‘Clicked’ drugs: researchers prove the remarkable chemistry in humans
, independently invented the tetrazine ligation — a fast reaction that snaps together a nitrogen-rich tetrazine with a partner containing a strained carbon–carbon double bond. Shasqi, Tagworks and the MSKCC team are all using versions of this reaction that employ tetrazine andOnce a drug has found its target, it must be freed from its click partner so that it can get to work. To achieve that, Tagworks developed a variant of the tetrazine ligation that it calls ‘’.
Bertozzi says she’s excited about Shasqi’s trial because “there’s a potentially enormous benefit for our patient population. But if the details get worked out and optimized in that setting, there’s lots of other cancer applications as well.’ Their strategy is to put the targeting antibody in place first, before introducing the PET radioisotope. During the trial, clinicians will inject patients with a monoclonal antibody called hu5B1 that has been modified with a click-chemistry TCO group. This antibody latches on to the CA 19-9 antigen found on pancreatic cancer cells. When a tetrazine-based molecule that carries copper-64 is injected into the bloodstream, it clicks with the TCO on the tumor cells within minutes.
In Tagworks’ system, the chemotherapeutic agent MMAE is connected to the antibody via a TCO-based linker. After first administering this ADC to a patient and allowing it to bind to tumor cells, doctors would inject a tetrazine to trigger a click-to-release reaction that frees MMAE. The approach has already shown success in mouse models of. Tagworks spent several years honing the chemistry of its click molecules to make sure that they offer the right balance of stability and reactivity.
Shasqi is also working with a clickable MMAE prodrug, albeit in a different configuration than Tagworks, and has recently published promisingfrom a mouse model of gastric cancer. The company plans further animal studies and hopes to take a clickable MMAE prodrug into a phase 1 trial in the future. “We’ve already done one, and I’m pretty sure we can do it again,” says Mejía Oneto.
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