Today's paper is authored by the Covalent Bioscience science team, and is an overview of the science underlying their catalytic antibody (or catabody) approach to clearing amyloids of various sorts from aged tissues. It isn't open access, unfortunately, but the paper is, as usual, available to the world thanks to the ethical civil disobedience of the Sci-Hub team. Amyloids are solid deposits formed by one of the very small number of proteins in the body that can become misfolded or otherwise altered in ways that cause other molecules of the same protein to also alter in the same way. These errant proteins aggregate into structures that are surrounded by a halo of damaging biochemistry that degrades cell function or kills cells, and, once started, this aggregation can spread through tissues over time.
The Covalent Bioscience team believes that natural catalytic antibodies are the primary way by which our biochemistry tries to clear out amyloids - but evidently, amyloid generation overwhelms this mechanism as aging progresses. Catalytic antibodies act as catalysts for reactions that break down amyloids. Because one catalytic antibody can do this for many amyloid molecules, they have the potential to be a highly efficient basis for therapy. The process of development is to identify natural catalytic antibodies specific to a target amyloid, improve on their structure and function, establish ways to manufacture these improved versions at scale, and then deliver them in large numbers as a therapy.
Covalent Bioscience is a fair way into the preclinical development phase of this project for catabodies targeting transthyretin amyloid, a cause of heart disease and other conditions, and the amyloid-β associated with the early stages of Alzheimer's disease. The paper is an interesting read, and recommended if you'd like greater insight into catabodies as a novel form of therapy to remove misfolded proteins.
Thirty seven proteins misfold into particulate and soluble aggregates. The misfolding process is accelerated by age-associated metabolic disturbances, for example, increased generation of advanced glycation end products and lipid peroxidation end products. Misfolded self-protein aggregates are a significant cause of aging, exemplified by appearance of lumbar spinal stenosis and carpal tunnel syndrome due to misfolded transthyretin in 40-50% of humans older than 50 years age and cardiac myopathy at a later age. About 15-20% of humans show at least mild cognitive impairment due to Alzheimer disease, thought to be triggered by misfolded amyloid β aggregates starting around age 65 years.
Our studies suggest that specific, constitutively produced catabodies are the primary proteostatic mediators in the blood of humans that destroy the disease-causing misfolded self-protein aggregates. In contrast, text-book portrayals of humoral immunity focus on IgG class antibodies that mature within days to weeks following stimulation with the foreign (non-self) antigens. The observed catabody properties display clear departures from classical immunology rules. Our perspective of constitutive catabodies specific for the disease-causing misfolded self-proteins is conditioned by the organismal survival requirements during Darwinian evolution. As the problem of protein misfolding is an intrinsic organismal weakness that is even more ancient than the threat of extinction due to the external microbes, eliminating amyloid disease at an early age can safely be assumed to serve as a strong selective pressure for evolving a constitutive immune defense against the misfolded proteins, i.e., the specific germline gene-encoded catabodies.
Catabodies outperformed ordinary antibodies in two significant aspects. By definition, a catalyst is re-used again and again to inactivate and destroy large quantities of the harmful target. First, we proved in side-by-side tests that a small catabody amount permanently removes the target with efficacy far superior to an ordinary antibody (which can only bind reversibly to the target on a 1:1 basis). Human IgM catabodies selectively destroyed misfolded but not normally folded transthyretin into non-aggregable fragments without potential for initiating or sustaining systemic amyloid disease. Likewise, human catabody fragments digested amyloid-β into non-toxic and non-aggregable fragments without potential for initiating or sustaining Alzheimer's disease. Second, while ordinary antibodies form stable immune complexes that inevitably induce inflammation, the catabody-substrate complexes are too transient to activate inflammatory cells. Catabodies are particularly valuable if large amounts of the target are to be removed, as is required for effectively treating amyloid diseases. In such diseases, the inflammatory damage induced by an ordinary antibody will be so great that the favorable amyloid removal effect is essentially canceled out.
Many things go wrong in human aging, and if humans live long enough something or the other invariably goes wrong. The phenomenon of constitutive catabodies is not limited to the misfolded transthyretin and amyloid-β disease-causing proteins. We identified catabodies to additional amyloid-forming proteins (misfolded tau, immunoglobulin light chains). Indeed, the value of the Catabody Platform likely extends to virtually any of the innumerable proteins that contribute directly or indirectly in disease and damage to various organ systems in aging, including the protein targets involved in increased susceptibility of humans to microbial infections and autoimmune, neurological, cardiovascular, and neoplastic disease. Specific catabodies can be generated on-demand either from the constitutive or immunogen-induced antibody repertoires.
We subscribe to the view that preventing age-associated dysfunctional processes before they have caused substantial damage is the preferred medical strategy for prolonging healthy lives. Prophylactic vaccines against infectious microbes have improved public health enormously. We suggest that lessons from our vaccine approach for microbes are valuable in developing safe and efficacious anti-amyloid longevity vaccines. The central requirements for such longevity vaccines is inducing long-lasting synthesis of catabodies with epitope specificity suitable for destroying the disease-causing misfolded self-proteins without interfering in the physiological functions of the properly folded conformations of these proteins.
Our vision is to bypass the mechanism-based limitations of ordinary antibodies and vaccines for fulfilling important unmet medical needs: (a) Intrinsic inability of ordinary antibodies to bind the target with stoichiometry greater than 1:1; (b) The inevitable activation of inflammatory pathways upon antibody-target binding that not only cause unacceptable side effects but also reduce efficacy through functional antagonism pathways, as seen in numerous failed trials of antibodies in patients with Alzheimer's disease; and (c) Failure of ordinary vaccines to induce protective immunity to certain protein epitopes because of immune check-point suppressor mechanisms.
The lead products generated from our Catabody Platform have not shown these limitations. Success in early stage human trials of any one lead catabody will make the entire underlying technology more attractive, thus encouraging development of additional catabodies and vaccines for new disease targets. For instance, transthyretin amyloid disease and Alzheimer's disease are but 2 of 56 amyloid diseases caused by misfolded proteins. Our findings suggest that destruction of misfolded proteins by catabodies extends beyond the targets described in this article. The Catabody Platform is enabled to utilize both innate immunity and immunogen-induced acquired immunity for generating catabodies to virtually any target protein.