Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 888 - PubMed (original) (raw)
Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 888
Galina Obmolova et al. Mol Immunol. 2012 Jun.
Abstract
Human CC chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), is a member of the β chemokine family whose actions are mediated through the G-protein-coupled receptor CCR2. Binding of CCL2 to its receptor CCR2 triggers calcium mobilization and chemotaxis. CCL2 is implicated in the pathogenesis of certain inflammatory diseases and cancer. CNTO 888, a neutralizing human anti-CCL2 antibody, was derived by antibody phage display. The antibody binds human CCL2 with high affinity (K(D)=22 pM) and inhibits CCL2 binding to its receptor. The crystal structure of the CNTO 888 Fab alone and in complex with the monomeric form of CCL2 (P8A variant) was determined at 2.6 Å and 2.8 Å resolution, respectively. CNTO 888 recognizes a conformational epitope encompassing residues 18-24 and 45-51 that overlaps the mapped receptor binding site. The epitope of CNTO 888 does not overlap with the dimerization site of CCL2, and thus its inhibitory activity is not expected to result from interference with the oligomeric state of CCL2. Comparison of the X-ray-determined epitopes of CNTO 888 and another CCL2-neutralizing antibody, 11K2, provides insight into the molecular basis of antibody selectivity and functional inhibition.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Similar articles
- Structure activity relationships of monocyte chemoattractant proteins in complex with a blocking antibody.
Reid C, Rushe M, Jarpe M, van Vlijmen H, Dolinski B, Qian F, Cachero TG, Cuervo H, Yanachkova M, Nwankwo C, Wang X, Etienne N, Garber E, Bailly V, de Fougerolles A, Boriack-Sjodin PA. Reid C, et al. Protein Eng Des Sel. 2006 Jul;19(7):317-24. doi: 10.1093/protein/gzl015. Epub 2006 May 8. Protein Eng Des Sel. 2006. PMID: 16682434 - Identification of CCR2-binding features in Cytl1 by a CCL2-like chemokine model.
Tomczak A, Pisabarro MT. Tomczak A, et al. Proteins. 2011 Apr;79(4):1277-92. doi: 10.1002/prot.22963. Epub 2011 Feb 14. Proteins. 2011. PMID: 21322034 - Neutralization of NGF-TrkA receptor interaction by the novel antagonistic anti-TrkA monoclonal antibody MNAC13: a structural insight.
Covaceuszach S, Cattaneo A, Lamba D. Covaceuszach S, et al. Proteins. 2005 Feb 15;58(3):717-27. doi: 10.1002/prot.20366. Proteins. 2005. PMID: 15625712 - Synthesis by native chemical ligation and crystal structure of human CCL2.
Grygiel TL, Teplyakov A, Obmolova G, Stowell N, Holland R, Nemeth JF, Pomerantz SC, Kruszynski M, Gilliland GL. Grygiel TL, et al. Biopolymers. 2010;94(3):350-9. doi: 10.1002/bip.21390. Biopolymers. 2010. PMID: 20091676 - Synthesis and biological characterization of human monocyte chemoattractant protein 1 (MCP-1) and its analogs.
Kruszynski M, Stowell N, Das A, Seideman J, Tsui P, Brigham-Burke M, Nemeth JF, Sweet R, Heavner GA. Kruszynski M, et al. J Pept Sci. 2006 Jan;12(1):25-32. doi: 10.1002/psc.680. J Pept Sci. 2006. PMID: 15942931
Cited by
- Roles of omental and bone marrow adipocytes in tumor biology.
Cha YJ, Koo JS. Cha YJ, et al. Adipocyte. 2019 Dec;8(1):304-317. doi: 10.1080/21623945.2019.1643189. Adipocyte. 2019. PMID: 31334678 Free PMC article. Review. - ALTHEA Gold Libraries™: antibody libraries for therapeutic antibody discovery.
Valadon P, Pérez-Tapia SM, Nelson RS, Guzmán-Bringas OU, Arrieta-Oliva HI, Gómez-Castellano KM, Pohl MA, Almagro JC. Valadon P, et al. MAbs. 2019 Apr;11(3):516-531. doi: 10.1080/19420862.2019.1571879. Epub 2019 Feb 26. MAbs. 2019. PMID: 30663541 Free PMC article. - International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.
Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, Horuk R, Sparre-Ulrich AH, Locati M, Luster AD, Mantovani A, Matsushima K, Murphy PM, Nibbs R, Nomiyama H, Power CA, Proudfoot AE, Rosenkilde MM, Rot A, Sozzani S, Thelen M, Yoshie O, Zlotnik A. Bachelerie F, et al. Pharmacol Rev. 2013 Nov 11;66(1):1-79. doi: 10.1124/pr.113.007724. Print 2014. Pharmacol Rev. 2013. PMID: 24218476 Free PMC article. Review. - Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy.
Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Vacchelli E, et al. Oncoimmunology. 2014 Jan 1;3(1):e27048. doi: 10.4161/onci.27048. Oncoimmunology. 2014. PMID: 24605265 Free PMC article. Review. - Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting.
Xu M, Wang Y, Xia R, Wei Y, Wei X. Xu M, et al. Cell Prolif. 2021 Oct;54(10):e13115. doi: 10.1111/cpr.13115. Epub 2021 Aug 31. Cell Prolif. 2021. PMID: 34464477 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous