Scholarlink

<p>Targeted degradation of extracellular proteins via endo-lysosomal pathways constitutes a promising therapeutic strategy by enabling irreversible target removal and potentially reducing systemic effects of antigen accumulation. In this study, we present a systematic approach for the design and evaluation of Biological Degraders (BioDegs) that leverage receptor-mediated uptake through triantennary N-acetylgalactosamine (TGN) induced activation of the asialoglycoprotein receptor (ASGPR). While this principle has been established, there is still a lack about molecular determinants that influence uptake efficiency. Using interleukin-6 (IL-6) and its soluble receptor (sIL-6R) as therapeutically relevant model antigens, we systematically compared a range of BioDeg formats, including full-length antibodies (siltuximab, tocilizumab), a VHH against IL-6, and an IL-6 binding decoy-receptor design, with respect to binding affinity, thermal stability, cellular uptake, lysosomal trafficking, and degradation efficiency in HepG2 cells. Our results demonstrate that combined properties of scaffold architecture and receptor engagement critically influence degradation outcomes. This work provides a comparative framework for BioDeg design and highlights key parameters for developing lysosome-targeting degraders for extracellular proteins.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Glycan-based biological degraders targeting the cytokine immune axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月11日

查看全文
  • Michelle Seifert,
  • Tim Kollenkirchen,
  • Andreas Ernst,
  • Samaneh Rasoulinejad,
  • Sarah M. S. Koellner,
  • Ann-Kathrin Schneider,
  • Marcin Luzarowski,
  • Nicole Lübbehusen,
  • Di Wu,
  • Aimo Kannt,
  • Schara Safarian

摘要

Targeted degradation of extracellular proteins via endo-lysosomal pathways constitutes a promising therapeutic strategy by enabling irreversible target removal and potentially reducing systemic effects of antigen accumulation. In this study, we present a systematic approach for the design and evaluation of Biological Degraders (BioDegs) that leverage receptor-mediated uptake through triantennary N-acetylgalactosamine (TGN) induced activation of the asialoglycoprotein receptor (ASGPR). While this principle has been established, there is still a lack about molecular determinants that influence uptake efficiency. Using interleukin-6 (IL-6) and its soluble receptor (sIL-6R) as therapeutically relevant model antigens, we systematically compared a range of BioDeg formats, including full-length antibodies (siltuximab, tocilizumab), a VHH against IL-6, and an IL-6 binding decoy-receptor design, with respect to binding affinity, thermal stability, cellular uptake, lysosomal trafficking, and degradation efficiency in HepG2 cells. Our results demonstrate that combined properties of scaffold architecture and receptor engagement critically influence degradation outcomes. This work provides a comparative framework for BioDeg design and highlights key parameters for developing lysosome-targeting degraders for extracellular proteins.