Ultrahigh-DAR antibody-drug conjugates: advancing the next generation of targeted therapy

Conventional antibody-drug conjugates (ADCs) are typically limited to drug-to-antibody ratios (DARs) of ≤8 because of restricted conjugation sites and unfavorable physicochemical properties at higher DARs, including increased hydrophobicity, aggregation, and rapid systemic clearance. Consequently, most clinically approved ADCs rely on highly potent cytotoxic payloads (e.g. IC₅₀ < 1 nM), which can result in significant off-target toxicities. This mini-review summarizes recent advances in next-generation ultrahigh-DAR antibody therapeutics, with a particular focus on two emerging platforms: antibody polymer conjugates (APCs) and antibody-nanoparticle conjugates (ANCs). We discuss their design principles, structural features, and strategies for achieving high payload loading while preserving antigen recognition and favorable pharmacokinetic properties. Recent advances in APCs and ANCs demonstrate that polymer and nanomaterial engineering can overcome the conventional DAR limitations of ADCs, enabling substantially greater payload loading per targeting antibody without compromising targeting performance. These ultrahigh-DAR platforms also expand the range of deliverable payloads, facilitating the development of therapeutics with diverse mechanisms of action beyond traditional ultrapotent cytotoxic agents. Ultrahigh-DAR antibody therapeutics represent a promising next generation of targeted drug delivery systems. By integrating advances in polymer and nanomaterial engineering, APCs and ANCs have the potential to broaden the therapeutic landscape of antibody-based medicines and enable safer, more effective targeted therapies across a wide range of diseases.