Targeted Cancer Drugs With Punch: The Next Big Class of Antibodies

5/16/12Follow @xconomy

[Updated: 11 am PT, 6/5/12] One of the big dreams in biotech over the past 35 years has been to make drugs that work like “smart bombs” by destroying tumors while minimizing collateral damage. Scientists have learned this is no easy thing, but now that a couple of these types of drugs have been shown to work, a new wave of companies is emerging to see if they can finally turn this vision into reality.

Targeted antibody drugs have been around for a long time, and have been shown to do a lot of good for patients. Some of the world’s best-selling medicines are designed to specifically hone in on cancer cells while mostly sparing healthy tissues. Yet it’s only been in the last several years that a couple of companies—Seattle Genetics and Genentech—have shown proof in clinical trials that they can go a step further than what’s been done with so-called “naked” antibodies. The concept is simple: Take a regular antibody, link it to a toxin, and design the combination so that it unleashes a killer payload on tumors. Done right, you ought to have a drug with more punch than traditional antibodies or chemotherapy.

The idea of making “empowered” or “armed” antibodies is known more formally in industry circles as the antibody-drug conjugate (ADC) business. Most previous attempts to amplify antibodies in the past failed because the toxins broke off and started floating around the bloodstream. That meant the drug never got to the right place, and the treatment caused similar side effects to standard chemotherapy. Seattle Genetics overcame that hurdle with the FDA approval last year of its lymphoma drug brentuximab vedotin (Adcetris). And Genentech is in late-stage trials of its souped-up version of Herceptin called trastuzumab emtansine (T-DM1). Both of these drugs have shown in clinical trials that they can be powerful anti-tumor weapons in very sick cancer patients. And not surprisingly, these successes have inspired a new group of genetic engineers to see what they can do to turn antibody-drug conjugates into mainstream cancer medicines.

“We as an industry now have a lot of experience with naked antibodies for cancer, and some of them are very good, but we know they aren’t perfect,” says Bill Newell, the CEO of South San Francisco-based Sutro Biopharma, a venture-backed startup. “They aren’t magic bullets. But I think as people recognize the valuable contribution antibodies have made to cancer, they naturally ask themselves, ‘how can we make them better?’ Essentially, antibodies are good, but antibodies with a payload may be even better.”

There is so much enthusiasm for the emerging antibody-drug conjugate movement that there’s even a World ADC Summit, now in its third year, scheduled for this October in San Francisco. Given the increasing interest among venture-backed companies that are seeking to come up with new antibody-drug conjugates, or provide new enabling technologies, I thought it would useful to put together a list of companies seeking to play a role. If I’ve overlooked a company you know of, please send me a note at ltimmerman@xconomy.com so I can update the list.

T-DM1. Image courtesy of Genentech

Genentech (South San Francisco). The biotech giant, part of Switzerland-based Roche, has the broadest and deepest experience with antibody-drug conjugates in the world. The company uses technology from Seattle Genetics and ImmunoGen in some cases to make ADCs, but it also has its own proprietary techniques which it doesn’t license outside the company. Genentech has had its most high-profile success with T-DM1, but that’s just one of 25 different antibody-drug conjugates in various stages of development, from discovery through late clinical trials. Nine of Genentech’s 38 cancer drugs in clinical trials—roughly one-fourth of the portfolio—belong to this new class of empowered antibodies. “We’ve really invested heavily in this technology and have the breadth and depth of our pipeline to show for it,” says Genentech spokeswoman Krysta Pellegrino. For a detailed rundown of Genentech’s ADC programs, click here.

Seattle Genetics (Bothell, WA). Seattle Genetics (NASDAQ: SGEN) is one of the two mainstays of the armed antibody field, along with Waltham, MA-based ImmunoGen (NASDAQ: IMGN). The company was founded in 1998 after Bristol-Myers Squibb closed down a Seattle research center that had been dedicated to developing antibody-drug conjugate technology. Besides its work on the new lymphoma drug Adcetris, the company lists six other empowered antibodies in clinical and preclinical development on its website. The company also licenses out its antibody-drug linking technology to other drug developers working on specific projects. The list of collaborators includes Genentech, Bayer, Celldex Therapeutics, Progenics Pharmaceuticals, Astellas Pharma, Daiichi Sankyo, Millennium:Takeda, GlaxoSmithKline, Genmab, Pfizer, and Abbott Laboratories.

ImmunoGen (Waltham, MA). ImmunoGen (NASDAQ: [[ticker:IMGN]) is the other stalwart of the empowered antibody world, having been founded way back in 1981. The company has never made a profit in all those years, and has had some very lean years, but it has been resurgent of late. That’s because it licensed its antibody-drug linking technology more than a decade ago to Genentech, which has used it to make T-DM1. That drug isn’t yet FDA approved, but it passed a pivotal clinical trial back in March, which was the last major milestone it needed to clear before seeking the regulatory green-light. ImmunoGen stands to collect a modest royalty on that product, and like Seattle Genetics, it seeks to use its antibody-drug conjugate technology for its own internal drug candidates, while also making some money by licensing it to other companies working on specific projects. Eli Lilly, Novartis, Amgen, Genentech, Biotest, Bayer, and Sanofi are among its collaborators.

Bristol-Myers Squibb (New York). The pharmaceutical company (NYSE: BMY), which once invested so heavily in antibody-drug conjugates, doesn’t say much publicly about its efforts to amplify antibodies these days, but both Seattle Genetics and ImmunoGen list Bristol-Myers as a competitor in their annual reports filed with the Securities and Exchange Commission. Bristol-Myers has told investors that it is developing an antibody-drug conjugate against a target called CD70, which is still in early development. That would appear to put Bristol-Myers in competition with Seattle Genetics, which is also aiming an empowered antibody against the CD70 marker, for patients with renal cell carcinoma and non-Hodgkin’s lymphoma.

Pfizer (New York). The pharmaceutical giant (NYSE: PFE) used to sell an antibody-drug conjugate called gemtuzumab ozogamicin (Mylotarg) until it pulled it off the market in 2010 at the FDA’s request because of safety concerns. But that wasn’t the end of Pfizer’s work in the field. The company has a new product candidate, inotuzumab ozogamicin, in development for slow-growing “indolent” non-Hodgkin’s lymphoma and acute lymphocytic leukemia. That program is in mid-stage clinical development, according to Pfizer’s website. The drug is also being tested in combination with Roche’s rituximab (Rituxan) in a pivotal study for patients with relapsed/refractory aggressive non-Hodgkin’s lymphoma, the company says. [Updated to include information on pivotal study.]

Sutro Biopharma (South San Francisco). Sutro is built on technology from Stanford University for making antibody drugs through a faster and cheaper method that doesn’t require the standard incubation in living cells. The company, founded in 2003, has raised about $60 million in venture capital from a group that includes Skyline Ventures, Amgen Ventures, Lilly Ventures, and Alta Partners. Over the past year, it has turned increasing attention toward using its technology to make antibody-drug conjugates. The company is betting that one of its advantages will be in “site-specific” modifications, in which it can bind a toxin to the exact same spot on a Y-shaped antibody every time in its manufacturing process. Previous technologies have lacked that precision, CEO Bill Newell says, which could end up affecting the consistency of the final product. Sutro has had research partnerships with pharma companies before, including Pfizer, but part of its next challenge will be to find partners willing to license its ADC technology.

Ambrx (San Diego). This private San Diego company, co-founded by prominent chemist Peter Schultz, has raised more than $100 million since its founding to engineer various improvements into protein drugs. For the past several years, it has focused attention on making antibody-drug conjugates. It lists two antibody-drug conjugate programs in preclinical development on its website, one of which is part of a partnership with Pfizer. Former CEO Steve Kaldor said as far back as January 2010 that Genentech’s success with T-DM1 stirred a lot of interest among Big Pharma partners in new and interesting ways of linking antibodies to toxins. “It’s been amazing to see. T-DM1 is floating a lot of other boats,” Kaldor said at the time.

CytomX Therapeutics (South San Francisco). This company, founded with technology from UC Santa Barbara, secured $30 million in financing a couple years ago from Third Rock Ventures and Roche Venture Fund to engineer antibodies with enhanced properties. The company didn’t say much specifically at the time about what it planned to do with the money, but has now publicly stated its desire to make an antibody-drug conjugate against the EGF receptor. That molecular target has been well-validated as a good target for “naked” antibody drugs like Eli Lilly’s cetuximab (Erbitux). CytomX is betting it can make a targeted drug that’s more potent than cetuximab or Amgen’s panitumumab (Vectibix).

Fabrus (San Diego). This company has a geeky sense of humor, since its name is the shortened version of “Functional Antibodies R Us.” Fabrus, founded in 2007 at a Pfizer-supported incubator in San Diego, is more about creating diverse libraries of antibody drugs than about making ADCs, at least according to its website. But it formed a partnership in 2010 with San Diego-based Ambrx in which Fabrus will contribute its antibody library and screening technologies, while Ambrx will look to modify them to add toxins.

Allozyne (Seattle). Allozyne was founded in 2004 with technology from Caltech. The idea is to make “site-specific” modifications on protein drugs, including antibodies. The Allozyne technology essentially calls for snipping out a certain amino acid found in the backbone of protein drugs, and replacing it with a genetically modified amino acid that can stick like Velcro to other molecules. That’s supposed to enable Allozyne to attach molecules to its protein drugs in a highly consistent fashion, which the FDA likes to see. Its lead product candidate is a longer-lasting protein drug for multiple sclerosis, not an antibody drug conjugate. But the company said in an SEC filing in October that it is seeking to make an antibody drug conjugate called AZ05 “in order to provide a potent and highly targeted delivery of the cytotoxic drug to solid tumors.” The company cut a small number of its scientific staff in January after it fell short in its bid to go public, and hasn’t provided an update on AZ05 since.

Igenica (Burlingame, CA). This antibody drug developer made news in June 2010 when it raised a $24 million Series B financing round from The Column Group, 5AM Ventures, and OrbiMed Advisors. The company didn’t say anything about working on antibody drug conjugates in that press release, but it did advertise a job listing for a research associate in April 2011 in which it said, “this is an exciting opportunity for a highly motivated protein chemistry associate to support our core drug discovery activities toward the development of novel cancer antibody based therapeutics. The successful candidate will assist in the synthesis of various small molecule drug analogs and in the preparation of antibody-drug conjugates.”

Celtic Therapeutics/ADC Therapeutics (Lausanne, Switzerland). Celtic Therapeutics Management, a global private equity firm, said in March that it is plowing $50 million into a new antibody-drug conjugate company with the rather obvious name of ADC Therapeutics. This new company said it is starting out with a pipeline of 10 proprietary antibody drug conjugate development programs, licensed from London-based Spirogen, for malignancies of the prostate, breast, kidneys, lungs, and blood. Celtic said the new company is developing “best‐in‐class warhead and linker chemistry.” The chemical warheads, developed over the past decade by scientists at Spirogen and University College, London, are supposed to minimize the resistance that tumors often develop to new drugs.

Centrose (Madison, WI). This startup company says it has a variation on the traditional antibody-drug conjugate technology. Its Extracellular Drug Conjugates (EDCs) are made of an antibody and a chemical linker to another drug. The difference is that the drug doesn’t need to get internalized into tumor cells—the EDC is only supposed to work in synergy when both the antibody and the drug bind with their targets simultaneously. Centrose says this technology enables it to go after molecular targets that have previously been inaccessible. Chief business officer Steve Worsley says the company has struck a couple of partnerships with Big Pharma companies, although he isn’t naming names. “ADCs are a white hot field,” Worsley says. “Our Big Pharma partners are telling us, I can go after internalizing ADC targets, but you allow us to go after wider range of targets. That’s something we’re interested in.”

Wilex (Munich, Germany). Wilex obtained its antibody-drug conjugate technology through the November 2010 acquisition of Heidelberg Pharma. At the time, Wilex said it planned to use the technology to improve antibodies, both in development, and those on the market. The company doesn’t say much specific about the status of its ADC work, other than that it has more than one product candidate in preclinical development.

Mersana Therapeutics (Cambridge, MA). This company is built on a biodegradable polymer technology that it calls its “Fleximer” technology. This platform has been used to help make certain chemotherapy drugs more effective, enabling them to accumulate in tumors. But Mersana also sees potential in using its polymer technology to connect antibodies to cell-killing payloads. Chief scientific officer Timothy Lowinger told my colleague Arlene Weintraub the company was inspired by the example set by Seattle Genetics with its new lymphoma drug. “You’re not prolonging someone’s life for two or three months but really seeing the tumor shrink away,” Lowinger said. “This is realizing the dream of the magic bullet.”

[Added: 11 am, 6/5/12]

Immune Pharmaceuticals (Herzliya, Israel). Immune Pharmaceuticals recently was awarded $1 million from the Israeli government to support a pair of antibody drug development programs, including one in which it is attempting to bind antibodies with drug-loaded nanoparticles. The technology, which the company calls NanoMabs, was developed initially at Hebrew University by a team led by Professor Shimon Benita.

Redwood Bioscience (Emeryville, CA). This startup company is founded on technology for what it calls “aldehyde tagging,” which came from the lab of Carolyn Bertozzi at UC Berkeley. The method is designed to enable scientists to have “more control over the number and placement of drug payloads on the targeting antibodies than is possible with existing techniques,” CEO Karen Boezi said in a company statement in April 2010. That should make the composition of antibody-drug conjugates more consistent from vial to vial, which could help the drug be more effective and less toxic.

PolyTherics (London). This company, which attracted seed financing from The Wellcome Trust a decade ago, primarily hangs its hat on its ability to do “site-specific” modifications on protein drugs to make it easier to effectively attach polymers, which make the drugs last longer in the bloodstream. But this same technology can be used to amp up antibodies. Last month, Polytherics formed a research collaboration with London-based Spirogen in which it look to co-develop souped-up antibodies for cancer. PolyTherics will do the site specific modifications to the antibodies, while Spirogen will pitch in its cell-killing compounds to be attached.

Synthon (Nijmegen, the Netherlands). This company, which makes generic drugs, went into the cutting-edge business of souped-up antibody drugs last June through the acquisition of Syntarga, another Netherlands-based drugmaker. Syntarga, on its website, says that it is looking to address one of the limitations of ADC drug development—namely that tumor cells sometimes don’t have enough target receptors on the cell surface that the drug can bind to. To tackle that problem, the company said it is developing highly potent drugs to attach to antibodies and is engineering ways to attach greater numbers of those potent payloads to the antibody.

Spirogen (London). This private company has been around for a decade, and has a lead drug candidate (not an ADC) in mid-stage clinical trials. But last year, Spirogen put a feather in its cap through a partnership to develop antibody-drug conjugates with Genentech. Its technology for amping up antibodies is built on pyrrolobenzodiazepines (PBDs) which it says can be engineered into potent cell-killing agents linked to antibodies. Financial terms of Spirogen’s deal with Genentech weren’t disclosed, but the company did contribute some of its intellectual property to the founding of Switzerland-based ADC Therapeutics earlier this year, the company that debuted with a $50 million investment. Some bold statements were made earlier this year when ADC Therapeutics was founded earlier this year by former Pfizer executive Peter Corr and Stephen Evans-Freke. “I’ve been around cancer drug development for 30 years,” Evans-Freke told Bloomberg News. “Peter and I agree this is the most exciting program in our respective careers. We’ve got people knocking down the door trying to get access to Spirogen’s chemistry.”

ADC Biotechnology (North Wales, U.K.). This company secured grants and investments worth 450,000 pounds (about $700,000) last December to develop technology which it says should lower the manufacturing costs of antibody-drug conjugates. [Added: 1:30 pm PT, 5/17/12]

Tube Pharmaceuticals (Vienna, Austria). This company was founded last July with $1 million in government seed funding, and technology from the Helmholtz Centre for Infection Research in Germany. The technology is based on what it calls “tubulysins” which it describes as “a new class of natural substances with outstanding toxicity against dividing cells, including cancer cells.” It says the tubulysins can be attached to almost any kind of carrier molecule, such as antibodies, peptides, or polymers. The technology is in preclinical development.

AnaptysBio (San Diego). This company, which has struck a couple of recent partnerships with Gilead Sciences and Celgene, describes itself mainly as an antibody discovery shop. But it also sees applications for making souped-up antibodies. “Our approach is to generate antibodies that have high levels of internalization, which would make them better candidates for linker-toxin fusion as ADCs,” says CEO Hamza Suria. AnaptysBio also notes on its website that its chief scientist, David King, “led the development of a new class of antibody-drug conjugates” in his previous job at Princeton, NJ-based Medarex, before it was acquired by Bristol-Myers Squibb.

Nerviano Medical Sciences (Milan, Italy). The largest pharmaceutical R&D center in Italy struck a multi-year research collaboration with Genentech in October 2008 to help develop antibody drug conjugates. Nerviano’s task is to synthesize and manufacture drug reagents, which Genentech uses to generate antibody-drug conjugates. Terms of the deal weren’t disclosed, although Nerviano said it negotiated for an upfront fee, milestone payments, and a percentage royalty on future product sales.

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