Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL-13 antibodies with different IL-13 neutralization mechanisms.
Numerous animal and in vitro studies suggest that neutralization of IL-13 is an attractive approach for therapeutic intervention in asthma. In this paper we describe preclinical pharmacokinetics (PK), interspecies scaling, and biodistribution of two humanized anti-IL-13 IgG1 monoclonal antibodies, Ab-01 and Ab-02, with different IL-13 neutralization mechanisms. PK parameters of Ab-01 and Ab-02 following IV or SC dosage to mouse, rat, cynomolgus monkey, and sheep, were similar. After IV administration, the elimination of anti-IL-13 antibodies was slow in all species tested and the serum clearance ranged from 0.13 mL/h/kg in monkeys to 0.81 mL/h/kg in mice. Both anti-IL-13 antibodies appeared to be confined primarily to the vascular space, as volume of distribution was relatively small (<120 mL/kg) in all species and tissue-to-serum concentration ratios (in mice and rats) were low (<0.5) in the tissues examined. The elimination half-life ranged from 3-6 days in mice to 14-17 days in monkey and sheep. In monkeys, PK parameters appeared to be approximately linear in the 1-100 mg/kg dose range. Following SC administration, the bioavailability of anti-IL-13 antibodies was 60-90% in all species tested. PK profile of Ab-02 in the model of acute airway inflammation (induced by Ascaris challenge) was, in general, similar to that in unchallenged monkeys; however, volume of distribution and clearance tended to decrease in Ascaris-challenged animals. Allometric scaling suggested that anti-IL-13 antibodies would likely to have a favorable PK profile, such as slow clearance and long terminal half-life, following IV or SC administration to humans.
Vugmeyster
Yulia
Y
Department of Drug Safety and Metabolism, One Burtt Road, Wyeth Research, Andover, MA 01810, USA. yvugmeyster@wyeth.com <yvugmeyster@wyeth.com>
Szklut
Pamela
P
Tchistiakova
Lioudmila
L
Abraham
William
W
Kasaian
Marion
M
Xu
Xin
X
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013045:Species Specificity; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D018793:Interleukin-13