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.
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.
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.