Best Stimulus Spending ?

Robert Waldmann

I have a proposal for targetted temporary spending which will have a huge immense disproportionate social benefit. It is not, shall we say, very controversial as it comes under the NIH budget — the one the house and senate are competing to pump up most.

Oh and it might save Senator Specter’s life (not that I am accusing him of conflict of interest).

The aim is to find one off spending which sure doesn’t involve hiring more civil servants which is actually useful. The proposal (not frankly my personal idea) is

$ 6 million (that’s million with an m) for GMP DOTA-biotin and biotinylated galactosylated albumin.

I think that strong evidence is available in the published literature that this will save the lives of people with lymphoma. I mean evidence much stronger than any evidence in economics, although much too indirect to be called evidence in biology.

$ 6 million once. Huge benefits. Explanation after the jump. I promise you that I am absolutely serious.

The medical background. A lymphoma is a solid tumor made of transformed white blood cells. The most common kind of lymphoma is Hodgkin’s lymphoma which used to kill very quickly and now is usually cured by chemotherapy. Hodgkin’s lymphoma is one of the few great successes of chemotherapy (which also works for leukemia in children and Wilm’s tumor and usefully complements surgery for many tumors). However, sopme people still die of Hodgkin’s lymphoma. Great success is not 100% success. Another common kind of lymphoma is B-cell lymphoma — a cancer of the cells which produce antibodies. In this case the odds are grim.

A possible approach to treating cancer is to direct radioactive isotopes to the tumor using antibodies which stick to tumor specific antigens. Some success has been reported in the treatment of leukemia (where the cancer is not a tumor but circulating cells in the blood). However, getting antibodies into tumors is slow — we have evolved a system that means that antibodies stay in the blood and they are big and tumors are cramped. This means that radioactive isotopes are never well targeted to tumors much of the radiation remaining in the blood.

A possible solution is the Pre-targetting (TM) technology developed by Donald Axworthy and Louis Theodore (in alphabetical order) and patent pending and owned by Aletheon Inc (which last I heard basically consisted of Axworthy and Theodore).

The idea is to use the extremely tight affinity between a small molecule biotin (a vitamin) and streptavidin (a protein which binds biotin very avidly). Lymphomas have known antigens (in fact proteins on their surfaces) which aren’t found on cells which we need. A radioactive antibody which sticks to this antigen should, in principal, be a good therapy. However, as noted above, a lot of the antibody stays in the blood. The Aletheon approach is to make a hyrbrid protein which is basically the tumor specific antibody and streptavidin together. This is injected into the patient. Some slowly slowly sticks to the tumor. Some stays in the blood.

Then they add a “clearing agent” biotinylated galactosylated albumin. The biotin sticks to the hybrid antibodies. Galactosylated proteins are removed from the blood by the liver (unless there is a molecule of sialic acid stuck to the galactose). So the hybrid antibody-streptavidin is removed from the blod.

Then radioactive biotin is given IV. It is a small molecule which quickly goes diffuses into among other places the tumour. The radioactive biotin sticks to the streptavidin stuch to the tumor and stays there. All of this is a description of experimental results with human tumors implanted into nude mice.

To make biotin radioactive they make a molecule which consists of biotin and a chelating agent DOTA (it’s still a small molecule and easy to synthesis). a chelating agent is a molecule with two negatively charged bits sticking off like crab claws (chele in Italian and I guess Latin). These bind ions charged +2 very tightly. One such ion is disolved Ytrium90 which is radiactive.

At least 2 such antibodies are available. I will discuss the simple antibodies (without the streptavidin part) which are both approved for sale as pharmaceuticals.

Anti-CD25 streptavidin and Anti-CD20-streptavidin. Anti-CD25 (daclizumab, zenapax) does not stick to normal cells. It does stick to activated T-cells (of which usually we have none) and, in some cases, to Hodgkin’s cells. It can bind specifically to only lymphoma cells (in some cases of Hodgkins). It basically always binds to cells in lymph nodes (that is where the tumor is).

Anti-CD20 (rituximab) is specific for B-cells (the cells which make antibodies). A loss of B-cells is actually not a life threatening crisis as there are anti-sera (lots of antibodies) specific for most known pathogens which can be used in case a patient gets an infection and doesn’t have B-cells. Also they come back after a while. In contrast, B-cell lymphomas basically usually kill.

So what’s the problem ? Well see all the experiments are in mice, because there is no DOTA-biotin or biotinylated galactosylated albumin up to FDA standards for use in humans (that’s what GMP means it stands for good manufacturing practice).

There are firms which specialize in making things to FDA GMP standards. They charge for this service. It would cost around $ 6 million and take 6 months to have reagents in hand ready for desperate patients in a phase 1 study.

Absurdly, the NIH hasn’t been able to find $6 million in its huge budget, because they had forecast an even huger budget and basically committed the money. Now everything is reversed. There is a strong desire for one off spending, especially one off NIH spending, especially especially one off NIH spending which could save Senator Arlen Specter’s life.

So it’s bound to happen right ?

Hah. It might or might not and a blogswarm might save some lives right now.

I am absolutely totally serious.