LEGO Linkers for ADCs

Antibody-drug conjugates (ADCs) couple the potency of a cytotoxic agent with the selectivity of an antibody. But despite early promise of the technology, only five ADCs have received market approval to date (we explored the potential of ADCs to move to the forefront of the targeted therapy space here). In an effort to develop more stable and predictable ADCs, an investigational team based at the Brigham and Women’s Hospital in Boston, US, has been using computational simulations to focus on improving a crucial element: the linker (1).

“Our goal is to engineer next-generation treatments for unmet medical needs from simple building blocks and strategies that facilitate rapid translation to the clinics. ADCs fall into this category as they leverage existing technologies,” explains team leader Shiladitya Sengupta, Associate Bioengineer at Brigham and Women's Hospital and Associate Professor of Medicine at Harvard Medical School. “The challenge in bringing them to market lies in the linker technology used to create them.” Classic linkers rely on covalent interactions, which can easily “fall apart” in circulation and limit the choice of payload; the researcher's paper, published in Nature Biomedical Engineering, notes that Mylotarg, an FDA-approved ADC, loses 50 percent of its toxic payload within two days because of the older generation linker technologies used to hold it together.

Using molecular docking and molecular dynamics simulations, the team designed a LEGO-like linker that allowed drug payloads and antibodies to self assemble into ADCs. “The self-assembly we observed inspired us to name our approach MAGNET ADCs,” said Sengupta, noting the origin of the acronym: “multivalent and affinity-guided antibody empowerment technology.” Even though MAGNET ADCs are held together by weaker, non-covalent bonds, the high specificity results in increased stability. To prove the point, the Boston-based team put their MAGNET ADCs to the test in a model for human lung cancer, showing that they could maintain stability for up to 14 days and with low levels of toxicity in vitro. 

“Though we tested our technology in a model for lung cancer, the therapeutic and diagnostic applications of MAGNET ADCs are varied. Our MAGNET-linkers target conserved sequences in the antibodies and, therefore, any antibody can be used to build an ADC. The possibility of targeting diseases beyond cancer is real,” says Sengupta.

The team has now turned their focus to engineering drugs that activate B cells in cancer.