《The Pharmacologic Basis for Antibody-Auristatin Conjugate》.pdf

0022-3565/09/3303-932–938$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 330, No. 3 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 155549/3501515 JPET 330:932–938, 2009 Printed in U.S.A. The Pharmacologic Basis for Antibody-Auristatin Conjugate Activity Stephen C. Alley, Xinqun Zhang, Nicole M. Okeley, Martha Anderson, Che-Leung Law, Peter D. Senter, and Dennis R. Benjamin Seattle Genetics, Inc., Bothell, Washington Received April 24, 2009; accepted June 3, 2009 ABSTRACT Antibody-drug conjugates (ADCs) made with auristatin antimitotic first time point (1 h) had the highest antibody and total auristatin agents have shown significant preclinical and clinical oncology concentrations with low unconjugated auristatin concentrations, D o activity. SGN-75 is composed of the anti-CD70 antibody h1F6 with the exception of organs expected to be involved in hepato- w n conjugated to monomethylauristatin F through a noncleavable biliary clearance of the ADC, where total and unconjugated au- l o