Peter Senter gives an insider’s view of how Seattle Genetics beat the odds and launched a successful antibody-drug conjugate
By: Nina Notman
It was a tough call. Bristol-Myers Squibb, Peter Senter’s employer for over a decade, had announced it was closing the site where he worked and relocating his projects nearly 3,000 mi (about 4,800 km) east. “I had to make a decision: Should I keep the safety and security of a big pharmaceutical company, or should I go off and do something risky but potentially more rewarding?” he recalls.
Senter decided to take the leap. In 1998, after one false start, he landed on his feet as director of chemistry at Seattle Genetics, a biotech start-up looking for success in the then-struggling area of antibody-drug conjugates (ADCs). ADCs are cancer therapeutics that rely on monoclonal antibodies to deliver small-molecule drugs directly to tumors.
Over the past 20 years, Senter has participated in the growth of the company from 10 people when he started to 1,400 today. “A lot of people in biotechnology change companies every couple of years,” Senter says. “It's fantastic that I've been able to stay in a place long enough to help solve some serious problems.”
The approval of Seattle Genetics’ first, and so far only, drug came in 2011. Adcetris (brentuximab vedotin) consists of the cell-killing agent monomethylauristatin E attached through a dipeptide linker to an anti-CD30 antibody. Developing this early entrant to the ADC field earned Senter and his Seattle Genetics colleagues a 2018 Heroes of Chemistry Award from the American Chemical Society.
Adcetris was initially approved for use in patients with two types of lymphoma that hadn’t responded to other therapies. “It's since also been approved for frontline therapy of Hodgkin lymphoma and CD30-positive non-Hodgkin lymphoma,” Senter says.
Only when Adcetris’s ADC reaches CD30-expressing cancer cells does it release its drug payload. Once the ADC is inside the tumor cell, proteases attack the linker and release monomethylauristatin E. This targeted approach reduces toxicity-related side effects.
Senter’s chemistry group developed the linker chemistry, designed a scalable synthesis to monomethylauristatin E, and worked out the conjugation chemistry that delivers the drug to tumor cells. The premature breakage of linkers, releasing toxic agents into the bloodstream, was a significant issue with early ADC attempts, Senter says. Overall, he credits his company’s success to “figuring out the technological aspects of ADCs but also selecting the appropriate place to apply the discoveries that we made.”
Seattle Genetics targeted a rare disease, which enabled the company to use the US Food and Drug Administration’s accelerated “breakthrough therapy” approval process. The firm also chose indications where “it would be relatively straightforward to do clinical trials and figure out if we were having an impact,” Senter explains. It took just five years from starting Phase I trials to gaining approval for the first indications.
Seattle Genetics has a number of other ADCs in preclinical and clinical trials for various cancers. “We have antibody-drug conjugates that are going to read out in pivotal clinical trials this year,” Senter says. “It's quite possible that we will be a multiproduct company.” It has also licensed its ADC technologies to other biotechnology and pharmaceutical companies. “Genentech has an ADC called polatuzumab vedotin for the treatment of non-Hodgkin lymphoma that utilizes our technology,” Senter says. It’s currently in a Phase III clinical trial. “AbbVie also has a promising late-stage ADC being tested in brain cancer that utilizes one of our auristatin drug linkers.”
Senter still leads the chemistry group. His team is continuing to seek new anticancer agents, expand the choice of connecting linkers, and further develop the conjugation technology. “I believe that we've just begun to develop the technologies that are going to be used in antibody-drug conjugates in the future,” he says.