Cell-Free Approach To Antibody-Drug Conjugates

When Trevor Hallam, chief scientific officer at Sutro Biopharma, a South San Francisco-based specialist in antibody-drug conjugates, spoke before an ADC conference in Sutro’s hometown last month, he delivered the news that the company has successfully engineered a “dual-warhead” ADC—a protein antibody carrying two cytotoxins.

During his presentation at the same conference last year, Hallam claimed that Sutro’s cell-free protein synthesis technology will take the inside track in the discovery and development of accurately targeted ADCs in less time than it takes to bring forward such therapies using the standard method of working with living cells.

ADCs work by using an antibody’s affinity for a tumor cell as a kind of guidance system for delivering cytotoxic therapies directly to a cancer. Sutro is among the firms emerging as the new wave in ADCs, which to date have made some improvement in cancer care over traditional cancer therapies that load patients with potent cancer drugs.

So far, only two ADCs have been approved—Roche’s Kadcyla for breast cancer and Seattle Genetics’ Adcetris for lymphoma. Battling with the tumor cell’s natural defense mechanisms, these drugs still require redundant loading of cytotoxins.

Sutro claims a distinct advantage over its competitors that are trying to develop more effective ADCs: the ability to manufacture antibodies from ribosomes and other transcriptional and translational machinery extracted from Escherichia coli rather than from living cells themselves. Sutro’s cell-free technology, developed by founder James R. Swartz, allows it to link cytotoxic compounds to antibodies in a matter of hours, work that takes weeks or even months with a delicate cell-based approach. That’s because cells have to be bred and kept alive, which is time-consuming and limits the range of work that can be done. Crafting ADCs with ribosomes and other cell components allows for faster experimentation.

Sutro’s technology, which is also applicable to protein therapeutics such as bispecific antibodies, has already garnered three partnerships. The company joined with Pfizer in 2010 for unspecified peptide therapies, and with Sanofi Pasteur early this year for vaccines. But Sutro’s partnership with Celgene, signed last December, focuses on its primary objective—the development of ADCs carrying two cytotoxic warheads targeted at cancer.

William J. Newell, Sutro’s chief executive officer, claims that the company has reached a tipping point with its technology. “People have come to understand that this is a disruptive platform that has the potential to transform some very important therapeutic areas,” he says. “We are on the cusp of demonstrating that.”

The first ADCs did achieve therapeutic success, Newell says, but their impact has been limited. Because companies attach cytotoxins to the antibody using natural lysine and cysteine residues as handles, they get a mixture of ADCs with varying numbers of small molecules attached to each antibody. Sutro, in contrast, incorporates nonnatural amino acids, which enable tailoring of cytotoxin numbers and location, plus the conjugation of more than one kind of cytotoxin.

Hallam points to Kadcyla, which couples the antibody trastuzumab, the active agent in the breast cancer drug Herceptin, with the cytotoxin DM1. He says that in the drug, which uses a linking technology developed by Immuno­Gen, the cytotoxin and antibody are conjugated imprecisely, creating a mix of ADCs with different numbers of warheads and preventing the antibody from finding its way efficiently to the tumor cell. “There is a huge mixture of different species in one product,” he says. “Only 1% of the warheads get to the tumor.”

Gregory Reyes, senior vice president of drug discovery at Celgene, says the cell-free platform for drug discovery and manufacturing prompted his firm’s partnership with Sutro. “We thought their ability to make, very rapidly, a number of modifications to optimize the point at which you incorporate your nonnatural amino acid for site specificity was incredibly important,” he says.

One year into the partnership, Celgene is working with Sutro on three projects in preclinical development—a protein therapeutic, an ADC, and a bispecific antibody. “Sutro has made substantial progress on our ADC project,” Reyes says.

He cautions that the Food & Drug Administration will need to formalize a strategy for vetting therapies developed through Sutro’s platform. “We have kept close contact with Sutro to understand what they have done and what they are doing to see that FDA is apprised of developments,” he says. Sutro plans to meet with regulators early next year, according to Newell. He is optimistic, noting that the company has already given a training session for reviewers, at the agency’s invitation, on development of cell-free protein therapies.

Gregory Landes, a consultant with DNA Bridges, says he is intrigued by the potential of Sutro’s cell-free technology. “It is a pretty elegant platform,” says Landes, who attended Hallam’s presentation at the recent ADC conference. “When I first heard about it, I pooh-poohed it. But they have a few reports out now showing they can do this pretty consistently with a broad class of proteins. And they can do it quite quickly.”

Landes agrees with Newell that site specificity constitutes the new wave in ADC development. Although Landes sees a Sutro competitor, Ambryx, as the innovator in site specificity, he says Sutro may have a significant leg up going forward. “Ambryx probably did not anticipate a cell-free system that can do it.”

Newell and Hallam contend that Sutro’s platform has added significantly to the speed and flexibility with which the firm is developing site-specific ADCs. They claim, among other things, that the cell-free platform allows a broader palette of chemistries for linking cytotoxins than would be feasible with a living cell. And Sutro is ready to put its ADC technology to the test, starting with its partnership with Celgene, Newell says.

“We are competitive now,” he says. “We can design, we can manufacture, and we have a regulatory process coming through.”