长效广泛中和HIV-1单克隆抗体VRC07-523LS在暴露于HIV-1的新生儿中的安全性、耐受性和药代动力学

Safety, Tolerability, and Pharmacokinetics of Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC07-523LS in Newborn Infants Exposed to HIV-1.

作者信息

Cunningham Coleen K, McFarland Elizabeth J, Muresan Petronella, Capparelli Edmund V, Perlowski Charlotte, Johnston Benjamin, Bone Frederic, Purdue Lynette, Yin Dwight E, Moye Jack, Spiegel Hans M L, Majji Sai, Theron Gerhard B, Mujuru Hilda A, Purswani Murli, Alvarez Grace, Deville Jaime G, Chambers Carrie, Brown Emily, Harding Paul A, Tobin Nicole H, Low Kwang, Gama Lucio

机构信息

Department of Pediatrics, University of California, Irvine, Orange, CA 92868, USA.

Division of Infectious Diseases, Children's Hospital of Orange County, Orange, CA 92868, USA.

出版信息

J Pediatric Infect Dis Soc. 2025 Feb 6;14(2). doi: 10.1093/jpids/piaf002.

DOI:10.1093/jpids/piaf002

PMID:39821046

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11799610/

Abstract

BACKGROUND

Vertical HIV-1 transmission despite antiretroviral therapy may be mitigated by the use of long-acting, broadly neutralizing, monoclonal antibodies (bNAb) such as VRC07-523LS. The present study was designed to determine the safety and pharmacokinetics of VRC07-523LS.

METHODS

VRC07-523LS, 80 mg/dose, was administered subcutaneously after birth to non-breastfed (cohort 1; N = 11, enrolled in USA) and breastfed (cohort 2; N = 11, enrolled in South Africa and Zimbabwe) infants exposed to HIV-1. Breastfed infants (cohort 2) received a second 100-mg dose at 12 weeks if still receiving breastmilk. All infants received antiretroviral prophylaxis in addition to VRC07-523LS. VRC07-523LS levels were compared to VRC01 levels, as determined previously in this study.

RESULTS

Local reactions (all grade ≤ 2) occurred after dose 1 in 18% of infants in cohort 1 and after doses 1 and 2 in 100% of infants in cohort 2. The VRC07-523LS dose at birth (mean 26 mg/kg) achieved a mean ± SD plasma level of 222.3 ± 71.6 mcg/mL by 24 hours and 18.4 ± 7.2 mcg/mL at week 12, prior to dose 2. The pre-established target of ≥ 10 mcg/mL at week 12 was met in 94% of infants. The terminal half-life of VRC07-523LS was observed to be 39.2 ± 5.0 days. At week 4 and week 8, bNAb levels were significantly higher (P ≤ .002) after one dose of VRC07-523LS, compared to one dose of VRC01 (20 mg/kg). No infant included in the study acquired HIV-1.

CONCLUSIONS

VRC07-523LS was well tolerated with pharmacokinetics that support further studies of potent long-acting bNAbs together with antiretrovirals to prevent HIV-1 acquisition in infants.

摘要

背景

尽管接受了抗逆转录病毒治疗，但使用长效、广泛中和的单克隆抗体（bNAb）如VRC07-523LS可能会减轻HIV-1的垂直传播。本研究旨在确定VRC07-523LS的安全性和药代动力学。

方法

对暴露于HIV-1的非母乳喂养婴儿（队列1；N = 11，在美国入组）和母乳喂养婴儿（队列2；N = 11，在南非和津巴布韦入组）在出生后皮下注射80mg/剂量的VRC07-523LS。母乳喂养婴儿（队列2）如果在12周时仍在接受母乳喂养，则接受第二剂100mg的药物。所有婴儿除接受VRC07-523LS外，还接受抗逆转录病毒预防。将VRC07-523LS的水平与本研究先前测定的VRC01水平进行比较。

结果

队列1中18%的婴儿在第1剂后出现局部反应（均为≤2级），队列2中100%的婴儿在第1剂和第2剂后出现局部反应。出生时VRC07-523LS的剂量（平均26mg/kg）在24小时时达到平均±标准差血浆水平222.3±71.6mcg/mL，在第2剂前的第12周时为18.4±7.2mcg/mL。94%的婴儿在第12周达到预先设定的≥10mcg/mL的目标。观察到VRC07-523LS的终末半衰期为39.2±5.0天。在第4周和第8周时，与一剂VRC01（20mg/kg）相比，一剂VRC07-523LS后的bNAb水平显著更高（P≤.002）。本研究中纳入的婴儿均未感染HIV-1。