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==Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12==
<StructureSection load='4lmq' size='340' side='right'caption='[[4lmq]], [[Resolution|resolution]] 2.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4lmq]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LMQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LMQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.773&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lmq OCA], [https://pdbe.org/4lmq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lmq RCSB], [https://www.ebi.ac.uk/pdbsum/4lmq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lmq ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SDF1_HUMAN 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.<ref>PMID:8752281</ref> <ref>PMID:11069075</ref> <ref>PMID:11859124</ref> <ref>PMID:16107333</ref> <ref>PMID:18802065</ref> <ref>PMID:19255243</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:23812669</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4lmq" style="background-color:#fffaf0;"></div>

==See Also==
*[[C-X-C motif chemokine 3D structures|C-X-C motif chemokine 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adams C]]
[[Category: Barck K]]
[[Category: Carano RD]]
[[Category: Chiang NY]]
[[Category: Clark R]]
[[Category: Clark S]]
[[Category: Coons M]]
[[Category: Corpuz R]]
[[Category: Damico-Beyer LA]]
[[Category: Ferrara N]]
[[Category: Gribling P]]
[[Category: Kelley RF]]
[[Category: Lee WP]]
[[Category: Li B]]
[[Category: Quintana L]]
[[Category: Suto E]]
[[Category: Takkar R]]
[[Category: Ultsch M]]
[[Category: Wang J]]
[[Category: Wang W]]
[[Category: Wong T]]
[[Category: Xiang H]]
[[Category: Yao J]]
[[Category: Zhong Z]]