Title : Abzymes (catalytic antibodies) as a Generation of Unique Biomarkers, Biocatalysts, Potential Targets and Translational Tools towards Nanodesign-driven Antibody Engineering and Precision Medical Practice: From magic bullet to precision weapon
Abstract:
Antibodies (Abs) endowed with catalytic (enzymatic) properties (DNA- and RNA-hydrolizing, proteolytic ones and others) have been isolated from the serum of patients with different chronic diseases. Disease-associated abzymes may have been "induced" by the Ag implicated in the disease and might precisely control a wide variety of physiological processes and thus are important drug targets. Regarding abzymes, their phenomenal property mentioned is buried in the Fab-fragment of the Ig molecule and is appearing to sound as a functional (Ag-binding and enzymatic) property of the Ab molecule.
The primary translational potential of abzymes (Ab-proteases, predominantly) and thus of this knowledge is in the rational design of new therapeutics to exploit the role of the key pathways in influencing disease. The latter is a brand-new field of chemical engineering. For instance, abzymes can selectively cleave the peptide bonds of the virus coat protein, thereby preventing the virus from binding to target cells.
Selective chemical modification of abzymes can be used to create novel proteins, particularly enzymes and Abs, with altered specificities and catalytic activities. Abzymes can be chemically 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 pro-teolysis could thus be applied to isolate from Ig molecules catalytic domains containing seg-ments to exert proteolytic activity and then be used as therapeutic modifiers. Ab-based thera-peutics have entered the central stage of drug discovery as a result of a major shift in focus of many biotech and biopharma companies. Modification strategies should soon yield a wide spectrum of novel biomolecules whose activities are optimized for therapeutic applications.
Catalytic Abs can be artificially engineered, or elicited by immunizations. Their mechanisms of action include nucleophilic catalysis, induction of conformational strain, coordination with metal ions, and stabilization of transition states. The latter means that catalytic Abs made it feasible to develop new biocatalysts, which are widely used in chemistry, biology, life sciences and medicine.
Abzymes can be programmed and reprogrammed to suit the needs of the body metabolism. Or biodesigned for the development of principally new catalysts with no natural counterparts.
A catalytic antibody has multiple functions compared with a monoclonal antibody (Mab) because it possesses unique features to digest antigens enzymatically. Therefore, many catalytic Abs, including their subunits, are developed. Moreover, several evidence-based cases demonstrate the potential for a new method of creating catalytic Abs from the corresponding monoclonal Abs.
Recent applications of abzymes with clinical significance include the conversion of cocaine to a non-psychoactive form, the degradation of nicotine, activation of prodrugs for targeted chemotherapy, protection from ultraviolet radiation, inhibition of HIV infectivity, and the destruction of aggregates of β-amyloid implicated in Alzheimer's disease.
Of tremendous value are Ab-proteases directly affecting remodeling of tissues. By changing sequence specificity one may reach reduction of a density of the negative proteolytic effects with-in the myelin sheath and thus minimizing scales of demyelination.
The immobilization of abzyme has been successful and will greatly promote the process of industrialization. Thus, abzyme study has an important value in theory and practice for biology, chemistry and medicine. Further studies on 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 pre-vent the disorder at subclinical stages in persons-at-risks to secure the efficacy of preventive, prophylactic and restorative manipulations.
