Wednesday, December 4, 2024
12/4/2024
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.
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