Title : Antibody-proteases as a generation of unique biomarkers, potential targets and translational tools towards design-driven bio- and chemical engineering and personalized and precision medical practice
Abstract:
Biomarkers and targets as being crucial parts of the ligand-receptor tandems have induced an impulse to prompt the development of an upgraded concept of the targeted therapy. 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 have been described in autoimmune manifestations for more than a decade in a variety of disorders. 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 explanation for the origin of abzymes in pathological conditions is based on idiotypic network and exacerbated self-recognition in autoimmune disease 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 identified in autoimmune conditions, was first registered in patients and persons-at-risk at the subclinical stages prior to the clinical illness. And the activity of the Ab-proteases revealed significant correlation with scales of autoimmune inflammation and the disability of the patients as well. Moreover, sequence-specific Ab-proteases have proved to be greatly informative and thus valuable as biomarkers to monitor chronic autoimmune diseases at both subclinical and clinical stages! Characterization of the mechanisms of catalytic antibodies has provided fundamental insights into the evolution of binding and catalytic functions in nature. The field has also had a broader influence on bio- and chemical engineering – biologists and chemists are increasingly incorporating the biological idea of molecular diversity into their efforts to synthesize molecules with new functions. Thus the field of antibody catalysis has come full circle, starting with the realization that immunological diversity can be programmed to generate new chemical functions, and ending with the understanding that antibodies all along have had a remarkable catalytic role. So the primary translational potential of abzymes 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 architecture. By changing sequence specificity one may reach reduction of a density of the negative proteolytic effects within the damaged tissue and thus minimizing scales of autoimmune inflammation. In this context, targeted Ab-mediated proteolysis could be applied to isolate from Ig molecules catalytic domains directed against autoaggressive epitopes or domains containing segments to exert proteolytic activity and then be used as therapeutic modifiers. An important goal in the design of catalytic antibodies is the development of general rules relating hapten structure to the corresponding catalytic groups in the antibody combining site. 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 thus an important goal in the design of catalytic antibodies is the development of general rules relating hapten structure to the corresponding catalytic groups in the antibody combining site. In this sense, Ab-proteases can be reprogrammed to suit the standards of healthcare standards. Or could be designed for the development of principally new catalysts with no natural counterparts. The translational research of abzymes is a brand-new field of enzyme engineering, which provides people with a reasonable way to design proteins suitable for market needs, that is, artificially design and produce enzymes. Utilizing the high specificity of the antibody produced by the immune system, a series of highly specific abzymes can be obtained. The immobilization of abzyme has been successful and will greatly promote the process of industrialization. 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. In the future, catalytic antibodies may provide a new repertoire of tailor-made, enzyme-like, catalysts with possible applications in biology, medicine, and biotechnology. So 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.
