Heidi Ledford in Nature:
After decades of frustration, efforts to develop antibodies that can ferry drugs into cancer cells — and minimize damage to healthy tissue — are gathering steam. The next generation of these ‘weaponized antibody’ therapies, called antibody–drug conjugates (ADCs), is working its way through clinical trials. Researchers will gather to discuss this renaissance on 30 November at the Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany. The improvements come after the first wave of experimental ADCs failed to deliver on its promise. “Initially there was a lot of excitement, and then slowly many of them did not work,” says Raffit Hassan, a cancer researcher at the US National Cancer Institute in Bethesda, Maryland. Now, he says, there are two new ADCs in phase III clinical trials, and many more in earlier-stage testing.
The concept that underlies these drugs is simple: repurposing an antibody as a vehicle to deliver a toxic drug into a cancer cell. When the antibody in an ADC seeks out and docks onto a tumour cell, the cell takes it up and cleaves the molecular links that bind the drug to the antibody. This frees the drug to kill the cell from within. But this approach has proved tricky to realize. Sometimes the molecular linkers are too tight, and do not release the drug inside the cell. Sometimes they are too unstable, and release the drug near healthy cells — limiting the dose that can be administered. Even the drugs themselves can be problematic: because most are toxic mainly to rapidly dividing cells, they can leave behind the slowly dividing cells that seed some tumours. And some have had trouble penetrating more than a few cell layers into their target tumours.