UCSF

The field of antibody engineering focuses on improving the antibody scaffold for their desired needs, whether that’s delivering cytotoxic payloads as an antibody-drug-conjugate (ADC) or generating bispecific antibodies (bsIgGs) to gain tissue specificity. To date, the field has created top-selling therapies on the market. Antibodies can elicit a therapeutic effect in a variety of ways from, direct inhibition to T-cell recruitment. This thesis project seeks to both improve and expand the current toolbox of antibody modalities. Chapters 1 and 2 describe the development and optimization of a technology termed Antibody-Based PROTACs (AbTACs) for the degradation of cell surface proteins. We demonstrate that the cell-surface E3 ligases RNF43 and ZNRF3 can be co-opted via a bsIgG to induce the targeted degradation of a range of clinically relevant proteins, including PD-L1 and EGFR. Chapter 3 expands on redox-reactive oxaziridine reagents to label biotinylated biomolecules, including antibodies and DNA. Despite being solvent-exposed, the resulting conjugates are exceedingly stable and, we were able to generate both antibody-drug conjugates and flow cytometry reagents. Chapter 4 models a hypothetical antibody therapeutic to treat COVID-19 infections. We look at the required in-vitro neutralization values and link that to patient dosing and production capacities for a large pharmaceutical company trying to deliver these molecules to patients. Chapter 5 describes a sociological meta-analysis of gender diversity in chemistry publishing. We generated a dataset of name-predicted genders of both first and corresponding authors in a range of journals since 2005. The resulting analysis demonstrated the disparity in gender diversity in scientific publishing that has shown little to no signs of improvement over the last 16 years.