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Principal Investigator: Xin Ge
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $390,000
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
As important signaling molecules, proteases precisely control a wide variety of physiological processes both in
health and in diseases, and thus represent one of the largest families of pharmaceutical targets. Despite decades
of intensive efforts, conventional drug discovery strategies have only achieved a limited success by targeting a
small fraction of all therapeutically relevant proteases. It is because small-molecule inhibitors are often lack of
specificity and/or appropriate pharmacokinetic properties required for effective and safe protease-based therapy.
In these aspects, monoclonal antibodies (mAbs) are emerging as attractive alternatives with significant
advantages such as high selectivity, long serum half-life, potential to cross the blood-brain barrier, and as
inducible prodrugs. Since the invention of hybridoma technology, tremendous progress has been made in mAb
discovery and engineering. However, routine discovery of protease-inhibiting mAbs is still a considerable
challenge in general, due to the incompatibility of human antibody paratope for enzyme inhibition, and lack of
functional high-throughput screening methods. My laboratory has been committed to the development of
streamlined methodologies that facilitate the generation of therapeutic mAbs as safe and effective protease
inhibitors. Over the past five years, we have made significant progress, and established a series of novel
technologies, including camelid-inspired convex paratope human antibody libraries, and inhibition-based rather
than binding-based selection/screening methods. Combining these enabling approaches, we discovered,
characterized, and optimized panels of potent and specific mAbs inhibiting numerous proteases of biomedical
importance. Furthermore, our protease inhibitory mAbs have shown significant therapeutic efficacy in mouse
models of cancers, neuropathic pains, obesity, and stroke. By overcoming longstanding challenges, these
achievements have opened the exciting opportunity. In the next five years, we will extend our powerful
technologies to many other well-documented proteases, of which therapeutic inhibitors are urgently needed.
Furthermore, we will develop additional technologies to achieve unique and therapy-desirable features: (1)
function-specific (substrate-dependent) inhibition, (2) broad-spectrum inhibition on a group of proteases, and (3)
epitope-specific inhibition by rational design. Overall, it has been estimated that proteases account for 5-10%
of all drug targets have been studied for pharmaceutical development. The completion of proposed research will
unambiguously advance therapeutic mAb developments targeting biomedically important proteases, e.g. against
the present danger, SARS-CoV-2, by inhibiting TMPRSS2 (type II transmembrane serine protease) as a broad
neutralization approach without the unwanted antibody-dependent enhancement.
Terms: <Acceleration><Achievement><Achievement Attainment><Antibodies><Antibody Binding Sites><Antibody-Dependent Enhancement><Antigenic Determinants><Antiproteases><Apoplexy><BBB crossing><Binding><Binding Determinants><Blood Serum><Brain Vascular Accident><Cancer Model><CancerModel><Cancers><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical Treatment Moab><Development><Disease><Disorder><Drug Kinetics><Drug Precursors><Drug Targeting><Endopeptidase Inhibitors><Engineering><Enzyme Inhibition><Epitheliasin Gene><Epitopes><Esteroproteases><Family><Generations><Half-Life><Health><High Throughput Assay><Human><Hybridomas><Laboratories><MAb Therapeutics><Malignant Neoplasms><Malignant Tumor><Membrane><Methodology><Methods><Modern Man><Molecular Interaction><Monoclonal Antibodies><Obesity><Organism-Level Process><Organismal Process><PRSS10><Paratopes><Pathogenesis><Pathology><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Pharmaceutical Agent><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Physiologic Processes><Physiological Processes><Pro-Drugs><Prodrugs><Property><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteolytic Enzymes><Public Health><Research><SARS-CoV-2 inhibitor><Series><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Serum><Severe acute respiratory syndrome coronavirus 2 inhibitor><Signaling Molecule><Specificity><Stroke><TMPRSS2><TMPRSS2 gene><Technology><Therapeutic><Therapeutic Intervention><Therapeutic Monoclonal Antibodies><Treatment Efficacy><Viral Diseases><Virus Diseases><adiposity><antibody combining site><antibody inhibitor><antibody libraries><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><blood-brain barrier crossing><bloodbrain barrier crossing><brain attack><cerebral vascular accident><cerebrovascular accident><corpulence><developmental><drug discovery><high throughput screening><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibiting antibody><inhibitor drug><inhibitor therapeutic><inhibitor therapy><intervention efficacy><intervention therapy><invention><mAbs><malignancy><membrane structure><monoclonal Abs><monoclonal antibody drugs><mouse model><murine model><neoplasm/cancer><neuropathic pain><new technology><novel technologies><painful neuropathy><pharmaceutical><programs><rational design><screening><screenings><small molecular inhibitor><small molecule inhibitor><stroked><strokes><success><therapeutic agent development><therapeutic development><therapeutic efficacy><therapeutic mAbs><therapy efficacy><viral infection><virus infection><virus-induced disease>