4 ms·

Yeah the brain is a privileged site, a fancy way of saying it's not like places that have ready bloodflow with very little to separate the organ. The blood brai

by entee 11y ago

Yeah the brain is a privileged site, a fancy way of saying it's not like places that have ready bloodflow with very little to separate the organ. The blood brain barrier is a real problem in drug development, but it's not that surprising that there is in fact a way around it for the immune system. As the parent mentions, there's been lots of evidence stretching back years that the brain isn't totally isolated from the immune system. This paper (quite amazing and important work btw) just elaborates how that happens. The press release from the university is a little hyperbolic, but this is good and important work.

daveguy 11y ago
I would say this work is incredibly important. Like you said, the blood-brain barrier is a significant obstacle in pharmaceutical research. One thing pharma companies are very good at is producing antibody based drugs and their derivatives. By conjugation of molecules to the antibodies that are accepted through this pathway, essentially hitching a ride in the process, the blood-brain barrier could essentially be eliminated in drug development. Delivery method is one of the most important and difficult aspects of drug development. Characterization of this process is definitely a breakthrough.
- entee 11y ago
  Coupling small molecules to antibodies is tricksy :-P. There have been a lot attempts at doing that (the first I recall is from the late 90's but possibly even earlier), but not many have made it into actual clinical practice. Turns out that the linkage is important, the pharmacokinetics can get complicated and getting the proper concentration in the bloodstream can be difficult. That said I've heard people are getting this kind of strategy to work more recently, particularly in oncology. But of course, better understanding and finding an alternative method around the blood brain barrier is absolutely critical to drug development. It's a huge issue for any small molecule treatment for neurological disease, and regardless of how you conjugate or what you conjugate it to (now that we know something about it, maybe a full antibody isn't required, you could maybe get nearly the same effect with a shorter peptide), this is a breakthrough.
  - daveguy 11y ago
    I was thinking more of larger protein-antibody conjugates and I agree it probably doesn't need to be a whole antibody. Still a lot more to learn, but very exciting for central nervous system pharma development.
    - dnautics 11y ago
      If you don't use the whole antibody, the serum half life us capped in the knees because the body gets rid of serum proteins without glycosylation. In the case if antibodies, glycosylation is on the heavy chain FC region. The first protein antibody conjugates were to couple ricin to antibodies in the late 80s. Ricin's warhead polypeptide chain conveniently has a single cysteine residue that they tried to conjugate to antibodies using disulfide exchange. Of course this was not kind to the antibodies, and the structural disruption is very likely one of the reasons this strategy failed miserably. In general the challenge for ADC is that attaching your drug to an antibody is nontrivial, and the titer is tricky. How many of your molecule does it require to take down a cell? 100? 1,000,000? Can you deliver that number of molecules to each cell, that start reliably conjugated to a large molecule, after yield losses as a result of molecular decoupling?
- amelius 11y ago
  I wonder if the converse is also true: drugs that are attached to antibodies that don't need to (and are not supposed to) enter the brain, could in fact enter the brain. Also, why haven't such bbb-crossings been seen before?

by entee 11y ago

daveguy 11y ago

I would say this work is incredibly important. Like you said, the blood-brain barrier is a significant obstacle in pharmaceutical research. One thing pharma companies are very good at is producing antibody based drugs and their derivatives. By conjugation of molecules to the antibodies that are accepted through this pathway, essentially hitching a ride in the process, the blood-brain barrier could essentially be eliminated in drug development. Delivery method is one of the most important and difficult aspects of drug development. Characterization of this process is definitely a breakthrough.

entee 11y ago
Coupling small molecules to antibodies is tricksy :-P. There have been a lot attempts at doing that (the first I recall is from the late 90's but possibly even earlier), but not many have made it into actual clinical practice. Turns out that the linkage is important, the pharmacokinetics can get complicated and getting the proper concentration in the bloodstream can be difficult. That said I've heard people are getting this kind of strategy to work more recently, particularly in oncology. But of course, better understanding and finding an alternative method around the blood brain barrier is absolutely critical to drug development. It's a huge issue for any small molecule treatment for neurological disease, and regardless of how you conjugate or what you conjugate it to (now that we know something about it, maybe a full antibody isn't required, you could maybe get nearly the same effect with a shorter peptide), this is a breakthrough.
- daveguy 11y ago
  I was thinking more of larger protein-antibody conjugates and I agree it probably doesn't need to be a whole antibody. Still a lot more to learn, but very exciting for central nervous system pharma development.
  - dnautics 11y ago
    If you don't use the whole antibody, the serum half life us capped in the knees because the body gets rid of serum proteins without glycosylation. In the case if antibodies, glycosylation is on the heavy chain FC region. The first protein antibody conjugates were to couple ricin to antibodies in the late 80s. Ricin's warhead polypeptide chain conveniently has a single cysteine residue that they tried to conjugate to antibodies using disulfide exchange. Of course this was not kind to the antibodies, and the structural disruption is very likely one of the reasons this strategy failed miserably. In general the challenge for ADC is that attaching your drug to an antibody is nontrivial, and the titer is tricky. How many of your molecule does it require to take down a cell? 100? 1,000,000? Can you deliver that number of molecules to each cell, that start reliably conjugated to a large molecule, after yield losses as a result of molecular decoupling?
amelius 11y ago
I wonder if the converse is also true: drugs that are attached to antibodies that don't need to (and are not supposed to) enter the brain, could in fact enter the brain. Also, why haven't such bbb-crossings been seen before?