Pharmacokinetics and lung distribution of a humanized anti-RAGE antibody in wild-type and RAGE-/- mice.
A neutralizing antibody to the receptor for the advanced glycation end products (anti-RAGE Ab) was developed as a potential treatment of acute and chronic inflammatory conditions. Previous pharmacology studies demonstrated efficacy of the anti-RAGE antibody in the mouse model of sepsis. We examined pharmacokinetics and lung distribution of [125I]anti-RAGE Ab in RAGE-/- and wild-type (129S5) mice following single IV administration. Serum pharmacokinetics of [125I]anti-RAGE Ab was similar in RAGE-/- and 129S5 mice, with the total body clearance of 0.3 mL/hr/kg and the elimination half-life of 11-12 days, suggesting the target expression had limited impact on overall elimination of [125I]anti-RAGE Ab from mice. [125I]Anti-RAGE Ab accumulated in the lung of 129S5 mice, with ~4% of total dose retained in the lung at days 6-27 and the lung AUC0-∞ of ~300% of that in serum. The SDS-PAGE analysis suggested that most of retained lung radioactivity was attributed to intact antibody. No accumulation of radioactivity was observed in the lung of RAGE-/- mice, indicating that lung uptake of [125I]anti-RAGE Ab was target-dependent in wild-type mice. These data suggest that the anti-RAGE Ab was able to localize to the site of RAGE expression, the lung, and support the findings in the previous pharmacology studies.
Vugmeyster
Yulia
Y
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Andover, MA, USA. yulia.vugmeyster@pfizer.com
DeFranco
David
D
Pittman
Debra D
DD
Xu
Xin
X
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic