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.
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Andover, MA, USA. yulia.vugmeyster@pfizer.com
Yulia
Y
Vugmeyster
David
D
DeFranco
Debra D
DD
Pittman
Xin
X
Xu
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