Intra-channel bi-epitopic crosslinking unleashes ultrapotent antibodies targeting NaV1.7 for pain alleviation.

IF 11.7 1区 医学 Q1 CELL BIOLOGY
Cell Reports Medicine Pub Date : 2024-11-19 Epub Date: 2024-10-25 DOI:10.1016/j.xcrm.2024.101800
Yaning Zhang, Yanchao Ding, Ziyan Zeng, Rui Zhu, Peiyuan Zheng, Shilong Fan, Qingjuan Cao, Hang Chen, Weishuai Ren, Mengling Wu, Luyao Wang, Juanjuan Du
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引用次数: 0

Abstract

Crucial for cell activities, ion channels are key drug discovery targets. Although small-molecule and peptide modulators dominate ion channel drug discovery, antibodies are emerging as an alternative modality. However, challenges persist in generating potent antibodies, especially for channels with limited extracellular epitopes. We herein present a bi-epitopic crosslinking strategy to overcome these challenges, focusing on NaV1.7, a potential analgesic target. Aiming to crosslink two non-overlapping epitopes on voltage-sensing domains II and IV, we construct bispecific antibodies and ligand-antibody conjugates. Enhanced affinity and potency are observed in comparison to the monospecific controls. Among them, a ligand-antibody conjugate (1080-PEG7-ACDTB) displays a two-orders-of-magnitude improvement in potency (IC50 of 0.06 ± 0.01 nM) and over 1,000-fold selectivity for NaV1.7. Additionally, this conjugate demonstrates robust analgesic effects in mouse pain models. Our study introduces an approach to developing effective antibodies against NaV1.7, thereby initiating a promising direction for the advancement of pain therapeutics.

通道内双表位交联释放出针对 NaV1.7 的超强抗体,从而缓解疼痛。
离子通道对细胞活动至关重要,是药物研发的关键目标。虽然小分子和多肽调节剂在离子通道药物研发中占主导地位,但抗体正成为一种替代方式。然而,在产生强效抗体方面仍然存在挑战,尤其是针对细胞外表位有限的通道。我们在此提出一种双表位交联策略来克服这些挑战,重点研究潜在的镇痛靶点 NaV1.7。为了交联电压传感结构域 II 和 IV 上两个不重叠的表位,我们构建了双特异性抗体和配体-抗体共轭物。与单特异性对照组相比,它们的亲和力和效力都有所增强。其中,配体-抗体共轭物(1080-PEG7-ACDTB)的效力提高了两个数量级(IC50 为 0.06 ± 0.01 nM),对 NaV1.7 的选择性超过 1000 倍。此外,这种共轭物在小鼠疼痛模型中显示出强大的镇痛效果。我们的研究介绍了一种开发有效的 NaV1.7 抗体的方法,从而为疼痛治疗学的发展开辟了一个充满希望的方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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