BUSINESS

TARGET PRACTICE Protein drugs linked to radioisotopes emerge as a promising therapeutic class

£TICE radioisotopes emerge tic class

NEWS BUREAU MICHAEL MCCOY, C&EN NORTHEAST

WHEN THE CANCER TREAT-

ment Bexxar was ap­proved by the Food & Drug Administration in June, it became just the

second marketed drug to combine radia­tion and monoclonal antibody therapy But many more such treatments are in the pipeline, promising hope for cancer pa­tients and a new source of profits for phar­maceutical companies.

Behind the scenes, a second group of companies is poised to benefit from the commercialization of this new class of ther­apy. These firms—notably Dow Chemical and MDS Nordion—compose what is to­day a very small fraternity that supplies in­gredients and services to developers of ra­diolabeled biopharmaceutical proteins.

Bexxar, discovered by the biotech firm Corixa and developed in partnership with GlaxoSmithKline, is indicated for non-Hodgkin's lymphoma patients who do not respond to other treatments. The partners call it a dual-action therapy because it pairs the tumor-targeting ability of tositumomab—a monoclon­al antibody (MAb)—with the cancer-killing radioisotope iodine-131.

Separately, radiation and protein therapies have long histories: Radia­tion has been used to treat cancer since the 1960s, and interferon, the first biotech cancer drug, was approved in 1986. However, they came together for the first time only last year with the approval of I DEC Pharmaceuti­cals' Zevalin, which treats non-Hodgkin's lymphoma with a combi­nation of a MAb and yttrium-90.

combination was seen as the ultimate in cancer treatment during the early 1990s by companies including Dow, which owned Marion Merrell Dow at the time. Howev­er, problems arose both with the proteins and with the chelating agents often need­ed to attach the radioisotope.

Dow exited the drug business altogeth­er in 1995, but a small group of the firm's scientists continued to work on improv­ing pharmaceutical chelation chemistry, according to Keith Frank, a senior Dow scientist in radiopharmaceutical develop­ment. Their work led to non-protein-based radiation therapies like Quadramet, a bone cancer treatment that combines the chelat­ing agent EDTMP with samarium-153, and Iotrex, the active component of a brain tu­mor treatment based on iodine-125. Both products were out-licensed and are now commercial therapies.

While Dow was developing chelating agents, MDS Nordion was busy on the ra­dioisotope side of the emerging business. Claudette M. David, Nordion's vice pres­ident for therapeutic products, explains that the firm started out as a division of Atomic Energy of Canada Ltd. and was charged with developing peaceable uses of radioactivity

Nordion was a pioneer in the develop­ment of cobalt-60 as a cancer treatment and later worked with Dow, manufactur­ing Quadramet for Phase III clinical trials. Today, it manufactures Iotrex, the Dow-developed radiation source, for a system developed by Proxima Therapeutics.

David says her company has no signifi­cant competition in the radiolabeling of proteins, a contention borne out by the fact that both Corixa and IDEC turned to Nordion for their isotope needs. In June, Nordion extended its deal with Corixa to radiolabel the antibody in Bexxar. And Nordion is expanding its Ottawa, Ontario, complex with a new radiopharma facility slated to open at the end of the year; the unit's first product will be sterile yttrium-90 for Zevalin.

David attributes the lack of competi­tion to Nordion's unique position at the

crossroads of the nuclear and drug industries, where it is hit from both sides with stringent and often con­tradictory regulations. For example, pharmaceutical rules call for air to flow out of a processing area to pro­tect the product, whereas nuclear rules mandate that air flow in, to pro­tect workers and the environment. "You have to design unique engi­neering solutions in order to meet both requirements," she says.

Dow, likewise, considers itself without major challengers on the chelation side of the business. In June, seeking to capitalize on this position, it set up a new business, ChelaMed radiopharmaceutical services, that offers Dow expertise to the drug industry

Maureen Acker, business develop­ment manager for ChelaMed, notes that Dow can provide customers with a proven track record; strength in nuclear, synthetic organic, and process chemistry; and the ability to integrate its chelating agents into cur­rent Good Manufacturing Practices (cGMP)-compliant pharmaceutical manufacturing.

W h a t Dow can't t rumpet yet, however, is a hand in a marketed ra­diolabeled protein. The iodine-131 in

INDUSTRY OBSERVERS say this class of drugs' long road to market wasn't for lack of trying. Radiation is an ef­fective cancer treatment, but it is dif­ficult to direct and can be devastating to nontargeted parts of the body Pro­teins like MAbs, on the other hand, are adept at selectively targeting dis­eased cells, but they often have inad­equate therapeutic effectiveness on their own.

Attaching a radioisotope to a MAb can solve both problems. Indeed, the

ACTIVE MDS Nordion technicians label an antibody with iodine-131 in a hot cell at Nordion's Ottawa facility.

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Bexxar attaches itself to amino acid residues in the MAb and doesn't need to be linked with a chelating agent. And MX-DTPA, the chelating agent used in Zevalin, was developed years ago by Martin W. Brechbiel, a chemist at the National Can­cer Insti tute, and obtained by I D E C through a series of licensing agreements. MX-DTPAis manufactured for IDEC by Hauser Contract Research Organization.

Frank points out that the two current drugs, each more than 10 years in the mak­ing, were conceived with what at the time

was proven radioisotope and chelant tech­nology Iodine-131, for example, was famil­iar to researchers and FDA because it had a historical use in thyroid cancer treatment.

However, iodine has a tendency to de­tach from the MAb and can accumulate in the body Also, because iodine-131 emits high levels of gamma radiation, iodine-based treatments can require longer hospital stays than do treatments with other isotopes.

Following Zevalin's approval, Acker says, biotech company interest in yttrium is on the rise. And university researchers, often harbingers of future commercial develop­ment, are working with lutetium-177. The right compound, such as MeO-DOTA, Dow's premier chelating agent, can tie these isotopes into a stable complex that links with a targeting protein to deliver the cancer-killing payload precisely where it's needed, she says.

BECAUSE THE DRUG industry advanced cautiously while it waited to learn the fate of Bexxar and Zevalin, most radiolabeled proteins are still in early stages of devel­opment. An exception is Antisoma's pem-tumomab, an yttrium- 90 labeled MAb in Phase I I I trials for ovarian cancer and Phase II trials for gastric cancer. Last No­vember, Antisoma sold Roche the rights to pemtumomab and three other drugs in a deal that could be worth $500 million if all products make it to market.

Other companies developing radiola­beled proteins include Human Genome Sciences (HGS), Immunomedics, Avidex, and Cytogen. In September, Dow signed a

development agreement with Avidex fo­cused on attaching radioisotopes to Avidex's EsoDex monoclonal T-cell re­ceptor, and Dow has been collaborating with HGS since 2000.

More deals are in the works, Acker says, under a structure in which Dow receives initial funding for feasibility studies, then gets subsequent milestone and royalty pay­ments for progress toward regulatory ap­proval. Interestingly, Dow, the world's biggest chemical company, functions in such arrangements much like small biotech

firms do in their alliances with large drug companies.

Although Dow has a strong position in the chelating agent field, a few other, smaller firms are hot on its trail. One is Mac-rocyclics, set up three years ago to commercialize chelant tech­nology that emerged from the labs of A. Dean Sherry, a chem­istry professor at the Universi­ty of Texas, Dallas.

Andrew Moxey manager of business and technology development, explains that Macrocyclics started out as a research-scale supplier, but that for the past year it has been developing c G M P knowledge and larger scale capacity to make the DOTA-based chelants in which it specializes. In the interim, the company is partnering with an outside firm that provides cGMP manufacturing.

Moxey acknowledges that his company can't match Dow for size and breadth of expertise, but he figures it has an advantage in speed of response and meeting specific customer needs. "This business is our existence," he points out. Macrocyclics has several drug industry customers, he adds, including one that is about to enter Phase I clinical trials with a prostate cancer treatment.

HGS is typical of companies in this field in that it is pursuing both labeled and un­labeled versions of its proteins. Also like other firms, it boasts promising drug can­didates but has no expertise in either ra-diochemistry or chelation. Not surpris­ingly, the company is partnering with both Dow and MDS Nordion.

One of HGS's discoveries is a B-lym-phocyte stimulator protein that it calls BLyS. David C. Stump, the firm's senior vice president of drug development, ex­

plains that BLyS has three potential ther­apeutic avenues: It can be administered to victims of autoimmune diseases that are deficient in it, it can be suppressed in arthritis and other patients that make too much of it, and it can be harnessed to de­liver radiation to B-cell tumors like non-Hodgkin's lymphomas.

BLyS has already been approved as an orphan drug for the treatment of patients with common variable immunodeficien­cy, or CVID. And in May 2002 , HGS launched Phase I clinical trials on Lym-phoRad-131, an iodine-labeled version of BLyS intended to treat multiple myeloma and non-Hodgkin's lymphoma. MDS Nordion is conducting the labeling at its Ottawa facility

Separately, since October 2000, HGS has worked with Dow to develop alterna­tive versions of BLyS that employ chelants to incorporate isotopes like yttrium.

Craig A. Rosen, president of R&D at HGS, says the company chose iodine for LymphoRad because it was a known per­former, didn't require a chelating agent, and could be handled by Nordion at a single facility. He says the yttrium-la­beled produc t developed wi th Dow

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works well in animal models but that clinical development as a companion to LymphoRad would require a strong busi­ness case.

Stump is bullish on the prospects for the nascent field of radiolabeled biophar-maceuticals. "It's all about targeting and specificity," he says. "Get your pharma­ceutical agent to the site and have it work effectively with no collateral damage." And although HGS is targeting the same B-cell cancers as Corixa and IDEC are, Stump maintains that the field is still wide open. "We're grateful that Bexxar and Zevalin have made it to the front line," he says, "but we see room for improvement." •

Many more combination treatments are in the pipeline, promising hope for cancer patients and a new source of profits for pharmaceutical companies.

TIGHTLY WOUND Dow Chemical's MeO-DOTA chelating agent complexes a radioactive metal while linking to a monoclonal antibody.

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