BNhMAb, the first structure for the virion configuration of the GPC of any arenavirus. Additional newly solved structures for GPC:BNhMAb complexes and derivation of escape mutants have informed the design and evaluation of optimally formulated BNhMAb cocktails targeting independent neutralizing epitopes. We plan to expand upon this extensive body of work to support completion of pre-clinical evaluation of Arevirumab-3 and functionally enhanced derivatives with improved pharmacological properties toward first-in-human clinical studies with this novel class of LF therapeutics. In studies proposed under Specific Aim 1, we will complete the pre-clinical evaluation of Arevirumab-3. Completion of Chemistry, Manufacturing and Control Data (CMC), preclinical pharmacology and toxicology in animal models of LF, including prophylactic interval and recrudescence evaluations, will enable the filing of an Investigational New Drug (IND) application toward clinical studies with Arevirumab-3 The protective activity of non-neutralizing LASV huMAbs in animal models of LF will be evaluated in studies proposed in Specific Aim 2. The protective efficacy of non-neutralizing LASV huMAbs will be evaluated and down-selected in guinea pigs. If non-neutralizing protective huMAbs (NNPhuMAbs) are identified, the activity of this class of antibodies will be further evaluated in NHP models of LF, either individually or in rationally designed cocktails. In studies proposed under Specific Aim 3, we will design enhanced immunotherapeutics via Fc effector and computational optimization, bi-specific antibody engineering (BsAbs), “designer” production cell lines that attach specific glycans, and surveillance data inputs. Enhancement of immunotherapeutic cocktails with Fc engineering, evaluation of BsAbs, machine learning algorithms, and CRISPR/Cas9-based generation of NS0 or CHO production cell lines with designer modifications will define characteristics of next generation LF immunotherapeutics. Surveillance of circulating and emerging clinical LASV strains will educate the design of LF immunotherapeutics with robust clinical characteristics and sustained potency. Under Specific Aim 4, we propose studies to valuate in vivo protection and PK of optimized BNhMAbs, NNPhMAbs, and BsAbs. In vivo evaluation of optimized LASV antibodies in established models of LF will educate advanced pre-clinical evaluation of second generation immunotherapeutics with improved pharmacological properties. The studies proposed in Project 1 are expected to result in the filing of an IND application for Arevirumab-3 in Year 3 and a Pre-IND for a 2nd generation therapeutic at the conclusion of the 5-year performance period.

LASSA热（LF）是西非的一种通常致命的病毒出血热（VHF）。三个组合 从西非患者衍生出的广泛中和人类单克隆抗体（BNHMAB） 幸存的LF（arevilumab-3）救出了100％的非人类灵长类动物（NHP），即使在延迟启动后 感染后8天治疗。最近，我们解决了LASSA前融合形式的晶体结构 与BNHMAB结合的病毒糖蛋白复合物（GPC），这是第一个用于病毒构型的结构 任何体育症病毒的GPC。 GPC的其他新解决结构：BNHMAB复合物和推导 逃生突变体已告知最佳配方BNHMAB鸡尾酒的设计和评估 独立中和表位。我们计划扩大这项广泛的工作以支持完成 arevirumab-3的临床前评估和功能增强的衍生品，并提高 通过这种新型的LF疗法，用于首次人类临床研究的药理特性。在 根据特定目标1提出的研究，我们将完成对arevirumab-3的临床前评估。 完成化学，制造和控制数据（CMC），临床前药理学和毒理学的完成 LF的动物模型，包括预防间隔和复发性评估，将使能够提交 研究性新药（IND）应用于arevirumab-3的临床研究 在特定目标中提出的研究中，将评估LF动物模型中的非中和LASV Humabs 2。将在几内亚评估和下调非中和LASV Humab的保护效率 猪。如果确定了非中和保护的Humabs（Nnphumabs），则该类别的抗体活性 将在单独或理性设计的鸡尾酒中进一步评估LF的NHP模型。在研究中 根据特定目标3提出的建议，我们将通过FC效应器和 计算优化，双特异性抗体工程（BSABS），“设计师”生产细胞系 附加特定的聚糖和监视数据输入。用足球俱乐部增强免疫治疗鸡尾酒 基于NS0的工程，BSABS评估，机器学习算法和CRISPR/CAS9 或具有设计人员修改的CHO生产细胞系将定义下一代LF的特征 免疫治疗药。循环和新兴临床LASV菌株的监视将教育设计 具有强大临床特征和持续效力的LF免疫治疗药。在特定目标4下，我们 提案研究重视体内保护和优化的BNHMAB，NNPHMAB和BSAB的PK。体内 在既定LF模型中对优化LASV抗体的评估将教育先进的临床前 评估第二代免疫疗法具有改善的药物特性。研究 预计项目1中提出的提议将导致第3年的arevirumab-3提交IND申请 在5年表现期结束时，第二代疗法的预先介绍。