From Payload-First Toward Dual-Mechanism Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are often described as simple carriers that shuttle cytotoxic payloads to tumors. However, many backbones, exemplified by trastuzumab, are potent biologics whose pharmacology is eroded by conjugation. In this Perspective, we introduce the concept of an antibody exposure deficit. This represents the systematic reduction in both antibody mass and systemic exposure delivered by an ADC relative to its approved unconjugated monoclonal antibody. We show how payload type, drug-to-antibody ratio (DAR), linker and payload-linker hydrophobicity, and conjugation architecture together drive this deficit. Site-specific DAR 1 formats can mitigate this deficit, unlike higher-DAR constructs such as antibody-polymer conjugates, where the monoclonal antibody serves primarily as a carrier for effective payloads. This defines a landscape of ADC design to which fragment crystallizable (Fc) activity modulation adds further complexity. Altogether, these strategies span the continuum of possible ADC constructs.