A cheaper better way to manufacture herceptin, avastin, perjeta, TDM-1...Sheila would

[Lani]

have approved.

My first memory of Sheila was her posting of her fight to get the price of herceptin under control at her hospital by taking her case to the media

Now it appears there may be a way to produce these drugs (and others) far more cheaply and without relieving Chinese hamsters of their ovaries

I am sure she would have approved and celebrated with our site's honorary mascot,Tipsy..oops, Tiptoe (the Chinese hamster who so selflessly offered her ovary(ies):

Public release date: 10-Dec-2012
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Contact: Kim McDonald
kmcdonald@ucsd.edu
858-534-7572
University of California - San Diego
Biologists engineer algae to make complex anti-cancer 'designer' drug

Biologists at UC San Diego have succeeded in genetically engineering algae to produce a complex and expensive human therapeutic drug used to treat cancer.

Their achievement, detailed in a paper in this week's early online issue of The Proceedings of the National Academy of Sciences, opens the door for making these and other "designer" proteins in larger quantities and much more cheaply than can now be made from mammalian cells.

"Because we can make the exact same drug in algae, we have the opportunity to drive down the price down dramatically," said Stephen Mayfield, a professor of biology at UC San Diego and director of the San Diego Center for Algae Biotechnology or SD-CAB, a consortium of research institutions that is also working to develop new biofuels from algae. Their method could even be used to make novel complex designer drugs that can't be produced in any other systems--drugs that could be used to treat cancer or other human diseases in new ways.

"You can't make these drugs in bacteria, because bacteria are incapable of folding these proteins into these complex, three-dimensional shapes," said Mayfield. "And you can't make these proteins in mammalian cells because the toxin would kill them."

The advance is the culmination of seven years of work in Mayfield's laboratory to demonstrate that Chlamydomonas reinhardtii, a green alga used widely in biology laboratories as a genetic model organism, can produce a wide range of human therapeutic proteins in greater quantity and more cheaply than bacteria or mammalian cells.

Mayfield and his colleagues achieved their first breakthrough five years ago when they demonstrated they could produce a mammalian serum amyloid protein in algae. The following year, they succeeded in getting algae to produce a human antibody protein. In 2010, they demonstrated that more complex proteins—human therapeutic drugs, such as human vascular endothelial growth factor, or VEGF, used to treat patients suffering from pulmonary emphysema—could be produced in algae. (http://ucsdnews.ucsd.edu/newsrel/sci...icProteins.asp)

Then in May of this year, Mayfield's group working with another team headed by Joseph Vinetz from UC San Diego's School of Medicine, engineered algae to produce an even more complex protein—a new kind of vaccine that, preliminary experiments suggest, could protect billions of people from malaria, one of the world's most prevalent and debilitating diseases. (http://ucsdnews.ucsd.edu/pressreleas...ne_from_algae/)

"What the development of the malarial vaccine showed us was that algae could produce proteins that were really complex structures, containing lots of disulfide bonds that would still fold into the correct three-dimensional structures," said Mayfield. "Antibodies were the first sophisticated proteins we made. But the malarial vaccine is complex, with disulfide bonds that are pretty unusual. So once we made that, we were convinced we could make just about anything in algae."

In their latest development, the scientists genetically engineered algae to produce a complex, three-dimensional protein with two "domains"—one of which contains an antibody, which can home in on and attach to a cancer cell and another domain that contains a toxin that kills the bound cancer cells. Such "fusion proteins" are presently created by pharmaceutical companies in a complex, two-step process by first developing the antibody domain in a Chinese hamster, or CHO, cell. The antibody is purified, then chemically attached to a toxin outside of the cell. Then the final protein is repurified.

"We have a two-fold advantage over that process," said Mayfield. "First, we make this as a single protein with the antibody and toxin domains fused together in a single gene, so we only have to purify it one time. And second, because we make this in algae rather than CHO cells, we get an enormous cost advantage on the production of the protein."

The fusion protein the researchers in his laboratory produced from algae is identical to one that is under development by pharmaceutical companies with a proposed cost of more than $100,000. This same protein could be produced in algae for a fraction of that price, they report in their paper. And the UCSD researchers—Miller Tran, Christina Van, Dan Barrera and Jack Bui at the UC San Diego Medical School—confirmed that the compound worked like the more expensive treatment: it homed in on cancer cells and inhibited the development of tumors in laboratory mice.

Mayfield said such a fusion protein could not have been produced in a mammalian CHO cell, because the toxin would have killed it. But because the protein was produced in the algae's chloroplasts—the part of algal and plant cells where photosynthesis takes place—it did not kill the algae.

"The protein was sequestered inside the chloroplast," Mayfield said. "And the chloroplast has different proteins from the rest of the cell, and these are not affected by the toxin. If the protein we made were to leak out of the chloroplast, it would have killed the cell. So it's amazing to think that not one molecule leaked out of the chloroplasts. There are literally thousands of copies of that protein inside the chloroplasts and not one of them leaked out."

Mayfield said producing this particular fusion protein was fairly straightforward because it involved fusing two domains—one to recognize and bind to cancer cells and another to kill them. But in the future, he suspects this same method could be used to engineer algae to produce more complex proteins with multiple domains.

"Can we string together four or five domains and produce a designer protein in algae with multiple functions that doesn't exist in nature? I think we can?" he added. "Suppose I want to couple a receptor protein with a series of activator proteins so that I could stimulate bone production or the production of neurons? At some point you can start thinking about medicine the same way we think about assembling a computer, combining different modules with specific purposes. We can produce a protein that has one domain that targets the kind of cell you want to impact, and another domain that specifies what you want the cell to do."

###
The research project was supported by grants from the National Science Foundation and The Skaggs Family Foundation.

[karen z]

Lani,
Many thanks for this post (and what great news). I think Sheila would have approved as well.

[chrisy]

Wow, very interesting! I wonder tho, how the FDA would respond to these - and by the time you adequately trialled all these possible combinations would it still be as cost effective? Overall tho, VERY exciting stuff.

[ElaineM]

Thanks for posting this.

[Pray]

I sure hope this happens soon. Thanks again Lani.

[Rolepaul]

Biolex in Pittsboro North Carolina has pushed this concept for many years without success. The initial work at lab scale is easy, but getting it to commercial scale that is economical is much harder. There is a facility in San Diego that purifies the Xanthan used in food ingredients from kep, and another in Hawaii that did pharmaceuticals and biofuels from algae, but it is a hard thing to do. I know as this is my field. I do wish the product line luck, but it will be a tough place to go.

[Lani]

Dr. Ronald Levy of Stanford has been trying to grow drugs specific for individual patients in tobacco plants for about 15 years.

I had never heard of any group successfully making such complex drugs before

Yes, herceptin is expensive. But the retail price FAR FAR exceeds the wholesale price, sometimes by a factor of 10 !!

[sarah]

wow! as usual Lani, your posts are illuminating.
thanks
sarah

[Rolepaul]

Lani is right. The cost to produce a 440 mg vial of Trastuzumab is estimated at about $400, with the fermentation portion (okay this is where I have to estimate based on my experience on growing tippy cells) probably taking $100 of the 440 mg vial. Genentech Roche sells that vial for $2500, and the hospitals charge about $3500 per 120 mg dosing (including nurse time, tubing, and such). A reduction in price on the fermentation end from $100 to $25 would result in a reduction of the price for a single treatment of about $20 from the original $3500. This same concept was going to be done in goat and/or sheep milk and never proved viable. The patent will run out pretty quick on Herceptin, so then the generics will kick in, but generic injectibles do not see all that great of a price reduction. Again, this is from someone that has been in drug manufacturing for over 30 years. I am not sure what is needed to cut the cost and still hae safe treatments.

[sarah]

yes but cost is a major problem for some people. The question also is, if a drug company knew of a cheap, patent free drug, would it develop it? say like aspirin??? and yet obviously aspirin is profitable or is it just a brand name identification???. the fact that some older drugs are being used for totally different uses is also interesting. Because drugs are connected to survival, cost becomes a very touchy subject for patients. Genetech didn't want to pursue Herceptin and stopped funding it, Dr. Slamon had to get outside funding to finish his work and then Genetech profited enormously from it so again costs came into that, what if he hadn't found outside money? most of us on this site would be dead. And then there's the fact that Medicare can't negotiate for the price it pays for drugs unlike the rest of the world, is this morally right. cost where life is concerned is a very sensitive issue. If I had lived in the US, there is no doubt in my mind that I would have not been allowed to continue on Herceptin for 6 years, again cost enters a right to life decision. very troubling. As patients I think we would all like to see the price of drugs become cheaper and more available while understanding the risks and costs involved in creating these drugs. But when it's a question of life and death, it becomes a difficult subject when wherever you can afford a drug becomes a survival issue.

[Rolepaul]

Price does enter into the cost of drugs. Genentecch is owned by Roche, a Swiss holding company that is closely held by a few family members with controlling interest. Same with Novartis. These families control the industry, but the hospitals are also to blame.
As for being alive or not, Nina would not be alive in most countries. Interathecal trastuzumab, IT Topotecan, IV Trastuzumab, and IV Navelbine (oh and the Neupogen) costs have been picked up by the insurance company or the cancer center, with us paying about $4800 in total of the $800,000 in bills. For Nina to be alive today (exactly one year after spinal nerve involvement was found) is nothing short of a miracle. The amount of fighting done with the people involved at the cancer center and insurance company is minimal compared to the frustration of being able to see her only three or four days every two weeks for eight months due to treatment out of the area.
If it can be done less expensively, you need more people like me. We do not make the money that stock brokers, good real estate agents, and others do. We do it because we like to make people healthy. 7500 people get to say hello to their children and grandchildren because of a product I make. We doubled production in six years and reduced scrap material by 90%. Cheaper, faster, better can be done with the right team.

[sarah]

I agree with what you say. I also believe people in the stock market and financial world earn more than they contribute and they sure can create havoc. So yes, you guys contribute much more and effect lives in a meaningful and helpful way.
And I wish you could see your wife more often and what you do is appreciated. I hope your wife gets well soon and can return home so you don't have to make that long commute to see her. I can only imagine how hard it is for both of you. Your love shines through your posts.
By the way did you see the film about Dr. Slamon called Living Proof, it's very emotional and shows how tough it is to create a viable treatment. Also at that point Roche wasn't involved, only Genetech. Happy to have Herceptin and we know it's just the beginning as you are more aware of than many of us. and all the people who work to create those drugs and doctors and nurses are definitely appreciated.
Take care of yourself and all the best for your wife and her treatment working well and that you get to spend every day close to each other again very soon.
hugs and love
health and happiness
sarah

[Rolepaul]

Nina was able to come home in September, but flies to Houston every two weeks to get Intrathecal treatment. She gets IV treatment there each time, with a treatment in Raleigh every fourth week. This gets her 3 out of 4 IV Herceptin and Navelbine, and every two weeks IT Herceptin and Topotecan. It is amazing to watch them draw sixteen mls out of the Ommaya reservoir at her hairline, then put in the 5 mls of IT Herceptin, 5 mls of Topotecan, and six mls of the fluid that was withdrawn. About ten minutes altogether start to finish. That is what is keeping her alive. $5300 per treatment. That is better than a lawyer makes! Then back on the plane and home. Duke is not certain about doing it, which would save $800-1000 per month in travel. Any way, I know the people at Genentech that were working on it originally and the ones that were part of the team where they travelled to get the Mayastine conjugated. All I can tell you about my past is that I have done all of these and understand what it takes. Once you do it ten or so times, it becomes a whole lot easier.

[sarah]

Hello, good that you and Nina have strong scientific brains and can find the best treatment. Hopefully somewhere nearer home will start to offer the same treatment.
If letters to a nearby hospital would help, let me know and I'll send one just let me know how I should phrase it.
Nina's obviously an exceptional woman and you, a loving husband which I think really helps recovery. My husband has been my terrific supporter and when we lived in the US, dealt with the insurance companies and never said a negative word about anything, just asked me what I wanted and got it. It was great because, as a professional women, I thought I could handle it all!!! but after the first call to our excellent (so we thought!) insurance, I was hysterical and crying my eyes out. My husband said, that's the last call you make, I'll take over now, you just get well. In our support group in France we have several single women or women who's partners have left with the diagnosis and it's really hard but luckily no insurance issues to deal with.
Hope you and Nina get to spend a nice Christmas and New Year together.
hugs and love
sarah