BISPECIFIC TETHERS (miniBiTs) – A PLATFORM TECHNOLOGY FOR THE TREATMENT OF INFLUENZA INFECTIONS

Influenza is a global public health concern, affecting approximately 1 billion people worldwide each year, resulting in 3-5 million severe cases and 300,000-500,000 reported fatalities, according to the World Health Organization (WHO). Despite the availability of influenza vaccines, their effectiveness has consistently been low over the past decade, with inadequate vaccine coverage, particularly in the United States, where influenza takes a heavy toll every season, impacting public health and economy. Currently available antivirals like oseltamivir and baloxavir are effective when administered very early in infection, reducing the sickness duration by a day or two. However, their efficacy diminishes with delayed administration, highlighting the need for improved influenza therapeutics, especially for severe and later-stage infections. This dissertation presents a platform technology for influenza treatment and demonstrates its versatility in treating other indications such as solid tumors. The proposed technology, a small-molecule based bispecific immune cell tether (miniBiT), can form molecular bridges between target cells and immune effector cells either via the recruitment of endogenous human antibodies or, direct interaction with the immune cell surface receptors in order to mediate killing of the target cells. This dissertation consists of five chapters. Chapter 1 outlines the global influenza burden, its economic impact, discusses influenza virology, and the limitations of currently available medical countermeasures, providing insight into the existing gaps and challenges in influenza treatment. Chapter 2 details the design, synthesis, and preclinical evaluation of a ligand-hapten miniBiT that forms immune complexes with virus particles and infected cells by recruiting endogenous human antibodies. Chapter 3 covers the design, synthesis, and evaluation of a ligand-mFc (monomeric Fc fragment of human IgG1) miniBiT, which forms immune complexes with virus particles and infected cells by directly engaging the immune cell surface receptors. Chapter 4 elaborates on the design, synthesis, and evaluation of a ligand-folate miniBiT that recruits activated macrophages to virus particles and infected cells. Finally, Chapter 5 delves into the extended application of the miniBiT platform in treating solid tumors.