Antibody–drug conjugates (ADCs) have transformed cancer treatment by delivering potent cytotoxic drugs directly to tumor cells. But because each ADC recognizes only a single molecular target, many cancers become difficult to treat as tumors evolve into a patchwork of cells with different biological characteristics. A preclinical study published in Nature describes a modular strategy that enables existing antibodies and ADCs to assemble inside the body, allowing them to engage multiple tumor targets without creating entirely new drugs.
Researchers at Washington University School of Medicine modified FDA-approved antibodies and HER2-directed ADCs with complementary chemical groups that bond together through bioorthogonal “click chemistry” after sequential administration. The resulting complexes produced stronger antitumor activity than conventional ADC therapy in mouse models of pancreatic, gastric, and breast cancer.
The work addresses a longstanding obstacle for ADCs: they are most effective when nearly every tumor cell displays the same molecular target.
“Strategies that enhance ADC delivery to the tumor without requiring uniformly high antigen expression are needed to address heterogeneous and treatment-resistant tumors,” the authors write.
To test that concept, the researchers paired HER2-directed ADCs with antibodies targeting either HER2 or EGFR, a receptor frequently associated with treatment resistance. Because the molecules assemble after entering the circulation, the approach offers a modular alternative to engineering entirely new bispecific antibodies.
The strategy proved particularly effective in cancers with low, ultralow, negative, or heterogeneous HER2 expression, expanding activity into tumors that often respond poorly to existing HER2-targeted therapies.
“This strategy enabled targeted delivery of HER2-directed ADCs… to EGFR-high or EGFR-low cancer cells across the spectrum of HER2 expression,” the authors conclude.
The improved targeting translated into substantially better outcomes in the pancreatic cancer model. About 90% of treated mice survived for 120 days, whereas animals receiving conventional ADC therapy survived less than 80 days on average. The researchers also optimized the platform to reduce off-target drug accumulation in the liver, an important consideration for limiting toxicity.
Rather than relying exclusively on one receptor to deliver therapy, the system can exploit interactions between multiple tumor-associated receptors to improve drug uptake.
“The therapeutic benefit probably reflects a combination of bioorthogonal chemistry-driven ligation and tumor receptor biology rather than exclusively receptor colocalized assembly,” the authors write.
The click chemistry platform also may accelerate development of precision therapies. The linking molecules can be manufactured in as little as one to three days, making it possible to rapidly pair different clinically approved antibodies and ADCs for individual tumor profiles. Although demonstrated using HER2-targeted therapies, the researchers say the modular approach could be adapted to many receptor combinations and cancer types. They are particularly interested in applying the technology to difficult-to-treat tumors such as brain cancers, where improving drug delivery remains a major challenge.
“Beyond direct cytotoxic delivery, the modular customization of this approach offers potential for immune modulation, diagnostic imaging and combinatorial payload strategies,” the authors conclude. “As such, this approach provides a flexible foundation for the optimization of antibody-based therapeutics in oncology and other diseases.”
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