Merck Jumps into Antibody-Drug Conjugates With Ambrx Deal
Jun18

Merck Jumps into Antibody-Drug Conjugates With Ambrx Deal

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...

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Seattle Genetics & ImmunoGen on a Roll
Oct11

Seattle Genetics & ImmunoGen on a Roll

The good news keeps coming for companies developing antibody-drug conjugates, which enable the targeted delivery of powerful chemo drugs. (click here for more info on how they work). On the clinical side, ImmunoGen and Roche have released a promising set of data for T-DM1, their drug linking trastuzumab with DM1, a derivative of the microtubule-disrupting agent maytansine, while Seattle Genetics and Millennium Pharmaceuticals offered the latest validation for SGN-35. Meanwhile, ImmunoGen sealed a deal with Novartis worth up to $240 million. First to the clinical results: Although the trial was relatively small, ImmunoGen’s T-DM1 appeared to be as good at shrinking tumors as a combination of Herceptin and chemotherapy in patients with HER-2 positive, metastatic breast cancer. Importantly, patients in the T-DM1 arm experience significantly milder side effects than those taking the Herceptin/chemo combo. For example, 66.2% of patients in the chemo arm experienced complete hair loss, compared to 1.5% in the T-DM1 arm, and 57.4% of the Herceptin/chemo patients experienced neutropenia, or white blood cell count lowering, vs. 7.5% of the patients in the T-DM1 arm. In a note to investors, RBC Capital Markets’ analyst Jason Cantor called the results “particularly groundbreaking” because no chemotherapy drug was added into the T-DM1 treatment arm. The trial “is significant validation of ImmunoGen’s technology and antibody-drug conjugation technology, in general.” In August, ImmmunoGen and Roche had a setback when after FDA refused to accept their biologics license application for T-DM1 based on the Phase II data offered up in the filing. Roche had already started a Phase III study, and Cantor expects Roche to try again with FDA in mid-2012, putting a potential launch in the first half of 2013. The positive data for T-DM1 comes on the heels of strong results for Seattle Genetics’ antibody-drug conjugate, SGN-35. Last month, the Seattle-based biotech said the drug was able to shrink tumors in 75% of people with Hodgkin’s lymphoma who had failed to see results with other treatments. Seattle Genetics expects to file a BLA for SGN-35 in the first half of 2011, with approval expected in the second half of the year. Today, Seattle Genetics and Millennium said that SGN-35 shrank all or some tumors in 86% of patients with anaplastic large-cell lymphoma. Look for more data in both Hodgkin’s lymphoma and in ALCL in December during the American Society of Hematology annual meeting. On the deal front, Novartis is coughing up $45 million upfront and up to $200 million in milestones to apply ImmunoGen’s antibody-drug conjugate technology (which it calls “TAP” for targeted antibody payload) to a select number of targets. ImmunoGen could also score research funding and additional support if...

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