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在一项1b/2a期婴儿克列罗韦单抗试验中，高滴度抗药物抗体的产生与第150天之后的呼吸道合胞病毒（RSV）暴露有关。

Development of High-Titer Antidrug Antibodies in a Phase 1b/2a Infant Clesrovimab Trial Are Associated With RSV Exposure Beyond Day 150.

作者信息

Thambi Nithya, Phuah Jia Yao, Staupe Ryan P, Tobias Lori M, Cao Yu, McKelvey Troy, Railkar Radha A, Aliprantis Antonios O, Arriola Carmen Sofia, Maas Brian M, Vora Kalpit A

机构信息

Department of Epidemiology.

Department of Infectious Diseases and Vaccines.

出版信息

J Infect Dis. 2025 Mar 17;231(3):e488-e496. doi: 10.1093/infdis/jiae582.

DOI:10.1093/infdis/jiae582
PMID:39590882
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11911791/
Abstract

BACKGROUND

Clesrovimab is a human half-life-extended monoclonal antibody in phase 3 evaluation for the prevention of respiratory syncytial virus (RSV) disease in infants. Antidrug antibodies (ADA) were observed at late time points in a phase 1b/2a study where clesrovimab was well tolerated with an extended half-life of approximately 45 days.

METHODS

Serum samples at days 150, 365, and 545 postdose were assayed for ADA titers. Samples with high ADA titers were characterized for their binding specificity to the Fab or the YTE portion of clesrovimab. RSV serum neutralization (SNA) titers were also measured on ADA-positive and ADA-negative infants. Additionally, a D25 (site Ø) competitive enzyme-linked immunosorbent assay (ELISA) was performed on ADA-positive available samples to determine RSV exposure. Local surveillance data was used to ascertain RSV circulation during the trial.

RESULTS

High ADA titers were observed in a minority of infants at days 365 and 545 for all doses tested. Additionally, all high-titer ADA-positive infants had ADA directed towards the YTE epitope of clesrovimab. Moreover, these infants demonstrated robust RSV-SNA and had D25 competitive antibodies suggesting an RSV exposure after day 150, coinciding with the epidemiological data.

CONCLUSIONS

RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics.

CLINICAL TRIALS REGISTRATION

NCT03524118.

摘要

背景

Clesrovimab是一种人源半衰期延长的单克隆抗体，正处于3期评估阶段，用于预防婴儿呼吸道合胞病毒（RSV）疾病。在1b/2a期研究的后期时间点观察到了抗药抗体（ADA），该研究中clesrovimab耐受性良好，半衰期约为45天。

方法

在给药后第150、365和545天检测血清样本中的ADA滴度。对高ADA滴度的样本进行表征，以确定其与clesrovimab的Fab或YTE部分的结合特异性。还对ADA阳性和ADA阴性婴儿的RSV血清中和（SNA）滴度进行了测量。此外，对ADA阳性的可用样本进行了D25（位点Ø）竞争性酶联免疫吸附测定（ELISA），以确定RSV暴露情况。利用当地监测数据确定试验期间RSV的传播情况。

结果

在所有测试剂量下，少数婴儿在第365天和545天观察到高ADA滴度。此外，所有高滴度ADA阳性婴儿的ADA均针对clesrovimab的YTE表位。此外，这些婴儿表现出强大的RSV-SNA，并具有D25竞争性抗体，表明在第150天后有RSV暴露，这与流行病学数据一致。

结论

给药后150天以上婴儿的RSV暴露与ADA的产生以及高RSV-SNA滴度相关，对药代动力学无影响。

临床试验注册

NCT03524118。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/f57cd76812de/jiae582f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/c84cb0d173e7/jiae582f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/5afb84fde818/jiae582f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/b02d0655b735/jiae582f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/f57cd76812de/jiae582f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/c84cb0d173e7/jiae582f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/5afb84fde818/jiae582f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/b02d0655b735/jiae582f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbda/11911791/f57cd76812de/jiae582f4.jpg

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