Worwa Gabriella, Davis Carl W, Klim Sarah E, Turcinovic Jacquelyn, Agans Krystle N, Borisevich Viktoriya, Geisbert Joan B, Cross Robert W, Crane Anya, Holbrook Michael R, Sanchez-Lockhart Mariano, Kugelman Jeffrey R, Patino Galindo Juan A, Geisbert Thomas W, Ahmed Rafi, Kuhn Jens H, Ollmann Saphire Erica, Palacios Gustavo, Crozier Ian
Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University , Atlanta, Georgia, USA.
J Virol. 2025 Jul 22;99(7):e0029625. doi: 10.1128/jvi.00296-25. Epub 2025 Jun 10.
UNLABELLED: A cocktail of human monoclonal antibodies 1C3 and 1C11 previously protected macaques from a lethal exposure to either Ebola virus (EBOV) or Sudan virus (SUDV). 1C3 is of particular interest because its paratope strongly binds with unique stoichiometry to the glycoprotein head of several orthoebolaviruses, resulting in neutralization of EBOV and SUDV. Therefore, we evaluated the protective activity of 1C3 as a standalone therapeutic in macaques exposed to either EBOV or SUDV. Two doses of 1C3 monotherapy, administered 4 and 7 days post-exposure, did not protect SUDV-exposed macaques and partially protected EBOV-exposed macaques. Notably, in a macaque that succumbed to EBOV infection, we identified two mutually exclusive escape mutations that emerged immediately after the first dose and resulted in two amino acid changes at the 1C3 binding site. We also detected a subconsensus treatment-emergent mutation likely affecting the 1C3 binding site in all three deceased SUDV-exposed macaques. Our findings highlight combination treatment with 1C11 as critical for protection, particularly against SUDV, and activity of unpartnered 1C3 as susceptible to rapid EBOV and SUDV escape under therapeutic pressure. IMPORTANCE: A cocktail of human monoclonal antibodies 1C3 and 1C11 previously protected macaques exposed to a lethal dose of either Ebola virus (EBOV) or Sudan virus (SUDV). Since the unique binding characteristics of 1C3 are of particular interest, we evaluated its protective activity as monotherapy in macaques exposed to either EBOV or SUDV. Two doses of 1C3 alone did not protect SUDV-exposed macaques and only partially protected EBOV-exposed macaques. Importantly, failure to protect was associated with the rapid emergence of previously -identified escape mutations at the 1C3 binding site, highlighting the importance of its use in combination with 1C11 for protection against fatal disease outcome and avoiding rapid EBOV and SUDV escape. Findings have broader implications for the wise use of combination-based monoclonal antibody therapeutics to improve outcomes and prevent resistance in filovirid diseases.
未标记：人源单克隆抗体1C3和1C11的组合先前曾保护猕猴免受埃博拉病毒（EBOV）或苏丹病毒（SUDV）致死剂量的感染。1C3尤其引人关注，因为其互补决定区以独特的化学计量比与多种正埃博拉病毒的糖蛋白头部紧密结合，从而中和EBOV和SUDV。因此，我们评估了1C3作为单独治疗药物对感染EBOV或SUDV的猕猴的保护活性。在暴露后4天和7天给予两剂1C3单药治疗，未能保护感染SUDV的猕猴，仅部分保护了感染EBOV的猕猴。值得注意的是，在一只死于EBOV感染的猕猴中，我们发现了两个相互排斥的逃逸突变，这些突变在第一剂药物后立即出现，并导致1C3结合位点发生两个氨基酸变化。我们还在所有三只死于SUDV感染的猕猴中检测到一个可能影响1C3结合位点的亚共识治疗性突发突变。我们的研究结果强调，与1C11联合治疗对于保护，尤其是针对SUDV的保护至关重要，并且未与其他药物联用的1C3的活性在治疗压力下易受到EBOV和SUDV快速逃逸的影响。 重要性：人源单克隆抗体1C3和1C11的组合先前曾保护暴露于致死剂量埃博拉病毒（EBOV）或苏丹病毒（SUDV）的猕猴。由于1C3独特的结合特性尤其引人关注，我们评估了其作为单药治疗对感染EBOV或SUDV的猕猴的保护活性。两剂单独的1C3未能保护感染SUDV的猕猴，仅部分保护了感染EBOV的猕猴。重要的是，未能起到保护作用与1C3结合位点先前已确定的逃逸突变迅速出现有关，这突出了将其与1C11联合使用对于预防致命疾病结局以及避免EBOV和SUDV快速逃逸的重要性。这些发现对于明智地使用基于组合的单克隆抗体疗法以改善治疗效果并预防丝状病毒疾病中的耐药性具有更广泛的意义。
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