Multivalent CXCR4-targeting nanobody formats differently affect affinity, receptor clustering, and antagonism

Anbuhl, Stephanie M.; Dervillez, Xavier; Neubacher, Saskia; Schriek, Angela I.; Bobkov, Vladimir; de Taeye, Steven W.; Szpakowska, Martyna; Siderius, Marco; Grossmann, Tom N.; Chevigné, Andy; Smit, Martine J.; Heukers, Raimond

doi:10.1016/j.bcp.2024.116457

Biochemical Pharmacology

2024

DOI: 10.1016/j.bcp.2024.116457

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Multivalent CXCR4-targeting nanobody formats differently affect affinity, receptor clustering, and antagonism

Stephanie M. Anbuhl,

Xavier Dervillez,

Saskia Neubacher

et al.

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2024

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Cited by 1 publication

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Disruption of basal CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

Mobach,

Bergkamp,

et al. 2024

Preprint

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The chemokine receptor CXCR4 is overexpressed in many cancers and contributes to pathogenesis, disease progression, and resistance to therapies. CXCR4 is known to form oligomers, but the potential functional relevance in malignancies remain elusive. Using a newly established nanobody-based BRET method, we demonstrate that oligomerization of endogenous CXCR4 on lymphoid cancer cell lines correlates with enhanced expression levels. Specific disruption of CXCR4 oligomers reduced basal cell migration and pro-survival signaling via changes in the phosphoproteome, indicating the existence of basal CXCR4-oligomer-mediated signaling. Oligomer disruption also inhibited growth of primary CLL 3D spheroids and sensitized primary malignant cells to clinically used Bcl-2 inhibitor venetoclax. Given its limited efficacy in some patients and the ability to develop resistance, sensitizing malignant B-cells to venetoclax is of clinical relevance. Taken together, we established a new, non-canonical and critical role for CXCR4 oligomers in lymphoid neoplasms and demonstrated that selective targeting thereof has clinical potential.

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Disruption of basal CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

Mobach,

Bergkamp,

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Multivalent CXCR4-targeting nanobody formats differently affect affinity, receptor clustering, and antagonism

Cited by 1 publication

References 48 publications

Disruption of basal CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

Disruption of basal CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

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