West Coast Editor
In late 2002, when Northwest Biotherapeutics Inc. and Medarex Inc. entered their development deal, NBI was touting one drug target in the pact - the gene CXCR4 - as particularly important.
Recently, Bothell, Wash.-based NBI was granted a U.S. patent related to antibodies taking aim at the gene, which is activated by the lack of oxygen, causing tumor cells to migrate and attack specific organs, as noted in a Nature "News & Views" paper in the fall of 2003.
Alton Boynton, president and chief operating officer of NBI, said CXCR4 allows tumor cells to find, as if by a magnet, areas in the body that secrete the CXCL12 ligand and set up a micro-metastatic lesion that eventually grows.
"It's rare to find a protein that has three different activities in cancer - proliferation, migration and invasion," Boynton said, noting that much research has been published since NBI began investigating CXCR4 in 1997.
"It was very surprising to see a chemokine receptor come out of this, and be highly overexpressed in glioblastoma," he said, adding that CXCR4 is overexpressed in 70 percent of cancers.
"For example, bone secretes the ligand, and also the lung," Boynton said. "That's one of the reasons why, in breast and prostate cancer, it attaches to bone."
The patent specifically covers ways of preventing the proliferation of any cell overexpressing CXCR4, and the use of antibodies targeting malignant metastatic cells that overexpress it.
Other companies are investigating the gene - it's involved in the entry of HIV into CD4-positive cells - but none are known to be testing antibodies. Because of NBI's new patent, "with respect to antibodies, they'd have to come through us. No question about it," he said.
In the deal with Princeton, N.J.-based Medarex, the latter got from NBI therapeutic development and commercialization rights to MDX-070, a fully human antibody to prostate-specific membrane antigen (which since has reached Phase II testing), along with rights to two more cancer-related disease targets, as well as certain patents related to the acquired targets for developing antibody drugs. (See BioWorld Today, Dec. 12, 2002.)
The agreement gave NBI a much-needed $3 million in funding, potential future royalties and certain diagnostic rights for two of the three cancer-related disease targets acquired by Medarex, targets that previously were co-owned by the companies. NBI regained all rights to five potential additional cancer-related disease targets, including CXCR4.
"The preclinical work is essentially done," Boynton told BioWorld Today. "As soon as we obtain financing we'll be able to work very aggressively" on further advancement.
Financing has been an issue for NBI, which entered a recapitalization deal disclosed in April with Toucan Capital II LP, of Bethesda, Md., under which NBI would get up to $40 million through the issuance of new securities to Toucan and a syndicate of investors. Following the deal, Toucan and the syndicate together would own more than 90 percent of the outstanding stock.
So far, NBI has gained about $4.4 million in loans, and sold about $1.3 million in Series A preferred stock through the Toucan deal, Boynton said.
"It's at their option to continue funding the company, and we do so on a bi-monthly basis," he said. "We have gone through eight different bridge loans."
The company's shares trade on the Over-the-Counter Bulletin Board (OTC BB: NWBT) and ended Friday at 21 cents, down 1 cent.
How far away from the clinic is a drug that targets CXCR4?
"Realistically, it's a matter of humanizing a murine antibody that we have and manufacturing it," Boynton said. "That's a year." The cost is "half a million to humanize an antibody, maybe a little cheaper than that," he added.
Whether NBI will continue to seek funding or will partner the effort is yet to be decided.
"We'll look at all options," Boynton said.
Although glioblastoma seems promising, the first indication to be tackled also is undecided, and will depend on "what the landscape looks like out there with respect to that particular one and what the competition is" - as well as what a partner might want to do, he said.
At the start of this year, NBI gained FDA clearance to start a Phase III trial with its lead product, DCVax-Prostate, for non-metastatic hormone-independent prostate cancer. No FDA-approved drug exists for the indication. (See BioWorld Today, Feb. 2, 2005.)
DCVax-Prostate comes from NBI's dendritic cell-based immunotherapy platform. White blood cells are separated from the patient's blood at a clinical site and shipped to a processing center, where peripheral mononuclear cells are isolated, put in vials and stored in liquid nitrogen.
The cells are thawed and cultured for seven days with processing and maturation factors, after which they are put in vials again, frozen, tested, released and shipped back to the clinical site for injection, or they might be pulsed with tumor lysate, tumor-related antigens or antigen-associated peptides, then frozen, tested, released and shipped for use.
"We have a Phase II for glioblastoma, which has also cleared the FDA," Boynton said. That trial would test another DCVax product for glioblastoma multiforme. The brain cancer trial is expected to start later this year. Preclinical work is complete for a Phase I trial for non-small-cell lung cancer and head and neck cancer.
Regarding CXCR4, NBI also has patents pending on other methods of targeting the receptor and the ligand CXCL12, he said.