Title : Antibody-proteases as natural and translational tools of the next step generation to be applied for biodesign-driven biotech and personalized and precision medical practice
Abstract:
Biomarkers may aid in diagnosing disease, predicting disease onset, and selecting appropriate therapy. Meanwhile, antibody (Ab)-based proteomics play a very important role in biomarker discovery and validation, facilitating the high-throughput evaluation of candidate markers.
An important aspect in the validation of biomarkers and/or targets discovered in such a heterogeneous source of proteins as blood is their adequate biological validation through the understanding of their exact role in relevant pathophysiological processes. In this respect, proteomics technologies enabling pathway analysis, such as mass cytometry, bring great hope for future clinical applications.
Ab-based technologies remain the main solution to address this challenge since they reach higher sensitivity. Because Ab-related function by binding specific antigens (Ags), attempts to identify Ab biomarkers have so far involved using Ags to capture Abs that are overproduced in disease.
Along with canonical Abs, some of the families proven to occur are Abs possessing with catalytic (proteolytic) activity (catAbs or abzymes) and thus to belong to Abs with a feature of functionality! In this context, Abs against myelin basic protein/MBP and cardiac myosin (CM) endowing with proteolytic activity (Ab-proteases with functionality) are of great value to monitor autoimmune demyelination and/or autoimmune myocarditis (AIM) to illustrate the evolution of multiple sclerosis (MS) and myocardial autoimmunity conditions, respectively.
Anti-MBP autoAbs from MS and AIM patients exhibit specific proteolytic cleavage of MBP and CM, respectively, which, in turn, markedly differed between: (i) MS and AIM patients and healthy controls; (ii) different clinical MS and/or AIM courses; (iii) EDSS scales of demyelination and cardiac autoimmunity scores, on to correlate with the disability of MS and/or AIM patients to predict the transformation prior to changes of the clinical courses.
Ab-mediated proteolysis of MBP and CM was shown to be sequence-specific whilst demonstrating sites of preferential proteolysis to be located within the immunodominant regions of MBP and CM, respectively.
The activity of MBP- and CM-targeted Ab-proteases was first registered at the subclinical stages 1-3 years prior to the clinical stages of the disorders (preillness conditions) of both MS and AIM. About 15-25% of the direct MS- and AIM-related relatives were seropositive for low-active Ab-proteases from which 22-28% of the seropositive relatives established were being monitored for 2-3 years whilst demonstrating a stable growth of the Ab-associated proteolytic activity. Moreover, some of the low-active Ab-proteases in the compromized persons at MS- and/or AIM-related risks (at the subclinical stages), and primary clinical and MRT manifestations observed were coincided with the activity to have its mid-level reached.
As we might see, Abs can assist in the determination of staging, grading, and primary therapy selection, and after diagnosis, for monitoring therapy, additional therapy selection, or monitoring recurrent diseases. In this sense, the activity of Ab-proteases in combination with the sequence-specificity would confirm a high subclinical and predictive value of the tools as applicable for personalized monitoring protocols.
And the primary translational potential of this knowledge being rooted in the rational design of the new Ab-driven therapeutics and based on principles of natural and artificial biocatalysts, has started up exploiting the role of the key pathways in influencing disease. And improvements in biodesign-inspired engineering technologies, combined with bioinformatics-driven algorithms suggesting that catalytic Abs (Ab-proteases, in this cases) being natural or design-driven ones, play a valuable role in the living systems, have opened the way to new applications for those proteins as translational tools.
The last years have seen a major upturn in the fortune of therapeutic Abs, approved for clinical use. Ab-based therapeutics have entered the center stage of drug discovery as a result of a major shift in focus of many biopharma companies. This success, for instance, can be related to the engineering of mAbs into chimeric Abs, or humanized ones, which have had a major effect on immunogenicity, effector function and half-life. Emerging have created a vast range of novel, Ab-based therapeutics, which specifically target biomarkers of disease in this sense, 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. The latter would suit the needs of the body metabolism or could be designed for the development of principally new catalysts with no natural counterparts So, Ab-protease-driven engineering would offer the ability to enhance or alter their sequence-specific activity to expand the clinical utility of the absolutely new tools.
In this context, immunotherapy is emerging as a promising route towards the Ab-mediated selective targeting, and future developments in intracellular Ab technology may enhance the therapeutic potential of such Ab-derived therapies. So, targeted Ab-mediated proteolysis could be applied to isolate from Ig molecules catalytic domains directed against immunogenic autoepitopes or domains containing segments to exert targeted proteolytic activity.
Meanwhile, the next important step in the direction of the innovations-based approach should be their early adoption in clinics for future medical interventions! And we have made the first step in this direction to improve the management of chronic autoimmune conditions.
The field of therapeutic Abs has become a dominant force in the therapeutics market. In the future, studies evaluating synergistic effects of catalytic Abs will greatly benefit the further development of Ab therapeutics. And we might believe and expect that autoimmune diseases are promisingly suited and evidence-based models to support the above-mentioned strategy because of the rapidly expanding Hi-Tech innovations and design-inspired translational resources, including ABZYMES technologies and the development of biomarkers and the potential modifying treatments.
Furthermore, the identification of novel biomarkers may improve the efficacy and specificity of Ab-based therapy for human diseases.
