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<p>The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is synthesized as transmembrane TNF-α (tmTNF-α) where proteolytic processing releases soluble TNF-α (sTNF-α). tmTNF-α can act as either a ligand by activating TNF receptors, or a receptor that transmits reverse (outside-to-inside) signalling after binding to native receptors. All TNF-α therapies bind tmTNF-α and induce reverse signalling which can result in immunosuppression leading to infection. We present crystal structures of two anti-TNF-α Variable New Antigen Receptors (VNARs) in complex with sTNF-α via two distinct epitopes. The VNAR-D1 recognizes an epitope that selectively engages sTNF-α while VNAR-C4 binds an epitope that partially overlaps with other biologic therapies. In activated CD4<sup>+</sup> T cells, our VNARs do not induce reverse signalling in contrast to currently available therapies. Our findings suggest that neutralization through a unique mechanism may lead to anti-TNF-α agents with an improved safety profile that will benefit high-risk patients.</p>

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The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月29日

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  • Obinna C. Ubah,
  • Eric W. Lake,
  • Kendahl L. Ott,
  • Stella Priyanka,
  • Sasha Celeda,
  • Jayden L. West,
  • Gihan S. Gunaratne,
  • Ke Shi,
  • Nicholas H. Moeller,
  • Andrew J. Porter,
  • Hideki Aihara,
  • David Kosoff,
  • Aaron M. LeBeau,
  • Caroline J. Barelle

摘要

The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is synthesized as transmembrane TNF-α (tmTNF-α) where proteolytic processing releases soluble TNF-α (sTNF-α). tmTNF-α can act as either a ligand by activating TNF receptors, or a receptor that transmits reverse (outside-to-inside) signalling after binding to native receptors. All TNF-α therapies bind tmTNF-α and induce reverse signalling which can result in immunosuppression leading to infection. We present crystal structures of two anti-TNF-α Variable New Antigen Receptors (VNARs) in complex with sTNF-α via two distinct epitopes. The VNAR-D1 recognizes an epitope that selectively engages sTNF-α while VNAR-C4 binds an epitope that partially overlaps with other biologic therapies. In activated CD4+ T cells, our VNARs do not induce reverse signalling in contrast to currently available therapies. Our findings suggest that neutralization through a unique mechanism may lead to anti-TNF-α agents with an improved safety profile that will benefit high-risk patients.