Title : Antibody-proteases as translational biomarkers, targets and potential tools of the next step generation as applicable for design-driven 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 implementation of diagnostic, predictive and prognostic biomarkers of the next step generation becomes the Holy Grail of platforms, algorithms and protocols, which are the crucial for Personalized & Precision Medicine (PPM).
High impact of Ab-proteases is valuable to monitor both clinical and subclinical courses of chronic autoimmune inflammation to predict stepwise transformations of the course, starting from the pre-illness and to prognosticate the clinical illness finally. This information would allow to design algorithms 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 antibodies/Abs) to predict and prognosticate risks of the chronification, complications and thus disabling. 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 transition states of chemical reaction, can catalyse many different reactions, and were thus called catalytic Abs (catAbs) or abzymes (derived from Ab and enzymes), which thus to belong to Abs with a feature of functionality.
Abs endowed with enzymatic properties including DNA- and RNA-hydrolyzing Abs (DNA and RNA-abzymes) and Ab proteases, have been isolated from the serum of patients with different systemic autoimmune conditions. 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 capacity to provide targeted proteolytic effect.
The activity of Ab-proteases was registered in persons-at-risk at the subclinical stages of clinical autoimmune conditions 1-2 years prior to the clinical illness. And their activity revealed significant correlation with scales of autoimmune inflammation and the disability of the patients as well.
The primary translational potential of Ab-proteases 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 proteolysis could thus be applied to isolate from Ig molecules catalytic 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 biopharma 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 utility of the absolutely new tools.
Ab-proteases can be programmed and reprogrammed to suit the needs of the body metabolism or 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. 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 efficacy of preventive, prophylactic and restorative manipulations.
