Antibody neutralization of CXCL10 in vivo is dependent on binding free and not endothelial bound chemokine: implications for the design of a new generation of anti-chemokine therapeutic antibodies [Glycobiology and Extracellular Matrices]

In order to improve our understanding of properties that confer successful inhibition of chemokines in vivo, we have analyzed anti-murine (m) CXCL10 monoclonal antibodies (mAb) having different characteristics. 1B6 displays potent inhibition of cell recruitment in vitro with an IC50 of 0.5 nM but has demonstrated little efficacy in various animal models of human disease. On the contrary, 1F11 has shown efficacy in several models of inflammation, yet is less potent at inhibiting chemotaxis in vitro with an IC50 of 21 nM. Furthermore, we observed that 1B6 displays a rapid dose-dependent clearance (t1/2 10-60 hrs) in contrast to 1F11 that presents a dose proportional pharmacokinetic profile and a half-life of 12 days. Moreover, 1B6 recognizes glycosaminoglycan (GAG)-bound CXCL10, resulting in target mediated clearance, which was corroborated using CXCL10-deficient mice. In contrast to 1B6, 1F11 inhibits the interaction of CXCL10 with GAGs, does not recognize GAG-bound CXCL10 and does not display target mediated drug disposition. Confirming previous animal studies, 1B6 was poor at reversing glycemia in a model of type 1 diabetes, while 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 to 1B6. We therefore concluded that targeting chemokines with antibodies recognizing the more abundant GAG-bound form of the chemokine, such as with 1B6, may not be the optimal strategy to achieve disease control.

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