Beyond ADCs: Antibody-encapsulated drug for targeted cancer therapy

Abstract

Antibody-drug conjugates (ADCs) have transformed cancer treatment by covalently linking the monoclonal antibody with cytotoxic payload, yet their clinical potential remains constrained by intrinsic limitations: heterogeneous drug-to-antibody ratios, linker instability, manufacturing complexity, and drug resistance. These challenges highlight the need for fundamentally different drug formulation and delivery platforms. Antibody-encapsulated drugs (AEDs) leverage the single protein encapsulation technology to enable one antibody to noncovalently encapsulate a predefined number of payload molecules. AEDs allow for a fixed drug-to-antibody ratio, mitigate premature drug release, simplify manufacturing, and expand the range of compatible payloads and protein molecules. Preclinical investigation of trastuzumab-encapsulated actinomycin D, a HER2-targeted AED, has demonstrated potent antitumor activity across cancer models with varying HER2 expression levels, alongside a favorable toxicity profile in animal models. The broader translational feasibility of the single protein encapsulation platform is further supported by ongoing clinical trials of albumin-encapsulated therapeutics. Together, these advances position AED as a promising next-generation targeted cancer therapy that complements and potentially extends beyond conventional ADCs, offering a compelling strategy to overcome existing resistance mechanisms and therapeutic limitations.