A WashU Medicine team reported a modular “click-to-assemble” strategy to improve antibody–drug conjugate performance in heterogeneous tumors, using engineered antibodies and sequential dosing to form a higher-order complex inside the body. The approach, described in Nature, pairs trans-cyclooctene and tetrazine moieties to trigger bioorthogonal ligation at tumor sites. Across pancreatic, gastric, and breast cancer models—including settings with low, ultralow, or heterogeneous HER2 expression—the clicked constructs slowed or halted tumor progression. The study also framed a key limitation of conventional ADCs: reliance on a single antigen can accelerate resistance when target expression varies. Senior author Patrícia Ribeiro Pereira said the strategy lets developers repurpose existing antibodies rather than build a full new platform per target, with the preclinical intent of improving uptake and resistance profiles without sacrificing modularity.