Mapp Biopharmaceutical, Inc., San Diego, CA 92121;
Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555.
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2023332118.
The COVID-19 pandemic has reemphasized the need to identify safe and scalable therapeutics to slow or reverse symptoms of disease caused by newly emerging and reemerging viral pathogens. Recent clinical successes of monoclonal antibodies (mAbs) in therapy for viral infections demonstrate that mAbs offer a solution for these emerging biothreats. We have explored this with respect to Junin virus (JUNV), an arenavirus classified as a category A high-priority agent and the causative agent of Argentine hemorrhagic fever (AHF). There are currently no Food and Drug Administration-approved drugs available for preventing or treating AHF, although immune plasma from convalescent patients is used routinely to treat active infections. However, immune plasma is severely limited in quantity, highly variable in quality, and poses significant safety risks including the transmission of transfusion-borne diseases. mAbs offer a highly specific and consistently potent alternative to immune plasma that can be manufactured at large scale. We previously described a chimeric mAb, cJ199, that provided protection in a guinea pig model of AHF. To adapt this mAb to a format more suitable for clinical use, we humanized the mAb (hu199) and evaluated it in a cynomolgus monkey model of AHF with two JUNV isolates, Romero and Espindola. While untreated control animals experienced 100% lethality, all animals treated with hu199 at 6 d postinoculation (dpi) survived, and 50% of animals treated at 8 dpi survived. mAbs like hu199 may offer a safer, scalable, and more reproducible alternative to immune plasma for rare viral diseases that have epidemic potential.
新型冠状病毒肺炎疫情再次强调，需要确定安全且可大规模应用的疗法，以减缓或逆转新出现和重现的病毒病原体引起的疾病症状。最近在病毒感染的治疗中，单克隆抗体（mAb）的临床成功表明，mAb 为这些新兴的生物威胁提供了一种解决方案。我们已经针对胡宁病毒（JUNV）进行了探索，JUNV 是一种被归类为 A 类高优先级制剂的沙粒病毒，也是阿根廷出血热（AHF）的病原体。目前，尚无获得美国食品和药物管理局批准的药物可用于预防或治疗 AHF，尽管恢复期患者的免疫血浆通常用于治疗活动性感染。然而，免疫血浆在数量上严重受限，质量高度可变，并且存在重大安全风险，包括输血传播疾病的传播。mAb 提供了一种高度特异性和一致有效的替代免疫血浆的方法，可以大规模生产。我们之前描述了一种嵌合 mAb cJ199，它在 AHF 的豚鼠模型中提供了保护。为了使该 mAb 适应更适合临床使用的形式，我们对其进行了人源化（hu199），并在 AHF 的食蟹猴模型中用两种 JUNV 分离株 Romer 和 Espindola 对其进行了评估。在未治疗的对照组动物中，100%的动物死亡，而在感染后 6 天（dpi）用 hu199 治疗的所有动物均存活，在感染后 8 天（dpi）治疗的 50%的动物存活。像 hu199 这样的 mAb 可能为具有流行潜力的罕见病毒性疾病提供了一种更安全、可大规模应用且更可重复的免疫血浆替代方案。
