Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

• DOI: 10.1074/jbc.m113.498436
• Publication Date: 2013-08-27T03:05:27Z
• Authors: David Maussang; Azra Mujić-Delić; Francis J. Descamps; Catelijne Stortelers; Peter Vanlandschoot; Marijke Stigter-v...; Henry F. Vischer; Maarten van Roy; Maria Vosjan; Maria Gonzalez-Pa...; Guus A.M.S. van D...; Pascal Merchiers; Philippe van Rompaey; Martine J. Smit
• Keywords: Receptors, CXCR; 0301 basic medicine; Arrestins; Reverse Transcriptase Polymerase Chain Reaction; Mice, Nude; Single-Domain Antibodies; Binding, Competitive; Chemokine CXCL12; Tumor Burden; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; Radioligand Assay; 03 medical and health sciences; HEK293 Cells; Head and Neck Neoplasms; Cell Line, Tumor; NIH 3T3 Cells; Animals; Humans; Female; Camelids, New World; Signal Transduction

The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or interference (si)RNA has shown promising therapeutic benefits models. With increased interest and effectiveness biologicals inhibiting receptors we made use "Nanobody platform" target CXCR7. Previously showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools efficiently tackle difficult drug targets such as receptors. In this study developed characterized highly selective potent Nanobodies against Interestingly, CXCR7-targeting displayed antagonistic properties contrast previously reported agents. Several high affinity CXCR7-specific potently inhibited CXCL12-induced β-arrestin2 recruitment vitro. A wide variety biopsies was profiled, showing for first time expression head neck cancer. Using a patient-derived CXCR7-expressing cancer xenograft model nude mice, growth by Nanobody therapy. Mechanistically, did not inhibit cell cycle progression but instead reduced secretion angiogenic CXCL1 cells vitro, thus acting here inverse agonists, subsequent angiogenesis vivo. Hence, novel class inhibitors, further substantiate relevance targeting cancer.Background: atypical various types cancer.Results: were generated show inhibition signaling Anti-CXCR7 reduce angiogenesis.Conclusion: formation.Significance: therapies are potential treatments Background: Results: angiogenesis. Conclusion: formation. Significance: