An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation

Abstract

IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC₅₀ of ∼4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4–6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.

• Inflammation
• mouse
• chemokine
• IP-10
• monoclonal antibody

Acknowledgements

We thank David Chang, Byron Taylor, Germein Linares, KariLynn Howard, and Emmanuel Sablan for expert technical assistance and useful scientific discussions. We also thank Scott Silbiger of Amgen Inc. for editorial assistance in the preparation of this manuscript. Except for Gabriele S. Campanella at Massachusetts General Hospital, all authors were employees of Amgen Inc. at the time the work was performed.

This paper is dedicated to the memory of Dr. George Doellgast — a trusted colleague, scientist and friend who will be greatly missed by all who had the privilege of knowing and working with him.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.