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Pharmacological characterization of PF‐00547659, an anti‐human MAdCAM monoclonal antibody
Author(s) -
Pullen N,
Molloy E,
Carter D,
Syntin P,
Clemo F,
FincoKent D,
Reagan W,
Zhao S,
Kawabata T,
Sreckovic S
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00137.x
Subject(s) - addressin , monoclonal antibody , cell adhesion molecule , in vivo , pharmacology , in vitro , antibody , immunology , extravasation , cell adhesion , biology , adhesion , chemistry , biochemistry , microbiology and biotechnology , organic chemistry
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 β 7 + 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 K d values of 5.1 and 16.1 pmol·L −1 respectively and blocked the adhesion of α 4 β 7 + leukocytes to MAdCAM with similar potency. MECA‐367 and PF‐00547659 induced a similar, dose‐dependent two‐ to threefold increase in circulating populations of β 7 + memory T‐cells in the mouse and macaque; without affecting the β 7 ‐ populations. Conclusions and implications: PF‐00547659 has potential utility in the treatment of inflammatory conditions by blocking tissue homing of activated α 4 β 7 + 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.