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

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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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