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白细胞介素-13抗体lebrikizumab的结合、中和及内化作用

Binding, Neutralization and Internalization of the Interleukin-13 Antibody, Lebrikizumab.

作者信息

Okragly Angela J, Ryuzoji Aya, Wulur Isabella, Daniels Montanea, Van Horn Robert D, Patel Chetan N, Benschop Robert J

机构信息

Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.

BioTechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.

出版信息

Dermatol Ther (Heidelb). 2023 Jul;13(7):1535-1547. doi: 10.1007/s13555-023-00947-7. Epub 2023 Jun 13.

DOI:10.1007/s13555-023-00947-7
PMID:37310643
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10307934/
Abstract

INTRODUCTION

IL-13 is the primary upregulated cytokine in atopic dermatitis (AD) skin and is the pathogenic mediator driving AD pathophysiology. Lebrikizumab, tralokinumab and cendakimab are therapeutic monoclonal antibodies (mAb) that target IL-13.

METHODS

We undertook studies to compare in vitro binding affinities and cell-based functional activities of lebrikizumab, tralokinumab and cendakimab.

RESULTS

Lebrikizumab bound IL-13 with higher affinity (as determined using surface plasma resonance) and slower off-rate. It was more potent in neutralizing IL-13-induced effects in STAT6 reporter and primary dermal fibroblast periostin secretion assays than either tralokinumab or cendakimab. Live imaging confocal microscopy was employed to determine the mAb effects on IL-13 internalization into cells via the decoy receptor IL-13Rα2, using A375 and HaCaT cells. The results showed that only the IL-13/lebrikizumab complex was internalized and co-localized with lysosomes, whereas IL-13/tralokinumab or IL-13/cendakimab complexes did not internalize.

CONCLUSION

Lebrikizumab is a potent, neutralizing high-affinity antibody with a slow disassociation rate from IL-13. Additionally, lebrikizumab does not interfere with IL-13 clearance. Lebrikizumab has a different mode of action to both tralokinumab and cendakimab, possibly contributing to the clinical efficacy observed by lebrikizumab in Ph2b/3 AD studies.

摘要

引言

白细胞介素-13（IL-13）是特应性皮炎（AD）皮肤中主要上调的细胞因子，是驱动AD病理生理学的致病介质。瑞莎珠单抗、曲罗芦单抗和森达吉单抗是靶向IL-13的治疗性单克隆抗体（mAb）。

方法

我们进行了研究，以比较瑞莎珠单抗、曲罗芦单抗和森达吉单抗的体外结合亲和力和基于细胞的功能活性。

结果

瑞莎珠单抗与IL-13的结合亲和力更高（使用表面等离子体共振测定），解离速率更慢。在STAT6报告基因和原代表皮成纤维细胞骨膜蛋白分泌试验中，它在中和IL-13诱导的效应方面比曲罗芦单抗或森达吉单抗更有效。使用活细胞成像共聚焦显微镜，以A375和HaCaT细胞为模型，确定单克隆抗体对IL-13通过诱饵受体IL-13Rα2内化进入细胞的影响。结果表明，只有IL-13/瑞莎珠单抗复合物被内化并与溶酶体共定位，而IL-13/曲罗芦单抗或IL-13/森达吉单抗复合物未被内化。

结论

瑞莎珠单抗是一种强效、具有中和作用的高亲和力抗体，与IL-13的解离速率较慢。此外，瑞莎珠单抗不干扰IL-13的清除。瑞莎珠单抗与曲罗芦单抗和森达吉单抗的作用模式不同，这可能是瑞莎珠单抗在2b/3期AD研究中观察到临床疗效的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/b020870b77f1/13555_2023_947_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/47c05cb72c10/13555_2023_947_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/422aeb541f7c/13555_2023_947_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/a599cb137255/13555_2023_947_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/8c6fc81c0706/13555_2023_947_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/c1087458419d/13555_2023_947_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/b020870b77f1/13555_2023_947_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/47c05cb72c10/13555_2023_947_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/422aeb541f7c/13555_2023_947_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/a599cb137255/13555_2023_947_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/8c6fc81c0706/13555_2023_947_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/c1087458419d/13555_2023_947_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74bd/10307934/b020870b77f1/13555_2023_947_Fig6_HTML.jpg

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