Pharmacological characterization of PF‐00547659, an anti‐human MAdCAM monoclonal antibody
Open Access
- 28 April 2009
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 157 (2), 281-293
- https://doi.org/10.1111/j.1476-5381.2009.00137.x
Abstract
Background and purpose: The adhesion molecule mucosal addressin cell adhesion molecule (MAdCAM) plays an essential role in the recruitment of lymphocytes to specialized high endothelial venules of the gastrointestinal tract and in their excessive tissue extravasation observed in inflammatory conditions, such as Crohn's disease. We have characterized the in vitro pharmacological properties of two monoclonal antibodies blocking MAdCAM, MECA-367 and PF-00547659, and determined their pharmacokinetic/pharmacodynamic profiles in vivo. Experimental approach: Functional adhesion assays and surface plasmon resonance were used to characterize, in vitro, the pharmacological properties of MECA-367 and PF-00547659. The in vivo effects of MECA-367 and PF-00547659 on restriction of β7+ memory T lymphocytes were determined in mice and macaques, respectively, over the pharmacological dose range to confirm pharmacokinetic/pharmacodynamic relationships. Key results: MECA-367 and PF-00547659 bound with high affinity to mouse and human MAdCAM with Kd values of 5.1 and 16.1 pmol·L−1 respectively and blocked the adhesion of α4β7+ leukocytes to MAdCAM with similar potency. MECA-367 and PF-00547659 induced a similar, dose-dependent two- to threefold increase in circulating populations of β7+ memory T-cells in the mouse and macaque; without affecting the β7- populations. Conclusions and implications: PF-00547659 has potential utility in the treatment of inflammatory conditions by blocking tissue homing of activated α4β7+ leukocytes. The characterization of a rodent cross-reacting antibody as a surrogate for PF-00547659 in the search for potential pharmacological biomarkers and the determination of efficacious doses was effective in addressing the restricted orthologous cross-reactivity of PF-00547659 and the challenges this poses with respect to efficacy and safety testing.Keywords
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