Key metrics to expanding the pipeline of successful antibody-drug conjugates

Abstract

Although the recent FDA approval of six new antibody-drug conjugates (ADCs) is promising, attrition of ADCs during clinical development remains high. The inherent complexity of ADCs is a double-edged sword that provides opportunities for perfecting therapeutic action while also increasing confounding factors in therapeutic failures. ADC design drives their pharmacokinetics and pharmacodynamics, and requires deeper analysis than the commonly used C_max and area under the curve (AUC) metrics to scale dosing to the clinic. Common features of current FDA-approved ADCs targeting solid tumors include humanized IgG1 antibody domains, highly expressed tumor receptors, and large antibody doses. The potential consequences of these shared features for clinical pharmacokinetics and mechanism of action are discussed, and key design aspects for successful solid tumor ADCs are highlighted.

Keywords: immunotherapy; intratumor drug distribution; translational pharmacokinetics.