Antibody Neutralization of CXCL10in VivoIs Dependent on Binding to Free and Not Endothelial-bound Chemokine: IMPLICATIONS FOR THE DESIGN OF A NEW GENERATION OF ANTI-CHEMOKINE THERAPEUTIC ANTIBODIES.
To improve our understanding of properties that confer successful inhibition of chemokinesin vivo, we analyzed anti-murine CXCL10 monoclonal antibodies (mAb) having different characteristics. 1B6 displayed potent inhibition of cell recruitmentin vitrowith an IC50of 0.5 nm but demonstrated little efficacy in various animal models of human disease. On the contrary, 1F11 showed efficacy in several models of inflammation yet was less potent at inhibiting chemotaxisin vitrowith an IC50of 21 nm Furthermore, we observed that 1B6 displayed a rapid dose-dependent clearance (t½10-60 h) in contrast to 1F11, which presented a dose-proportional pharmacokinetic profile and a half-life of 12 days. Moreover, 1B6 recognized glycosaminoglycan (GAG)-bound CXCL10, resulting in target-mediated clearance, which was corroborated using CXCL10-deficient mice. In contrast to 1B6, 1F11 inhibited the interaction of CXCL10 with GAGs, did not recognize GAG-bound CXCL10, and did not display target-mediated drug disposition. Confirming previous animal studies, 1B6 was poor at reversing glycemia in a model of type 1 diabetes, whereas 1F11 induced early and prolonged control of diabetes. Furthermore, when using 1A4, a subsequently generated anti-mCXCL10 mAb that shares the property with 1F11 of being unable to recognize CXCL10 immobilized on GAG, we observed a similar superior control of diabetes as compared with 1B6. We therefore concluded that targeting chemokines with antibodies such as 1B6 that recognize the more abundant GAG-bound form of the chemokine may not be the optimal strategy to achieve disease control.
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Pauline
P
Bonvin
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Franck
F
Gueneau
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Vanessa
V
Buatois
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Maud
M
Charreton-Galby
Pharmazentrum Frankfurt/ZAFES Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany, and.
Stanley
S
Lasch
Pharmazentrum Frankfurt/ZAFES Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany, and.
Marie
M
Messmer
Pharmazentrum Frankfurt/ZAFES Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany, and.
Urs
U
Christen
the Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Andrew D
AD
Luster
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Zoë
Z
Johnson
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Walter
W
Ferlin
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Marie
M
Kosco-Vilbois
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland.
Amanda
A
Proudfoot
From Novimmune SA, chemin des Aulx 14, 1228 Plan-les-Ouates, Geneva, Switzerland, nfischer@novimmune.com.
Nicolas
N
Fischer
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D054357:Chemokine CXCL10; D006025:Glycosaminoglycans
chemokine; chemotaxis; glycosaminoglycan; monoclonal antibody; pharmacokinetics; therapeutic inhibition