A new generation of antibody-drug conjugates for cancer patients

After a decade-long trickle of antibody-drug conjugates (ADCs), the US Food and Drug Administration in 2019 approved three new ADCs to treat various cancers. That burst of activity brought the total number of FDA-approved ADCs on the market to seven, a definite uptick to end the decade.

ADCs are antibodies connected to cell-killing, small-molecule payloads via chemical linkers. To fight cancer, the antibodies hook up to proteins on the surfaces of tumor cells. Once the ADCs are there, the tumor cells engulf the ADCs; rip up the linkers via chemical, enzymatic, or biological processes; and release the small-molecule payloads. The payloads then kill the tumor cells. These therapies were conceived to act like guided missiles, delivering cancer-killing drugs exclusively to cancerous cells and sparing healthy cells.

The recent flurry of approvals portends a comeback for ADCs, many of which did not fare well in the clinic in the past decade. Companies have learned from past setbacks and made chemical advances that are enabling a new generation of more finely tuned ADCs. Some deliver more payload molecules on each ADC with the hopes of drilling deeper into solid tumors. Others use more-potent payload molecules. Still others connect the antibody to the linker with greater precision.

And while earlier failures prompted some companies to abandon the therapeutic approach, others still see enormous potential. There are 89 ADCs from dozens of companies currently in human clinical trials, according to a study that Beacon Targeted Therapies compiled for the news agency Reuters earlier this year.

There are a lot of moving parts in an ADC, and there’s no generic formula for success, says Andy Polson, who works on the therapy at Genentech. How the antibody chemically connects to the drug, the number of drugs on each antibody, the stability of the chemical linker, and whether the payload works in a particular tumor type are all important facets to the technology, he explains.

Balancing all those needs when creating an ADC, Polson says, is a relatively large drug development undertaking. Although we typically think of ADCs as guided missiles, he says, that’s only partially true. “What you’re really doing is preferentially delivering it to the tumor and causing greater accumulation in the tumor than you do elsewhere in the body. It’s better than systemic chemotherapy, but still—you’re putting a very potent drug into the body, and that’s going to have side effects.”

David Satijn, vice president of new antibody products at Genmab, which has paired ADCs with its own antibody products, agrees. “We want to kill tumor cells, but we don’t want to harm the nontumor cells, and at the moment, that’s still a challenge,” he says. “So, in a nutshell, we’re looking for better drug linkers and drug payloads.”

Penelope Drake, director of R&D at Catalent Biologics, says a lot of ADCs showed promise in shrinking tumors in mice. “But the problem was that didn’t translate to efficacy in the clinic,” she says. It’s likely that those ADCs didn’t fare well in people because of dose-limiting toxicities. “They just couldn’t give enough ADC to achieve efficacy,” she says.


“We now understand that the resulting bond is susceptible to a slow elimination,” Lyon says. What would happen is that the C–S bond attaching the antibody to the linker would break, regenerating the maleimide ring that was the linker’s reactive handle. When this happens in the bloodstream, the linker-payload combo can subsequently react with cysteine residues on other proteins or biological thiols like the antioxidant glutathione.

But Lyon says that he and his colleagues realized that a different chemical reaction was also taking place at this attachment point on the ADC: a hydrolysis reaction can spring open the succinimide ring that results from the thiol-maleimide reaction. “When this occurs, the linker can no longer undergo the elimination pathway and is essentially completely stable—so ring hydrolysis leads to stability.”