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Are Monoclonal Antibodies Sufficient to Prevent and Treat Alzheimer’s Disease? Here’s the Surprise Answer.
So far, none of the monoclonal antibodies (MABs) that target amyloid-beta (Abeta) to prevent or treat Alzheimer’s disease (AD) have succeeded in clinical trials.
The more prominent MABs for use against AD include solanezumab (Eli Lilly), BAN2401 (Biogen, Eisai), aducanumab (Biogen), gantenerumab (Chugai, Hoffmann La-Roche), and crenezumab (AC Immune, Genentech, Hoffmann La-Roche).
These MABs target Abeta monomers and aggregates, with the sequence of Abeta aggregation occurring roughly as follows: soluble Abeta monomers → soluble Abeta oligomers (consisting of two or more monomers) → soluble Abeta protofibrils (large Abeta oligomers) → insoluble Abeta fibrils → insoluble Abeta plaques. Both Abeta oligomers and Abeta plaques play a role in neuronal dysfunction in AD.
Aggregates of Abeta 42, a peptide consisting of 42 amino acids, are located predominantly in brain parenchyma (which consists of neurons and glia cells). Abeta 40 is located predominantly in the brain’s blood vessels.
Since MABs for AD recognize different epitopes of Abeta, the anti-Abeta activity of one such MAB is distinct from another.
Solanezumab, for example, recognizes soluble monomeric Abeta. BAN2401 selectively binds soluble Abeta protofibrils. Aducanumab binds to and clears insoluble Abeta plaques. Gantenerumab also acts to disassemble and degrade insoluble Abeta plaques; it also may inhibit synaptic dysfunction mediated by small Abeta oligomers. Crenezumab targets Abeta monomers and soluble and insoluble aggregates of Abeta; it also promotes disaggregation of Abeta plaques.
About MABs and other drugs in clinical trials for AD, Science reported in 2017: “No significant new drug for Alzheimer’s has been approved in the past 14 years, despite massively expensive trials aimed at tackling the disease. The pipeline has been littered with big failures, which have come in a steady drumbeat of defeat and discouragement.”
Given this grim setting, the most important question to be asked of AD research at the moment is this: Why has no biopharmaceutical company been able to develop an effective, disease-modifying drug to prevent or treat AD? The answer likely has to do with the increasingly evident mismatch between the monotherapeutic capabilities of such drugs–as in monoclonal antibodies for AD that singularly target Abeta–and the complexity of the AD-related disease process. There is in fact growing expert opinion in the scientific literature that monotherapy is not up to the task.
For example, in 2011 scientists from the Salk Institute for Biological Studies, the Research Institute of Pharmaceutical Sciences at Musashino University in Japan, the Molecular Neurosciences Department at the Scripps Research Institute, and the Laboratorium für Physikalische Chemie in Switzerland reported in the science journal, PLoS One: “[T]he currently most widely used approach to drug discovery is to identify a single molecular target and then to make a drug that alters this target. Unfortunately, drugs for AD that were developed through this approach have all failed in clinical trials, perhaps because one target is not sufficient or because the targets are also critical for normal brain function so that their inactivation results in toxicity.” In 2014, a review of AD-related drug design reported in Current Neuropharmacology: “Alzheimer’s disease is a complex neurodegenerative disorder with a multifaceted pathogenesis. So far, the therapeutic paradigm ‘one-compound-one-target’ has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable.” And in 2015, researchers reported in the British Journal of Pharmacology: “Alzheimer’s disease is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies… This may explain why it is currently widely accepted that a more effective therapy for AD would result from multifunctional drugs, affecting more than one brain target involved in the disease pathology.”
This analysis likely explains the “steady drumbeat of defeat” of an entire class of MABs for AD that have been developed and tested by world-class biopharmaceutical companies for the past twenty years. Given the apparent futility of the “one compound-one target” model of biopharmaceuticals as applied to AD, it might be time to combine the high-specificity, high-affinity monotargeting of MABs with a mixture of pleiotropic (multitargeting) natural compounds so as to finally activate a pleiotropic strategy against a multidimensional disease process.
The idea would be for certain biopharmaceutical agents to perform core treatment functions, such as the reported ability of Biogen’s aducanumab to clear insoluble Abeta plaques from the brain, while a carefully designed mixture of pleiotropic compounds, therapeutically speaking, would diffusely target almost everything else. This would include the mechanistic capabilities to prevent vasogenic edema and microhemorrhage in the brain that to date have complicated the clinical trials involving MABs that can disaggregate and clear insoluble Abeta plaques.
This would involve resolving endothelial cell dysfunction, blood-brain barrier disruption, and Abeta 40 deposits in cerebral blood vessels as underlying pathogenic elements of cerebral amyloid angiopathy (CAA), which likely underlies both edema and microhemorrhage in the brain as a consequence of certain MABs for AD.
Because a carefully designed mixture of pleiotropic compounds also would bind to virtually all toxic species of Abeta, in addition to reducing the production of Abeta in the first place, such a mixture would significantly broaden the Abeta-targeting capabilities of any MAB for AD.
About reducing production of Abeta, the ingredients of the same pleiotropic mixture have been shown to enhance the proteolytic activity of alpha secretase (ADAM10) and its neuroprotective cleavage product, sAPPalpha, while also inhibiting the Abeta-generating activity of beta-secretase (BACE1).
The compounds that comprise the mixture to which I am referring also have been shown to inhibit Abeta aggregation, reduce Abeta toxicity, enhance Abeta clearance, improve synaptic function, reduce tau hyperphosphorylation, reduce tau aggregation, enhance tau clearance, and reduce oxidative stress and aberrant neuroinflammation.
The same compounds also have been shown to favorably modify many other AD-relevant biological processes, including increasing the activity of neprilysin, which is a key amyloid-degrading enzyme. And this same mixture of compounds would be ideal for years or decades of non-toxic post-MAB maintenance therapy.
Overall, the mixture of pleiotropic compounds would enhance the safety and therapeutic performance of virtually any MAB for AD, and the combination MAB/pleiotropic mixture would permit biopharmaceutical companies that have terminated attempts to treat mild to moderate AD to revisit those efforts with a far-better likelihood of success.
The same pleiotropic mixture also could be applied to tau-targeting drugs to significantly enhance the safety and effectiveness of those efforts as well.
The answer to the question posed by the title of this piece is that MABs by themselves are probably not sufficient to prevent or treat AD, and that biopharmaceutical companies would do better to import pleiotropic capabilities with additive and synergistic benefits when combined with the narrower targeting MABs, leading for the first time to a disease-modifying capability to safely and effectively prevent and treat AD.
Howard Friel is author with Sally Frautschy of A Paradigm Shift to Prevent and Treat Alzheimer’s Disease: From Monotargeting Pharmaceuticals to Pleiotropic Plant Polyphenols (Academic Press/Elsevier, August 2017). The mechanistic capabilities of some elements of the mixture of pleiotropic compounds referenced above are presented in that book.
Disclosure: Howard Friel is inventor and original assignee of a provisional patent application with the USPTO, titled: “A mixture of pleiotropic compounds to help prevent and treat Alzheimer’s disease (AD) in combination with monoclonal antibodies for use against AD.” Friel has developed an analytical framework that permits the development of optimal combinations of pleiotropic mixtures with MABs for AD and other chronic disease. He can be reached at email@example.com
For a limited time you can download a chapter on “Monotargeting versus Multitargeting” from A Paradigm Shift to Prevent and Treat Alzheimer’s Disease, below:
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