From Genentech Inc.'s Avastin to Biogen Idec Inc.'s Zevalin, nearly twenty FDA-approved monoclonal antibodies are currently used to treat patients in various indications.
Add that to the more than 100 that are in the industry's pipeline, and they add up to one thing. Well, two things, actually: better medications, hopefully, but also an intensifying monoclonal antibody production crunch for sure.
"The problem around current production is getting more acute. And there is a massive bolus of products marching through clinical development that will lead to production shortages," Bruce Steel told BioWorld Today.
Steel is CEO of newcomer Rincon Biosciences Inc., a San Diego biotechnology firm that is one of several second-generation companies hoping to address the shortages by using plants as production factories. One could say that Rincon hopes to offshore the production of antibodies; the company's production plant of choice is aquatic, the eukaryotic alga Chlamydomonas reinhardtii. Rincon announced a multiprotein deal Friday with Biogen Idec to evaluate Rincon's eukaryotic algae production platform for therapeutic non-glycosylated proteins.
Currently, monoclonal antibodies are produced through fermentation by Chinese hamster ovary, or CHO-based, cell culture systems; Steel said there are several advantages of algal production over CHO. The first is that production in plants is a lot cheaper.
"There is a 30- to 50-fold reduction in capital cost," he said. "In CHO-based expression, the rule of thumb is that producing 1 kg of product per year takes $2 million in facilities. So to support an average product launch takes $200 million in facilities."
With production in C. reinhardtii, Steel estimated that cost will be closer to $5 million to $10 million.
Production costs also are lower. "Depending on the antibody, the current cost of a kilogram of antibodies is anywhere from $150 for unpurified antibodies to $1,000 for purified ones," Steel said. "Our expectation is that we can do this for less than $10."
Finally, the technology is faster. In cell culture, it takes about 12 months to go from an inserted gene to an expressed protein; in C. reinhardtii, the same steps take three months. Plant production also is more readily scalable, which in turn means that production scale-up needs to happen later in the clinical trial cycle. With CHO-based systems, the investments for scale-up need to happen during Phase II trials.
"Because we're so elastic," Steel said, "we wouldn't need to scale up until later in the process, in Phase III trials." Besides the inherent advantage of needing money later in the development game, that also would presumably lead to fewer investments into antibodies that later fail.
Altogether, if the technology pans out, those advantages would add up to a lower cost for monoclonal antibodies.
Two weeks ago, Rincon announced a manufacturing deal with Kailua-Kona, Hawaii-based Mera Pharmaceuticals. That agreement calls for Mera to perform pilot studies for Rincon at its Hawaii research and production facility over the next several months. If the first round of studies is successful, Rincon would expect to exercise an option to use the technology to develop its own production capability.
Second Time's The Charm?
The idea of producing monoclonal antibodies in plants is not new, but earlier companies that tried to produce monoclonal antibodies in crop plants such as corn and tobacco have generally not prospered. Besides a faster growth cycle, indoor growth, or containment, is one of the biggest advantages algae have over earlier attempts. C. reinhardtii will be grown "in a plastic bag in a greenhouse," Steel said. "From our point of view, if you're not in containment, then it's game over."
Containment, of course, has two facets: the actual risk that a genetically modified organism will escape and cause harm, and the public perception of that risk. However, Steel said that "we shouldn't have any significant issues, even from a public perception standpoint." He clarified that "in Hawaii, [GMO's] to be concerned about would be papaya and sugar cane, because those are major local crops." C. reinhardtii has no relatives in Hawaii, and the companies are working closely with the Hawaii Department of Agriculture. The algae that Mera produces as nutraceuticals are different strains from C. reinhardtii; "If you go to the health food store and buy blue-green algae, that's a different thing," Steel said.
Finally, C. reinhardtii are freshwater algae, and Hawaii is, of course, surrounded by a whole lot of salt water. "So even if it did get out, it would just die on the lava fields," he said.
Another company working in the same general business is Pittsboro, N.C.-based Biolex Inc., which recently announced an extended deal with Centocor Inc. (See BioWorld Today, March 22, 2005.)
Biolex uses the LEX System, which couples natural characteristics of a higher-order aquatic plant, the Lemna, with genetic engineering and protein recovery methods.
Steel pointed out that due to differences in technology, Rincon and Biolex are "unlikely to be competing on a product-by-product basis." Biolex uses its system to produce glycosylated proteins in the Lemna plant's nucleus, while Rincon uses the chloroplasts of unicellular algae for production. In C. reinhardtii, no post-translational modification, including glycosylation, takes place.
Whether a glycosylated or an unglycosylated protein is preferable depends on the specific therapeutic, so overall, Steel views the two technologies as more complementary than competitive. "To the extent that Biolex is successful, that's great news for us," he said.
Steel dated the birth of the company to August 2004, when Rincon licensed the intellectual property to the technology, which was developed in the laboratory of Stephen Mayfield at the Scripps Research Institute in La Jolla, Calif. That intellectual property includes one issued patent, which Steel termed a blocking patent for the production of proteins in chloroplasts, as well as one allowed patent and several applications. Rincon has just more than 10 employees. The company expects to announce further deals, but also has in-house therapeutic development programs.
Rincon is currently operating with funds from what Steel terms "a friends and family convertible note," and is actively fund-raising for a Series A round, which it expects to close within a few months.