S19 Targeted Drug Delivery and ADME of Antibody-Drug Conjugates

Stephen C. Alley , Seattle Genetics, Inc., Bothell, WA
Antibody-drug conjugates (ADCs) offer the opportunity to use the specificity of antibodies to deliver cytotoxic agents to tumors and avoid systemic exposure of normal tissues to the drug. Conjugation is therefore expected to significantly alter the pharmacokinetics and biodistribution of the drug. ADCs made with tubulin interacting auristatins, synthetic analogs of the natural product dolastatin 10, have been investigated for their ability to target drug to tumor cells. This presentation will describe the pharmacokinetics and disposition of auristatin ADCs, showing their ability to deliver drug to tumors and release drug in target cells. Mass spectrometry techniques allowed the determination of the structure of the released drug and the serum pharmacokinetics. The tumor and tissue disposition of antibody, conjugated drug, and released drug were also determined. The released drug was found to be localized to and retained by the tumor in preference to normal tissues and serum.