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Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2¹

Dorien M. de Groot^*, Gerard Vogel^*, John Dulos^*, Leonie Teeuwen^*, Karin Stebbins, Jörg Hamann, Bronwyn M. Owens, Hans van Eenennaam^*, Ebo Bos^* and Annemieke M. Boots^2,*

^* Schering-Plough Research Institute, Oss, The Netherlands; Schering-Plough Research Institute, Cambridge, MA 02143; and Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

CD97 is a member of the EGF-TM7 family of adhesion class receptors, with a proposed role in inflammatory cell recruitment. Neutralization of murine CD97 with the anti-mCD97 mAb 1B2 was efficacious in prevention of murine collagen-induced arthritis, a model with features resembling rheumatoid arthritis. Here, the therapeutic potential of neutralizing CD97 in arthritis was studied with emphasis on the 1B2 pharmacokinetics. Mice with established arthritis were treated with anti-mCD97 or anti-TNF- serum. Ab pharmacokinetics and biodistribution were studied in diseased and nondiseased mice using labeled 1B2. The impact of CD97 expression on Ab pharmacokinetics was studied using CD97 knockout mice. Treatment with 1B2 showed an efficacy comparable to anti-TNF- treatment. Pharmacokinetic analysis of 1B2 in wild-type and CD97 knockout mice indicated a dose-dependent Ab clearance, due to specific interaction with CD97. Biodistribution studies showed accumulation of 1B2 in spleen and lung. In vitro studies using murine splenocytes revealed that CD97 when bound to Ab was internalized. Moreover, soluble CD97 was detected in the supernatant, suggesting Ag shedding. Finally, in arthritic mice, higher levels of soluble CD97 were found and 1B2 treatment led to specific targeting of inflamed paws, resulting in a higher clearance rate of 1B2 in arthritic mice than in wild-type mice. In conclusion, our data support a therapeutic value of CD97 neutralization in experimental arthritis. The pharmacokinetic profile of the 1B2 Ab illustrates the complexity of Ab elimination from an organism and stresses the importance of understanding Ag-Ab interactions when developing therapeutic mAbs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by Schering-Plough Research Institute, Oss, The Netherlands.

² Address correspondence and reprint requests to Dr. A. M. Boots, Department of Pharmacology, Schering-Plough Research Institute, Molenstraat 110, Oss, The Netherlands. E-mail address: mieke.boots{at}spcorp.com

³ Abbreviations used in this paper: EGF, epidermal growth factor; CIA, collagen-induced arthritis; GPCR, G protein-coupled receptor; KO, knockout; PBST, PBS/0.01% Tween 20; RA, rheumatoid arthritis; TM7, seven-span transmembrane; wt, wild type.