Read with caution!

This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.

Potential immunological approaches to treating prion disease fall broadly into two categories.  I’m just beginning to learn a bit about the immune system, but to my basic understanding:

  • Active immunization is inoculation with an antigen (in this case PrP) in order to induce the body to develop its own antibodies against the antigen.  Vaccination usually refers to active immunization.  I reviewed progress on active immunization for prion diseases in the anti-PrP vaccines post.
  • Passive immunization is providing the body with already-made antibodies.  This is the subject of today’s post.

In the early 2000s, in vitro experiments showed that antibodies against PrP could completely ‘cure’ infected cell cultures, permanently ending the production of PrPSc [Enari 2001, Peretz 2001 (ft)].  These experiments used the 6H4 and Fab D18 antibodies respectively.  I had always thought of the immune system as attacking and destroying antigens, but cell cultures don’t have an immune system.  The antibodies weren’t destroying PrP, they were blocking it.  In studying the antibodies’ mechanism of action, Enari reported that 6H4 ‘occludes’ either PrPC, PrPSc, or both – presumably meaning it gets in the way of their interaction with each other.  Peretz found that other antibodies which bound similar amounts of PrP didn’t inhibit PrPSc formation as effectively as did Fab D18, suggesting that the particular epitope at which Fab D18 binds to PrP (mouse codons 132-156) was indispensible for the PrPC to PrPSc conversion.  Peretz suggested this site might be a good target for drug development.

This was all promising news, so a couple of years later, White 2003 applied the passive immunization approach in vivo.  White produced two new antibodies, ICSM 35 and ICSM 18, by inoculating PrP knockout mice with human PrP – unlike wild-type mice, the knockouts lack immunological tolerance to PrP, and so will develop antibodies if exposed. ICSM 35 binds to human PrPC and PrPSc alike at amino acids 91-110 and ICSM 18 binds to amino acids 146-159, strongly in PrPC and less strongly in PrPSc.

Surprisingly, ICSM 18, the one that mostly binds healthy PrPC and doesn’t bind much to diseased PrPSc, turned out to be the more therapeutically effective of the two, at least as measured by accumulation of PrPSc in the spleen.  And also interestingly, both antibodies appeared not to have activated the immune system to destroy PrP itself, nor PrP-producing cells.  PrPC levels were unchanged in spleens of treated mice versus controls, suggesting the antibodies worked the same way Enari’s and Peretz’s antibodies had worked in cell culture – just by occluding PrP, not destroying it.  And there was no evidence that PrP-producing cells had been destroyed – a good sign from the standpoint of preventing an autoimmune response.

In terms of mouse survival, all of the animals that were infected peripherally and treated starting 7 or 30 days post infection (dpi) with either antibody survived, apparently unscathed.  The experiment only followed them up to 500 days, but they were all alive and without symptoms at that time, while all the controls had died around 197 days.

White also tried treating mice only once they developed clinical signs of scrapie.  Sadly, this didn’t work – survival was no different from controls.  White also infected groups of mice by intracerebral injection, and treated them starting at 7 dpi, 30 dpi or once clinical signs had appeared, and none of these approaches significantly extended survival either.

That’s probably not too surprising – the blood brain barrier doesn’t let many large proteins such as antibodies through.  Meanwhile the expression level of PrP is much higher in the brain than in most of the periphery [Novartis BioGPS].  So once prion infection has taken hold in the brain, peripheral administration may just not get enough antibodies to where it counts.

But that’s no reason to give up on the passive immunization approach.  How to get antibodies across the blood brain barrier appears to be an active and ongoing area of research, particularly for treating brain tumors [reviewed in Lampson 2011].  And a new approach for getting antibodies into the brain to treat Alzheimer’s made a splash a couple of years ago – scientists created ‘bispecific’ antibodies that each bind to two proteins – the therapeutic target, and a transferrin that is hijacked to gain entry through the BBB [Atwal 2011, Yu 2011, commentary in Nature News].  Finally, direct administration of antibodies into the cerebrospinal fluid would be a risky but potentially effective approach to bypassing the BBB.

update 2013-05-15: A recent study has shown slightly more success with anti-PrP antibodies administered intravenously at the time of clinical onset [Ohsawa 2013]. Ohsawa used 31C6 antibodies, which target PrP amino acids 143-149.  Ohsawa’s treated mice did not live significantly longer than controls (though they had a slight trend towards longer survival), but PrPSc accumulation appeared to be reduced.  The most important finding, though, was simply that the antibody could be detected in the brain.  This is consistent with reports from other studies that a small fraction of peripherally administered antibodies do cross the blood-brain barrier, and so simply giving an enormous dose of antibodies can boost the amount that reaches the brain [Chung 2010].  Ohsawa gave each mouse 0.5 mg of antibody per week, Chung used 1 mg 5 days/week.  An earlier study by the Horiuchi group found an 8% extension of survival in mice treated at clinical onset by direct intraventricular infusion [Song 2008 (ft)].  But even Song’s intraventricular infusion did not reach all brain regions equally, with good penetrance surrounding the ventricles and limited penetrance in the cortex and cerebellum.