Under a new binational partnership to be announced Tuesday, a Baja California aquaculture firm and a Ventura County biotech company plan to make a protein vital to many experimental cancer drugs and vaccines.
Medical researchers around the world buy the purified protein, called keyhole limpet hemocyanin, to develop these drugs. The protein is found in the blood of an obscure marine snail called the giant keyhole limpet.
To provide an additional source, Ostiones Guerrero SA de CV in Baja California, has teamed up with Stellar Biotechnologies of Port Hueneme.
If U.S. regulatory approvals are obtained, and an on-site suitability study is successful, the partners will grow the giant keyhole limpets in an aquaculture farm at La Chorera, a small, isolated fishing community on the Pacific Ocean west of San Quintín and about 180 miles south of San Diego.
It will take about three years to get enough data from the aquaculture project to satisfy drug regulators in the United States and other countries that the protein meets medical standards, said Frank Oakes, CEO of Stellar Biotechnologies.
|An adult giant keyhole limpet at Stellar Biotechnologies' aquaculture facility. They require 5 years to fully mature. The KLH protein can be extracted 3 times a year.— Stellar Biotechnologies|
The protein is also used in drugs being tested against metastatic breast cancer, stage 3 melanoma, neuroblastoma, multiple myeloma and other cancers.
As more drugs using this protein advance in clinical trials, and especially when these drugs reach the market, demand is expected to grow.
However, giant keyhole limpets occur only along sections of the Pacific Coast stretching from Monterey to Baja California. And if the limpets in this area were to be damaged by disease or environmental stress, keyhole limpet hemocyanin could suddenly be in short supply.
While the companies are not disclosing financial details, it’s a major project, Oakes said.
“We will make significant capital investments in that aquaculture compound, which we think will create a tremendous asset for the state of Baja California, for Ostiones Guerrero, and for Stellar Biotechnologies,” Oakes said.
Last year, Ostiones Guerrero obtained several new permits to harvest a 38-square mile area along the Pacific Coast, that fronts its fishing operations at La Chorera, which includes an abalone farm. The permitted area is rich in sea life and encompasses a volcanic island about six miles offshore, San Martín Island.
“That rocky underwater terrain creates an ideal ecosystem for mollusks in general, including abalone, clams, sea snails, crabs, lobster, all different kinds of species,” said Ron Hoff, a California native who is technical director for Ostiones Guerrero.
The area is also a habitat for the giant keyhole limpet – megathura crenulata – a species that Ostiones Guerrero recently obtained a federal permit to harvest.
"The underwater rocks are literally covered with them,” Hoff said.
While Ostiones Guerrero’s commercial permit allows it to harvest 12 metric tons of keyhole limpet annually, the plan is to farm them onshore at La Chorera, “right next to an ecosystem where they’re naturally thriving,” Hoff said.
Stellar Biotechnologies has developed aquaculture methods it’s now using on land, and intends to use in the Ostiones partnership. Under the partnership, blood will regularly be harvested from cultivated keyhole limpets under a method Oakes says doesn’t harm the animals.
The partnership began after Ostiones Guerrero contacted Stellar.
At the request of the company’s owner, Reyes Guerrero Sandoval, Hoff said he began researching the species – and quickly realized the potential. His inquiries led him to contact the California company, known for producing the protein.
“It became obvious that we needed to work with these guys," Hoff said. "Immediately, they showed a lot of interest.”
“Frank Oakes brought his director of operations down, they went out, they dove, to see the keyhole limpets in the water. We immediately started working on putting a collaboration agreement together.”
Ostiones Guerrero has a commercial permit to take out 12 metric tons a year of giant keyhole limpets, Hoff said, but the plan is to farm them onshore. “The local conditions and are ideal for the giant keyhole limpets,” Hoff said. “It makes sense to put aquaculture facilities right next to an ecosystem where they’re naturally thriving.”
On Tuesday, Ostiones Guerrero and Stellar Technologies are scheduled to officially announce their agreement. The agreement “will set the direction for our two companies to begin working together to help Stellar expand their ability to produce KLH,” Hoff said. The method is an eco-friendly one, he said, “that should help guarantee the species’ long-term survival.”
The first step would involve a suitability study, Hoff said, and involve the construction of an onsite power generation and seawater intake infrastructure at La Chorera, a small, relatively isolated fishing community located on the Pacific Ocean west of San Quintin. If that goes well, the partners would set out to built a limpet hatchery, a facilities where they would grow, a laboratory to extract the KLH and purification for export to pharmaceutical markets.”
Oakes said he became interested in KLH about 20 years ago, when approval of a bladder cancer drug was held up because the drug maker could not fully explain to federal regulators where the protein came from. He saw that drug companies needed a steady and reliable source of this protein.
Stellar Biotechnologies was the result. With federal and state grants, the company developed the aquaculture methods needed to grow the giant keyhole limpets, safely extract blood and process it to pharmaceutical specifications.
"We acquired oceanfront property from the U.S. Navy through base privatization, and built a small business that supports dozens of companies that are developing therapeutic vaccines," Oakes said.
Giant keyhole limpets can be considered the West Coast's reply to the horseshoe crab, another invertebrate that produces blood useful for medical research. However, horseshoe crabs reproduce prolifically, Oakes said, while the limpets grow slowly. That's why the ability to harvest limpet blood without harming them is so important. The animals can live decades if treated properly.
Ostiones provides "second site" security, Oakes said, so if anything puts one location out of production, the other site can continue unaffected.
"They have the rights to actually plant and farm animals on the ocean bottom," Oakes said. "They have a great site with very clean water ... and you know the difficulties in developing anything along the coastline in California."
The giant keyhole limpet is round, its single shell covered with dark purple flesh. It is related to and resembles abalone. Like abalone, it's edible. In the center of its shell is a breathing hole, thought to resemble a keyhole.
These limpets grow along the San Diego coastline. Their ability to grow in hyper-saline water was tested, along with that of other local sea life, as part of the approval process for the Poseidon desalination plant in Carlsbad.
Kim Janda, a scientist at The Scripps Research Institute, has used keyhole limpet hemocyanin, or KLH, to help research a heroin vaccine. He has since switched to another protein, inactivated tetanus toxin, but the cost is much greater.
One disadvantage of KLH is that it's a large protein, which can complicate its use, Janda said. For example, it can't be studied with a common method of analyzing molecules called mass spectrometry. And the giant keyhole limpet's rarity is a concern, he said.
Vaccine researchers value the hemocyanin from giant keyhole limpets because it stimulates the immune system and at the same time easily carries antigens, molecules from the organism the vaccine is developed against, said John Cashman, founder of the Human BioMolecular Research Institute in San Diego. This makes it a highly efficient substance for use in making antibodies.
"We've made antibodies to cocaine, we made antibodies to organophosphates for detection of nerve agents," Cashman said.
Because the protein is so large and complex, it can't be synthesized in the laboratory. So the protein is largely collected the old-fashioned way, by divers who bring in the limpets.
Keyhole limpet hemocyanin is the oxygen-carrying protein in the animal’s blood, called hemolymph. Unlike hemoglobin, which uses iron to hold oxygen, hemocyanin uses copper. And while the hemoglobin protein of vertebrates is contained in cells, the copper-containing hemocyanin protein circulates free in the hemolymph.
In the presence of oxygen, the hemolymph turns an intense blue, becoming colorless after releasing the oxygen.
Cashman said he's been concerned because the sources of KLH are so limited."If you opened up a new source that could make clinical grade KLH, that would be a real boon to the industry."
Article written by Sandra Dibble & Bradley Fikes, San Diego Union Tribune