Title : Antibody-proteases as translational tools of the next-step generation to be applied for biotech, bioindustry and personalized and precision medical practice
Abstract:
Biomarkers as being a part of the ligand-receptor tandems have induced an impulse to prompt the development of an upgraded concept of the targeted therapy. So, the identification, impact and im-plementation of diagnostic, predictive and prognostic biomarkers of the next step generation be-comes the Holy Grail of platforms, algorithms and protocols, which are the crucial for Personalized & Precision Medicine (PPM). High impact of Ab-proteases can be used to monitor both clinical and subclinical courses of chronic autoimmune inflammation in autoimmune thyroiditis (AIT), multiple sclerosis (MS) and autoim-mune myocarditis (AIM) to predict stepwise transformations of the course, starting from the pre-illness and to prognosticate the clinical illness finally. This information can allow to design the al-gorithms for combinatorial (preventive, prophylactic, therapeutic and rehabilitative) treatment, whilst developing unique tools for individually therapy for a number of diseases, such as a group of autoimmune diseases which holds a particular position. Among the best-validated canonical biomarkers are autoimmunity-related ones (including antibod-ies/Abs) to predict and prognosticate risks of the chronification, complications and thus disabling. The latter is so much valuable and important since chronic autoimmune inflammation course is structured to consist from different stages including subclinical and clinical ones. According to classical conception, Abs are specific proteins produced by the immune systems with exclusive function of Ag binding. But Abs against chemically stable analogues modelling the transi-tion states of chemical reaction, can catalyse many different reactions, and were thus called catalyt-ic Abs (catAbs) or abzymes (derived from Ab and enzymes), which thus to belong to Abs with a fea-ture of functionality. Abs endowed with enzymatic properties have been described in human autoimmune manifestations for more than a decade in a variety of disorders. DNA- and RNA-hydrolyzing Abs (DNA and RNA-abzymes) have been isolated from the serum of patients with different systemic autoimmune dis-eases, including systemic erythematosus (SLE) and rheumatoid arthritis (RA). Proteolytic Abs (Ab-proteases) specific for thyroglobulin (Tg), cardiac myosin (CM) and myelin basic protein (MBP) have been reported in patients with autoimmune thyroiditis (AIT), autoimmune myocarditis (AIM) and multiple sclerosis (MS), respectively.
Disease-associated abzymes may have been "induced" by the Ag implicated in the disease. Secondly, the increased occurrence of abzymes in pathology may result from the loss of repressive control over abzyme-producing clones generated spontaneously under physiological conditions. A third explana-tion for the origin of abzymes in pathological conditions is based on idiotypic network and exacer-bated self-recognition in autoimmune disease The abzymes may complement the general alteration of the immune response. In this sense, Ab-proteases as the second stage of the discoveries in the area mentioned, would represent Abs to pro-vide the additional but highly targeted proteolytic effects. It is known that proteases precisely con-trol a wide variety of physiological processes and thus are important drug targets. Meanwhile, canonical autoAbs play neither predictive nor discriminative role to affect the pre-early and/or subclinical stage of autoimmune conditions. So, there is urgently needed for biomarkers, which could clarify pathology (including subclinical one), monitor disease progression, response to treatment, and prognosis in the autoimmune inflammation. Overall, OMICS-related approaches can develop different therapeutic and diagnostic aspects of autoimmune conditions, from biomarker dis-covery to PPM. Regarding abzymes, their phenomenal property mentioned is buried in the Fab-fragment of the Ig molecule and is appearing to sound as a functional property of the Ab molecule. In this sense, Ab-proteases as a significant portion of the big family of abzymes represent Abs endowed with a capaci-ty to provide targeted proteolytic effect. The activity of Ab-proteases being identified in AIM, AIT and MS patients was first registered in the patients and persons-at-risk at the subclinical stages 1-2 years prior to the clinical illness. And the activity of the Ab-proteases revealed significant correlation with scales of autoimmune inflam-mation and the disability of the patients as well. Moreover, sequence-specific Ab-proteases being studied in MS patients and persons-at-risk, have proved to be greatly informative and thus valuable as biomarkers to monitor chronic autoimmune diseases at both subclinical and clinical stages! Therefore, the proposed predictive value of the tar-geted Ab-proteases for the development of the above-mentioned autoimmune disorders is being challenged! So, the activity of Ab-proteases and its dynamics tested would confirm a high subclini-cal and predictive value of the tools as applicable for monitoring protocols! The primary translational potential of abzymes and thus of this knowledge is in the rational design of new therapeutics to exploit the role of the key pathways in influencing disease. Of tremendous value are Ab-proteases directly affecting remodelling of tissues with multilevel architectonics (for instance, myelin or cardiac muscle). By changing sequence specificity one may reach reduction of a density of the negative proteolytic effects within the myelin sheath and thus minimizing scales of demyelination. The traditional goal of Ab engineering is to combine various Ab domains to generate customized Abs that show specialized binding properties, optimal half-lives and desirable effector functions. Abs can be engineered to make proteins of higher affinity or smaller molecular variants that retain or change the functional properties of the original Ab. In this context, targeted Ab-mediated prote-olysis could thus be applied to isolate from Ig molecules catalytic domains directed, in MS human and animal models, against encephalitogenic autoepitopes or domains containing segments to exert proteolytic activity and then be used as therapeutic modifiers. Ab-based therapeutics have entered the central stage of drug discovery as a result of a major shift in focus of many biotech and bio-pharma companies. And as the outcome of the latest initiatives, modified recombinant Abs have been designed to be more cytotoxic to enhance effector functions (bivalent Abs), whilst integrating canonical cytotoxic and upgraded catalysing (proteolytic) features. So, Ab-protease engineering would offer the ability to enhance or alter their sequence-specific activity to expand the clinical util-ity of the absolutely new tools. In this sense, Ab-proteases can be programmed and reprogrammed to suit the requests and standards of regenerative medicine and re-myelination, in particular. In this sense and in terms of PPM, Ab-proteases can be programmed and re-programmed to suit the needs of the body metabolism or could be designed for the development of principally new catalysts with no natural counterparts So, further studies on Ab-mediated MBP degradation and other targeted Ab-mediated proteolysis may provide biomarkers of new generations and thus a supplementary tool for assessing the disease progression and predicting disability of the patients and persons-at-risks. We are now experiencing a Renaissance primarily driven by the design-driven biotechnologies. And the new approach is needed to secure artificial or edited Ab-proteases as unique translational probes to diagnose, to monitor, to control and to treat and rehabilitate autoimmune conditions patients at clinical stages and to prevent the disorder at subclinical stages in persons-at-risks to secure the effi-cacy of preventive, prophylactic and restorative manipulations.
Audience Take Away
- To implement special technologies into the lab practice and to be used the latter for monitoring the autoimmune inflammation
- To get the clinical hospitals re-armed with technologies of the next step generation
