Wu Richard L, Houser Katherine V, Gaudinski Martin R, Widge Alicia T, Awan Seemal F, Carter Cristina A, Holman LaSonji A, Saunders Jamie, Hendel Cynthia S, Eshun Aba, Whalen William R, Wang Xiaolin, Arthur Anita, Cunningham Jennifer E, Beck Allison, Casazza Joseph P, Yamshchikov Galina V, Rothwell Ro Shauna, Strom Larisa, Dittakavi Tejaswi, Happe Myra, Hickman Somia P, Conan-Cibotti Michelle, Carlton Kevin, Zhang Lily, Huang Yunda, Capparelli Edmund V, Castro Mike, Lin Bob C, O'Connell Sarah, Flach Britta S, Bailer Robert T, Narpala Sandeep R, Serebryannyy Leonid, McDermott Adrian B, Arnold Frank J, Gall Jason G, Vazquez Sandra, Berkowitz Nina M, Gordon Ingelise J, Chen Grace L, Kwong Peter D, Huang Jinghe, Pierson Theodore C, Connors Mark, Mascola John R, Zhou Tongqing, Doria-Rose Nicole A, Koup Richard A, Dropulic Lesia K
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; US Public Health Service Commissioned Corps, Rockville, MD, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Lancet HIV. 2025 Jul;12(7):e485-e495. doi: 10.1016/S2352-3018(25)00041-4. Epub 2025 May 20.
Broadly neutralising antibodies (bNAbs) have shown promise as both prevention and treatment strategies against HIV-1. The clinical effectiveness of bNAbs depends on enhancing their neutralisation breadth and extending their serum half-lives. In this study, we aimed to assess the safety, tolerability, pharmacokinetic profile, and neutralisation activity in serum of N6LS, a HIV-1 bNAb.
In this first-in-human, dose-escalation, open-label, phase 1 trial, healthy adult participants (aged 18-50 years) who were HIV-1 negative were recruited to the National Institutes of Health Clinical Center (Bethesda, MD, USA). Three groups received one intravenous administration of N6LS at 5 mg/kg (n=3), 20 mg/kg (n=3), or 40 mg/kg (n=3); one group received one subcutaneous administration of 5 mg/kg N6LS (n=3); two groups received three administrations of either 5 mg/kg subcutaneous (n=5) or 20 mg/kg intravenous (n=5) N6LS every 12 weeks; and two groups received one subcutaneous administration of either 5 mg/kg (n=5) or 20 mg/kg (n=5) N6LS with ENHANZE drug product (EDP), recombinant human hyaluronidase PH20. The primary objectives were the safety and tolerability of N6LS with and without EDP. All participants who received N6LS were included in the primary safety analyses. This trial is registered at ClinicalTrials.gov, NCT03538626, and is complete.
Between June 18, 2018, and April 11, 2022, we enrolled 33 healthy adults (19 female individuals and 14 male individuals). One participant did not receive N6LS and one participant was lost to follow-up after 8 weeks. N6LS had an encouraging safety profile similar to other HIV-1 bNAbs, with no serious adverse events. Local reactogenicity was observed after administration of N6LS, with the most common symptom being mild to moderate injection site pain or tenderness in subcutaneous groups, reported in six of eight participants. All ten participants who received N6LS with EDP had mild to severe injection site erythema, which, despite being graded as severe in size, was generally not noticed by participants or deemed bothersome, and resolved without intervention. Systemic reactogenicity was mild in all groups. N6LS had an overall mean serum half-life of 48·6 days and retained its broad and potent neutralisation characteristics in serum. EDP administration increased N6LS bioavailability. No functional anti-drug antibodies to N6LS were detected following administration.
N6LS showed a promising safety and pharmacokinetics profile while retaining its potent neutralisation characteristics in serum, making it a promising candidate for inclusion in HIV-1 prevention and therapeutic combination strategies. The addition of EDP can enable safe subcutaneous administration of higher doses and larger volumes of N6LS, supporting additional methods for prophylactic and therapeutic bNAb administration.
US National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health.
广泛中和抗体（bNAbs）已显示出作为预防和治疗HIV-1策略的前景。bNAbs的临床有效性取决于增强其中和广度并延长其血清半衰期。在本研究中，我们旨在评估HIV-1 bNAb N6LS的安全性、耐受性、药代动力学特征以及血清中的中和活性。
在这项首次人体、剂量递增、开放标签的1期试验中，HIV-1阴性的健康成年参与者（年龄18 - 50岁）被招募到美国国立卫生研究院临床中心（马里兰州贝塞斯达）。三组分别接受一次静脉注射5 mg/kg（n = 3）、20 mg/kg（n = 3）或40 mg/kg（n = 3）的N6LS；一组接受一次皮下注射5 mg/kg的N6LS（n = 3）；两组每12周接受三次皮下注射5 mg/kg（n = 5）或静脉注射20 mg/kg（n = 5）的N6LS；两组接受一次皮下注射5 mg/kg（n = 5）或20 mg/kg（n = 5）的N6LS与增强型药物产品（EDP），即重组人透明质酸酶PH20。主要目标是评估N6LS在有或无EDP情况下的安全性和耐受性。所有接受N6LS的参与者都纳入主要安全性分析。该试验已在ClinicalTrials.gov注册，编号为NCT03538626，且已完成。
在2018年6月18日至2022年4月11日期间，我们招募了33名健康成年人（19名女性和14名男性）。一名参与者未接受N6LS，一名参与者在8周后失访。N6LS具有与其他HIV-1 bNAbs相似的令人鼓舞的安全性，未出现严重不良事件。注射N6LS后观察到局部反应原性，最常见的症状是皮下注射组中轻度至中度的注射部位疼痛或压痛，8名参与者中有6名报告有此症状。所有10名接受N6LS与EDP联合治疗的参与者都出现了轻度至重度的注射部位红斑，尽管红斑面积分级为重度，但参与者通常未注意到，也不认为困扰，且无需干预即可消退。所有组的全身反应原性均较轻。N6LS的总体平均血清半衰期为48.6天，并且在血清中保留了其广泛而有效的中和特性。EDP的使用增加了N6LS的生物利用度。给药后未检测到针对N6LS的功能性抗药抗体。
N6LS显示出有前景的安全性和药代动力学特征，同时在血清中保留了其强大的中和特性，使其成为纳入HIV-1预防和治疗联合策略的有前景的候选药物。添加EDP可以实现更高剂量和更大体积的N6LS的安全皮下给药，支持预防性和治疗性bNAb给药的更多方法。
美国国立卫生研究院国家过敏和传染病研究所内部研究项目。
