have that knock-out punch. Their power comes from their payloads: lethal drugs tethered to the antibody that remain harmless until the conjugate releases them inside cancer cells (see 'Seek and destroy'). But for decades, developers have struggled to get the crucial elements to work together: the antibody, the drug it carries and the linker that binds the two. Seattle Genetics' conjugate, Adcetris (brentuximab vedotin), seems to have overcome the hurdles; it combines a synthetic poison called vedotin with an antibody that targets CD30, a protein found on many lymphoma cells. In July, an FDA advisory committee voted unanimously in support of accelerated approval for Adcetris after Seattle Genetics reported that 94% of the 102 people with Hodgkin's lymphoma in a trial of the treatment saw their tumours shrink, and 73% achieved partial or complete remission. "This drug is wildly active," said panellist Mikkael Sekeres, an oncologist at the Cleveland Clinic in Ohio, after the vote. The accelerated approval means that the drug can now be prescribed by doctors while Seattle Genetics conducts follow-up clinical studies. Mark Monane, a senior analyst at the investment-banking firm Needham & Company in New York, predicts that the drug will bring in up to US$400 million a year in sales. Its like a game of whack-a-mole. You knock out one toxicity and another shows up.Janice Reichert, an analyst at the Tufts Center for the Study of Drug Development in Boston, Massachusetts, expects more approvals to follow. Between 2000 and 2005, only six antibodydrug conjugates entered the clinic for the first time, she says. From 2005 to 2009, 15 more joined their ranks. Now, 25 are currently in cancer clinical trials more than at any other time. Two have reached late-stage clinical trials: trastuzumab emtansine, a breast-cancer therapy jointly developed by biotechnology firms Genentech, based in South San Francisco, and ImmunoGen in Waltham, Massachusetts; and inotuzumab ozogamicin, a lymphoma therapy developed by Pfizer in New York.Pitfalls remain. The only other conjugate to ever win accelerated approval from the FDA, a different version of Pfizer's lymphoma therapy, was pulled from the market last year after further tests showed that the drug offered no benefits over standard chemotherapy. Many blame the failure on a linker that fell apart in the bloodstream, boosting toxicity and limiting the dose that could be used. Seattle Genetics had to pull one of its antibodies from clinical trials for similar reasons, says Siegall. As a result, the company developed a linker that is degraded by the enzymes that are most active inside the cell. ImmunoGen, Seattle Genetics' main competitor, has struggled to find the right drug to couple to its antibodies. For years, the company attempted to use ricin, a toxin produced by castor beans. But ricin triggered a dangerous immune response. ImmunoGen now steers clear of complex proteins and picks small-molecule poisons that are less likely to attract the attention of the immune system. A lingering problem for the field is a lack of control over how many drug molecules attach to each antibody. More control would help standardize each dose and lessen the