Improving Amyloid-Targeting Antibodies for Immunotherapy

In this research, partly funded by the SENS Research Foundation, the authors investigate improvements to one type of immunotherapy aimed at clearance of amyloid. Amyloids of numerous types build up in tissues with aging to cause harm and disrupt normal function, including the amyloid β associated with Alzheimer's disease and the transthyretin amyloid implicated in heart failure. Efficient means of clearing amyloid must be a part of any future toolkit of rejuvenation therapies, as its presence is one of the noteworthy differences between old tissue and young tissue:

Alzheimer's disease (AD) is the most common of ~30 amyloid disorders that are currently incurable and often fatal. These diseases involve the extracellular self aggregation of a peptide or protein that forms amyloid deposits on organs. AD is a particularly complex disease since it involves the aberrant aggregation of amyloid β peptides (Aβ) and the microtuble-associated tau protein. Other debilitating amyloid disorders, are caused by mutant and wild-type forms of a blood transport protein transthyretin (TTR) that primarily deposit in the heart and/or nerves.

Passive vaccination with humanized anti-amyloid monoclonal antibodies (mAbs) is a primary immunotherapeutic approach for amyloid diseases. A recent novel therapeutic approach for AD has been to boost a patient's pool of amyloid-reactive IgGs using human intravenous immunoglobulin (IVIg). IVIg contains a diverse repertoire of pooled polyclonal human IgGs (pAbs), including anti-amyloid IgGs, from plasmas of thousands of normal individuals. Anti-amyloid pAbs isolated from normal human blood have demonstrated therapeutic potential not only for AD but for other amyloid diseases.

Recently, IVIg was tested in a 18-month phase 3 clinical trial for mild to moderate AD. The antibody did not meet its primary endpoints, but subgroup analysis indicated that IVIg had a slight beneficial effect for AD patients that were ApoE4 carriers and had moderate disease. Presumably, IVIg's ineffectiveness may have been because its anti-amyloid activity was not potent enough, and patients may have benefited more from an IVIg-like preparation that had enhanced activity. However, the development of a more viable and potent therapeutic reagent than IVIg has been hampered by our current poor understanding on its anti-amyloid activity.

We now report the following finding on pAb conformer's binding to amyloidogenic aggregates: pAb aggregates have greater activity than monomers (high molecular weight (HMW) species > dimers > monomers). Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg) had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of IVIg IgGs. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Our findings strongly indicate that an IgG's anti-amyloid activity is enhanced when they aggregate (Dimers and HMW species), and is an intrinsic property that likely has physiological and clinical significance.



Do we expect that taking out amyloids would actually improve the brain, in the sense of improving cognition (say)? Or would taking out amyloids stop the damage from accumulating further?

Posted by: Daniel Lemire at September 18th, 2015 8:10 AM

@Daniel Lamire: Some of both. The later stages of amyloidosis conditions involve harms that are caused by amyloid and which are not going to be immediately fixed by removing them, such as death of normally long-lived cell populations with low replacement rates. Some of the harms are ongoing and require the presence of amyloid, such as disrupted cellular and tissue function that doesn't rise to the level of cell death.

In the case of treatment starting before pathology becomes severe you don't have to worry about other damage too much. But for treating people who are in late stages of disease, you do.

Posted by: Reason at September 18th, 2015 11:06 AM

Perhaps related is the blood-brain-barrier (BBB) role in clearing amyloid.
It appears that down-regulating the occludin and claudin-5 proteins makes the BBB junctions more permeable to amyloid-beta, increasing clearance ---

"Autoregulated paracellular clearance of amyloid-β across the BBB"

This may be related to findings that ultrasound can improve Alzheimer's --
"Experimental ultrasound treatment targets Alzheimer's brain plaque"

And, that ultrasound reduces occludin and claudin-5 --
"Mechanism of low-frequency ultrasound in opening blood-tumor barrier by tight junction"

"Utilizing Ultrasound to Transiently Increase BBB Permeability, Modulate of the Tight Junction Proteins, and Alter Cytoskeletal Structure"

Posted by: Lou Pagnucco at September 18th, 2015 1:29 PM

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