دورية أكاديمية
CXCR4-Specific Nanobodies as Potential Therapeutics for WHIM syndrome.
| العنوان: | CXCR4-Specific Nanobodies as Potential Therapeutics for WHIM syndrome. |
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| المؤلفون: | de Wit RH; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Heukers R; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Brink HJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Arsova A; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Maussang D; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Cutolo P; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Strubbe B; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Vischer HF; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Bachelerie F; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.)., Smit MJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.H.d.W., R.H., H.J.B., A.A., D.M., H.F.V, M.J.S.); Inflammation Chemokines and Immunopathology, INSERM, Faculté de Médicine-Université Paris-Sud, Université Paris-Saclay, Clamart, France (P.C., F.B.); and Ablynx N.V., Zwijnaarde, Belgrium (B.S.) mj.smit@vu.nl. |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Oct; Vol. 363 (1), pp. 35-44. Date of Electronic Publication: 2017 Aug 02. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Antibody Specificity*, Immunologic Deficiency Syndromes/*immunology , Immunologic Deficiency Syndromes/*therapy , Receptors, CXCR4/*immunology , Single-Chain Antibodies/*immunology , Single-Chain Antibodies/*therapeutic use , Warts/*immunology , Warts/*therapy, HEK293 Cells ; Humans ; Immunologic Deficiency Syndromes/genetics ; Mutation ; Primary Immunodeficiency Diseases ; Receptors, CXCR4/genetics ; Warts/genetics |
| مستخلص: | WHIM syndrome is a rare congenital immunodeficiency disease, named after its main clinical manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, which refers to abnormal accumulation of mature neutrophils in the bone marrow. The disease is primarily caused by C-terminal truncation mutations of the chemokine receptor CXCR4, giving these CXCR4-WHIM mutants a gain of function in response to their ligand CXCL12. Considering the broad functions of CXCR4 in maintaining leukocyte homeostasis, patients are panleukopenic and display altered immune responses, likely as a consequence of impairment in the differentiation and trafficking of leukocytes. Treatment of WHIM patients currently consists of symptom relief, leading to unsatisfactory clinical responses. As an alternative and potentially more effective approach, we tested the potency and efficacy of CXCR4-specific nanobodies on inhibiting CXCR4-WHIM mutants. Nanobodies are therapeutic proteins based on the smallest functional fragments of heavy chain antibodies. They combine the advantages of small-molecule drugs and antibody-based therapeutics due to their relative small size, high stability, and high affinity. We compared the potential of monovalent and bivalent CXCR4-specific nanobodies to inhibit CXCL12-induced CXCR4-WHIM-mediated signaling with the small-molecule clinical candidate AMD3100. The CXCR4-targeting nanobodies displace CXCL12 binding and bind CXCR4-wild type and CXCR4-WHIM (R334X/S338X) mutants and with (sub-) nanomolar affinities. The nanobodies' epitope was mapped to extracellular loop 2 of CXCR4, overlapping with the binding site of CXCL12. Monovalent, and in particular bivalent, nanobodies were more potent than AMD3100 in reducing CXCL12-mediated G protein activation. In addition, CXCR4-WHIM-dependent calcium flux and wound healing of human papillomavirus-immortalized cell lines in response to CXCL12 was effectively inhibited by the nanobodies. Based on these in vitro results, we conclude that CXCR4 nanobodies hold significant potential as alternative therapeutics for CXCR4-associated diseases such as WHIM syndrome. (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (CXCR4 protein, human) 0 (Receptors, CXCR4) 0 (Single-Chain Antibodies) |
| SCR Disease Name: | WHIM syndrome |
| تواريخ الأحداث: | Date Created: 20170804 Date Completed: 20171009 Latest Revision: 20191210 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1124/jpet.117.242735 |
| PMID: | 28768817 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.117.242735 |