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Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells

Author

Listed:
  • Nicola Fenderico

    (University Medical Center Utrecht)

  • Revina C. Scherpenzeel

    (Utrecht University)

  • Michael Goldflam

    (Isogenica Ltd., Chesterford Research Park
    Pepscan Therapeutics)

  • Davide Proverbio

    (Attana AB
    NovAliX)

  • Ingrid Jordens

    (University Medical Center Utrecht)

  • Tomica Kralj

    (University Medical Center Utrecht)

  • Sarah Stryeck

    (Medical University of Graz)

  • Tarek Z. Bass

    (Attana AB)

  • Guy Hermans

    (Isogenica Ltd., Chesterford Research Park)

  • Christopher Ullman

    (Isogenica Ltd., Chesterford Research Park
    Paratopix Ltd.)

  • Teodor Aastrup

    (Attana AB)

  • Piet Gros

    (Utrecht University)

  • Madelon M. Maurice

    (University Medical Center Utrecht)

Abstract

Wnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced β-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected. Structural analysis reveal that individual VHHs variably employ divergent antigen-binding regions to bind a similar surface in the third β-propeller of LRP5/6, sterically interfering with Wnt3/3a binding. Importantly, anti-LRP5/6 VHHs block the growth of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids through stem cell exhaustion and collective terminal differentiation. Thus, VHH-mediated targeting of LRP5/6 provides a promising differentiation-inducing strategy for treatment of Wnt-hypersensitive tumors.

Suggested Citation

  • Nicola Fenderico & Revina C. Scherpenzeel & Michael Goldflam & Davide Proverbio & Ingrid Jordens & Tomica Kralj & Sarah Stryeck & Tarek Z. Bass & Guy Hermans & Christopher Ullman & Teodor Aastrup & Pi, 2019. "Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08172-z
    DOI: 10.1038/s41467-018-08172-z
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    Cited by:

    1. Alice Fletcher & Dean Clift & Emma Vries & Sergio Martinez Cuesta & Timothy Malcolm & Francesco Meghini & Raghothama Chaerkady & Junmin Wang & Abby Chiang & Shao Huan Samuel Weng & Jonathan Tart & Edm, 2023. "A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Erwin De Genst & Kylie S. Foo & Yao Xiao & Eduarde Rohner & Emma de Vries & Jesper Sohlmér & Nevin Witman & Alejandro Hidalgo & Terje R. S. Kolstad & William E. Louch & Susanne Pehrsson & Andrew Park , 2022. "Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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