Antibody drug conjugates (ADCs) are an important class of biotherapeutics in oncology. To date, nine ADCs have received regulatory approval in different countries with many more in the early- and late-stage clinical development. ADCs have complex molecular structures consisting of a monoclonal antibody (mAb) covalently bound with a cytotoxic payload through a chemical linker. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics (also referred to as payload).
Typically, 3 different analytes are quantified in preclinical and clinical studies - conjugate, total antibody and unconjugated payload. The value of measuring all 3 analytes across the spectrum of clinical development is not clear. In earlier (Phase 1) studies, analyzing all analytes is important to understand the disposition of the molecule as well as exposure-response relationships. In late-stage studies however, this adds significant development cost and unnecessary patient burden and its value in decision making is not clear. The cytotoxic payloads, upon release from the ADC, are considered to behave like small molecules. As a result, evaluating the drug-drug interaction (DDI) potential associated with payloads is important in clinical development of ADCs. However, given the relatively high potency and low systemic exposure of cytotoxic payloads, DDI consideration for ADCs might be different from traditional small molecules. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened an ADC working group to create a database that includes 26 ADCs with 6 unique payloads. Additionally, the 9 approved ADCs were evaluated. These analyses support the strategy of PK characterization of all three analytes in early-phase development and progressively minimizing the number of analytes to be measured in the late-phase studies. The systemic concentrations of unconjugated payload are usually too low to serve as a DDI perpetrator; however, the potential for unconjugated payloads as a victim still exists. A data-driven and risk-based decision tree was developed to guide the assessment of a circulating payload as a victim of DDI.