Merck today has jumped into what has become one of the hottest areas in oncology, antibody-drug conjugates, through a deal with San Diego-based Ambrx. Merck will pay $15 million upfront and up to $288 million in milestones for access to Ambrx’s site-specific protein conjugation technology.
Coincidentally, on the cover of today’s magazine, we take a look at the future of antibody-drug conjugate technology. Although people have been working on ADCs for three decades, interest in the approach has reached fever pitch after last year’s approval Seattle Genetics’ lymphoma drug Adcetris and the recent hubbub at ASCO over positive interim Phase III data for Genentech’s T-DM1.
The idea behind ADCs is simple: use a targeted antibody to deliver a highly potent chemotherapeutic to a cancer cell, sparing healthy cells. But current ADC technology has limitations. This week’s cover story looks at efforts to improve upon each component—the antibody, the small molecule, and the “linker” that connects the two.
Ambrx is focused on the antibody, using site specific protein conjugation technology to better control how many and where small molecules are placed on an antibody. Currently, companies manufacturing ADCs (most using technology from Seattle Genetics or ImmunoGen) wind up with a heterogenous product—each ADC has anywhere from zero to eight small molecules attached to the protein, but on average, 3.5 to four small molecule “payloads” linked. The placement of the payloads on the antibody also varies, leading to families of conjugates. As I explain in today’s story, even among the ADCs with four small molecules attached, some have all the cytotoxins clustered in one region, but they might be spread out on others.
Ambrx incorporates a nonnatural amino acid into the antibody to allow precise placement of the drug payload. As I explain:
Ambrx can insert p-acetyl-phenylalanine onto two sites of the antibody. The phenyl- alanine derivative has been modified to include a ketone that acts as a functional group for conjugation to the linker and small molecule.
Although Ambrx can attach more than two chemistry “handles” to the antibody, its studies have shown that two small molecules make the most sense. “You really want to be mindful about preserving the native structures and function of the antibody, while trying to optimize therapeutic activity,” says Chief Technology Officer Ho Cho. “The more you stray away from that, the more risks there are in drug development.”
The beauty of site-specific conjugation, researchers say, is that it allows them to me- thodically determine which ADC variety is the most active. “We can specifically attach whatever payload-linker combo we wish and do quantitative experiments to find out how it works,” Cho says. His team tests biophysical stability, pharmacokinetics, and efficacy to understand how much of the drug can be given before toxicity kicks in.
The ADCs in the current clinical pipeline are all to combat cancer, but Ambrx believes its site-specific conjugation technology will open the door to using ADCs in other therapeutic areas. As Cho told me, the heterogeneous nature of current ADCs has limited their use. “What we’re excited about is taking this into non-oncology indications,” Cho says. “We’ve started to generate some interesting pre-clinical data sets…This is where Ambrx really thinks the field is moving.”
It’s worth noting is that Ambrx was founded by Scripps Research Institute’s Peter Schultz, who Merck recently appointed head of Calibr, a San Diego-based non-profit funded by the big pharma firm that will act as a vehicle for academic scientists to turn their ideas into drug candidates. For more on Calibr, click here.
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