Design and Delivery of Nanobody Fusions as Immunotherapy for COVID19

Abstract

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has infected millions of lives worldwide, causing a significant number of deaths. Despite the development of several drugs and vaccines, the emergence of new variants creates the need for alternative therapeutic approaches. In this study, we demonstrate the potential of a nanobody binder, E11, to target a conserved site and bind to most variants of SARS-CoV-2 with nanomolar binding affinity. We also explore the use of novel nanobody fusions with E11, synthesized both genetically and chemically, to specifically bind to SARS-CoV spike-expressing cells with high affinity and recruit polyclonal IgGs. Our results show that these fusions can effectively activate effector functions, including Complement Dependent Cytotoxicity, of both mouse and human polyclonal IgGs against SARS-CoV-2 infected cells. Moreover, our fusions demonstrate their ability to target almost all currently known variants SARS- CoV-2. To our knowledge, this is the first nanobody-nanobody fusion to show selective elimination of SAR-CoV-2 virus-infected cells in vitro at nanomolar range. Our findings suggest that E11-based nanobody fusions may serve as a promising therapeutic approach against COVID-19, especially in the context of emerging variants.