| Structural highlights
Function
[SDF1_HUMAN] Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to another C-X-C chemokine receptor CXCR7, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and CXCR7, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of CXCR7 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
PURPOSE: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities.EXPERIMENTAL DESIGN: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities.RESULTS: 30D8, a hamster antibody against mouse and human CXCL12alpha, CXCL12beta, and CXCL12gamma, was shown to dose-dependently block CXCL12alpha binding to CXCR4 and CXCR7, and CXCL12alpha-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-alpha antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12alpha complex in combination with mutational analysis revealed a "hot spot" around residues Asn44/Asn45 of CXCL12alpha and part of the RFFESH region required for CXCL12alpha binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats.CONCLUSION: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans. Clin Cancer Res; 1-13. (c)2013 AACR.
Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12.,Zhong C, Wang J, Li B, Xiang H, Ultsch M, Coons M, Wong T, Chiang NY, Clark S, Clark R, Quintana L, Gribling P, Suto E, Barck K, Corpuz R, Yao J, Takkar R, Lee WP, Damico-Beyer LA, Carano RD, Adams C, Kelley RF, Wang W, Ferrara N Clin Cancer Res. 2013 Jul 15. PMID:23812669[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833-5. PMID:8752281 doi:10.1038/382833a0
- ↑ Moepps B, Braun M, Knopfle K, Dillinger K, Knochel W, Gierschik P. Characterization of a Xenopus laevis CXC chemokine receptor 4: implications for hematopoietic cell development in the vertebrate embryo. Eur J Immunol. 2000 Oct;30(10):2924-34. PMID:11069075
- ↑ Braun M, Wunderlin M, Spieth K, Knochel W, Gierschik P, Moepps B. Xenopus laevis Stromal cell-derived factor 1: conservation of structure and function during vertebrate development. J Immunol. 2002 Mar 1;168(5):2340-7. PMID:11859124
- ↑ Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005 Oct 21;280(42):35760-6. Epub 2005 Aug 17. PMID:16107333 doi:M508234200
- ↑ Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. J Immunol. 2008 Oct 1;181(7):4632-7. PMID:18802065
- ↑ Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol. 2009 May;75(5):1240-7. doi: 10.1124/mol.108.053389. Epub 2009 Mar , 2. PMID:19255243 doi:10.1124/mol.108.053389
- ↑ Zhong C, Wang J, Li B, Xiang H, Ultsch M, Coons M, Wong T, Chiang NY, Clark S, Clark R, Quintana L, Gribling P, Suto E, Barck K, Corpuz R, Yao J, Takkar R, Lee WP, Damico-Beyer LA, Carano RD, Adams C, Kelley RF, Wang W, Ferrara N. Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12. Clin Cancer Res. 2013 Jul 15. PMID:23812669 doi:10.1158/1078-0432.CCR-13-0943
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