Pharmacological characterization of PF-00547659, an anti-human MAdCAM monoclonal antibody.
OBJECTIVE
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.


METHODS
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 beta(7) (+) memory T lymphocytes were determined in mice and macaques, respectively, over the pharmacological dose range to confirm pharmacokinetic/pharmacodynamic relationships.


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 alpha(4)beta(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 beta(7) (+) memory T-cells in the mouse and macaque; without affecting the beta(7) (-) populations.


CONCLUSIONS
PF-00547659 has potential utility in the treatment of inflammatory conditions by blocking tissue homing of activated alpha(4)beta(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.
Pullen
N
N
Pfizer Global Research and Development, Sandwich, Kent, UK. nick.pullen@pfizer.com
Molloy
E
E
Carter
D
D
Syntin
P
P
Clemo
F
F
Finco-Kent
D
D
Reagan
W
W
Zhao
S
S
Kawabata
T
T
Sreckovic
S
S
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003429:Cross Reactions; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D016130:Immunophenotyping; D008252:Macaca fascicularis; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D017931:DNA Primers