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

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

  • Cell Rep Med. 2024 Oct 22:101800. doi: 10.1016/j.xcrm.2024.101800.
Yaning Zhang 1,  Yanchao Ding 2,  Ziyan Zeng 2,  Rui Zhu 2,  Peiyuan Zheng 2,  Shilong Fan 3,  Qingjuan Cao 2,  Hang Chen 2,  Weishuai Ren 2,  Mengling Wu 2,  Luyao Wang 2,  Juanjuan Du 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China; Peking University-Tsinghua University-National Institute Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China.
  • 3 The Technology Center for Protein Sciences, Tsinghua University, Beijing 100084, China.
  • 4 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China. Electronic address: dusps@tsinghua.edu.cn.
PMID: 39461335 DOI: 10.1016/j.xcrm.2024.101800
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.

Keywords

Na(V)1.7; analgesia; antibody conjugate; avidity; biparatopic antibody; bispecific antibody; ion channel; pain; selectivity; sodium channel.

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