In January, Seattle Genetics of Bothell, Washington, entered a $208 million deal with Pfizer to use the biotech firm’s monoclonal antibody (mAb)-drug conjugate (ADC) technology for a single oncology target. The agreement comes on the heels of a partnership inked by Novartis to access ImmunoGen’s tumor-activated prodrug (TAP) linker technology. The Basel-based pharma agreed to pay ImmunoGen of Waltham, Massachusetts, $45 million upfront and up to $200 million per target for constructing ‘souped up’antibodies for several cancer targets.“There’s been an inflection point over the last six months,” says Eric Dobmeier, Seattle Genetics’ chief business officer. ImmunoGen’s President and CEO, Daniel Junius, agrees: ADCs are in vogue, he says, because they offer cancer therapies that are “more potent but less toxic”(Table 1). Within a year, he foresees~ 20 ADCs in the clinic. Currently, the companies furthest ahead are Dobmeier’s company and Genentech of S. San Francisco, California. On February 28, Seattle Genetics submitted a biologic license application (BLA) for brentuximab vedotin (SGN-35) for the treatment Hodgkin’s lymphoma and anaplastic large cell lymphoma (ALCL). Brentuximab vedotin comprises a chimeric IgG1 mAb targeting CD30 conjugated to the antimicrotubule agent monomethyl auristatin E (MMAE) by means of a valine-citrulline peptide linker. After the ADC is taken up by CD30-bearing cells, the linker is cleaved by lysosomal proteases and MMAE is released into the cytosol where it binds to microtubules and arrests the cell cycle between G2 and M, leading to apoptosis. More advanced still is Genentech’s T-DM1 (trastuzumab emtansine), which is a combination of the company’s blockbuster Herceptin (trastuzumab) and the antimitotic cytotoxin N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine (termed DM1), indicated for use in HER2-positive breast cancers. In this case, the chemistry used to conjugate Herceptin to an average of 3.5 DM1 molecules is ImmunoGen’s nonreducible TAP linker technology—the thioether succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate. Unlike other linker technologies that are cleaved in vivo, the TAP linker remains intact in the cytosol. Once the ADC has selectively bound HER2 receptors on the surface of breast tumor cells through its mAb portion, the ADC is internalized and the mAb progressively degraded by proteases until the DM1 molecules are released into the cytosol to bind to microtubules, leading to cell cycle arrest and apoptosis. Genentech expects to submit data from its current phase 3 trial of T-DM1 in metastatic breast cancers for approval in 2012. According to Bret Holley, senior biotech analyst at Oppenheimer in New York City, these two drugs “have the most mature proof of concept for [ADC] technology,” he says.

The concept of hooking cytotoxic payloads to mAbs that target tumor cells has long been a holy grail for antibody engineers. Success has proved elusive, however, with companies exploring several different types of cleavable linkers (that is, disulfide-based linkers, hydrazone linkers and peptide linkers) as well as ImmunoGen’s noncleavable linker.“It has taken decades for the technology to catch up,” says Peter Senter, vice president of chemistry at Seattle Genetics.“A lot of early clinical trials in ADCs failed because they used