Sutro Aims to Deliver Anti-Tumor “Warheads” More Precisely

10/1/13Follow @tanseyverse

One of the big-tent biotechnology conferences opening this month focuses on a drug strategy that could be dubbed the targeted chemical warfare approach to cancer treatment.

The much-watched developers of a new drug class called antibody-drug conjugates will convene at World ADC San Francisco 2013 on Oct. 14 to swap insights about the growing number of these armed warheads of the pharmaceutical pipeline.

Among the headliners, presenting on one of the key topics at the conference, is South San Francisco-based Sutro Biopharma. Sutro sees its novel method of manufacturing biological drugs as a gateway to more precisely targeted therapies, including antibody-drug conjugates. An antibody-drug conjugate drug combines, for example, a tumor-seeking antibody with an extra payload—a toxic drug that kills the targeted cancer cells.

Interest in the tactic has intensified with the approval this year of Roche’s new treatment for metastatic breast cancer, ado-trastuzumab emtansine (Kadcyla), which couples the antibody trastuzumab—the agent in Roche’s drug Herceptin—with the toxin DM1 through a linker compound from ImmunoGen. Other drug giants such as Pfizer and Abbott are also striving to develop their own antibody-drug conjugates.

But, according to Sutro, many antibody-drug conjugates contain a mixture of various forms of the intended compound, due to the challenges of current manufacturing methods. Some of the antibodies may have multiple toxic “warheads” attached, at varying positions; others may have none; and some may have the toxin attached in a spot that prevents the drug from sticking to a tumor cell, says Sutro’s chief scientific officer Trevor Hallam. As a result, as little as one percent of the toxin may actually get into the cancer cell to battle the disease.

Trevor Hallam

Trevor Hallam

“Ninety-nine percent is dosed to the patient and is of no use,” Hallam says. “There’s a huge opportunity to improve that.”

Sutro’s aim is to produce only the single version of an antibody-drug conjugate that is most effective against a disease. Its manufacturing method allows it to dictate consistent, pinpoint placement of toxic payloads on antibodies that are also reproduced faithfully, Hallam says. What’s more, the method permits the attachment of two different toxins to the same antibody—a potential combination therapy contained in the same drug, he says.

The need for better control of warhead placement—a simmering topic at last year’s ADC summit—is now moving to the forefront, Hallam says. He’ll be the lead speaker at an Oct. 15 panel on site-specific drug conjugation at the World ADC summit, followed by experts from Pfizer, Burlingame, CA-based Igenica, and other companies.

Sutro has radically streamlined the drug manufacturing process that originally led to the founding of the biotechnology industry—the genetic engineering of microbes and other cells that can crank out proteins, antibodies and other complex biological molecules that are tough to make by the traditional chemical synthesis that produces simpler drugs. Genentech of South San Francisco, now a division of Roche, pioneered this bioengineering method to make drugs such as its antibody trastuzumab, a breast cancer therapy.

Through genetic engineering, companies now modify algae, bacteria, and other cells to produce transportation fuels and industrial enzymes as well as drugs. But the hitch is, they can’t tinker with the cells’ DNA to the point that their engineering kills the cells. Sutro has freed itself from those restraints by pulling out of bacteria only the parts of the cell required to make proteins—a small molecular manufacturing unit called the ribosome, and some other components. Thus, Sutro can engineer tweaks in its cell extracts that would have killed a bacterial cell, because the company doesn’t need to sustain the growth of a living cell culture.

“We don’t have to worry about it,” says Hallam.

Sutro’s extracts of cell parts crank out only a single protein at a time, instead of the host of biomolecules a living cell would be constantly constructing to maintain its outer walls and its internal furniture, such as the cell nucleus. The absence of all those extra proteins in the manufacturing tank makes it easier for Sutro to isolate and purify the one protein it wants to produce, Hallam says.

The cell-free method is also quick, compared with fine-tuning the genetic engineering of a different living cell to produce each new protein that might be of interest as a drug candidate. Sutro, by contrast, can produce any kind of protein using one of its standard cell extracts taken from 70 different strains of bioengineered bacteria, Hallam says. The DNA that codes for the desired protein is added to the reaction vessel, and cell extract components transcribe it into RNA, which the ribosome then uses as a manufacturing template. This means Sutro can rapidly produce an array of many different proteins, and screen them all to find the ones most likely to be effective against a particular illness.

In a demonstration project that took about five weeks, Sutro made 400 variations of trastuzumab—each linked to a toxin at different selected spots—through a genetic engineering maneuver that would have been deadly to a living cell, Hallam says. The tactic involves the use of artificial amino acids that don’t occur naturally in cells, and a non-natural way of reading part of the DNA code. Based on lab tests, Sutro predicts that the best candidate among its 400 experimental antibody-drug conjugates would have the same clinical impact as ado-trastuzumab emtansine, but with a fifth of the toxic warhead load. If a pharmaceutical company conducted a similar study using living cells to manufacture hundreds of such drug candidates, it might take six to nine months, Hallam says.

“This is not just a manufacturing platform,” says Sutro’s CEO William Newell of the company’s cell-free method. “It’s a manufacturing and (drug) discovery platform.”

Both capabilities were tapped last year by Summit, NJ-based Celgene (NASDAQ: CELG) , which is collaborating with Sutro to design antibody-drug conjugates and another new type of double-threat drug called a bispecific antibody, which has two different ways of recognizing a cancer cell or other particular cell type. Celgene, which has not disclosed its disease targets, has also assigned Sutro to manufacture one of its own antibodies.

Since 2011, Sutro has been collaborating with Pfizer on peptide drug candidates, and early this year it signed an agreement with Sanofi Pasteur to develop vaccines. The disease targets of these joint projects have not been revealed.

The deals come with “robust economics’’ such as upfront payments and potential milestone payments and royalties, Newell says. Sutro has raised more than $60 million from investors, and has about 60 employees.

Government agencies and global charities are getting interested in Sutro’s technology as a resource for rapid vaccine development and production in the face of emerging infectious diseases and pandemics, Newell says. The company has developed a method to freeze-dry its cell extracts, which could then be shipped throughout the world and cheaply assembled into manufacturing “pods” as small as a mobile home, he says.

Sutro is also in discussions about the use of its technology to manufacture “biosimilars”—versions of expensive biologic drugs that are losing patent protection.

However, Newell says, the company can’t pursue every avenue at once. He sees the “sweet spot” for Sutro’s current growth in the development of its own antibody-drug conjugates and bispecific antibodies as drug candidates in oncology. Sutro is focusing on an intriguing group of cancer drug targets called immune checkpoints, which can signal the immune system to bypass tumor cells that it might otherwise destroy. Big pharmaceutical companies are also hot on the trail for inhibitors of immune checkpoints, and Bristol-Myers Squibb already markets such a drug, the melanoma therapy ipilimumab (Yervoy). Sutro is aiming to seek FDA permission to start clinical trials for its own drug candidate for targeted tumor therapy by mid-2014.

“Sutro has two ways of delivering a one-two punch: bispecifics and combination warheads,” Newell says.

Bernadette Tansey is a freelance journalist based in Berkeley, CA. Follow @tanseyverse

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  • Jerry Jeff

    My understanding is that full-length antibodies are hard to produce, even in mammalian cells, because the post-translational processing (glycosylation and disulfide bond formation) has to be perfect every time. It’s not hard to imagine how Sutro can deal with the disulfides in vitro, but what about glycosylation?