Recent Advances in Anti-Amyloid Passive Immunization

Passive immunotherapy involves the delivery of an agent, such as a monoclonal antibody, that spurs the immune system to attack specific targets. This response lasts for as long as the agents are consistently delivered as a therapy, and most are short-lived molecules, meaning that passive immunotherapies are easily halted. This is thus an attractive approach in fields such as cancer treatment and amyloid clearance where there is still a fair degree of uncertainty in the differences between animal models and human patients, and trials that accidentally cause harm are rare but not unheard of. The ability to stop a treatment immediately if results are unexpected is very helpful for all involved.

In recent years researchers have been making progress in the development of useful amyloid antibodies capable of instructing the immune system to clear the amyloid β that is associated with Alzheimer's disease. To take a broader point of view, this is an important class of technology for the near future of rejuvenation therapies after the SENS model. Success against amyloid β using antibodies and passive immunization would mean that success against other forms of extracellular aggregate that contribute to the aging process is also plausible via this methodology. I think that at this point success is just a matter of time, of finding good enough antibodies or related agents, a process that unfortunately isn't turning out to be as rapid or as cheap as anyone would like it to be. In that light it is good that this line of development is attached to a comparatively well-funded field of medical research.

The first paper linked below is a great example of the way in which today's biotechnology is already catching up with the science fiction of a few decades past. Here we have living cells converted into drug manufactories, encapsulated in an implant that secretes the drug at a slow pace, and the whole set in motion to clear some proportion of unwanted metabolic waste so as to slow the pace at which dementia develops - to slow one aspect of aging by consistently removing some fraction of the damage that causes it. All of that engineering is actually the fairly reliable part of the equation, for all that it tends to sound more interesting and impressive than the biochemistry involved in producing antibodies. The challenge in this field is to find a means of control over immune activities that is much, much more effective at clearing unwanted amyloids and other forms of harmful extracellular waste than the present crop of antibodies.

A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml.

In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoforms (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly.

We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.

Comments

Note the antibody technology to develop PFIZERS ponezumab is based on patented ANTISENILIN platform.
ANTISENILIN was developed by Dr. Daniel Chain, son of Dr. Ernst Chain ( nobel price for penicillin, http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/chain-facts.html ) and founder of INTELLECT NEUROSCIENCES.

https://globenewswire.com/news-release/2012/11/28/507983/10013867/en/Intellect-Neurosciences-Announces-New-Findings-Supporting-its-Patented-ANTISENILIN-Platform-Technology-for-the-Treatment-of-Alzheimer-s-Disease.html

Posted by: Karl at March 12th, 2016 1:04 PM

Alzheimer's has got to be more than just beta amyloid. So many antibodies against it have now failed. I remember michael rae arguing that a certain percentage of people in trials were miselected, but even so you'd still expect some people to benefit. I hope the rest of the SENS program isn't as intractable as this area.

Posted by: Jim at March 13th, 2016 6:24 AM

@Jim: just to be clear, it's never been our position that Alzheimer's dementia is caused simply and entirely by Abeta. I actually tried to make that clear in what I think is likely the very comment that you're remembering about the problems with previous trials: by the time someone is already clinically demented, the brain is already suffering from extensive damage over and above Abeta, including pathological tau aggregates and widespread loss of cholinergic neurons.

It's most likely that a large amount of that damage is itself secondary to Abeta, such that if you intervened early enough to clear beta-amyloid from the aging brain you would avert Alzheimer's altogether. It's for this reason, as I mentioned in the comment linked above, that initiating trials in people who are either in the very earliest stages of AD or are even in earlier stages (mild cognitive impairment) and screening for the actual presence of substantial Abeta (the combination of which features is termed "prodromal AD") is the most important of the design improvements in the new trials of beta-amyloid vaccines.

You wrote that "So many antibodies against [Abeta] have now failed [and] a certain percentage of people in trials were miselected ... you'd still expect some people to benefit." As explained in that blog post, a key line of evidence supporting this approach and the so-called "amyloid cascade" hypothesis of AD is exactly that some people have benefited, albeit very modestly: secondary analyses stratifying by stage of disease and neuropathology burden find small decelerations in the trajectory of the disease in early-stage and amyloid-burdened subjects. Before the early trials of AN-1792 were abandoned as a result of ~6% of the immunized patients developed meningoencephalitis, the subgroup of subjects with the highest titers of anti-Abeta antibodies appeared to have an even more substantial slowing of the disease. But, again, we already know from other studies that early-stage AD and even MCI are really too late in the disease process to expect beta-amyloid vaccines to prevent dementia when administered as a monotherapy.

And, of course, even if the "amyloid cascade" is wrong and one of the other neurodegenerative aging lesions riddling the aging and especially AD brain is the primary etiological as well as proximately causal driver of AD dementia, we'll still need to remove Abeta from the AD brain. Indeed, even absence of the disproportionate and early burden of AD that marks a brain on its way to a diagnosis of AD — and even after clearing Abeta out of the aging brain with rejuvenation biotechnology — smaller amounts of malformed tau and other extracellular and intracellular aggregates will continue to accumulate in the aging brain due to other aging processes, so such people would continue to suffer with other, rarer forms of dementia until these forms of damage, too, are removed or repaired.

But they would happen at significantly later ages, both because they would not be accelerated by Abeta and because there are no "pure" age-related dementias: Alzheimer's patients have microinfarcts and white matter lesions that are the key drivers of vascular dementia, and Lewy bodies which are key drivers of Lewy body dementia (LBD) — and vice versa. So keeping well ahead of Abeta would also delay clinical onset of LBD, frontotemporal dementia, most cases of vascular dementia, etc. But we will only eliminate age-related dementia once we clear out all the cellular and molecular damage of aging from the aging brain – and do so while people's brains are still sufficiently intact to be rescued, and then periodically "wash, rinse, and repeat."

Fortunately, work in all of these areas continues apace. Immunotherapies are now being tested to Clinical trials of immunotherapies to clear Lewy bodies from the brain are now underway; early trials are underway with one tau-clearing immunotherapy from AbbVie and C2N and another passive tau vaccine from AC Immune and Johnson & Johnson/Janssen; and as Dr. Jean Hébert highlighted the other day in a comment on FightAging!, earlier-stage research continues to advance toward true neuronal replacement therapy. (You can see Dr. Hébert presenting some of his own work on a strategy for neuronal replacement at Rejuvenation Biotechnology 2014).

As Dr. Hébert said in his comment, "The question remains, when? Certainly, a concerted effort by neuroscientists, engineers, and physicians with the right financial backing would accelerate achieving this goal." Such, of course, is true of the entire spectrum of rejuvenation biotechnologies; at SENS Research Foundation, we focus on those that are being neglected by others, applying critical-path analysis to ensure that we are not over and over again caught in a situation where individual therapies that are otherwise ready for prime time fail when given in isolation.

Posted by: Michael at March 13th, 2016 1:36 PM

Thanks for the comprehensive reply Micheal. Now i'm wondering if you can't just give healthy aged volunteers abeta antibodies to see if they have a lower incidence of alzhiemers?

Posted by: Jim at March 14th, 2016 10:34 AM

Sure ... if you can convince a drug company to recruit several thousand normal fifty-year-olds who are willing to come in, undergo a PET scan to check out their brain amyloid burden, then follow up once a month for intravenous injection, a periodic followup PET, bloodwork, etc, for 2-3 decades ... pay for the trial ... and convince several regional clinical centers' IRBs and the FDA that subjecting ostensibly healthy low-risk individuals to a completely unproven experimental therapy for a substantial fraction of their remaining life expectancy is ethically acceptable.

Then we'll find out if it works around 2045.

Posted by: Michael at March 14th, 2016 12:32 PM

Well I was thinking more along the lines of creating some Immusoft style plasma cells producing abeta antibodies and giving them to people in Colombia via some company like BioViva.

Posted by: Jim at March 14th, 2016 5:13 PM

Michael, thank you very much for your input. Reason and many others (including me) are fully aware that the current biggest problem is regulation because it drives up cost infinitely. I fully understand that the safety of new interventions is important but there is not a single study on PubMed that evaluates how many people have died because new interventions have not been made available to them or could not leave research labs due to extreme regulation. Therefore I fully agree with Jim. Why not offer these new therapies offshore or in less regulated countries? We are free human beings and as long as potential volunteers are fully aware of the risk, I see no problem.

Posted by: Waverunner at March 15th, 2016 8:20 AM

I guess the real problem here is the lack of a reliable diagnostic tool for determining if people are 'pre-Alzheimers'. I am aware that researchers are working on these, but I don't know how close to reality they are?

Posted by: Jim at March 16th, 2016 12:47 AM

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