Title : Antibody-proteases as translational tools of the next-step generation to be applied through biodesign-driven translational biotech in personalized and precision neurology practice
Abstract:
Multiple Sclerosis (MS) is a complex neurodegenerative pathology featuring with inflamma-tion, demyelination, and neurodegeneration. Due to the heterogeneity of MS-related clinical and even subclinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients and/or persons-at-risk. Molecular biomarkers which are easily quantifiable, enable individual decisions and are an important step on the way to a personalized therapy, come from the areas of immunology due to the causal pathology-driven mechanisms and can excellently complement other dis-ease characteristics. For a long time, numerous potential biomarkers that provide meaning-ful information related to the development of MS-related pathology, have been identified. But MS continues to be extremely unpredictable, with more unanswered questions than ab-solute certainties, the finding of it seems still a long way off. Therefore, to date, there re-mains no single reliable biomarker that can provide information on the prognosis of MS, distinguish between the different clinical courses of MS, and also predict responses to a spe-cific form of treatment.
Abs against Myelin Basic Protein/MBP endowing with proteolytic activity (Ab-proteases with functionality) are of great value to monitor demyelination to illustrate the evolution of Mul-tiple Sclerosis (MS). Anti-MBP auto Abs from MS patients exhibited sequence-specific proteo-lytic cleavage of MBP, which, in turn, markedly differed between: (i) MS and healthy con-trols; (ii) different clinical MS; (iii) EDSS scales of demyelination scores to correlate with the disability of MS patients to predict the transformation prior to changes of the clinical cours-es. Ab-mediated proteolysis of MBP was shown to be sequence-specific whilst demonstrating five sites of preferential proteolysis to be located within the immunodominant regions of MBP and to fall inside into 5 sequences fixed. Some of the latter (with the highest encephali-togenic properties) were proved to act as a specific inducer of EAE and to be attacked by the MBP-targeted Ab-proteases in MS patients with the most severe (progredient) clinical cours-es. The other ones whilst being less immunogenic happened to be EAE inducers very rare but were shown to be attacked by Ab-proteases in MS patients with moderate (remission-type) clinical courses.
The activity of MBP-targeted Ab-proteases was first registered at the subclinical stages 1-2 years prior to the clinical manifestations of MS. About 24% of the direct MS-related relatives were seropositive for low-active Ab-proteases from which 22-28% of the seropositive rela-tives established were being monitored for 2 years whilst demonstrating a stable growth of the Ab-associated proteolytic activity. Moreover, some of the low-active Ab-proteases in per-sons at MS- related risks (at the subclinical stages), and primary clinical and MRT manifes-tations observed were coincided with the activity to have its mid-level reached. Registration in the evolution of highly immunogenic Ab-proteases would illustrate either risks of trans-formation of subclinical stages into clinical ones, or risks of exacerbations to develop.
The activity of Ab-proteases in combination with the sequence-specificity would confirm a high subclinical and predictive (translational) value of the tools as applicable for personal-ized monitoring protocols. The translational potential of this knowledge is in the rational design of new diagnostic tools and new targeted therapeutics based on principles of artificial biocatalysts and bio design and to exploit the role of the key pathways in influencing disease. The last years have seen a major upturn in the fortune of Therapeutic Abs, approved for clinical use. This success 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. 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 metabo-lism or could be designed for the development of principally new catalysts with no natural counterparts. 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 to suit the neurodegenerative pathology standards.
The dearth of knowledge about the pathology of MS and the clinical variation in MS sub-types makes it implausible to establish a single ideal biomarker which guarantees the full evaluation of the disease. Moreover, there remains a need for a panel of validated bi-omarkers that are capable of predicting and monitoring the efficiency of the growing num-ber of treatment strategies available, with the aim of reducing the recurrence of relapses, and stopping the progression and disability of patients with MS. So, the next important step in the direction of the innovations-based approach should be early adoption of Ab proteases as biomarkers of the next step generation in clinics for future medical interventions! Neuro-degenerative diseases are promisingly suited models for PPM because of the rapidly expand-ing design-driven innovations including ABZYMES Technologies and the development of pa-thology-valuable biomarkers and the potential modifying treatments. And we have made the first step in this direction to improve the management of MS. With advances in our under-standing of Ab-protease functions and properties coupled with improvements in immune and protein engineering we can expect that Ab-protease therapeutics will gain regulatory ap-proval and make significant contributions in healthcare in the near-term.
Further studies on targeted Ab-mediated proteolysis may provide a translational tool for pre-dicting demyelination conditions illustrating the crucial feature of neurodegenerative pathol-ogy, and thus the disability of the MS patients and/or persons-at-risk.
