Development of novel bispecific antibody modalities for targeted degradation and anti-viral therapeutic applications
Monoclonal antibodies have created tremendous value for patients, with six of the top ten selling FDA approved drugs being monoclonal antibodies. Generally, monoclonal antibodies work by blocking protein function or inducing cell death via effector functions, such as antibody-dependent cellular toxicity. Though monoclonal antibodies have been greatly successful for various targets and diseases, some disease contexts could benefit from added functionality. For example, on-target, off-tumor toxicity is common when using a monoclonal antibody to target a disease protein that is also expressed on normal cells, as is the case with human epidermal growth factor receptor in breast cancer. Bispecific or bifunctional antibodies, which can recognize two different antigens or have dual functionalities, have the potential to offer greater selectivity, efficacy, and functionality compared to monoclonal antibodies. Various forms of bispecific antibodies exist to date, including bispecific IgGs, which add disease specificity by targeting a disease-specific protein and the target protein simultaneously, bispecific T cell engagers, which enable recruitment of cytotoxic T cells to tumor cells, and antibody-drug conjugates, which involve the tumor specific delivery of a highly cytotoxic small molecule payload using antibody-induced receptor internalization. Here, I describe three novel approaches using bifunctional antibody-based technologies. In Chapter 1, I describe the use of bispecific antibody-cytokine fusions, termed KineTACs, which can be applied as a novel strategy for the targeted degradation of cell surface and extracellular proteins. In Chapter 2, I highlight an orthogonal targeted degradation approach using antibody-drug conjugates in which the antibody recruits a cell surface E3 ligase, and the small molecule binds a cell surface multi-pass membrane protein, enabling its degradation. In Chapter 3, I describe the use of bispecific VH-Fab IgGs targeting different epitopes on the Spike protein as a novel anti-viral strategy against SARS-CoV-2 virus.