Recordered Friday, September 11, 2020
Co-Chairs: William O. Iverson, DVM, Consultant; and Nancy E. Everds, DVM, DACVP, Seattle Genetics
Antibody-drug conjugates (ADCs), which use a specific antibody to deliver a toxic payload to target cells, hold great promise to increase efficacy and reduce adverse side effects, especially for oncology drugs. Six ADC molecules have received marketing approval in the US over the past 18 years. Nonclinical safety assessment has proven challenging as many ADCs still have steep dose-response curves and low therapeutic indices. Toxicities in many different organs and tissues have been seen, including bone marrow, skin, liver, kidney, eye, gastrointestinal tract, and nervous system. ADC-related toxicities may be more challenging to predict and manage than those seen with small molecules or unconjugated antibodies. This has led to more sophisticated engineering of antibodies, linkers, and drugs to increase internalization of drug by target cells, decrease off-target toxicity, and decrease bystander effects. This course will give an overview of synthesis and mechanisms of representative ADCs, and the clinical and anatomic pathology findings associated with different classes of agents, including immunomodulatory molecules and PROTACS.