Pharma Strategy Blog

The beauty of social media is that sometimes someone shares something monumental before you even pick it up yourself in a journal you’re subscribed to. I love that – it’s a great way to see how others find things with what I call ‘interestingness’.  This morning, John Carroll of Fierce Biotech tweeted something that gave me goosebumps.

What was hot this morning you may all be wondering?

Crossing the blood-brain barrier (BBB)?

Wow, now that is something that really grabs my attention!  Normally, when you try to target drugs to the brain, you find that the endothelium acts as an impenetrable and largely impervious layer that forces you to keep adding more and more drug in an effort to get a small amount through.  This approach obviously increases side effects and the reality is so little drug actually gets through that efficacy is severely limited.

It also explains why we haven’t made much progress with brain related diseases such as Alzheimer’s, Parkinson’s and Glioblastoma (a malignant brain cancer).

We’ve talked a bit about nanotechnology on this blog and it’s companion, Biotech Strategy Blog, as a way to make things small enough to potentially cross the BBB, but I was keen to see what this was all about.  Enthusiastically, I checked out the original article in Science and Translational Medicine myself (see references below).  The editorial commentary associated with it began:

“As impenetrable as the walls of ancient Troy, the tight endothelial cell layer of the blood-brain barrier (BBB) allows only a few select molecules to enter the brain. Unfortunately, this highly effective fortress blocks passage of therapeutic antibodies, limiting their usefulness for treating diseases of the brain and central nervous system.”

Oof, a tad dramatic perhaps, but what did the Genentech scientists do that was different?

Well, the research team were looking at using a BACE-1 antibody to block the enzyme involved in amyloid production, but the BBB prevented little drug from getting through, despite higher doses.

The engineers then developed a new antibody to take advantage of the fact that cells need iron by creating an antibody with two arms:

• One arm held anti-BACE1 drug
• The other arm hosted a receptor called transferrin that carries iron to brain cells, providing a ferry across the barrier

In other words, they made use of the body’s natural transport system in much the same way the Trojan horse carried men.  Perhaps the analogy wasn’t so dramatic after all…

This novel approach allowed the scientists to use lower concentrations of the new drug to get the active therapy through.  This should limit side effects and hopefully, increase efficacy.  According to the authors:

“BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer’s disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.”

Note my emphasis… I can just see the anti-immunisation crowd up in arms before we even get started on this.

Implications of this research

The obvious potential benefits from this novel approach are in Alzheimer’s Disease research, although I caution that we still need to see results from human trials.

However, what piques my interest is how the technological approach of the iron receptor could be used for other brain diseases such as Parkinson’s Disease and brain tumours such as glioblastoma (GBM), which is a nasty malignant cancer limited by how much drug we can get inside the tumour cells. It crossed my mind that it might not take long for Genentech scientists and engineers to use the iron transport concept to bolt together a new monoclonal antibody combining the transferrin receptor and bevacizumab (Avastin), which is already approved as a treatment for GBM. Who knows how that might pan out, but the idea is very appealing indeed.

It is the development and spreading of novel and creative ideas like these that really excites me as a scientist and reminds me what I loved about it as kid.

Crazy Deranged Fools

This idea is so creative, so simple, so brilliant that I’m giving the Genentech scientists my Crazy Deranged Fool (CDF) award of the month for having the temerity to try something so boldly different – check out Hugh’s cartoon at Gaping Void to find out what that is!

References:

Atwal, J., Chen, Y., Chiu, C., Mortensen, D., Meilandt, W., Liu, Y., Heise, C., Hoyte, K., Luk, W., Lu, Y., Peng, K., Wu, P., Rouge, L., Zhang, Y., Lazarus, R., Scearce-Levie, K., Wang, W., Wu, Y., Tessier-Lavigne, M., & Watts, R. (2011). A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-  Production in Vivo Science Translational Medicine, 3 (84), 84-84 DOI: 10.1126/scitranslmed.3002254